Amarin V Hikma 252-254

Case 2:16-cv-02525-MMD-NJK Document 252 Filed 08/30/19 Page 1 of 38
1 Nicholas J. Santoro (Nev. Bar No. 532)

Jason D. Smith (Nev. Bar No. 9691)
2 SANTORO WHITMIRE, LTD.
3 10100 W. Charleston Blvd., Suite 250
Las Vegas, Nevada 89135
4 Tel.: (702) 948-8771
Fax: (702) 948-8773
5 E-mail: nsantoro@santoronevada.com,
jsmith@santoronevada.com
6
7 Christopher N. Sipes (admitted pro hac vice)

Einar Stole (admitted pro hac vice)
8 Michael N. Kennedy (admitted pro hac vice)
Megan P. Keane (admitted pro hac vice)
9 Eric R. Sonnenschein (admitted pro hac vice)
Alaina M. Whitt (admitted pro hac vice)
10
Han Park (admitted pro hac vice)
11 Jordan L. Moran (admitted pro hac vice)
COVINGTON & BURLING LLP
12 One CityCenter, 850 Tenth Street, NW
Washington, DC 20001
13 Tel.: (202) 662-6000
Fax: (202) 662-6291
14
E-mail: csipes@cov.com, estole@cov.com,
15 mkennedy@cov.com, mkeane@cov.com
esonnenschein@cov.com, awhitt@cov.com,
16 hpark@cov.com, jmoran@cov.com
17 Attorneys for Plaintiffs Amarin Pharma, Inc. and
Amarin Pharmaceuticals Ireland Limited
18
19 UNITED STATES DISTRICT COURT

FOR THE DISTRICT OF NEVADA
20
AMARIN PHARMA, INC. et al., Case No.: 2:16-cv-02525-MMD-NJK
21
22 Plaintiffs, (Consolidated with 2:16-cv-02562-MMD-

NJK)
23 v.
AMARIN’S OPPOSITION TO
24 HIKMA PHARMACEUTICALS USA INC., et DEFENDANTS’ MOTION FOR
al., SUMMARY JUDGMENT
25
26 Defendants. ORAL ARGUMENT REQUESTED
27
1 TABLE OF CONTENTS
2 I. INTRODUCTION AND FACTUAL BACKGROUND ...................................................... 1

3 II. SUMMARY OF THE ARGUMENT ................................................................................... 4
4 III. STATEMENT OF UNDISPUTED AND DISPUTED MATERIAL FACTS ....................... 6
5
A. Response to Defendants’ Statement of Undisputed Facts .......................................... 6
6
B. Plaintiffs’ Statement of Additional Undisputed Facts................................................ 9
7
IV. SUMMARY JUDGMENT LEGAL STANDARD .............................................................. 9
8
V. FACT ISSUES REMAIN FOR TRIAL ON AMARIN’S INDUCED
9 INFRINGEMENT CLAIMS.............................................................................................. 10
10 A. Defendants’ Product Labels Will Induce Clinicians to Administer Their
11 Generic Products to Severely Hypertriglyceridemic Patients for At Least 12
Weeks. ................................................................................................................... 11
12
1. Clinicians Understand the Indications and Usage Section to
13 Encourage, Recommend, or Suggest the Use of Defendants’ ANDA
Products for at Least 12 Weeks .................................................................. 12
14
2. The Clinical Studies Section Further Encourages, Recommends, or
15 Suggests that Clinicians Use Defendants’ Generic Products for at
16 Least 12 Weeks .......................................................................................... 17
17 B. Defendants’ Product Labels Will Induce Clinicians to Administer Their

Generic Products to Treat Severe Hypertriglyceridemia and Achieve Specific
18 Claimed Effects on TGs, LDL-C, and Apo B ......................................................... 20
19 1. Defendants Labels Will Induce Clinicians to Use Defendants’
Products to Reduce TGs By About 25%. .................................................... 22
20
2. Defendants Labels Will Induce Clinicians to Use Defendants’
21
Products to Treat Severe Hypertriglyceridemia and Expect Patients to
22 Experience No Substantial Increase in LDL-C and a Reduction in
Apo B. ....................................................................................................... 23
23
C. Defendants’ Product Labels Will Induce Clinicians to Administer Their
24 Generic Products to Severely Hypertriglyceridemic Patients Who Do Not
Receive Concurrent Lipid Altering Therapy ........................................................... 25
25
26 VI. FACT ISSUES REMAIN FOR TRIAL ON AMARIN’S CONTRIBUTORY

INFRINGEMENT CLAIMS.............................................................................................. 26
27
i
A. Use of Defendants’ Generic Products For Less Than 12 Weeks Is Not a

1
Substantial Use....................................................................................................... 27
2
1. Defendants’ Products Are Not “Suitable” for Noninfringing Use................ 27
3
2. Any Noninfringing Use for Defendants’ Products Is Not “Substantial”....... 29
4
B. Use of Defendants’ Generic Products to Achieve Effects Other Than the
5 Effects on TGs, LDL-C, and Apo B Recited in the Claims Are Not
Substantial Uses ..................................................................................................... 29
6
VII. CONCLUSION ................................................................................................................. 30
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
ii
TABLE OF AUTHORITIES
1
2 Cases Page(s)
3 Allergan Sales, LLC v. Sandoz, Inc.,

211 F. Supp. 3d 907, 923 (E.D. Tex. 2016) .............................................................................11
4
Anderson v. Liberty Lobby, Inc.,
5 477 U.S. 242 (1986) .............................................................................................................9, 10
6 AstraZeneca LP v. Apotex, Inc.,
633 F.3d 1042 (Fed. Cir. 2010)................................................................................4, 10, 16, 19
7
8 Aydin Corp. v. Loral Corp.,

718 F.2d 897 (9th Cir. 1983) .....................................................................................................9
9
Bayer Schering Pharma AG v. Lupin, Ltd.,
10 676 F.3d 1316 (Fed. Cir. 2012)........................................................................................ passim
11 Bio Tech. Gen. Corp. v. Duramed Pharm., Inc.,
325 F.3d 1356 (Fed. Cir. 2003)................................................................................................10
12
DSU Med. Corp. v. JMS Co.,
13
471 F.3d 1293 (Fed. Cir. 2006)................................................................................................10
14
Eli Lilly & Co. v. Teva Parenteral Meds.,
15 845 F.3d 1357 (Fed. Cir. 2017)........................................................................................ passim
16 First Nat’l Bank v. Cities Serv. Co.,

391 U.S. 253 (1968) ...............................................................................................................5, 9
17
Fujitsu Ltd. v. Netgear Inc.,
18
620 F.3d 1321 (Fed. Cir. 2010)................................................................................................26
19
Genentech, Inc. v. Trustees of Univ. of Penn.,
20 871 F. Supp. 2d 963 (N.D. Cal. 2012) .....................................................................................11
21 GlaxoSmithKline LLC v. Glenmark Pharm. Inc.,

No. CV 14-877-LPS-CJB, 2017 WL 8948973 (D. Del. May 23, 2017) .................................10
22
Grunenthal GmbH v. Alkem Labs. Ltd.,
23 919 F.3d 1333 (Fed. Cir. 2019)..........................................................................................19, 26
24
i4i Ltd. P’ship v. Microsoft Corp.,
25 598 F.3d 831 (Fed. Cir. 2010)........................................................................................6, 26, 28
26 Impax Labs., Inc. v. Actavis Labs. FL, Inc.,

No. CV 15-6934 (SRC), 2018 WL 1863826 (D.N.J. Apr. 18, 2018) ................................10, 19
27
iii
Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd.,

1
323 F. Supp. 3d 566, 585–86 (D. Del. 2018) ...........................................................................11
2
Sanofi v. Glenmark Pharmaceuticals Inc., USA,
3 204 F. Supp. 3d 665, 683–84 (D. Del. 2016) ...................................................12, 15, 19, 20, 24
4 Sanofi v. Watson Labs. Inc.,

875 F.3d 636 (Fed. Cir. 2017).......................................................................................... passim
5
Shire LLC v. Amneal Pharms., LLC,
6 No. 11-3781(SRC), 2014 WL 2861430 (D.N.J. June 23, 2014)..............................................19
7
Takeda Pharm. v. West-Ward Pharm. Corp.,
8 785 F.3d 625 (Fed. Cir. 2015)......................................................................................10, 17, 18
9 Tyco Healthcare Grp. LP v. Biolitec, Inc.,

No. C-08-3129 MMC, 2010 WL 3324893 (N.D. Cal. Aug. 23, 2010) ...................................26
10
Vanda Pharms. v. West-Ward Pharms.,
11 887 F.3d 1117 (Fed. Cir. 2018)........................................................................................ passim
12 Vita-Mix Corp. v. Basic Holding, Inc.,
13 581 F.3d 1317 (Fed. Cir. 2009)..........................................................................................26, 27
14 Wyeth v. Sandoz, Inc.,

703 F. Supp. 2d 508 (E.D.N.C. 2010)......................................................................................11
15
Statutes
16
35 U.S.C. § 271(b) .....................................................................................................................1, 10
17
35 U.S.C. § 271(c) .....................................................................................................................1, 26
18
19 Other Authorities
20 21 C.F.R. § 201.57(c)(15) ..............................................................................................................17
21 21 C.F.R. § 314.92(a)(1) ............................................................................................................4, 16
22
23
24
25
26
27
iv
1 TABLE OF ABBREVIATIONS
2 ’728 Patent U.S. Patent No. 8,293,728 (filed Jan. 12, 2012) (Defs.’ Ex. 5)
3 Amarin Plaintiffs Amarin Pharma, Inc. and Amarin Pharmaceuticals
Ireland Limited
4
ANDA Abbreviated New Drug Application
5 apo B apolipoprotein B
6 Budoff Amarin’s clinical infringement expert, Matthew Budoff, M.D.
7 Budoff Opening Rept. Opening Expert Report of Matthew Budoff, M.D., dated March
10, 2019 (Ex. 9)
8
Budoff Reply Rept. Reply Expert Report of Matthew Budoff, M.D., dated June 10,
9 2019 (Ex. 10)
Defs.’ Br. Defendants’ Motion for Summary Judgment of Noninfringement
10 (ECF No. 236)
11 Defs.’ Ex. exhibit attached to the Declaration of Claire A. Fundakowski
(ECF No. 237)
12
Defendants Defendants Hikma Pharmaceuticals USA Inc., Hikma
13 Pharmaceuticals International Limited, Dr. Reddy’s Laboratories,
Inc. and Dr. Reddy’s Laboratories, Ltd.
14
EPA eicosapentaenoic acid
15 Ex. exhibit to Amarin’s Opposition to Defendants’ Motion for
Summary Judgment of Noninfringement
16
Fisher Defendants’ clinician expert, Edward Fisher, M.D.
17
FDA U.S. Food and Drug Administration
18
Heinecke Defendants’ validity expert, Jay Heinecke, M.D.
19 LDL-C low-density lipoprotein cholesterol
20 Mathers Defendants’ regulatory expert, Peter Mathers
21 Peck Amarin’s regulatory expert, Carl Peck, M.D.
22 Peck Rept. Reply Expert Report of Carl C. Peck, M.D., dated June 10, 2019
(Ex. 12)
23 Sheinberg Defendants’ clinician expert, Jonathan Sheinberg, M.D.
24 Sheinberg Rebuttal Rept. Rebuttal Expert Report of Jonathan I. Sheinberg, M.D., F.A.C.C.,
on Noninfringement of the Asserted Claims of the Patents-in-
25 Suit, dated May 10, 2019 (Ex. 13)
26 TG triglyceride
27 Vascepa Label Vascepa Prescribing Information (2017) (Defs.’ Ex. 13)
v
1 I. INTRODUCTION AND FACTUAL BACKGROUND

2 Defendants have moved for summary judgment of noninfringement, arguing that Amarin
3 cannot show that, after FDA approval of their ANDAs, Defendants will induce infringement of any
4 asserted claim under 35 U.S.C. § 271(b), or contribute to infringement of any asserted claim under
5 35 U.S.C. § 271(c). For the reasons explained below, Defendants’ motion should be denied.
6 Defendants acknowledge that the induced infringement question here turns on how clinicians
7 would understand the instructions for use that accompany Defendants’ proposed generic products,
8 known as the “prescribing information” or “label.” But Defendants’ motion ignores both the plain
9 text of the prescribing information and expert testimony explaining that clinicians would understand
10 the prescribing information to encourage, recommend, or suggest use of their products in ways that
11 infringe the asserted method of treatment claims. Defendants also fundamentally mischaracterize the
12 law of induced and contributory infringement. Defendants suggest that, if a drug’s label instructs a
13 range of possible uses (e.g., an indefinite duration of administration), it does not induce any particular
14 use within that range. This is contrary to Federal Circuit precedent: “evidence that the product
15 labeling that Defendants’ seek would inevitably lead some physicians to infringe establishes the
16 requisite intent for inducement.” Eli Lilly & Co. v. Teva Parenteral Meds., 845 F.3d 1357, 1369
17 (Fed. Cir. 2017); see also Vanda Pharms. v. West-Ward Pharms., 887 F.3d 1117, 1132 (Fed. Cir.
18 2018) (“Even if not every practitioner will prescribe an infringing dose, that the target dose range
19 ‘instructs users to perform the patented method’ is sufficient to ‘provide evidence of [West-Ward’s]
20 affirmative intent to induce infringement.”). Amarin will present expert testimony at trial, including
21 admissions from Defendants’ experts, establishing that the Federal Circuit’s test is met. Defendants
22 invite the Court to disregard that testimony and resolve hotly-disputed factual issues against the non-
23 movant, Amarin. The Court should decline Defendants’ invitation and deny this motion.
24 * * * * *
25 This Hatch-Waxman patent infringement action arises from Defendants’ desire to obtain
26 FDA approval to market generic copies of Amarin’s Vascepa product. The active ingredient in
27 Vascepa is a highly purified omega-3 fatty acid called ethyl-eicosapentaenoic acid (“EPA” or
1
1 “icosapent ethyl”), and is FDA-approved “to reduce triglyceride (TG) levels in adult patients with
2 severe (> 500 mg/dL) hypertriglyceridemia.”1 Vascepa Label, § 1 (Defs.’ Ex. 13). While
3 Defendants disparage the invention they seek to copy by observing that “Amarin did not invent
4 purified EPA” (Defs. Br. at 1), Amarin scientists were the first to recognize its utility in treating
5 severe hypertriglyceridemia. Amarin scientists were also the first to recognize EPA’s unique ability
6 to treat severe hypertriglyceridemia while avoiding the adverse effects associated with prior
7 therapies, such as a substantial rise in LDL-C (the so-called “bad cholesterol) that accompanied the
8 reduction in TGs in those therapies. As Defendants’ own experts concede, Vascepa was the first, and
9 remains the only, product approved for the treatment of severe hypertriglyceridemia that reduces
10 triglycerides without raising LDL-C. See Heinecke Deposition Tr. 143:9–144:10 (Ex. 2); Fisher Dep
11 Tr. 271:23–272:8 (Ex. 3).
12 Indeed, in the pivotal 12-week, double-blind “MARINE” clinical trial supporting approval of
13 Vascepa®, Vascepa was shown to both avoid an increase in LDL-C and actually reduce apo B (a
14 measure of the number of pro-atherogenic particles in the blood). See Vascepa Label, § 14. And, as
15 a result of the recent REDUCE-IT cardiovascular outcome trial, Vascepa is the only drug approved
16 for treatment of severe hypertriglyceridemia that has also been shown to provide cardiovascular
17 benefit to patients on top of a statin. Heinecke Tr. 147:7-13.
18 The learnings from the MARINE trial form the basis for the prescribing information (or
19 label) at the heart of Defendants’ Motion. That prescribing information informs clinicians how to
20 safely and effectively use Vascepa to treat their patients with severe hypertriglyceridemia, and what
21 clinically meaningful effects to expect. Several aspects of the label are relevant to this motion. For
22 example, the “Indications and Usage” section states that Vascepa is indicated “to reduce triglyceride
23 (TG) levels in adult patients with severe (> 500 mg/dL) hypertriglyceridemia.” Vascepa Label, § 1.
24
1
“Hypertriglyceridemia” refers to elevated triglyceride levels in the blood. Elevated TG levels are
25 associated with several diseases and disorders, including pancreatitis and cardiovascular disease.
26 Hypertriglyceridemia patients are divided into three classes based on the level of TGs: borderline
high (150–199 mg/dl), high (200–499 mg/dl), and severe (≥ 500 mg/dl).
27
2
1 The " Dosage and Administration" section states that "[t ]he daily dose of V ASCEPA is 4 grams per
2 day." Vascepa Label,§ 2. The "Clinical Studies" section describes the results of the MARINE trial,
3 including how the patients ' lipid levels were affected by 12 weeks of treatment with Vascepa:
4 Table 2. :Mtdiao Bascliot> alld Perceot Chaogt> from B.ascliJte .in Lipid Parame-ters in
Patients with Severe Hyper(riglycer idemia (~00 mg/dL)
5 VA.SCEPA -' g/duy Pl.:n:chtJ Difference (9'5%
N='76 N=?s Coondence
6 Paramercr Baseline % Change Bnscline o/e Change lnrc.n·al)
TG(mgldL) ~0 -r I 703 -10 (-:n (-47. -211
7 lDL-C (mg/dl) 9l p: !«) - ."'1 f-!'(- 13, +8)
Non-IIDL-C (mg/dL) 225 -8 219 ~8 -18 (-25, - ll)
TC (nU!fdL) 254 -1 256 +8 ·L6 (·22. · 11)
8
9
HDL-C (m.g/dL)
VLDL-C (mg/dL)
27
123
-4
-20 I
27
124
' 0
-I -I
~ (-IJ. +2)
-29 (-43, -14)
Apo B (mg/dL) Ill 4 118 +.j .Q.r (-14. -3)
•-. Clw~e= Median Peroent ~e from Ra'll!lmc
10 D1ffcrcr~ce= Median of 1VASC EPA ~~ Chon£c - Placebo ~• C lwlscJ (llodgcs-lchmann Esttmate)
f>"\'alucs from Wtlcmxon mnk-sum Lest
11 'p·\'llluc <: 0.00 I (prima~ e llicacy endpointJ
"JH31Ue <;: 0 (15 (~i.l)' SOC()Jld<lf)' eJYrcacy endpoints determin<'fllll be ~fltL.:tically significant a.eoord ifl8 [1'1 the Jll\l·~i f11CJ
12 11mltirle cnmt\:tri!lnn ptnced11te)
13 Vascepa Label, § 14 (annotations added) . As shown here, patients' TG levels were reduced 27%
14 compared to baseline and 33% compared to placebo; their LDL-C levels were reduced 5% compared
15 to baseline and 2% compared to placebo; and their apo B levels were reduced 4% compared to
16 baseline and 9% compared to placebo. The Clinical Studies section ftuiher states that "The reduction
17 in TG observed with V ASCEPA was not associated with elevations in LDL-C levels relative to
18 placebo." Vascepa Label, § 14.
19 2
The 15 asselted patent claims, see Appendix A, are all drawn to methods of treating patients
20 with severe hypertriglyceridemia by administering 4 grams of EPA, consistent with the V ascepa
21 label. Each asselted claim ftuiher tracks the approved V ascepa label by requiring treatment for at
22 least 12 weeks, as disclosed in the Clinical Studies section. The label also comes with a patient
23 infonna.tion leaflet that instm cts patients "[d]o not .. . stop taking V ASCEPA without talking to yom
24
2
Amarin is asse1ting the following claims in this case: Claims 1, 13, and 16 of the '728 Patent
25 (Defs.' Ex. 5); Claim 14 ofthe '715 Patent (Defs.' Ex. 6); Claims 1, 7 an d 8 of the '677 Patent
(Defs.' Ex. 7); Claims 1, 7, and 8 of the '652 Patent (Defs.' Ex. 8); Claims 4, 7, and 17 of the
26
'560 Patent (Defs.' Ex. 9); an d Claims 1 and 5 of the '929 Patent (Defs.' Ex. 10).
27
3
1 doctor.” Vascepa Label, at 9–10. Both sides’ clinician experts agree that indefinite (i.e., enduring)
2 treatment is required for the vast majority of patients with severe hypertriglyceridemia in order to
3 keep their TG levels below 500 mg/dL. Therefore, when prescribing Vascepa according to the label,
4 clinicians expect and intend that their patients will be on the medication for more than 12 weeks, as
5 Defendants’ experts concede. See, e.g., Fisher Tr. 72:14 (“one way of phrasing [the indication] is for
6 the duration; meaning longer than 12 weeks.”). Many of the asserted claims are also drawn to
7 methods of treatment that avoid rises in LDL-C or reduce apo B, capturing the benefits of the
8 claimed treatment observed in the MARINE study.
9 As Defendants acknowledge, their proposed labels—which are included as part of their
10 ANDAs pending with FDA—are “materially identical to the Vascepa label.” Defs.’ Br. at 12 n.18.3
11 In fact, Defendants’ regulatory expert agreed that “defendants did not change or omit any material
12 information from the Vascepa labeling in drafting their own proposed labeling,” Mathers Tr. 36:10–
13 14 (Ex. 4); see also id. at 33:8–34:2 (agreeing that the Defendants’ labels and the Vascepa label are
14 identical). It is worth noting that FDA provides avenues for generic ANDA filers to attempt to
15 deviate in certain respects from the relevant branded product’s prescribing information. See Mathers
16 Tr. 37:3–17; see also 21 C.F.R. § 314.92(a)(1) (“[C]onditions of use for which approval cannot be
17 granted because of . . . an existing patent may be omitted [from a generic product’s label].”).
18 Defendants here have chosen to copy Vascepa’s label.
19 II. SUMMARY OF THE ARGUMENT
20 By seeking approval for a “bioequivalent” product and copying Vascepa’s label as their own,
21 Defendants thus represent to FDA, clinicians, and patients that the same clinical effects achieved
22 with Vascepa will also be achieved with their products. Because the Vascepa and Defendants’ labels
23 instruct physicians to use the product according to the asserted claims in carrying out the safe and
24 effective use of the product, Defendants induce infringement of the claims: “[E]vidence that the
25 product labeling that Defendants seek would inevitably lead some physicians to infringe establishes
26 3
For this reason, like Defendants’ brief, Amarin’s brief also cites to the Vascepa label.
27
4
1 the requisite intent for inducement.” Eli Lilly, 845 F.3d at 1369; see also AstraZeneca LP v. Apotex,
2 Inc., 633 F.3d 1042, 1060 (Fed. Cir. 2010). Nevertheless, Defendants’ motion seeks various escape
3 hatches to avoid a finding of infringement. No such escape hatch exists.
4 First, with respect to inducement, Defendants acknowledge that the question of their intent
5 revolves around their proposed prescribing information. See, e.g., Defs.’ Br. at 8–9. But
6 Defendants’ selective reading of that labeling directly conflicts with Federal Circuit precedent. In
7 Hatch-Waxman cases where, as here, a generic ANDA filer is accused of inducing infringement of a
8 method of treatment patent, intent to induce infringement is established when “the label, taken in its
9 entirety” “recommend[s] or suggest[s] to a physician” that the drug used in the claimed method of
10 treatment is safe and effective for causing the combination of effects described in the patent claims.
11 Bayer Schering Pharma AG v. Lupin, Ltd., 676 F.3d 1316, 1324 (Fed. Cir. 2012) (emphases added).
12 Thus, Defendants cannot ignore aspects of the label, such as the Clinical Studies section, that help
13 establish their intent to induce. See, e.g., Sanofi v. Watson Labs. Inc., 875 F.3d 636, 645–46 (Fed.
14 Cir. 2017) (relying on the Clinical Studies section of the label); Vanda, 887 F.3d at 1131 (relying on
15 the Pharmacokinetics section of the label). See, e.g., infra Section V.A.2. Here, the labels taken as a
16 whole instruct physicians that the product may be administered to a patient for 12 weeks or more so
17 as to reduce her TGs without increasing LDL-C, and need not be co-administered with a lipid-
18 altering drug to control LDL-C levels. And under Federal Circuit law, the label’s direction of
19 infringing use establishes intent regardless of whether the odd patient discontinues treatment
20 prematurely, or chooses to use the product with a statin. See infra Section V.A.
21 The Federal Circuit has also recognized that expert testimony establishing how clinicians
22 interpret the label is critical in the induced infringement analysis. Bayer, 676 F.3d at 1324; see also,
23 e.g., Vanda, 887 F.3d at 1131 (affirming a finding of induced infringement based on expert testimony
24 to explain that the “laboratory tests” described in the product label referred to the “genotyping tests”
25 described in the patent claims). Here, the parties’ experts agree that physicians consider prescribing
26 information as a whole in making prescribing judgments. Budoff Tr. 127:14–22 (Ex. 5); Mathers Tr.
27 117:4–8; Peck Tr. 142:10–22 (Ex. 6). Moreover, Defendants’ clinical expert, Dr. Sheinberg, agreed
5
1 that
2 Sheinberg Tr. 227:13–22 (Ex. 7).
3 Granting Defendants’ motion would require simply ignoring this expert testimony which, at
4 minimum, establishes genuine issues of material fact concerning Defendants’ intent to induce. See
5 infra Section V.
6 Second, Defendants repeatedly assert that Plaintiffs’ contributory infringement claims fail
7 because Defendants’ generic products are “suitable for substantial noninfringing use.” See, e.g.,
8 Defs.’ Br. at 18. Defendants would erase the word “substantial” from the legal standard, asserting
9 that any conceivable noninfringing use precludes contributory infringement. But determining
10 whether a noninfringing use is “substantial” involves consideration of “not only the use’s frequency,
11 but also the use’s practicality, the invention’s intended purpose, and the intended market.” i4i Ltd.
12 P’ship v. Microsoft Corp., 598 F.3d 831, 851 (Fed. Cir. 2010). Here, Defendants cannot show that
13 the non-infringing use meets any of these criteria. See infra Section VI.
14 III. STATEMENT OF UNDISPUTED AND DISPUTED MATERIAL FACTS
15 A. Response to Defendants’ Statement of Undisputed Facts
16 Defendants’ statement of “undisputed material facts,” Defs.’ Br. at 6–8, contains facts
17 wrongly identified as “undisputed,” while omitting other allegedly undisputed facts upon which they
18 appear to rely, in violation of Local Rule 56-1.4 Defendants’ “undisputed material facts” are disputed
19 as follows:
20 Response to Defendants’ ¶ 1a: Amarin agrees that “[e]ach of the 15 asserted claims requires
21
4
22 Defendants appear to rely on at least the following purported facts missing from their statement of
undisputed material facts: (1) “The ‘Clinical Studies’ section of the label . . . merely describes
23 exemplary effects of the drug, as opposed to the ‘Indications and Usage’ or ‘Dosage and
Administration’ sections, which instruct how to use it.” Defs.’ Br. at 12; (2) “‘some physicians will
24 find some of the data in the clinical studies is helpful, [others] will find it irrelevant to their
practices.’” Id.; (3) “those median numbers—i.e., the overall midpoints of the values reported for the
25 [MARINE] study’s 76 patients—do not predict icosapent’s effects in a real-world patient, or even in
26 the individual patients in the study.” Defs.’ Br. at 19; (4) “In practice, it is even less common [than
25%] for patients to receive Vascepa without concurrent statin therapy.” Defs.’ Br. at 26.
27
6
1 administering icosapent to a patient” with severe hypertriglyceridemia (TG ≥500 mg/dL) “for at least
2 ‘12 weeks.’”
3 Response to Defendants’ ¶ 1b: Amarin does not dispute that fourteen of the asserted claims
4 “further require at least one of the following effects: (i) a reduction in triglycerides that is
5 ‘statistically significant’ or ‘of at least about’ 10%, 20%, or 25%; (ii) no increase, no ‘substantial[]’
6 increase, no ‘statistically significant’ increase, or no ‘more than 5%’ increase in LDL-C levels; or
7 (iii) a reduction in ‘apolipoprotein B.’”
8 Response to Defendants’ ¶ 1c: Amarin does not dispute that “[f]our asserted claims require
9 that the patient ‘not receive concurrent lipid altering therapy,’ e.g., a statin.”
10 Response to Defendants’ ¶ 1d: Amarin agrees that the specification in the asserted patents
11 states that TG reduction can occur in a shorter period of time than 12 weeks. However, maintaining
12 that reduction in severely hypertriglyceridemic patients requires enduring treatment that generally
13 continues for well beyond 12 weeks, and the patent specification (e.g., in the Patent Example),
14 describes treatment of severely hypertriglyceridemic patients for 12 weeks and more. See ‘728
15 Patent, at 13:26–34, 14:61–63 (Defs.’ Ex. 5).
16 Response to Defendants’ ¶ 2a: Amarin agrees that the MARINE Clinical Study Report states
17 that for the group of subjects receiving 4 g of Vascepa per day, “the maximum effect on fasting TG
18 reduction occurred by Week 4.” And that “[f]rom Week 4 to Week 12, the TG-lowering effects were
19 maintained in the . . . 4 g group[] while TG levels increased in the placebo group.” Defs.’ Ex. 11
20 (FDA Medical Review for Vascepa) at 67. Only the 12-week results, and not the 4-week results,
21 appear in the product labels. Vascepa Label, § 14; see also Mathers Tr. 96:23-97:8.
22 Response to Defendants’ ¶ 2b: Amarin agrees that the MARINE Clinical Study reported that
23 “about 21% of patients” in the placebo group achieved an endpoint TG of <500 mg/dL. Amarin
24 disputes that these patients “kept triglyceride levels from becoming ‘very high’ with diet and exercise
25 alone.” Patients with baseline TG <500 mg/dL were ineligible to be included in the study.
26 Responses to Defendants’ ¶¶ 2c–e: Amarin agrees that the MARINE Clinical Study reported
27 that the third quartile of patients in the 4 g treatment arm showed “no reduction in triglycerides,” “a
7
1 greater-than-5% increase in LDL-C”, and a 3.8% “increase in Apo B.” MARINE further reported
2 median reductions in TGs of 27% and 33%, LDL-C of 5% and 2%, and apo B of 4% and 8.5%,
3 compared to baseline and placebo, respectively.
4 Response to Defendants’ ¶ 2f: Amarin does not dispute that the MARINE Clinical Study
5 reported that “[a]bout 25% of patients concurrently received a statin while on Vascepa therapy.”
6 Response to Defendants’ ¶ 3a: Amarin does not dispute that Defendants’ proposed product
7 labels “[a]re indicated solely ‘as an adjunct to diet to reduce triglyceride (TG) levels in adult patients
8 with severe (≥500 mg/dL) hypertriglyceridemia.’”
9 Response to Defendants’ ¶ 3b: Amarin disputes that Defendants’ proposed product labels
10 “have ‘no explicit instruction . . . to use the drug for at least 12 weeks.’” For example, as Amarin’s
11 clinician expert noted, Budoff Tr. 200:2–5;
12 Budoff Opening Rept.5 ¶ 127 (Ex. 9); Budoff Reply Rept. ¶¶ 66–71 (Ex. 10); Peck Tr. 148:4–12, and
13 the clinical studies section
14 Budoff Tr. 146:6–15. See also Budoff
15 Opening Rept. ¶¶ 123–26; Budoff Reply Rept. ¶¶ 43–58
16
17
18 Response to Defendants’ ¶ 3c: Amarin agrees that the Clinical Studies Section of
19 Defendants’ proposed product label informs clinicians that 25% of patients receiving Vascepa in the
20 MARINE study were “concurrently receiving a statin,” and thus necessarily informs clinicians that
21 75% of patients were not concurrently receiving a statin. Mathers Tr. 68:1–12. Defendants’
22 regulatory expert, Mr. Mathers, acknowledged that Vascepa is approved for the treatment of severely
23 hypertriglyceridemic patients who are not receiving other lipid-altering drugs (such as a statin), id. at
24
5
Dr. Budoff’s Opening Expert Reports addressing DRL’s ANDA Product are the same in all material
25 respects to the statements and opinions in Dr. Budoff’s Opening Expert Report addressing Hikma’s
26 ANDA Product. Budoff Decl. ¶ 4 (Ex. 8). Thus, although this brief cites to Dr. Budoff’s Hikma
report, the statements referenced apply equally to both Hikma’s and DRL’s infringement.
27
8
1 67:5–14, and that the Clinical Studies section of the Vascepa label informs clinicians that the drug is
2 safe and effective for patients who are not receiving concomitant statin therapy or other lipid-altering
3 medication, id. at 76:10–18.
4 B. Plaintiffs’ Statement of Additional Undisputed Facts
5 1. All fifteen of the asserted patent claims are directed to the treatment of severe
6 hypertriglyceridemia. See Appendix A (all claims directed to treatment of patients with fasting
7 baseline TG levels of 500 mg/dl or greater).
8 2. Severe hypertriglyceridemia is a chronic condition. See, e.g., Sheinberg Tr. 143:22–
9 25; Budoff Tr. 194:12–22; id. at 203:15–19; Budoff Reply Rept. ¶¶ 46–65; Peck Tr. 136:7–9.
10 3. Most clinicians who treat severely hypertriglyceridemic patients with Vascepa will
11 administer the drug for 12 weeks or more. Budoff Tr. 90:13–15; Sheinberg Tr. 134:21–135:5;
12 Budoff Opening Rept. ¶ 123; Budoff Reply Rept. ¶ 49.
13 4. There are no differences between the Vascepa label and Defendants’ labels that are
14 material to induced infringement. Defs.’ Br. at 12 n.18; Mathers Tr. 33:8–34:2.
15 5. Defendants did not seek to omit any information in the Vascepa label from their own
16 labels. Mathers Tr. 36:10–14.
17 6. The Vascepa label reports a median reduction in TGs of at least about 25%, a median
18 reduction in apo B, and a median reduction in LDL-C, compared to both baseline and placebo and
19 expressly states that “the reduction in TG observed with VASCEPA was not associated with
20 elevations in LDL-C levels relative to placebo.” See Vascepa Label, § 14.
21 IV. SUMMARY JUDGMENT LEGAL STANDARD
22 Summary judgment is proper only when the pleadings, depositions, answers to
23 interrogatories, and admissions on file, together with the affidavits, if any, show that “there is no
24 genuine dispute as to any material fact and the movant is entitled to judgment as a matter of law.”
25 Fed. R. Civ. P. 56(a). A genuine dispute exists whenever there is a sufficient evidentiary basis on
26 which a reasonable fact-finder could rely to find for the nonmoving party. See Anderson v. Liberty
27 Lobby, Inc., 477 U.S. 242, 248 (1986). “The amount of evidence necessary to raise a genuine issue
9
1 of material fact is enough ‘to require a jury or judge to resolve the parties’ differing versions of the
2 truth at trial.’” Aydin Corp. v. Loral Corp., 718 F.2d 897, 902 (9th Cir. 1983) (quoting First Nat’l
3 Bank v. Cities Serv. Co., 391 U.S. 253, 288–89 (1968)). At summary judgment, a court’s function is
4 not to weigh the evidence and determine the truth, but to determine whether there is a genuine issue
5 for trial. See Anderson, 477 U.S. at 249. Indeed, at summary judgment the evidence of the
6 nonmovant is “to be believed, and all justifiable inferences are to be drawn in his favor.” Anderson,
7 477 U.S. at 255.
8 V. FACT ISSUES REMAIN FOR TRIAL ON AMARIN’S INDUCED INFRINGEMENT
CLAIMS
9
10 Anyone who “actively induces infringement of a patent shall be liable as an infringer.” 35
11 U.S.C. § 271(b). Establishing inducement requires evidence showing that the accused infringer
12 “possessed specific intent to encourage another’s infringement.” DSU Med. Corp. v. JMS Co., 471
13 F.3d 1293, 1306 (Fed. Cir. 2006). “Infringement is a question of fact.”6 AstraZeneca v. Apotex, 633
14 F.3d at 1056. In a Hatch-Waxman case, the intent prong is shown so long as the product label, read
15 as a whole, encourages, promotes, recommends, or suggests that clinicians use the generic product in
16 a manner that infringes the patent. Vanda, 887 F.3d at 1129; Bayer, 676 F.3d at 1324; see also
17 Takeda Pharm. v. West-Ward Pharm. Corp., 785 F.3d 625, 631 (Fed. Cir. 2015) (active inducement
18 shown when the label “suggest[s] that an infringing use ‘should’ be performed”). “In sum, evidence
19 that the product labeling that Defendants seek would inevitably lead some physicians to infringe
20 establishes the requisite intent for inducement.” Eli Lilly, 845 F.3d at 1369.
21 Contrary to Defendants’ implication, see Defs.’ Br. at 10 n.17, courts frequently decline to
22 conclude as a matter of law that a generic ANDA filer’s label does not induce infringement.7 In fact,
23
6
Defendants incorrectly contend that Plaintiffs must carry a “heavy burden” of showing induced and
24 contributory infringement. See, e.g., Defs.’ Br. at 15. At trial, Amarin bears the burden of proving
infringement by a mere preponderance of the evidence. Vanda, 887 F.3d at 1125. This burden is no
25 “heav[ier]” because Amarin is pursuing induced and contributory infringement.
7
26 See Impax Labs., Inc. v. Actavis Labs. FL, Inc., No. CV 15-6934 (SRC), 2018 WL 1863826, at *10
(D.N.J. Apr. 18, 2018) (denying defendant’s motion for summary judgment because the question of
27 (continued…)
10
1 it is only when “the label, taken in its entirety, fails to recommend or suggest to a physician that [the
2 drug] is safe and effective for inducing the claimed combination of effects in patients” is intent to
3 induce infringement lacking. Bayer, 676 F.3d at 1324 (emphases added). As the phrase “the label,
4 taken in its entirety” implies, the inquiry is not limited to the Indications and Usage section.8
5 Moreover, determining what a product label “recommend[s] or suggest[s] to a physician” requires
6 reading the product label from the viewpoint of the clinician. Bayer, 676 F.3d at 1324; see also
7 Vanda, 887 F.3d at 1131 (citing expert testimony that clinicians read “laboratory tests” in the product
8 label as encouraging clinicians to perform the “genotyping tests” described in the asserted patent
9 claims).
10 A. Defendants’ Product Labels Will Induce Clinicians to Administer Their Generic
11 Products to Severely Hypertriglyceridemic Patients for At Least 12 Weeks
12 The asserted patent claims describe a method of treating severe hypertriglyceridemia by
13 administering 4 grams per day of purified EPA for at least 12 weeks. Amarin will show at trial that
14 clinicians will read Defendants’ product labels as a whole—the “Indications and Usage” and
15
16 specific intent to induce infringement is a question for the finder of fact); GlaxoSmithKline LLC v.
Glenmark Pharm. Inc., No. CV 14-877-LPS-CJB, 2017 WL 8948973, at *17 (D. Del. May 23,
17 2017), report and recommendation adopted, No. CV 14-877-LPS-CJB, 2017 WL 2536431 (D. Del.
June 9, 2017) (denying defendants’ motion for summary judgment where a factfinder could
18 reasonably conclude that doctors would interpret the labels as instructing use consistent with the
asserted patent claims); see also Bio Tech. Gen. Corp. v. Duramed Pharm., Inc., 325 F.3d 1356 (Fed.
19
Cir. 2003) (reversing the grant of summary judgment and remanding for factual determination of
20 whether consumers using product in accordance with package instructions would infringe patent);
Allergan Sales, LLC v. Sandoz, Inc., 211 F. Supp. 3d 907, 923 (E.D. Tex. 2016), aff’d in part, rev’d
21 in part, 717 F. App’x 991 (Fed. Cir. 2017) (denying motion for summary judgment of
noninfringement because genuine disputes of material fact remained whether defendant’s label
22 encouraged infringement); Genentech, Inc. v. Trustees of Univ. of Penn., 871 F. Supp. 2d 963, 977
23 (N.D. Cal. 2012) (same); Wyeth v. Sandoz, Inc., 703 F. Supp. 2d 508, 523 (E.D.N.C. 2010) (same).
8
See, e.g., Bayer, 676 F.3d at 1324 (considering what “the label, taken in its entirety” recommends
24 or suggests to a physician); see also Vanda, 887 F.3d at 1131 (relying on the Pharmacokinetics
section of the product label), Sanofi v. Watson, 875 F.3d at 645–46 (relying on the Clinical Studies
25 section of the product label), Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd., 323 F.
26 Supp. 3d 566, 585–86 (D. Del. 2018) (Bryson, J.) (relying on the Pharmacokinetics section and
“dosing instructions and clinical data” in the product label).
27
11
1 “Clinical Studies” sections in particular—as encouraging, suggesting, or recommending use of 4

2 grams per day of Defendants’ generic products for at least 12 weeks. See, e.g., Budoff Opening
3 Rept. ¶¶ 122–128; Budoff Reply Rept. ¶¶ 39–87; Peck Rept. ¶¶ 166–203 (Ex. 12). Defendants are of
4 the contrary opinion (Defs.’ Br at 11), but their argument ignores the Federal Circuit’s directive to
5 consider what “the label, taken in its entirety” recommends or suggests to clinicians. See Bayer, 676
6 F.3d at 1324. Amarin will show that a clinician, understanding that severe hypertriglyceridemia is a
7 chronic condition, would understand the indication in the label to refer to indefinite treatment, and
8 would understand the clinical studies portion of the label to convey that treatment would need to last
9 for at least 12 weeks. A finding of infringement would be perfectly in line with Federal Circuit cases
10 considering similar patents and similar labeling. Both sides’ experts agreed with the essential aspects
11 of this argument, which utterly precludes summary judgment. Defendants ignore or discount all of
12 this evidence.
13 Defendants’ faulty logic is illustrated by the reasoning in a recent district court opinion which
14 found infringement on strikingly similar facts, with respect to a claim directed to treatment “for at
15 least 12 months.” Sanofi v. Glenmark Pharmaceuticals Inc., USA, 204 F. Supp. 3d 665, 683–84 (D.
16 Del. 2016), aff’d, 875 F.3d 636 (Fed. Cir. 2017). There, as here, the Indications and Usage section of
17 the labels did not limit the duration of the treatment. Id. at 683. There, as here, expert testimony
18 established that the indicated use was for a “chronic disorder” for which clinicians intended
19 administration of the drug “indefinitely.” Id. There, as here, the label reported a clinical trial and the
20 length of that trial would further encourage clinicians to administer for at least the claimed duration
21 of 12 months. Id. at 683–84. The same result should be reached here with respect to the “12 weeks”
22 limitations. At an absolute minimum, there is a genuine dispute of material fact as to whether the
23 label encourages, recommends, or suggests that clinicians administer Defendants’ products for 12
24 weeks, thus precluding a ruling that Defendants lack intent to induce as a matter of law.
25 1. Clinicians Understand the Indications and Usage Section to Encourage,
Recommend, or Suggest the Use of Defendants’ ANDA Products for at
26 Least 12 Weeks
27 The Indications and Usage section of Defendants’ product labels, by itself, will inevitably
12
1 lead some clinicians to infringe, thus establishing the requisite intent to induce clinicians'
2 infringement. The record evidence, including admissions fi:om Defendants' expe11s, shows that the
3 clear majority of clinicians who prescribe Vascepa in accordance with Defendants' labels will, as a
4 result, administer Vascepa to their severely hype1iriglyceridemic patients for far longer than 12
5 weeks. Defendants' attempt to refhte this proposition is lmsuppOii ed by evidence, much less
6 evidence that would be sufficient to resolve the issue against Amarin as a matter oflaw.
7 The Indications and Usage section states that Defendants' generic products will be "indicated
8 as an adjlmct to diet to reduce triglyceride (TG) levels in adult patients with severe (2: 500 mg/dL)
9 hype1iriglyceridemia." Vascepa Label, § 1; see also Budoff Reply Rept. mJ 47-48. Unlike with
10 some other approved dmgs, there is no time limit on how long a clinician is to administer Vascepa.9
11
12 BudoffTr. 194:12- 22; see also BudoffOpening Rept. ~23;
13 BudoffReply Rept. mJ 4<H55; Peck Rept. mJ 130, 170-75.

14 And this is for good reason-both sides ' expe11s also agree that severe hypeliriglyceridemia
15 is a chronic condition, which infon ns how a clinician would inte1p ret the lack of a time limit on
16 administration in the Indications and Usage section. Budoff Tr. 203:17- 19
17
18
19
20 Sheinberg Tr. 143:22- 25 (emphasis added). Amarin's clinical expe11 agrees
21 that severe hype1iriglyceridemia is a chronic disease. BudoffTr. 194:12- 22; see also Budoff Reply
22 Rept. ~ 49; Peck Tr. 136:7- 9. And, as a chronic condition, physicians would also lmderstand that if a
23 severely hype1i riglyceridemic patient stops treatment, their TG levels will retum back to pretreatment
24
25 9
When a dmg is meant for other than long-ten n treatment, the IJH J'U U '""'
26 of treatment. Budoff
27
13
1 (“baseline”) levels. Budoff Tr. 93:23–25

2 ; Sheinberg Tr. 144:16–25
3
4
5 In recognition of the need for long-term therapy, the Patient Information leaflet
6 attached to Defendants’ product labels states: “Do not . . . stop taking VASCEPA without talking to
7 your doctor.”10 Vascepa Label, at 9–10; see also Peck Tr. 138:9–14; Peck Rept. ¶ 193.
8 These facts, upon which both sides’ experts agree, establish that clinicians would read the
9 Indication and Usage section as conveying that Vascepa is approved as safe and effective to reduce
10 patients’ TG levels to below 500 mg/dl and keep them there. Fisher Tr. 72:3–8; see also id. 67:18–
11 24; see also Budoff Reply Rept. ¶ 44; Peck Tr. 54:1–8; Peck Rept. ¶ 196. Both sides experts agree
12 that most prescribers would understand this to require more than 12 weeks of Vascepa. Defendants’
13 expert, Dr. Fisher, for example, when asked how long most doctors would follow the approved
14 Indication and keep their patient on Vascepa, answered “for the duration; meaning longer than 12
15 weeks.” Fisher Tr. 72:9-15. Thus, to avoid a regression back to their pretreatment levels, clinicians
16 administer the medication indefinitely. Indeed, Dr. Sheinberg emphasized
17
18 Sheinberg Tr. 139:20–21, 141:20-24. Clinicians therefore

19 understand the approved indication for Vascepa to generally require administration for 12 weeks or
20 more in order to reduce triglycerides below 500 mg/dl and keep them there.
21 Unsurprisingly, then, indefinite administration (i.e., at least 12 weeks of Vascepa) represents
22 how both sides’ clinical experts treat their own patients. As Dr. Sheinberg explains,
23
24
25 10
Defendants’ expert Mr. Mathers noted that the Vascepa Patient Information leaflet is not
26 “separate” from the label, Mathers Tr. 125:9–126:1, and can be “taken into account in a prescribing
decision,” Mathers Tr. 122:11–123:15.
27
14
1 Sheinberg Rebuttal Rept. ~ 119 (Ex. 13); see
3 Sheinberg Tr. 135:3-1 5.
5 Budoff Tr. 111 :7- 25. That clinicians read the
6 indication as encouragmg long-tenn treatment (for at least 12 weeks) is also shown by the
7 widespread clinical practice of prescribing patients three to four months of Vascepa at a time and
8 scheduling a follow-up appointment with the patient at least three months after initiating Vascepa
9 therapy. Sheinberg Tr. 233: 18- 234:6
10 Sheinberg Tr. 139:21- 25 -
11 Budoff Tr. 114:24-25
12 Budoff Opening Rept. ~ 124-26;
13 BudoffReply Rept. ~ 52 .
14 Against this backdrop, Defendants' insistence that "the labels never characterize severe
15 hypertriglyceridemia as a chronic condition," Defs.' Br. at 11, falls flat. As does Defendants'
16 contention that the Comi should ignore "[i]nfmmation outside the label." Id at 13. It is well-
17 established, in Federal Circuit law (see supra Section II) and in common sense, that clinicians do not
18 read prescribing infmm ation in a vacumn, but
19
20
21
22 Budoff Reply Rept. ~ 37. In fact, this case has more
23 compelling evidence that Defendants intend to induce clinicians ' infringement than the comi had in
24
25
26
27
15
1 Sanofi v. Glenmark. There, as here, the court in Sanofi was presented with an indication that did not
2 limit the duration and expert testimony that clinicians generally intend indefinite administration. 204
3 F. Supp. 3d at 683 (finding induced infringement). But here, experts have further testified that the
4 indication itself teaches keeping TGs below 500 mg/dl, which will require more than 12 weeks
5 administration. See Fisher Tr. 72:4–8.; see also id. 67:18–24.
6 The Federal Circuit has likewise relied on clinicians’ background knowledge in this context.
7 For example, in Vanda, the asserted method claim required “performing or having performed a
8 genotyping assay on the biological sample.” 887 F.3d at 1121. Although the label at issue in Vanda
9 did not literally refer to “a genotyping assay,” the Federal Circuit affirmed the district court’s reliance
10 on expert testimony to conclude that “when the label states that ‘laboratory tests’ are available to
11 identify poor metabolizers, the label is referring to ‘genotyping tests.’” Id. at 1131. Under
12 Defendants’ view, the patent holder in Vanda would have been out of luck because the label did not
13 use the exact words “genotyping assay.” Obviously, that is not the law.
14 Nor can Defendants avoid infringement because the label does not specifically exclude the
15 possibility that a clinician or patient might choose to discontinue use before 12 weeks and still be
16 within the contours of the indication. See Defs.’ Br. at 7, 11. This possibility is entirely consistent
17 with a finding of inducement under the governing legal standard, which provides that the “requisite
18 intent for inducement” is established when “the product labeling that Defendants seek would
19 inevitably lead some physicians to infringe.” Eli Lilly, 845 F.3d at 1369 (emphasis added). Not that
20 it matters in light of this precedent, but the evidence here shows that, in reality,
21
22 Budoff Tr. 200:23–201:1. Dr. Sheinberg agreed

23
24 Sheinberg Tr. 135:3–15.

25 * * * * *
26 If Defendants genuinely believed that severe hypertriglyceridemia could be successfully
27 treated in less than 12 weeks, they could have petitioned FDA to approve labeling that excluded
16
1 administration for 12 weeks or more. See 21 C.F.R. § 314.92(a)(1); see also Mathers Tr. 37:3–17.
2 There is no evidence in the record that either Defendant has ever sought to do so. The Court is
3 entitled to take this into account as part of the intent inquiry. See AstraZeneca v. Apotex, 633 F.3d at
4 1058 (affirming the district court’s induced infringement finding where, despite being aware of
5 infringement issues presented by its label, Apotex proceeded with its plans to distribute its generic
6 drug product without revising the label to avoid infringement). In any event, the record evidence
7 precludes any finding, much less as a matter of law, that the Indication and Usage section does not
8 instruct using Vascepa for at least 12 weeks.
9 2. The Clinical Studies Section Further Encourages, Recommends, or
Suggests that Clinicians Use Defendants’ Generic Products for at Least 12
10 Weeks
11 The data reported in the Clinical Studies section resulted from the MARINE trial, which cost
12 Amarin tens of millions of dollars to conduct over a period of years. And while Defendants now
13 deprecate the data’s value to physicians, see Defs.’ Br. at 12–13, both sides’ experts agree that the
14 Clinical Studies section of a label serves a critical role when clinicians make their treating
15 decisions.12 FDA, for example, explains that this section of the label is meant to provide “concise,
16 accurate summaries of information from studies concerning a drug’s effectiveness (and sometimes
17 safety) that practitioners consider important to clinical decision making.” FDA, Guidance for
18 Industry: Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products
19 — Content and Format, at 2 (January 2006), https://www.fda.gov/media/72140/download (Ex. 14)
20 (emphasis added); see 21 C.F.R. § 201.57(c)(15) (“Th[e Clinical Studies] section must discuss those
21 clinical studies that facilitate an understanding of how to use the drug safely and effectively.”); see
22 also Peck Rept. ¶¶ 154–158. In view of FDA’s guidance, the fact that the MARINE data is included
23 in the Vascepa labeling signifies that the data is important for clinicians to consider.
24
12
See Sheinberg Tr. 152:16–153:2, 184:8–22; Mathers Tr. 135:5–18, 170:3–7; Budoff Tr. 146:6–15,
25 203:4–19; Peck Tr. 124:21–125:4, 133:3–11. Heinecke Tr. 344:22–345:3 (testimony from another
26 of Defendants’ clinician experts that the Lovaza label teaches clinicians that treatment with Lovaza
will likely lead to a large increase in severely hypertriglyceridemic patients’ LDL-C).
27
17
1 The MARINE data describe the effects that patients experienced after 12 weeks of treatment
2 with Vascepa. Vascepa Label, § 14. With that in mind, both sides’ experts agree that this section
3 encourages, recommends, or suggests to clinicians that they treat their severely hypertriglyceridemic
4 patients with the product for at least 12 weeks. See Mathers Tr. 82:10–15; Budoff Tr. 192:24–193:5,
5 203:4–19; Budoff Opening Rept. ¶ 127; Budoff Reply Rept. ¶¶ 66–71; Peck Tr. 124:16–125:4,
6 147:4–16; Peck Rept. ¶¶ 186–92. Thus, the Court should conclude that a clinician would understand
7 that the Clinical Studies section confirms that the label directs at least 12 weeks of use.13
8 Defendants seek to deny the import of the Clinical Studies section by arguing that the data
9 describes only an “infringing mode” for their product, as opposed to a suggestion to a clinician to
10 treat for at least 12 weeks to achieve the described effects. Defs.’ Br. at 12. There is no support in
11 either the record or Federal Circuit precedent for this reading. Even Takeda v. West-Ward, on which
12 Defendants rely, did not hold that the product label merely described a possible infringing use.
13 Rather, the issue there was a mismatch between the patented method, directed to treating “acute
14 gout,” and the product’s indication which was directed to “prophylaxis of gout” (i.e., preventing
15 gout, not treating acute gout). Takeda, 785 F.3d at 630. The label’s only arguable reference to acute
16 gout was an instruction that “[i]f you have a gout flare while taking [the product], tell your healthcare
17 provider.” Id. Considering a motion for a preliminary injunction (not a summary judgment motion),
18 the Court refused to accept this “vague language” as sufficient to “infer from those instructions an
19 affirmative intent to infringe the patent.” Id. at 631, 632; see also Eli Lilly, 845 F.3d at 1369
20 (describing the label in Takeda as only “tenuously related to the use covered by the asserted claims”).
21 But here, the Clinical Studies section expressly discusses a 12-week course of treatment. Combined
22 with a physician’s understanding that the indication is to treat a chronic condition, this constitutes
23 clear direction to treat for at least 12 weeks. See Sanofi, 204 F. Supp. 2d at 683.
24
13
Other sections of the label also encourage long-term use of the drug, including the description of
25 “2-year” and “6-month” carcinogenicity studies in the Nonclinical Toxicology Section, Vascepa
26 Label, § 13.1, and the express instruction to patients not to stop taking the medication without talking
to their doctor in the Patient Information., Vascepa Label, §§ 17.1.
27
18
1 Nor is the Clinical Studies section "merely describ[ing] exemplruy effects of the dmg" and
2 runmmting only to an "incidental reference" to an infringing use, as Defendants would have it. Defs'
3 Br. at 12. Defendants' logic would categorically excluded the Clinical Study section of a label from
4 the inducement analysis, which is once again contrruy to Federal Circuit precedent. 14 For exrunple,
5 in Sanofi v. Watson, the Comt's affinnance of an inducement fmding expressly relied on expe1t
6 testimony "that a person of ordinruy skill in the rut would read the dmg label and understand that the
7 only FDA-approved use of [the product] came out of the [clinical trial described in the label]". 875
8 F.3d at 645; see also Vanda, 887 F.3d at 1131 (relying on phannacokinetic section oflabel to help
9 show intent).
10 Even Grunenthal GmbH v. Alkem Labs. Ltd., 919 F.3d 1333 (Fed. Cir. 2019), upon which
11 Defendants (enoneously) rely, confinns the impmtance of the Clinical Studies section in infonning
12 the scope of the induced use. In Grunenthal, the patent was directed to management of nemopathic
13 pain, and the generic defendants omitted the patent holder's indication for management of
14 nemopathic pain from their prescribing infmmation, seeking approval only for management of
15 "severe chronic pain." Id. at 1339. In response to the ru·gument that severe chronic pain could
16 include nemopathic pain, the Federal Circuit observed that the generics had omitted not just the
17 indication for nemopathic pain, but also all of the clinical studies in the Clinical Studies section
18 conceming nemopathic pain. Id. at 1339-40. As the Comt emphasized, the "proposed labels cite
19 chronic lower back pain studies, a type of pain that Cross-Appellants and FDA defined as
20
21
22
23
24
25
26
27
19
1 nociceptive [that is, non-neuropathic].” Id. Grunenthal thus confirms the relevance of the Clinical
2 Studies section in understanding the scope of use induced by proposed labels.15
3 * * * * *
4 Defendants’ product labels establish Defendants’ intent to encourage, recommend, or suggest
5 to clinicians that they administer Vascepa to their severely hypertriglyceridemic patients for at least
6 12 weeks. As the court in the strikingly similar Sanofi v. Glenmark case explained, the “additional
7 clues in the labels that suggest long-term treatment, and the experts’ testimony that prescribing
8 physicians generally intend to treat patients with [the drug] for longer than [the claimed duration],
9 together demonstrate by a preponderance of the evidence that Defendants’ labels encourage
10 administering the drug for at least [the claimed duration].” 204 F. Supp. 3d at 684. Here, the record
11 contains testimony from both sides’ experts confirming that Defendants’ labels would induce
12 administration for at least 12 weeks. To grant summary judgment on this issue would elevate
13 Defendants’ legally-incorrect and factually-unsupported arguments over Amarin’s facts.
14 B. Defendants’ Product Labels Will Induce Clinicians to Administer Their Generic
Products to Treat Severe Hypertriglyceridemia and Achieve Specific Claimed
15 Effects on TGs, LDL-C, and Apo B
16 Fourteen asserted claims also describe specific effects that—based on the clinical trial that
17 formed the basis of FDA approval—clinicians expect when treating their severely
18 hypertriglyceridemic patients with purified EPA. These claims recite one or more of the following
19 effects: (a) a reduction in TGs that is either a specific percent (10%–25%) or statistically significant,
20
15
Defendants also wrongly rely on Shire LLC v. Amneal Pharms., LLC, No. 11-3781(SRC), 2014
21 WL 2861430, at *4–5 (D.N.J. June 23, 2014). See Defs.’ Br. at 10–11. As the same judge later
22 recognized, the Shire decision conflicts with Federal Circuit case law. Impax Labs., Inc. v. Actavis
Labs. FL, Inc., No. 15-6934(SRC), 2018 WL 1863826, at *10 (D.N.J. Apr. 18, 2018) (“Furthermore,
23 the general argument that [the defendant] makes here is one that the Federal Circuit has rejected.”);
see also id. at *11–12 (discussing AstraZeneca v. Apotex, 633 F.3d at 1059–60 and Eli Lilly, 845
24 F.3d at 1368). Indeed, in Impax, the court denied the defendant’s motion for summary judgment of
noninfringement because “[a] reasonable finder of fact could also find that the label evidence,
25 together with other circumstantial evidence, is sufficient for a finding that [the defendant] had the
26 specific intent to induce infringement.” Impax, 2018 WL 1863826, at *13. Accordingly, “[t]he
question of specific intent to induce infringement is a matter for the finder of fact at trial.” Id.
27
20
1 (b) no increase in LDL-C or no increase that is substantial, statistically significant, 5% or less, (c) a
2 reduction in apo B or a statistically significant reduction in apo B. See Appendix B (listing the
3 affected claims and the corresponding claim language).
4 The levels of these lipids play a critical role in the treatment of severe hypertriglyceridemia,
5 see Peck Rept. ¶ 160, and that role is apparent from Defendants’ own labels. For example, as
6 explained in the Dosage and Administration section, doctors “[a]ssess lipid levels before initiating
7 therapy.” Vascepa Label, § 2. The Patient Information leaflet also states that clinicians will continue
8 to monitor these lipid levels throughout treatment: “Your doctor may do blood tests to check your
9 triglyceride and other lipid levels while you take VASCEPA.” Vascepa Label, at 9–10; see also
10 Peck Rept. ¶ 165. Mr. Mathers agreed that the Patient Information leaflet will reinforce the
11 instruction elsewhere in the label “that the physician may do blood tests to check triglycerides and
12 other lipid levels while the patient is taking Vascepa.” Mathers Tr. 134:4–9.
13 As explained below, clinicians expect that each claimed effect will occur when treating
14 severely hypertriglyceridemic patients using Defendants’ products according to the claimed methods.
15 As Defendants’ expert explained,
16 Sheinberg Tr. 217:9–14; accord Budoff Tr. 152:3-6. Clinicians
17 generally arrive at these expectations based on clinical study results. See Section V.A.2; see also,
18 e.g., Budoff Opening Rept. ¶¶ 63–64; Budoff Reply Rept. ¶¶ 33–36; Peck Tr. 154:3–5; Peck Rept.
19 ¶¶ 221–225, 227. In this case, the relevant clinical study is the MARINE study, the results of which
20 are described in the labels’ Clinical Studies section. Based on that data, clinicians will expect that
21 their severely hypertriglyceridemic patients will experience at least about a 25% reduction in TGs,
22 and that this reduction will not be associated with a substantial increase in patients’ LDL-C levels (or
23 no rise at all). See, e.g., Budoff Opening Rept. ¶¶ 143–49, 180–83; Budoff Reply Rept. ¶¶ 95–102,
24 114–29; Peck Rept. ¶¶ 226–29. Patients will also experience reductions in their apo B levels.
25 Vascepa Label, § 14; see also, e.g., Budoff Opening Rept. ¶¶ 241–42; Budoff Reply Rept. ¶¶ 141–
26 51. Given these expectations, Defendants’ labels are evidence of their intent that clinicians prescribe
27 Vascepa to achieve these lipid results. Defendants’ argument to the contrary should be rejected.
21
1 1. Defendants Labels Will Induce Clinicians to Use Defendants’ Products to

Reduce TGs By About 25%.
2
3 The Clinical Studies section encourages, recommends, or suggests to clinicians that they can
4 expect a TG reduction that exceeds 25%: a 27% reduction in patients’ TG levels compared to
5 baseline (the patient’s beginning TG level), and a 33% reduction in TGs compared to placebo
6 control. Vascepa Label, § 14. This is the only data in the labels that clinicians can use to form their
7 expectations, and this was the data that FDA found relevant to establishing how to safely and
8 effectively use the drug. Budoff Tr. 147:4–8
9 ; see also, e.g., Budoff Reply Rept. ¶¶ 98–102, 121; Peck Rept. ¶¶ 160–
10 61, 221–25.
11 Defendants nonetheless argue that this data does not “predict icosapent’s effects in a real-
12 world patient,” Defs.’ Br. at 19. This argument is surprising, considering that (a) the clinical data
13 was accepted by FDA as the basis for allowing Vascepa to be administered to patients; and
14 (b) Defendants rely on the same data to get FDA approval for their products to be administered to
15 patients. See Peck Rept. ¶¶ 89, 154–58. In any event, inducement does not require a showing that
16 every patient who takes Vascepa experiences the exact same effects on lipids that appears in the
17 label. Rather, it is enough that the label will “inevitably lead some physicians to infringe.” Eli Lilly,
18 845 F.3d at 1369. Here, the MARINE data in the label is “median” data, meaning that just over half
19 of the patients experienced a 27% reduction compared to baseline or greater and a 33% reduction
20 compared to placebo. Vascepa Label, § 14; see also, e.g., Budoff Opening Rept. ¶ 181; Budoff
21 Reply Rept. ¶ 105. And as Dr. Sheinberg conceded,
22 Sheinberg Tr. 154:4–7.
23 Accordingly, the median data reported in the label will inevitably lead some clinicians to infringe,
24 which in turn demonstrates Defendants’ intent to induce infringement of these claims. See also
25 Budoff Tr. 152:18–24
26 At a minimum,
27 to the extent that the parties disagree about whether Vascepa’s clinical study data, which Defendants
22
1 have adopted to obtain approval of their own generic products, accurately predicts Vascepa's real-
2 world effects on a patient, that disagreement is a classic fact issue precluding summmy judgment.
3 2. Defendants Labels Will Induce Clinicians to Use Defendants' Products to

Treat Severe Hypertriglyceridemia and Expect Patients to Experience No
4 Substantial Increase in LDL-C and a Reduction in Apo B
5 For essentially the Saine reasons reviewed above, the Clinical Studies section encourages,
6 recommends, or suggests to clinicians to expect that after administering Defendants ' products to
7 severely hypertriglyceridemic patients for 12 weeks, those patients will experience approximately a
8 5% reduction in LDL-C compared to baseline and a 2% reduction compm·ed to placebo control.
9 Vascepa Label, § 14. Similm·ly, this section encourages, recommends, or suggests to clinicians to
10 expect a 4% reduction in apo B compm·ed to baseline and a 9% reduction compm·ed to placebo
11 control. Vascepa Label, § 14. Not only are these effects appm·ent from the data reported in the
12 Clinical Studies section, but below the table, the labels specifically state that these effects will occur,
13 and thus, encourage, recommend, or suggest that doctors should expect these effects. Vascepa Label,
14 § 14. Expe11s on both sides agree with this reading.16
15 Defendants' attempt to diminish the impmiance of the data in the Clinical Studies section
16 should be rejected for the reasons stated above. See, e.g. , supra Section V.A.2. Defendants also
17 chm·acterize the claimed effects on LDL-C and apo B as "off-label" uses, meaning that they m·e uses
18 that m·e outside the approved indication for Defendants' products. See Defs.' Br. at 20-22.
19 Defendants are inconect.
20 The claimed LDL-C and apo B effects refer to additional treatment effects that cliniciallS
21
22
23
24
25 ascepa to they can

26 administer Vascepa to their severely hype1i riglyceridemic patients so as to reduce triglycerides
without raising LDL-C, conect?" A: I think that's a fair prediction."); see also Peck Rept. ~ 227.
27
23
1 should expect when administering the product in accordance with the approved label to reduce
2 triglycerides in patients with severe hypertriglyceridemia. Defendants’ own regulatory expert, Mr.
3 Mathers, conceded that such use was not off-label. Mathers Tr. 156:11-18; see also Peck Rept.
4 ¶¶ 228–35. Similarly, Defendants’ expert Dr. Sheinberg was asked
5
7 Sheinberg Tr. 188:20–189:2. Dr. Sheinberg agreed

8
9 Sheinberg Tr. 189:13–18; see also
10 Budoff Tr. 140:1–9
11
12
13 Budoff Opening Rept. ¶ 147; Budoff Reply Rept. ¶ 116; Peck

14 Rept. ¶¶ 226–27.
15 In this regard, Defendants mistakenly contend that the Federal Circuit’s opinion in Bayer v.
16 Lupin bars a finding of inducement for those claims that recite effects on LDL-C and apo B. See
17 Defs.’ Br. at 20. Bayer actually supports Amarin’s position. The patent at issue in Bayer required
18 administration to a patient in need of three separate effects. Bayer, 676 F.3d at 1319 (“1. A method
19 of simultaneously achieving . . . a gestagenic effect, antiandrogenic effect, and an antialdosterone
20 effect in a female patient in need thereof.”). Thus, practicing the claimed method would require that
21 a physician “determine that all three effects are needed by a specific . . . patient,” and also meant that
22 inducement required the label to contain an indication for all three effects. Id. at 1323–24.
23 Defendants ignore that the Bayer court contrasted the claims in Bayer with claims that would “claim
24 a method of achieving a[n indicated] effect in a patient in need of [the effect] in which the drug used
25 to achieve [that effect] has two generally beneficial additional effects.” Id. at 1323 (emphasis added).
26 This describes the asserted claims in this case, which are directed to a method of achieving the
27 indicated effect—reduction of TGs in a patient with severe hypertriglyceridemia—where the drug
24
1 (Defendants’ products) also will have “two generally beneficial additional effects”—the absence of
2 an increase in LDL-C and a reduction in apo B (depending on the claim at issue).
3 C. Defendants’ Product Labels Will Induce Clinicians to Administer Their Generic
Products to Severely Hypertriglyceridemic Patients Who Do Not Receive
4 Concurrent Lipid Altering Therapy
5 Four of the fifteen asserted patent claims are directed to the treatment of severe
6 hypertriglyceridemia with highly purified EPA where the patient “does not receive concurrent lipid
7 altering therapy.” See ‘728 Patent, Claims 1, 13, 16; ‘715 Patent, Claim 14. When, as here, a label
8 describes that a drug is safe and effective for both monotherapy and combination therapy, then that
9 label encourages, recommends, or suggests both. In fact, the Federal Circuit recently affirmed a
10 finding of induced infringement (after a bench trial) where the label demonstrated that the drug was
11 safe and effective as either monotherapy or in combination with “conventional therapy,” but the
12 patent claims covered only the combination therapy. Sanofi, 875 F.3d at 645 n.2. The district court
13 found that the fact that “over half” of the patients were on combination therapy with conventional
14 therapy and that the combination therapy “did not decrease positive outcomes . . . would encourage at
15 least some physicians to administer [the drug]” in combination therapy. Sanofi v. Glenmark, 204 F.
16 Supp. 3d at 683. Based on the label teaching both manners of administration, the district court
17 concluded (and was affirmed), that “Defendants knew that their proposed labels would inevitably
18 lead some physicians to administer [the drug in combination therapy].” Id. (quotation marks
19 omitted).
20 Like the label at issue in Sanofi, Defendants’ labels encourage, recommend, or suggest that
21 clinicians will administer Defendants’ products as adjunctive monotherapy or in combination therapy
22 with an additional lipid altering therapy. Budoff Reply Rpt. ¶ 190; Budoff Tr. 165:15–17
23 ; Peck Tr. 49:16–19,
24 103:6–23; Peck Rept. ¶¶ 212–13. In particular, in the Clinical Studies section, the labels explain that
25 “twenty-five percent of patients [in the MARINE Clinical Study] were on concomitant statin
26 therapy” and thus clinicians appreciate that 75% of the study subjects were administered only
27 Vascepa without any concurrent additional lipid-altering therapy. Vascepa Label, § 14. With or
25
1 without a statin, Vascepa was safe and effective. As Dr. Budoff explained,
2
4 Budoff
5 Tr. 166:11–18; see also Peck Rept. ¶¶ 213–15. Defendants’ experts agree that some clinicians will
6 read the label as encouraging, recommending, or suggesting that they prescribe Defendants’ products
7 without a concurrent lipid altering therapy. Mathers Tr. 70:16–22 (“Q: So you would agree that
8 some prescribers will follow the Vascepa labeling to administer their products to adult patients with
9 severe hypertriglyceridemia who are not on a statin or other lipid-altering drug, correct? A: They
10 could do that.”); see also Sheinberg Tr. 207:17–208:18
11 Thus, the language in Defendants’ labels “would
12 inevitably lead some physicians to infringe” the “without concurring lipid altering therapy” claims.
13 Eli Lilly, 845 F.3d at 1369.
14 VI. FACT ISSUES REMAIN FOR TRIAL ON AMARIN’S CONTRIBUTORY
15 INFRINGEMENT CLAIMS17
16 “Contributory infringement imposes liability on one who embodies in a non-staple device the
17 heart of a patented process and supplies the device to others to complete the process and appropriate
18 the benefit of the patented invention.” Vita-Mix Corp. v. Basic Holding, Inc., 581 F.3d 1317, 1327
19 (Fed. Cir. 2009). An ANDA filer contributorily infringes a method claim if the ANDA filer will,
20 upon FDA approval, sell the product knowing it is especially made or especially adapted for use that
21 infringes the patent claims, and the product is not a staple article or commodity of commerce suitable
22 for substantial noninfringing use. 35 U.S.C. § 271(c). The patent owner need only establish by a
23 preponderance of the evidence that (i) the ANDA filer had knowledge of the patent; (ii) the Proposed
24
25 17
Plaintiffs do not oppose Defendants’ Motion to the extent it relates to contributory infringement of
26 the claims that require administration of EPA to patients who do not receive “concurrent lipid
altering therapy.” See ‘728 Patent, Claims 1, 13, 16; ‘715 Patent, Claim 14.
27
26
1 ANDA Product has no substantial noninfringing uses; and (iii) the Proposed ANDA Product is a
2 material part of the invention described in the patent claims. See Fujitsu Ltd. v. Netgear Inc., 620
3 F.3d 1321, 1326 (Fed. Cir. 2010).
4 Defendants contest the “substantial noninfringing use” and “especially made for or adapted”
5 prongs, but contest these two prongs on the same basis. Defs.’ Br. at 14–18, 23–24, 25–26. A
6 substantial noninfringing use is one that is more than a use that is unusual, far-fetched, illusory,
7 impractical, occasional, aberrant, or experimental. Vita-Mix, 581 F.3d at 1327. Determining whether
8 a use is substantial takes into account not only the use’s frequency, but the use’s practicality, the
9 invention’s intended purpose, and the intended market. i4i Ltd. P’ship, 598 F.3d at 851 (upholding a
10 verdict of contributory infringement despite three non-infringing ways of using accused code, based
11 on evidence that those uses would deprive a user of the benefit of the accused feature). Conflicting
12 expert testimony as to whether a noninfringing use is substantial often requires “weigh[ing] the
13 testimony of all experts” and “ma[king] credibility determinations,” thus precluding summary
14 judgment. See Grunenthal, 919 F.3d at 1340–41; see also Tyco Healthcare Grp. LP v. Biolitec, Inc.,
15 No. C-08-3129 MMC, 2010 WL 3324893, at *5 (N.D. Cal. Aug. 23, 2010) (denying motion for
16 summary judgment on contributory infringement where there was competing expert testimony
17 regarding whether a noninfringing use was “substantial”).
18 A. Use of Defendants’ Generic Products For Less Than 12 Weeks Is Not a
19 Substantial Use
20 Like their induced infringement arguments, Defendants’ attempt to avoid liability for
21 contributory infringement is based on incorrect interpretations of the law and an incomplete depiction
22 of expert deposition testimony. In particular, Defendants’ arguments focus on whether their products
23 have any noninfringing use. See Defs.’ Br. at 14–18. Defendants would improperly erase
24 “substantial” from the statute. Defendants arguments thus fail because they utilize the incorrect legal
25 standard.
26 1. Defendants’ Products Are Not “Suitable” for Noninfringing Use
27 The asserted claims are directed to the treatment of severe hypertriglyceridemia using 4
27
1 grams per day of highly purified EPA for at least 12 weeks. This is the same use for which
2 Defendants seek approval. See Defs.’ Br. at 7 (undisputed fact 3(a)). And, as explained in Section
3 V.A.1, treatment of severe hypertriglyceridemia requires that the patient’s TGs are reduced and
4 maintained below 500 mg/dl to persistently avoid the risk of developing pancreatitis. See, e.g.,
5 Fisher Tr. 72:4–8 (agreeing that indication refers to “keeping triglycerides below 500 milligrams per
6 deciliter in a severely hypertriglyceridemic patient.”). And, as also discussed above, clinicians
7 recognize that the only way to accomplish this treatment is through long-term treatment (i.e., at least
8 12 weeks). See supra note 11. Accordingly, the uses described in the claims represent the only
9 substantial use for Defendants’ products. Upon approval, Defendants would supply those products
10 for administration to patients, who will be treated with them according to the claims. Defendants’
11 products thus “embod[y] . . . the heart of the patented process and suppl[y] [their products] to others
12 to complete the process and appropriate the benefit of the patented invention.” Vita-Mix, 581 F.3d at
13 1327.
14 Defendants nonetheless assert that Defendants’ products are not “especially made” to be used
15 for at least 12 weeks. Defs.’ Br. at 15. Defendants ignore that their products will be especially made
16 for the treatment of severe hypertriglyceridemia. Vascepa Label, § 1. And, expert deposition
17 testimony establishes that the treatment of severe hypertriglyceridemia requires long-term therapy,
18 and thus at least 12 weeks of therapy, to reduce and maintain TGs below 500 mg/dl. See Section
19 V.A.1. In view of this testimony, other statements outside the label suggesting that the products will
20 be suitable for reducing TGs in less than 12 weeks (Defs.’ Br. at 16) are beside the point. The
21 indication for Vascepa is directed to reducing and maintaining patients’ TGs below 500 mg/dl. Thus,
22 even assuming that Vascepa reduced TGs below 500 mg/dl in shorter than 12 weeks, treatment of
23 this condition requires long-term therapy to maintain the TG reduction. See supra Section V.A.
24 Nor can Defendants’ misreading of the patent specification, see Defs.’ Br. at 15, support their
25 argument. The specification simply notes that reductions in TGs begin about 1 week after the
26 treatment with purified EPA begins. See, e.g., ‘728 Patent, 3:65–4:6. The patent specification does
27 not establish that a shorter duration of treatment will reduce TGs below 500 mg/dl, nor does it
28
1 demonstrate that a shorter duration will keep TGs below 500 mg/dl.
2 2. A ny N oninfringing Use for Def endants' Products Is N ot "Substantial"
3 Even if Defendants' products are "suitable" for shmter than 12-week treatment duration, such
4 use is not "substantial." All pa1ties' expe1ts agree that when prescribing Vascepa for severely
5 hypeltriglyceridemic patients, clinicians' intend "indefinite" treatment. See Section V.A.l. It is
6 difficult to imagine how a use that is contra1y to how clinicians treat severely hypeltriglyceridemic
7 patients could be a "substantial" use. See i4i Ltd. P 'ship, 598 F.3d at 851 ("In assessing whether an
8 asserted noninfi:inging use was 'substantial,' the jmy was allowed to consider not only the use 's
9 frequency, but also the use 's practicality, the invention 's intended pmpose, and the intended
10 market."). Defendants ' attempt to show othe1wise is based on chenypicking Dr. Budoff s deposition
11 testimony . See Defs.' Br. at 15. The testimony Defendants cite acknowledged only
12
13
14
15
17 clinicians will use Defendants' products for less than 12 weeks, and clinicians' intent to use the
18 products long ten n to persistently reduce severely hype1triglyceridemic patients' TG levels, there is
19 no substantial noninfringing use for Defendants ' products. See i4iLtd. P 'ship, 598 F.3d at 851.
20 B. Use of Defendants' Generic Products to Achieve Effects Other Than the Effects
21 on TGs, LDL-C, and Apo B Recited in the Claims Are Not Substantial Uses
22 Defendants also argue that they will not contribute to clinicians infringing the fomteen claims
23
18
24 BudoffTr. 254:11- 23
111 :7-11
25
26
27
29
1 that recite specific effects on TGs, LDL-C, and apo B (see Appendix B) because, according to
2 Defendants, a substantial number of patients will not experience effects consistent with these claim
3 limitations. See Defs.’ Br. at 23–24. As discussed above, more than half of the patients in the
4 MARINE Clinical Study experienced lipid effects that exceeded the lipid effects in the claims. (See
5 supra Section V.B). Although individual patients can respond to treatment in unexpected ways,
6 clinicians’ treating intent is to achieve similar effects in their patients. See Budoff Reply Rept.
7 ¶¶ 104–09. For example, clinicians do not use Vascepa to cause an increase in their patients’ LDL-
8 C. Budoff Tr. 136:12–13 see also
9 id. 245:1–20.
10 Accordingly, when considering not only the frequency with which Vascepa is used to
11 achieve effects other than those recited in the claims, but also the invention’s intended purpose to
12 achieve the effects described in the claims, Defendants cannot establish that they are entitled to
13 judgment as a matter of law.
14 VII. CONCLUSION
15 For the foregoing reasons, Amarin respectfully requests that the Court deny Defendants’
16 Motion for Summary Judgment of Noninfringement.
17 DATED: August 30, 2019 Respectfully submitted,
18
/s/ Jason D. Smith
10100 W. Charleston Blvd., Suite 250
21 Las Vegas, NV 89135
22 Tel: (702) 948-8771 / Fax: (702) 948-8773
E-mail: nsantoro@santoronevada.com,
23 jsmith@santoronevada.com

26 Megan P. Keane (admitted pro hac vice)
Eric R. Sonnenschein (admitted pro hac vice)
27 Alaina M. Whitt (admitted pro hac vice)
30

1
Jordan L. Moran (admitted pro hac vice)
2 COVINGTON & BURLING LLP
One CityCenter, 850 Tenth Street, NW
3 Washington, DC 20001
Tel: (202) 662-6000 / Fax: (202) 662-6291
4 E-mail: csipes@cov.com, estole@cov.com,
mkennedy@cov.com, mkeane@cov.com,
5
7 Attorneys for Plaintiffs Amarin Pharma, Inc.

and Amarin Pharmaceuticals Ireland Limited
8
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31
1 CERTIFICATE OF SERVICE
2 I hereby certify that on August 30, 2019, I caused true and correct copy of AMARIN’S
3 OPPOSITION TO DEFENDANTS’ MOTION FOR SUMMARY JUDGMENT to be filed
4 with the Clerk of the Court using the Court’s CM/ECF system, and service was thereby effected
5 electronically to the following counsel of record in this matter and deposited for mailing in the
6 U.S. Mail, postage prepaid and address to:
7 Wayne A. Shaffer Michael D. Rounds

LAXALT & NOMURA, LTD. Ryan James Cudnik
8 9790 Gateway Drive, Suite 200 Brownstein Hyatt Farber Schreck, LLP
9 Reno, NV 89521 5371 Kietzke Lane
Tel: (775) 322-1170 Reno, NV 89511
10 Email: wshaffer@laxalt-nomura.com Email: mrounds@bhfs.com,
rcudnik@bhfs.com
11 George C. Lombardi
WINSTON & STRAWN LLP Constance S. Huttner
12
35 W. Wacker Drive Frank D. Rodriguez
13 Chicago, IL 60601 Caroline Sun
Tel: (312) 558-5969 Beth Finkelstein
14 Email: glombard@winston.com James Barabas
Windels Marx Lane & Mittendorf, LLP
15 Charles B. Klein 1 Giralda Farms, First Floor
Claire A. Fundakowski Madison, New Jersey 07940
16
WINSTON & STRAWN LLP Email: chuttner@ windelsmarx.com
17 1700 K Street N.W. frodriguez@ windelsmarx.com
Washington, D.C. 20006 csun@ windelsmarx.com
18 Tel: (202) 282-5000 bfinkelstein@ windelsmarx.com
Email: cklein@winston.com, jbarabas@windelsmarx.com
19 cfundakowski@winston.com
Attorneys for Defendants Dr. Reddy’s
20
Eimeric Reig-Plessis Laboratories, Inc. and Dr. Reddy’s
21 WINSTON & STRAWN LLP Laboratories, Ltd
101 California Street
22 San Francisco, CA 94111
Tel: (415) 591-6808
23 Email: ereigplessis@winston.com
24
Attorneys for Defendants Hikma
25 Pharmaceuticals USA, Inc. and Hikma
Pharmaceuticals International Limited
26 /s/ Rachel Jenkins
An employee of Santoro Whitmire
27

4 Tel.: (702) 948-8771
Fax: (702) 948-8773
6

10
13 Tel.: (202) 662-6000
Fax: (202) 662-6291
14
18

20
21
22 Plaintiffs, (Consolidated with 2:16-cv-02562-MMD-

NJK)
23 v.
APPENDIX OF EXHIBITS TO AMARIN’S
24 HIKMA PHARMACEUTICALS USA INC., et OPPOSITION TO DEFENDANTS’
al., MOTION FOR SUMMARY JUDGMENT
25
26 Defendants. ORAL ARGUMENT REQUESTED
27
1
1 INDEX
2 Exhibit 1: Declaration of Alaina M. Whitt in support of Amarin’s Opposition to Defendants’
3 Motion for Summary Judgment
4 Exhibit 2: Excerpts from the deposition transcript of Jay W. Heinecke, M.D., dated July 17,
5 2019
6 Exhibit 3: Excerpts from the deposition transcript of Edward A. Fisher, M.D., dated July 2,
7 2019
8 Exhibit 4: Excerpts from the deposition transcript of Peter R. Mathers, dated June 27, 2019
9 Exhibit 5: Excerpts from the deposition transcript of Matthew Budoff, M.D., dated July 17,
10 2019 (Filed Under Seal)
11 Exhibit 6: Excerpts from the deposition transcript of Carl C. Peck, M.D., dated July 1, 2019
12 Exhibit 7: Excerpts from the deposition transcript of Jonathan I. Sheinberg, M.D., dated July
13 2, 2019 (Filed Under Seal)
14 Exhibit 8: Declaration of Matthew Budoff, M.D., dated August 30, 2019
15 Exhibit 9: Excerpts from Opening Expert Report of Matthew Budoff, M.D. Regarding
16 Hikma’s ANDA Product and Vascepa, dated March 10, 2019 (Filed Under Seal)
17 Exhibit 10: Reply Expert Report of Matthew Budoff, M.D. Regarding Defendants’ ANDA
18 Products and Vascepa, dated June 10, 2019 (Filed Under Seal)
19 Exhibit 11: Declaration of Carl C. Peck, M.D., dated August 30, 2019
20 Exhibit 12: Excerpts from the Reply Expert Report of Carl C. Peck, M.D., dated June 10,
21 2019
22 Exhibit 13: Excerpts from the Rebuttal Expert Report of Jonathan I. Sheinberg, M.D.,
23 F.A.C.C., on Noninfringement of the Asserted Claims of the Patents-in-Suit,
24 dated May 10, 2019 (Filed Under Seal)
25 Exhibit 14: FDA, Guidance for Industry: Clinical Studies Section of Labeling for Human
26 Prescription Drug and Biological Products — Content and Format (January
27
2
1 2006), https://www.fda.gov/media/ 72140/download (AMRN-PEXP-0010187–

2 211)
3 Appendix A: Asserted Patent Claims
4 Appendix B: Asserted Claims Describing Specific Effects on TGs, LDL-C, and/or Apo B
5
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Case 2:16-cv-02525-MMD-NJK Document 253-1 Filed 08/30/19 Page 1 of 4
EXHIBIT 1
Declaration of Alaina M. Whitt

3
4 Tel.: (702) 948-8771
Fax: (702) 948-8773
6
Christopher N. Sipes (admitted pro hac vice)
7
10 Han Park (admitted pro hac vice)
11
13 Tel.: (202) 662-6000
Fax: (202) 662-6291

18

20
21
Plaintiffs, (Consolidated with 2:16-cv-02562-MMD-
22 NJK)
23 v.
24 HIKMA PHARMACEUTICALS USA INC., et DECLARATION OF ALAINA M. WHITT

al., IN SUPPORT OF AMARIN’S
25 OPPOSITION TO DEFENDANTS’
Defendants. MOTION FOR SUMMARY JUDGMENT
26
27
001
1 I, Alaina M. Whitt, hereby declare as follows:

2 1. I am an attorney and a member of the District of Columbia and Illinois bars. I am
3 an associate with the law firm of Covington & Burling LLP, One CityCenter, 850 Tenth Street,
4 NW, Washington, DC 20001. I have been admitted pro hac vice in this matter to represent
5 Plaintiffs Amarin Pharma Inc. and Amarin Pharmaceuticals Ireland Limited (collectively,
6 “Plaintiffs” or “Amarin”). I make this Declaration in support of Amarin’s Opposition to
7 Defendants’ Motion for Summary Judgment of Noninfringement.
8 2. I have personal knowledge of the matters stated herein, and if called as a witness, I
9 could and would testify competently thereto.
10 3. Exhibit 2 is a true and correct excerpted copy of the deposition transcript of Jay W.
11 Heinecke, M.D., dated July 17, 2019.
12 4. Exhibit 3 is a true and correct excerpted copy of the deposition transcript of Edward
13 A. Fisher, M.D., dated July 2, 2019.
14 5. Exhibit 4 is a true and correct excerpted copy of the deposition transcript of Peter
15 R. Mathers, dated June 27, 2019.
16 6. Confidential Exhibit 5 is a true and correct excerpted copy of the deposition
17 transcript of Matthew Budoff, M.D., dated July 17, 2019.
18 7. Exhibit 6 is a true and correct excerpted copy of the deposition transcript of Carl
19 C. Peck, M.D., dated July 1, 2019.
20 8. Confidential Exhibit 7 is a true and correct excerpted copy of the deposition
21 transcript of Jonathan I. Sheinberg, M.D., dated July 2, 2019.
22 9. Confidential Exhibit 9 is a true and correct excerpted copy of the Opening Expert
23 Report of Matthew Budoff, M.D., Regarding Hikma’s ANDA Product and Vascepa, dated March
24 10, 2019.
25 10. Confidential Exhibit 10 is a true, correct, and complete copy of the Reply Expert
26 Report of Matthew Budoff, M.D., Regarding Defendants’ ANDA Products and Vascepa, dated
27 June 10, 2019
-2-
002
003
EXHIBIT 2
Excerpts from the deposition transcript of
Jay W. Heinecke, M.D., dated July 17, 2019
Page 1
1

4 DISTRICT OF NEVADA
5 __________________________________
6 AMARIN PHARMA, INC., et al., )
)
7 )
)
8 Plaintiffs, ) Case No.:
) 2:16-cv-02525-MMD-NJK
9 vs. )
) Consolidated with:
10 ) 2:16-cv-02562-MMD-NJK
HIKMA PHARMACEUTICALS USA INC., )
11 et al., )
)
12 )
)
13 Defendants. )
___________________________________)
14
15
16
17 VIDEOTAPED DEPOSITION OF
18 JAY W. HEINECKE, M.D.
19 San Francisco, California
20 Wednesday, July 17, 2019
21
22
23 Reported by Stenographer
MARY J. GOFF
24 CSR No. 13427
Job No. 162979
25
TSG Reporting - Worldwide 877-702-9580

001
Page 2 Page 3
1 1 APPEARANCES:
2 2
3 3 For Plaintiffs
4 Videotaped Deposition of 4 COVINGTON & BURLING
5 JAY W. HEINECKE, M.D., Volume I, taken on behalf of 5 BY: CHRISTOPHER SIPES, ESQ.
6 Plaintiffs, at Winston & Strawn LLP, 101 California 6 ERIC SONNENSCHEIN, ESQ.
7 Street, San Francisco, California 94111, beginning 7 One City Center
8 at 8:04 a.m. and ending at 4:12 p.m., on July 17, 8 850 Tenth Street, NW
9 2019, before MARY J. GOFF, California 9 Washington, DC 20001
10 Certified Shorthand Reporter No. 13427. 10
11 11
12 12
13 13
14 14 For Defendants
15 15 Winston & Strawn
16 16 BY: EIMERIC REIG-PLESSIS, ESQ.
17 17 101 California Street
18 18 San Francisco, California 94111
19 19
20 20
21 21
22 22
23 23
24 24
25 25
Page 4 Page 5
1 APPEARANCES CONTINUED: 1 INDEX
2 2 WITNESS EXAMINATION
3 For Dr. Reddy's Laboratories Defendants 4 Volume I
4 Windells Marx Lane & Mittendorf 5
5 BY: CONSTANCE HUTTNER, ESQ. 6 BY MR. SIPES 9
6 Attorney at Law 7 BY MR. REIG-PLESSIS --
7 8
One Giralda Farms
9
8 Madison, New Jersey 07940 10 NUMBER DESCRIPTION PAGE
9 (appeared via phone) 11 Exhibit 1 Opening Expert Report of Jay W. 12
10
Heinecke, M.D. on Invalidity of the
11 12 Asserted Claims of the Patents-in-Suit
12 13
14 Exhibit 2 Rebuttal Expert Report of Jay W. 12
13
14
Heinecke, M.D. on Invalidity of the
ALSO PRESENT: Joseph T. Kennedy, Amarin EVP, GC 15 Asserted Claims of the Patents-in-Suit
15 Videographer: 16
16 Marcus Majers 17 Exhibit 3 Reply Report of Jay W. Heinecke, M.D. 12
17 on Invalidity of the
18 Asserted Claims of the Patents-in-Suit
18
19
19
20 Exhibit 4 Application No. 21-656 48
20
Approved Labeling
21 21 AMRN-PEXP-0001915-932
22 22
23 Exhibit 5 PDR, 62 Edition, 2008 113
23
24
AMRN00290591-94
24
25 25
2
002
Page 6 Page 7
1 EXHIBITS CONTINUED: PAGE 1 EXHIBITS CONTINUED: PAGE
2 Exhibit 6 NIASPAN niacin extended-release 115 2 Exhibit 14 Current Therapeutic Research 242
tablets Clinical and Experimental, Vol 56
3 AMRN-PEXP-0001692-712 3 No. 1, 1995
4 ICOSAPENT_DFNDTS00006159-68
5 Exhibit 7 Atherosclerosis, 26 (1977)603-609 122 4
AMRN-PEXP-0008180-186 5 Exhibit 15 Eicosapentaenoic Acid Effect on 263
6 Lars Carson article, On the Rise... Hyperlipidemia in Menopausal
7 6 Japanese Women by Kurabayashi, et al.
8 Exhibit 8 Article from the Journal of Clinical 134 ICOSAPENT_DFNDTS00006237-44
Lipidology, Pilot Study... 7
9 AMRN00621043-49 8 Exhibit 16 US Patent 8,293,728 276
10 AMRN-PEXP-000000122
11 Exhibit 9 Regulator Rebuffs Merck's 160 9
Cholesterol Drug article 10 Exhibit 17 Methods of Treating and/or 288
12 Peter Mitchell 28 May Preventing Cardiovascular Diseases
AMRN-PEXP-0009429-431 11 and Disorder
13 12 Exhibit 18 Effects of Eicosapentaenoic Acid 304
14 Exhibit 10 Tredaptive, Pelzont, and Trevaclyn 171 on Major Coronary Events in
suspended across the UE 13 Hypercholesterolaemic Patients
15 AMRN-PEXP-0009110-112 (JELIS) Yokoyama, et al.
16 Exhibit 11 When Good Cholesterol Turns Bad 185 14 AMRN03151311-319
Oram and Heinecke 15 Exhibit 19 Epadel Capsules 300, Approval 316
17 ICOSAPENT_DFNTS00008961-69
18 Exhibit 12 Purified eicosapentaenoic and 215 16
docosahexaenoic acids... 17 Exhibit 20 Publication No. WO 2008/004900 A1 329
19 ICOSAPENT-DFNDTS00006520-29 ICOSAPENT_DFNTS00007108-150
20 Exhibit 13 A Review of Omega-3 Ethyl Esters 236 18
for Cardiovascular Prevention and 19
21 Treatment of Increased Blood 20
Triglyceride Levels by 21
22 Clemens von Schacky 22
23 23
24 24
25 25
Page 8 Page 9
1 San Francisco, California 10:20 1 With me is my colleague, Eric 08:04
2 July 17, 2019 10:20 2 Sonnenschein; and Joe Kennedy of Amarin 08:04
3 8:04 a.m. 10:20 3 Pharmaceuticals. 08:04
4 10:20 4 MR. REIG-PLESSIS: I'm Eimeric Reig of 08:04
5 THE VIDEOGRAPHER: Good morning. This is 08:02 5 Winston & Strawn, on behalf of the Hikma Defendants 08:04
6 the start of media labeled No. 1 of the video 08:02 6 and the witness. 08:04
7 recorded deposition of Dr. Jay W. Heinecke, in the 08:02 7 THE VIDEOGRAPHER: And has anyone joined 08:04
8 matter of Amarin Pharma, Inc., et al, versus Hikma 08:03 8 on the phone yet? 08:04
9 Pharmaceuticals USA Inc., et al., in the United 08:03 9 MR. REIG-PLESSIS: I don't think so. 08:04
10 States District Court, District of Nevada, 08:03 10 MR. SIPES: Okay. Great. 08:04
11 Case No.: 2:16-cv-02525-MMD-NJK; Consolidated 08:03 11 JAY W. HEINECKE, M.D., 08:04
12 with: 2:16-cv-02562-MMD-NJK. 08:03 12 being first duly sworn or affirmed to testify to the 08:04
13 This deposition is being held at Winston & 08:03 13 truth, the whole truth, and nothing but the truth, 08:04
14 Strawn, 101 California Street, San Francisco, 08:03 14 was examined and testified as follows: 08:04
15 California, on July 17, 2019, at approximately 08:03 15 EXAMINATION 08:04
16 8:04 a.m. 08:03 16 BY MR. SIPES: 08:04
17 My name is Marcus Majers. I'm the legal 08:03 17 Q Good morning. Thank you for coming in 08:04
18 video specialist from TSG Reporting, Inc., 08:03 18 this morning. 08:04
19 headquartered at 747 Third Avenue, New York, 08:03 19 Could you please state your name and spell 08:04
20 New York. The court reporter is Mary Goff, in 08:03 20 it for the record? 08:04
21 association with TSG Reporting. 08:03 21 A Yes. My name is Jay Walter Heinecke, 08:04
22 Will all counsel present please introduce 08:04 22 H E I N E C K E; J A Y; Walter, W A L T E R. 08:04
23 themselves. 08:04 23 Q And where do you reside? 08:04
24 MR. SIPES: Christopher Sipes of Covington 08:04 24 A I reside in Seattle, Washington. 08:04
25 & Burling LLP, on behalf of the Plaintiff. 08:04 25 Q And you are currently employed? 08:04
3
003
Page 10 Page 11
1 A I'm currently provide by the University of 08:04 1 that fair? 08:05
2 Washington. 08:04 2 A Yes. 08:05
3 Q And what is your work address? 08:04 3 Q This is not an endurance test. If at some 08:05
4 A My work address would be the University of 08:05 4 time you need a break, let me know and we'll try to 08:05
5 Washington, 850 Republican Street, Seattle 98109. 08:05 5 endeavor to find a good breaking point for you. 08:05
6 Q Okay. Have you been deposed before? 08:05 6 A Okay. 08:05
7 A I have never been deposed as an expert 08:05 7 Q You understand that the court reporter is 08:05
8 witness. 08:05 8 taking down a transcript, so you'll need to answer 08:05
9 Q You have been deposed as a fact witness? 08:05 9 audibly with verbal responses? 08:05
10 A As a what? 08:05 10 A I do. 08:06
11 Q Have you been deposed as a fact witness? 08:05 11 Q Also, you -- your counsel may from time to 08:06
12 Have you ever been deposed in any capacity? 08:05 12 time object, but you'll need to answer the 08:06
13 A I have. 08:05 13 questions, if you understand them, unless you're 08:06
14 Q Okay. How many times? 08:05 14 instructed not to answer by counsel. 08:06
15 A One time. 08:05 15 Do you understand? 08:06
16 Q Okay. I will go through the rules. I 08:05 16 A I understand. 08:06
17 suspect you -- you know them, having been through 08:05 17 Q Is there any reason why you cannot give 08:06
18 it. 08:05 18 complete and truthful testimony today? 08:06
19 But first, you understand that you are 08:05 19 A No, not that I'm aware after. 08:06
20 under oath today and are required to answer my 08:05 20 Q Okay. And as far as you're -- you don't 08:06
21 questions truthfully? 08:05 21 have any medical condition or medications that might 08:06
22 A Yes. 08:05 22 interfere with your ability to answer truthfully? 08:06
23 Q If you don't understand a question, please 08:05 23 A No. 08:06
24 let me know and I will attempt to clarify it. 08:05 24 Q Let me hand to you three documents that 08:06
25 Otherwise, I will assume that you understood it; is 08:05 25 have been marked as Exhibits 1, 2, and 3 in the 08:06
Page 12 Page 13
1 case. 08:06 1 Q We can go through them one at a time, I -- 08:07
2 (Exhibit 1 was marked for identification 08:06 2 A Okay. 08:07
3 and is attached to the transcript.) 08:06 3 Q -- think is easiest. 08:07
4 (Exhibit 2 was marked for identification 08:06 4 A Fine. 08:07
5 and is attached to the transcript.) 08:06 5 Q And Exhibit 1 is the -- your opening 08:07
6 (Exhibit 3 was marked for identification 08:06 6 report -- 08:07
7 and is attached to the transcript.) 08:06 7 A Yes. 08:07
8 A Okay. 08:06 8 Q -- in this case, correct? 08:07
9 Q (BY MR. SIPES) Do you recognize 08:06 9 And you have signed it on or about 08:07
10 Exhibits 1, 2, and 3 as the reports that you 08:06 10 March 11 of 2019? 08:07
11 prepared in this case? Since you have Exhibit 1 in 08:06 11 A Yes. 08:07
12 your hands, if you would turn to page 241 of 08:07 12 Q And you understand that you -- you signed 08:07
13 Exhibit 1, if you're looking for your signature. 08:07 13 your expert report under penalty of perjury? 08:07
14 A Thank you. 08:07 14 A Yes. 08:07
15 Q That -- that is your signature -- 08:07 15 Q And did you endeavor to make what you 08:07
16 A Yes -- 08:07 16 stated in your opening report -- and first of all, 08:08
17 Q -- on page 241 of Exhibit 1? 08:07 17 is it all right if we refer to your -- Exhibit 1 as 08:08
18 A -- that's my signature on -- 08:07 18 your opening report? 08:08
19 Q And you -- why don't we deal with 08:07 19 A That's fine. 08:08
20 Exhibit 1. 08:07 20 Q And did you endeavor to -- to make your 08:08
21 A You -- 08:07 21 statements in Exhibit 1 to be as truthful and 08:08
22 Q You have got it in front of you. 08:07 22 accurate as possible? 08:08
23 A Yeah. Yeah. 08:07 23 A I endeavored to make the statements as 08:08
24 Do I need to look at the signatures on the 08:07 24 truthful and accurate as possible. 08:08
25 other ones as well? 08:07 25 Q Are you aware of any errors or corrections 08:08
4
004
Page 14 Page 15
1 that you need to make -- 08:08 1 here? 08:08
2 A When I -- 08:08 2 Q Why not. It's on page 69. 08:08
3 Q -- sitting here now? 08:08 3 THE COURT REPORTER: Please watch the 08:08
4 A -- was looking through it, I did notice 08:08 4 cross-talk. Thank you. 08:08
5 some very minor typos here and there. I can't 08:08 5 A I'm sorry? 08:08
6 explicitly remember which ones -- 08:08 6 Q (BY MR. SIPES) We need to make sure we 08:09
7 Q All right. 08:08 7 don't talk over each -- 08:09
8 A -- there were, but there were some minor 08:08 8 A Okay. 08:09
9 errors. 08:08 9 Q -- other. 08:09
10 Q Was there any substantive issues that you 08:08 10 A Excuse me. 08:09
11 had with the report? 08:08 11 Q And that's your signature on page 69 of 08:09
12 A No, not that I'm aware of. 08:08 12 Exhibit 2? 08:09
13 Q All right. Why don't we turn to 08:08 13 A Yes, it is. 08:09
14 Exhibit 2. Exhibit 2 is the rebuttal report that 08:08 14 Q And again, you -- you understand that you 08:09
15 you prepared in the case; is that correct? 08:08 15 signed under penalty of perjury, your rebuttal 08:09
16 A Yes. 08:08 16 report? 08:09
17 Q And is it all right if we refer to 08:08 17 A Yes. 08:09
18 Exhibit 2 as your rebuttal report? 08:08 18 Q And you endeavored to make it as truthful 08:09
19 A Let me just look at the Table of Contents 08:08 19 and accurate as possible? 08:09
20 here for a second. 08:08 20 A I did. 08:09
21 Q Sure. 08:08 21 Q Are you aware of any errors in your 08:09
22 A Okay. Yes. 08:08 22 rebuttal report? 08:09
23 Q So we can refer to Exhibit 2 as your 08:08 23 A Again, I think there may have been some 08:09
24 rebuttal report? 08:08 24 minor typos in it, but no major errors. 08:09
25 A Yes. And should I look at my signature 08:08 25 Q Okay. And nothing of substance that you 08:09
Page 16 Page 17
1 are aware of? 08:09 1 Q And so in the fall of 2018? 08:10
2 A Nothing of substance that I am aware of. 08:09 2 A Yes. 08:10
3 Q Okay. Then turning to Exhibit 3, can we 08:09 3 Q And who reached out to retain you? 08:10
4 refer to Exhibit 3 as your reply report? 08:09 4 A It was somebody at Bud Barner. I can't 08:10
5 A Yes. 08:09 5 recall their name right now, but it was a assistant 08:10
6 Q And if you will turn to page 82. 08:09 6 to one of the attorneys on the case. 08:10
7 A On page 82, my signature is there -- 08:09 7 Q And they were counsel for which party? Do 08:10
8 Q All right. And -- 08:09 8 you recall? 08:10
9 A -- and signed June 7 -- 08:09 9 A What do you mean? 08:10
10 Q -- okay. 08:09 10 Q You understand that there are two 08:10
11 A -- 2019. 08:09 11 Defendants in the case? Well, let me -- are you 08:10
12 Q And again, did -- you understand that you 08:09 12 aware that there are two sets of defendants -- 08:10
13 signed your reply report under penalty of perjury, 08:09 13 A Yes -- 08:10
14 correct? 08:10 14 Q -- in the case? 08:10
15 A I understand that. 08:10 15 A -- I am aware of that. 08:10
16 Q And are you aware of any errors in your 08:10 16 Q There is the Hikma -- 08:10
17 reply report? 08:10 17 A Right. 08:10
18 A Some minor typos, but no major errors. 08:10 18 Q -- defendants? 08:10
19 Q Okay. And nothing of substance? 08:10 19 A Right. 08:10
20 A Correct. 08:10 20 THE COURT REPORTER: Wait. 08:10
21 Q Are Exhibits 1, 2, and 3 the only reports 08:10 21 Q (BY MR. SIPES) And -- 08:10
22 you prepared in this matter? 08:10 22 A This -- this is a little bit complicated, 08:10
23 A Yes. 08:10 23 as you may be aware, because I believe there was a 08:11
24 Q When were you retained? 08:10 24 change in ownership of the -- of one of the 08:11
25 A Approximately nine months ago. 08:10 25 companies and the legal counsel for that. 08:11
5
005
Page 18 Page 19
1 Q So -- so that doesn't -- so one of the 08:11 1 A I'm sorry. I'm sorry. Excuse me. 08:11
2 answers was originally filed by Roxane. 08:11 2 Q (BY MR. SIPES) And in forming your 08:11
3 Are you aware of that? 08:11 3 opinions in this case, have you spoken with anyone 08:11
4 A I am not aware of that. 08:11 4 other than lawyers? 08:11
5 Q Okay. So that became the Hikma Westward 08:11 5 A I have not. 08:11
6 Defendants? You're aware that one set of the 08:11 6 Q Okay. You have not spoken with any of the 08:11
7 defendants is -- is Hikma -- 08:11 7 other experts retained in the case, I take it? 08:11
8 A Yes -- 08:11 8 A I have not. 08:11
9 Q -- Pharmaceuticals -- 08:11 9 Q Okay. And you have not conferred with any 08:11
10 A -- I'm -- 08:11 10 of your colleagues in the field? 08:11
11 Q -- correct? 08:11 11 A I have not. 08:11
12 A -- aware of that. 08:11 12 Q And did you speak with anyone other than 08:12
13 Q And there's another set of defendants, 08:11 13 counsel to prepare for deposition today? 08:12
14 Dr. Reddy's labora -- 08:11 14 A I did not. 08:12
15 A Yes. 08:11 15 Q All right. Let me ask you to look at 08:12
16 Q -- tory? 08:11 16 the -- your CV, which is attached -- 08:12
17 Do you understand that you're here to 08:11 17 A Yes. 08:12
18 provide testimony on behalf of both -- 08:11 18 Q -- to Exhibit 1 -- 08:12
19 A Yes. 08:11 19 A Um-hum. 08:12
20 Q -- of the defendants? 08:11 20 Q Is your CV current -- current and 08:12
21 THE COURT REPORTER: Wait. 08:11 21 accurate? 08:12
22 MR. REIG-PLESSIS: Just wait until he's 08:11 22 A It was current at the time that I provided 08:12
23 done -- 08:11 23 the CV to the lawyers. 08:12
24 A Okay. 08:11 24 Q And -- and do you recall when that was? 08:12
25 MR. REIG-PLESSIS: -- answering [sic] -- 08:11 25 A I believe it was around the time that they 08:12
Page 20 Page 21
1 first contacted me. 08:12 1 but I have had some interactions with the FDA in 08:13
2 Q So around the fall of -- 08:12 2 terms of other things I have been involved with. 08:13
3 A Yes. 08:12 3 Q And what have you been involved with that 08:13
4 Q -- 2018? 08:12 4 you have had interactions with FDA? 08:13
5 Are there additional things to update 08:12 5 A There was a company trying to get a drug 08:13
6 since then? 08:12 6 approved by the FDA, and they sought my counsel on a 08:13
7 A I believe we have had a number of 08:12 7 specific point related to some of the things 08:13
8 subsequent publications that appeared since this was 08:12 8 involved in the case. 08:13
9 submitted. 08:12 9 Q What was the name of the company. 08:13
10 Q Okay. Is there anything else that would 08:12 10 A Oh, I can't remember. This is probably 08:13
11 appear on your current -- on your -- on a current 08:12 11 10 years ago. 08:13
12 CV? 08:12 12 And it was a -- one of these orphan 08:13
13 A Not that I'm aware of. 08:12 13 fund kind of -- or orphan drug kind of companies 08:13
14 Q You are not a lawyer, correct? 08:12 14 that was trying to get a special application for a 08:13
15 A I am not a lawyer. 08:12 15 drug that affected HDL cholesterol. 08:13
16 Q Have you had any legal training? 08:12 16 And my area of expertise is HDL 08:13
17 A No. 08:13 17 cholesterol, and so they sought my opinion about how 08:13
18 Q Okay. Do you consider yourself an expert 08:13 18 that might influence what was going on in their -- 08:13
19 in patent law? 08:13 19 Q Was it -- 08:14
20 A I do not. 08:13 20 A -- application. 08:14
21 Q Have you ever worked at FDA? 08:13 21 Q -- was it is a drug whose purpose was to 08:14
22 A No. 08:13 22 raise HDL cholesterol? 08:14
23 Q Do you consider yourself an expert in drug 08:13 23 A No. 08:14
24 regulatory law? 08:13 24 MR. REIG-PLESSIS: And, Dr. Heinecke, I'll 08:14
25 A I'm not an expert in drug regulatory law, 08:13 25 just caution you -- 08:14
6
006
Page 22 Page 23
1 A Yes. 08:14 1 never been directly involved in trying to develop a 08:15
2 MR. REIG-PLESSIS: -- to the extent that 08:14 2 drug. 08:15
3 you have any confidentiality agreement or that 08:14 3 Q And has your consulting work for 08:15
4 there's any confidentiality concern with your work 08:14 4 pharmaceutical companies involved drugs targeting 08:15
5 for another company that's not involved in this 08:14 5 HDL? 08:15
6 case, to make sure you don't reveal any -- 08:14 6 A Yes. 08:15
7 A Okay. 08:14 7 Q Okay. Have you consulted for companies on 08:15
8 MR. SIPES: -- any confidential details. 08:14 8 drugs targeting other lipid parameters? 08:15
9 A That -- that's very helpful. 08:14 9 A That's a little complicated to explain. 08:15
10 I don't recall if I have a confidentiality 08:14 10 So one of my areas of expertise is 08:15
11 agreement with the company, so I guess it would be 08:14 11 oxidative damage of proteins and one of the targets 08:15
12 best if I don't discuss this. 08:14 12 for oxidative damages, LDL and HDL. 08:15
13 Q (BY MR. SIPES) And -- and the time frame 08:14 13 So I have been consulted in terms of 08:15
14 would have been around 2009? 08:14 14 oxidation processes and how that might affect LDL 08:15
15 A Approximately. 08:14 15 and HDL and atherogenesis, but nothing directly in 08:15
16 Q Okay. And it was a drug in the 08:14 16 terms of altering lipid levels or HDL or LDL 08:15
17 cardiovascular area? 08:14 17 cholesterol levels. 08:15
18 A No, it was not. 08:14 18 Q Have you ever consulted with regard to any 08:15
19 Q Okay. And have you ever -- other than 08:14 19 drug containing an omega-3 fatty acid? 08:15
20 that one instance, have you been involved in other 08:14 20 A I have not. 08:15
21 attempts to develop a method of treatment approved 08:14 21 Q Okay. Have you ever consulted for Hikma? 08:15
22 by FDA? 08:14 22 A No. 08:16
23 A I have consulted in a very general way 08:14 23 Q Other than this case? 08:16
24 with several pharmaceutical companies over the years 08:14 24 A No. 08:16
25 on areas related to my area of expertise, but I have 08:14 25 Q Have you ever consulted for Dr. Reddy's 08:16
Page 24 Page 25
1 laboratory? 08:16 1 taken the position that they can pursue consulting 08:16
2 A No. 08:16 2 work with other companies? Are you still going 08:16
3 Q Have you ever consulted for Boehringer 08:16 3 refuse answer the question? 08:16
4 Ingelheim? 08:16 4 MR. REIG-PLESSIS: Well, I think it 08:17
5 A No. 08:16 5 depends if he has a third-party confidentiality 08:17
6 Q You have consulted for Merck, I take it? 08:16 6 agreement. I don't know if that would say whether 08:17
7 A Yes. 08:16 7 or not he does or not. And so -- 08:17
8 Q What was your work -- was your work for 08:16 8 A I can answer that though. I'll go ahead 08:17
9 Merck related to the laro -- laro -- 08:16 9 and choose to answer the question. 08:17
10 (Ms. Hutton joined the conference via 08:16 10 It did not involve that at all. 08:17
11 phone at 8:16 a.m.) 08:16 11 Q (BY MR. SIPES) Okay. 08:17
12 MR. SIPES: Who just joined? 08:16 12 A I was never involved with that project. 08:17
13 (Constance S. Huttner joined via phone 08:16 13 Q Okay. Were -- were you involved for any 08:17
14 conference at 8:16 a.m.) 08:16 14 company with a CETP inhibitor? 08:17
15 MS. HUTTNER: Connie Huttner. Sorry I'm 08:16 15 A I was consulted on CETP inhibitors. 08:17
16 late. 08:16 16 Q And you consult -- did you consult for 08:17
17 Q (BY MR. SIPES) Did you consult for Merck 08:16 17 GSK? 08:17
18 with regard to their laropiprant product? 08:16 18 A Yes. 08:17
19 A I'm not sure of where or not I'm under a 08:16 19 Q Now, tell me -- your work for GSK, did it 08:17
20 confidentiality agreement with that consulting work, 08:16 20 involve Lovaza or Omacor in any way? 08:17
21 and so I would have to say that I don't think I can 08:16 21 A No, it did not. 08:17
22 discuss that in this context. 08:16 22 Q Okay. Was your consulting work for GSK in 08:17
23 Q There is company -- there is a protective 08:16 23 the cardiovascular area? 08:17
24 order in this case. You're aware of that? 08:16 24 A Yes. 08:17
25 Are you aware that the defendants have 08:16 25 Q You are board-certified in internal 08:17
7
007
Page 26 Page 27
1 medicine? 08:17 1 Q How would you distinguish the practice of 08:18
2 A Yes. 08:17 2 cardiology from the practice of endocrinology? 08:18
3 Q And you have a certification in 08:17 3 MR. REIG-PLESSIS: Objection to form. 08:18
4 endocrinology? 08:17 4 A That's a very broad question. There are 08:18
5 A Yes. 08:17 5 certainly similarities between the two areas. We 08:18
6 Q Do you have a board certification in 08:17 6 both deal, for example, with patients at increased 08:18
7 cardiology? 08:17 7 risk of cardiovascular disease, but there are also 08:18
8 A I do not. 08:17 8 clearly many, many differences. 08:18
9 Q Do you hold yourself out as a -- to 08:17 9 Cardiologists tend to focus specifically 08:18
10 patients as a cardiologist? 08:18 10 on diseases of the heart involving structural 08:18
11 A I do not. 08:18 11 diseases like atherosclerosis or arrhythmias. 08:18
12 Q Do you consider yourself an expert in 08:18 12 In contrast, endocrinologists tend to 08:18
13 cardiology? 08:18 13 focus much more on metabolic factors like lipids and 08:18
14 A No. 08:18 14 diabetes. 08:19
15 Q How would you distinguish endocrinology 08:18 15 So that would be in a very broad sense, a 08:19
16 from cardiology? 08:18 16 sub -- a beginning of a description of how they 08:19
17 MR. REIG-PLESSIS: Objection to form. 08:18 17 would be different from one another. 08:19
18 Q (BY MR. SIPES) Well, let me ask you: 08:18 18 Q (BY MR. SIPES) This case involves a 08:19
19 Would you distinguish that -- endocrinology -- 08:18 19 disorder known as severe hypertriglyceridemia. 08:19
20 A Maybe -- 08:18 20 Are you aware of that? 08:19
21 Q -- from cardiology? 08:18 21 A Yes. 08:19
22 A -- you could clarify the question. 08:18 22 Q And that involves patients whose 08:19
23 Q Are -- are you familiar with the practice 08:18 23 triglycerides are above 500? 08:19
24 of cardiology? 08:18 24 A That's one definition of what high 08:19
25 A I am. 08:18 25 triglycerides are. 08:19
Page 28 Page 29
1 Q That -- that's the definition that's used 08:19 1 way than we do. 08:20
2 by ATP III, correct? 08:19 2 Q We did give you the courtesy of numbering 08:20
3 A Yes. 08:19 3 your -- 08:20
4 Q And do you view that as a -- a 08:19 4 A No. 08:20
5 cardiovascular disease? 08:19 5 Q -- paragraphs. 08:20
6 A I do not. 08:19 6 A That's nice. Yes. 08:20
7 Q What -- what is your view of the category 08:19 7 Q And in paragraph 9 of your opening report, 08:20
8 for severe hypertriglyceridemia? 08:19 8 you -- you reference that you worked in the lipid 08:20
9 A I consider it to be a metabolic disease 08:19 9 clinic at the University of Washington from 1984 to 08:20
10 with a consequence that it can have an effect on 08:19 10 1991. 08:20
11 cardiovascular risk. And that would come back to 08:19 11 Do you see that? 08:20
12 the difference between cardiologists and 08:19 12 A Yes. 08:20
13 endocrinologists. 08:19 13 Q Do you still work -- well, first of all, 08:20
14 Q And let me ask you to -- to look in your 08:19 14 does the lipid clinic at the University of -- 08:20
15 opening report -- 08:19 15 University of Washington still exist? 08:20
16 A Yes. 08:19 16 A Yes, it does. 08:20
17 Q -- at paragraph 9. 08:19 17 Q Do you continue to work there? 08:20
18 A Yes. 08:20 18 A I do not. 08:20
19 Q You note that you worked in the lipid 08:20 19 Q When you worked there from 1984 to 1991, 08:20
20 clinic in the University of Washington from 1984 to 08:20 20 you saw -- you worked one-half day a week, seeing 08:20
21 1991? 08:20 21 about six patients a week; is that correct? 08:20
22 A Wait a second. I'm on page 9. 08:20 22 A Typically six to seven patients. 08:21
23 Q Oh, I'm sorry. Paragraph -- it's 08:20 23 Q During that time, did you see patients 08:21
24 paragraph -- 08:20 24 with severe hypertriglyceridemia? 08:21
25 A Yeah, I know. You guys do it a different 08:20 25 A I saw many patients with severe 08:21
8
008
Page 30 Page 31
1 hypertriglyceridemia. 08:21 1 and we would use statins. 08:22
2 Q And -- and so we're on the same page, for 08:21 2 Q And fibric acid derivatives are referred 08:22
3 purposes of this definition, can we define that as 08:21 3 to as fibrates? 08:22
4 triglycerides over 500? 08:21 4 A Yes. 08:22
5 A Well, actually, if you're talking about 08:21 5 Q And then in '92 -- or in '92, you moved to 08:22
6 chylomicronemia syndrome, you typically do not see 08:21 6 the Wash -- Washington University, St. Louis, 08:22
7 that in patients that have triglyceride levels less 08:21 7 correct? 08:22
8 than a thousand milligrams per deciliter. 08:21 8 A Yes. 08:22
9 And I saw many patients who had had 08:21 9 Q Did you continue to see patients when you 08:22
10 triglyceride levels above a thousand milligrams per 08:21 10 moved? 08:22
11 deciliter. 08:21 11 A I did. 08:22
12 If we use the ATP III guidelines, it would 08:21 12 Q And were you working in a lipid -- a lipid 08:22
13 be above 500 milligrams per deciliter. 08:21 13 clinic there? 08:22
14 Q And how did you treat patients with severe 08:21 14 A I was working in a lipid clinic there. 08:22
15 hypertriglyceridemia when you were working in the 08:21 15 Q And did you continue to see, among other 08:22
16 lipid clinic from '84 to '91? 08:21 16 things, patients with very high triglycerides? 08:22
17 A Well, that's a very broad question. I 08:21 17 A At Washington University, which was a more 08:22
18 would need to have more specific information. 08:21 18 general lipid clinic than the one at the University 08:22
19 Q Did you prescribe drugs to treat for high 08:21 19 of Washington, there was a much lower frequency of 08:22
20 triglycerides? 08:21 20 patients with high triglycerides, reflecting the 08:22
21 A I did. 08:21 21 overall prevalence of that disorder in the 08:22
22 Q And what drugs did you prescribe during 08:21 22 population. 08:22
23 that time frame? 08:21 23 Q And did you -- during that -- and you were 08:22
24 A We used a variety of drugs. We typically 08:22 24 in Washington University in St. Louis for what 08:22
25 used fibric acid derivatives; we would use niacin, 08:22 25 period of time? 08:22
Page 32 Page 33
1 A From about 1992 to 2002. 08:22 1 and patients were typically staying within one set 08:24
2 Q And during that time, did the way that you 08:23 2 of physicians. And so it was much less common to 08:24
3 treated very high triglycerides change? 08:23 3 get unusual cases at the medical centers. 08:24
4 A Not dramatically, no. 08:23 4 In -- in other words, the simple way of 08:24
5 Q And then in 2002, you returned to the 08:23 5 putting it was: When I was in training, places like 08:24
6 University of Washington? 08:23 6 the University of Washington had a high referral 08:24
7 A Yes. 08:23 7 rate for complicated and specialized cases. That's 08:24
8 Q And do you continue to see patients? 08:23 8 no longer true in the current medical reimbursement 08:24
9 A No. Around 2008, I no longer saw patients 08:23 9 system. 08:24
10 in clinic. 08:23 10 Q You're aware that Lovaza was approved for 08:24
11 Q So when would you say is the last time you 08:23 11 the treatment of very high triglycerides beginning 08:24
12 saw patients who had triglyceride levels over 500? 08:23 12 in 2004, correct? 08:24
13 A Okay. Probably around 2008. Even at that 08:23 13 A Yes. 08:24
14 juncture, I was not see very many patients with 08:23 14 Q Have you seen and treated patients with 08:24
15 hypertriglyceridemia. 08:23 15 very high triglycerides since 2004? 08:24
16 Q And why is that? 08:23 16 A Since 2004? 08:24
17 A The nature of the clinic had changed 08:23 17 I can't be sure of that. I did for sure 08:24
18 because of the reimbursement system. When I was 08:23 18 when I was at the University of Washington in 08:24
19 seeing patients back in the '90s and 1980s, as a 08:23 19 training. I'm not sure I saw any patients that had 08:24
20 fellow, medicine -- Medicare -- or excuse me -- 08:23 20 had chylomicronemia syndrome when I was in my 08:24
21 insurance would pay for patients from outside places 08:23 21 subsequent practice. 08:24
22 to go to the University of Washington to see a 08:23 22 Q Now, chylomicronemia syndrome is one type 08:25
23 specialty clinic. 08:23 23 of very high triglycerides, correct? 08:25
24 By the time I was at the University of 08:23 24 A No. Chylomicronemia syndrome is a 08:25
25 Washington, they were favoring provider care things, 08:23 25 manifestation of having very high triglycerides. 08:25
9
009
Page 34 Page 35
1 Q It is possible for patients to have very 08:25 1 high triglycerides after 2004? 08:26
2 high triglycerides without having chylomicronemia 08:25 2 A I honestly can't remember. 08:26
3 syndrome, correct? 08:25 3 Q Okay. So when you were prescribing fish 08:26
4 A Yes. 08:25 4 oil supplements, do you think that might have been 08:26
5 Q And have you seen patients who have very 08:25 5 prior to approval of Lovaza? 08:26
6 high triglycerides who do not have chylomicronemia 08:25 6 A Yes, it was. 08:26
7 syndrome in your career? 08:25 7 Q And do you recall what fish oil 08:26
8 A Yes. 08:25 8 supplements you would prescribe? 08:26
9 Q Okay. And we'll just come back to it. Do 08:25 9 A So our practice -- and again, this is 08:26
10 you recall -- have you ever prescribed Lovaza to a 08:25 10 based on what I learned from my mentors at the 08:26
11 patient which triglycerides over 500? 08:25 11 University of Washington. And in particular, John 08:26
12 A So when I was in training, we did not use 08:25 12 Brenzell and Alan Chait, who were both specialists 08:26
13 Lovaza -- and in my clinical practice -- because it 08:25 13 in -- in triglyceride disorders. 08:26
14 was a very expensive medication, and there was 08:25 14 In fact, they were among the principal 08:26
15 strong evidence that generic fish oil derivatives 08:25 15 people who first described chylomicronemia syndrome. 08:26
16 were equally effective at lowering triglycerides. 08:25 16 Their practice was to tell patients to 08:26
17 So my practice was not to use Lovaza, but 08:25 17 pick a single preparation of a fish oil and to stick 08:26
18 to use fish oil commercially available as a dietary 08:25 18 with that. The rationale being, it's known that 08:26
19 supplement. 08:25 19 different fish oils vary in their relative 08:26
20 Q And -- and when would this have been that 08:25 20 proportion of the omega-3 fatty acids. 08:27
21 you were choosing fish oil supplements over Lovaza? 08:26 21 And if you switch between different 08:27
22 A Basically my entire career. 08:26 22 preparations, you might be changing the relative 08:27
23 Q And Lovaza was not approved until 2004? 08:26 23 ratios of the fatty -- fatty acids in there, and 08:27
24 A Right. 08:26 24 that could affect outcome. 08:27
25 Q So do you think you saw patients with very 08:26 25 So the point was to stick with one product 08:27
Page 36 Page 37
1 and to empirically to treat to lower the 08:27 1 would you recommend a particular dosing of fish oil 08:28
2 triglycerides. 08:27 2 supplements? 08:28
3 Q And was there a particular ratio of 08:27 3 A Again, I think that's very broad. You 08:28
4 omega-3 fatty acids that you preferred to recommend? 08:27 4 might have a triglyceride level of 550 or you might 08:28
5 A No. It -- of course, that's difficult to 08:27 5 have a triglyceride level of 2,000. And those are 08:28
6 know in -- in practice because you don't often have 08:27 6 different clinical scenarios typically. 08:28
7 that information available. 08:27 7 Q So let's take 550. What dosing of fish 08:28
8 We used the practical and empiric approach 08:27 8 oil supplements would you recommend for a 08:28
9 of having to pick one particular manufacturer and to 08:27 9 triglyceride level of -- 08:28
10 stay with that, and that worked very effectively for 08:27 10 A We -- 08:28
11 us. 08:27 11 Q -- 500? 08:28
12 Q And what dosing on -- with fish oil 08:27 12 A -- typically would start with 2 to 4 grams 08:28
13 supplements would you recommend -- and this would 08:27 13 a day -- 08:28
14 have been, I take it, probably before 2004? 08:27 14 Q And -- 08:28
15 A Yeah, most of my experience was before 08:27 15 A -- of fish oil. 08:28
16 2004. 08:27 16 Q -- how many -- 08:28
17 Q What dosing of fish oil supplements would 08:27 17 THE COURT REPORTER: Wait. 08:28
18 -- 08:27 18 Q (BY MR. SIPES) Sorry. How many capsules 08:28
19 A Oh -- 08:27 19 would that be? 08:28
20 Q -- you recommend? 08:27 20 A That would vary depending on what the 08:28
21 A -- again, that's a very broad question. 08:27 21 manufacturer was. 08:28
22 It would depend on what the clinical circumstances 08:27 22 Q Do you recall roughly how many capsules? 08:28
23 were. And if you could be a bit more specific or 08:28 23 A I generally believe that they were 1-gram 08:28
24 outline a more specific scenario. 08:28 24 capsules, and so that would typically be four a day. 08:28
25 Q For patients with triglycerides over 500, 08:28 25 Q Okay. So your recollection is that the 08:28
10
010
Page 138 Page 139

1 receiving a combination of omega-3 fatty acid and 10:36 1 A I'm seeing 11 percent, not 17 percent. 10:37
2 niacin was 17 percent compared to placebo, correct? 10:36 2 Q The 11 percent is relative to baseline, 10:37
3 MR. REIG-PLESSIS: Objection to form. 10:36 3 correct? 10:37
4 A Are we referring to the 121 post-LDL-C 10:36 4 A Wait a minute. Are these percents or 10:37
5 versus 110? 10:36 5 milligrams per deciliter? It says "milligrams per 10:38
6 Q (BY MR. SIPES) I'm refer -- the -- the 10:36 6 deciliter" up at the top of the column. 10:38
7 percentage increase in LDL-C from the omega-3 fatty 10:36 7 Q And then you'll see under "LDL-C," it goes 10:38
8 acid plus niacin group was 11 percent, correct? 10:36 8 "Pre, Post, and Percent Change." 10:38
9 A Yes. 10:36 9 Do you see that? 10:38
10 Q And the placebo group, the change in LDL-C 10:36 10 A Yes. 10:38
11 was a decrease in 6 percent, correct? 10:36 11 Q So the percent change in LDL-C for the 10:38
12 A Yes. 10:36 12 omega-3 fatty acid plus niacin group was 11 percent, 10:38
13 Q So the -- compared to placebo, the 10:36 13 correct -- 10:38
14 combination of omega-3 fatty acid and niacin group 10:37 14 A Yes. 10:38
15 saw a 17 -- 17 percent increase in LDL-C, correct? 10:37 15 Q -- for baseline? 10:38
16 MR. REIG-PLESSIS: Objection to form. 10:37 16 Compared to placebo, the change was 10:38
17 A I don't see any evidence of statistical 10:37 17 17 percent increase, correct? 10:38
18 significance in this comparison, so one cannot say 10:37 18 A Yes. 10:38
19 that they're different. 10:37 19 Q Okay. Now, the -- one of the purposes of 10:38
20 Q (BY MR. SIPES) There was a numerical 10:37 20 the study was to see whether the coadministration of 10:38
21 increase, but it was not statistically significant? 10:37 21 an omega-3 fatty acid with niacin would reduce the 10:38
22 A Yes. 10:37 22 flushing -- 10:38
23 Q All right. And the -- the numerical 10:37 23 A Yes. 10:38
24 increase was a positive -- was a 17 percent increase 10:37 24 Q -- from niacin? 10:38
25 compared to placebo, correct? 10:37 25 And the conclusion from the authors was 10:38
Page 140 Page 141

1 that the omega-3 fatty acid failed to reduce 10:38 1 to be taken with a lot of caveats, this particular 10:40
2 flushing from niacin, correct? 10:38 2 study. 10:40
3 MR. REIG-PLESSIS: Objection to form. 10:38 3 Q Okay. 10:40
4 A Where is that stated? 10:39 4 A Now, having said that -- go ahead. 10:40
5 Q (BY MR. SIPES) If you will look under 10:39 5 Q The -- well, go ahead. Let -- if you want 10:40
6 "Flushing Reaction" on page 214 under Table 2, do 10:39 6 finish -- 10:40
7 you see the "Conclusion" is, There was no evidence 10:39 7 A This is -- this is what the authors -- 10:40
8 for a reduction in flushing in the group taking 10:39 8 Q Okay -- 10:40
9 omega-3 fatty acid plus niacin compared to those 10:39 9 A -- concluded. 10:40
10 taking niacin alone? 10:39 10 Q Okay. 10:40
11 A That's what the authors state, yes. 10:39 11 A And I think they note in the discussion, 10:40
12 Q So with regard to the purpose of reducing 10:39 12 some of these same limitations that I have just 10:40
13 flushing from niacin by coadministering omega-3 10:39 13 mentioned. 10:40
14 fatty acids, the study did not succeed? 10:39 14 Q Are you aware of any clinical study which 10:40
15 A Well, I think you have to put this study 10:39 15 has found that omega-3 fatty acids are effective to 10:40
16 into context. Again, there's a number of serious 10:39 16 reduce flushing from niacin? 10:40
17 limitations with this particular study. 10:39 17 A I'm not aware of any, no. 10:40
18 There were only seven to eight patients 10:39 18 Q All right. So let me come back to the 10:40
19 per group. There was a lot of groups, which always 10:39 19 list of medication for very high triglycerides that 10:40
20 makes statistical comparison more difficult to do. 10:39 20 you have in your rebuttal report, paragraph 137. 10:40
21 It raises issues of multiple comparisons and not 10:39 21 A All right. Which -- which exhibit is 10:40
22 correcting for that. 10:39 22 this? 10:40
23 So -- and I also think that, in my 10:40 23 Q That's Exhibit 2. And paragraph 137 is on 10:40
24 experience anyways, these rating scales for flushing 10:40 24 page 50. 10:40
25 are not particularly accurate, so I think this has 10:40 25 A Okay. 10:41
36
011
Page 142 Page 143

1 Q The -- do you have a list of -- of 10:41 1 Q (BY MR. SIPES) All right. In terms of the 10:42
2 products to -- to -- that are FDA approved to treat 10:41 2 list of products that are approved to treat very 10:42
3 very high triglycerides? 10:41 3 high triglycerides, the only product that has been 10:42
4 A Yes. 10:41 4 shown to reduce triglycerides in very high 10:42
5 Q And that's fibrates, niacin, Lovaza, 10:41 5 triglyceride patients without raising LDL-C is 10:42
6 EPANOVA, and Omtryg. 10:41 6 VASCEPA, correct? 10:42
7 Do you see that? 10:41 7 MR. REIG-PLESSIS: Objection to form. 10:42
8 A Yes, I do. 10:41 8 A Can you restate the question so you're -- 10:42
9 Q And of course, VASCEPA is also approved to 10:41 9 Q (BY MR. SIPES) There -- you have -- the 10:42
10 treat very high triglycerides? 10:41 10 list of products which have been approved to reduce 10:42
11 A Yes. 10:41 11 triglycerides in very high triglyceride patients is 10:42
12 Q Statins are not approved to treat very 10:41 12 fibrates, niacin, Lovaza, EPANOVA, Omtryg, and 10:42
13 high triglycerides, correct? 10:41 13 VASCEPA, correct? 10:42
14 A Correct. 10:41 14 A Yes. 10:42
15 Q And the reason for that is the TG-lowering 10:41 15 Q Of those products, the only product that 10:42
16 effect of statins is -- is very modest, correct? 10:41 16 has been shown to reduce triglycerides in patients 10:42
17 A I -- I don't think that's quite correct. 10:41 17 with very high triglycerides without raising LDL-C 10:42
18 Q Okay. 10:41 18 is VASCEPA, correct? 10:42
19 A Actually, statins will lower triglycerides 10:41 19 MR. REIG-PLESSIS: Objection to form. 10:42
20 by up to 50 percent in people with high 10:41 20 A Okay. And I -- I would -- I would add -- 10:42
21 triglycerides or very high triglyceride levels. 10:41 21 again, we're talking about median changes typically 10:42
22 Q Do you understand why statins are not 10:41 22 in these clinical studies. 10:43
23 approved to treat very high triglycerides? 10:41 23 But oftentimes there are many patients who 10:43
24 MR. REIG-PLESSIS: Objection to form. 10:41 24 do not get these benefits. And you can actually see 10:43
25 A I am not aware of the reason why. 10:42 25 an increase in LDL-C cholesterol, for example, in 10:43
Page 144 Page 145

1 patients, even though the overall means go down or 10:43 1 Q -- it is after 2008? 10:44
2 medians. So I think you have to interpret in 10:43 2 A Yes. 10:44
3 this -- in that context. 10:43 3 Q The MARINE trial demonstrated that VASCEPA 10:44
4 Q (BY MR. SIPES) But focus then on -- on 10:43 4 reduced triglycerides in very high triglyceride 10:44
5 medians. What happens to median patients? 10:43 5 patients without raising LDL-C, correct? 10:44
6 The only product approved for treatment of 10:43 6 MR. REIG-PLESSIS: Objection to form. 10:44
7 very high triglycerides that has been shown to 10:43 7 A It demonstrated that certain specific 10:44
8 reduce triglycerides without raising LDL-C is 10:43 8 doses of VASCEPA, if I recall correctly, had that 10:44
9 VASCEPA, correct? 10:43 9 effect. 10:44
10 A Yes. 10:43 10 Q (BY MR. SIPES) The dose was 4 grams per 10:44
11 MR. REIG-PLESSIS: Objection to form. 10:43 11 day, correct? 10:44
12 Q (BY MR. SIPES) And the study that 10:43 12 A Yes. 10:44
13 demonstrated that is the MARINE trial, correct? 10:43 13 THE COURT REPORTER: 4 grams? 10:44
14 MR. REIG-PLESSIS: Same objection. 10:43 14 MR. SIPES: 4 grams. Why don't we take a 10:44
15 A That's post the 2008 date that we're 10:43 15 break. 10:44
16 talking about here for the patents, are we -- is it 10:43 16 MR. REIG-PLESSIS: Yeah, I was about to 10:44
17 not? 10:43 17 say -- 10:44
18 Q (BY MR. SIPES) That -- do you know when 10:43 18 THE VIDEOGRAPHER: This marks the end of 10:44
19 MARINE published? 10:43 19 media file labeled numbered 2. Off the record at 10:44
20 A I think it was in 2004 or 2014. Sometime 10:43 20 10:45 a.m. 10:44
21 around there. 10:43 21 (A break was taken from 10:45 a.m. to 10:44
22 Q It may be around 2010-2011 -- 10:43 22 10:59 a.m.) 10:44
23 A Yeah. 10:43 23 THE VIDEOGRAPHER: This marks the 10:52
24 Q -- but -- 10:43 24 beginning of media file labeled No. 3. Back on the 10:57
25 A Yeah. Yeah. 10:43 25 record at 10:59 a.m. 10:58
37
012
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1 Q (BY MR. SIPES) Let me ask you to turn to 10:58 1 groundbreaking evidence and that VASCEPA builds on 10:59
2 your rebuttal report -- report. That would be 10:58 2 that evidence. 10:59
3 Exhibit 2. 10:58 3 Q And fibrates and niacin have not been 10:59
4 Paragraph 35, you -- you quote Amarin as 10:58 4 shown to reduce cardiovascular risk on top of a 10:59
5 saying that JELIS supports VASCEPA being clinically 10:58 5 statin, correct? 10:59
6 distinct from fibrates or niacin and being uniquely 10:58 6 A That's correct. 11:00
7 positioned to plausibly provide CV benefit to 10:58 7 Q So VASCEPA is the only agent approved for 11:00
8 patients at high CV risk due to their atherogenic 10:58 8 treatment of very high triglycerides that has also 11:00
9 lipid profile, specifically elevated TG despite 10:58 9 been shown to provide cardiovascular benefit to 11:00
10 therapy -- statin therapy. 10:58 10 patients on statin, correct? 11:00
11 Do you see that? 10:58 11 A It's correct to state that it's the only 11:00
12 A Yes. 10:58 12 agent approved by the FDA based on very stringent 11:00
13 MR. SIPES: And -- and just for the sake 10:58 13 clinical -- clinical data, yes. 11:00
14 of the court reporter, JELIS is all caps, J E L I S. 10:58 14 Q Okay. And if you turn to -- to 11:00
15 Q (BY MR. SIPES) Do you agree with this 10:58 15 paragraph 65 of your rebuttal report -- you quote 11:00
16 statement that you quote from Amarin? 10:59 16 Dr. Toth as saying, The fact that VASCEPA avoids 11:01
17 A I believe that JELIS was the first study 10:59 17 substantial LDL-C -- LDL-C increases in persons with 11:01
18 to provide convincing evidence that EPA, as 10:59 18 very high triglycerides gives the doctor the 11:01
19 monotherapy on top of a statin, would lower 10:59 19 flexibility to treat such patients in stepwise 11:01
20 cardiovascular risk. 10:59 20 fashion to start first with VASCEPA as monotherapy 11:01
21 Q And do you think that the showing in JELIS 10:59 21 to address pancreatitis risk; and then once TGs are 11:01
22 supports VASCEPA being clinically distinct from 10:59 22 lowered below 500 milligrams per deciliter, to add a 11:01
23 fibrates or niacin on its basis of being able to 10:59 23 statin, in combination with VASCEPA, to lower 11:01
24 reduce cardiovascular risk on top of a statin? 10:59 24 cardiovascular risk. 11:01
25 A I believe that JELIS provided the 10:59 25 Do you see that? 11:01
Page 148 Page 149

1 A Yes. 11:01 1 Q With respect to -- VASCEPA can be 11:02
2 Q Do you agree with Dr. Toth that VASCEPA 11:01 2 administered to very high triglyceride patients 11:02
3 avoids substantial LDL-C increases in persons with 11:01 3 without raising LDL-C, correct? 11:02
4 very high triglycerides and gives doctors the 11:01 4 A Yes. 11:03
5 flexibility to treat such patients in stepwise 11:01 5 Q And Lovaza will typically increase LDL-C 11:03
6 fashion? 11:01 6 in patients with very high triglycerides, correct? 11:03
7 A It provides one option for doctors to do 11:02 7 MR. REIG-PLESSIS: Objection to form. 11:03
8 that. Although, there can be other options 11:02 8 A Can you restate that question, please? 11:03
9 available as well, such as combining omega-3 fatty 11:02 9 Q (BY MR. SIPES) The -- the prescribing 11:03
10 acids with a statin therapy, for example. 11:02 10 information for Lovaza reports that LDL-C goes up 11:03
11 Q The -- the difference would be with 11:02 11 when administered to patients with very high 11:03
12 Lovaza, the statin would be added initially in order 11:02 12 triglycerides, correct? 11:03
13 to counteract the rising LDL-C seen with Lovaza, 11:02 13 MR. REIG-PLESSIS: Objection to form. 11:03
14 correct? 11:02 14 A Actually, it shows that in some patients, 11:03
15 A Well, I think -- I think the situation is 11:02 15 it goes up with omega-3 fatty acids, so in no way do 11:03
16 a little bit more complicated than that. First of 11:02 16 all patients treated with omega-3 fatty acids have 11:03
17 all, there's no evidence that -- I prefer to call it 11:02 17 an increase in LDL cholesterol. 11:03
18 EPA, since JELIS also showed the same thing. 11:02 18 Q (BY MR. SIPES) Is Lovaza, when 11:03
19 There's no evidence that the benefits of 11:02 19 administered to very high triglyceride patients, 11:03
20 EPA in reducing cardiovascular risk in these 11:02 20 typically prescribed in combination with a statin to 11:03
21 patients relates to changes in LDL cholesterol or 11:02 21 guard against a rise in LDL-C? 11:03
22 triglycerides. 11:02 22 A Say -- I'm sorry. Say it again. 11:03
23 And so I think that the idea that it's 11:02 23 Q Is Lovaza, when administered to very high 11:03
24 working because it's avoiding the increase in LDL-C 11:02 24 triglyceride patients, typically coadministered with 11:03
25 is not substantiated by the clinical data here. 11:02 25 a statin in order to guard against a rise in LDL-C? 11:03
38
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Page 150 Page 151

1 A Not necessarily. That's a very 11:04 1 For example, if you had a young 11:05
2 complicated question. 11:04 2 childbearing woman, right, who was potentially at 11:05
3 Again, you're -- you're really making a 11:04 3 risk for having -- not at risk, but potentially able 11:05
4 very broad statement when the issue with 11:04 4 to get pregnant, that might change your medical 11:05
5 hypertriglyceridemic patients is -- is much more 11:04 5 management of what's going on. 11:05
6 complex than that. 11:04 6 So it is not routine to always include a 11:05
7 As I alluded to earlier, the major concern 11:04 7 statin or something else to lower LDL cholesterol in 11:05
8 in these patients is chylomicronemia syndrome. 11:04 8 these people, especially since many patients can 11:05
9 There are oftentimes reasons -- precipitating 11:04 9 control their triglycerides without an omega-3 fatty 11:05
10 reasons such as alcohol use or steroid use that may 11:04 10 acid at all if you eliminate the precipitating 11:05
11 be causing the problem to appear. 11:04 11 factor. 11:05
12 And so in these patients, for example, you 11:04 12 Q Is it correct that in patients with 11:05
13 might -- might not need -- first of all, even if -- 11:04 13 triglycerides of 500 milligrams per deciliter or 11:05
14 even if they do -- let me start over again. 11:04 14 higher, the first concern is avoiding pancreatitis? 11:05
15 Even if they are on high -- if they -- 11:04 15 A Yes. Usually. I -- there's no such thing 11:05
16 even if they begin with high levels of triglycerides 11:04 16 as always, so I think we have to be careful about 11:05
17 and are placed on an omega-3 fatty acid, there are 11:04 17 making very broad statements. But generally, that 11:05
18 many patients who do not experience an increase in 11:04 18 is correct. 11:05
19 LDL-C, so it is not necessary in those patients to 11:04 19 Q Once the patient's triglyceride levels are 11:05
20 worry about the increase in LDL-C. 11:04 20 brought below 500, attention turns to addressing 11:06
21 Secondly, the major issue is lowering the 11:04 21 cardiovascular risk, generally, correct? 11:06
22 triglycerides to prevent chylomicronemia syndrome. 11:04 22 A Not necessarily. Again, it depends. 11:06
23 It's a secondary issue to worry about 11:05 23 In young patients, there may not be so 11:06
24 cardiovascular risk. And again, in these patients, 11:05 24 much concern. The rise in L -- there may be an 11:06
25 there are many different factors that go into that. 11:05 25 increase in LDL cholesterol compared to what they 11:06
Page 152 Page 153

1 had before, but it still may be at a relatively low 11:06 1 either be on a statin at that time or put on a 11:07
2 level that's relatively safe. 11:06 2 statin once the triglycerides are brought below 500? 11:07
3 So I think it's hard to general -- make a 11:06 3 MR. REIG-PLESSIS: Objection to form. 11:07
4 general statement like that about what you are going 11:06 4 A I'm -- I'm -- I'm trying to grasp what you 11:07
5 to do. 11:06 5 are saying. You mean in some kind of a quantitative 11:07
6 Q Would -- would you say that most patients 11:06 6 statement of how many patients? 11:07
7 who have very high triglycerides will also be at 11:06 7 Q (BY MR. SIPES) Would you say a majority of 11:07
8 cardiovascular risk? 11:06 8 patients with very high triglycerides will either be 11:07
9 A I -- I can't agree with that statement. 11:06 9 put on a statin at that point or after their 11:07
10 In fact, the majority of the patients that 11:06 10 triglycerides are brought below 500? 11:07
11 I saw -- and I wouldn't -- I would be careful here, 11:06 11 A Again, I would have to know more clinical 11:07
12 because I can't really quantify it accurately. 11:06 12 characteristics about the population. 11:07
13 But we certainly saw many, many patients 11:06 13 Q Do you believe that patients with very 11:08
14 who were quite young with very high triglyceride 11:06 14 high triglycerides who take EPA will see a reduction 11:08
15 levels in their -- in their late teens and early 11:06 15 in cardiovascular risk if they stay on EPA for two 11:08
16 20s, 30s where it was a theoretical concern, 11:06 16 years or more? 11:08
17 perhaps, if the LDL cholesterol was higher than 11:06 17 A Formally, we don't know the answer to that 11:08
18 before. 11:07 18 question. 11:08
19 But it depended on how high the LDL 11:07 19 In JELIS, the levels of triglycerides were 11:08
20 cholesterol was; it depended on what the status was 11:07 20 below 500. The entry requirement, assuming that we 11:08
21 of the patient, and it depended on their other 11:07 21 can use REDUCE-IT as evidence, those patients were 11:08
22 medical conditions. So I -- I don't think you can 11:07 22 between 150 and 500 milligrams per deciliter. 11:08
23 make a universal prescription like that. 11:07 23 Also, they were all on statins. So those 11:08
24 Q Can you make an estimate of the percentage 11:07 24 are all different in terms of the clinical scenario. 11:08
25 of patients with very high triglycerides who will 11:07 25 And it changes the equation, so I'm not sure that 11:08
39
014
Page 338 Page 339

1 dose of 4 grams for periods of time including at 03:48 1 mean, the insert here, is they cite a range of study 03:49
2 least 12 weeks? 03:48 2 periods between six and 16 weeks. 03:49
3 A I'm -- I'm still not quite following what 03:48 3 I believe this has to do more with the 03:49
4 you are trying to get at here. I apologize. 03:48 4 claim's construction, and so I think that -- I think 03:49
5 Q I -- 03:48 5 that this would be a reasonable recommendation. I 03:49
6 A I know. 03:48 6 don't think it necessarily means an indication has 03:49
7 Q -- I'm trying to understand whether it 03:48 7 to be that or that it has to be precisely that. 03:49
8 remains your testimony, what you wrote in your 03:48 8 It's based on this. I think it has to do 03:50
9 report, that -- 03:48 9 with the claim construction. 03:50
10 A That it has to be at least 12 weeks? 03:48 10 Q Okay. 03:50
11 Q That it would include at least 12 weeks. 03:48 11 A But I would have to defer to my -- you 03:50
12 A It would include at least 12 weeks. 03:48 12 know, my legal advice on exactly that point. 03:50
13 That's what I say there, so I guess I'll stick with 03:49 13 Q I think the problem with -- so when you 03:50
14 that. 03:49 14 were saying "this," you were pointing to certain 03:50
15 Q Okay. So just so that we can get a clear 03:49 15 documents, but -- 03:50
16 transcript, it is your testimony that a physician 03:49 16 A Yes. 03:50
17 would understand -- would -- would be taught by the 03:49 17 Q -- in the transcript, it won't be clear -- 03:50
18 Lovaza prescribing information "Clinical Study" 03:49 18 A Well, I'm quoting -- I'm -- let me 03:50
19 section that a mixture of EPA and DHA was effective 03:49 19 specifically say I'm quoting levels of at least 03:50
20 and FDA approved to reduce triglyceride levels in 03:49 20 500 milligrams per deciliter out of the 03:50
21 patients with baseline triglyceride levels of at 03:49 21 paragraph 43. 03:50
22 least 500 milligrams per deciliter, including when 03:49 22 And then I'm referring back to the PDR 03:50
23 administered with a daily dose of 4 grams for 03:49 23 thing showing a range of different treatment 03:50
24 periods of time including at least 12 weeks? 03:49 24 intervals and presenting this data, which indicates 03:50
25 A I -- I think what I'm interpreting this to 03:49 25 that if you want to determine whether or not it's 03:50
Page 340 Page 341

1 working, which is -- may be different from a 03:50 1 do that in terms of the treatment. 03:51
2 clinical indication for treatment, that it has -- it 03:50 2 Q (BY MR. SIPES) And when you were saying 03:51
3 could be a range of different values. 03:50 3 "this," I thought you -- you were looking at the 03:51
4 Q Okay. So try to -- let me just ask you a 03:50 4 Lovaza prescribing information? 03:51
5 clean question without the "this" in it hopefully. 03:50 5 A Yes -- 03:51
6 A physician -- scratch that. 03:50 6 Q Okay. 03:51
7 The Lovaza -- the "Clinical Study" section 03:50 7 A -- I would have to go back and look at 03:51
8 of the Lovaza prescribing information marked as 03:50 8 that more carefully. 03:51
9 Exhibit 5 teaches a physician that a mixture of EPA 03:51 9 Q All right. But you do -- you do agree 03:52
10 and DHA is effective and FDA approved to re -- 03:51 10 that the "Clinical Study" section of the Lovaza PDR 03:52
11 reduce triglyceride levels in patients with baseline 03:51 11 is teaching the effectiveness of EPA and DHA to 03:52
12 triglyceride levels of at least 500 milligrams per 03:51 12 reduce triglyceride levels of patients with a 03:52
13 deciliter for a range of different durations, 03:51 13 baseline triglyceride level of at least 03:52
14 including when administered at a daily dose of 03:51 14 500 milligrams per deciliter at a daily dose of 03:52
15 4 grams per day for periods of time of at least 03:51 15 4 grams a day over the periods of time prescribed in 03:52
16 12 weeks; for example, 16 weeks' duration? 03:51 16 the "Clinical Study" section? 03:52
17 A Well, I -- I think what they're -- 03:51 17 A Well, there are two different studies, and 03:52
18 MR. REIG-PLESSIS: Objection to form. 03:51 18 so they're referring specifically to those two 03:52
19 A -- yeah, I -- I think that what they're 03:51 19 different patient populations. 03:52
20 trying to get here is to include these two studies 03:51 20 I think it seems -- you know, I don't 03:52
21 to indicate what the possibilities are for people on 03:51 21 think it would be unreasonable to generalization to 03:52
22 and off statins in the various levels of 03:51 22 either populations. But the specific data cited 03:52
23 triglycerides. 03:51 23 here is for these specific clinical populations. 03:52
24 I would have to go back to the indications 03:51 24 Q And then the next sentence that you have 03:52
25 to get a specific idea of how long you would need to 03:51 25 in paragraph 43 -- 03:52
86
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1 A Yes. 03:52 1 Lovaza -- that the "Clinical Study" section of the 03:53
2 Q -- is, The Lovaza PDR taught that this 03:52 2 Lovaza -- of the Lovaza prescribing information 03:53
3 method of treatment was associated with an increase 03:52 3 teaches physicians that the method of treatment 03:53
4 in LDL-C levels in some patients. 03:52 4 described in the Lovaza prescribing information is 03:53
5 Do you see that? 03:52 5 associated with an increase in LDL-C levels? 03:53
6 A Yes. 03:52 6 A And I think, again, that's overly broad. 03:53
7 Q And when you refer to "this method of 03:52 7 I think that it can be associated with an increase 03:54
8 treatment," you're referring to administration of 03:52 8 in LDL-C levels. 03:54
9 4 grams per day of a mixture of EPA and DHA to 03:53 9 It's -- clearly is not in all patients. I 03:54
10 patients with very high triglycerides, correct? 03:53 10 think you're -- again, you're making very broad 03:54
11 A I -- I think you're rephrasing my 03:53 11 statements. 03:54
12 statement, and I would like to stay with what I have 03:53 12 Q All right. So let me -- let me try that 03:54
13 said right here. 03:53 13 again. The "Clinical Study" section of the Lovaza 03:54
14 Q Okay. Well, what does "this method of 03:53 14 prescribing information teaches physicians that use 03:54
15 treatment" refer to? 03:53 15 of Lovaza in very high triglyceride patients is 03:54
16 A I -- to the Lovaza. 03:53 16 associated with an increase in LDL-C levels in some 03:54
17 Q Okay. To the Lovaza treatment of patients 03:53 17 patients? 03:54
18 with very high triglycerides, correct? 03:53 18 A I'm just -- may I read? I just want to -- 03:54
19 A Yes. 03:53 19 the day is late, so -- I'll point out that in 03:54
20 Q Okay. So -- and the -- and again, what 03:53 20 Table 1, the increase in LDL cholesterol in the 03:55
21 you are citing for the rise in LDL-C is the 03:53 21 synth -- synth statin-treated patients versus the 03:55
22 "Clinical Study" section of the Lovaza prescribing 03:53 22 others is very small, and it may be borderline 03:55
23 information? 03:53 23 statistically significant. 03:55
24 A That's correct. 03:53 24 But whether that's clinically significant 03:55
25 Q So you -- it's your testimony that the 03:53 25 or not I think is a different situation. So I think 03:55
Page 344 Page 345

1 this goes back to -- I -- I need to have more 03:55 1 with an increase in LDL-C levels in some patients? 03:56
2 information about exactly what you are trying to get 03:55 2 A I -- I think that's a reasonable 03:56
3 me to say here -- 03:55 3 statement. 03:56
4 Q The -- 03:55 4 Q Okay. Let me ask you turn to 03:56
5 A -- before I can -- 03:55 5 paragraph 119 of your report -- of your reply 03:56
6 Q -- the synth statin group is a -- is not 03:55 6 report, Exhibit 3. 03:56
7 the very high triglyceride group, correct? 03:55 7 A I'm sorry? What -- where am I being 03:56
8 A No. I understand. 03:55 8 referred to? 03:56
9 Q Okay. And the very high triglyceride 03:55 9 Q The reply report, Exhibit 3 -- 03:56
10 group is Table 2 in the Lovaza label? 03:55 10 A 46. 03:56
11 A All right. Wait a second. Okay. I think 03:55 11 Q -- paragraph 111. 03:56
12 I might have been misinterpreting it, because I said 03:55 12 A Paragraph 111. Okay. 03:57
13 "these two studies." 03:55 13 Q So you'll see in the middle there's a 03:57
14 And I may have been looking -- I was just 03:55 14 sentence that begins, Those other potential options. 03:57
15 discussing this. I was seeing the two different 03:55 15 Do you see that? 03:57
16 tables here. 03:56 16 A Yes. 03:57
17 So this Table 2 is summarizing the results 03:56 17 Q Okay. Those other potential options, 03:57
18 from two different studies. Okay. So yes, I think 03:56 18 however, are not relevant to my opinion that it 03:57
19 I made a misinterpretation -- 03:56 19 would have been obvious to try purified EPA based on 03:57
20 Q Okay. 03:56 20 prior art references that focused on two known 03:57
21 A -- of that statement. 03:56 21 omega-3 fatty acids, EPA and DHA. It would have 03:57
22 Q So let me try it again. The "Clinical 03:56 22 been at least obvious to try either one of these 03:57
23 Study" section of the Lovaza prescribing information 03:56 23 compounds. 03:57
24 teaches physicians that the method of treating very 03:56 24 Do you see that? 03:57
25 high triglyceride patients with Lovaza is associated 03:56 25 A Yes. 03:57
87
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1 Q Would it have been obvious to try pure 03:57 1 DHA -- 03:58
2 DHA? 03:57 2 A Yes. 03:58
3 A I believe so. I mean, the composition, as 03:57 3 Q -- in what way would pure DHA have been 03:58
4 we have already reviewed of Lovaza, you call it 03:57 4 tried? 03:58
5 roughly 50/50. I would say it's 60 percent EPA, 03:57 5 A Well, I think -- so there's a set of -- a 03:58
6 40 percent DHA. 03:57 6 set of possibilities. Right. It's a table. 03:58
7 But I don't -- I don't think that makes a 03:57 7 They both could lower triglycerides, and 03:58
8 material difference in my argument. Those are the 03:57 8 they both could increase LD -- actually, there are 03:58
9 two major components. It's well established that 03:57 9 more possibilities. I believe they both could lower 03:58
10 fish oil lowers triglycerides. 03:58 10 LDL cholesterol and increase -- excuse me -- let me 03:58
11 It would seem to me obvious that if one 03:58 11 start over again. 03:58
12 were concerned about something like an increase in 03:58 12 The two major components of Lovaza are DHA 03:59
13 LDL cholesterol, that it might -- it would be 03:58 13 and EPA. So we have two effects that we're 03:59
14 worthwhile testing that hypothesis to see if it was 03:58 14 considering here. 03:59
15 correct. 03:58 15 One is the triglyceride lowering, and the 03:59
16 And in fact, there are -- as we have 03:58 16 other is the impact on LDL cholesterol. So it's 03:59
17 cited, there are studies out there that did exactly 03:58 17 possible one agent or both had both effects, one 03:59
18 that. 03:58 18 agent or both did not. 03:59
19 Q And what would have been the expectation 03:58 19 I mean, I -- I think probably it's very 03:59
20 of a person of ordinary skill in the art in March of 03:58 20 likely that one of them would have increased LDL 03:59
21 2008 about the outcome of a trial with a pure DHA 03:58 21 cholesterol or one of them was not increasing the 03:59
22 compound? 03:58 22 LDL cholesterol while still lowering triglycerides. 03:59
23 A Can you -- that's -- outcome of what trial 03:58 23 It's a -- it's a formal poss -- 03:59
24 and where -- what are we looking at? 03:58 24 possibility. It's just a logic tree. Right. 03:59
25 Q When -- when you suggest trying pure 03:58 25 Q It's possible that both agents could have 03:59
Page 348 Page 349

1 raised LDL-C, as well as lowered triglycerides? 03:59 1 almost -- first of all, again, we need more clinical 04:00
2 A That's all -- 03:59 2 information here. Is the patient a thousand? 04:01
3 MR. REIG-PLESSIS: Objection to form. 03:59 3 2,000? 500? 04:01
4 A -- well, it's -- I think, again, coming 03:59 4 So I think one of these distinctions is 04:01
5 back to the logic table, if you constructed it that 03:59 5 you're not likely to get chylomicronemia syndrome if 04:01
6 way, it would be possible, yes. 04:00 6 your TGs are less than a thousand. And in fact, 04:01
7 Q (BY MR. SIPES) Let me ask you to look at 04:00 7 probably now we know less than 1,500. 04:01
8 your opening report, paragraph 338. 04:00 8 The issue is when you're in the 500 to a 04:01
9 A Is that Exhibit 1? 04:00 9 thousand range -- and actually, it doesn't have to 04:01
10 Q That's Exhibit 1. 04:00 10 even be 500. That's just the region where they're 04:01
11 A By the end of day I'm going to -- 04:00 11 being cautious here. 04:01
12 Q At the end of day we come back to 04:00 12 You can get a dramatic increase in your 04:01
13 Exhibit 1. 04:00 13 triglycerides, for example, by a drinking bout or 04:01
14 A Okay. 04:00 14 something like that or starting a new medication 04:01
15 Q And paragraph 338 is on page 117. 04:00 15 here. So I think it depends on the clinical 04:01
16 At the end of paragraph 338, you say, It 04:00 16 scenario. 04:01
17 would have been obvious to a patient consuming a 04:00 17 If I saw a patient who had had 04:01
18 Western diet with pure EPA. 04:00 18 chylomicronemia syndrome and had -- had a very high 04:01
19 Do you see that? 04:00 19 triglyceride level, that would indicate something 04:01
20 A Yes. 04:00 20 different than seeing somebody with a triglyceride 04:01
21 Q In your opinion, would it have been 04:00 21 level of 600 who had never had chylomicronemia 04:01
22 obvious to treat a patient with very high 04:00 22 syndrome and was referred in asymptomatically 04:02
23 triglycerides and withhold diet and lifestyle 04:00 23 because somebody was concerned about the possibility 04:02
24 counseling? 04:00 24 of chylomicronemia syndrome. 04:02
25 A That would -- that would be an adjunct 04:00 25 Q So is it fair to say then that there are 04:02
88
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1 at least some patients with very high triglycerides 04:02 1 A Where is that? Page 12? 04:03
2 where a physician will treat the triglycerides with 04:02 2 Q Page -- it's on page 12. It's paragraph 04:03
3 a triglyceride-lowering agent like VASCEPA, but the 04:02 3 33 of your opening report. 04:03
4 counseling might involve not undue drinking, but it 04:02 4 A Okay. So I think this actually 04:03
5 won't remove the patient from a Western diet? 04:02 5 illustrates this point. These are pretty broad 04:03
6 A I'm -- I'm sorry. Restate that. Won't 04:02 6 dietary guidelines here. This is not narrowing it 04:03
7 remove -- 04:02 7 down to anything very specific, in all honesty. 04:03
8 Q Well -- 04:02 8 Q So in your -- in forming your opinions 04:03
9 A -- the patient in a Western -- 04:02 9 about it being obvious in treating a patient 04:03
10 Q -- what I'm trying to understand -- so 04:02 10 consuming a Western diet, you did apply the 04:03
11 you're saying there are some patients for whom the 04:02 11 construction of a Western diet? 04:03
12 patient will continue to continued to consume a 04:02 12 A Yes, I did. 04:03
13 Western -- it would have been obvious to -- where 04:02 13 Q Okay. And I take it in your opinion, it 04:03
14 the patient continues to consume a Western diet? 04:02 14 is -- it would be obvious for a doctor to treat very 04:03
15 A Well, you know, there's actually a debate 04:02 15 high triglycerides in some patients where, whatever 04:03
16 on this point. And what do you mean exactly by "a 04:02 16 counseling is going on, the patient consumes a 04:03
17 Western diet"? 04:02 17 Western diet? 04:03
18 Is that something high in fat? Is that 04:02 18 A Yes, I would agree with that. 04:03
19 something high in carbohydrate? I -- you know, I 04:02 19 Q And what would be the characteristics of 04:03
20 think that's, in my mind, the issue of what a 04:02 20 such a patient with very high triglycerides where 04:03
21 Western diet is is not very well defined. 04:02 21 even with diet and lifestyle counseling, the -- the 04:03
22 Q Do you recall in the claim construction 04:02 22 patient continues to consume a Western diet? 04:04
23 agreement -- and if you will look on page 12 of your 04:03 23 MR. REIG-PLESSIS: Objection to form. 04:04
24 report, you'll see it. There's a definition of a 04:03 24 A I'm not -- could you rephrase that 04:04
25 Western diet. 04:03 25 question, please? 04:04
Page 352 Page 353

1 Q (BY MR. SIPES) Would there be -- for 04:04 1 THE VIDEOGRAPHER: This marks the end of 04:05
2 example, would that be a patient whose triglycerides 04:04 2 media file labeled No. 7. Off the record at 04:05
3 was closer to 500 than 2,000? 04:04 3 4:06 p.m. 04:05
4 A Would -- would what be? 04:04 4 (A break was taken from 4:06 p.m. to 04:05
5 Q The patient for whom it would be 04:04 5 4:11 p.m.) 04:05
6 reasonable to treat very high triglycerides where 04:04 6 THE VIDEOGRAPHER: This marks the 04:10
7 the diet and exercise counseling kept the patient on 04:04 7 beginning of media file labeled No. 8. Back on the 04:10
8 a Western diet. 04:04 8 record at 4:11 p.m. 04:10
9 MR. REIG-PLESSIS: Objection to form. 04:04 9 MR. SIPES: I have no further questions at 04:10
10 A I -- I'm sorry. I'm just not -- I know -- 04:04 10 this time. 04:10
11 I -- 04:04 11 MR. REIG-PLESSIS: And, Dr. Heinecke, I 04:10
12 Q (BY MR. SIPES) That's all right. 04:04 12 have no questions for you either. Thank you for 04:10
13 A -- yeah. 04:04 13 your time. 04:10
14 Q So it is your testimony that it would be 04:04 14 A Thank you very much. 04:10
15 obvious to treat a patient consuming a Western diet 04:04 15 MR. SIPES: Thank you very much for coming 04:10
16 with pure EPA, correct? 04:04 16 in. 04:10
17 A If you were concerned about acutely 04:04 17 A It was quite on interesting experience. 04:10
18 lowering their triglyceride levels because of 04:04 18 MR. SIPES: We just need to go off the 04:10
19 clinical scenarios, it would be -- yes, it would be 04:04 19 record. 04:10
20 obvious to try it as a potential therapeutic 04:04 20 THE VIDEOGRAPHER: I will go ahead and 04:10
21 intervention. 04:04 21 conclude. This concludes today's deposition of 04:10
22 Q Okay. 04:04 22 Dr. Jay W. Heinecke, on July 17, 2019, which 04:10
23 MR. SIPES: Why don't question take a 04:04 23 consists of eight media files. 04:10
24 break. Let me confer with my colleagues, but we're 04:04 24 The original media files will remain in 04:10
25 pretty close to finishing. 04:05 25 the custody of TSG Reporting, Inc. Off the record 04:11
89
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1 1
at 4:12 p.m. 04:11
2 2
04:11
3 3
(TIME NOTED: 4:12 p.m.)
4 4 I, JAY W. HEINECKE, M.D., do hereby declare
5 5 under penalty of perjury that I have read the
6 6 foregoing transcript; that I have made any
7 corrections as appear noted, in ink, initialed by
7
8 me, or attached hereto; that my testimony as
8
9 contained herein, as corrected, is true and correct.
9
10 EXECUTED this_______ day of_________________,
10
11 20____, at___________________, ___________________.
11
12 (City) (State)
12
13
13
14
14 _______________________
15
16
16
17
17
18
18
19 19
20 20
21 21
22 22
23 23
24 24
25 25
Page 356 Page 357

1 2 DATE OF DEPOSITION:
I, MARY J. GOFF, CSR No. 13427, Certified
2 Shorthand Reporter of the State of California, 3 NAME OF WITNESS:
3 certify; 4 Reason Codes:
4 That the foregoing proceedings were taken 5 1. To clarify the record.
5 before me at the time and place herein set forth, at 6 2. To conform to the facts.
6 which time the witness declared under penalty of 7 3. To correct transcription errors.
7 perjury; that the testimony of the witness and all 8 Page ______ Line ______ Reason ______
8 objections made at the time of the examination were 9 From _____________________ to _____________________
9 recorded stenographically by me and were thereafter
10 Page ______ Line ______ Reason ______
10 transcribed under my direction and supervision; that
11 11 From _____________________ to _____________________
the foregoing is a full, true, and correct
12 12 Page ______ Line ______ Reason ______
transcript of my shorthand notes so taken and of the
13 testimony so given; 13 From _____________________ to _____________________
14 That before completion of the deposition, 14 Page ______ Line ______ Reason ______
15 review of the transcript (XX) was ( ) was not 15 From _____________________ to _____________________
16 requested: ( ) that the witness has failed or 16 Page ______ Line ______ Reason ______
17 refused to approve the transcript. 17 From _____________________ to _____________________
18 I further certify that I am not financially 18 Page ______ Line ______ Reason ______
19 interested in the action, and I am not a relative or 19 From _____________________ to _____________________
20 employee of any attorney of the parties, nor of any 20 Page ______ Line ______ Reason ______
21 of the parties.
21 From _____________________ to _____________________
22 I declare under penalty of perjury under the
23 22 Page ______ Line ______ Reason ______
laws of California that the foregoing is true and
24 23 From _____________________ to _____________________
correct, dated this 30th day of July, 2019.
_________________________ 24
25 MARY GOFF 25 ________________________
90
019
Page 356
1 I, MARY J. GOFF, CSR No. 13427, Certified
2 Shorthand Reporter of the State of California,
3 certify;
4 That the foregoing proceedings were taken
5 before me at the time and place herein set forth, at
6 which time the witness declared under penalty of
7 perjury; that the testimony of the witness and all
8 objections made at the time of the examination were
9 recorded stenographically by me and were thereafter
10 transcribed under my direction and supervision; that
11 the foregoing is a full, true, and correct
12 transcript of my shorthand notes so taken and of the
13 testimony so given;
14 That before completion of the deposition,
15 review of the transcript (XX) was ( ) was not
16 requested: ( ) that the witness has failed or
17 refused to approve the transcript.
18 I further certify that I am not financially
19 interested in the action, and I am not a relative or
20 employee of any attorney of the parties, nor of any
21 of the parties.
22 I declare under penalty of perjury under the
23 laws of California that the foregoing is true and
24 correct, dated this 30th day of July, 2019.
_________________________
25 MARY GOFF

020
EXHIBIT 3
Edward A. Fisher, M.D., dated July 2, 2019
Page 1
1 IN THE UNITED STATES DISTRICT COURT.
FOR THE COUNTY OF NEVADA
2 --------------------------------------------X
AMARIN PHARMA, INC., et. al.
3
PLAINTIFF,
4
v.
5
HIKMA PHARMACEUTICALS USA INC., et al.

6
7 DEFENDANTS.
--------------------------------------------X
8 Case No.: 2:16-cv-02525-MMD-NJK
9
10 VIDEOTAPED DEPOSITION OF
11 EDWARD A. FISHER, M.D., M.P.H., Ph.D.
12 Madison, New Jersey
13 Tuesday, July 2, 2019
14
15
16
17
18
19
20 Reported by:
21 Rebecca Schaumloffel, CLR, RPR, CCR-NJ
22 Job No: 162977
23
24
25

001
Page 2 Page 3
1 1 A P P E A R A N C E S:
2
2 July 2, 2019 3 COVINGTON & BURLING
3 8:39 a.m. Attorneys for the Plaintiff
4 One CityCenter
4
850 Tenth Street, NW
5 5 Washington, D.C. 20001
6 BY: CHRISTOPHER SIPES, ESQ.
6 DANIEL FARNOLY, ESQ.
7 Videotaped deposition of EDWARD A. 7
8
8 FISHER, M.D., M.P.H., Ph.D., held at the 9 WINDELS MARX LANE & MITTENDORF
9 offices of WINDELS MARX LANE & MITTENDORF, Attorneys for Dr. Reddy's
10 Laboratories
10 LLP, One Giralda Farms, Suite 380, Madison, One Giralda Farms
11 New Jersey 07940 before Rebecca Schaumloffel, 11 Madison, New Jersey 07940
12 a Certified Livenote Reporter, Registered BY: CONSTANCE HUTTNER, ESQ.
12 CAROLINE SUN, ESQ.
13 Professional Reporter, Certified Court 13
14
14 Reporter of New Jersey, and Notary Public of 15 WINSTON & STRAWN
15 the States of New York, New Jersey, Delaware, Attorneys for the Defendant
16 1700 K Street, N.W.
16 and Pennsylvania.
Washington, D.C. 20006
17 17 BY: EIMERIC REIG-PLESSIS, ESQ.
18 (Telephonically)
18
19 19
20 ALSO PRESENT:
20
21 21
22 Tom Del Vecchio, videographer
22
23 23
24 * * *
24
25 25
Page 4 Page 5
1 THE VIDEOGRAPHER: Good morning. 08:39AM 1 reporter please swear in or affirm the 08:41AM
2 This is the start of media labeled 08:39AM 2 witness. 08:41AM
3 number one of the video recorded 08:39AM 3 EDWARD A. FISHER, M.D., M.P.H., Ph.D.,
4 deposition of Dr. Edward A. Fisher in 08:39AM 4 called as a witness, having been first duly
5 the matter of Amarin Pharma, Inc. et 08:39AM 5 sworn by a Notary Public of the States of
6 al., Plaintiffs, versus Hikma 08:39AM 6 New York, New Jersey, Pennsylvania, and
7 Pharmaceuticals USA Inc., Defendants, 08:39AM 7 Delaware, was examined and testified as
8 in the United States District Court, 08:39AM 8 follows:
9 District of Nevada, case number 08:39AM 9 EXAMINATION BY
10 2:16-cv-02525-MMD-NJK. 08:39AM 10 MR. SIPES: 08:41AM
11 This deposition is being held at 08:39AM 11 Q. Dr. Fisher, thank you for coming 08:41AM
12 the office of Windels, Marx, Lane & 08:39AM 12 in this morning. Could you please state your 08:41AM
13 Mittendorf, LLP, One Giralda Farms, 08:40AM 13 name and spell it for the record? 08:41AM
14 Madison, New Jersey 07940. Today is 08:40AM 14 A. Edward A. Fisher, F-I-S-H-E-R. 08:41AM
15 Tuesday, July 2, 2019. The time is 08:40AM 15 Q. Where do you reside? 08:41AM
16 approximately 8:40 a.m. 08:40AM 16 A. Scarsdale, New York. 08:41AM
17 My name is Thomas Del Vecchio, 08:40AM 17 Q. Where are currently employed? 08:41AM
18 and I am the legal video specialist 08:40AM 18 A. New York University School of 08:41AM
19 from TSG Reporting Inc. headquartered 08:40AM 19 Medicine. 08:41AM
20 at 747 Third Avenue, New York, New 08:40AM 20 Q. And that's in New York State? 08:41AM
21 York. The Court Reporter today is 08:40AM 21 A. That's in New York State, east 08:41AM
22 Rebecca Schaumloffel. Will the Court 08:40AM 22 side of Manhattan. 08:41AM
23 Reporter please -- sorry, excuse me. 08:41AM 23 Q. Have you been deposed before? 08:41AM
24 All counsel will be noted on the 08:41AM 24 A. Once. 08:41AM
25 stenographic record. Will the 08:41AM 25 Q. Was that in connection with the 08:41AM
2
002
Page 6 Page 7
1 Amgen v. Sanofi case? 08:41AM 1 A. That's okay. 08:42AM
2 A. It was. 08:41AM 2 Q. Also, it's not an endurance test. 08:42AM
3 Q. Roughly when was that? 08:41AM 3 If at some point you need to take a break, 08:42AM
4 A. Three, four years ago. 08:41AM 4 let me know, and I will endeavor to 08:42AM
5 Q. You served as an expert for 08:41AM 5 accommodate you. I just would ask that you 08:42AM
6 Amgen? 08:41AM 6 answer any pending questions first. 08:42AM
7 A. Yes, I did. 08:41AM 7 A. Okay. 08:42AM
8 Q. That's defending their PCSK9 08:41AM 8 Q. Is there any reason why you 08:42AM
9 inhibitor? 08:41AM 9 cannot give complete and truthful testimony 08:42AM
10 A. That's correct. 08:41AM 10 today? 08:42AM
11 Q. You understand that you are under 08:41AM 11 A. No. 08:42AM
12 oath today and are required to answer my 08:41AM 12 Q. You are not on any medications or 08:42AM
13 questions truthfully? 08:42AM 13 medical conditions that would interfere with 08:42AM
14 A. Yes, I do. 08:42AM 14 your ability to tell the truth? 08:42AM
15 Q. If you don't understand a 08:42AM 15 A. No. 08:42AM
16 question, please let me know, and I will 08:42AM 16 Q. You were retained to provide 08:42AM
17 attempt to clarify it. Otherwise, I will 08:42AM 17 opinions in this case regarding the patents 08:42AM
18 assume that you understood it. 08:42AM 18 at issue, correct? 08:42AM
19 Is that fair? 08:42AM 19 A. Correct. 08:42AM
20 A. Yes. 08:42AM 20 Q. When were you retained? 08:42AM
21 Q. Just to point out, we have a 08:42AM 21 A. Earlier this year, in about 08:42AM
22 court reporter here, as you can see, so you 08:42AM 22 March. 08:42AM
23 will need to answer all the questions audibly 08:42AM 23 Q. Which entities retained you? 08:42AM
24 with verbal responses. 08:42AM 24 A. I was contacted by a company 08:43AM
25 Is that okay? 08:42AM 25 called Doar, D-O-A-R, that apparently is in 08:43AM
Page 8 Page 9
1 the business of finding matching expert 08:43AM 1 that's been marked as Fisher Exhibit 1 as the 08:44AM
2 witnesses in cases, and they got my name from 08:43AM 2 Expert Report that you prepared in this case? 08:44AM
3 however they get names of experts in areas, 08:43AM 3 A. At least the front page. I won't 08:44AM
4 and then asked for my CV; must have sent it 08:43AM 4 go through the middle, but there is my 08:44AM
5 to people representing Hikma, and then I got 08:43AM 5 signature. Yep, I do. 08:44AM
6 contacted by them saying that the law firm 08:43AM 6 Q. Is this the only Expert Report 08:44AM
7 wanted to use me. 08:43AM 7 that you have prepared in this case? 08:44AM
8 Q. And you understand that you are 08:43AM 8 A. Yes, it is. 08:44AM
9 here on behalf of both Hikma and Dr. Reddy's 08:43AM 9 Q. And if you will turn to the last 08:44AM
10 Laboratories? 08:43AM 10 page, Page 69, that's your signature? 08:44AM
11 A. Yes. 08:43AM 11 A. Right. 08:44AM
12 Q. So your opinions are on behalf of 08:43AM 12 Q. And you signed it on May 10th of 08:44AM
13 both entities, Hikma and Dr. Reddy's, 08:43AM 13 2019; is that correct? 08:44AM
14 correct? 08:43AM 14 A. I did. 08:44AM
15 A. Yes. 08:43AM 15 Q. Do you recall, did you sign it -- 08:44AM
16 MR. SIPES: I will ask the Court 08:43AM 16 what time of day did you sign the report? 08:44AM
17 Reporter to mark this as Fisher 08:43AM 17 A. That, I don't remember. It was 08:44AM
18 Exhibit 1. 08:43AM 18 during -- I was in my office at work. So it 08:44AM
19 (Whereupon, Fisher Exhibit 1, 08:43AM 19 was, broadly speaking, in the daytime. 08:44AM
20 responsive Expert Report of Edward A. 08:43AM 20 Q. Do you recall, was it in the 08:44AM
21 Fisher M.D., M.P.H., Ph.D. was marked 08:43AM 21 morning or was it in the afternoon? 08:44AM
22 for identification as of this date by 08:43AM 22 A. It wasn't a major event. So 08:44AM
23 the Reporter.) 08:43AM 23 probably in the afternoon. I wanted to -- 08:44AM
24 Q. Dr. Fisher, do you recommend -- 08:44AM 24 usually I want to get things done before I 08:45AM
25 excuse me. Do you recognize the exhibit 08:44AM 25 leave for the day. So I would think it was 08:45AM
3
003
Page 10 Page 11
1 in the afternoon. But, like I said, it 08:45AM 1 knowledge, those are the people that I had 08:46AM
2 didn't have a big impact. 08:45AM 2 direct contact with. 08:46AM
3 Q. All right. Did you prepare the 08:45AM 3 Q. Did you work with anyone who was 08:46AM
4 report yourself? 08:45AM 4 not a lawyer in preparing your report? 08:46AM
5 A. I had help. I had meetings with 08:45AM 5 A. I did not get the job description 08:46AM
6 the team and reviewed lots of papers, 08:45AM 6 of each person who is in that room. So I do 08:46AM
7 documents. I also had worked in the area of 08:45AM 7 not know. 08:46AM
8 fish oils going back to 1989. So I had 08:45AM 8 Q. Did you confer with any other 08:46AM
9 already some experience in the issues, some 08:45AM 9 experts in this case in forming your 08:46AM
10 of the issues. But we worked on it together. 08:45AM 10 opinions? 08:46AM
11 Q. When you say "we," you and 08:45AM 11 A. No. 08:46AM
12 lawyers for Hikma and DRL? 08:45AM 12 Q. To the best of your knowledge, 08:46AM
13 A. Correct. 08:45AM 13 you did not work with anyone who was a 08:46AM
14 Q. Do you recall which lawyers you 08:45AM 14 scientific expert rather than a lawyer in 08:46AM
15 worked with? 08:45AM 15 forming your opinions or drafting your report 08:46AM
16 A. Well, the lead person was Connie. 08:45AM 16 in this case? 08:46AM
17 Q. Ms. Huttner? 08:45AM 17 A. I didn't ask. So in the last 08:47AM
18 A. Ms. Huttner. 08:45AM 18 case with the Amgen, I know that some of the 08:47AM
19 MS. HUTTNER: I am officially 08:45AM 19 lawyers were actually Ph.Ds who -- or got a 08:47AM
20 Ms. Huttner in the deposition. 08:45AM 20 law degree or just Ph.Ds. I would say I 08:47AM
21 A. And then, you know, behind the 08:46AM 21 assumed on no basis that there could have 08:47AM
22 scenes, first meeting was with Beth 08:46AM 22 been somebody in that room who was a 08:47AM
23 Finkelstein. There was somebody, I think, 08:46AM 23 science-trained person and not a lawyer, but 08:47AM
24 from a Washington office, a young woman 08:46AM 24 I cannot -- I cannot tell you the answer one 08:47AM
25 worked with Caroline Sun, Ms. Sun. To my 08:46AM 25 way or the other because I didn't ask, and 08:47AM
Page 12 Page 13
1 when the introductions going around the room, 08:47AM 1 A. The JELIS Study, the REDUCE-IT 08:48AM
2 I frequently, no matter what group I'm in, I 08:47AM 2 Study. A lot of prior art. Mori. They are 08:48AM
3 nod my head, and I quickly forget the 08:47AM 3 all identified, you know, in Dr. Heinecke's 08:48AM
4 person's name, what they do, things like 08:47AM 4 report, the documents associated with the 08:49AM
5 that. 08:47AM 5 report, Mori, Hayashi. Some of these 08:49AM
6 Q. Do you recall anyone, when you 08:47AM 6 Japanese names I can't pronounce. 08:49AM
7 were forming your opinions in this case, 08:47AM 7 Kurabayashi. That one was about 08:49AM
8 anyone you were working with providing you 08:47AM 8 post-menopausal women. The ADA Frequent 08:49AM
9 with technical information or scientific 08:47AM 9 Guidelines. The -- it wasn't a paper, but 08:49AM
10 information that was relevant to your 08:47AM 10 the denial of the Amarin petition to the FDA 08:49AM
11 consideration beyond what you were reading in 08:47AM 11 for the -- their closing off the ANCHOR 08:49AM
12 the documents or knew yourself? 08:48AM 12 Study, the CoRD Study, niacin studies, the 08:49AM
13 MS. HUTTNER: You can answer the 08:48AM 13 AIM-HIGH studies related to agents that 08:49AM
14 question yes or no. 08:48AM 14 reduced triglycerides. 08:49AM
15 A. No. 08:48AM 15 Q. Did you speak with any of the 08:49AM
16 Q. What did you do to prepare for 08:48AM 16 experts that have been retained in this 08:49AM
17 today's deposition? 08:48AM 17 case -- 08:49AM
18 A. I went over my report. I read 08:48AM 18 A. No. 08:49AM
19 over the reports of Jay Heinecke, Peter Toth, 08:48AM 19 Q. -- to prepare for the deposition? 08:49AM
20 Preston Mason, Dr. Ismail. I reviewed 08:48AM 20 A. No. 08:49AM
21 scientific papers that I thought were key. 08:48AM 21 MS. HUTTNER: Dr. Fisher, you 08:49AM
22 And met here yesterday and Friday to go over 08:48AM 22 need to wait after the question so I 08:50AM
23 points and go over my own report. 08:48AM 23 can object if appropriate. 08:50AM
24 Q. Which were the scientific papers 08:48AM 24 MR. SIPES: Ms. Court Reporter, 08:50AM
25 that you thought were key? 08:48AM 25 mark this as Fisher Exhibit 2. 08:50AM
4
004
Page 14 Page 15
1 (Whereupon, Fisher Exhibit 2, 08:50AM 1 asserted claims of the Patents-in-Suit that 08:51AM
2 Exhibit B to Dr. Fisher's Expert 08:50AM 2 had been originally included and then 08:51AM
3 Report was marked for identification 08:50AM 3 removed. I take it you did not review the 08:51AM
4 as of this date by the Reporter.) 08:50AM 4 Rebuttal Expert Report of Jay Heinecke in 08:51AM
5 MS. HUTTNER: Just for the 08:50AM 5 forming your opinions set forth in your 08:51AM
6 record, Fisher 1 does not include 08:50AM 6 Expert Report, correct? 08:51AM
7 Exhibits A and B; is that correct? 08:50AM 7 A. That is correct. 08:51AM
8 MR. SIPES: That's right. We 08:50AM 8 Q. Have you reviewed it since? 08:51AM
9 just missed -- marked as Exhibit 2 -- 08:50AM 9 A. I have. 08:51AM
10 MS. HUTTNER: Yes, Exhibit B. 08:50AM 10 Q. I note that paragraph 48 of your 08:51AM
11 Q. Dr. Fisher, do you recognize 08:50AM 11 Expert Report, Exhibit 1 -- is it all right 08:51AM
12 Fisher Exhibit 2 as the exhibit that you -- 08:50AM 12 if we refer to Exhibit 1 as your Expert 08:51AM
13 that was attached to your report that sets 08:50AM 13 Report in this case? 08:51AM
14 forth the materials that you considered in 08:50AM 14 A. Yes, it is. 08:51AM
15 forming your opinions in this case? 08:50AM 15 Q. You state in paragraph 48, "I 08:51AM
16 A. Yes, I do. 08:51AM 16 understand that the Opening and Rebuttal 08:52AM
17 Q. And I will note that this is the 08:51AM 17 Expert Reports of Jay Heinecke contain a more 08:52AM
18 corrected version of Exhibit 2 that we were 08:51AM 18 detailed discussion of Vascepa and related 08:52AM
19 sent that deleted a reference to your 08:51AM 19 clinical studies as well as relevant prior 08:52AM
20 reviewing the Rebuttal Expert Report of Jay 08:51AM 20 art, which I incorporated here by reference." 08:52AM
21 Heinecke. 08:51AM 21 Did you mean to correct that to 08:52AM
22 Did I pronounce that correctly, 08:51AM 22 refer only to the Opening Report? 08:52AM
23 is it Heinecke? 08:51AM 23 A. Yes, because I did not read the 08:52AM
24 A. Yes. 08:51AM 24 Rebuttal Report at the time I prepared this. 08:52AM
25 Q. Jay Heinecke on invalidity of the 08:51AM 25 Q. So I take it you don't mean to 08:52AM
Page 16 Page 17
1 incorporate the Rebuttal Expert Reports 08:52AM 1 A. He brings up a lot of prior art 08:53AM
2 discussion into your report? 08:52AM 2 that I think is relevant to the topics that I 08:53AM
3 A. In this written report, no, 08:52AM 3 was asked to give an opinion on. So there is 08:53AM
4 because I didn't read it before. 08:52AM 4 an overlap in prior art in the field that he 08:53AM
5 Q. Were you involved at all in the 08:52AM 5 used and I used. 08:53AM
6 preparation of Dr. Heinecke's Opening Report? 08:52AM 6 Q. I take it in terms of the 08:53AM
7 A. No, I was not. 08:52AM 7 opinions that you formed in this case, you 08:53AM
8 Q. So I take it Dr. Heinecke's 08:52AM 8 set them forth in your report, correct? 08:53AM
9 Opening Report is not written in your words; 08:52AM 9 A. Correct. 08:53AM
10 is that correct? 08:52AM 10 MR. SIPES: I will mark the next 08:53AM
11 A. That is correct. 08:52AM 11 exhibit as Fisher Exhibit 3. 08:53AM
12 Q. Do you intend to provide 08:52AM 12 MS. HUTTNER: Chris, I apologize 08:53AM
13 testimony in this case based on 08:52AM 13 but I am going to have to take a bio 08:53AM
14 Dr. Heinecke's words? 08:52AM 14 break at some near point so whenever 08:53AM
15 MS. HUTTNER: I will object to 08:52AM 15 it is convenient. I realize it is a 08:53AM
16 the question and instruct the witness 08:52AM 16 short -- 08:54AM
17 not to answer. 08:52AM 17 (Whereupon, Fisher Exhibit 3, 08:54AM
18 MR. SIPES: On what basis? 08:53AM 18 Exhibit A to Dr. Fisher's Expert 08:54AM
19 MS. HUTTNER: On the basis that 08:53AM 19 Report was marked for identification 08:54AM
20 any discussion about his potential 08:53AM 20 as of this date by the Reporter.) 08:54AM
21 testimony in this case is privileged. 08:53AM 21 MS. HUTTNER: Just for the 08:54AM
22 Q. Well, let me ask you, what do you 08:53AM 22 record, Exhibit 3 is -- was originally 08:54AM
23 mean when you say that you are incorporating 08:53AM 23 Exhibit A to the Fisher report. 08:54AM
24 Dr. Heinecke's Opening Report into your 08:53AM 24 Q. Dr. Fisher, do you recognize 08:54AM
25 report? 08:53AM 25 Exhibit 3 as the CV that you attached as 08:54AM
5
005
Page 18 Page 19
1 Exhibit A to your report? 08:54AM 1 A. No. 08:55AM
2 A. I do. 08:54AM 2 Q. Do you consider yourself an 08:55AM
3 Q. Okay. Is it current and 08:54AM 3 expert in the drug approval process? 08:55AM
4 accurate? 08:54AM 4 A. Not in the technical or legal 08:55AM
5 A. I have gotten one award since 08:54AM 5 aspects. I can evaluate the studies. 08:55AM
6 then. 08:54AM 6 Q. The clinical studies? 08:55AM
7 Q. What is the award you got? 08:54AM 7 A. Yes. 08:55AM
8 A. I am named the 1989 -- I am named 08:54AM 8 Q. You have expertise in reviewing 08:55AM
9 the 2019 Distinguished Visiting Fellow At the 08:54AM 9 and understanding clinical studies on 08:55AM
10 Institute of Advanced Studies at the 08:54AM 10 pharmaceuticals, correct? 08:55AM
11 University of Birmingham in England for 08:54AM 11 A. Yes, I do. 08:55AM
12 November and December. 08:54AM 12 Q. Have you ever developed a method 08:55AM
13 Q. Other than that, the CV is 08:54AM 13 of treatment approved by FDA? 08:55AM
14 complete and accurate, to your knowledge? 08:54AM 14 A. No. 08:55AM
15 A. Yes. 08:55AM 15 Q. Have you ever developed a method 08:55AM
16 Q. And you are not a lawyer, 08:55AM 16 of treatment that has been tested in a 08:55AM
17 correct? 08:55AM 17 clinical trial? 08:55AM
18 A. I am not a lawyer. 08:55AM 18 A. No. 08:55AM
19 Q. You have had no legal training, 08:55AM 19 Q. Are you -- is it okay, when we 08:55AM
20 correct? 08:55AM 20 refer to clinical trials, we are talking 08:55AM
21 A. No. 08:55AM 21 about trials in human beings, correct? 08:55AM
22 Q. So you consider yourself an 08:55AM 22 A. Yes, I understand. 08:55AM
23 expert in patent law, I take it? 08:55AM 23 Q. Have you ever done any work 08:56AM
24 A. In the law of patents, no. 08:55AM 24 advising any company with regard to an 08:56AM
25 Q. And you have never worked at FDA? 08:55AM 25 omega-3 product other than your work in this 08:56AM
Page 20 Page 21
1 case? 08:56AM 1 any of the defendants? 08:57AM
2 A. No. 08:56AM 2 A. No. 08:57AM
3 Q. Just to run through them, you 08:56AM 3 Q. I don't know if you are aware 08:57AM
4 have done no consulting work regarding 08:56AM 4 that Hikma's predecessor was Roxane 08:57AM
5 Lovaza, correct? 08:56AM 5 laboratories, are you aware of that? 08:57AM
6 A. Not that I recall. 08:56AM 6 A. Yeah, I was told that. 08:57AM
7 Q. You are aware that Lovaza used to 08:56AM 7 Q. Did you ever do any work for 08:57AM
8 be called Omacor? 08:56AM 8 Roxane Laboratories? 08:57AM
9 A. Yes. 08:56AM 9 A. No. 08:57AM
10 Q. And you have done no work 08:56AM 10 Q. Have you ever done any work for 08:57AM
11 advising companies with regard to Vascepa 08:56AM 11 Boehringer Ingelheim, Roxane's parent? 08:57AM
12 other than your work in this case? 08:56AM 12 A. No. They -- I gave a seminar 08:57AM
13 A. Correct. 08:56AM 13 there in their Connecticut facility years ago 08:57AM
14 Q. And you have done no work 08:56AM 14 on my research. I was invited to give a talk 08:57AM
15 advising companies with regard to Epanova? 08:56AM 15 on my atherosclerosis research; just a 08:57AM
16 A. No. 08:56AM 16 seminar, spend a day at a Round Table and 08:57AM
17 Q. Have you done any work advising 08:56AM 17 come home. 08:57AM
18 companies with regard to omega-3 dietary 08:56AM 18 Q. In Richfield? 08:57AM
19 supplements? 08:56AM 19 A. Yes. 08:57AM
20 A. No. 08:56AM 20 Q. Have you ever performed any work 08:57AM
21 Q. Do you do any consulting work for 08:56AM 21 for Amarin? 08:57AM
22 dietary supplement companies? 08:56AM 22 A. Amarin? 08:57AM
23 A. No. 08:56AM 23 Q. Amarin. 08:57AM
24 Q. Have you ever done any work, 08:56AM 24 A. No. 08:57AM
25 aside from the work in this litigation, for 08:56AM 25 Q. If you will turn to your CV to 08:57AM
6
006
Page 22 Page 23
1 Page 13. There is a reference to work you do 08:57AM 1 working on this project? 08:58AM
2 under a grant for dyslipidemia and 08:58AM 2 A. Well, you see the funding started 08:58AM
3 atherosclerosis regression from the NIH and 08:58AM 3 May 8, 2015; so approximately a year before 08:58AM
4 the National Heart Lung and Blood Institute. 08:58AM 4 that, because you have to get clinical data 08:59AM
5 Is that what NHLBI stands for? 08:58AM 5 for the grant proposal, and Dr. Goldberg, 08:59AM
6 A. Correct. 08:58AM 6 actually, he was at Columbia Medical School, 08:59AM
7 Q. Do you see that? 08:58AM 7 and he was recruited to be Chief of 08:59AM
8 A. I do. 08:58AM 8 Endocrinology at NYU about five years ago 08:59AM
9 Q. And that's a grant from NIH that 08:58AM 9 when this started. So we started to 08:59AM
10 has a Dr. Karen Bornfeldt of the University 08:58AM 10 collaborate when he joined NYU. 08:59AM
11 of Washington as the principal investigator, 08:58AM 11 Q. So you and Dr. Goldberg submitted 08:59AM
12 correct? 08:58AM 12 the grant proposal roughly in 2014; is that 08:59AM
13 A. It does. 08:58AM 13 correct? 08:59AM
14 Q. And then you are working on one 08:58AM 14 A. About that, correct. 08:59AM
15 of the subprojects for that project, too, 08:58AM 15 Q. Is it an annual cycle; do you 08:59AM
16 with Dr. Ira Goldberg of the University of 08:58AM 16 submit a revised proposal every year? 08:59AM
17 Washington? 08:58AM 17 A. No. Each year you submit what's 08:59AM
18 A. No. Ira Goldberg is at New York 08:58AM 18 called a non-competing renewal because funds 08:59AM
19 University; a colleague of mine at NYU. 08:58AM 19 available is approved for five years, and 08:59AM
20 Q. And the work you are doing 08:58AM 20 then the renewal application just went in in 08:59AM
21 concerns the effects of hypertriglyceridemia 08:58AM 21 May. So for another five-year cycle. 08:59AM
22 on HDL function in atherosclerosis 08:58AM 22 Q. And the -- what is in the 08:59AM
23 regression? 08:58AM 23 proposal in the renewal? 08:59AM
24 A. That is correct. 08:58AM 24 MS. HUTTNER: Objection. 08:59AM
25 Q. And how long have you been 08:58AM 25 Q. Is it a review of the research 08:59AM
Page 24 Page 25
1 you have been doing under the grant? 08:59AM 1 tissues for either energy use or storage. 09:00AM
2 A. Well, you have to put in a 08:59AM 2 So, he has a number of mouse 09:00AM
3 progress report of what we have done up until 09:00AM 3 models that he has created through the years 09:01AM
4 that time. 09:00AM 4 in which they have knocked out or inactivated 09:01AM
5 Q. Other than the grant proposal and 09:00AM 5 the LPL in different tissues to create 09:01AM
6 the renewal you just submitted, do you make 09:00AM 6 different degrees of hypertriglyceridemia. 09:01AM
7 progress reports on a regular basis under the 09:00AM 7 So I am a -- considered a world's 09:01AM
8 grant? 09:00AM 8 expert on getting rid of plaque using mouse 09:01AM
9 A. We do every year. 09:00AM 9 models. So we wanted to know whether or not 09:01AM
10 Q. And that summarizes the work you 09:00AM 10 we could manifest changes in the ability of 09:01AM
11 have done on the topic? 09:00AM 11 lowering LDL cholesterol using a variety of 09:01AM
12 A. Correct. 09:00AM 12 tricks in the mouse world on improving the 09:01AM
13 Q. And what is the sort of research 09:00AM 13 plaque if the triglycerides were high, and if 09:01AM
14 you have been doing on the effects of 09:00AM 14 there was impairment of the regression of the 09:01AM
15 hypertriglyceridemia on an HDL function in an 09:00AM 15 plaque when we lowered the LDL cholesterol, 09:01AM
16 atherosclerosis regression? 09:00AM 16 was it attributable to changes in the 09:01AM
17 MS. HUTTNER: Objection. You 09:00AM 17 function of HDL. 09:01AM
18 can answer. 09:00AM 18 Q. And lipoprotein lipase is an 09:01AM
19 THE WITNESS: I can answer? 09:00AM 19 enzyme that will convert VLDL lipoproteins to 09:01AM
20 MS. HUTTNER: Yes. 09:00AM 20 LDL, correct? 09:01AM
21 A. The -- Dr. Goldberg is an expert 09:00AM 21 A. That is correct. 09:01AM
22 in the action of an enzyme called lipoprotein 09:00AM 22 Q. Have you studied, as part of this 09:01AM
23 litmus and that takes off triglycerides from 09:00AM 23 grant, the effects of DHA or EPA on the 09:02AM
24 the circulating VLDL and chylomicron 09:00AM 24 function of the lipoprotein lipase enzyme? 09:02AM
25 particles and the fatty acids that enter 09:00AM 25 A. No. 09:02AM
7
007
Page 26 Page 27
1 Q. Have you done any work under the 09:02AM 1 into my first funding in my own name in 1993, 09:03AM
2 grant on the effects of EPA or DHA? 09:02AM 2 part of a program project grant on 09:03AM
3 A. Not on this grant. 09:02AM 3 lipoprotein metabolism, and when I moved to 09:03AM
4 Q. Have you studied the effects of 09:02AM 4 Mount Sinai in 1995, I applied for what's 09:03AM
5 EPA and DHA on lipoprotein lipase under other 09:02AM 5 called an R01, an individual research grant, 09:03AM
6 grants? 09:02AM 6 because I left the program project group in 09:03AM
7 A. Not on lipoprotein lipase, no. 09:02AM 7 Philadelphia. So I have had three different 09:03AM
8 Q. What are the effects of EPA and 09:02AM 8 grants in a row under my own name from the 09:03AM
9 DHA that you have studied? 09:02AM 9 NIH to study the liver and omega-3 fatty 09:03AM
10 A. Well, I have been funded by the 09:02AM 10 acids. 09:04AM
11 NIH, another grant. It has the deceptive 09:02AM 11 Q. And those grants are ongoing 09:04AM
12 name, perhaps, of just saying molecular 09:02AM 12 today? 09:04AM
13 regulation of Apo B degradation, and that's a 09:02AM 13 A. Well, I have one still ongoing. 09:04AM
14 current grant that I hold, and we worked 09:02AM 14 Q. So you continue to make progress 09:04AM
15 through the years, starting in 1989, 09:02AM 15 reports and grant renewals under that? 09:04AM
16 actually, my first paper with EPA and DHA, on 09:02AM 16 A. I do. 09:04AM
17 how those fatty acids can regulate the output 09:02AM 17 MR. SIPES: Ms. Huttner, did you 09:04AM
18 of VLDL from the liver. 09:03AM 18 want to take a break? 09:04AM
19 Q. And that's a grant that began in 09:03AM 19 MS. HUTTNER: Yes, that would be 09:04AM
20 '89. Is it still ongoing? 09:03AM 20 great. Thank you. 09:04AM
21 A. Well, so I was funded under a -- 09:03AM 21 MR. SIPES: Let's take a break. 09:04AM
22 I was a young assistant professor, and so I 09:03AM 22 THE VIDEOGRAPHER: The time is 09:04AM
23 was taken under the wing of a senior 09:03AM 23 approximately 9:04 a.m.; we are off 09:04AM
24 investigator, Julian Marsh, at the Medical 09:03AM 24 the record. 09:04AM
25 College of Pennsylvania, and that morphed 09:03AM 25 (Whereupon, a recess was held.) 09:09AM
Page 28 Page 29
1 THE VIDEOGRAPHER: The time is 09:09AM 1 A. No. I use my knowledge from the 09:10AM
2 approximately 9:10 a.m. We are back 09:10AM 2 field. 09:10AM
3 on the record. 09:10AM 3 Q. And did you give the students 09:10AM
4 BY MR. SIPES: 09:10AM 4 reading materials? 09:10AM
5 Q. Dr. Fisher, do you teach medical 09:10AM 5 A. They get a core syllabus from the 09:10AM
6 students? 09:10AM 6 coordinator of the teaching at NYU. 09:11AM
7 A. I do. 09:10AM 7 Q. Who is the coordinator of 09:11AM
8 Q. And do you teach medical students 09:10AM 8 teaching at NYU? 09:11AM
9 about atherosclerosis? 09:10AM 9 A. Micky Rindler. 09:11AM
10 A. I do. 09:10AM 10 MS. HUTTNER: You are asking at 09:11AM
11 Q. And do you teach medical students 09:10AM 11 the present point in time? 09:11AM
12 about the regulation of lipoproteins such as 09:10AM 12 MR. SIPES: Yes. 09:11AM
13 LDL? 09:10AM 13 A. Micky Rindler. 09:11AM
14 A. I do. 09:10AM 14 Q. And do you prepare presentations 09:11AM
15 Q. Do you teach medical students 09:10AM 15 that you give to medical students? 09:11AM
16 about lipid abnormalities such as 09:10AM 16 A. It depends on the format. There 09:11AM
17 hypercholesterolemia and 09:10AM 17 are two -- yes, in case of a lecture, but 09:11AM
18 hypertriglyceridemia? 09:10AM 18 there are small group discussions which are 09:11AM
19 A. I do. 09:10AM 19 to bring up -- go into more detail in points 09:11AM
20 Q. Do you teach medical students 09:10AM 20 in the curriculum. 09:11AM
21 about factors such as EPA and DHA that 09:10AM 21 Q. And when you teach about 09:11AM
22 regulate the secretion of VLDL by the liver? 09:10AM 22 atherosclerosis, do you have a presentation 09:11AM
23 A. I do. 09:10AM 23 that you give medical students? 09:11AM
24 Q. When you teach those subjects, do 09:10AM 24 A. I do. 09:11AM
25 you use a textbook? 09:10AM 25 MS. HUTTNER: Objection. 09:11AM
8
008
Page 30 Page 31
1 Q. And, similarly, when you teach 09:11AM 1 Q. And you prepared the 09:12AM
2 about lipid abnormalities, do you have a 09:11AM 2 presentations that you give at the AHA or the 09:12AM
3 presentation that you give to medical 09:11AM 3 NLA? 09:12AM
4 students? 09:11AM 4 MS. HUTTNER: Objection. 09:12AM
5 MS. HUTTNER: Objection. 09:11AM 5 A. I do. 09:12AM
6 A. No. Well, let me qualify that. 09:11AM 6 Q. And have you talked to the AHA or 09:12AM
7 Yes, it's provided -- that is provided to me. 09:11AM 7 the NLA -- to be clear, the AHA is the 09:12AM
8 Q. Who provides it to you? 09:11AM 8 American Heart Association, correct? 09:12AM
9 A. Micky Rindler. 09:11AM 9 A. Correct. 09:12AM
10 Q. Do you know who prepared it? 09:12AM 10 Q. And the NLA is the National Lipid 09:12AM
11 A. Mainly -- my understanding is he 09:12AM 11 Association, correct? 09:12AM
12 does. 09:12AM 12 A. Correct. 09:12AM
13 Q. I take it you are comfortable 09:12AM 13 Q. And have you talked to the AHA, 09:12AM
14 teaching from the presentation? 09:12AM 14 have you given talks at the AHA -- now I have 09:12AM
15 A. Yes. Well, he sends it in 09:12AM 15 got myself screwed up. Let me start over 09:13AM
16 advance. So if I had any objection, I would 09:12AM 16 again. 09:13AM
17 tell him. 09:12AM 17 The talks to the AHA or the NLA 09:13AM
18 Q. You give talks to associations 09:12AM 18 that you have given, do you prepare those 09:13AM
19 such as the National Lipid Association? 09:12AM 19 presentations yourself? 09:13AM
20 A. I do. 09:12AM 20 MS. HUTTNER: Objection. 09:13AM
21 Q. Do you talk to the ACC as well? 09:12AM 21 A. I do. 09:13AM
22 A. Some of my trainees have taught 09:12AM 22 Q. You do some consulting work for 09:13AM
23 but I have not. 09:12AM 23 research pharmaceutical companies, do you 09:13AM
24 Q. Okay. How about the AHA? 09:12AM 24 not? 09:13AM
25 A. Yes. 09:12AM 25 A. I do. 09:13AM
Page 32 Page 33
1 Q. And you have consulted, for 09:13AM 1 targets that they were pursuing in 09:14AM
2 example, for Merck, correct? 09:13AM 2 atherosclerosis. 09:14AM
3 A. Yes. 09:13AM 3 Q. And was one of those targets HDL 09:14AM
4 Q. When have you consulted for 09:13AM 4 levels? 09:14AM
5 Merck? 09:13AM 5 A. Yes. 09:14AM
6 A. Not in awhile. I am trying to 09:13AM 6 Q. And did you -- was this in 09:14AM
7 think; the last time was maybe five years 09:13AM 7 connection with Merck's development of the 09:14AM
8 ago. 09:13AM 8 laropiprant/niacin combination product? 09:14AM
9 Q. And do you recall when it started 09:13AM 9 A. That was at one meeting, yes. 09:14AM
10 -- when you started consulting for Merck? 09:13AM 10 Q. And the laropiprant/niacin 09:14AM
11 A. Oh, Merck, somewhere in the 09:13AM 11 combination project that Merck was developing 09:14AM
12 probably late 90s, early part of the century. 09:13AM 12 was called Cordaptive in the United States 09:14AM
13 Q. And you are a member of the Merck 09:13AM 13 and Tredaptive in Europe, correct? 09:14AM
14 Global Advisory Board for Atherosclerosis, 09:13AM 14 A. Yeah. 09:14AM
15 correct? 09:13AM 15 Q. Is it okay if we refer to it is 09:14AM
16 A. I was. Actually, I do not know 09:13AM 16 as Cordaptive or Tredaptive? 09:14AM
17 if it still exists. 09:13AM 17 A. Yes. 09:14AM
18 Q. You were a member of the Merck 09:14AM 18 Q. For some reason I have trouble 09:14AM
19 Global Advisory Board for Atherosclerosis? 09:14AM 19 saying laropiprant. 09:14AM
20 A. Yes. 09:14AM 20 A. I can't pronounce the Japanese 09:14AM
21 Q. And what did you do for the Merck 09:14AM 21 name, so I don't have a double standard. 09:14AM
22 Global Advisory Board for Atherosclerosis? 09:14AM 22 Q. You were also a member of the 09:15AM
23 A. They would have a meeting twice a 09:14AM 23 Merck Speakers Bureau? 09:15AM
24 year, and they would present a particular 09:14AM 24 A. Correct. 09:15AM
25 project that they wanted some feedback for 09:14AM 25 Q. When were you a member of the 09:15AM
9
009
Page 34 Page 35
1 Merck Speakers Bureau? 09:15AM 1 A. No. 09:16AM
2 A. Probably around the same time. 09:15AM 2 Q. You were not involved in any of 09:16AM
3 Q. Sometime late 90s? 09:15AM 3 the clinical studies on the product, correct? 09:16AM
4 A. Late 90s to -- for about ten 09:15AM 4 A. No. 09:16AM
5 years. 09:15AM 5 Q. Did NYU enroll patients in the 09:16AM
6 Q. And what did you do as a member 09:15AM 6 Cordaptive clinical study? 09:16AM
7 of the Merck Speakers Bureau? 09:15AM 7 A. Not that I recall. 09:16AM
8 A. There were two activities. One 09:15AM 8 Q. For each of those roles for 09:16AM
9 was they sponsored two academic institutions 09:15AM 9 Merck, you were compensated? 09:16AM
10 by coming to give a seminar on my research, 09:15AM 10 A. Yes. 09:16AM
11 and the other were, I guess you would call 09:15AM 11 Q. Roughly how much money did you 09:16AM
12 them promotional talks giving a talk 09:15AM 12 receive from Merck over your time working for 09:16AM
13 summarizing the benefits of statin to reduce 09:15AM 13 Merck? 09:16AM
14 the risk of cardiovascular disease to 09:15AM 14 A. It varied. But the Global 09:16AM
15 doctors. 09:15AM 15 Advisory Board was twice a year, and so I 09:16AM
16 Q. And that would have been in 09:15AM 16 remember each time it was a $3,000 honorarium 09:16AM
17 connection with Merck's simvastatin product? 09:15AM 17 so $6,000 for the year. And then the talks, 09:16AM
18 A. Yes. 09:15AM 18 depends on the number of talks. Each talk 09:16AM
19 Q. Did you ever prepare talks 09:15AM 19 was about $2,000 and some years I gave, in 09:16AM
20 concerning Cordaptive or Tredaptive? 09:15AM 20 the early part, lots of talks, and then 09:16AM
21 A. No. 09:15AM 21 towards the end, actually, very few talks. 09:16AM
22 Q. Other than the one meeting you 09:15AM 22 Q. You also received a grant from 09:17AM
23 mentioned where they presented work on 09:15AM 23 Merck to study the effects of niacin on VLDL 09:17AM
24 Cordaptive, did you have any involvement with 09:16AM 24 metabolism? 09:17AM
25 the development of the Cordaptive product? 09:16AM 25 A. I did. 09:17AM
Page 36 Page 37
1 Q. Did you make a report to Merck on 09:17AM 1 Q. Have you been disappointed with 09:18AM
2 that research? 09:17AM 2 the way the clinical trials have turned out 09:18AM
3 A. I did. 09:17AM 3 with niacin? 09:18AM
4 Q. Was that ever published in a 09:17AM 4 MS. HUTTNER: Objection. 09:18AM
5 publication? 09:17AM 5 A. As putting on my clinician hat, I 09:18AM
6 A. No. It's a sore point with the 09:17AM 6 wish that they turned out better, yes. 09:18AM
7 post doc who is the first author, and it's 09:17AM 7 Q. Do you believe the problem with 09:18AM
8 sitting on my computer to send out. 09:17AM 8 niacin is that the understanding of the 09:18AM
9 Q. And what were your conclusions 09:17AM 9 clinical effects was wrong or were the 09:18AM
10 about the effects of niacin on VLDL 09:17AM 10 studies poorly done? 09:18AM
11 metabolism? 09:17AM 11 MS. HUTTNER: Objection. 09:18AM
12 A. That we discovered a -- we think 09:17AM 12 A. I think every study has 09:18AM
13 we discovered, the peer reviewers will tell 09:17AM 13 deficiencies and people have picked apart, 09:18AM
14 us their opinion, but a novel mechanism by 09:17AM 14 for example, AIM-HIGH, the design of that. 09:18AM
15 which niacin reduces the secretion of VLDL 09:17AM 15 We go back to hats of vats trials in which 09:18AM
16 triglycerides. 09:17AM 16 the results were much more exciting. It's a 09:18AM
17 Q. Do you view yourself as one of 09:17AM 17 relative feeling but because we have had Greg 09:19AM
18 the leading experts on the effects of niacin 09:17AM 18 Brown, who is the leader in that area, 09:19AM
19 on lipoproteins? 09:17AM 19 published studies in which niacin reduced the 09:19AM
20 A. I am an expert. It's hard to 09:17AM 20 quantitative measure of plaque with recurrent 09:19AM
21 rank. I don't know what basis. I think once 09:17AM 21 events. 09:19AM
22 this is published, my position will go up the 09:17AM 22 So I think it's, in part, patient 09:19AM
23 ladder, but right now I have no -- the basic 09:17AM 23 selection and also in the era of statins, 09:19AM
24 science of how things work in the liver, I am 09:18AM 24 where most things are add-ons, it's just 09:19AM
25 the leading expert. 09:18AM 25 harder to show a benefit. 09:19AM
10
010
Page 38 Page 39
1 Q. Achieving cardiovascular risk 09:19AM 1 A. Yes. 09:20AM
2 reduction in patients with well-controlled 09:19AM 2 Q. Were you surprised by the 09:20AM
3 LDL-C on statins is difficult? 09:19AM 3 reduction in stroke in the REDUCE-IT trial? 09:20AM
4 MS. HUTTNER: Objection. 09:19AM 4 A. Given that that had not been 09:21AM
5 Can I hear the question back, 09:19AM 5 found to be the case in some other studies, 09:21AM
6 please? 09:19AM 6 it was a surprise, but atherosclerosis, 09:21AM
7 (Record read.) 09:19AM 7 whether it's in the coronary arteries or in 09:21AM
8 MS. HUTTNER: Objection; vague. 09:20AM 8 the carotid arteries, there are some 09:21AM
9 A. It's more difficult because the 09:20AM 9 treatments that affect both favorably. 09:21AM
10 effectiveness, as statins become more potent 09:20AM 10 Statins, for example, which are 09:21AM
11 in LDLs on treatment get lower, it's harder 09:20AM 11 well-established, lower heart attack risk, 09:21AM
12 to show an additional benefit. 09:20AM 12 actually, are not as effective on strokes 09:21AM
13 Q. Were you surprised by the results 09:20AM 13 either. 09:21AM
14 of REDUCE-IT? 09:20AM 14 Q. Similarly, in JELIS, there was 09:21AM
15 A. No. In that, again, having 09:20AM 15 not a reduction in sudden cardiac death, 09:21AM
16 followed the fish oil field for awhile, we 09:20AM 16 correct? 09:21AM
17 had the JELIS Study which showed that there 09:20AM 17 MS. HUTTNER: Objection. 09:21AM
18 was reduction in risk. So, in terms of 09:20AM 18 A. Correct. 09:21AM
19 concept, no. 09:20AM 19 Q. Were you surprised by the results 09:21AM
20 Q. Now, in the JELIS Study there was 09:20AM 20 in REDUCE-IT showing 25% reduction in sudden 09:21AM
21 not improvement in incidence of stroke, 09:20AM 21 cardiac death? 09:21AM
22 correct? 09:20AM 22 A. No. Because there was -- there 09:21AM
23 A. Correct. 09:20AM 23 was a lot of prior art, prior literature that 09:21AM
24 Q. In REDUCE-IT stroke, incidence of 09:20AM 24 the omega 3s decrease arrythmia. The former 09:21AM
25 stroke was reduced by 25%, correct? 09:20AM 25 Chair of Medicine at Mass General was a 09:22AM
Page 40 Page 41
1 leader in this area. So, and, in fact, there 09:22AM 1 Q. And you have also done consulting 09:23AM
2 were recommendations of using omega 3s to 09:22AM 2 work for AstraZeneca, correct? 09:23AM
3 prevent the ventricular tachycardia 09:22AM 3 A. Yes. I am trying to remember. I 09:23AM
4 fibrillation after a heart attack. So this 09:22AM 4 would have to say yes because I definitely 09:23AM
5 had been already put out there. 09:22AM 5 visited them. Yes. 09:23AM
6 Q. Now, Lovaza has a warning for 09:22AM 6 Q. Was that in connection with 09:23AM
7 atrial fibrillation, correct? 09:22AM 7 Crestor? 09:23AM
8 A. Yes. 09:22AM 8 A. Once I gave a seminar on my own 09:23AM
9 Q. How is that consistent with your 09:22AM 9 research and I, you know, not recalling what 09:23AM
10 view that fish oils help with arrythmia? 09:22AM 10 the other event was or events except that I 09:23AM
11 A. Well, it's ventricular arrythmia 09:22AM 11 assume that it was a statin-related advisory 09:23AM
12 that you die from not from atrial 09:22AM 12 board. I also had a research grant from them 09:23AM
13 fibrillation; so different mechanisms. 09:22AM 13 for my research. 09:24AM
14 Q. Do you know, is there a 09:22AM 14 Q. And what research was AstraZeneca 09:24AM
15 difference between DHA and DPA on arrythmia? 09:22AM 15 supporting; what did your research report 09:24AM
16 A. I do not know if there is a 09:22AM 16 show was AstraZeneca supporting? 09:24AM
17 difference. 09:22AM 17 A. We had shown that there was a 09:24AM
18 Q. You have done consulting work for 09:22AM 18 particular factor called CCR7 which is a 09:24AM
19 Takeda as well, correct? 09:22AM 19 chemokine receptor that helps some types of 09:24AM
20 A. Yes. 09:22AM 20 macrophages move. 09:24AM
21 Q. What have you done for Takeda? 09:22AM 21 When we published this paper and 09:24AM
22 A. That takes me back. That is when 09:22AM 22 the proceedings in the National Academy of 09:24AM
23 they had their Pioglitazone program. So I 09:22AM 23 Science that when CCR7 was upregulated, cells 09:24AM
24 was on their advisory board for diabetes and 09:23AM 24 came out of the plaque and the plaque shrunk 09:24AM
25 atherosclerosis. 09:23AM 25 in mice. 09:24AM
11
011
Page 62 Page 63
1 which ones, rather than focusing on 09:47AM 1 related to my expert witness in that case. 09:48AM
2 biomarkers, were cardiovascular outcome 09:47AM 2 Q. And I take it you are defending 09:48AM
3 trials on PCSK9s? 09:47AM 3 Amgen's patents which would cover both 09:48AM
4 A. I think ODYSSEY is definitely 09:47AM 4 products, correct? 09:48AM
5 one. The results are so similar between the 09:48AM 5 A. Correct. 09:48AM
6 companies, I actually do not keep the 09:48AM 6 Q. And is it -- in your view, are 09:48AM
7 separate names in my head. 09:48AM 7 the patents important for purposes of 09:48AM
8 Q. Although I take it you are 09:48AM 8 protecting the work of the clinical trial -- 09:48AM
9 defending Amgen's product against Sanofi's 09:48AM 9 MS. HUTTNER: Objection. 09:48AM
10 product, correct? 09:48AM 10 Q. -- that were done to establish a 09:48AM
11 A. Correct. 09:48AM 11 cardiovascular benefits of PCSK9? 09:49AM
12 Q. And Amgen's product is Praluent? 09:48AM 12 MS. HUTTNER: Dr. Fisher, I 09:49AM
13 A. Is Repatha. 09:48AM 13 would cation you that to the extent 09:49AM
14 Q. Repatha. Praluent is Sanofi's 09:48AM 14 the question would require you to 09:49AM
15 product? 09:48AM 15 reveal communications with counsel for 09:49AM
16 A. Correct. 09:48AM 16 Amgen or whatever the other entity was 09:49AM
17 Q. Their advertising has failed on 09:48AM 17 that you worked for, that you should 09:49AM
18 me. 09:48AM 18 be cautious, and also I believe there 09:49AM
19 MS. HUTTNER: Have you finished 09:48AM 19 is a confidentiality order in that 09:49AM
20 your answer? 09:48AM 20 case. 09:49AM
21 A. I was going to say that both -- I 09:48AM 21 To the extent -- 09:49AM
22 have no bias in the efficacy of the competing 09:48AM 22 THE WITNESS: There is. 09:49AM
23 products. They both work very well because 09:48AM 23 MS. HUTTNER: -- that neither of 09:49AM
24 they are really the same antibody. So in 09:48AM 24 those are concerns are implicated -- 09:49AM
25 that regard. So my selective memory is not 09:48AM 25 BY MR. SIPES: 09:49AM
Page 64 Page 65
1 Q. Your opinion, is it your belief 09:49AM 1 caution I gave before. 09:50AM
2 that the patents are important to protecting 09:49AM 2 A. My role was the obviousness, and 09:50AM
3 the investment in the cardiovascular outcome 09:49AM 3 so I do not feel comfortable giving an 09:50AM
4 trials -- 09:49AM 4 opinion on that. 09:50AM
5 MS. HUTTNER: If you have such 5 Q. And your opinion in that case 09:50AM
6 -- 6 were that the patents were not obvious, 09:50AM
7 THE COURT REPORTER: I'm sorry, 7 correct? 09:50AM
8 hold on. I can only take one person 8 A. Correct. 09:50AM
9 at a time. I need the question again. 9 Q. And the priority date in that 09:50AM
10 MR. SIPES: Let me ask my 10 case was early 2008, correct? 09:50AM
11 question first. 11 A. Yes. 09:50AM
12 Q. In your opinion, are the patents 09:49AM 12 Q. If you will turn to Page 23 of 09:50AM
13 important for protecting the investment in 09:49AM 13 Feingold, Fisher Exhibit 4? 09:50AM
14 the cardiovascular outcome trials that 09:49AM 14 MS. HUTTNER: Are we going by 09:50AM
15 demonstrated the benefits of PCSK9 09:49AM 15 the page numbers at the top? 09:50AM
16 inhibitors? 09:49AM 16 MR. SIPES: I think those are 09:50AM
17 MS. HUTTNER: I am going to 09:49AM 17 the only pages. 09:50AM
18 object to the question on the grounds 09:49AM 18 MS. HUTTNER: Okay. 09:50AM
19 that was not the subject of expert 09:49AM 19 A. Page? 09:50AM
20 testimony by this witness in that 09:49AM 20 Q. 23. 09:50AM
21 case. I don't know whether this is 09:49AM 21 A. 23. Okay. 09:50AM
22 the subject of expert testimony by 09:49AM 22 Q. Under "Therapeutic Approach" -- 09:50AM
23 anyone. If he has a personal opinion 09:49AM 23 you see the section "Therapeutic Approach"? 09:50AM
24 on that subject, he can provide it. 09:49AM 24 A. Yes. 09:50AM
25 But, again, I will give you the 09:49AM 25 Q. The last sentence in that first 09:50AM
17
012
Page 66 Page 67
1 paragraph says, "If patients are willing and 09:50AM 1 In paragraph 49 -- 09:52AM
2 able to make major changes in their diet it 09:50AM 2 A. Wait, I turned to Page 49, sorry. 09:52AM
3 is possible to achieve significant reductions 09:51AM 3 I am definitely not a lawyer. 09:52AM
4 in LDL cholesterol levels but this seldom 09:51AM 4 Q. It's on Page 16, if that helps. 09:52AM
5 occurs in clinical practice." 09:51AM 5 A. Okay. 09:52AM
6 Do you see that? 09:51AM 6 Q. You see at the bottom of Page 16, 09:52AM
7 A. Yes. 09:51AM 7 in paragraph 49 of your report, you state, 09:52AM
8 Q. Do you agree with that sentence? 09:51AM 8 "By referring to Vascepa as adjunct therapy 09:52AM
9 A. I agree that the lifestyle 09:51AM 9 to diet, the indication is informing doctors 09:52AM
10 changes are the hardest to get people to 09:51AM 10 that this drug therapy may or may not be 09:52AM
11 follow, but I also have to point out that we 09:51AM 11 necessary, or otherwise warranted, to reduce 09:52AM
12 are obligated to recommend that because, as 09:51AM 12 triglyceride levels in adult patients with 09:52AM
13 you know, in the label of any lipid-lowering 09:51AM 13 very high mg/dL) hypertriglyceridemia or to 09:52AM
14 medication is that they are an adjunct to the 09:51AM 14 maintain triglyceride levels below that 09:53AM
15 lifestyle changes. 09:51AM 15 level." 09:53AM
16 Q. But do you agree that in clinical 09:51AM 16 Do you see that? 09:53AM
17 practice patients are seldom able to conform 09:51AM 17 A. Yes. 09:53AM
18 to a lipid-lowering guide? 09:51AM 18 Q. Vascepa's indication informs 09:53AM
19 A. Well, we have a -- again, in 09:51AM 19 doctors that it may sometimes be necessary to 09:53AM
20 enriched practice and highly motivated 09:51AM 20 keep severely hypertriglyceridemic patients 09:53AM
21 patients, but in general, I would agree with 09:51AM 21 on Vascepa in order to reduce triglycerides 09:53AM
22 the difficulty. I would agree with what they 09:51AM 22 below 500 milligrams per deciliter and 09:53AM
23 said. 09:51AM 23 maintain them below that level, correct? 09:53AM
24 Q. Let me ask you to turn to 09:51AM 24 A. Yes. 09:53AM
25 paragraph 49 of your report. 09:51AM 25 Q. How often do you find, in 09:53AM
Page 68 Page 69
1 treating severely hypertriglyceridemic 09:53AM 1 when no longer necessary to keep 09:54AM
2 patients, is TG-lowering therapy not 09:53AM 2 triglycerides below 500 mg/dL - also 09:54AM
3 necessary to maintain triglyceride levels 09:53AM 3 constitutes an off-label use." 09:54AM
4 below 500 milligrams per deciliter? 09:53AM 4 Do you see that? 09:54AM
5 A. It's -- I can't give you an exact 09:53AM 5 A. Yes. 09:54AM
6 number. I would say it's a minority. 09:53AM 6 Q. I was going to ask you, how do 09:54AM
7 Q. So the majority of patients will 09:53AM 7 you determine when it is no longer necessary 09:55AM
8 need to stay on their TG-lowering medication 09:53AM 8 to use Vascepa to keep triglycerides below 09:55AM
9 in order to keep their triglycerides below 09:53AM 9 500 milligrams per deciliter? 09:55AM
10 500 milligrams per deciliter, correct? 09:53AM 10 A. You would have to have a trial 09:55AM
11 A. Yes, but I can't say it's well 09:53AM 11 where you take them off and see what happens. 09:55AM
12 documented because you fear -- this 09:54AM 12 Q. And, in your experience, do 09:55AM
13 pancreatitis you can die from, right? So 09:54AM 13 doctors do that? 09:55AM
14 whether or not someone will maintain off of 09:54AM 14 A. Some; some in our practice 09:55AM
15 it, off the medication with a lifestyle 09:54AM 15 because -- a part of it is you use no more 09:55AM
16 change or not is frequently not tested 09:54AM 16 medications than is necessary. A lot of it 09:55AM
17 because the risk is you go out and have a Big 09:54AM 17 is patient driven. Even with statins, the 09:55AM
18 Mac and bingo. So it's frequently a patient 09:54AM 18 patient will say or blood pressure 09:55AM
19 is kept on it just as a prophylaxis, 09:54AM 19 medications will say doc, can you try me, I 09:55AM
20 practically. 09:54AM 20 have lost a lot of weight, I exercise. Can 09:55AM
21 Q. And you may have answered my 09:54AM 21 you try lowering my dose or taking me off of 09:55AM
22 question, but if you will turn to paragraph 09:54AM 22 this? And in response to that, if there 09:55AM
23 53 in your report, the last sentence reads, 09:54AM 23 is -- assuming -- first of all, it's not just 09:55AM
24 "Continuing to use Vascepa after successful 09:54AM 24 what the patient reports. If the patient 09:55AM
25 treatment according to the indication - i.e., 09:54AM 25 comes in at obese and now is BMI of 22, you 09:55AM
18
013
Page 70 Page 71
1 say, okay, it's worth a try. If they are 09:55AM 1 to lose weight, you have got to change your 09:57AM
2 coming in and they have a bag of Doritos and 09:56AM 2 diet and then good-bye. Realistically, say 09:57AM
3 they are still, you know, big, and they say I 09:56AM 3 it's going to take about six months, but the 09:57AM
4 have made all these changes, can I get off 09:56AM 4 studies show dramatic improvements with a 09:57AM
5 this medicine, I don't think you are ready 09:56AM 5 relatively modest weight loss, but there has 09:57AM
6 yet, you know, so use your clinical judgment. 09:56AM 6 to be some weight loss. Bariatric surgery is 09:57AM
7 Q. But I take it it takes a couple 09:56AM 7 the most impressive because even before you 09:57AM
8 of years for a patient to go from being, say, 09:56AM 8 start losing weight, there is some metabolic 09:57AM
9 obese to being slim and ready to get off 09:56AM 9 alteration that the operation does that their 09:57AM
10 their medication? 09:56AM 10 metabolic parameters start changing within 09:57AM
11 A. Usually, in my experience, if -- 09:56AM 11 days, when they were measured carefully 09:57AM
12 six months. A motivated patient can make a 09:56AM 12 within days. 09:57AM
13 huge change, actually, in six months. The 09:56AM 13 So but going back, you don't 09:57AM
14 weight loss -- the interesting thing about 09:56AM 14 necessarily need to have somebody come in 09:57AM
15 weight loss is that you don't have to get to 09:56AM 15 looking like a beanpole. It's a much more 09:57AM
16 your high school weight to get metabolic 09:56AM 16 modest evidence. 09:57AM
17 benefits. It's about 5%. The usual figure 09:56AM 17 Q. Is it fair to say that in most 09:57AM
18 as quoted, if you can lose 5% of your weight, 09:56AM 18 cases a physician will follow the Vascepa 09:57AM
19 assuming most of that is your visceral 09:56AM 19 indication to keep triglycerides below 09:57AM
20 adipose tissue, your gut, you start getting 09:56AM 20 500 milligrams per deciliter in a severely 09:58AM
21 improvements in your -- all your lipid 09:56AM 21 hypertriglyceridemic patient for a couple of 09:58AM
22 parameters, your blood sugar, etc. 09:56AM 22 years -- 09:58AM
23 So we give people, we tell them, 09:56AM 23 MS. HUTTNER: Objection. 09:58AM
24 because you want them to be realistic, 09:57AM 24 Q. -- before taking the patient off? 09:58AM
25 because you just tell someone, oh, you have 09:57AM 25 MS. HUTTNER: Objection. 09:58AM
Page 72 Page 73
1 Assumes facts not in evidence. Lacks 09:58AM 1 quick as possible, and then to sustain that, 09:59AM
2 of foundation. 09:58AM 2 well, then, it's a clinical judgment, 09:59AM
3 Q. So let's come back to paragraph 09:58AM 3 basically, and the patient and the factors we 09:59AM
4 53. You refer to the indication of Vascepa 09:58AM 4 already discussed so I won't go over it. 09:59AM
5 as keeping triglycerides below 500 milligrams 09:58AM 5 Q. I take a lot of those factors 09:59AM
6 per deciliter in a severely 09:58AM 6 will be observation of the patient and how 09:59AM
7 hypertriglyceridemic patient, correct? 09:58AM 7 the patient is doing with diet and all these 09:59AM
8 A. Yes. 09:58AM 8 other things? 09:59AM
9 Q. How long would you say most 09:58AM 9 A. Yeah, the blood test, the -- you 09:59AM
10 doctors will follow that and keep their 09:58AM 10 know, reducing the triglycerides when you -- 09:59AM
11 patient on Vascepa? 09:58AM 11 particularly if you are overweight, you have 09:59AM
12 MS. HUTTNER: Objection; 09:58AM 12 a lot of metabolic changes. Reducing the 09:59AM
13 foundation. 09:58AM 13 triglycerides will not change your hemoglobin 09:59AM
14 A. One way of phrasing is for the 09:58AM 14 A1c, for example, which is a big parameter to 09:59AM
15 duration; meaning longer than 12 weeks 09:58AM 15 follow. It won't change your blood pressure. 09:59AM
16 although, as you know, this will maybe come 09:58AM 16 It won't change lots of things. So you put 09:59AM
17 up later, the label or the claims, the claims 09:58AM 17 it in context of the cardiovascular risk 10:00AM
18 of the invention is treatment of about 09:58AM 18 factors as well. 10:00AM
19 12 weeks. So within four weeks the 09:58AM 19 Q. And coming to that, then, if we 10:00AM
20 triglycerides come down; it's very rapid. 09:59AM 20 turn to Feingold, Page 25. 10:00AM
21 So you don't need to go long to 09:59AM 21 A. Okay. 10:00AM
22 see the reduction, but --so there are two 09:59AM 22 Q. Do you see at the top, there is a 10:00AM
23 components, right? One is the -- how much 09:59AM 23 sentence that begins "If the serum 10:00AM
24 time you need to get them below 500 when it 09:59AM 24 triglycerides are very high"? 10:00AM
25 works. Usually, you hope, actually, it's as 09:59AM 25 MS. HUTTNER: I'm sorry, where 10:00AM
19
014
Page 74 Page 75
1 are you? 10:00AM 1 reduction, correct? 10:01AM
2 A. The third line from the top? 10:00AM 2 A. Yes. 10:01AM
3 Q. Yes. So if the serum -- so 10:00AM 3 Q. Is such step-wise approach to 10:01AM
4 Feingold, Page 25 says, "If the serum 10:00AM 4 severe hypertriglyceridemia common, in your 10:01AM
5 triglycerides are very high (greater than 10:00AM 5 experience? 10:01AM
6 500-1000 mg/dl), where there is an increased 10:00AM 6 A. Yes. 10:01AM
7 risk for pancreatitis and hyperviscosity 10:00AM 7 Q. And the fact that the 10:01AM
8 syndromes, initial pharmacological therapy is 10:00AM 8 cardiovascular risk is addressed after the 10:01AM
9 directed at the elevated triglycerides and 10:00AM 9 pancreatitis risk is a reflection of how 10:01AM
10 the initial drug choice is either a fibrate 10:00AM 10 serious pancreatitis is, correct? 10:01AM
11 or high dose omega-3--fatty acids (3-4 grams 10:00AM 11 A. Yes. Also it brings up, I 10:01AM
12 EPA/DHA per day.) After lowering 10:00AM 12 forgot, the hyperviscosity syndrome which is 10:01AM
13 triglycerides to less than 500 mg/dl, which 10:00AM 13 basically sludging of your blood. It's 10:01AM
14 may require more than one drug, statin 10:01AM 14 essentially you get a stroke because the 10:01AM
15 therapy should be initiated if the LDL 10:01AM 15 blood just congeals in your brain which, 10:02AM
16 cholesterol and/or non-HDL cholesterol is not 10:01AM 16 obviously, is not good. 10:02AM
17 at goal." 10:01AM 17 Q. I take it that the risks from 10:02AM
18 Do you see that? 10:01AM 18 very high triglycerides are so serious that 10:02AM
19 A. Yes. 10:01AM 19 they take precedence even over preventing 10:02AM
20 Q. What Feingold is describing there 10:01AM 20 cardiovascular events? 10:02AM
21 on Page 25 is what -- is step-wise therapy 10:01AM 21 A. Yes. 10:02AM
22 addressing the severe hypertriglyceridemia 10:01AM 22 Q. Now, the Feingold book recommends 10:02AM
23 with a TG-lowering agent first and then once 10:01AM 23 for initial treatment of severe 10:02AM
24 the triglycerides are brought below 500, then 10:01AM 24 hypertriglyceridemia either omega-3 fatty 10:02AM
25 turning to CS -- cardiovascular risk 10:01AM 25 acids or fibrates. 10:02AM
Page 76 Page 77
1 Do you see that? 10:02AM 1 MS. HUTTNER: Objection. 10:03AM
2 A. Yes. 10:02AM 2 A. Starting patients on it is, we 10:03AM
3 Q. Feingold does not recommend 10:02AM 3 feel -- well, I feel in my practice was 10:03AM
4 niacin as initial therapy, correct? 10:02AM 4 starting low and going higher. I never had a 10:03AM
5 A. Yes. 10:02AM 5 problem in considering using it because of 10:04AM
6 Q. And I think that's consistent 10:02AM 6 the side effects in case the high dose wasn't 10:04AM
7 with your practice -- 10:02AM 7 tolerated. We would bring people up and 10:04AM
8 A. Yes. 10:02AM 8 frequently, actually, I had lots of patients 10:04AM
9 Q. -- as well? 10:02AM 9 on niacin that tolerated. I didn't get -- I 10:04AM
10 A. Yes. 10:02AM 10 didn't need to go to maximal dose where you 10:04AM
11 Q. And is the reason for that 10:02AM 11 definitely run the risk of the side effects 10:04AM
12 because of the side effects of niacin? 10:02AM 12 and had the triglyceride lowering that I 10:04AM
13 A. Yes. Because you have to use it 10:02AM 13 wanted. But these were typically in the 10:04AM
14 -- in the patient which we have used it who 10:02AM 14 group on the right of his cartoon herein. 10:04AM
15 is not in this pancreatitis risk group, you 10:02AM 15 Q. Those are people with 10:04AM
16 slowly titrate up niacin, even the extended 10:02AM 16 triglycerides below 500? 10:04AM
17 versions, Niaspan or the Tredaptive, had it 10:03AM 17 A. Correct. But I would say we 10:04AM
18 ever been approved. And that takes time. 10:03AM 18 would -- yeah, we would add this triple 10:04AM
19 You bring them up slowly over months. You 10:03AM 19 therapy. 10:04AM
20 don't just zap them with 2 grams of niacin. 10:03AM 20 We had an unusual collection of 10:04AM
21 So the side effects of putting somebody on a 10:03AM 21 very high triglyceride patients at NYU 10:04AM
22 large dose of niacin is not -- and 10:03AM 22 because we were also the teaching faculty for 10:04AM
23 triglycerides is -- is a problem, yes. 10:03AM 23 Bellevue which was renown for its HIV program 10:05AM
24 Q. And the uses of niacin are 10:03AM 24 right from the beginning, and the antivirals 10:05AM
25 limited by the side effects? 10:03AM 25 for the HIV caused severe 10:05AM
20
015
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1 he is known for just putting on a good show. 03:49PM 1 Vascepa for the treatment of very high 03:50PM
2 Q. And for how long has he been 03:49PM 2 triglycerides, right? 03:50PM
3 known for putting on a good show? 03:50PM 3 A. Right. With no -- yes. Just 03:50PM
4 A. Probably since, I would say, for 03:50PM 4 leave it at that. 03:51PM
5 about ten years now. Very smart. 03:50PM 5 Q. Dr. Nissen goes on to say in the 03:51PM
6 Q. The O'Riordan article quotes 03:50PM 6 O'Riordan article, "The semisynthetic 03:51PM
7 Dr. Steven Nissen as saying that he "was 03:50PM 7 ethyl-EPA, which does not include (DHA) in 03:51PM
8 impressed with the MARINE data, although he 03:50PM 8 the formulation and has no effect on 03:51PM
9 expressed the same caveats about trial size, 03:50PM 9 LDL-cholesterol levels, is a reel advance in 03:51PM
10 duration, and lack of peer review." 03:50PM 10 treatment of elevated triglycerides." 03:51PM
11 Do you see that? 03:50PM 11 MS. HUTTNER: Objection. That 03:51PM
12 A. I am reading that now. 03:50PM 12 simply mischaracterized the article. 03:51PM
13 Q. Now, of course, the lack of peer 03:50PM 13 He is not quoted to that effect. 03:51PM
14 review that he is referring to, this was 03:50PM 14 That's not a quote. That's a -- 03:51PM
15 before FDA review of the MARINE trial, 03:50PM 15 that's what stated in the article by 03:51PM
16 correct? 03:50PM 16 the authors of the article. There is 03:51PM
17 A. Yes. 03:50PM 17 no indication it was actually said by 03:51PM
18 Q. FDA has since reviewed the MARINE 03:50PM 18 Dr. Blumenthal. 03:51PM
19 data and concluded that it was appropriate 03:50PM 19 THE WITNESS: Nissen. 03:51PM
20 for approval of Vascepa for treatment of very 03:50PM 20 MS. HUTTNER: Nissen, sorry. 03:51PM
21 high triglycerides, correct? 03:50PM 21 Maybe you want to rephrase. 03:51PM
22 A. Could you repeat that? 03:50PM 22 BY MR. SIPES: 03:51PM
23 Q. FDA has, since the O'Riordan 03:50PM 23 Q. Do you see that? 03:51PM
24 article, reviewed the MARINE clinical data 03:50PM 24 A. I see that that's how it is -- he 03:51PM
25 and concluded that it supports approval of 03:50PM 25 has been paraphrased and his direct quote is 03:51PM
Page 268 Page 269

1 in the next sentence, but this is -- again, 03:51PM 1 that's their product, right? 03:52PM
2 just from his manner of speaking, this is 03:51PM 2 Q. Do you -- 03:52PM
3 plausible that he said it's a real advance 03:51PM 3 A. I am just looking at the next 03:52PM
4 because he also said it's a medical miracle 03:51PM 4 paragraph that he says that he would like to 03:52PM
5 that we got to .1% change. 03:52PM 5 see a head-to-head comparison, which, to me, 03:52PM
6 Q. The next sentence of the article 03:52PM 6 implicit is that he thinks there might be the 03:52PM
7 issue says, "The semisynthetic ethyl-EPA, 03:52PM 7 same benefit. It's an open question. 03:52PM
8 which does not include (DHA) in the 03:52PM 8 Q. He would like to see a 03:53PM
9 formulation and has no effect on 03:52PM 9 head-to-head comparison between Lovaza -- 03:53PM
10 LDL-cholesterol levels, is a real advance in 03:52PM 10 A. Lovaza and Amarin 10 -- AMR101 03:53PM
11 the treatment of elevated triglycerides, he 03:52PM 11 which is, I guess, what became Vascepa. 03:53PM
12 told heartwire." 03:52PM 12 Q. Now, in the time since 2010 when 03:53PM
13 Do you see that? 03:52PM 13 MARINE was done, Amarin has done two 03:53PM
14 A. Yes. 03:52PM 14 additional clinical trials, ANCHOR and 03:53PM
15 Q. Then it goes on to quote, "'It 03:52PM 15 REDUCE-IT, correct? 03:53PM
16 gives you all the benefit without the 03:52PM 16 A. Yes. 03:53PM
17 downside' said Nissen. 'It's an interesting 03:52PM 17 Q. And REDUCE-IT is a large 03:53PM
18 wrinkle. There's still room for small 03:52PM 18 cardiovascular outcome trial, correct? 03:53PM
19 companies to do innovative things in this 03:52PM 19 A. Yes. 03:53PM
20 field.'" 03:52PM 20 Q. Do you know, in this time, since 03:53PM
21 Do you see that? 03:52PM 21 2010, has GSK done any clinical trials on 03:53PM
22 A. Yes. 03:52PM 22 Lovaza? 03:53PM
23 Q. And the small company he is 03:52PM 23 A. I am not remembering any. It 03:53PM
24 referring to is Amarin, correct? 03:52PM 24 doesn't mean there wasn't. 03:53PM
25 A. I would assume since they -- 03:52PM 25 Q. Based on the labeling and the 03:53PM
68
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1 clinical studies reported in the Lovaza 03:53PM 1 Exhibit 5, Table 1 is in high triglycerides, 03:55PM
2 labeling, Lovaza raises LDL-C in very high 03:53PM 2 not very high, correct? 03:55PM
3 triglyceride patients, correct? 03:54PM 3 A. Yeah. I agree. 03:55PM
4 A. In that Table 2 that was 03:54PM 4 Q. And -- 03:55PM
5 reported, yes. 03:54PM 5 A. I agree. 03:55PM
6 Q. Are you aware of any clinical 03:54PM 6 Q. If you will look at the LDL-C 03:55PM
7 study of a TG-lowering agent in very high 03:54PM 7 values, the LDL-C for the Lovaza plus 03:56PM
8 triglyceride patients that did not result in 03:54PM 8 simvastatin group, in any event, was reported 03:56PM
9 increased LDL-C aside from EPA? 03:54PM 9 as an increase of 0.7%, correct? 03:56PM
10 MS. HUTTNER: Objection. 03:54PM 10 A. Right, because of the placebo. 03:56PM
11 Mischaracterizes the record. Assumes 03:54PM 11 Q. Well, the difference from placebo 03:56PM
12 facts not in evidence. 03:54PM 12 was 3.5%, correct? 03:56PM
13 A. Well, going back to the Lovaza 03:54PM 13 A. Um-hum. 03:56PM
14 label, when given with a statin background, 03:54PM 14 Q. So even in the high triglyceride 03:56PM
15 there was no increase in the LDL, but I don't 03:54PM 15 group, Lovaza showed some increase in LDL-C, 03:56PM
16 recall a study in part because, I guess, it's 03:54PM 16 correct? 03:56PM
17 such a rare condition that the -- that the 03:54PM 17 A. In the median. In the median 03:56PM
18 issue that you bring up, the increase in 03:55PM 18 value, correct. 03:56PM
19 LDL-C was not considered a topic to be 03:55PM 19 Q. But in the very high triglyceride 03:56PM
20 investigated. 03:55PM 20 group, it showed a substantial increase, 03:56PM
21 Q. The table that you referred to 03:55PM 21 correct? 03:56PM
22 with Lovaza and the statin, that was 03:55PM 22 A. Yes. 03:56PM
23 Exhibit 5, Fisher Exhibit 5, correct? 03:55PM 23 Q. So the TG-lowering medications 03:56PM
24 A. Correct. 03:55PM 24 for severe hypertriglyceridemia are niacin, 03:56PM
25 Q. So if you look at Fisher 03:55PM 25 fibrates, Lovaza, and Vascepa and other 03:56PM
Page 272 Page 273

1 omega-3 fatty acids, correct? 03:57PM 1 the Prevention of Clinical
2 A. Yes. 03:57PM 2 Cardiovascular Disease A Scientific
3 Q. Of all those TG-lowering 03:57PM 3 Advisory from the American Heart
4 medications, niacin, fibrates, Lovaza, and 03:57PM 4 Association dated" April 11, 2017 was
5 EPA, are you aware of any study in very high 03:57PM 5 marked for identification as of this
6 triglyceride patients other than with EPA 03:57PM 6 date by the Reporter.) 03:58PM
7 that showed a reduction in triglycerides 03:57PM 7 Q. Dr. Fisher, I have asked the 03:58PM
8 without a rise in LDL? 03:57PM 8 Court Reporter to mark as Fisher Exhibit 14 a 03:58PM
9 MS. HUTTNER: Objection; assumes 03:57PM 9 document entitled "AHA Science Advisory 03:58PM
10 facts not in evidence. 03:57PM 10 Omega-3 Polyunsaturated Fatty Acid (Fish Oil) 03:58PM
11 Mischaracterizes. 03:57PM 11 Supplementation and the Prevention of 03:58PM
12 A. I -- none come to mind, but I 03:57PM 12 Clinical Cardiovascular Disease A Scientific 03:58PM
13 haven't reviewed that particular point in 03:57PM 13 Advisory from the American Heart Association 03:58PM
14 detail. 03:57PM 14 dated" April 11, 2017. 03:58PM
15 Q. You didn't review that point for 03:57PM 15 Do you see that? 03:58PM
16 purposes of forming your opinions in this 03:57PM 16 A. I do. 03:58PM
17 case, correct? 03:57PM 17 Q. This is the Siscovick article 03:58PM
18 A. That is correct. 03:57PM 18 that you cite in your report, correct? 03:58PM
19 MR. SIPES: Let me ask the Court 03:57PM 19 A. Yes. 03:58PM
20 Reporter to mark this as Fisher 03:57PM 20 Q. I think you mentioned that one of 03:58PM
21 Exhibit 14. 03:58PM 21 the members of the AHA, who has been very 03:59PM
22 (Whereupon, Fisher Exhibit 14, 22 involved in studying fish oil, was Penny 03:59PM
23 document entitled "AHA Science 23 Kris-Etherton, correct? 03:59PM
24 Advisory omega-3 Polyunsaturated Fatty 24 A. That is correct. 03:59PM
25 Acid (Fish Oil) Supplementation and 25 Q. And she is one of the authors of 03:59PM
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1 the Siscovick paper, correct? 03:59PM 1 these exercises, this committee of writers 04:00PM
2 A. I'm looking. Yes. 03:59PM 2 prepared this document which then was 04:00PM
3 Q. If you will turn to page e880. 03:59PM 3 reviewed by different segments of the AHA and 04:00PM
4 A. Okay. 03:59PM 4 then published as an advisory. 04:00PM
5 Q. In e880, there is a reference on 03:59PM 5 Q. Are you a member of the American 04:00PM
6 the right-hand column, the second paragraph. 03:59PM 6 Heart Association Science Advisory 04:00PM
7 Do you see "This advisory was 03:59PM 7 Coordinating Committee? 04:00PM
8 approved"? 03:59PM 8 A. I am not. 04:00PM
9 A. Yes. 03:59PM 9 Q. Were you in September of 2016? 04:00PM
10 Q. And it states, "This advisory was 03:59PM 10 A. No. 04:01PM
11 approved by the American Heart Association 04:00PM 11 Q. Have you ever been a member of 04:01PM
12 Science Advisory and Coordinating Committee 04:00PM 12 the American Heart Association Executive 04:01PM
13 on September 12, 2016, and the American Heart 04:00PM 13 Committee? 04:01PM
14 Association Executive Committee on 04:00PM 14 A. No. 04:01PM
15 January 10, 2017;" correct? 04:00PM 15 Q. And the Siscovick article that 04:01PM
16 A. Yes. 04:00PM 16 you cite was published in the spring of 2017, 04:01PM
17 Q. So the Siscovick article that you 04:00PM 17 correct? 04:01PM
18 cite in your report is an official Scientific 04:00PM 18 A. Yep, April 11, 2017. 04:01PM
19 Advisory from the American Heart Association, 04:00PM 19 Q. If you will turn to page e869. 04:01PM
20 correct? 04:00PM 20 You will see there is -- in the right-hand 04:01PM
21 A. It is. 04:00PM 21 column, a section titled "Prevention of 04:01PM
22 Q. And it reflects the opinions of 04:00PM 22 Cardiovascular Disease Mortality in Diabetes 04:02PM
23 the American Heart Association as an 04:00PM 23 Mellitus/Prediabetes." 04:02PM
24 organization, correct? 04:00PM 24 Do you see that? 04:02PM
25 A. Yes. Having participated in 04:00PM 25 A. Yes. 04:02PM
Page 276 Page 277

1 Q. And then the last paragraph of 04:02PM 1 previously." "As noted previously, except 04:04PM
2 that section reads, "Overall, the current 04:02PM 2 for JELIS, all of the RCTs," random clinical 04:04PM
3 evidence from randomized clinical trials 04:02PM 3 trials, "used low doses of omega-3 PUFA 04:04PM
4 suggests no benefit of omega-3 04:02PM 4 supplements. Higher doses of omega-3 PUFA 04:04PM
5 polyunsaturated fatty acid supplementation 04:02PM 5 supplements are being studied in ongoing RCTs 04:04PM
6 among patients with or at risk for diabetics 04:02PM 6 (REDUCE-IT)" is specifically cited and the 04:04PM
7 mellitus to prevent cardiovascular disease 04:02PM 7 STRENGTH study that we mentioned before. 04:05PM
8 (Treatment is not indicated.)" 04:02PM 8 "Additionally, most of the RCTs 04:05PM
9 Do you see that? 04:02PM 9 were of relatively" -- so when I read "more 04:05PM
10 A. I do. 04:02PM 10 relatively short-term duration of omega-3 04:05PM
11 Q. Do you agree with the 04:02PM 11 PUFA intake." So "We acknowledge that a lack 04:05PM
12 recommendation of the AHA advisory, that 04:02PM 12 of evidence of a benefit differs from 04:05PM
13 omega-3 fatty acids are not indicated for the 04:02PM 13 evidence of a lack of effect." 04:05PM
14 reduction of cardiovascular risk in patients 04:02PM 14 So if I take that, which is now 04:05PM
15 with or at risk for diabetes mellitus -- 04:02PM 15 they are summing up their philosophy, and go 04:05PM
16 MS. HUTTNER: Objection. 04:02PM 16 back to the section you just called our 04:05PM
17 Q. -- as of 2017? 04:02PM 17 attention to, I read that as there was 04:05PM
18 A. As of 2017. Let me just read -- 04:03PM 18 insufficient evidence; not evidence against 04:05PM
19 I need a few minutes to look at this. That's 04:03PM 19 it, there is insufficient evidence to 04:05PM
20 the ORIGIN study. 04:03PM 20 recommend it. 04:05PM
21 Well, based on the study THAT 04:04PM 21 Q. Okay. And I want to just be 04:05PM
22 they used and we went over ORIGIN ourselves 04:04PM 22 clear, omega PUFA, that's the same thing as 04:05PM
23 and then comparing that with what they say 04:04PM 23 omega-3 fatty acids, correct? 04:05PM
24 later is that the -- on page e879, at the 04:04PM 24 A. Yes. 04:05PM
25 very bottom on the right "As noted 04:04PM 25 Q. So what the AHA Science Advisory 04:05PM
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1 Q. If you will turn to page e874, it 04:10PM 1 A. Yes. 04:11PM
2 states, "Overall there is no proven benefit 04:10PM 2 Q. So, in fact, the study that had 04:11PM
3 of omega-3 PUFA supplementation as a means to 04:10PM 3 looked at EPA, prior to 2017, the JELIS Study 04:11PM
4 reduce the risk of stroke among patients 04:10PM 4 had not seen EPA to improve the incidence of 04:11PM
5 without a history of stroke," correct? 04:10PM 5 stroke, correct? 04:11PM
6 A. Right. 04:10PM 6 MS. HUTTNER: Objection; 04:11PM
7 Q. And do you agree with that 04:10PM 7 mischaracterization. 04:11PM
8 conclusion as of 2017? 04:10PM 8 A. They did not report any 04:12PM
9 A. Well, if you start off saying 04:10PM 9 protection from stroke in JELIS. 04:12PM
10 that there are no reports from RCTs or 04:10PM 10 Q. Now, the secondary prevention of 04:12PM
11 omega-3, PUFA supplements on stroke 04:10PM 11 stroke, once again, discusses the JELIS 04:12PM
12 prevention, then, certainly, you have no 04:11PM 12 trial, do you see that, on e874 of the 04:12PM
13 basis to make a strong recommendation of any 04:11PM 13 Siscovick article? 04:12PM
14 type. 04:11PM 14 A. Yes. 04:12PM
15 Q. Is REDUCE-IT the first study to 04:11PM 15 Q. And there they are discussing the 04:12PM
16 show a reduction in the risk of stroke among 04:11PM 16 Saito 2008 article, correct? 04:12PM
17 patients without a history of stroke? 04:11PM 17 A. Let me read that. These things 04:12PM
18 A. Well, assuming this is accurate, 04:11PM 18 that start off no RCT have been designed to 04:12PM
19 that 2017 there were no RCTs of omega-3 fatty 04:11PM 19 examine, influence, very influential 04:12PM
20 acids on stroke prevention and REDUCE-IT does 04:11PM 20 statement. 04:12PM
21 have that end point, I would say that has to 04:11PM 21 Okay. So I have read this, okay. 04:13PM
22 be new information. 04:11PM 22 Q. So they reviewed a subanalysis of 04:13PM
23 Q. And you recall that in JELIS, in 04:11PM 23 JELIS, correct? 04:13PM
24 fact, there was not a reduction in first 04:11PM 24 A. Right. 04:13PM
25 incidence of stroke, correct? 04:11PM 25 Q. And the conclusion of the AHA 04:13PM
Page 284 Page 285

1 Science Advisory Panel is even with the 04:13PM 1 as of October 2017, at least the majority of 04:14PM
2 subanalysis in JELIS, overall, there was no 04:13PM 2 the Panel did not view the evidence as 04:14PM
3 evidence of benefit of omega-3 PUFA 04:13PM 3 sufficient to warrant a recommendation for 04:14PM
4 supplementation as a means to reduce the risk 04:13PM 4 the use of omega-3 fatty acids for any aspect 04:14PM
5 of recurrent stroke or other cardiovascular 04:13PM 5 of -- reducing any aspect of cardiovascular 04:14PM
6 disease among patients with a prior stroke, 04:13PM 6 disease, correct? 04:14PM
7 correct? 04:13PM 7 A. For primary prevention of heart 04:14PM
8 A. Yeah, I think that's an 04:13PM 8 attacks and stroke or primary and secondary 04:15PM
9 unfortunate choice of word "no." There is 04:13PM 9 prevention of stroke, that is clear. We 04:15PM
10 insufficient. Meaning these are the data. 04:13PM 10 didn't talk about secondary prevention of CHD 04:15PM
11 They do report a 6.8% versus 10.5 and it's 04:13PM 11 and SVP among patients with prevalent CV. 04:15PM
12 statistically significant because the 04:13PM 12 These did a little bit better. Class IIa 04:15PM
13 confidence interval didn't go past 1, so I 04:13PM 13 recommendation and a minority of authors 04:15PM
14 would say there is insufficient evidence 04:13PM 14 refers slightly lower, Class IIb. 04:15PM
15 based on that study for benefit. I think -- 04:13PM 15 So the categories we discussed in 04:15PM
16 it's unfair to the almost 1,000 patients who 04:14PM 16 detail, yes, they did not find sufficient 04:15PM
17 were subjects in here, if you add that up to 04:14PM 17 evidence in this report. But more favorable 04:15PM
18 two groups to just say, hah, no evidence, 04:14PM 18 to some of the others, if you look at their 04:15PM
19 okay, you contributed nothing of value to our 04:14PM 19 Table 8, there is some variation. 04:15PM
20 understanding. But "insufficient," I will 04:14PM 20 Q. It's fair to say that the 04:15PM
21 not argue against. To make a treatment 04:14PM 21 REDUCE-IT results have substantially changed 04:15PM
22 recommendation, that would be insufficient. 04:14PM 22 the situation with regard to the clinical 04:16PM
23 Q. So fair to say that the American 04:14PM 23 evidence supporting the use of omega-3 fatty 04:16PM
24 Heart Association, when they took a look at 04:14PM 24 acids and specifically EPA alone to address 04:16PM
25 all the evidence on the omega-3 fatty acids, 04:14PM 25 cardiovascular risk, correct? 04:16PM
72
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1 A. It certainly is a prominent study 04:16PM 1 Cholesterol Education program and have an 04:17PM
2 that's been widely discussed. We used it in 04:16PM 2 ATP4. It's a bit of mystery why -- I know 04:17PM
3 our journal club as soon as it came out. So 04:16PM 3 it's not the topic germane, but it's a 04:17PM
4 it definitely has increased the discussion 04:16PM 4 mystery why that committee disbanded when it 04:17PM
5 around fish oils in general and not just the 04:16PM 5 did, and it has not reconvened. It's a real, 04:17PM
6 EPA. 04:16PM 6 I think, disservice to good patient care. 04:17PM
7 Q. Do you believe that the REDUCE-IT 04:16PM 7 MR. SIPES: I have no further 04:17PM
8 trial is going to change clinical practice 04:16PM 8 questions at this time. 04:17PM
9 with regard to addressing residual 04:16PM 9 MS. HUTTNER: Okay. I need ten 04:17PM
10 cardiovascular risk in patients receiving a 04:16PM 10 minutes with counsel and then come 04:18PM
11 statin? 04:16PM 11 back. 04:18PM
12 MS. HUTTNER: Objection; calls 04:16PM 12 THE VIDEOGRAPHER: The time is 04:18PM
13 for speculation. Beyond the scope. 04:16PM 13 4:18 p.m.; we are off the record. 04:18PM
14 A. The ADA recommendations have some 04:16PM 14 (Whereupon, a recess was held.) 04:33PM
15 influence. I sort of -- whatever Darwinian 04:16PM 15 THE VIDEOGRAPHER: The time is 04:33PM
16 is the right phrase, I am interested as -- to 04:17PM 16 4:33 p.m.; we are back on the record. 04:33PM
17 see what the other, I will say, guidelines, 04:17PM 17 MS. HUTTNER: We have no 04:33PM
18 real opinion guidelines committees 04:17PM 18 questions for Dr. Fisher at this time. 04:33PM
19 incorporate going forward. 04:17PM 19 MR. SIPES: Thank you, Dr. 04:33PM
20 Q. What are the other key guidelines 04:17PM 20 Fisher. I appreciate your time. 04:33PM
21 in your review? 04:17PM 21 THE WITNESS: You are welcome. 04:33PM
22 A. I think the National Lipid 04:17PM 22 Thank you. 04:33PM
23 Association, the American College of 04:17PM 23 THE VIDEOGRAPHER: The time is 04:33PM
24 Cardiology, the American Heart Association, 04:17PM 24 approximately 4:34 p.m., July 2, 2019. 04:33PM
25 and if they ever revive the National 04:17PM 25 This is the end of media number five 04:34PM
Page 288 Page 289

1 and completes the videotaped 04:34PM 1
2 deposition of Dr. Edward A. Fisher. 04:34PM 2 EXHIBITS
3 We are off the record. 04:34PM 3
4 (Whereupon, at 4:34 p.m., the 4
5 Examination of this Witness was
6 concluded.)
5 EXHIBIT EXHIBIT PAGE
7
6 NUMBER DESCRIPTION
8 7 Exhibit 1 Responsive Expert 8
9 __________________________ 8 Report of Edward A.
EDWARD A. FISHER, M.D., M.P.H., Ph.D. 9 Fisher M.D., M.P.H.,
10 10 Ph.D.
Subscribed and sworn to before me 11 Exhibit 2 Exhibit B to Dr. 14
11 this _____ day of __________ 2019. 12 Fisher's Expert Report
12 __________________________ 13 Exhibit 3 Exhibit A to Dr. 17
NOTARY PUBLIC
13
14 Fisher's Expert Report
14
15 Exhibit 4 Document entitled 56
15 16 "Diabetes and
16 17 Dyslipidemia" by
17 18 Kenneth R. Feingold MD
18 19 and Carl Grunfeld MD,
19 20 Ph.D
20
21
21 Exhibit 5 AMRN01187779 through 107
22
22 '7780
23
23 Exhibit 6 Document from the 160
24
24 European Heart Journal
25 25 in 2011 entitled
73
020
Page 290 Page 291

1 1
2 "Triglyceride-rich 2 Exhibit 9 Article from the 210
3 lipoproteins and 3 Current Therapeutic
4 high-density 4 Research, Volume 56,
5 lipoprotein 5 Number 1 1995
6 cholesterol in 6 Exhibit 10 Document entitled WO 219
7 patients at high risk 7 2008/004900 published
8 of cardiovascular 8 January 10, 2008
9 disease: evidence and 9 Exhibit 11 Article entitled 232
10 guidance for 10 "Purified
11 management." 11 eicosapentaenoic and
12 Exhibit 7 Document entitled 181 12 docosahexaenoic acids
13 "Cardiovascular 13 have differential
14 Disease and Risk 14 effects on serum
15 Management: Standards 15 lipids and
16 of Medical Care in 16 lipoproteins, LDL
17 Diabetes - 2019" 17 particle size,
18 Exhibit 8 Document entitled 197 18 glucose, and insulin
19 "Eicosapentaenoic Acid 19 in mildly
20 Effect on 20 hyperlipidemic men,"
21 Hyperlipidemia in 21 first author, Trevor
22 Menopausal Japanese 22 A. Mori published in
23 Women" 23 the American Journal
24 24 of Clinical Nutrition
25 25 in the year 2000
Page 292 Page 293

1 1
2 Exhibit 14 Document entitled "AHA 272
2 Exhibit 12 Paper entitled 255
3 Science Advisory
3 "Effects of EPA on
4 coronary artery 4 omega-3
5 disease in 5 Polyunsaturated Fatty
6 hypercholesterolemic 6 Acid (Fish Oil)
7 patients with multiple 7 Supplementation and
8 risk factors: 8 the Prevention of
9 Sub-analysis of 9 Clinical
10 primary prevention 10 Cardiovascular Disease
11 cases from the Japan 11 A Scientific Advisory
12 EPA Lipid Intervention 12 from the American
13 Study (JELIS) with 13 Heart Association
14 Saito as the first 14 dated" April 11, 2017
15 author from the 15
16 Journal of 16
17 Atherosclerosis 2008. 17 INDEX
18 Exhibit 13 Document entitled 258 18
19 "MARINE: Ethyl-EPA 19 EXAMINATION BY PAGE
20 Reduces Triglyceride 20 MR. SIPES 5
21 Levels Without Raising 21
22 LDL Cholesterol" by 22
23 Michael O'Riordan, 23 INFORMATION AND/OR DOCUMENTS REQUESTED
24 November 30, 2010 24 INFORMATION AND/OR DOCUMENTS PAGE
25 25 (NONE)
74
021
Page 294
1
2 C E R T I F I C A T E
3
4 STATE OF NEW YORK )

: SS.:
5 COUNTY OF NASSAU )
6
7 I, REBECCA SCHAUMLOFFEL, a Notary

8 Public for and within the State of New York,
9 do hereby certify:
10 That the witness whose examination
11 is hereinbefore set forth was duly sworn and
12 that such examination is a true record of the
13 testimony given by that witness.
14 I further certify that I am not
15 related to any of the parties to this action
16 by blood or by marriage and that I am in no
17 way interested in the outcome of this matter.
18 IN WITNESS WHEREOF, I have hereunto
19 set my hand this 10th day of July, 2019.
20
21
22 __________________________
23 REBECCA SCHAUMLOFFEL
24
25

022
EXHIBIT 4
Peter R. Mathers, dated June 27, 2019
Page 1
2 DISTRICT OF NEVADA
3
4 ___________________________
)
5 AMARIN PHARMA, INC., ) Case No.
et al., ) 2:16-cv-02525
6 )
Plaintiffs, ) Consolidated with
7 )
vs. ) Case No.
8 ) 2:16-cv-02562
HIKMA PHARMACEUTICALS USA, )
9 INC., et al., )
)
10 Defendants. )
___________________________)
11
12
13
14 DEPOSITION OF PETER R. MATHERS
15 Washington, DC
16 June 27, 2019
17
18
19
20
21
22
23
24 Reported by: John L. Harmonson, RPR
25 Job No. 162975

001
Page 2 Page 3
1 1 APPEARANCES
2 2
3 3 On behalf of the Plaintiffs and Counterclaim
4 4 Defendants:
5 June 27, 2019 5 COVINGTON & BURLING
6 9:01 a.m. 6 850 Tenth Street, NW
7 7 Washington, DC 20001
8 8 BY: CHRISTOPHER SIPES, ESQ.
9 Deposition of PETER R. MATHERS, held at the 9 JORDAN MORAN, ESQ.
10 offices of Winston & Strawn LLP, 1700 K Street, 10 EINAR STOLE, ESQ.
11 N.W., Washington, D.C., pursuant to the Federal 11
12 Rules of Civil Procedure, subject to such 12 On behalf of the Hikma Defendants and
13 stipulations as may be recited herein or attached 13 Counterclaim Plaintiffs:
14 hereto, before John L. Harmonson, a Registered 14 WINSTON & STRAWN
15 Professional Reporter and Notary Public of the 15 1700 K Street, NW
16 District of Columbia, who officiated in 16 Washington, DC 20006
17 administering the oath to the witness. 17 BY: CLAIRE FUNDAKOWSKI, ESQ.
18 18
19 19 On behalf of the Dr. Reddy's Defendants and
20 20 Counterclaim Plaintiffs:
21 21 WINDELS MARX LANE & MITTENDORF
22 22 One Giralda Farms
23 23 Madison, NJ 07940
24 24 BY: BETH FINKELSTEIN, ESQ. (by phone)
25 25
Page 4 Page 5
1 ALSO PRESENT: 1 EXAMINATION INDEX
2 DAVID CHRONIGER, Legal Video Specialist 2
3 3 WITNESS PAGE
4 4 PETER J. MATHERS
5 5 Examination by Mr. Sipes 9
6 6 Examination by Ms. Fundakowski 181
7 7 Examination by Mr. Sipes 185
8 8 ***
9 9
10 10 EXHIBIT INDEX
11 11 PAGE
12 12 Exhibit 1 . . . . . . . . . . . . . . . . 12
13 13 Rebuttal Expert Report of Peter R. Mathers
14 14 on Non-Infringement of the Asserted Claims
15 15 of the Patents-In-Suit
16 16 Exhibit 2 . . . . . . . . . . . . . . . . 22
17 17 Materials Considered
18 18 Exhibit 3 . . . . . . . . . . . . . . . . 24
19 19 Curriculum Vitae of Peter J. Mathers
20 20 Exhibit 4 . . . . . . . . . . . . . . . . 31
21 21 Final Amarin label; AMRN03132167 - 3132181
22 22 Exhibit 5 . . . . . . . . . . . . . . . . 31
23 23 Hikma proposed labeling; WWICO-NV-002835 -
24 24 2843
25 25
2
002
Page 6 Page 7
1 EXHIBIT INDEX (Cont.'d) 1 EXHIBIT INDEX (Cont.'d)
2 PAGE 2 PAGE
3 Exhibit 6 . . . . . . . . . . . . . . . . 31 3 Exhibit 11 . . . . . . . . . . . . . . . . 107
4 Dr. Reddy's proposed labeling; 4 Prescribing information;
5 DRLEEPA 0095591 - 95647 5 AMRN-PEXP-0009835 - 9879
6 Exhibit 7 . . . . . . . . . . . . . . . . 49 6 Exhibit 12 . . . . . . . . . . . . . . . . 113
7 Guidance for Industry, Distributing 7 Indications and Usage Section of Labeling
8 Scientific and Medical Publications on 8 for Human Prescription Drug and Biological
9 Unapproved New Uses, Recommended 9 Products, Content and Format;
10 Practices 10 AMRN-PEXP-0010242 - 10261
11 Exhibit 8 . . . . . . . . . . . . . . . . 89 11 Exhibit 13 . . . . . . . . . . . . . . . . 135
12 Center for Drug Evaluation and Research, 12 Guidance for Industry, Clinical Studies
13 Application Number: 202057Orig1s000, 13 Section of Labeling for Human Prescription
14 Medical Review(s); ICOSAPENT_DFNDT00015424 14 Drug and Biological Products, Content and
15 15567 15 Format; AMRN-PEXP-0010187 - 10211
16 Exhibit 9 . . . . . . . . . . . . . . . . 99 16
17 Guidance for Industry, Dosage and 17
18 Administration Section of Labeling for 18
19 Human Prescription Drug and Biological 19
20 Products, Content and Format; 20
21 AMRN-PEXP-0010229 - 10241 21
22 Exhibit 10 . . . . . . . . . . . . . . . . 105 22
23 Prescribing information; 23
24
24 ICOSAPENT_DFNDT00015711 - 15751
25 25
Page 8 Page 9
1 ------------------------------------------------- 1 Whereupon,
2 PROCEEDINGS 2 PETER R. MATHERS,
3 9:01 a.m. 3 after having been first duly sworn or affirmed,
4 ------------------------------------------------- 4 was examined and did testify under oath as
5 THE VIDEOGRAPHER: This is the start 09:01 5 follows:
6 of tape labeled number 1 of the videotaped 09:01 6 EXAMINATION
7 deposition of Peter Mathers, in the matter 09:01 7 BY MR. SIPES: 09:02
8 of Amarin Pharma, Inc., et al. v. Hikma 09:01 8 Q. Mr. Mathers, could you please state 09:02
9 Pharmaceuticals USA, et al., in the court: 09:01 9 your name and spell it for the record. 09:02
10 United States District Court for the 09:01 10 A. Peter Mathers, P-e-t-e-r, 09:02
11 District of Nevada, Case Number 09:01 11 M-a-t-h-e-r-s. 09:02
12 2:16-cv-02525-MMD-NLK. 09:01 12 Q. And where do you reside? 09:02
13 This deposition is being held at 1700 09:01 13 A. In Chevy Chase, Maryland. 09:02
14 K Street, Northwest, Washington, D.C., on 09:01 14 Q. And are you currently employed? 09:02
15 June 27, 2019, at approximately 9:02. 09:01 15 A. Yes, I am. 09:02
16 My name is David Chroniger from TSG 09:02 16 Q. And where are you employed? 09:02
17 Reporting, Inc., and I am the legal video 09:02 17 A. I'm employed at Kleinfeld Kaplan & 09:02
18 specialist. The court reporter is John 09:02 18 Becker, LLP, in Washington, D.C. 09:02
19 Harmonson in association with TSG Reporting. 09:02 19 Q. You've been deposed before, correct? 09:03
20 Will counsel please introduce 09:02 20 A. I have. 09:03
21 yourselves. 09:02 21 Q. Roughly how many times? 09:03
22 (Whereupon, counsel placed their 22 A. Five or six. 09:03
23 appearances on the video record.) 23 MR. SIPES: Why don't we pause for a 09:03
24 24 minute for anyone who is on the phone to 09:03
25 25 identify themselves. 09:03
3
003
Page 10 Page 11
1 MS. FINKELSTEIN: This is Beth 09:03 1 reporter right here who will be typing your 09:04
2 Finkelstein from Windels Marx on behalf of 09:03 2 responses, so you must answer the questions 09:04
3 the Dr. Reddy's defendants. 09:03 3 audibly with verbal responses. Do you 09:04
4 MR. SIPES: Is there anyone else on 09:03 4 understand? 09:04
5 the phone? 09:03 5 A. Yes. 09:04
6 All right. 09:03 6 Q. Is there any reason why you cannot 09:04
7 BY MR. SIPES: 09:03 7 give complete and truthful testimony today? 09:04
8 Q. So, Mr. Mathers, I'm sure you're quite 09:03 8 A. No. 09:04
9 familiar with the deposition process, but I'll 09:03 9 Q. You are not on any drugs or any 09:04
10 just go over a few of the ground rules anyway. 09:03 10 medical conditions that would impair your ability 09:04
11 You understand that you are under oath 09:03 11 to answer truthfully, correct? 09:04
12 today and are required to answer my questions 09:03 12 A. No, I'm not. 09:04
13 truthfully, correct? 09:03 13 Q. You were retained to provide opinions 09:04
14 A. Yes. 09:03 14 regarding issues relating to patent infringement 09:04
15 Q. If you don't understand a question, 09:03 15 in this case, correct? 09:04
16 please let me know and I'll attempt to clarify 09:03 16 A. Relating to patent infringement, yes. 09:04
17 it. Otherwise I will assume you understood it. 09:03 17 Q. Who retained you to provide those 09:04
18 Is that fair? 09:03 18 opinions? 09:04
19 A. Yes. 09:03 19 A. A company called Hikma and also 09:04
20 Q. This is not an endurance test. If at 09:03 20 Dr. Reddy's. 09:04
21 some point you need to take a break, we'll try to 09:04 21 Q. So you're here to provide testimony on 09:04
22 accommodate you. I just ask that you answer any 09:04 22 behalf of both the Hikma and Dr. Reddy's 09:04
23 pending question first. Is that all right? 09:04 23 defendants, correct? 09:04
24 A. All right. 09:04 24 A. Yes. 09:04
25 Q. You understand that there is a court 09:04 25 MR. SIPES: Let me ask the court 09:05
Page 12 Page 13
1 reporter to mark this as Mathers Exhibit 1. 09:05 1 A. Yes. 09:06
2 (Exhibit 1 marked for identification 2 Q. Did you sign your expert report on or 09:06
3 and attached hereto.) 3 about May 10th of 2019? 09:06
4 BY MR. SIPES: 09:05 4 A. Yes, I did. 09:06
5 Q. Mr. Mathers, I've asked the court 09:05 5 Q. And is it okay if we refer to Mathers 09:06
6 reporter to mark as Mathers Exhibit 1 a document 09:05 6 Exhibit 1 as your report in this case? 09:06
7 entitled "Rebuttal Expert Report of Peter R. 09:05 7 A. Sure. 09:06
8 Mathers on Non-Infringement of the Asserted 09:05 8 Q. And then you'll see above your 09:06
9 Claims for the Patents-in-Suit." 09:05 9 signature it says: "I hereby declare that all of 09:06
10 Do you see that? 09:05 10 the statements made herein are true of my own 09:06
11 A. Yes. 09:05 11 knowledge and that all statements made on 09:06
12 Q. And this is your expert report in this 09:05 12 information and belief are believed to be true; 09:06
13 matter, correct? 09:05 13 and further that these statements were made with 09:06
14 A. Yes, it is. 09:05 14 knowledge that willful false statements and the 09:06
15 Q. And is this the only report that you 09:05 15 like so made are punishable by fine or 09:06
16 prepared for this case? 09:05 16 imprisonment, or both, under Section 1001 of 09:06
17 A. Yes. 09:05 17 Title 18 of the United States Code." 09:06
18 Q. And if you'll turn to the last page of 09:05 18 Do you see that? 09:06
19 the report, which is page 72, do you see there is 09:05 19 A. Yes. 09:06
20 a signature? 09:05 20 Q. So you understand that the opinions 09:06
21 A. Yes. 09:05 21 you express in your report are your sworn 09:06
22 Q. Is that your signature? 09:05 22 testimony in this case? 09:06
23 A. Yes, it is. 09:05 23 A. Yes. 09:06
24 Q. And then above -- and by your 09:05 24 Q. And do you believe that the statements 09:06
25 signature is the date May 10, 2019? 09:06 25 you make in your report are true and correct? 09:06
4
004
Page 14 Page 15
1 A. Yes. 09:06 1 the Winston & Strawn lawyers are representing 09:07
2 Q. And did you review the report 09:06 2 Hikma? 09:07
3 carefully before signing it to make sure that it 09:06 3 A. Yes. 09:07
4 was true and correct? 09:07 4 Q. Did you work at all with any of the 09:07
5 A. Yes, I did. 09:07 5 attorneys representing Dr. Reddy's Labs? 09:07
6 Q. Did anyone help you prepare your 09:07 6 A. I believe in some meetings that I had 09:08
7 report? 09:07 7 that they were on the phone, on a conference 09:08
8 A. I prepared it in conjunction with the 09:07 8 call, but I don't remember meeting any of them. 09:08
9 attorneys at Winston & Strawn. 09:07 9 Q. And are you confident, sitting here 09:08
10 Q. And tell me about the drafting 09:07 10 today, that the opinions expressed in the report 09:08
11 process. How did the drafting process work? 09:07 11 reflect your truthful opinions? 09:08
12 A. We discussed the issues involved and 09:07 12 A. Yes. 09:08
13 came up with a draft that ultimately was massaged 09:07 13 Q. And are you aware of any errors or 09:08
14 into this version of the report. 09:07 14 other corrections you would like to make in your 09:08
15 Q. And when you say "massaged," what do 09:07 15 report? 09:08
16 you mean? 09:07 16 A. There are a couple of instances that I 09:08
17 A. Well, there were -- there were drafts 09:07 17 might clarify if I were questioned about them. 09:08
18 that were revised. 09:07 18 Q. Could you give me some examples? 09:08
19 Q. And did you revise the drafts? 09:07 19 A. Well, without finding them, after 09:08
20 A. Yes. 09:07 20 reviewing Dr. Peck's report, P-e-c-k, his report, 09:09
21 Q. Did lawyers at Winston & Strawn revise 09:07 21 I noticed some of his characterizations of my 09:09
22 the draft? 09:07 22 comments and thought that they were 09:09
23 A. Yes, I think they made some changes to 09:07 23 mischaracterizations. And when I looked at my 09:09
24 it. 09:07 24 statement, I felt like maybe it could have been 09:09
25 Q. Did you work -- do you understand that 09:07 25 worded more specifically so that he wouldn't be 09:09
Page 16 Page 17
1 able to mischaracterize it. 09:09 1 which the drug might be prescribed to someone who 09:11
2 Q. Could you give me some examples in 09:09 2 is on a Western diet. They would be 09:11
3 your report? 09:09 3 transitioned. 09:11
4 A. The example I'm thinking of is about 09:09 4 Q. So it would be consistent with the 09:11
5 the Western diet issue where he read my report as 09:09 5 labeling for a physician to counsel a patient 09:11
6 suggesting that it would be off-label if Vascepa 09:09 6 with very high triglycerides and administer 09:11
7 was prescribed to a patient who had been on a 09:09 7 Vascepa at the same time? 09:11
8 Western diet before they got the drug. And that 09:09 8 A. Yes. The requirement is that the -- 09:11
9 was not my intention to say, that that would be 09:09 9 the indication is that Vascepa is an adjunct to 09:11
10 off label because they were using it before they 09:10 10 diet and -- as elaborated in the rest of the 09:11
11 got the drug. But my statement was -- wasn't 09:10 11 indication statement, and that's what I -- I 09:11
12 that specific and could have been -- and for that 09:10 12 think that's consistent. 09:11
13 reason I thought it was misconstrued. 09:10 13 Q. Are there any other clarifications 09:11
14 Q. So is it your opinion that a patient 09:10 14 that you would like to make, that you're aware 09:11
15 who is receiving a Western diet and then receives 09:10 15 that you would like to make, sitting here? 09:11
16 both dietary counseling and is administered 09:10 16 A. Not that I recall. 09:11
17 Vascepa by a doctor is on label? 09:10 17 Q. So other than that one clarification 09:11
18 MS. FUNDAKOWSKI: Objection; form. 09:10 18 about Western diet, to the best of your knowledge 09:11
19 BY MR. SIPES: 09:10 19 right now, your report is truthful and accurate 09:11
20 Q. Do you understand the question? 09:10 20 and as clear as you would like it? 09:11
21 A. Well, what I -- what I meant to say is 09:10 21 A. Yes. I'm not remembering another 09:12
22 that I -- I did not intend to say that someone 09:10 22 instance, but Dr. Peck characterized a number of 09:12
23 who was on a Western diet could not then be 09:10 23 my statements and, if I had to clarify them, I 09:12
24 prescribed Vascepa in the scenario that you 09:10 24 would do so. 09:12
25 describe. That seems like the typical way in 09:10 25 Q. When were you first retained in this 09:12
5
005
Page 18 Page 19
1 matter? 09:12 1 Pharmaceuticals is related to West-Ward? 09:13
2 A. I believe it was mid-April. 09:12 2 A. Yes. 09:13
3 Q. Mid-April of 2019? 09:12 3 Q. Have you ever done any advisory work 09:13
4 A. Yes. 09:12 4 for West-Ward? 09:13
5 Q. And who retained you? Scratch that. 09:12 5 A. If I did, it was a long time ago. 09:13
6 Who first reached out to you? 09:12 6 Q. Like 20 years ago or more? 09:13
7 A. The name is escaping me, but it's a 09:12 7 A. 15 or more. And I'm not sure whether 09:14
8 colleague of Ms. Fundakowski at Winston & Strawn. 09:12 8 I was engaged by West-Ward or was addressing 09:14
9 Q. Okay. And when you were first 09:12 9 issues involving West-Ward on behalf of another 09:14
10 retained, were you retained on behalf of both 09:12 10 client. So I'm familiar with the name and I have 09:14
11 companies, or were you first retained by Hikma? 09:13 11 had things to do with products they sell but... 09:14
12 A. The engagement letter specifies both. 09:13 12 Q. And what products would those be? 09:14
13 I'm not sure when -- whether it was on the first 09:13 13 A. I don't recall. 09:14
14 call or whether it was a little bit later that I 09:13 14 Q. It was so long ago that you don't 09:14
15 found out that it was -- that the engagement 09:13 15 recall -- 09:14
16 would be for both companies. I wasn't focused on 09:13 16 A. Yes. 09:14
17 that. I'm not sure I was told until -- until the 09:13 17 Q. -- what drugs were involved? 09:14
18 engagement letter said so. 09:13 18 A. Definitely. 09:14
19 Q. Prior to your engagement in this 09:13 19 Q. You understand Hikma is actually the 09:14
20 matter, was Hikma a client of yours? 09:13 20 successor here to Roxane Pharmaceuticals? 09:14
21 A. No. 09:13 21 A. I'm not sure I knew that. 09:14
22 Q. Have you ever done any legal advisory 09:13 22 Q. Have you ever done any legal work for 09:14
23 work for Hikma? 09:13 23 Roxane Pharmaceuticals? 09:14
24 A. No. 09:13 24 A. Yes. Yes, and that was probably 20 09:14
25 Q. You're aware that Hikma 09:13 25 years ago. 09:14
Page 20 Page 21
1 Q. Okay. So do you recall what products 09:14 1 retained you to provide advice about a matter 09:16
2 were involved with your work for Roxane 09:14 2 that's recent enough that you can remember? 09:16
3 Pharmaceuticals? 09:14 3 A. That's correct. 09:16
4 A. I think our firm did some work for 09:14 4 Q. What did you do to prepare for today's 09:16
5 them on their opioid products, and I'm not sure 09:15 5 deposition? 09:16
6 what else. I'm wondering if they -- if 09:15 6 A. I had a meeting yesterday with 09:16
7 Boehringer had something to do with the GI 09:15 7 Ms. Fundakowski and one of her partners, and I 09:16
8 product that I was engaged as an expert for by 09:15 8 reviewed my report and also reviewed Dr. Peck's 09:16
9 Covington. But that's -- I'm not sure whether it 09:15 9 report when I got that a week or two ago. 09:16
10 was Roxane -- 09:15 10 Q. And did you review any other documents 09:16
11 Q. That would have been on the other 09:15 11 to prepare for the deposition? 09:16
12 side, you're talking about? 09:15 12 A. Last night I reviewed a decision in 09:17
13 A. Okay, there you go. 09:15 13 the -- of a district court in a decision -- in a 09:17
14 Q. So do you recall any work you did for 09:15 14 case brought by Amarin against FDA, a draft 09:17
15 Roxane Pharmaceuticals? 09:15 15 consent judgment that wasn't signed by the judge 09:17
16 A. Other than what I referred to from the 09:15 16 in that case but was signed by the parties. 09:17
17 '90s or before. 09:16 17 And that's what I remember reviewing. 09:17
18 Q. The opioids? 09:16 18 Q. The district court decision you 09:17
19 A. Yeah. 09:16 19 reviewed, did that concern the First Amendment? 09:17
20 Q. What about Dr. Reddy's Laboratories? 09:16 20 A. Yes. 09:17
21 Have you done any work for Dr. Reddy's 09:16 21 Q. Prior to last night, had you reviewed 09:17
22 Laboratories? 09:16 22 the court decision or the consent decree 09:17
23 A. I don't believe so. 09:16 23 previously in connection with forming opinions in 09:17
24 Q. So to the best of your recollection 09:16 24 this case? 09:17
25 sitting here, none of the defendants have ever 09:16 25 A. No. I was aware of that litigation, 09:17
6
006
Page 22 Page 23
1 that that litigation had occurred and the related 09:18 1 Exhibit 2 complete with regard to all of the 09:19
2 litigation for the Caronia case, but I had -- I 09:18 2 materials that you considered in forming your 09:19
3 hadn't taken that into account in drafting this 09:18 3 opinions in this case? 09:19
4 report, for instance. 09:18 4 A. Yes. 09:19
5 Q. And you don't discuss either that 09:18 5 Q. Did you have any conversations that 09:19
6 opinion or consent decree in your report, 09:18 6 helped you in forming your opinions or drafting 09:19
7 correct? 09:18 7 your report other than with lawyers? 09:19
8 A. Correct. 09:18 8 A. No. 09:19
9 MR. SIPES: I'll ask the court 09:18 9 Q. Have you ever spoken with any of the 09:19
10 reporter to mark this as Mathers Exhibit 2. 09:18 10 technical experts on either side of the case? 09:19
11 (Exhibit 2 marked for identification 11 A. No. 09:20
12 and attached hereto.) 12 Q. Did you have conversations with 09:20
13 BY MR. SIPES: 09:19 13 lawyers that helped you form your opinions in the 09:20
14 Q. Mr. Mathers, do you recognize Mathers 09:19 14 case? 09:20
15 Exhibit 2 as Exhibit 2 to your report entitled 09:19 15 A. Well, I discussed my opinions, and I 09:20
16 "Materials Considered in Rebuttal Expert Report 09:19 16 guess that was helpful. But they were my 09:20
17 of Peter R. Mathers on Non-Infringement of the 09:19 17 opinions. 09:20
18 Asserted Claims of the Patents-in-Suit"? 09:19 18 Q. Was there any -- 09:20
19 A. Yes. 09:19 19 A. They certainly assisted me with the 09:20
20 Q. Did you prepare Mathers Exhibit 2 or 09:19 20 descriptions of the patent law and the relevant 09:20
21 was it prepared for you? 09:19 21 standards that are set forth in the report. 09:20
22 A. I think the compilation of things that 09:19 22 Those are -- I think it says that those are 09:20
23 were considered was -- was prepared by Winston & 09:19 23 things that I don't otherwise have independent 09:20
24 Strawn. 09:19 24 expertise in. That's not the scope of my 09:20
25 Q. To the best of your knowledge, is 09:19 25 practice. 09:20
Page 24 Page 25
1 Q. So the patent law issues, the 09:20 1 and attached hereto.)
2 statements of patent law that you have in your 09:20 2 BY MR. SIPES: 09:22
3 report came from your conversations with counsel? 09:20 3 Q. Mr. Mathers, do you recognize Mathers 09:22
4 A. Yes. 09:20 4 Exhibit 3 as the curriculum vitae that you 09:22
5 Q. Is there anything else in the report 09:20 5 attached as Exhibit 1 to your report? 09:22
6 that would have come from your conversations with 09:20 6 A. Yes. 09:22
7 counsel? 09:20 7 Q. Is Mathers Exhibit 3 complete and 09:22
8 A. Well, I was made aware of some of the 09:21 8 accurate, to the best of your knowledge? 09:22
9 documents that are on this list, and certainly 09:21 9 A. Yes. 09:22
10 the patents are a good example of that. But also 09:21 10 Q. And just to confirm, you're not a 09:22
11 some of the expert panel reports and things like 09:21 11 physician, correct? 09:22
12 that that I hadn't had occasion to be -- to study 09:21 12 A. Correct. 09:22
13 or be aware of previously. 09:21 13 Q. Do you have any medical training? 09:22
14 Q. I take it the statements of regulatory 09:21 14 A. No. 09:22
15 law and of FDA review of labeling, those are 09:21 15 Q. Have you ever worked at FDA? 09:22
16 opinions you formed on your own, correct? 09:21 16 A. No. 09:22
17 A. Yes. 09:21 17 Q. You're not an expert in patent law, 09:22
18 Q. Have you spoken with anyone other than 09:21 18 correct? 09:22
19 lawyers about this matter? 09:21 19 A. Correct. 09:22
20 A. Other than the fact that I was 09:21 20 Q. Do you have any learning in lipid 09:22
21 undertaking it, no. Well, those were lawyers 09:21 21 science? 09:23
22 too. 09:21 22 A. I think that would be a stretch to 09:23
23 MR. SIPES: I'm going to ask the court 09:21 23 say. 09:23
24 reporter to mark this as Mathers Exhibit 3. 09:21 24 Q. So you would not -- 09:23
25 (Exhibit 3 marked for identification 25 A. No. 09:23
7
007
Page 26 Page 27
1 Q. You would not consider yourself an 09:23 1 A. Yes. 09:24
2 expert in lipid science? 09:23 2 Q. Do you have hypercholesterolemia? 09:24
3 A. No. 09:23 3 A. I think that's the right term. 09:24
4 Q. Do you have expertise in pharmacology? 09:23 4 Q. And so you have been diagnosed with 09:24
5 A. No. 09:23 5 hypercholestero -- strike that. 09:24
6 Q. You have no experience treating 09:23 6 You have high cholesterol? 09:24
7 hypertriglyceridemia? 09:23 7 A. I take Lipitor, and I've taken it for 09:24
8 A. Other than myself. 09:23 8 a long time. 09:24
9 Q. I'll come to that. 09:23 9 Q. And Lipitor is a statin? 09:24
10 A. Okay. 09:23 10 A. It is. 09:24
11 Q. You've never treated another person 09:23 11 Q. And you've been on Lipitor for a long 09:24
12 with hypertriglyceridemia? 09:23 12 period of time? 09:24
13 A. No. 09:23 13 A. Yeah. Probably 15 years. 09:24
14 Q. And you have experience with being 09:23 14 Q. And do you come on and off Lipitor, or 09:24
15 treated with hypertriglyceridemia? 09:23 15 have you stayed on it continuously? 09:24
16 A. Well, I misstated that too. It's 09:23 16 A. I have -- well, the dose was increased 09:24
17 lipids generally. 09:23 17 over a period of time, maybe a year or two. But 09:24
18 Q. Okay. You have no experience yourself 09:23 18 I've been on that dose continuously since. 09:24
19 with hypertriglyceridemia? 09:23 19 Q. Do you have any experience with 09:24
20 A. Correct. 09:23 20 omega-3 nutritional supplements? 09:24
21 Q. And you have no experience with severe 09:23 21 A. I am familiar with them. 09:25
22 hypertriglyceridemia? 09:23 22 Q. Do you have any experience with them? 09:25
23 A. No. 09:23 23 A. I have -- nutritional supplements? 09:25
24 Q. You have experience with other lipid 09:23 24 I've taken them in the past. 09:25
25 abnormalities? 09:24 25 Q. Have you done any legal work in 09:25
Page 28 Page 29
1 connection with omega-3 nutritional supplements? 09:25 1 Q. Have you done any legal work with 09:26
2 A. I have not. 09:25 2 regard to dietary supplements, any dietary 09:26
3 Q. Have you done any legal work -- 09:25 3 supplement? 09:26
4 A. Well, wait a minute. No, I'm 09:25 4 A. Yes. 09:26
5 confusing it with a different supplement. No is 09:25 5 Q. Which dietary supplements? 09:26
6 the answer. 09:25 6 A. Well, our firm has a number of clients 09:26
7 Q. And just to be clear, do you have any 09:25 7 who make a range of dietary supplements. I've 09:26
8 work advising any company with regard to any 09:25 8 worked with them on some of those. The ones that 09:26
9 omega-3 product other than your work in this 09:25 9 I've worked on most extensively I believe are 09:26
10 case? 09:25 10 folic acid products or prenatal vitamins. 09:26
11 A. No, not myself. 09:25 11 Q. But to the best of your knowledge, 09:26
12 Q. So you've never done any work relating 09:25 12 none of the nutritional supplements that you have 09:26
13 to Omacor or Lovaza? 09:25 13 worked on contain any omega-3 fatty acids? 09:27
14 A. No. 09:25 14 A. It's -- when I used to be engaged by 09:27
15 Q. You've never done any work with regard 09:25 15 KV Pharmaceutical, they had a range of prenatal 09:27
16 to Vascepa? 09:25 16 vitamins that I think may have included a version 09:27
17 A. No. 09:25 17 that had fish oil in it, or omega-3 fatty acid. 09:27
18 Q. You've never done any work with regard 09:25 18 They labeled it as a prescription drug along with 09:27
19 to Epanova? 09:25 19 the other ingredients. I think it also had folic 09:27
20 A. No. 09:25 20 acid in it. But that was -- that's the only one 09:27
21 Q. You've never done any work with regard 09:25 21 I recall that might have had omega-3s in it. 09:27
22 to Omtryg? Scratch that. 09:25 22 Q. What was the name of the product? 09:27
23 You've never done any work with regard 09:25 23 A. I don't recall which one had -- had 09:27
24 to Omtryg? 09:26 24 that ingredient in it. 09:28
25 A. No. 09:26 25 Q. But that was regulated as a drug, not 09:28
8
008
Page 30 Page 31
1 a dietary supplement? 09:28 1 A. Yes. 09:29
2 A. It was labeled as a drug. 09:28 2 Q. So of those 15 hours, about how much 09:29
3 Q. It was labeled as a drug. All right. 09:28 3 of that time was spent drafting your expert 09:29
4 Roughly when was that work done? 09:28 4 report? 09:29
5 A. Probably in the 2000s, before 2010, 09:28 5 A. More than half. 09:29
6 while they were in business. 09:28 6 Q. So maybe about eight or nine hours? 09:29
7 Q. And do you recall which omega-3 fatty 09:28 7 A. Yeah. 09:29
8 acids were in the product? 09:28 8 Q. And about how much time have you spent 09:29
9 A. No. 09:28 9 preparing for the deposition? 09:29
10 Q. You're being compensated for your work 09:28 10 A. Well, including the review of 09:29
11 on this matter, correct? 09:28 11 Dr. Peck's report, probably another 15 hours. 09:29
12 A. Yes. 09:28 12 Q. So to the best of your recollection, 09:29
13 Q. And is your compensation coming from 09:28 13 you've spent about 30 hours so far in this 09:29
14 both of the defendants? 09:28 14 matter? 09:29
15 A. Yes. 09:28 15 A. Yes. 09:30
16 Q. And you're being compensated at a rate 09:28 16 MR. SIPES: Let's mark this as Mathers 09:30
17 of $770 an hour, correct? 09:28 17 Exhibit 4. 09:30
18 A. Yes. 09:28 18 (Exhibit 4 marked for identification
19 Q. Roughly how much time have you billed 09:28 19 and attached hereto.)
20 on the matter so far? 09:28 20 MR. SIPES: This is Mathers Exhibit 5. 09:30
21 A. I think it's been about -- well, prior 09:28 21 (Exhibit 5 marked for identification
22 to preparing for the deposition, I think it was 09:29 22 and attached hereto.)
23 about 15 hours. 09:29 23 MR. SIPES: And this is Mathers 09:30
24 Q. That would be the total time for 09:29 24 Exhibit 6. 09:30
25 learning about the case and preparing the report? 09:29 25 (Exhibit 6 marked for identification
Page 32 Page 33
1 and attached hereto.) 1 version of Dr. Reddy's proposed labeling that you 09:32
2 BY MR. SIPES: 09:31 2 reviewed in forming your opinions in this case, 09:32
3 Q. Mr. Mathers, I've asked the court 09:31 3 correct? 09:32
4 reporter to mark as Mathers Exhibit 4 the Amarin 09:31 4 A. Yes. 09:32
5 approved prescribing information from March of 09:31 5 Q. If you'll turn to your report, Mathers 09:32
6 2017. Do you see that? 09:31 6 Exhibit 1, Paragraph 71. 09:32
7 A. Yes. 09:31 7 A. Yes. 09:33
8 Q. And you'll confirm for me if you look 09:31 8 Q. You start: "For purposes of this 09:33
9 on Exhibit 2, the materials you reviewed, this is 09:31 9 case, I understand that there are no material 09:33
10 the version of the Vascepa labeling that you 09:31 10 differences between Vascepa and defendants' 09:33
11 reviewed in forming your opinions in the case, is 09:31 11 proposed ANDA products, which are generic 09:33
12 it not? This is on page 3 of Exhibit 2. 09:31 12 versions of Vascepa." 09:33
13 A. Yes. 09:31 13 Do you see that? 09:33
14 Q. And Mathers Exhibit 5 is the version 09:31 14 A. Yes. 09:33
15 of Hikma's proposed labeling for their icosapent 09:31 15 Q. So the infringement analysis that you 09:33
16 ethyl product that you reviewed in forming your 09:31 16 conducted is the same for Hikma's product, DRL's 09:33
17 opinions in this case? 09:31 17 product, and for Vascepa, correct? 09:33
18 A. I'm just checking the date. 09:32 18 A. I don't know if it's correct to call 09:33
19 Q. Sure. If you look at the Bates 09:32 19 it an infringement analysis, contributing to an 09:33
20 numbers you'll see -- 09:32 20 infringement analysis, but yes, that's -- my 09:33
21 A. I don't know if there was more than 09:32 21 report applies to both -- both of those proposed 09:33
22 one version. 09:32 22 labels. 09:33
23 Q. -- the Bates numbers will match. 09:32 23 Q. And to Vascepa labeling as well, 09:33
24 A. Okay. I agree that's it, then. 09:32 24 correct? 09:33
25 Q. And then Mathers Exhibit 6 is the 09:32 25 A. Yes. It's my understanding. I didn't 09:33
9
009
Page 34 Page 35
1 compare them word to word, but it's my 09:33 1 Q. Later you'll refer to the three 09:35
2 understanding that they're the same. 09:34 2 labels. Do you see that? 09:35
3 Q. So your analysis of the application of 09:34 3 A. Yes. 09:35
4 the inducement standard is the same for Vascepa, 09:34 4 Q. There's other times further down, in 09:35
5 Hikma's proposed product, and DRL's proposed 09:34 5 the bottom line for example, you refer to the 09:35
6 product, correct? 09:34 6 draft labeling. Do you see that? 09:35
7 MS. FUNDAKOWSKI: Objection; form. 09:34 7 A. Yes. 09:35
8 THE WITNESS: I was not distinguishing 09:34 8 Q. And in Exhibit 2, for example, you 09:35
9 among the content of either -- any of those 09:34 9 refer to the package insert as well? 09:35
10 three. 09:34 10 A. Yes. 09:35
11 BY MR. SIPES: 09:34 11 Q. Is it correct that when you refer to 09:35
12 Q. So that if -- in your analysis you 09:34 12 the label, you mean the prescribing information 09:35
13 mostly discuss Vascepa's labeling in your report, 09:34 13 for the product, correct? 09:35
14 correct? 09:34 14 MS. FUNDAKOWSKI: Objection; form. 09:35
15 A. Yes. 09:34 15 THE WITNESS: Yes. I'm referring to 09:35
16 Q. But under your analysis, the same 09:34 16 the entire -- the entire document here I 09:35
17 analysis that you apply to Vascepa's labeling 09:34 17 regard as the label. Or it's officially 09:35
18 would apply equally to Hikma's proposed labeling 09:34 18 regarded as labeling, but sometimes I and 09:35
19 and DRL's proposed labeling, correct? 09:34 19 others call it a label. 09:35
20 A. Yes. 09:34 20 BY MR. SIPES: 09:35
21 Q. Now, if you'll look in Paragraph 71, 09:34 21 Q. You're using the terms "label," 09:35
22 at one point you refer to the approved 09:34 22 "labeling" and "package insert" and "prescribing 09:35
23 prescribing information. Do you see that? 09:35 23 information" interchangeably in your report, 09:35
24 That's in the second sentence. 09:35 24 correct? 09:36
25 A. Yes. 09:35 25 A. Yes. And to include both the -- the 09:36
Page 36 Page 37
1 specific prescribing information directed at 09:36 1 regulations, correct? 09:37
2 prescribers but also the information included 09:36 2 A. Yes. 09:37
3 which is directed at patients, the patient 09:36 3 Q. And that is a correct statement of the 09:37
4 information. 09:36 4 law, generic applicants can attempt to omit 09:37
5 Q. And for purposes of today's 09:36 5 aspects of a listed drug's labeling that are 09:37
6 deposition, is it okay if we also use the terms 09:36 6 protected by a patent so long as the differences 09:37
7 "label," "labeling," "prescribing information" 09:36 7 don't render the proposed drug product less safe 09:37
8 and "package insert" interchangeably? 09:36 8 or effective than the reference listed drug for 09:37
9 A. That would be fine. 09:36 9 all remaining non-protected conditions of use, 09:37
10 Q. Now, defendants did not change or omit 09:36 10 correct? 09:37
11 any material information from the Vascepa 09:36 11 A. Yes. 09:37
12 labeling in drafting their own proposed labeling, 09:36 12 Q. Neither DRL nor Hikma tried to omit 09:37
13 correct? 09:36 13 any portion of Vascepa labeling covered by 09:37
14 A. I believe that's correct. 09:36 14 Amarin's patents, correct? 09:37
15 Q. Now, if you look in Paragraph 70 of 09:36 15 A. I don't know if they tried or 09:37
16 your report, you note that "FDA regulations 09:36 16 considered. But the proposed labeling that I'm 09:37
17 permit ANDA applicants to omit aspects of the 09:36 17 aware of does not try to. 09:37
18 listed drug's labeling because those aspects are 09:36 18 Q. You have not investigated whether they 09:37
19 protected by patent, so long as the differences 09:37 19 had any discussions with FDA about potentially 09:38
20 do not render the proposed drug product less safe 09:37 20 omitting any portion of the labeling? 09:38
21 or effective than the reference listed drug for 09:37 21 A. I have not inquired and don't know if 09:38
22 all remaining non-protected conditions of use." 09:37 22 such discussions occurred. 09:38
23 Do you see that? 09:37 23 Q. But it is correct, for example, that 09:38
24 A. Yes. 09:37 24 neither DRL nor Hikma omitted any part of the 09:38
25 Q. And you're quoting a section of FDA's 09:37 25 Clinical Studies section, correct? 09:38
10
010
Page 38 Page 39
1 A. From their -- from their proposed 09:38 1 encourage, recommend, or promote infringement. I 09:39
2 prescribing information, no. 09:38 2 understand that merely describing an infringing 09:39
3 Q. In fact, FDA would not allow DRL or 09:38 3 mode is not the same as recommending, 09:39
4 Hikma to omit the description of the MARINE 09:38 4 encouraging, or promoting an infringing use, or 09:39
5 clinical trial from the generic labeling because 09:38 5 suggesting that an infringing use should be 09:39
6 doing so would render the generic product less 09:38 6 performed." 09:40
7 safe and effective for the treatment of severe 09:38 7 Do you see that? 09:40
8 hypertriglyceridemia than Vascepa, correct? 09:38 8 A. Yes. 09:40
9 MS. FUNDAKOWSKI: Objection; form. 09:38 9 Q. This is a statement that you got from 09:40
10 THE WITNESS: I haven't considered 09:38 10 lawyers, correct? 09:40
11 whether that might be permitted. 09:38 11 A. Yes. 09:40
12 BY MR. SIPES: 09:38 12 Q. The lawyers at Winston & Strawn gave 09:40
13 Q. So you do not have an opinion as to 09:38 13 you this statement that's in Paragraph 16, 09:40
14 whether or not they could carve out any portion 09:38 14 correct? 09:40
15 of the description of the MARINE clinical study 09:39 15 A. They gave me the explanation of that. 09:40
16 in their proposed labeling? 09:39 16 Q. You don't have an independent 09:40
17 A. That's correct. 09:39 17 understanding of the law of induced infringement, 09:40
18 Q. And you're not aware of whether or not 09:39 18 correct? 09:40
19 they even tried to do so? 09:39 19 A. Other than based on some discussion 09:40
20 A. Correct. 09:39 20 with Winston & Strawn about the case law this is 09:40
21 Q. I'm going to ask you to turn to 09:39 21 based on. But I didn't study that case law. 09:40
22 Paragraph 16. 09:39 22 Q. You deferred to the lawyers for 09:40
23 A. Yes. 09:39 23 Hikma -- 09:40
24 Q. You state: "I understand that in 09:39 24 A. Yes. 09:40
25 order to induce infringement, the label must 09:39 25 Q. -- in your understanding of inducement 09:40
Page 40 Page 41
1 to infringe? 09:40 1 connotation or nuance between the words 09:42
2 A. Yes. 09:40 2 "recommending," "encouraging," "promoting," or 09:42
3 Q. And do you have an understanding of 09:40 3 "suggesting." I think they generally have 09:42
4 the law of contributory infringement? 09:40 4 different meanings. So I wouldn't say that 09:42
5 A. As it's described starting on 09:40 5 they're the same. 09:42
6 Paragraph 18, that is my understanding of it. 09:40 6 Q. How would you distinguish between 09:42
7 Q. And your understanding of contributory 09:40 7 labeling that recommended infringing use and 09:42
8 infringement similarly came from your 09:41 8 labeling that suggested an infringing use? 09:42
9 conversations with the lawyers at Winston & 09:41 9 A. I think it would depend on -- on the 09:42
10 Strawn? 09:41 10 language and the context whether you could 09:42
11 A. Yes. 09:41 11 describe something as suggesting or recommending. 09:42
12 Q. You don't have any independent 09:41 12 But I don't know if it's a material difference. 09:42
13 understanding of the law of contributory 09:41 13 Q. For purposes of your opinions in this 09:42
14 infringement? 09:41 14 case, your view was that in order to induce 09:42
15 A. Correct. 09:41 15 infringement, the labeling must encourage, 09:42
16 Q. Okay. In Paragraph 16, when you refer 09:41 16 recommend, suggest, or promote the infringing 09:42
17 to an infringing mode, is that the same as an 09:41 17 use? 09:43
18 infringing use? 09:41 18 A. Correct. 09:43
19 A. Yes, I understand mode to refer to a 09:41 19 Q. And you, in Paragraph 61 of your 09:43
20 way of using the product. 09:41 20 report -- 09:43
21 Q. And then when you refer to -- when you 09:41 21 A. Well, I should clarify the previous 09:43
22 refer to suggesting that an infringing use should 09:41 22 answer. In order to infringe, the infringing use 09:43
23 be performed, is that the same as recommending an 09:41 23 needs to be recommended, encouraged, promoted, or 09:43
24 infringing use? 09:41 24 suggested, but that may not be enough if it 09:43
25 A. There -- there may be differences in 09:42 25 doesn't specifically encourage the patented use. 09:43
11
011
Page 66 Page 67
1 MS. FUNDAKOWSKI: Objection to form. 10:30 1 administration to patients with severe 10:31
2 THE WITNESS: No. What I'm saying is 10:30 2 hypertriglyceridemia whether or not they are 10:31
3 that they're not specifically recommending 10:30 3 receiving lipid-altering medication, correct? 10:31
4 the use of the product with -- they're not 10:30 4 A. Whether or not -- yes. 10:31
5 specifically suggesting that whether the 10:30 5 Q. It is an approved -- it is an approved 10:31
6 patient is or isn't using a statin is -- is 10:30 6 use of Vascepa to administer the product as an 10:31
7 relevant to the recommended use. They're 10:30 7 adjunct to diet to severely hypertriglyceridemic 10:31
8 not specifically recommending one way or the 10:30 8 patients who are not receiving other 10:31
9 other. They are making a general 10:30 9 lipid-altering medications, correct? 10:31
10 recommendation that it should be used 10:30 10 MS. FUNDAKOWSKI: Objection; form. 10:31
11 without regard to whether there's statins 10:30 11 THE WITNESS: It is within the 10:31
12 involved. 10:30 12 approved use to administer it to someone who 10:31
13 BY MR. SIPES: 10:30 13 is not taking any other lipid-altering 10:31
14 Q. To what patients does defendants' 10:30 14 agent. 10:32
15 proposed labeling instruct, encourage, and 10:30 15 BY MR. SIPES: 10:32
16 recommend administration of their product? 10:30 16 Q. It is an intended use of the product, 10:32
17 MS. FUNDAKOWSKI: Objection; form. 10:31 17 in FDA's view, to administer the product to 10:32
18 THE WITNESS: Well, it doesn't 10:31 18 severely hypertriglyceridemic patients who are 10:32
19 specifically recommend it to any patients. 10:31 19 not receiving other lipid-altering medications, 10:32
20 But the general patient population that it's 10:31 20 correct? 10:32
21 recommended for use in is the population 10:31 21 MS. FUNDAKOWSKI: Objection; form. 10:32
22 with severe hypertriglyceridemia. 10:31 22 THE WITNESS: As a general matter, 10:32
23 BY MR. SIPES: 10:31 23 it's within the scope of the approved and 10:32
24 Q. And defendants' proposed labeling 10:31 24 indicated use. 10:32
25 recommends, encourages, and instructs 10:31 25 BY MR. SIPES: 10:32
Page 68 Page 69
1 Q. And moreover, the administration of 10:32 1 Q. So an intended use of the product 10:33
2 the product to severely hypertriglyceridemic 10:32 2 described in the labeling is administration of 10:33
3 patients who are not on other lipid-altering 10:32 3 the product to severely hypertriglyceridemic 10:33
4 medications is expressly described in the 10:32 4 patients who are not receiving other 10:33
5 Clinical Studies section, correct? 10:32 5 lipid-altering medications, correct? 10:33
6 MS. FUNDAKOWSKI: Objection; form. 10:32 6 MS. FUNDAKOWSKI: Objection; form. 10:33
7 THE WITNESS: The population of the 10:32 7 THE WITNESS: It is within the 10:33
8 study is described in the Clinical Studies 10:32 8 indication statement and the clinical -- the 10:33
9 section, and it mentions that 25 percent of 10:32 9 clinical data section doesn't -- doesn't 10:33
10 the patients, I believe the number was, were 10:32 10 include a limitation on that. And no other 10:34
11 on statins and suggesting that 75 percent 10:32 11 part of the labeling includes a limitation 10:34
12 were not -- 10:32 12 either. 10:34
13 BY MR. SIPES: 10:32 13 BY MR. SIPES: 10:34
14 Q. So -- 10:32 14 Q. It's more than the Clinical Studies 10:34
15 A. -- in that study population. 10:32 15 section doesn't include a limitation. The 10:34
16 Q. So the defendants' proposed labeling 10:33 16 Clinical Studies section describes administration 10:34
17 describes in the Clinical Studies section 10:33 17 of the product to patients who are not on a 10:34
18 administration of Vascepa to severely 10:33 18 lipid-altering medication, correct? 10:34
19 hypertriglyceridemic patients who are not on 10:33 19 A. It describes that some of the patients 10:34
20 other lipid-altering medications, correct? 10:33 20 were taking statins and some of them were not. 10:34
21 A. It describes that they were included 10:33 21 Q. And a prescriber who prescribed a 10:34
22 in the study. 10:33 22 product -- scratch that. 10:34
23 Q. And that they were administered 10:33 23 A prescriber who prescribed Vascepa as 10:34
24 Vascepa, correct? 10:33 24 an adjunct to diet to reduce triglycerides in 10:34
25 A. Yes, in a study. 10:33 25 severely hypertriglyceridemic patients who are 10:34
18
012
Page 70 Page 71
1 not on other lipid-altering medications would be 10:34 1 "The Clinical Pharmacology section affirmatively 10:36
2 administering the product in accordance with the 10:34 2 instructs that Vascepa can be safely 10:36
3 approved labeling, correct? 10:35 3 co-administered statins, explaining that 'no 10:36
4 MS. FUNDAKOWSKI: Objection; form. 10:35 4 drug-drug interactions were observed' when 10:36
5 THE WITNESS: Yes. 10:35 5 Vascepa was co-administered with atorvastatin." 10:36
6 BY MR. SIPES: 10:35 6 Do you see that? 10:36
7 Q. That would be an on-label use, 10:35 7 A. Yes. 10:36
8 correct? 10:35 8 Q. And atorvastatin is another name for 10:36
9 A. It would not be off label. 10:35 9 Lipitor, correct? 10:36
10 Q. Do you distinguish between not being 10:35 10 A. Yes. 10:36
11 off label and being on label? 10:35 11 Q. That, as I recall, is the particular 10:36
12 A. Only in the sense that it's not -- 10:35 12 statin you happen to be on, correct? 10:36
13 it's not specifically recommended one way or 10:35 13 A. Yes. 10:36
14 another, but the distinction would be subtle if 10:35 14 Q. And so it's your sworn testimony that 10:36
15 there is one. 10:35 15 the Clinical Pharmacology section of the Vascepa 10:36
16 Q. So you would agree that some 10:35 16 labeling affirmatively instructs that Vascepa can 10:36
17 prescribers will follow the Vascepa labeling to 10:35 17 be safely co-administered with statins, correct? 10:36
18 administer their products to adult patients with 10:35 18 A. Yes. 10:36
19 severe hypertriglyceridemia who are not on a 10:35 19 Q. And similarly, defendants' proposed 10:37
20 statin or other lipid-altering drug, correct? 10:35 20 labeling affirmatively instructs through its 10:37
21 MS. FUNDAKOWSKI: Objection; form. 10:35 21 Clinical Pharmacology section that their products 10:37
22 THE WITNESS: They could do that. 10:35 22 can be safely administered with a statin, 10:37
23 BY MR. SIPES: 10:35 23 correct? 10:37
24 Q. Let me ask you to turn to Paragraph 10:35 24 A. The generic products? 10:37
25 196 of your report. You state in Paragraph 196: 10:35 25 Q. Correct. 10:37
Page 72 Page 73
1 A. Yes. 10:37 1 A. It instructs that you could do it. 10:38
2 Q. Do you want me to restate the 10:37 2 Q. So the proposed labeling affirmatively 10:38
3 question? 10:37 3 instructs that Vascepa can safely be 10:38
4 A. Yes, it's the same answer. 10:37 4 co-administered with a statin, correct? 10:38
5 Q. So in your view, the labeling, by 10:37 5 A. Yes. 10:38
6 instructing that there is no safety issue with 10:37 6 Q. And -- but the Clinical Pharmacology 10:38
7 co-administration with a statin, affirmatively 10:37 7 section doesn't describe the effective use of the 10:38
8 instructs physicians that it may be used that 10:37 8 product, correct? 10:38
9 way? 10:37 9 A. Which product? 10:38
10 MS. FUNDAKOWSKI: Objection; form. 10:37 10 Q. Of Vascepa. The clinical pharmacology 10:38
11 THE WITNESS: Well, it doesn't -- it 10:37 11 that you're quoting here, that no drug-drug 10:38
12 doesn't recommend one way or the other 10:37 12 interaction, that's a safety issue, correct? 10:38
13 whether you should take it with statins 10:37 13 A. Well, it could be an efficacy issue if 10:39
14 because that's a separate judgment to be 10:37 14 there was an interaction. But it's -- it's 10:39
15 made. But it doesn't -- it doesn't warn 10:38 15 not -- it's not addressing -- it doesn't say 10:39
16 about it or suggest that there would be a 10:38 16 whether it's addressing safety or effectiveness. 10:39
17 problem with doing so. 10:38 17 It simply says there were no interactions 10:39
18 BY MR. SIPES: 10:38 18 observed. 10:39
19 Q. Your phrase is "affirmatively 10:38 19 Q. I'm just looking at your statement, 10:39
20 instruct," correct? 10:38 20 Mr. Mathers. In Paragraph 196 you state that 10:39
21 A. Yes, I think I said that it did not 10:38 21 "The Clinical Pharmacology section affirmatively 10:39
22 affirmatively instruct that you should do it. 10:38 22 instructs that Vascepa can be safely 10:39
23 Q. Let's be clear. If you'll turn to 10:38 23 co-administered with states." 10:39
24 Paragraph 196 of your report. You state that it 10:38 24 A. Yes. 10:39
25 does affirmatively instruct, correct? 10:38 25 Q. So you're referring to the safe use of 10:39
19
013
Page 74 Page 75
1 the product, correct? 10:39 1 conclude that it's within the scope of the 10:40
2 A. That's correct. 10:39 2 approval. And that if the physician 10:40
3 Q. The instruction that Vascepa can 10:39 3 otherwise felt that a patient required a 10:40
4 effectively be used to treat severe 10:39 4 statin or didn't require a statin, they 10:40
5 hypertriglyceridemia when co-administered with a 10:39 5 could -- they could -- they could prescribe 10:40
6 statin is in the Clinical Studies section, 10:39 6 Vascepa with or without a statin. 10:41
7 correct? 10:39 7 BY MR. SIPES: 10:41
8 MS. FUNDAKOWSKI: Objection; form. 10:39 8 Q. Now, in Paragraph 120 of your report 10:41
9 THE WITNESS: I don't think the 10:39 9 you state the Clinical Studies section "suggests 10:41
10 Clinical Studies section suggests that it -- 10:39 10 that Vascepa can be safely and effectively 10:41
11 makes a specific statement about whether -- 10:40 11 administered to patients without regard to 10:41
12 makes a specific statement distinguishing 10:40 12 concomitant statin therapy, diabetes, or 10:41
13 between use with or without statins. It 10:40 13 triglyceride levels over 750 milligrams per 10:41
14 simply points out that the patient 10:40 14 deciliter." 10:41
15 population -- within the patient population 10:40 15 Do you see that? 10:41
16 in the study, some took statins and some did 10:40 16 A. Yes. 10:41
17 not. 10:40 17 Q. And that's your testimony, correct? 10:41
18 BY MR. SIPES: 10:40 18 A. Yes, that none of those distinctions 10:41
19 Q. Would a person -- would a physician 10:40 19 were found by FDA to affect the safety or 10:41
20 reading the Vascepa labeling understand that the 10:40 20 effectiveness of the drug. 10:41
21 product can be safely and effectively 10:40 21 Q. So a person of ordinary skill in the 10:41
22 co-administered with a statin? 10:40 22 art -- scratch that. 10:41
23 MS. FUNDAKOWSKI: Objection; form. 10:40 23 A physician would understand from the 10:41
24 THE WITNESS: A physician would see no 10:40 24 Clinical Studies section of the Vascepa labeling 10:41
25 restriction on that use, and so would 10:40 25 that Vascepa can be safely and effectively 10:41
Page 76 Page 77
1 administered to patients without regard to 10:42 1 Q. The Clinical Studies section of the 10:43
2 concomitant statin therapy, correct? 10:42 2 Vascepa labeling affirmatively instructs that 10:43
3 MS. FUNDAKOWSKI: Objection; form. 10:42 3 Vascepa can be safely and effectively 10:43
4 THE WITNESS: Yes. The physician 10:42 4 administered to patients who are not receiving 10:43
5 would understand that there is -- that the 10:42 5 concomitant statin therapy or other 10:43
6 use of concomitant statin therapy would not 10:42 6 lipid-altering medication, correct? 10:43
7 affect the safe and effective use of the 10:42 7 MS. FUNDAKOWSKI: Objection; form. 10:43
8 drug. 10:42 8 THE WITNESS: Well, the Clinical Data 10:43
9 BY MR. SIPES: 10:42 9 section doesn't affirmatively instruct 10:43
10 Q. So a physician would understand from 10:42 10 anything. It describes a study in which 10:43
11 the Clinical Studies section of the Vascepa 10:42 11 some patients received statins and some 10:43
12 labeling that Vascepa can be safely and 10:42 12 patients didn't. And the overall conclusion 10:44
13 effectively administered to patients who are not 10:42 13 was reached that the drug was effective in 10:44
14 receiving concomitant statin therapy or other 10:42 14 lowering triglycerides in that overall 10:44
15 lipid-altering medication? 10:42 15 patient population. I don't know that there 10:44
16 MS. FUNDAKOWSKI: Objection; form. 10:42 16 is -- the label certainly doesn't indicate 10:44
17 THE WITNESS: I would give the same 10:42 17 that a specific determination was made, and 10:44
18 answer. Yes. 10:42 18 if there was one, it's not reflected in the 10:44
19 BY MR. SIPES: 10:42 19 labeling, that patients on statins had 10:44
20 Q. And would you say that the Clinical 10:42 20 exactly the same experience as people 10:44
21 Studies section affirmatively instructs that 10:43 21 without statins. It doesn't discuss a 10:44
22 Vascepa can be safely and effectively 10:43 22 supplemental analysis. 10:44
23 administered to patients without regard to 10:43 23 So that's why I'm not -- I don't think 10:44
24 concomitant statin therapy? 10:43 24 I'm agreeing that the -- that that section 10:44
25 A. Yes. 10:43 25 is instructing that you should take it one 10:44
20
014
Page 78 Page 79
1 way or the other. 10:44 1 physician that a specific determination of 10:46
2 BY MR. SIPES: 10:44 2 that was made. 10:46
3 Q. But it certainly is instructing that 10:44 3 BY MR. SIPES: 10:46
4 the drug is safe and effective either with or 10:44 4 Q. Would a physician, reading the Vascepa 10:46
5 without co-administration of other lipid-altering 10:45 5 labeling, understand that the Vascepa product was 10:46
6 medication? 10:45 6 safe and effective when co-administered with a 10:46
7 MS. FUNDAKOWSKI: Objection; form. 10:45 7 statin? 10:46
8 THE WITNESS: It's describing the data 10:45 8 MS. FUNDAKOWSKI: Objection; form. 10:46
9 on which FDA decided that the indication 10:45 9 THE WITNESS: As I said, I think -- I 10:46
10 statement was appropriate, and the 10:45 10 don't know if a physician would -- would be 10:46
11 indication statement does include that 10:45 11 able to conclude from the labeling that a 10:46
12 limitation. 10:45 12 specific determination would have been made, 10:46
13 BY MR. SIPES: 10:45 13 but the general determination had been made 10:46
14 Q. Which is to say -- scratch that. 10:45 14 and is reflected in the indication statement 10:46
15 A physician would understand from the 10:45 15 that the drug can safely and effectively be 10:46
16 labeling that the drug is safe and effective to 10:45 16 used without regard to whether it's being 10:47
17 be used in co-administration with a statin? 10:45 17 given with a statin. 10:47
18 MS. FUNDAKOWSKI: Objection; form. 10:45 18 BY MR. SIPES: 10:47
19 THE WITNESS: I think the physician 10:45 19 Q. Turn to Paragraph 43 of your report. 10:47
20 would understand that FDA approved the drug 10:45 20 You state: "The approved use of Vascepa is 10:47
21 for use to reduce triglycerides without -- 10:45 21 silent as a duration of treatment with Vascepa, 10:47
22 without regard to whether the person was 10:45 22 and accordingly leaves the duration of treatment 10:47
23 taking statins or not. And I don't know if 10:45 23 up to the discretion of the prescriber." 10:47
24 that's -- if that would -- I don't know if 10:45 24 Do you see that? 10:47
25 that reflects or would indicate to a 10:46 25 A. Yes. 10:47
Page 80 Page 81
1 Q. And is that your sworn testimony? 10:47 1 Dosage and Administration section include, quote, 10:49
2 A. Yes. 10:47 2 "the usual duration of treatment when treatment 10:49
3 Q. The defendants' proposed labeling does 10:47 3 duration should be limited." You quote that, 10:49
4 not limit the duration of treatment with the ANDA 10:47 4 correct? 10:49
5 product and leaves the duration of treatment up 10:47 5 A. Yes. 10:49
6 to the discretion of the prescriber as well, 10:47 6 Q. And neither the Vascepa labeling nor 10:49
7 correct? 10:48 7 defendants' proposed labeling includes the usual 10:49
8 A. Correct. 10:48 8 duration of treatment in the Dosage 10:49
9 Q. A prescriber would understand that if 10:48 9 Administration section, correct? 10:49
10 there were a safety or efficacy reason to limit 10:48 10 A. That's correct. 10:49
11 the duration of treatment, the labeling would 10:48 11 Q. Nothing in the Vascepa labeling or the 10:50
12 state that, correct? 10:48 12 defendants' proposed labeling contains a 10:50
13 MS. FUNDAKOWSKI: Objection; form. 10:48 13 limitation of use concerning the duration of 10:50
14 THE WITNESS: I'm not sure what a 10:48 14 treatment, correct? 10:50
15 prescriber would specifically understand. 10:48 15 A. Nothing in which section, indications 10:50
16 But certainly in the absence of a warning or 10:48 16 and dosage? 10:50
17 limitation, the prescriber would assume that 10:48 17 Q. Nothing in the Vascepa labeling 10:50
18 the duration of treatment would be within 10:48 18 contains no -- scratch that. 10:50
19 the prescriber's discretion. 10:48 19 No section of the Vascepa labeling 10:50
20 BY MR. SIPES: 10:48 20 contains a limitation of use concerning the 10:50
21 Q. And if you look to Paragraph 132 of 10:48 21 duration of treatment, correct? 10:50
22 your report, you quote FDA's regulations of 21 10:48 22 A. I believe that's correct. 10:50
23 CFR Section 201.57(c)(3)(i)(F). Do you see that? 10:49 23 Q. And similarly, no section of 10:50
24 A. Yes. 10:49 24 defendants' proposed labeling contains a 10:50
25 Q. And FDA's regulations require that the 10:49 25 limitation of use concerning duration of 10:50
21
015
Page 82 Page 83
1 treatment, correct? 10:50 1 would understand that Vascepa was shown to be 10:52
2 A. That's correct. 10:50 2 effective in reducing triglycerides when patients 10:52
3 Q. Now, Paragraph 120 of your report, you 10:50 3 were evaluated at 12 weeks." 10:52
4 state that the Vascepa labeling suggests that 10:50 4 Do you see that? 10:52
5 Vascepa can be safely and effectively 10:51 5 A. Yes. 10:52
6 administered to patients for a period of 12 10:51 6 Q. The Clinical Studies section of 10:52
7 weeks. 10:51 7 defendants' proposed labeling instructs 10:52
8 Do you see that? 10:51 8 physicians that the product is safe and effective 10:52
9 A. Yes. 10:51 9 in reducing triglycerides after administration 10:52
10 Q. The Clinical Studies section of 10:51 10 for 12 weeks, correct? 10:52
11 defendants' proposed labeling suggests that their 10:51 11 MS. FUNDAKOWSKI: Objection; form. 10:52
12 products can be safely and effectively 10:51 12 THE WITNESS: It describes a study 10:52
13 administered to patients for a period of 12 10:51 13 result at 12 weeks which indicate that the 10:52
14 weeks, correct? 10:51 14 drug was effective and the -- and that the 10:52
15 A. Yes. 10:51 15 safety conclusions flow from that and other 10:52
16 Q. And in Paragraph 143 of your report 10:51 16 data. But yes, that is correct. 10:52
17 you state: "To be sure, a physician reading the 10:51 17 BY MR. SIPES: 10:53
18 Clinical Studies section of the label would 10:51 18 Q. In Paragraph 74 of your report you 10:53
19 understand that Vascepa was shown to be effective 10:51 19 state you're reviewing here the New Drug 10:53
20 in reducing triglycerides when patients were 10:51 20 Application that Amarin submitted to obtain the 10:53
21 evaluated at 12 weeks." Correct? 10:51 21 initial approval for Vascepa. Correct? 10:53
22 A. I'm sorry, which paragraph? 10:51 22 A. Yes. 10:53
23 Q. Sorry. In Paragraph 143 of your 10:52 23 Q. And you note: "Amarin also submitted 10:53
24 report. You state: "To be sure, a physician 10:52 24 data from a Phase III clinical study called 10:53
25 reading the Clinical Studies section of the label 10:52 25 ANCHOR." 10:53
Page 84 Page 85
1 Do you see that? 10:53 1 depends, correct? 10:54
2 A. Yes. 10:53 2 A. Yes. Usually you need a Phase III 10:54
3 Q. And what is a Phase III clinical 10:53 3 study that is successful and that supports the 10:55
4 study? 10:53 4 approval, and then FDA will rely on that. 10:55
5 A. It's a -- one of the last stages of 10:53 5 Q. And it's true, is it not, that Amarin 10:55
6 clinical study of a drug which is designed to 10:53 6 conducted a large Phase III clinical study 10:55
7 generate the -- it's designed generally as 10:54 7 entitled ANCHOR? Correct? 10:55
8 adequate and well-controlled studies that are 10:54 8 A. That's my understanding. 10:55
9 intended to support the approval and the 10:54 9 Q. And ANCHOR is all caps, correct? 10:55
10 indication statements and to lead to an approval. 10:54 10 A. It must stand for something. 10:55
11 Q. And the Phase III clinical studies 10:54 11 Q. The names of Phase III clinical 10:55
12 tend to follow Phase I and Phase II studies, 10:54 12 studies tend to be all caps, are they not? 10:55
13 correct? 10:54 13 A. That's because they're acronyms 10:55
14 A. That's -- that's why they are in that 10:54 14 usually. I mean, they don't usually put periods 10:55
15 order. 10:54 15 between, so one would have to know that. They 10:55
16 Q. And Phase III clinical studies tend to 10:54 16 didn't just make that name up. But they probably 10:55
17 be the largest and most expensive of the 10:54 17 went to a lot of trouble to come up with the six 10:55
18 different phases, correct? 10:54 18 words that spell ANCHOR. 10:55
19 A. That's generally true, yes. 10:54 19 Q. Different companies seem to have 10:55
20 Q. And are Phase III clinical studies 10:54 20 different approaches to naming clinical studies, 10:55
21 sometimes referred to as pivotal clinical 10:54 21 correct? 10:55
22 studies? 10:54 22 A. Yeah. And this was very clever, 10:55
23 A. They can be. 10:54 23 MARINE, ANCHOR. It's like you're trying to do 10:55
24 Q. And by "pivotal clinical studies," 10:54 24 something with fish. 10:56
25 those are the studies on which FDA approval 10:54 25 Q. AstraZeneca tends to use interstellar 10:56
22
016
Page 86 Page 87
1 objects? 10:56 1 about there is the indication for treatment of 10:57
2 A. I don't recall but I believe. 10:56 2 patients with severe hypertriglyceridemia, which 10:57
3 Q. You note: "ANCHOR studied the 10:56 3 is greater than or equal to 500 milligrams per 10:57
4 efficacy of 2 or 4 grams of Vascepa in patients 10:56 4 deciliter, correct? 10:57
5 with triglyceride levels greater than or equal to 10:56 5 A. Yes. 10:57
6 200 and less than 500 milligrams per deciliter." 10:56 6 Q. And you've heard that referred to as 10:57
7 Do you see that? 10:56 7 the MARINE indication? 10:57
8 A. Yes. 10:56 8 A. Okay. I don't know if I have, but 10:57
9 Q. "According to FDA, since the ANCHOR 10:56 9 that's a way of describing it. 10:57
10 trial was conducted in a population different 10:56 10 Q. Maybe a better way of saying it is the 10:57
11 from that sought in the indication, ANCHOR would 10:56 11 indication was for treatment of severe 10:57
12 not support the indication for very high 10:56 12 hypertriglyceridemia. Is that better? 10:57
13 triglycerides greater than 500 milligrams per 10:56 13 A. Yes. 10:57
14 deciliter." Correct? 10:56 14 Q. And it's your understanding that FDA 10:57
15 A. Yes. 10:56 15 determined that the ANCHOR study could not be 10:57
16 Q. That is your testimony in Paragraph 74 10:56 16 used as evidence of Vascepa's effects in severely 10:57
17 of your report, correct? 10:56 17 hypertriglyceridemic patients, correct? 10:57
18 A. Yes. 10:56 18 A. That's my understanding, yes. 10:57
19 Q. And you're referring here to Amarin's 10:56 19 Q. And the reason why FDA determined that 10:57
20 submission of the ANCHOR clinical study results 10:56 20 ANCHOR would not provide evidence in support of 10:57
21 in support of the MARINE indication, correct? 10:56 21 the severely hypertriglyceridemic indication, it 10:58
22 A. That is my understanding. It was in 10:56 22 was the difference in triglyceride levels in 10:58
23 the NDA that resulted in the -- in the original 10:56 23 ANCHOR versus those for severe 10:58
24 approval and which relied on the MARINE study. 10:57 24 hypertriglyceridemia? 10:58
25 Q. And the indication that we're talking 10:57 25 MS. FUNDAKOWSKI: Objection; form. 10:58
Page 88 Page 89
1 THE WITNESS: Yes. 10:58 1 Q. So the medical review that you 10:59
2 BY MR. SIPES: 10:58 2 reviewed for purposes of forming your opinions in 10:59
3 Q. And in addition, you reviewed the 10:58 3 this case was the form that was available to the 10:59
4 medical review of the MARINE trial, correct? 10:58 4 public? 10:59
5 A. The review of the Vascepa -- medical 10:58 5 A. That's correct. 10:59
6 review of the Vascepa NDA, yes. 10:58 6 MR. SIPES: I'll ask the court 10:59
7 Q. You cite that in Paragraph 73 of your 10:58 7 reporter to mark this as Exhibit 8. 10:59
8 report? 10:58 8 (Exhibit 8 marked for identification
9 A. I do. 10:58 9 and attached hereto.)
10 Q. And you attach it as Exhibit A to your 10:58 10 BY MR. SIPES: 10:59
11 report, correct? 10:58 11 Q. I've asked the court reporter to mark 10:59
12 A. Yes. 10:58 12 as Exhibit 8 a document entitled "Center for Drug 10:59
13 Q. And you understand that the Vascepa 10:58 13 Evaluation and Research, Application Number: 11:00
14 medical review was a medical review that led up 10:58 14 202057Orig1s000, Medical Review(s)," bearing 11:00
15 to approval of the product for treatment of 10:58 15 Bates number ICOSAPENT_DFNDT00015424 through 11:00
16 severe hypertriglyceridemia? 10:58 16 15567. 11:00
17 A. Yes. 10:58 17 Mr. Mathers, would you confirm that 11:00
18 Q. And the Vascepa medical review is 10:58 18 what's been marked as Exhibit 8 is the Vascepa 11:00
19 available to the public on the FDA website, 10:59 19 medical review that you reviewed in forming your 11:00
20 correct? 10:59 20 opinions in the case? 11:00
21 A. In redacted form. 10:59 21 A. I see redactions. Does that indicate 11:00
22 Q. And the redacted form that you 10:59 22 this is the same version that was posted 11:00
23 reviewed for purposes of your opinions in this 10:59 23 publicly? 11:00
24 case? 10:59 24 Q. This is -- it is my understanding that 11:00
25 A. Yes. 10:59 25 the version we produced is a version that was 11:01
23
017
Page 90 Page 91
1 produced by defendants in the case that they 11:01 1 approval? 11:02
2 obtained from the FDA website. 11:01 2 A. It is -- I think it's relevant to 11:02
3 A. Okay. Then that would be the same one 11:01 3 the -- to the assessment of what the approval 11:02
4 that I reviewed. 11:01 4 means and what was intended. 11:02
5 Q. And -- 11:01 5 Q. If you'll turn to the medical review 11:02
6 A. This one is printed in color. I 11:01 6 page 67. If it helps you, that's on Bates number 11:02
7 appreciate that. 11:01 7 in the lower left ending in 15491. Do you see 11:03
8 Q. It's easier to read it in color. 11:01 8 that? 11:03
9 A. It's sometimes hard to follow the 11:01 9 A. That doesn't help me at all. 67 is 11:03
10 graphs when the results weren't in color. 11:01 10 easier to find. 11:03
11 Q. And in Paragraph 149 of your report 11:01 11 Q. Okay. We'll use the pages of the 11:03
12 you cite to the medical review as informing your 11:01 12 Vascepa medical review. That would probably be 11:03
13 opinion about the scope of FDA approval, correct? 11:01 13 easier. Is that all right? 11:03
14 A. Yes. 11:02 14 A. All right. 11:03
15 Q. And is it your opinion that the 11:02 15 Q. You'll see there is a section of the 11:03
16 medical review helps to inform an understanding 11:02 16 medical review, 6.1.9, "Discussion of Persistence 11:03
17 of the scope of FDA's approval? 11:02 17 of Efficacy and/or Tolerance Effects." Do you 11:03
18 MS. FUNDAKOWSKI: Objection; form. 11:02 18 see that? 11:03
19 THE WITNESS: It might be relevant to 11:02 19 A. Yes. 11:03
20 it. It provides -- its main value is to 11:02 20 Q. And it states: "The open-label 11:03
21 provide background on what the reviewers 11:02 21 extension of MARINE with data up to 40 weeks was 11:03
22 looked at and what they were thinking. 11:02 22 submitted as part of the 120 day update. 11:03
23 BY MR. SIPES: 11:02 23 However, as shown in the figure below, the 11:03
24 Q. But in this case, you use it, in part, 11:02 24 maximum TG-lowering effect of 4 grams Vascepa 11:03
25 to inform your understanding of the scope of FDA 11:02 25 occurred by Week 4 and the effects were 11:03
Page 92 Page 93
1 maintained throughout the study. The TG levels 11:03 1 MARINE clinical study, correct? 11:04
2 fluctuated with Vascepa 2-gram group and 11:03 2 A. Yes. 11:04
3 increased in the placebo group." 11:03 3 Q. The FDA medical review concluded that 11:05
4 Do you see that? 11:03 4 the 2-gram -- Vascepa administered at 2 grams a 11:05
5 A. Yes. 11:03 5 day reduced triglycerides; the maximum 11:05
6 Q. Were you aware that there was a 11:03 6 triglyceride reduction was at four weeks, but 11:05
7 40-week extension, an open-label extension study 11:03 7 that reduced level was not maintained through 12 11:05
8 done in addition to the 12-week MARINE trial? 11:04 8 weeks, correct? 11:05
9 A. Yes. 11:04 9 MS. FUNDAKOWSKI: Objection; form. 11:05
10 Q. And FDA's review of the MARINE 11:04 10 THE WITNESS: Yes, that's what it 11:05
11 clinical data concluded that the maximum 11:04 11 says. 11:05
12 reduction in TGs for administration of 4 grams 11:04 12 BY MR. SIPES: 11:05
13 daily occurred at Week 4 and that the TG 11:04 13 Q. And in fact, if you'll turn to page 54 11:05
14 reduction was maintained through 12 weeks of 11:04 14 of the Vascepa medical review, Exhibit 8, there 11:05
15 administration, correct? 11:04 15 is a statement "Reviewer Comment" in bold. Do 11:05
16 A. Yes. 11:04 16 you see that? 11:05
17 Q. And that's shown in the graph on 11:04 17 A. Yes. 11:05
18 page 68 of the medical review, that 4 grams of 11:04 18 Q. And it says: "Although the Vascepa 11:05
19 Vascepa in severely hypertriglyceridemic patients 11:04 19 2-gram dose reduced TG, the potency of the dose 11:05
20 achieved the lowest TG level at Week 4 and then 11:04 20 was such that there were wide fluctuations in TG 11:05
21 maintained that lower level through week 12, 11:04 21 levels. By Week 11, the slight improvements in 11:05
22 correct? 11:04 22 TG levels achieved at Week 4 were reduced back to 11:06
23 A. Yes. 11:04 23 almost the baseline TG. Within one week (from 11:06
24 Q. And you understand that Figure 16 on 11:04 24 Week 11 to Week 12) the mean percent change in TG 11:06
25 page 68 is the data obtained from the 12-week 11:04 25 changed from .20 percent to negative 9.78 11:06
24
018
Page 94 Page 95
1 percent. Wide fluctuations in TG were also 11:06 1 MS. FUNDAKOWSKI: Objection; form. 11:07
2 observed in the placebo group." 11:06 2 THE WITNESS: Well, it's a combination 11:07
3 Do you see that? 11:06 3 of having a smaller effect at the initial -- 11:07
4 A. Yes. 11:06 4 at the four-week measure but also that it 11:07
5 Q. I read that correctly, right? 11:06 5 didn't maintain it. 11:07
6 A. Yes. 11:06 6 BY MR. SIPES: 11:07
7 Q. The reviewer goes on to say at page 54 11:06 7 Q. So FDA defined treatment success for 11:07
8 of the Vascepa medical review: "The Vascepa 11:06 8 purposes of approval as both reducing 11:07
9 4-gram dose reached maximum effectiveness by Week 11:06 9 triglycerides in severely hypertriglyceridemic 11:07
10 4 and despite a slight decrease at Week 11 and 11:06 10 patients and maintaining that reduced level, 11:07
11 Week 12, showed none of the wide fluctuations 11:06 11 correct? 11:07
12 seen in Vascepa 2-gram or placebo. This reviewer 11:06 12 MS. FUNDAKOWSKI: Objection; form. 11:07
13 interprets this as a more potent effect of the 11:06 13 THE WITNESS: I don't know that that 11:07
14 Vascepa 4-gram dose; that is, the ability to 11:06 14 was their definition of treatment success. 11:07
15 eliminate the wide TG fluctuations seen in the 11:06 15 My understanding of the definition of 11:07
16 placebo group." 11:06 16 treatment success was reducing -- reducing 11:07
17 Did I read that correctly? 11:06 17 triglycerides below 500. 11:08
18 A. Yes. 11:06 18 BY MR. SIPES: 11:08
19 Q. And FDA approved the 4-gram dose of 11:06 19 Q. Is it your opinion that FDA viewed the 11:08
20 Vascepa but not the 2-gram dose, correct? 11:06 20 product as successful if it reduced triglycerides 11:08
21 A. Correct. 11:06 21 below 500 even if it did not maintain that level? 11:08
22 Q. FDA rejected the 2-gram dose because 11:07 22 A. I think with -- in the other tested 11:08
23 2 grams of Vascepa was not able to maintain the 11:07 23 dose where the result -- the reduction was much 11:08
24 TG-lowering effects of the drug through 12 weeks, 11:07 24 smaller and wasn't maintained, that they decided 11:08
25 correct? 11:07 25 that was not an acceptable level of 11:08
Page 96 Page 97
1 effectiveness. 11:08 1 A. That's correct. 11:09
2 Q. So FDA concluded that in order to be 11:08 2 Q. So defendants' proposed labeling shows 11:09
3 approvable, the drug had to both reduce 11:08 3 only the treatment effects that persist at 12 11:09
4 triglycerides and maintain the reduction for 12 11:08 4 weeks and not the effects achieved at four weeks, 11:09
5 weeks, correct? 11:08 5 correct? 11:09
6 MS. FUNDAKOWSKI: Objection; form. 11:08 6 A. The only clinical data provided is the 11:09
7 THE WITNESS: I don't know that that 11:08 7 data at 12 weeks -- are the data at 12 weeks. 11:09
8 was a criteria that they had established in 11:08 8 Q. And nothing in defendants' proposed 11:10
9 advance. It's what they applied. But those 11:08 9 labeling limits the approval they're seeking to 11:10
10 were noted differences between the two 11:08 10 simply achieving TG reduction below 500 11:10
11 doses, and the judgment was made that at the 11:08 11 milligrams per deciliter without maintaining that 11:10
12 higher dose the results were -- that the 11:09 12 reduction through 12 weeks, correct? 11:10
13 results indicated an effective treatment 11:09 13 MS. FUNDAKOWSKI: Objection; form. 11:10
14 that was maintained. So the conclusion was 11:09 14 THE WITNESS: The approval wasn't 11:10
15 reached that that was adequate evidence of 11:09 15 limited to -- to -- the -- that's not the 11:10
16 effectiveness supported by an adequate and 11:09 16 approved indication or the basis for it. 11:10
17 well-controlled trial. 11:09 17 BY MR. SIPES: 11:10
18 BY MR. SIPES: 11:09 18 Q. And -- 11:10
19 Q. The Vascepa labeling reports the 11:09 19 A. Plus the fact that they're required to 11:10
20 results at 12 weeks but not the results at four 11:09 20 use the same length. 11:10
21 weeks, correct? 11:09 21 Q. You don't believe that defendants 11:10
22 A. That's correct. 11:09 22 could omit from their proposed labeling the 11:10
23 Q. Defendants' proposed labeling for 11:09 23 clinical study results obtained at 12 weeks 11:10
24 their ANDA products describes only the 12-week 11:09 24 administration and use only the four-week 11:11
25 results and not the four-week results, correct? 11:09 25 results, correct? 11:11
25
019
Page 98 Page 99
1 A. That's not the type of change of 11:11 1 severely hypertriglyceridemic patient and 11:12
2 labeling that's permitted under Hatch-Waxman. 11:11 2 maintaining that reduction through 12 weeks or 11:12
3 Q. Defendants could not seek to omit the 11:11 3 more would not be using the product off label, 11:12
4 12-week clinical study results from their 11:11 4 correct? 11:12
5 labeling, correct? Scratch that. 11:11 5 MS. FUNDAKOWSKI: Objection; form. 11:12
6 Defendants could not omit the clinical 11:11 6 THE WITNESS: For 12 weeks or more? 11:12
7 study results from 12 weeks of administration 11:11 7 No. That's within the approved indication. 11:12
8 from their generic labeling, correct? 11:11 8 BY MR. SIPES: 11:12
9 A. I don't think they could omit them 11:11 9 Q. If FDA had believed that Vascepa 11:12
10 because they're in the reference drug labeling. 11:11 10 ceased to be effective after four weeks, it would 11:12
11 Q. But a generic company can seek to omit 11:11 11 have required a statement to that effect in the 11:13
12 labeling if such an omission did not render the 11:11 12 labeling, correct? 11:13
13 drug less safe or effective for its intended use 11:11 13 A. Well, that would -- that would be 11:13
14 than the pioneer product? 11:11 14 speculation, but it would be reasonable for FDA 11:13
15 MS. FUNDAKOWSKI: Objection; form. 11:11 15 to write the labeling differently in order to 11:13
16 THE WITNESS: Well, it's the -- I -- a 11:11 16 reflect that kind of data which indicates that 11:13
17 description of the clinical data that 11:12 17 there is such a limitation. 11:13
18 supports the approval is generally required 11:12 18 MR. SIPES: Let me ask the court 11:13
19 to appear in labeling, and I don't think 11:12 19 reporter to mark this as Mathers Exhibit 9. 11:13
20 that the generic company would be allowed to 11:12 20 (Exhibit 9 marked for identification
21 use different clinical data than the data 11:12 21 and attached hereto.)
22 that was put in the reference drug label. 11:12 22 BY MR. SIPES: 11:13
23 BY MR. SIPES: 11:12 23 Q. Mr. Mathers, I've asked the court 11:13
24 Q. A physician who prescribes Vascepa for 11:12 24 reporter to mark as Exhibit 9 a document entitled 11:14
25 purposes of reducing the triglyceride level in a 11:12 25 "Guidance for Industry, Dosage and Administration 11:14
Page 100 Page 101

1 section of Labeling for Human Prescription Drug 11:14 1 Exhibit 9, the dosage and administration labeling 11:15
2 and Biologic Products - Content and Format," 11:14 2 guidance. In the section "Basic Dosing 11:15
3 March 2010, bearing Bates numbers 11:14 3 Information," the bottom paragraph: "In 11:15
4 AMRN-PEXP-0010229 through 10241. 11:14 4 describing the dosage range and duration, if it 11:15
5 Do you see that? 11:14 5 is known that a drug provides no additional 11:15
6 A. Yes. 11:14 6 benefit above a certain dose or beyond a certain 11:16
7 Q. This Mathers Exhibit 9 is a guidance 11:14 7 duration of use, that dose or duration must be 11:16
8 document published by FDA describing the Dosage 11:14 8 identified." 11:16
9 Administration section of the labeling for human 11:14 9 Do you see that? 11:16
10 prescription drug and biologic products, correct? 11:14 10 A. Yes. 11:16
11 A. Yes. 11:14 11 Q. Did I correctly read the guidance 11:16
12 Q. And can we refer to this as the dosage 11:14 12 document? 11:16
13 and administration guidance? 11:14 13 A. Yes. 11:16
14 A. All right. 11:14 14 Q. And so it is FDA's position that if it 11:16
15 Q. Or dosage administration labeling 11:14 15 is known that a drug provides no benefit beyond a 11:16
16 guidance, perhaps? 11:14 16 certain duration of use, that duration must be 11:16
17 This is -- Mathers Exhibit 9 is final 11:14 17 identified, correct? 11:16
18 guidance, correct? 11:15 18 A. Yes. 11:16
19 A. Yes. 11:15 19 Q. And it would be identified in the 11:16
20 Q. And Mathers Exhibit 9 reflects FDA's 11:15 20 Dosage and Administration section of the drug 11:16
21 current views on the drafting of the Dosage and 11:15 21 labeling, correct? 11:16
22 Administration section of labeling for human 11:15 22 A. Yes. It could also be identified in 11:16
23 prescription drug products, correct? 11:15 23 other sections. It could be a limitation on use 11:16
24 A. I believe so. 11:15 24 in the Indications section, or in the Clinical 11:16
25 Q. So if you'll turn to page 2 of Mathers 11:15 25 Trials sections. But this is -- this is one 11:16
26
020
Page 114 Page 115

1 Q. This is FDA's recent guidance 11:33 1 Clinical Studies section of the labeling." 11:34
2 concerning the drafting of the Indications and 11:33 2 Do you see that? 11:34
3 Usage section of drug labeling, correct? 11:33 3 A. Yes. 11:34
4 A. From July 2018. 11:33 4 Q. So FDA is describing its approach to 11:34
5 Q. Would you refer to that as recent? 11:33 5 labeling where the drug is approved for long-term 11:34
6 A. Compared to others, sure. 11:33 6 use and there are no safety or efficacy concerns 11:34
7 Q. All right. It's a fair description? 11:33 7 from continued use of the drug, correct? 11:34
8 A. I'm not going to argue that it was 11:33 8 A. They are describing a reason not to 11:34
9 recent. 11:33 9 put in a limitation. 11:35
10 Q. All right. If you'll turn to page 13, 11:33 10 Q. And what FDA is saying is if a drug is 11:35
11 and you see: "If clinical trials evaluated the 11:33 11 approved for a chronic condition or for long-term 11:35
12 effectiveness of a drug for a chronic condition 11:34 12 use and there is no safety or effectiveness 11:35
13 only in short-term trials of sufficient duration 11:34 13 reason to limit the use, it will not put a 11:35
14 to support such an approval (e.g., drugs for 11:34 14 limitation on use in the Indications and Usage 11:35
15 major depressive disorder or hypertension), but 11:34 15 section but will instead indicate the length of 11:35
16 the drug is indicated for long-term use due to 11:34 16 the clinical trial in the Clinical Studies 11:35
17 the chronic nature of the condition and because 11:34 17 section, correct? 11:35
18 there is no known or anticipated safety or 11:34 18 MS. FUNDAKOWSKI: Objection; form. 11:35
19 efficacy concern from continued use, a 11:34 19 THE WITNESS: Yes. I don't think the 11:35
20 description of the duration of use from the 11:34 20 statement about including the information in 11:35
21 clinical trials or information about the lack of 11:34 21 the Clinical Studies section is a -- is a 11:35
22 longer term data generally should not be included 11:34 22 replacement for the kind of statement that 11:35
23 in the Indications and Usage section. 11:34 23 might be made in the Indications and Usage. 11:35
24 Information on the length of the clinical trials 11:34 24 They're simply saying that a statement is 11:35
25 should instead be discussed in detail in the 11:34 25 not necessary but the information would be 11:35
Page 116 Page 117

1 in the Clinical Studies section as it always 11:35 1 entirety for individual prescribing decisions." 11:37
2 would whether there was a limitation or not. 11:35 2 Correct? 11:37
3 BY MR. SIPES: 11:36 3 A. Yes. 11:37
4 Q. But what FDA is saying is if there is 11:36 4 Q. So it's FDA's position that a 11:37
5 no safety or effectiveness reason to limit the 11:36 5 prescriber should read the entire approved 11:37
6 duration of use, they will not put a duration 11:36 6 labeling in making their prescribing decisions, 11:37
7 statement in the Indications and Usage section, 11:36 7 correct? 11:37
8 correct? 11:36 8 A. Yes. And it's on the basis of that 11:37
9 A. Correct. 11:36 9 labeling principle that the labels are written 11:37
10 Q. And so the situation with the Vascepa 11:36 10 the way they are. 11:37
11 labeling is FDA did not see either a safety or an 11:36 11 MR. SIPES: Why don't we take a break. 11:37
12 effectiveness reason to put a limitation on the 11:36 12 MS. FUNDAKOWSKI: Okay. 11:37
13 duration of use in the Indications and Usage 11:36 13 THE VIDEOGRAPHER: We are off the 11:37
14 section, correct? 11:36 14 record, 11:38. 11:37
15 A. I believe that's the rationale on 11:36 15 (Recess taken.)
16 which there is no limitation in that section, 11:36 16
17 yes. 11:36 17
18 Q. Now, on page 2, FDA sets forth general 11:36 18
19 principles that it uses in drafting the 11:36 19
20 Indications and Usage section, correct? 11:36 20
21 A. Yes. 11:37 21
22 Q. And it states: "Other sections of the 11:37 22
23 labeling, as applicable, also provide essential 11:37 23
24 details that enable safe and effective use of the 11:37 24
25 drug, and labeling should be considered in its 11:37 25
30
021
Page 118 Page 119

1 ------------------------------------------------- 1 A. Okay. 12:21
2 AFTERNOON SESSION 2 Q. And there is something called 12:21
3 12:20 p.m. 3 medication guide, correct? 12:21
4 ------------------------------------------------- 4 A. Yes. 12:21
5 THE VIDEOGRAPHER: We are back on the 12:20 5 Q. And do you understand the difference 12:21
6 record, 12:20. 12:20 6 between the patient package insert, also known as 12:21
7 BY MR. SIPES: 12:20 7 the patient information, and the medication 12:21
8 Q. Mr. Mathers, did you discuss the 12:20 8 guide? 12:21
9 substance of your deposition testimony with 12:20 9 A. Yes. 12:21
10 counsel at the lunch break? 12:20 10 Q. What are the differences? 12:21
11 A. No, I didn't. 12:20 11 A. Well, a medication guide is -- is 12:21
12 Q. Do you understand that there are three 12:20 12 typically a mandatory handout that is required by 12:21
13 types of FDA-approved patient labeling? 12:20 13 REMS because of the extraordinary concerns about 12:21
14 MS. FUNDAKOWSKI: Objection to form. 12:21 14 safety or effectiveness of the product and the 12:22
15 THE WITNESS: Perhaps you can remind 12:21 15 need to assure that patients get certain 12:22
16 me of the three you're speaking of. 12:21 16 information. So there's a mandated requirement 12:22
17 BY MR. SIPES: 12:21 17 that pharmacists give those out to patients. 12:22
18 Q. Are you familiar with the patient 12:21 18 Q. And REMS is R-E-M-S, all caps, 12:22
19 package insert? 12:21 19 correct? 12:22
20 A. Yes. 12:21 20 A. Yes. 12:22
21 Q. And that's sometimes referred to as 12:21 21 Q. It's risk evaluation and mitigation 12:22
22 the patient information, correct? 12:21 22 strategy, correct? 12:22
23 A. Yes. 12:21 23 A. That is correct. 12:22
24 Q. There are instructions for use, 12:21 24 Q. And certain patient information is 12:22
25 correct? 12:21 25 also required to be issued, correct? 12:22
Page 120 Page 121

1 A. Well, there's state law requirements, 12:22 1 your report. In Paragraph 128 you refer to the 12:23
2 but I'm not sure there is mandatory requirements 12:22 2 patient information medication guide, which is to 12:24
3 to distribute materials that are made available 12:22 3 be detached and distributed to patients in 12:24
4 for patients but which may not be mandatory. 12:22 4 connection with Vascepa, correct? 12:24
5 Q. Do you recall that perhaps oral 12:22 5 A. Uh-huh. 12:24
6 contraceptives fall within the federal 12:22 6 Q. That's a mistake, correct? 12:24
7 requirement to provide patient information to 12:23 7 A. Yeah, that is. 12:24
8 patients? 12:23 8 Q. And in fact, the regulation you quote 12:24
9 A. They've had one for a long time. I'm 12:23 9 about the medication guide being detached and 12:24
10 not sure -- I'm not sure whether it's a special 12:23 10 distributed to patients does not apply to the 12:24
11 case or whether it falls into a category that 12:23 11 patient information in connection with Vascepa, 12:24
12 also applies to other products. 12:23 12 correct? 12:24
13 Q. But in any event, the patient 12:23 13 A. I think that's right. 12:24
14 information, the FDA-approved patient labeling is 12:23 14 Q. Did you draft Paragraph 128 of your 12:24
15 different and distinct from the medication guide, 12:23 15 report? 12:24
16 correct? 12:23 16 A. I don't recall. I don't recall 12:24
17 A. Yes. 12:23 17 drafting it. It may have been added during the 12:24
18 Q. And Vascepa does not have a medication 12:23 18 back-and-forth. 12:25
19 guide, correct? 12:23 19 Q. So it's possible that it was Hikma's 12:25
20 A. I believe it doesn't. I believe -- 12:23 20 counsel that made the mistake? 12:25
21 yes, I believe it does not. 12:23 21 A. It's possible. 12:25
22 Q. Defendants' generic products also will 12:23 22 Q. Does the fact that Vascepa has patient 12:25
23 not have a medication guide, correct? 12:23 23 information rather than a medication guide change 12:25
24 A. I think that's correct. 12:23 24 your opinions in any way? 12:25
25 Q. If you'll turn to Paragraph 128 of 12:23 25 A. No. No, I didn't -- I was not -- it 12:25
31
022
Page 122 Page 123

1 was my understanding that it wasn't the subject 12:25 1 this could reinforce the -- could either 12:26
2 of a REMS so that there would be an extra level 12:25 2 induce the physician to give it out or it 12:27
3 of scrutiny or mandatory steps that needed to be 12:25 3 could reinforce the physician in orally 12:27
4 taken in distributing the drug. So I wasn't sure 12:25 4 providing the type of information that's 12:27
5 this was something that fell into that category. 12:25 5 covered there so that the patient is 12:27
6 Q. So your opinions are the same, even 12:25 6 appropriately instructed. 12:27
7 recognizing that the patient information for 12:25 7 BY MR. SIPES: 12:27
8 Vascepa and defendants' product is not a 12:26 8 Q. In other words, the prescriber may 12:27
9 medication guide? 12:26 9 review the patient information and go over it 12:27
10 A. Correct. 12:26 10 with the patient and in that way be himself or 12:27
11 Q. Do you believe that the Vascepa 12:26 11 herself informed about the content of the patient 12:27
12 patient information impacts prescriber actions? 12:26 12 information? 12:27
13 MS. FUNDAKOWSKI: Objection; form. 12:26 13 A. Yes, it would be potentially 12:27
14 THE WITNESS: Well, it could in two 12:26 14 informative to both the prescriber and, if the 12:27
15 different ways. It could inform -- it 12:26 15 prescriber passes it on, to the patients. 12:27
16 provides information in a different context 12:26 16 Q. Now, the patient information is 12:27
17 that when a physician reads it, you know, it 12:26 17 different than the patient counseling 12:27
18 might be taken into account in a prescribing 12:26 18 information, correct? 12:27
19 decision. 12:26 19 A. The patient counseling information is 12:27
20 It also may obviously be actually 12:26 20 part of the prescribing information. 12:27
21 provided by the physician to the patients. 12:26 21 Q. The patient counseling information is 12:27
22 That's sort of what it's for, although that 12:26 22 directed to the prescriber and informs the 12:27
23 doesn't mean that they're necessarily handed 12:26 23 prescriber of information that he or she should 12:27
24 out. But the fact that -- the fact that 12:26 24 give to the patient? 12:28
25 there is a patient information piece like 12:26 25 A. Right. 12:28
Page 124 Page 125

1 Q. If you'll turn to Paragraph 158 of 12:28 1 Patient Counseling Information section. It's in 12:30
2 your report. You state: "The Indications and 12:28 2 the Patient Information doc -- 12:30
3 Usage section instructs initiating an 12:28 3 Q. So the information about the diet low 12:30
4 'appropriate lipid-lowering diet,' which the 12:28 4 in saturated fat, cholesterol, carbohydrates, and 12:30
5 Patient Counseling Information explains is a diet 12:28 5 low in added sugars that you quote from the 12:30
6 'low in saturated fat, cholesterol, 12:28 6 Vascepa labeling is not from the prescribing 12:30
7 carbohydrates, and low in added sugars.'" 12:28 7 information, correct? 12:30
8 Do you see that? 12:28 8 MS. FUNDAKOWSKI: Objection; form. 12:30
9 A. Yes. 12:28 9 THE WITNESS: Well, I don't know that 12:30
10 Q. Did I read your testimony at 12:28 10 I regard the patient information that's 12:30
11 Paragraph 158 correctly? 12:28 11 approved for use is wholly independent or 12:30
12 A. Yes. 12:28 12 separate from the prescribing information. 12:30
13 Q. If you'll look at the Vascepa 12:28 13 But it is a separate -- a separate document 12:31
14 labeling, can you confirm whether or not the 12:28 14 that is -- that is provided for that 12:31
15 information you're quoting about the diet low in 12:28 15 purpose. But yes, it is in -- yes. 12:31
16 saturated fat, cholesterol, carbohydrates, and 12:28 16 BY MR. SIPES: 12:31
17 low in added sugars in fact comes from the 12:28 17 Q. Just to be clear, the patient 12:31
18 patient counseling information? 12:29 18 information is not part of the prescribing 12:31
19 A. It's in the patient information -- 12:29 19 information, correct? 12:31
20 it's in the Patient Information section that 12:29 20 A. Well, it's not literally a part of the 12:31
21 follows the end of the labeling, the prescribing 12:30 21 structured prescribing information as it appears 12:31
22 information. 12:30 22 in the -- as it appears on the first several 12:31
23 Q. So the statement in your testimony at 12:30 23 pages of this document. But they are approved 12:31
24 Paragraph 158 is incorrect? 12:30 24 together, and I don't think -- I don't think 12:31
25 A. In that -- yes. It's not in the 12:30 25 they're -- they should be regarded as wholly 12:32
32
023
Page 126 Page 127

1 independent documents. But... 12:32 1 Q. That states that under usage 12:33
2 Q. Is it your opinion that the 12:32 2 considerations patients should be placed on an 12:33
3 information in the patient information serves to 12:32 3 appropriate lipid-lowering diet. Do you see 12:33
4 explain to prescribers the content of the 12:32 4 that? 12:33
5 prescribing information? 12:32 5 A. Yes. 12:33
6 MS. FUNDAKOWSKI: Objection; form. 12:32 6 Q. And that is the language that you 12:33
7 THE WITNESS: It could. If it's being 12:32 7 quote in Paragraph 158 of your report, right, "an 12:33
8 provided in order to be given to patients, 12:32 8 appropriate lipid-lowering diet"? 12:33
9 and assuming that the prescriber reads it, 12:32 9 A. Yes. Where it says Vascepa labeling, 12:33
10 they would appreciate that this is -- this 12:32 10 that's the first -- the first identified AMR in 12:33
11 is information about the drug. And it's not 12:32 11 page number and the second quote from the patient 12:34
12 inconsistent. It's just -- it's worded 12:32 12 information is the second page identified there. 12:34
13 differently so that it's more user friendly 12:32 13 Q. The prescribing information itself 12:34
14 for patients. It uses bullet points. But, 12:32 14 leaves it to the prescriber's discretion what 12:34
15 you know, it's formatted differently, but 12:32 15 sort of appropriate lipid-lowering diet should be 12:34
16 it's -- it's not -- it's not intended to be 12:33 16 recommended to patients, correct? 12:34
17 comprehensive, but it's intended to reflect 12:33 17 MS. FUNDAKOWSKI: Objection; form. 12:34
18 the information such as that which the 12:33 18 THE WITNESS: It doesn't -- it doesn't 12:34
19 patient counseling information, prescribing 12:33 19 specify in -- it doesn't dictate what that 12:34
20 information advises patients should be told. 12:33 20 diet should be. 12:34
22 Q. So looking at the Indications and 12:33 22 Q. Focusing just on the prescribing 12:34
23 Usage section of the prescribing information for 12:33 23 information, putting the patient information to 12:34
24 Vascepa -- 12:33 24 the side, nowhere in the prescribing information 12:34
25 A. Yeah. 12:33 25 for Vascepa is the appropriate lipid-lowering 12:34
Page 128 Page 129

1 diet described or otherwise explained, correct? 12:34 1 assuming that they know what would be a 12:36
2 MS. FUNDAKOWSKI: Objection; form. 12:34 2 lipid-lowering diet. 12:36
3 THE WITNESS: I don't think there is 12:34 3 BY MR. SIPES: 12:36
4 an elaboration on that in -- in the -- in 12:34 4 Q. So it would not be off label for a 12:36
5 any of the other sections of the prescribing 12:35 5 physician to administer Vascepa to a patient with 12:36
6 information. 12:35 6 severe hypertriglyceridemia who continued on a 12:36
7 BY MR. SIPES: 12:35 7 Western diet if the physician concluded that the 12:36
8 Q. It is left to the physician to decide 12:35 8 appropriate diet for that patient was that 12:36
9 the appropriate counseling for any particular 12:35 9 Western diet, correct? 12:36
10 patient, correct? 12:35 10 MS. FUNDAKOWSKI: Objection; form. 12:36
11 MS. FUNDAKOWSKI: Objection; form. 12:35 11 THE WITNESS: I -- I think that would 12:36
12 THE WITNESS: That's -- that's 12:35 12 depend on whether a Western diet could 12:36
13 generally true. It's true both in the sense 12:35 13 legitimately be described as a 12:36
14 that physicians don't have to follow -- they 12:35 14 lipid-lowering diet. 12:37
15 have the ability to prescribe off label and 12:35 15 BY MR. SIPES: 12:37
16 don't have to follow the instructions or 12:35 16 Q. And there is nothing in the 12:37
17 recommendations in the labeling. But 12:35 17 prescribing information that says one way or the 12:37
18 assuming that they want to follow the 12:35 18 other, correct? 12:37
19 recommendations in the labeling, they -- 12:35 19 A. Except in the patient information 12:37
20 they should be recommending placing -- they 12:36 20 where it characterizes what one might ordinarily 12:37
21 should be placing their patients on an 12:36 21 think is a lipid-lowering diet. 12:37
22 appropriate lipid-lowering diet, but what 12:36 22 Q. And, of course, the patient 12:37
23 form of that -- and exercise regimen. But 12:36 23 information is not strictly the prescribing 12:37
24 what specifically to recommend for that 12:36 24 information, correct? 12:37
25 purpose would be within their discretion 12:36 25 A. It is not within the specific sections 12:37
33
024
Page 130 Page 131

1 of the prescribing information. It's attached to 12:37 1 would be a scientific nutrition kind of question. 12:38
2 it. 12:37 2 Q. So sitting here today, it is more than 12:38
3 Q. So coming back to the question, it 12:37 3 possible that it would not be off label for a 12:38
4 would not be off label for a physician to 12:37 4 physician to administer Vascepa to a patient with 12:38
5 administer Vascepa to a patient with severe 12:37 5 severe hypertriglyceridemia who continued on a 12:38
6 hypertriglyceridemia who continued on a Western 12:37 6 Western diet if the physician concluded that that 12:38
7 diet if the physician concluded that that diet 12:37 7 was an appropriate lipid-lowering diet for that 12:38
8 was an appropriate lipid-lowering diet for that 12:37 8 patient, correct? 12:38
9 patient? 12:37 9 MS. FUNDAKOWSKI: Objection; form. 12:39
10 MS. FUNDAKOWSKI: Objection; form. 12:37 10 THE WITNESS: It's theoretically 12:39
11 THE WITNESS: I think that if a 12:37 11 possible, but I am not aware of the Western 12:39
12 physician thought it was a lipid-lowering 12:37 12 diet as defined for this litigation would be 12:39
13 diet but was just out to lunch, that the 12:38 13 the kind of diet that's contemplated by 12:39
14 fact that the physician thought it was a 12:38 14 this -- by the Indications section. 12:39
15 lipid-lowering diet wouldn't necessarily 12:38 15 BY MR. SIPES: 12:39
16 overcome the fact that they actually 12:38 16 Q. In your view, would the statement in 12:39
17 prescribed the product in violation of the 12:38 17 the patient information for Vascepa that your 12:39
18 requirement. 12:38 18 doctor may start you on a diet that is low in 12:39
19 BY MR. SIPES: 12:38 19 saturated fat, cholesterol, carbohydrates, and 12:39
20 Q. Do you know whether or not a physician 12:38 20 low in added sugars before giving you Vascepa 12:39
21 could conclude reasonably that for a particular 12:38 21 lead some physicians to prescribe a diet for 12:39
22 patient a diet meeting the requirements of a 12:38 22 patients that was low in saturated fat, 12:39
23 Western diet would be an inappropriate 12:38 23 cholesterol, carbohydrates, and low in added 12:39
24 lipid-lowering diet for that patient? 12:38 24 sugars? 12:39
25 A. I don't know that. That's a -- that 12:38 25 MS. FUNDAKOWSKI: Objection; form. 12:39
Page 132 Page 133

1 THE WITNESS: I think it would 12:39 1 Q. Would that encourage some physicians 12:41
2 reiterate the understanding of a physician 12:39 2 to do blood tests to monitor the triglycerides 12:41
3 as to what a lipid-lowering diet would be, 12:40 3 and other lipid levels in their patients who are 12:41
4 whether they choose to recommend that the 12:40 4 prescribed Vascepa for the treatment of severe 12:41
5 diet be low in all those things or how they 12:40 5 hypertriglyceridemia? 12:41
6 would implement that. I would think this 12:40 6 A. Again, it might remind them that 12:41
7 would influence the decision since it seems 12:40 7 that's an appropriate thing to do. I think it's 12:41
8 to be -- it seems to be a -- it may be an 12:40 8 a standard of care to monitor those things in 12:41
9 effective reminder of what would be a good 12:40 9 people who are -- who are in need of this kind of 12:41
10 lipid-lowering diet. 12:40 10 therapy. 12:41
11 BY MR. SIPES: 12:40 11 Q. And by "this kind of therapy," you're 12:41
12 Q. Would it encourage some doctors to 12:40 12 talking about Vascepa? 12:41
13 recommend a diet that is low in saturated fat, 12:40 13 A. Vascepa or statins. 12:41
14 cholesterol, carbohydrates, and low in added 12:40 14 Q. Well, Vascepa is indicated for severe 12:41
15 sugars for a patient when administering Vascepa 12:40 15 hypertriglyceridemia. 12:41
16 for the treatment of severe hypertriglyceridemia? 12:40 16 A. Yeah. 12:41
17 A. I think there is a chance that it 12:40 17 Q. Do you know whether statins are 12:41
18 would be taken into account, and that might be 12:40 18 indicated for severe hypertriglyceridemia? 12:41
19 the result. 12:40 19 A. No. But this is a -- this is a 12:41
20 Q. Similarly, just below that it says in 12:40 20 statement of fact, that your doctor may do blood 12:41
21 the patient information: "Your doctor may do 12:40 21 tests for both triglycerides and other lipids 12:41
22 blood tests to check your triglycerides and other 12:40 22 for -- because that's the condition that's being 12:42
23 lipid levels while you take Vascepa." 12:40 23 treated. 12:42
24 Do you see that? 12:41 24 Q. And similarly, in the Dosage and 12:42
25 A. Yes. 12:41 25 Administration section, the Dosage Administration 12:42
34
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1 section instructs physicians to assess lipid 12:42 1 prescribing information, correct? 12:43
2 levels before initiating therapy, correct? 12:42 2 A. Well, they're called out in the 12:43
3 A. Yes. 12:42 3 context of disclosing what was -- what was tested 12:43
4 Q. And then that instruction is 12:42 4 in the clinical trial. 12:43
5 reinforced by the patient information which 12:42 5 Q. And FDA instructs, does it not, that 12:43
6 states that the physician may do blood tests to 12:42 6 the Clinical Studies section should call out 12:43
7 check triglycerides and other lipid levels while 12:42 7 those parameters that are important to clinical 12:43
8 the patient is taking Vascepa, correct? 12:42 8 decision-making, correct? 12:43
9 A. Yes. 12:42 9 MS. FUNDAKOWSKI: Objection; form. 12:44
10 Q. And in terms of the lipid levels that 12:42 10 THE WITNESS: I think we -- I think 12:44
11 are identified in the labeling in the Clinical 12:42 11 you asked me that before. I think that's -- 12:44
12 Studies section, the lipid parameters that are 12:42 12 I don't remember if that's what you asked me 12:44
13 identified there are triglycerides, LDL-C, 12:42 13 before. 12:44
14 non-HDL-C, total cholesterol, HDL-C, VLDL-C and 12:43 14 BY MR. SIPES: 12:44
15 Apo B, correct? 12:43 15 Q. So maybe you can answer the question 12:44
16 MS. FUNDAKOWSKI: Objection; form. 12:43 16 now. 12:44
17 THE WITNESS: Those parameters were 12:43 17 A. I believe that is part of the labeling 12:44
18 the ones that I understand were tested 12:43 18 guidance regulations. 12:44
19 during the clinical trial, and those could 12:43 19 MR. SIPES: And why don't we mark -- 12:44
20 be relevant parameters to measure on a 12:43 20 let's mark this as the next exhibit, 12:44
21 routine basis and to monitor. There may 12:43 21 Exhibit 13. 12:44
22 also be others. 12:43 22 (Exhibit 13 marked for identification
23 BY MR. SIPES: 12:43 23 and attached hereto.)
24 Q. But those are the lipid levels that 12:43 24 BY MR. SIPES: 12:45
25 are specifically called out in the Vascepa 12:43 25 Q. Mr. Mathers, I've asked the court 12:45
Page 136 Page 137

1 reporter to mark as Mathers Exhibit 13 a document 12:45 1 that? 12:46
2 entitled "Guidance for Industry, Clinical Studies 12:45 2 A. Yes. 12:46
3 Section of Labeling for Human Prescription Drug 12:45 3 Q. And it refers to "The description of 12:46
4 and Biologic Products - Content and Format," 12:45 4 the study population should identify those 12:46
5 dated January 2006. 12:45 5 characteristics that are important for 12:46
6 Do you see that? 12:45 6 understanding how to interpret and apply the 12:46
7 A. Yes. 12:45 7 study results. The description thus should 12:46
8 Q. And you've reviewed this document that 12:45 8 identify important inclusion and exclusion 12:46
9 we refer to as Mathers Exhibit 13 before, 12:45 9 criteria, the demographic characteristics of the 12:46
10 correct? 12:45 10 studied population, baseline values of any 12:47
11 A. Yes. 12:45 11 clinically relevant variables important for 12:47
12 Q. This is the FDA's Clinical Studies 12:45 12 understanding the treatment effect, and other 12:47
13 section guidance, correct? 12:45 13 characteristics of the population that have 12:47
14 A. Yes. 12:46 14 important implications for the extent to which 12:47
15 Q. And as far as you know, does this 12:46 15 results can be generalized." 12:47
16 reflect FDA's current thinking on the drafting of 12:46 16 Do you see that? 12:47
17 the Clinical Studies section of prescription drug 12:46 17 A. Yes. 12:47
18 labeling? 12:46 18 Q. And first, the reference by FDA to the 12:47
19 A. As far as I know. 12:46 19 description of the study population should 12:47
20 Q. And Mathers Exhibit 13 is a final 12:46 20 identify those characteristics that are important 12:47
21 guidance. It's not a draft, correct? 12:46 21 for understanding how to interpret the results -- 12:47
22 A. That's correct. 12:46 22 how to interpret and apply the study results, do 12:47
23 Q. And if you'll turn to page 7 of the 12:46 23 you see that? 12:47
24 clinical studies labeling guidance, there is a 12:46 24 A. Yes. 12:47
25 section titled "Study Population." Do you see 12:46 25 Q. The reference FDA has to applying the 12:47
35
026
Page 138 Page 139

1 study results is a reference to prescribers 12:47 1 relevant, correct? 12:48
2 reading the study results and then applying the 12:47 2 A. They were -- they were clinically 12:48
3 learning from those study results to their own 12:47 3 relevant enough to include in the studies and 12:48
4 patients, correct? 12:47 4 they weren't excluded, so they met some threshold 12:48
5 MS. FUNDAKOWSKI: Objection; form. 12:47 5 of relevance. 12:48
6 THE WITNESS: Potentially. 12:47 6 Q. And the baseline levels that are 12:48
7 BY MR. SIPES: 12:47 7 reported in the Vascepa labeling include LDL-C, 12:48
8 Q. What else do you think it refers to? 12:47 8 triglycerides, and Apo B, correct? 12:48
9 A. Well, it also provides information 12:47 9 A. Among others, yes. 12:49
10 about the study that FDA relied on in approving 12:47 10 Q. And similarly, the defendants' 12:49
11 the drug. So they explain the approval decision. 12:48 11 proposed labeling includes as baseline values 12:49
12 Q. But the reference to how to apply the 12:48 12 triglycerides, LDL-C, and Apo B, correct? 12:49
13 study results, that's directed to prescribers, 12:48 13 A. Yes. 12:49
14 correct? 12:48 14 Q. The labeling -- the labeling -- I'm 12:49
15 A. Yes. 12:48 15 sorry, the clinical studies labeling guidance at 12:49
16 Q. And among other things, it says that 12:48 16 page 5 states at the top of the page: "When it 12:49
17 the clinical trial studies should provide 12:48 17 would be informative, the Clinical Studies 12:49
18 baseline values of any clinically relevant 12:48 18 section can also discuss other endpoints shown to 12:49
19 variables important for understanding the 12:48 19 be affected by the drug and endpoints that might 12:49
20 treatment effect. 12:48 20 have been expected to be influenced by the drug, 12:50
21 Do you see that? 12:48 21 but were not." 12:50
22 A. Yes. 12:48 22 Do you see that? 12:50
23 Q. So the baseline values that are 12:48 23 A. Yes. 12:50
24 reported in the Clinical Studies section are 12:48 24 Q. Do you know whether any of the 12:50
25 those values that are judged to be clinically 12:48 25 endpoints that were reported in the Vascepa 12:50
Page 140 Page 141

1 labeling in the Clinical Studies section were 12:50 1 LDL-C from administration of Vascepa? 12:51
2 endpoints that might have been expected to be 12:50 2 A. I don't -- I don't recall that detail 12:51
3 influenced by the drug but were not? 12:50 3 or whether I knew that. 12:51
4 A. I don't know whether they are expected 12:50 4 Q. Okay. So sitting here today, can you 12:51
5 to be affected or whether they were just 12:50 5 say one way or the other whether the LDL-C 12:51
6 important enough to measure to see what would 12:50 6 endpoint was one that FDA felt might have been 12:51
7 happen. 12:50 7 expected to be influenced by the drug but was 12:51
8 Q. The Clinical Studies section of the 12:50 8 not? 12:51
9 Vascepa approved labeling reports that LDL-C 12:50 9 A. I wouldn't be surprised if FDA advised 12:51
10 values were not affected, correct? 12:50 10 that it should be measured. I don't recall 12:51
11 MS. FUNDAKOWSKI: Objection to form. 12:50 11 whether there was any direction on that or 12:51
12 BY MR. SIPES: 12:50 12 whether it was -- whether it was -- whether it 12:51
13 Q. If you'll look at the Vascepa approved 12:50 13 was mentioned in the medical review. 12:52
14 labeling in the Clinical Studies section, it 12:50 14 Q. Coming back to the clinical studies 12:52
15 states: "The reduction in TG observed with 12:50 15 labeling guidance on page 5. 12:52
16 Vascepa was not associated with elevations in 12:50 16 A. Uh-huh. 12:52
17 LDL-C levels relative to placebo." Correct? 12:50 17 Q. There is a reference as well to 12:52
18 A. That is correct as far as the study 12:51 18 reporting endpoints in the Clinical Studies 12:52
19 data indicated. 12:51 19 section, is there not? Do you see that, 12:52
20 Q. And do you know whether or not FDA 12:51 20 composite endpoints, primary and secondary 12:52
21 asked Amarin to rule out the possibility of an 12:51 21 endpoints? 12:52
22 LDL-C rise from the treatment of severe 12:51 22 A. Yes. 12:52
23 hypertriglyceridemia -- scratch that. 12:51 23 Q. In this case the labeling is reporting 12:52
24 Do you know whether FDA asked Amarin 12:51 24 primary and secondary endpoints, is it not? 12:52
25 to power its clinical study to rule out a rise in 12:51 25 A. It does. 12:52
36
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1 clinical study result, correct? 13:02 1 BY MR. SIPES: 13:04
2 A. I think that's fair. 13:02 2 Q. That's true with most drugs, correct? 13:04
3 Q. The Vascepa labeling informs 13:03 3 A. Yes. 13:04
4 prescribers on the expected effects on lipid 13:03 4 Q. And it's standard in the industry to 13:04
5 parameters in treating patients with severe 13:03 5 report median values in most cases, correct? 13:04
6 hypertriglyceridemia with a 4-gram daily dose of 13:03 6 A. I don't know if it's -- I don't -- I 13:04
7 Vascepa, correct? 13:03 7 don't think it is always reported as median. 13:04
8 MS. FUNDAKOWSKI: Objection; form. 13:03 8 Sometimes it's means. 13:04
9 THE WITNESS: It informs them of the 13:03 9 Q. Do you know if it's most often median? 13:04
10 results of the study which measured those 13:03 10 A. I don't know. 13:04
11 parameters and presents them as median, 13:03 11 Q. And prescribers understand, 13:04
12 baseline, and percent change from baseline. 13:03 12 presumably, that you can't always get an 13:04
13 BY MR. SIPES: 13:03 13 individual patient to respond to a particular 13:05
14 Q. Those are the results that are most 13:03 14 drug, correct? 13:05
15 likely to occur, correct? 13:03 15 A. Yes. And again, as I said, even in 13:05
16 MS. FUNDAKOWSKI: Objection; form. 13:03 16 this study some people responded much -- with 13:05
17 THE WITNESS: Well, it's -- it's one 13:03 17 much greater changes, some didn't respond, and 13:05
18 way of describing the results of the study 13:03 18 some might have done very badly. 13:05
19 which are understandable and partially 13:03 19 Q. But the Clinical Studies section 13:05
20 informed readers of what might happen to a 13:04 20 instructs prescribers that to FDA's satisfaction 13:05
21 particular patient. But not -- these are -- 13:04 21 the drug was shown to be safe and effective in 13:05
22 particularly because these are median 13:04 22 patients with severe hypertriglyceridemia to 13:05
23 results, there -- there's results that are 13:04 23 reduce their triglyceride levels, correct? 13:05
24 potentially much higher and there's results 13:04 24 MS. FUNDAKOWSKI: Objection; form. 13:05
25 that are potentially much lower. 13:04 25 THE WITNESS: That's correct. And 13:05
Page 152 Page 153

1 that this -- and that the data here are -- 13:05 1 it says: "Group Results and Individual Subject 13:07
2 are part of the basis for making that 13:05 2 Data." 13:07
3 judgment. 13:05 3 A. I'm sorry, which page? 13:07
4 BY MR. SIPES: 13:05 4 Q. I'm sorry. Page 8. 13:07
5 Q. And in fact, even the conclusion that 13:05 5 A. Okay. 13:07
6 the drug was effective to reduce triglycerides 13:05 6 Q. You see there is a heading "Group 13:07
7 was based on the conclusion about the median 13:06 7 Results and Individual Subject Data"? 13:07
8 patient, correct? 13:06 8 A. Yes. 13:07
9 MS. FUNDAKOWSKI: Objection; form. 13:06 9 Q. It says: "In most cases, the 13:07
10 THE WITNESS: I don't know that the 13:06 10 treatment effect is presented as a mean or median 13:07
11 assessment only looked at medians. It 13:06 11 result accompanied by a measure of uncertainty or 13:07
12 looked at the data in -- there was a broader 13:06 12 distribution of results for the treated groups." 13:07
13 view of the data, but certainly that was -- 13:06 13 Correct? 13:07
14 this would be a significant part of the 13:06 14 A. Yes. 13:07
15 basis for concluding the drug works. 13:06 15 Q. So FDA's conclusion is that in most 13:07
16 BY MR. SIPES: 13:06 16 cases the most helpful information to prescribers 13:07
17 Q. And in fact, the data on the reduction 13:06 17 in making their prescribing decision is to be 13:07
18 in triglycerides in the Clinical Studies section 13:06 18 given mean or median results, correct? 13:07
19 is also median data, correct? 13:06 19 MS. FUNDAKOWSKI: Objection; form. 13:07
20 A. On this Table 2? 13:06 20 THE WITNESS: Well, I think this 13:07
21 Q. Yes. In the table on treatment 13:06 21 discussion suggests there's several 13:07
22 effects in the Clinical Studies section. 13:06 22 different ways in which the findings of a 13:07
23 A. Yes. 13:06 23 study can be conveyed in understandable 13:07
24 Q. And if you'll turn to the clinical 13:06 24 ways, and that's certainly one of them, and 13:08
25 studies guidance, Mathers Exhibit 13, you'll see 13:06 25 it seems to be the one that they used. 13:08
39
028
Page 154 Page 155

1 BY MR. SIPES: 13:08 1 patients with Vascepa so as to reduce 13:09
2 Q. In fact, they say that's the one they 13:08 2 triglycerides and lower Apo B levels, correct? 13:09
3 use in most cases, correct? 13:08 3 MS. FUNDAKOWSKI: Objection; form. 13:09
4 A. Yes. 13:08 4 THE WITNESS: They might, focusing on 13:09
5 Q. Some prescribers will understand the 13:08 5 this table of results. I think that that 13:09
6 Vascepa labeling to tell them that they can 13:08 6 could happen. But that would not be -- but 13:09
7 administer Vascepa to their severely 13:08 7 the -- the product isn't approved for that 13:10
8 hypertriglyceridemic patients so as to reduce 13:08 8 purpose. 13:10
9 triglycerides without raising LDL-C, correct? 13:08 9 BY MR. SIPES: 13:10
10 MS. FUNDAKOWSKI: Objection; form. 13:08 10 Q. But they would certainly understand 13:10
11 THE WITNESS: I think that's a fair 13:08 11 that from the labeling, correct? 13:10
12 prediction. 13:08 12 A. They could see the result here and 13:10
13 BY MR. SIPES: 13:08 13 have a feeling for why that might have a -- 13:10
14 Q. And that objective will be met in the 13:08 14 have -- have a basis to evaluate the possibility 13:10
15 majority of cases, correct? 13:08 15 that that would happen. 13:10
16 MS. FUNDAKOWSKI: Objection; form. 13:09 16 Q. And the prescriber's objective of 13:10
17 THE WITNESS: I don't know if 13:09 17 reducing triglycerides in a severely 13:10
18 statistics suggest that it will be the 13:09 18 hypertriglyceridemic patient and also lowering 13:10
19 majority of cases, but it is -- and you 13:09 19 Apo B levels would be met in a majority of cases, 13:10
20 couldn't predict which particular -- how a 13:09 20 correct? 13:10
21 particular patient will respond. But yes. 13:09 21 MS. FUNDAKOWSKI: Objection; form. 13:10
22 BY MR. SIPES: 13:09 22 THE WITNESS: Except that the -- well, 13:10
23 Q. And similarly, some physicians will 13:09 23 if that was their objective they -- this 13:10
24 read the Vascepa labeling to understand that they 13:09 24 might indicate that it would happen. 13:11
25 can treat their severely hypertriglyceridemic 13:09 25 BY MR. SIPES: 13:11
Page 156 Page 157

1 Q. And by "this," you're referring to the 13:11 1 THE WITNESS: Well, the intent or 13:12
2 Clinical Studies section? 13:11 2 desire not to increase LDL-C is an 13:12
3 A. Yes. 13:11 3 incidental result. The indication for use 13:12
4 Q. In your view, would a physician who 13:11 4 of the drug is to -- is just to reduce the 13:12
5 was prescribing Vascepa to a severely 13:11 5 triglycerides. 13:12
6 hypertriglyceridemic patient as an adjunct to 13:11 6 BY MR. SIPES: 13:12
7 diet so as to reduce triglycerides and not raise 13:11 7 Q. It is within the scope of the approved 13:13
8 LDL-C be prescribing the drug off label? 13:11 8 use of Vascepa for a physician to administer 13:13
9 A. Could you repeat the question? 13:11 9 Vascepa to a severely hypertriglyceridemic 13:13
10 Q. Yes. 13:11 10 patient with the intent to reduce triglycerides 13:13
11 Would a physician who prescribes 13:11 11 and also reduce Apo B, correct? 13:13
12 Vascepa as an adjunct to diet to a severely 13:11 12 MS. FUNDAKOWSKI: Objection; form. 13:13
13 hypertriglyceridemic patient with the intent to 13:11 13 THE WITNESS: I think -- I think if 13:13
14 reduce triglycerides and not raise LDL-C, is that 13:11 14 the motivation for taking the drug or 13:13
15 physician prescribing the product off label? 13:11 15 administering the drug is to reduce Apo B, 13:13
16 MS. FUNDAKOWSKI: Objection; form. 13:12 16 that sounds like an incidental -- it's 13:13
17 THE WITNESS: I don't -- I don't 13:12 17 either incidental or it's off label. 13:13
18 believe so. 13:12 18 BY MR. SIPES: 13:13
19 BY MR. SIPES: 13:12 19 Q. Which is it? If the physician is 13:13
20 Q. And so it is within the scope of the 13:12 20 prescribing Vascepa as an adjunct to diet to a 13:13
21 approved use for a physician to prescribe Vascepa 13:12 21 severely hypertriglyceridemic patient with the 13:13
22 as an adjunct to diet to treat a severely 13:12 22 intent to reduce triglycerides and also reduce 13:13
23 hypertriglyceridemic patient so as to reduce 13:12 23 Apo B, is that an off-label use? 13:13
24 triglycerides and not raise LDL-C, correct? 13:12 24 MS. FUNDAKOWSKI: Objection; form. 13:13
25 MS. FUNDAKOWSKI: Objection; form. 13:12 25 THE WITNESS: I think it's a 13:13
40
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Page 158 Page 159

1 combination of an on-label and off-label 13:13 1 manufacturers to promote a drug beyond the scope 13:15
2 use. 13:14 2 of approval of the drug, correct? 13:15
3 BY MR. SIPES: 13:14 3 A. Generally, that's correct. 13:15
4 Q. So you believe it would be an 13:14 4 Q. But if you turn to the clinical 13:15
5 off-label use? 13:14 5 studies guidance that we've just been discussing, 13:15
6 A. I think to take -- to administer it in 13:14 6 Mathers Exhibit 13, if you turn to page 11, FDA 13:15
7 order to reduce Apo B is not within the 13:14 7 notes that "Advertising and promotion make 13:15
8 indication. 13:14 8 frequent use of statements or data appearing in 13:15
9 Q. Even if it's an incident to reducing 13:14 9 the Clinical Studies section." 13:16
10 triglycerides in a severely hypertriglyceridemic 13:14 10 Do you see that? 13:16
11 patient? 13:14 11 A. Yes. 13:16
12 A. Repeat the question. 13:14 12 Q. And that's true, is it not? 13:16
13 Q. You believe that a physician's 13:14 13 A. Yes. 13:16
14 prescription of Vascepa to treat severe 13:14 14 Q. So FDA understands that the treatment 13:16
15 hypertriglyceridemia as an adjunct to diet by 13:14 15 effects reported in the Clinical Studies section 13:16
16 reducing triglycerides and also reducing Apo B 13:14 16 are a portion of the approved labeling that are 13:16
17 would be off label even though the effect on Apo 13:15 17 often used in promotional activities by the drug 13:16
18 B is in combination with the intent to reduce 13:15 18 manufacturer, correct? 13:16
19 triglycerides? 13:15 19 MS. FUNDAKOWSKI: Objection; form. 13:16
20 MS. FUNDAKOWSKI: Objection; form. 13:15 20 THE WITNESS: Yes. 13:16
21 THE WITNESS: Yeah, I think that would 13:15 21 BY MR. SIPES: 13:16
22 be extending -- would extend beyond the 13:15 22 Q. And FDA does not consider that 13:16
23 approved use of the drug. 13:15 23 promotion as off label, does it? 13:16
24 BY MR. SIPES: 13:15 24 A. It may or may not be. 13:16
25 Q. And FDA, of course, won't allow 13:15 25 Q. You're aware that Vascepa is promoted 13:16
Page 160 Page 161

1 for its ability to reduce triglycerides in 13:16 1 that there wasn't an objection might -- 13:18
2 severely hypertriglyceridemic patients without 13:16 2 assuming that the statement is true, would 13:18
3 raising LDL-C, are you not? 13:16 3 nevertheless potentially be regarded by FDA 13:18
4 A. I have seen promotional materials that 13:16 4 as off label but they wouldn't object to it. 13:18
5 make statements about -- about the other lipids. 13:16 5 BY MR. SIPES: 13:18
6 Q. And in fact you've seen that FDA 13:16 6 Q. Let me just make sure I understand 13:18
7 reviewed that promotional activity and did not 13:16 7 what you're saying. We'll come back to the 13:18
8 object to it, correct? 13:16 8 Vascepa approved labeling. 13:18
9 A. Yes. 13:17 9 A. Okay. 13:18
10 Q. So FDA does not view promoting Vascepa 13:17 10 Q. And look in the Clinical Studies 13:18
11 for treatment of severe hypertriglyceridemia by 13:17 11 section on page 7 of the Vascepa approved 13:18
12 reducing triglycerides without raising LDL-C is 13:17 12 labeling. 13:18
13 off label, does it? 13:17 13 A. Okay. 13:18
14 A. I did not see an objection to the 13:17 14 Q. The Vascepa approved labeling in the 13:18
15 inclusion of the statement about lipid effects. 13:17 15 Clinical Studies section states expressly "The 13:18
16 Q. So FDA does not view discussion of the 13:17 16 reduction in triglycerides observed with Vascepa 13:18
17 lipid effects in promotional material as off 13:17 17 was not associated with elevations in LDL-C 13:18
18 label, correct? 13:17 18 levels relative to placebo." 13:18
19 MS. FUNDAKOWSKI: Objection; form. 13:17 19 Do you see that? 13:18
20 THE WITNESS: I'm not sure -- I'm not 13:17 20 A. Yes. 13:18
21 sure of that because the FDA has -- has had 13:17 21 Q. Is it your testimony that a statement 13:18
22 to -- has had reason to limit its objections 13:17 22 by a drug manufacturer that in using Vascepa in 13:19
23 to promotional statements that it considers 13:18 23 accordance with the approved labeling, the 13:19
24 off label based on First Amendment 13:18 24 reduction in triglycerides observed with Vascepa 13:19
25 considerations. So I'm not sure of the fact 13:18 25 was not associated with elevations in LDL-C 13:19
41
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Page 166 Page 167

1 administration to severely hypertriglyceridemic 13:24 1 part to determine the intended uses in those 13:25
2 patients was not associated with elevations in 13:24 2 promotional claims? 13:25
3 LDL-C levels relative to placebo given that that 13:24 3 MS. FUNDAKOWSKI: Objection; form. 13:25
4 statement appears in the Clinical Studies section 13:24 4 THE WITNESS: The question of whether 13:25
5 of the approved labeling for the drug? 13:24 5 the -- there are two questions. One, you're 13:25
6 A. With appropriate context, that's 13:24 6 recommending a use that doesn't fall within 13:25
7 the -- there are other considerations about 13:24 7 the scope of the indications statement. The 13:25
8 appropriate promotion. 13:24 8 other one would be whether you're making 13:25
9 Q. But it is correct, is it not, that FDA 13:24 9 claims that are outside -- that are 13:25
10 would view that statement as creating an intended 13:24 10 inconsistent with the labeling. And one 13:25
11 use for the product of reducing triglycerides in 13:24 11 could be advised that -- I could advise 13:25
12 severely hypertriglyceridemic patients without 13:24 12 people that neither of those are true in 13:26
13 raising LDL-C, correct? 13:24 13 this case, that it is not off label and it's 13:26
14 MS. FUNDAKOWSKI: Objection; form. 13:25 14 not inconsistent. 13:26
15 THE WITNESS: I don't -- I don't see 13:25 15 BY MR. SIPES: 13:26
16 that as a -- as something that would be 13:25 16 Q. Which is to say FDA would say that 13:26
17 assessed as far as an intended use. It's a 13:25 17 recommending the use of Vascepa to reduce 13:26
18 promotional claim. 13:25 18 triglyceride levels in severely 13:26
19 MS. FUNDAKOWSKI: Counsel, it's been a 13:25 19 hypertriglyceridemic patients without raising 13:26
20 little over an hour. Can we take a break 13:25 20 LDL-C was consistent with the approved drug 13:26
21 soon? 13:25 21 labeling? 13:26
22 MR. SIPES: As soon as we finish this 13:25 22 MS. FUNDAKOWSKI: Objection; form. 13:26
23 up. 13:25 23 THE WITNESS: I think they can say 13:26
24 BY MR. SIPES: 13:25 24 that it's not -- that it is not 13:26
25 Q. Aren't promotional claims reviewed in 13:25 25 inconsistent. But I don't think they have 13:26
Page 168 Page 169

1 to decide that that's a different -- that is 13:26 1 more than one basis on which to argue to FDA 13:27
2 a different intended use than -- than is 13:26 2 that that's acceptable. 13:27
3 covered by the indications table. 13:26 3 BY MR. SIPES: 13:27
4 BY MR. SIPES: 13:26 4 Q. But the basis that we have here is 13:27
5 Q. But it would be a different use if 13:26 5 that it occurs in the Clinical Studies section of 13:28
6 that statement that the reduction in TG observed 13:26 6 the labeling, correct? 13:28
7 with Vascepa was not associated with elevations 13:27 7 A. That would certainly be one basis that 13:28
8 in the LDL-C levels relative to placebo was not 13:27 8 it would set. 13:28
9 present in the Clinical Studies section of the 13:27 9 MR. SIPES: Why don't we take a break. 13:28
10 label? 13:27 10 MS. FUNDAKOWSKI: Thank you. 13:28
11 MS. FUNDAKOWSKI: Objection; form. 13:27 11 THE VIDEOGRAPHER: We are off the 13:28
12 MR. SIPES: Let me rephrase it. 13:27 12 record, 1:28. 13:28
13 BY MR. SIPES: 13:27 13 (Recess taken.)
14 Q. The ability to promote the product -- 13:27 14 THE VIDEOGRAPHER: We are back on the 13:42
15 scratch that. 13:27 15 record, 1:42. 13:42
16 The ability to promote Vascepa on the 13:27 16 BY MR. SIPES: 13:42
17 basis that it reduces triglyceride levels in 13:27 17 Q. Mr. Mathers, the FDA's regulations 13:42
18 severely hypertriglyceridemic patients without 13:27 18 instruct that the Clinical Studies section must 13:42
19 raising LDL-C is predicated upon the existence of 13:27 19 discuss those clinical studies that facilitate an 13:42
20 that statement in the Clinical Studies section of 13:27 20 understanding of how to use the drug safely and 13:42
21 the labeling, correct? 13:27 21 effectively, correct? 13:42
22 MS. FUNDAKOWSKI: Objection; form. 13:27 22 A. Yes. 13:42
23 THE WITNESS: I'm not sure that's 13:27 23 Q. And in referring to an understanding 13:42
24 true. Even if it wasn't there, if it was 13:27 24 of how to use the drug safely and effectively, it 13:42
25 true, there could be, you know, more than -- 13:27 25 is referring to a prescriber's understanding, 13:42
43
031
Page 170 Page 171

1 correct? 13:42 1 labeling provides with regard to baseline lipid 13:43
2 A. Yes. 13:42 2 levels for administration of the drug are those 13:43
3 Q. So the goal of the Clinical Studies 13:42 3 set forth in the Clinical Studies section, 13:43
4 section is to facilitate a prescriber's 13:42 4 correct? 13:43
5 understanding of how to use the drug safely and 13:42 5 MS. FUNDAKOWSKI: Objection; form. 13:43
6 effectively, correct? 13:42 6 THE WITNESS: I don't know that 13:44
7 A. That's one of the goals, yes. 13:42 7 that's -- that I regard that as a suggestion 13:44
8 Q. And the Dosage and Administration 13:43 8 or guidance as to which levels to measure. 13:44
9 section provides instructions on how to 13:43 9 There could be others, and some of those may 13:44
10 administer the drug product in accordance with 13:43 10 not be necessary. But that's -- 13:44
11 its approved use, correct? 13:43 11 BY MR. SIPES: 13:44
12 A. Yes. 13:43 12 Q. It was previously your testimony, was 13:44
13 Q. And the Vascepa labeling instructs 13:43 13 it not, that the description of the diet in the 13:44
14 physicians to assess lipid levels before 13:43 14 patient information helps to explain to a 13:44
15 initiating therapy, correct? 13:43 15 prescriber an appropriate lipid-lowering diet in 13:44
16 A. Yes. 13:43 16 accordance with the Indications and Usage 13:44
17 Q. And similarly, the defendants' 13:43 17 section? 13:44
18 proposed labeling instructs physicians to assess 13:43 18 A. Yes. 13:44
19 lipid levels before initiating therapy, correct? 13:43 19 Q. Wouldn't a description of the baseline 13:44
20 A. Yes. 13:43 20 lipid levels in the Clinical Studies section help 13:44
21 Q. And the lipid levels before initiating 13:43 21 to explain to a prescriber what the appropriate 13:44
22 therapy would be the patient's baseline lipid 13:43 22 baseline lipid levels were for a patient to be 13:44
23 levels, correct? 13:43 23 administered Vascepa? 13:44
24 A. Yes, at that time. Yeah. 13:43 24 MS. FUNDAKOWSKI: Objection; form. 13:44
25 Q. And the only guidance that the 13:43 25 THE WITNESS: In a similar way by 13:44
Page 172 Page 173

1 giving data on a range of lipids, those -- a 13:44 1 Q. You don't have an understanding of 13:46
2 person reading the label might -- might 13:44 2 what the clinical relevance of the lipid 13:46
3 consider testing for those, but it might 13:45 3 parameters in the Clinical Studies section are 13:46
4 also consider testing for others. 13:45 4 for purposes of administration of Vascepa, 13:46
5 BY MR. SIPES: 13:45 5 correct? 13:46
6 Q. It is fair to say that the Clinical 13:45 6 A. Not the specific list of parameters 13:46
7 Studies section of the Vascepa labeling 13:45 7 that are listed there. I know they're not all of 13:46
8 facilitates a prescriber's understanding of 13:45 8 them, all the potentially relevant lipids, but 13:46
9 baseline lipid levels and in implementing the 13:45 9 they are the ones that are there. 13:46
10 instruction in the Dosage Administration section 13:45 10 Q. When you say they're not all of them, 13:46
11 to assess lipid levels before initiating therapy, 13:45 11 do you mean that there are additional potentially 13:46
12 correct? 13:45 12 relevant lipids beyond the ones described in the 13:46
13 MS. FUNDAKOWSKI: Objection; form. 13:45 13 Clinical Studies section? 13:46
14 THE WITNESS: I don't know that it 13:45 14 A. Yes. 13:46
15 facilitates the understanding of what should 13:45 15 Q. What other additional potentially 13:46
16 be tested. And, you know -- the data don't 13:45 16 relevant lipids might there be, lipid parameters 13:46
17 indicate which is important to measure. The 13:45 17 might there be? 13:47
18 baseline -- the baselines presented there 13:45 18 A. Oh, I'm not familiar with the entire 13:47
19 are baselines for patients in the study and 13:45 19 list of lipids. I know, again from personal 13:47
20 not the baselines for -- and the patient's 13:46 20 experience, when I've had my lipids tested, there 13:47
21 baselines may be completely different. It 13:46 21 is a longer list than they have here. 13:47
22 would be -- it's information that the 13:46 22 Q. Can you identify a potentially 13:47
23 prescriber would have which relates to 13:46 23 relevant lipid parameter which is not identified 13:47
24 potentially relevant lipids. 13:46 24 in the Clinical Studies section of the Vascepa 13:47
25 BY MR. SIPES: 13:46 25 labeling? 13:47
44
032
Page 174 Page 175

1 A. I don't think I could specifically 13:47 1 recognized disease or condition, that is, it is 13:48
2 identify one. For instance, I'm aware that 13:47 2 indicated only to reduce triglyceride levels when 13:48
3 there's subsets of different particle size and 13:47 3 they meet or exceed 500 milligrams per 13:48
4 particle size distribution which -- which aren't 13:47 4 deciliter." Correct? 13:48
5 included there. 13:47 5 A. Yes. 13:48
6 Q. Do you know whether particle size 13:47 6 Q. The Indications section itself does 13:48
7 distribution of any particular lipid particle 13:47 7 not provide an upper limit on triglyceride 13:48
8 would be clinically relevant in the treatment of 13:47 8 levels, correct? 13:48
9 severe hypertriglyceridemia? 13:48 9 A. No, it doesn't. 13:48
10 A. No. 13:48 10 Q. The Clinical Studies section sets 13:49
11 Q. And you had no discussions with any 13:48 11 forth an upper limit of 2000 milligrams per 13:49
12 clinician regarding the potential relevance of 13:48 12 deciliter for inclusion in the MARINE clinical 13:49
13 them -- 13:48 13 study, correct? 13:49
14 A. No. 13:48 14 A. I believe that's correct. 13:49
15 Q. Let me finish the question. 13:48 15 Q. Feel free to check. 13:49
16 A. Sorry. 13:48 16 A. 500 and 2000. 13:49
17 Q. You did not have a discussion with a 13:48 17 Q. But the upper limit on triglycerides 13:49
18 clinician regarding the potential relevance of 13:48 18 in the Clinical Studies section does not limit 13:49
19 any of the lipid parameters identified in the 13:48 19 the approved indication, correct? 13:49
20 Vascepa approved labeling Clinical Studies 13:48 20 A. No, it doesn't. 13:49
21 section, correct? 13:48 21 Q. The approved indication for Vascepa 13:49
22 A. Correct. 13:48 22 reflects FDA's judgment that the drug was safe 13:49
23 Q. Let me ask you to turn to Paragraph 97 13:48 23 and effective for reduction of triglycerides for 13:49
24 of your report. In Paragraph 97 you state: 13:48 24 patients with triglyceride levels of 500 13:49
25 "Vascepa is indicated for the manifestation of a 13:48 25 milligrams per deciliter or above without an 13:49
Page 176 Page 177

1 upper limit, correct? 13:49 1 if FDA made a specific safety and 13:51
2 A. Yeah, the approved indication does 13:49 2 effectiveness finding with respect to -- 13:51
3 not -- does not have an upper limit. 13:49 3 with respect to patients above -- with 13:51
4 Q. So it was FDA's judgment that the drug 13:49 4 triglycerides above 2000 when they didn't 13:51
5 was safe and effective for reduction of 13:50 5 have any evidence of that. 13:51
6 triglycerides for patients with triglyceride 13:50 6 BY MR. SIPES: 13:51
7 levels of 500 milligrams per deciliter or above, 13:50 7 Q. A physician who prescribed -- scratch 13:51
8 correct? 13:50 8 that. 13:51
9 MS. FUNDAKOWSKI: Objection; form. 13:50 9 A physician who administered Vascepa 13:51
10 THE WITNESS: Well, by not excluding 13:50 10 to a severely hypertriglyceridemic patient whose 13:51
11 it, they are extrapolating a finding from 13:50 11 triglyceride levels was 2500 milligrams per 13:51
12 the clinical trial to some extent, and they 13:50 12 deciliter would be using the product on label, 13:51
13 presumably concluded that there isn't a 13:50 13 correct? 13:51
14 reason to -- either isn't a reason to -- 13:50 14 A. Yes. 13:51
15 there isn't either a safety or effectiveness 13:50 15 MS. FUNDAKOWSKI: Objection; form. 13:51
16 reason to exclude them. 13:50 16 THE WITNESS: Sorry. 13:51
18 Q. And just to be clear, there is not a 13:50 18 Q. If you'll look at Paragraph 101. Turn 13:51
19 safety or effectiveness reason to exclude 13:50 19 to page 38. The second sentence of Paragraph 101 13:51
20 patients whose triglycerides are above 2000, 13:50 20 states: "FDA requires the Indications and Usage 13:51
21 correct? 13:50 21 section to cross-reference another section only 13:51
22 MS. FUNDAKOWSKI: Objection; form. 13:50 22 when doing so provides a clearer understanding of 13:52
23 THE WITNESS: Well, if there was one, 13:50 23 the scope of the approved indication to 13:52
24 FDA didn't -- dismissed it or found it to be 13:50 24 facilitate safe and effective prescribing 13:52
25 unnecessary to address. I just don't know 13:51 25 decisions regarding a limitation in use." 13:52
45
033
Page 182 Page 183

1 indication that relates to reducing triglyceride 14:23 1 Q. What do you mean by that, consistent 14:25
2 levels while also controlling LDL-C? 14:23 2 with the approved indication? 14:25
3 A. Not specifically, no. 14:24 3 A. Well, that the therapeutic use is to 14:25
4 Q. Did FDA approve Vascepa for any 14:24 4 affect triglycerides and to reduce them. And 14:25
5 indication that relates to reducing triglyceride 14:24 5 that's the approved use. 14:25
6 levels while also controlling Apo B? 14:24 6 Q. Does the approved use -- 14:25
7 A. No. 14:24 7 A. The approved use doesn't include 14:25
8 Q. Previously, counsel asked you some 14:24 8 reducing Apo B or anything about LDL-C, although 14:25
9 questions about whether certain uses would be off 14:24 9 the label describes what might happen. 14:26
10 label. Do you remember that? 14:24 10 Q. Does the label specifically encourage 14:26
11 A. I remember some of those questions. 14:24 11 reducing Apo B? 14:26
12 Q. For example, counsel asked would a 14:24 12 MR. SIPES: Objection; form. 14:26
13 physician who prescribes Vascepa as an adjunct to 14:24 13 THE WITNESS: I don't believe so. 14:26
14 diet to severely hypertriglyceridemic patients 14:24 14 BY MS. FUNDAKOWSKI: 14:26
15 with the intent to reduce triglycerides and not 14:24 15 Q. Does the label specifically encourage 14:26
16 raise LDL-C, is that physician prescribing the 14:24 16 not raising LDL-C? 14:26
17 product off label? And you answered, "I don't 14:24 17 A. Well, that's kind of a double 14:26
18 believe so." Is that right? 14:24 18 negative. I don't think it encourages -- I don't 14:26
19 MR. SIPES: Objection; leading. 14:25 19 think so. 14:26
20 THE WITNESS: The intent to -- the 14:25 20 Q. What do you mean when you say 14:26
21 intent to control triglycerides while hoping 14:25 21 something is an off-label use? 14:26
22 that the other -- the other parameters 14:25 22 A. Well, you're using the drug for a 14:26
23 aren't affected appears, to me, to be 14:25 23 purpose for which it was not approved. Are you 14:26
24 consistent with the approved indication. 14:25 24 using it in a way in which it wasn't approved? 14:26
25 BY MS. FUNDAKOWSKI: 14:25 25 Q. What do you mean by not approved? Not 14:27
Page 184 Page 185

1 approved by FDA? 14:27 1 documents relating to Amarin's pending 14:29
2 A. Yes. 14:27 2 supplemental NDA for a second indication. 14:29
3 Q. Is it possible for something to be on 14:27 3 We have not received those documents yet. 14:29
4 label that is within the scope of approval but 14:27 4 To the extent that production is 14:29
5 not something -- not a use that FDA specifically 14:27 5 relevant to the regulatory issues in this 14:29
6 approved? 14:27 6 case and specifically to Mr. Mathers' 14:29
7 MR. SIPES: Objection; form. 14:27 7 opinions and testimony, we reserve the right 14:29
8 THE WITNESS: Well, what do you mean 14:27 8 for Mr. Mathers to supplement his expert 14:29
9 by "specifically approved"? There's the 14:27 9 report. 14:29
10 general approval to reduce triglycerides 14:27 10 MR. SIPES: We have your statement. 14:29
11 but -- and within that are -- because there 14:28 11 We don't necessarily agree with it, but we 14:29
12 aren't a lot of limitations in the labeling, 14:28 12 understand what you're asking. 14:29
13 there are various potential uses that aren't 14:28 13 But I have a few follow-up questions, 14:29
14 specifically approved but don't necessarily 14:28 14 Mr. Mathers. 14:29
15 fall outside of the indication. 14:28 15 EXAMINATION
16 BY MS. FUNDAKOWSKI: 14:28 16 BY MR. SIPES: 14:29
17 Q. Understood. 14:28 17 Q. If you'll look at the Vascepa approved 14:29
18 At any point during this deposition 14:28 18 labeling, you recall Ms. Fundakowski asking you a 14:29
19 did we discuss the substance of your testimony? 14:28 19 couple of questions about what FDA had 14:29
20 A. Only when we were on the record. 14:28 20 specifically approved. Do you recall that? 14:29
21 MR. SIPES: Thank you. 14:28 21 A. Yes. 14:29
22 I do not have any further questions. 14:28 22 Q. There is a statement in the Clinical 14:29
23 I would just like to state for the record we 14:28 23 Studies section of Vascepa approved labeling that 14:30
24 had asked opposing counsel for their 14:28 24 states: "The reduction in TG observed with 14:30
25 regulatory correspondence and certain 14:29 25 Vascepa was not associated with elevations in 14:30
47
034
Page 186 Page 187

1 LDL-C levels relative to placebo." Correct? 14:30 1 A. Yes. 14:31
2 A. Yes. 14:30 2 Q. So FDA specifically approved the 14:31
3 Q. So FDA specifically approved the 14:30 3 statement in the Vascepa approved labeling that 14:31
4 statement in the Vascepa approved labeling that 14:30 4 Vascepa 4 grams per day reduced median TG, 14:31
5 the reduction in TG observed with Vascepa is not 14:30 5 VLDL-C, and Apo B levels from baseline relative 14:31
6 associated with elevations in LDL-C levels 14:30 6 to placebo in the context of treating severely 14:31
7 relative to placebo, correct? 14:30 7 hypertriglyceridemic patients, correct? 14:31
8 A. Yes. 14:30 8 MS. FUNDAKOWSKI: Objection to form. 14:31
9 MS. FUNDAKOWSKI: Objection; form. 14:30 9 THE WITNESS: Yes, they approved the 14:31
10 THE WITNESS: Yes. 14:30 10 statement describing those results. 14:31
12 Q. And similarly, defendants' proposed 14:30 12 Q. The statement the reduction in TG 14:31
13 labeling is seeking approval for labeling that 14:30 13 observed with Vascepa was not associated with 14:31
14 contains exactly the same statement, correct? 14:30 14 elevations in LDL-C levels relative to placebo in 14:31
15 A. Yes. 14:30 15 the Clinical Studies section relates to the use 14:31
16 Q. The Vascepa approved labeling states: 14:30 16 of Vascepa for the treatment of severe 14:31
17 "Vascepa 4 grams per day reduced median TG, 14:30 17 hypertriglyceridemia, correct? 14:31
18 VLDL-C, and Apo B levels from baseline relative 14:30 18 MS. FUNDAKOWSKI: Objection; form. 14:31
19 to placebo." Correct? 14:30 19 THE WITNESS: Yes, it relates to 14:31
20 A. Yes. 14:30 20 that -- to that use as it was studied in the 14:31
21 Q. And that statement is made in the 14:30 21 study. 14:31
22 context of clinical trial results in which 14:30 22 BY MR. SIPES: 14:31
23 Vascepa was administered as an adjunct to diet to 14:30 23 Q. In fact, pursuant to its regulations, 14:31
24 patients with severe hypertriglyceridemia, 14:30 24 FDA will not approve labeling that contains 14:31
25 correct? 14:31 25 information in the Clinical Studies section that 14:32
Page 188 Page 189

1 implies or suggests indications for uses or 14:32 1 MS. FUNDAKOWSKI: Objection; form. 14:33
2 dosing regimens not stated in the Indications and 14:32 2 THE WITNESS: Yes. These are relevant 14:33
3 Usage or Dosage Administration section, correct? 14:32 3 results even though only the first part of 14:33
4 A. That's correct. 14:32 4 that sentence, reduced median TG, is 14:33
5 Q. So FDA's approval of the Vascepa 14:32 5 included in the indication itself. 14:33
6 Clinical Studies section implies FDA's conclusion 14:32 6 MR. SIPES: Thank you. I have no 14:33
7 that the statement that the reduction in TG 14:32 7 further questions. 14:33
8 observed with Vascepa was not associated with 14:32 8 MS. FUNDAKOWSKI: Thank you. 14:33
9 elevations in LDL-C levels relative to placebo, 14:32 9 THE VIDEOGRAPHER: We are off the 14:33
10 that that statement was related to use of the 14:32 10 record, 2:33. 14:33
11 drug in connection with the approved indication, 14:32 11 (Deposition adjourned at 2:33 p.m.)
12 correct? 14:32 12
13 MS. FUNDAKOWSKI: Objection; form. 14:32 13
14 THE WITNESS: It's relevant to the 14:32 14
15 use, and it's a description of what the 14:32 15
16 study showed. 14:32 16
17 BY MR. SIPES: 14:32 17
18 Q. And similarly, the statement in the 14:32 18
19 Clinical Studies section of the Vascepa approved 14:32 19
20 labeling that Vascepa 4 grams per day reduced 14:33 20
21 median TG, VLDL-C, and Apo B levels from baseline 14:33 21
22 relative to placebo is relevant to the use of 14:33 22
23 Vascepa for treatment of severe 14:33 23
24 hypertriglyceridemia in accordance with the 14:33 24
25 approved Indications and Usage section, correct? 14:33 25
48
035
Page 191
1 C E R T I F I C A T E
2
3 DISTRICT OF COLUMBIA
4 I, JOHN L. HARMONSON, a Notary Public
5 within and for the District of Columbia, do
6 hereby certify:
7 That PETER R. MATHERS, the witness
8 whose deposition is hereinbefore set forth, was
9 duly sworn or affirmed by me and that such
10 deposition is a true record of the testimony
11 given by such witness.
12 That if the foregoing pertains to a
13 federal case, before completion of the
14 proceedings, review and signature of the
15 transcript [x] was [ ] was not requested.
16 I further certify that I am not related
17 to any of the parties to this action by blood or
18 marriage; and that I am in no way interested in
19 the outcome of this matter.
20 IN WITNESS WHEREOF, I have hereunto set
21 my hand this 11th day of July, 2019.
22
23 ______________________________
24 JOHN L. HARMONSON, RPR
My commission expires: 11/14/20
25

036
EXHIBIT 5
Matthew Budoff, M.D., dated July 17, 2019
(FILED UNDER SEAL)

EXHIBIT 6
Carl C. Peck, M.D., dated July 1, 2019
Case 2:16-cv-02525-MMD-NJK Document 253-6 Filed 08/30/19 Page 2CARL
AMARIN PHARMA, INC. v.
of 28 C. PECK, M.D.
HIKMA PHARMACUTICALS USA INC. July 1, 2019
Page 1 Page 3
1 THE UNITED STATES DISTRICT COURT 1 A P P E A R A N C E S:
2 DISTRICT OF NEVADA 2 WINSTON STRAWN, LLP
3 AMARIN PHARMA, INC. and AMARIN 3 Attorneys for the Defendant
PHARMACEUTICALS IRELAND LIMITED,
4 4 1700 K Street, NW
Plaintiffs,
5 vs. NO: 2:16-cv-02525- 5 Washington, DC 20006
MMD-NJK
6 Consolidated with: 6 cklein@winston.com
2:16-cv-02562-MMD-NJK
7 HIKMA PHARMACUTICALS USA INC, 7 BY: CHARLES B. KLEIN, ESQ.
et al.,
8 8 CLAIRE FUNDAKOWSKI, ESQ.
Defendants.
9 _________________________________/ 9 (By speakerphone.)
10 10
11 11 COVINGTON & BURLING, LLP
12 12 Attorneys for Plaintiffs
13 VIDEOTAPED DEPOSITION OF CARL C. PECK, M.D. 13 One City Center
14 San Francisco, California 14 850 Tenth Street, NW
15 Monday, July 1, 2019 15 Washington, DC 20001
16 16 estole@cov.com
17 17 BY: EINAR STOLE, ESQ.
18 18 JORDAN MORAN, ESQ.
19 19
20 20
21 21
22 22
23 Reported By: 23
24 LINDA VACCAREZZA, RPR, CLR, CRP, CSR. NO. 10201 24
25 25
Page 2 Page 4
1 1 APPEARANCES (CONT'D)
2 2 WINDELS MARX
3 3 Attorneys for Dr. Reddy Defendant
4 4 One Giralda Farms
5 July 1, 2019 5 Madison, New Jersey 07940
6 9:27 a.m. 6 Bfinkelstein@windelsmarx.com
7 7 BY: BETH C. FINKELSTEIN, ESQ.
8 8 (By speakerphone.)
9 Videotaped Deposition of CARL C. PECK, M.D., held 9
10 at 275 Battery Street, Suite 250, San Francisco, 10
11 California, pursuant to Subpoena before Linda 11
12 Vaccarezza, a Certified Shorthand Reporter of the 12
13 State of California. 13
14 14
15 15
16 16
17 17
18 18
19 19
20 20
21 21
22 22
23 23
24 24
25 25 Videogapher: Michael Barber
Min-U-Script® Barkley Court Reporters (1) Pages 1 - 4

001
of 28 C. PECK, M.D.
Page 5 Page 7
1 I N D E X
1 THE VIDEOGRAPHER: Good morning. My name
2 WITNESS: CARL C. PECK, M.D.
2 is Michael Barber. I'm a videographer associated
3 Examination by
3 with Barkley Court Reporters located at 201
4 MR. KLEIN.................................8
4 California Street, Suite 375, San Francisco,
5 E X H I B I T S
5 California 94111. The date it July 1st, 2019. The
6 Exhibit 1
6 time is 8:43 a.m.
7 Reply expert report of Carl C. 7 This deposition is taking place at
8 Peck, M.D..................................9
8 Covington Burling LLP in Palo Alto, California in
9 Exhibit 2 9 the matter of Amarin Pharma, Inc., et al., versus
10 Document marked "Exhibit B"................12 10 Hikma Pharmaceuticals, USA Inc., et al., in the
11 Exhibit 3 11 U.S. District Court, District of Nevada. Case
12 Document marked "Exhibit C"................20 12 number 216-cv-02525-MMD-NJK consolidated with
13 Exhibit 4 13 216-cv-02562.
14 Document marked "Exhibit A"................24 14 This is the videotaped deposition of Carl
15 Exhibit 5 15 C. Peck, MD, being taken on behalf of the
16 Letter to Jean-Marc Guettier, M.D. Dated 16 defendant. Counsel, would you please identify
17 March 1, 2017..............................74 17 yourselves for the record and state whom you
18 Exhibit 6 18 represent.
19 Code of Federal Regulations, Title 21, Food 19 MR. STOLE: Einar Stole of Covington
20 And Drugs.................................119 20 Burling LLP of Washington, D.C. representing
21 Exhibit 7 21 plaintiffs Amarin. I'm accompanied by my colleague
22 Clinical Study Report, Results of the Double 22 Jordan Moran also from Covington.
23 Blind Treatment Period....................160 23 MR. KLEIN: Charles Klein, Winston &
24 24 Strawn for defendant Hikma.
25 25 THE VIDEOGRAPHER: Thank you. Would the
Page 6 Page 8
1 EXHIBITS (CONT'D)
1 court reporter --
2 Exhibit 8
2 MR. KLEIN: We have someone on the phone,
3 Guidance For Industry of Clinical Studies
3 I think.
4 Section of Labeling For Human Prescription
4 MS. FINKELSTEIN. Hi. This is Beth
5 Drug and Biological Products..............167
5 Finkelstein from Windels Marx on behalf of
6 Exhibit 9
6 Dr. Reddy.
7 Vascepa Advertisement.....................181
7 CARL C. PECK,
8 -o0o-- 8 Having been duly sworn by the Certified
9 9 Shorthand Reporter, was examined and testified as
10 10 follows.
11 11 EXAMINATION
12 12 BY MR. KLEIN:
13 13 Q. Good morning, Dr. Peck.
14 14 A. Good morning.
15 15 Q. What's your full name?
16 16 A. Carl Curtis Peck.
17 17 Q. Where do you live?
18 18 A. I live in San Luis Obispo, California.
19 19 Q. Where do you work?
20 20 A. I work mostly in San Luis, Obispo,
21 21 California or Walnut Creek where we have a second
22 22 home and wherever I need to work otherwise.
23 23 Q. And what's the name of your employer?
24 24 A. I'm a consultant to a consultancy entitled
25 25 NDA Partners.

002
of 28 C. PECK, M.D.
Page 9 Page 11
1 Q. Have you been deposed before? 1 A. Yes, yes.

2 A. Yes, I have. 2 Q. We'll get to that later.
3 Q. About how many times? 3 A. Yeah.
4 A. I think about 15. 4 Q. Are you aware of any other corrections or
5 Q. Okay. You were retained by plaintiffs in 5 are there any other corrections you would like to
6 this case as an expert witness, right? 6 make to your report?
7 A. I was retained to respond to another 7 A. No.
8 witness in this case. I'm not sure whether -- I'm 8 Q. And this is a reply expert report. This
9 not sure what the legal definition is or the 9 is the only expert report you submitted in
10 definition of an expert witness. 10 connection with this case, correct?
11 Q. Okay. You submitted an expert report? 11 A. That's correct.
12 A. I submitted a report, yes. 12 Q. And you were responding to the report by
13 Q. And generally speaking, what's the area of 13 Mr. Mathers; is that right?
14 expertise covering the subject matter of your 14 A. That's correct.
15 report? 15 Q. Were you responding to the opinions of any
16 A. FDA regulations, labeling. I come with a 16 other expert retained by the defendants in this
17 perspective of a physician and a scientist. 17 case?
18 Q. You have an MD, right? 18 A. No.
19 A. I do. 19 Q. And does your expert report Peck Exhibit 1
20 Q. Let me give you what's been marked as Peck 20 contain all of the opinions you intend to offer at
21 Exhibit 1. 21 trial if called?
22 (Exhibit 1 was marked for identification.) 22 A. Yes.
23 BY MR. KLEIN: 23 Q. And sitting here today do you stand by the
24 Q. Dr. Peck, do you recognize Exhibit 1 as a 24 opinions set forth in your reply expert report?
25 copy of the reply expert report of Carl C. Peck, 25 A. I do.
Page 10 Page 12
1 MD? 1 Q. All right. Let's go to the next exhibit.

2 A. I do. 2 (Exhibit 2 was marked for identification.)
3 Q. And if you turn to the last page, is that 3 BY MR. KLEIN:
4 your signature? 4 Q. Dr. Peck, you've been handed what has been
5 A. Yes, it is. 5 marked as Peck Exhibit 2. It says Exhibit B on the
6 Q. Have you reviewed your report since 6 first page but it's Exhibit B to your reply report,
7 submitting it on June 10th, 2019? 7 right?
8 A. Yes, I have. 8 A. Yes.
9 Q. Are you aware of any corrections or 9 Q. And Exhibit 2, Peck Deposition Exhibit 2
10 mistakes to the report that you want to make on the 10 and Exhibit B to your reply report is a list of
11 record? 11 prior testimony?
12 A. I believe in reviewing it I've found a 12 A. Yes.
13 typo, which I'm not sure I can identify that at 13 Q. Okay. And Number 6 is the matter where
14 this moment, but it was not one that would 14 you pointed out there was a typographical error; is
15 substantively change the meaning of the sentence. 15 that right?
16 And there's one date that's in error in my list of 16 A. Yes.
17 recent depositions. 17 Q. And that should say on June 7, 2019?
18 Q. Oh, okay. That will be a separate 18 A. Yes?
19 exhibit. So did it pertain to a particular case? 19 Q. Are these -- so these are cases in which
20 A. Yes, it did. 20 you testified at trial or deposition?
21 Q. Which case? 21 A. Yes.
22 A. I think it is the last one that's listed. 22 Q. Okay. Over what type of period, five
23 It had a 2018 date. The date should be 2019. 23 year, four years?
24 Q. And that's in re: National Prescription 24 A. The last four years, I believe.
25 Opiates? 25 Q. Let me ask you about the matter that's

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Page 13 Page 15
1 listed under Number 2, the Connie Hartley matter? 1 Celexa and Lexapro marketing and sales practices
2 A. Yes. 2 litigation?
3 Q. Did that have anything to do with 3 A. Yes.
4 pharmaceuticals? 4 Q. What was the general nature of that case
5 A. Yes. 5 or --
6 Q. Tell me what is the nature of that case? 6 A. I believe it dealt with the issue of
7 A. This is a malpractice case. 7 off-label promotion.
8 Q. Did you provide any opinions in that case 8 Q. And was it a -- so you testified by
9 related to FDA regulatory issues? 9 deposition?
10 A. Yes, I did. 10 A. Yes.
11 Q. Generally speaking, what is the nature of 11 Q. And did you testify at trial?
12 your opinion in that case? 12 A. No.
13 A. The nature of my opinions in that case 13 Q. Is that case ongoing?
14 related to FDA regulation of drugs that were 14 A. No, I think that was settled.
15 prescribed by Nova Law, a physician to a patient, 15 Q. Do you know whether the case listed in
16 and the regulatory status of these drugs. 16 Paragraph 3 is ongoing?
17 Q. Whether they were approved or not? 17 A. I think that that has ended as well.
18 A. Whether in fact they even fell under the 18 Q. Number 5 is the Perrigo case?
19 Food and Drug Act. 19 A. Yes.
20 Q. I see. Did your opinions have anything to 20 Q. What's the general nature of that case?
21 do with FDA labeling? 21 A. The general nature as I understand it is a
22 A. No. 22 tax fraud case. But I'm not -- I wasn't brought in
23 Q. And you testified by deposition in that 23 to provide any opinions about the fraud or taxes.
24 case? 24 Q. What was the general nature of your
25 A. Yes. 25 opinions in that case?
Page 14 Page 16
1 Q. Did you testify at trial? 1 A. I was asked to respond to another expert's

2 A. No. This case in theory is still active 2 assertions with respect to FDA requirements for
3 but it's been postponed each year for another year. 3 generic drug approval.
4 Q. Okay. The matter listed under Paragraph 3 4 Q. Okay. Did your opinions deal with FDA
5 is AstraZeneca versus Taiva? 5 labeling issues?
6 A. Yes. 6 A. No.
7 Q. Do you recall -- is that a Hatch-Waxman 7 Q. And Number 6, in re: National Prescription
8 case? Do you mean what I mean by Hatch-Waxman? 8 Opiate litigation. Is that a product liability
9 A. Yes. 9 case?
10 Q. Was that a Hatch-Waxman case? 10 A. Indirectly. Well, it's mostly dealing
11 A. Yes, I think so. 11 with FDA regulation of advertising or promotion.
12 Q. Do you recall the product at issue? 12 Q. And did your opinions in that case have
13 A. No, I don't recall at this moment. 13 anything to do with FDA labeling issues?
14 Q. Do you remember anything about the nature 14 A. Yes.
15 of the expert opinion you offered in that case? 15 Q. How so?
16 A. At this moment I don't. 16 A. Well, as I'm sure you know, FDA regulates
17 Q. But you testified by deposition? 17 advertising and promotion of prescription
18 A. I did. 18 pharmaceuticals, and generally speaking, it's not
19 Q. Did you testify at trial? 19 legal to promote a drug beyond the wording in the
20 A. No. 20 label.
21 Q. Do you recall generally whether your 21 Q. Other than off-label issues did your
22 opinions in that case had anything to do with FDA 22 opinions in that case address FDA labeling issues?
23 labeling? 23 In other words, were your opinions in that
24 A. I don't recall at this moment. 24 case limited to whether certain advertising was
25 Q. If you go to Number 4, this is the in re: 25 off-label?

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of 28 C. PECK, M.D.
Page 17 Page 19
1 A. Yes, I think that's a fair summary. 1 I've provided expert information, expert testimony
2 Q. Have you ever offered an opinion as to 2 in a few cases of product liability.
3 whether a pharmaceutical product label infringes 3 Q. Okay. And had you offered opinion in
4 outside of the context of this case, infringes a 4 connection with a patent case other than the patent
5 patent? 5 cases listed in Peck Exhibit 2?
6 MR. STOLE: Objection to form. 6 A. I believe a few.
7 THE WITNESS: Would you repeat the 7 Q. Roughly how many times have you served an
8 question, please? 8 expert report in a litigation matter?
9 BY MR. KLEIN: 9 A. Roughly 15.
10 Q. Yeah. Have you ever offered an expert 10 Q. And how many times have you testified at
11 opinion that a pharmaceutical product label would 11 trial as an expert witness?
12 induce infringement of a patent? 12 A. Six or seven.
13 MR. STOLE: Same objection. 13 Q. And of those six or seven, how many were
14 THE WITNESS: What do you mean by 14 patent cases if you recall?
15 "induce"? 15 A. Just one or two I think.
16 BY MR. KLEIN: 16 Q. When were you engaged by the plaintiffs
17 Q. Let me back up. Have you ever -- putting 17 for this case?
18 aside this case, have you ever offered an opinion 18 A. April, I believe.
19 related to issues of patent infringement? 19 Q. April 2019?
20 A. Indirectly, yes. 20 A. Yes, April 2019.
21 Q. And which -- was it any of the cases that 21 Q. At that time had you been engaged by
22 we went over? 22 Amarin in any other capacity?
23 A. I think Number 1 and Number 3 dealt with 23 A. Not -- no.
24 Paragraph 4 infringement issues, but my deposition 24 Q. And today is your sole relationship with
25 concerned FDA regulatory aspects of the NDA. 25 Amarin related to your expert opinions in this case
Page 18 Page 20
1 Q. To the best of your recollection have you 1 or do you have any other relationships with Amarin?
2 ever offered an opinion in an expert report that a 2 MR. STOLE: Objection. Form.
3 particular pharmaceutical product label infringes a 3 THE WITNESS: Would you repeat the
4 patent? 4 question, please?
5 MR. STOLE: Objection. Form. 5 BY MR. KLEIN:
6 THE WITNESS: Indirectly, I believe so. 6 Q. Yeah. When I say "relationships," I'm not
7 I'm not a legal expert so I don't render an opinion 7 talking about whether you've use an Amarin drug or
8 on whether there has been an infringement; I'm 8 anything like this; I'm talking about a contractual
9 asked questions about the regulatory framework for 9 consulting relationship for example. Do you have
10 NDA or ANDA approval and the labels related to 10 any contractual relationships with Amarin today
11 those two types of approval. 11 other than your retention as an expert witness in
12 BY MR. KLEIN: 12 this case?
13 Q. Before this case have you ever offered an 13 A. No.
14 expert opinion that a pharmaceutical product label 14 Q. Before being retained by Amarin in this
15 will encourage a physician or a patient to infringe 15 case were you familiar with a drug Vascepa?
16 a patent? 16 A. No.
17 MR. STOLE: Hold on a second. 17 Q. Before being retained by Amarin were you
18 THE WITNESS: Not that I'm aware of. 18 familiar with a drug Lovaza?
19 BY MR. KLEIN: 19 A. No.
20 Q. Have you served as an expert in connection 20 Q. All right. Let's go to another exhibit.
21 with matters not listed in Peck Exhibit 2? 21 MR. STOLE: I'm just anticipating the
22 A. I don't think any of these actually 22 reach across the table.
23 concern product liability. 23 MR. KLEIN: Got it, got it.
24 Q. No. I'm asking -- 24 (Exhibit 3 was marked for identification.)
25 A. And in past years I have -- in past years 25 BY MR. KLEIN:

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of 28 C. PECK, M.D.
Page 21 Page 23
1 Q. Dr. Peck, you've been handed what's been 1 related to my report.

2 marked as Peck Exhibit 3 and the first page says 2 Q. Did you review Mr. Mathers' report?
3 Exhibit C but it's Exhibit C to your reply report. 3 A. I did.
4 Do you recognize this as the exhibit 4 Q. And I take it you haven't reviewed any
5 listing the materials you considered in connection 5 other reports submitted in this case; is that
6 with your June 10th, 2019 reply expert report? 6 right?
7 A. Yes. 7 A. That's correct.
8 Q. And how did you determine what materials 8 Q. And did you meet with anyone other than
9 to consider when preparing your expert report? In 9 the lawyers to help you prepare for the deposition?
10 other words, were materials given to you? Did you 10 A. No, I did not.
11 supply -- did you pull materials on your own or was 11 Q. And roughly how much time did you spend to
12 it a combination? 12 prepare for the deposition?
13 A. It was a combination. 13 A. Maybe 20, 24 hours.
14 Q. And what types of materials did you 14 Q. Did you review any documents other than
15 consider that were not given to you from the 15 those listed in Peck Exhibit 3 to help you prepare
16 lawyers? 16 for the deposition?
17 A. Mostly they were FDA regulations, FDA 17 A. No.
18 guidances that I pulled down from the FDA website 18 Q. Who wrote your expert report?
19 or from Google. 19 A. I wrote most of it but there was
20 Q. And as best as you can tell does Peck 20 collaboration. I asked for some text to be
21 Exhibit 3 accurately represent the materials you 21 generated or legal aspects of it for the patent
22 considered in connection with preparing your reply 22 listings and the relevant contents of the patents
23 expert report? 23 from counsel. And then I reviewed every word,
24 A. Yes. 24 edited as needed. And so every word in this report
25 Q. Do you know who else plaintiffs have 25 are my words.
Page 22 Page 24
1 retained as experts in this case? 1 Q. I take it the legal standard section, that
2 A. I saw the name of Dr. Budoff in the 2 came from counsel?
3 Mathers report but that's all I know. 3 A. That's correct.
4 Q. Do you know Dr. Budoff? 4 Q. Have you reviewed any deposition testimony
5 A. No. 5 or any deposition transcripts generated in
6 Q. Do you know Mr. Mathers? 6 connection with this case?
7 A. No. 7 A. No, I have not.
8 Q. So I gather you did not speak to any other 8 Q. Have you reviewed any pleadings filed in
9 experts retained by Amarin in this case? 9 this case like briefs?
10 A. That's correct. 10 A. I can't remember whether I saw the
11 Q. Or at least to your knowledge? 11 complaint. I may have seen the complaint.
12 A. That's correct. 12 Q. Did you review any court orders in this
13 Q. Do you know who else the defendants have 13 case?
14 retained as experts in this case other than 14 A. I'm not sure what the origin of the
15 Mr. Mathers? 15 confidentiality agreement. That may be a court
16 A. No, I do not. 16 order. I'm not really sure. But that would be the
17 Q. Did you speak with any employees of Amarin 17 only one.
18 to help you prepare your expert report? 18 Q. Okay. All right. Let's go to another
19 A. No, I did not. 19 exhibit.
20 Q. Roughly how much time have you spent in 20 (Exhibit 4 was marked for identification.)
21 connection with this case? 21 BY MR. KLEIN:
22 A. Roughly 60 hours. 22 Q. Dr. Peck, you have been handed what's been
23 Q. And putting aside communications with the 23 marked as Exhibit 4, Peck Exhibit 4, and the first
24 lawyers how did you prepare for the deposition? 24 page is Exhibit A. I'll represent to you it's
25 A. I reviewed my report. I reviewed exhibits 25 Exhibit A to your reply expert report. And if you

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of 28 C. PECK, M.D.
Page 45 Page 47
1 Q. When you use the phrase "encourage, 1 writing thousands of labels over more than 30
2 recommend and promote" in your opinions in your 2 years.
3 expert report, are you using that phrase in 3 BY MR. KLEIN:
4 connection with the legal standards discussed in 52 4 Q. Now, what's your understanding of what it
5 through 62 of your report or in some other manner? 5 means for an FDA approved label to encourage,
6 MR. STOLE: Objection to form. 6 recommend or promote a particular action?
7 THE WITNESS: As I said before, I'm not an 7 A. Well, as you will see in my report, I
8 attorney. I don't know exactly what these words 8 believe that the label teaches, instructs, and it's
9 mean because they have never been in this context 9 based on what FDA intends for the label to convey.
10 from a legal point of view. So I've taken their 10 And the physician aware of the label or having read
11 ordinary meaning and essentially translated that 11 the label interprets the label.
12 into what I know about what a label does and what 12 Q. And can you give me an example of how you
13 is the basis of the label from a regulatory point 13 determined whether the Vascepa label recommended,
14 of view and from a physician's interpretation point 14 encouraged or promoted a particular method of
15 of view. 15 treatment?
16 BY MR. KLEIN: 16 A. Well, I think each one of the opinions, I
17 Q. Are you offering any opinions in this case 17 basically have four opinions in there, provides my
18 that the Vascepa labeling and by extension 18 rationale in the report for understanding that the
19 defendant's generic labeling infringe a patent? 19 label teaches. The words in the label, the
20 MR. STOLE: Objection. Form. 20 physician's reading of the label teaches, for
21 THE WITNESS: I don't believe I have any 21 example, that administration of Vascepa and its use
22 opinion in here with respect to infringement. 22 is for 12 weeks or more.
23 BY MR. KLEIN: 23 Q. And do you agree that the scope of the FDA
24 Q. Okay. 24 approved method for Vascepa -- let me rephrase the
25 A. That's direct at least. 25 question.
Page 46 Page 48
1 Q. So is it fair to say that when you offer 1 Do you agree that the label for Vascepa
2 opinions with regard to whether Vascepa's label 2 permits use of the drug or permits certain uses of
3 encourages, recommends or promotes administration, 3 the drug even though the use may not be in the
4 you are offering opinions as to what in your view 4 indication section, for example, use of the drug
5 the label conveys to doctors and patients, but it 5 with a statin?
6 will be up to the court to determine whether in 6 MR. STOLE: Objection to form.
7 view of your opinions there is infringement or not; 7 THE WITNESS: Would you repeat that,
8 is that fair? 8 please?
9 MR. STOLE: Objection. Form. 9 BY MR. KLEIN:
10 THE WITNESS: I think that's fair to say. 10 Q. Yeah. It was poorly worded.
11 But I don't know for sure. I don't know what the 11 So the indication -- you're familiar with
12 court will do with my report. 12 the Vascepa label obviously?
13 BY MR. KLEIN: 13 A. I am.
14 Q. Now, other than using the phrase 14 Q. The indication for Vascepa does not
15 "encourage, recommend or promote," did you apply 15 address statins, correct?
16 any of the legal standards discussed in Paragraphs 16 MR. STOLE: Objection to form.
17 52 to 62 of your report in connection with your 17 THE WITNESS: The words in the indication
18 opinions? 18 section of the label for Vascepa do not include the
19 MR. STOLE: Objection. Form. 19 word "statin."
20 THE WITNESS: Well, not knowingly. As I 20 BY MR. KLEIN:
21 said I'm responding to Mr. Mathers' assertions with 21 Q. Okay. But is it your opinion that if a
22 which I disagree in the ordinary use of those 22 physician prescribed Vascepa with a statin that
23 words, and I use other words in some cases to 23 would still be within the scope of the FDA approval
24 explain how I see it from the point of view of 24 for Vascepa?
25 having read and interpreted and participated in 25 MR. STOLE: Objection to form.

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of 28 C. PECK, M.D.
Page 49 Page 51
1 THE WITNESS: What I understand and my 1 or promoting that use?

2 opinion is that the FDA -- that a physician -- 2 A. That's fair.
3 basically unregulated by FDA, by the way -- would 3 Q. So if the label is describing a use, a
4 manage a patient in the best interest of the 4 particular use, in your opinion the label is
5 patient according to the entire label. And would 5 encouraging, recommending or promoting that use; is
6 draw learning from every part of the label and 6 that right?
7 employ that in the decision to treat and the 7 MR. STOLE: Objection. Objection to form.
8 decision to monitor and which dose and et cetera. 8 Incomplete hypothetical.
9 BY MR. KLEIN: 9 THE WITNESS: Well, to the extent that
10 Q. What I'm getting at is in your opinion, 10 those are words that Mr. Mathers used in which he
11 does the Vascepa label permit the use of Vascepa in 11 asserted that the physician is limited to the words
12 combination with a statin to treat a patient with 12 in the indication section and would not be
13 triglycerides over 500? 13 otherwise induced by reading the rest of the label.
14 MR. STOLE: Objection to form. 14 That's a rough translation.
15 THE WITNESS: I'm having trouble with your 15 BY MR. KLEIN:
16 use of the word "label permit." But a physician 16 Q. Let me back up a little bit because I
17 would understanding from reading the label that 17 think it's important to clarify something you said
18 Vascepa can be used without a statin and with a 18 earlier. Doctors are not regulated by the FDA,
19 statin. 19 right?
20 BY MR. KLEIN: 20 A. Only indirectly, but yes, that's true.
21 Q. And so what I'm getting at is: How did 21 Q. And so a label does not constrain how a
22 you draw a distinction -- focusing on the phrase 22 doctor can use a particular drug, correct?
23 "encourage, recommend or promote" -- how did you 23 A. Well, there are other constraints on the
24 draw a distinction between a permitted use and an 24 physician's decision process that may come into
25 indicated use when assessing whether the label 25 play. But strictly speaking the label is a source
Page 50 Page 52
1 encourages, recommends or promotes a particular 1 of information, very important information that

2 action? 2 enables the physician to have an understanding of
3 MR. STOLE: Objection to form. 3 how to best use the drug.
4 THE WITNESS: Well, as I said before, you 4 Q. And so, for example, doctors are free to
5 know, "permit" implies that there's some directive 5 prescribe a drug off-label if they believe that
6 that a physician must follow. The point of view I 6 that use is in the best interest of a patient,
7 have is that the physician knows how to read a 7 correct?
8 label and take the information as a whole on the 8 MR. STOLE: Objection to form.
9 label to make a decision in favor of the benefit of 9 THE WITNESS: Well, I'm not sure what you
10 the patient. And FDA intends for that to happen. 10 mean by "off-label" in this question.
11 So the indication section is a very 11 BY MR. KLEIN:
12 limited statement with respect to the sort of 12 Q. Well, I'm really just -- there might be a
13 primary criterion for FDA's approval of the -- or 13 disconnect between the regulatory standards and the
14 say acceptance of the evidence of safe and 14 legal standards and I want to try to take baby
15 effectiveness for that primary indication. But 15 steps because in the real world, the real world may
16 elsewhere in the label is very important 16 not operate the same as the legal world. And I
17 information on the use of the drug that a physician 17 want to make sure we are on the same page.
18 would take into account when making a decision 18 So a doctor is not necessarily limited to
19 about whether to use, whether the patient is 19 the uses described in the label, correct?
20 eligible, whether to use this drug versus another 20 A. That is correct.
21 drug and how to otherwise monitor therapy. 21 Q. And a label doesn't necessarily require a
22 BY MR. KLEIN: 22 doctor to do anything, correct?
23 Q. And so is it your opinion that if a 23 Because as you said, doctors aren't
24 particular use falls within the scope of the label 24 regulated by the FDA. That's what I'm getting at.
25 as a whole, the label is encouraging, recommending 25 MR. STOLE: Objection to form.

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of 28C. PECK, M.D.
Page 53 Page 55
1 THE WITNESS: Well, I agree that doctors 1 maintain a lipid lowering diet and a good exercise
2 are not regulated by the FDA. Manufacturers are. 2 program is hard to achieve. And so that would be a
3 BY MR. KLEIN: 3 circumstance.
4 Q. Right. And you know, a doctor 4 BY MR. KLEIN:
5 theoretically could look at the Vascepa label and 5 Q. Have you spoken to any other physicians
6 decide to prescribe Vascepa for patients even if 6 who treat hypertriglyceridemia to assess how they
7 their triglycerides are under 500, correct? 7 treat patients with that condition?
8 MR. STOLE: Objection to form. 8 A. Not recently, no.
9 THE WITNESS: Theoretically, that's 9 Q. Have you ever?
10 possible. 10 A. Well, I'm sure I did in the past --
11 BY MR. KLEIN: 11 Q. Okay.
12 Q. But you would agree that the label is not 12 A. -- when I practiced medicine.
13 encouraging that use, right? 13 Q. Have you spoken to any physicians to
14 A. I would say that they -- that the label 14 assess how they use Vascepa?
15 doesn't teach that -- an expectation of efficacy 15 A. No, I have not.
16 and safety with respect to triglycerides or any 16 Q. Let me give you a more concrete
17 other matter. That information would not be coming 17 hypothetical. Please assume a patient has her very
18 from the label. 18 first triglyceride test and it's the results of
19 Q. So in your opinion would it be an 19 400. Okay. No known history of going above 500.
20 off-label use for a physician to prescribe Vascepa 20 And the doctor then prescribes Vascepa for that
21 in a patient whose triglycerides are below 500? 21 patient believing in good faith that Vascepa will
22 MR. STOLE: Objection. Form. 22 help lower the triglycerides. In your opinion
23 THE WITNESS: Well, to begin, most 23 would that that be an off-label or on-label
24 physicians will prescribe Vascepa for patients who 24 prescription?
25 have -- when they appear first in the office with a 25 MR. STOLE: Objection. Form.
Page 54 Page 56
1 triglyceride level above 500. A physician would 1 THE WITNESS: Well, I would have to know
2 understand that continued therapy is necessary to 2 what rationale the physician has for that.
3 maintain an under 500 if it reaches under 500. So 3 BY MR. KLEIN:
4 in that circumstance, yes, a physician would be 4 Q. So in your view the assessment of whether
5 treating it consistent with the label and 5 the prescription is on-label or off-label would
6 consistent with good practice to treat a patient 6 turn on the physician's intent?
7 whose triglyceride level has reached a level under 7 MR. STOLE: Objection to form.
8 500 due to Vascepa treatment. 8 THE WITNESS: As I said, it would be
9 BY MR. KLEIN: 9 important to understand what the physician knows
10 Q. I understand what you're getting at. I'm 10 about that patient. For example, family history.
11 -- I wasn't necessarily getting at that situation. 11 So the concept of off-label is really an
12 Let me back off and be more specific in my 12 advertising or promotion matter. The physician is
13 question. I just want to get the general confines 13 free to make a decision in favor of his patient
14 to make sure you and I are on the same page. 14 based upon his knowledge of the label and every
15 If the patient presents for the very first 15 other information that's available.
16 time to a doctor and the triglyceride level is 400 16 BY MR. KLEIN:
17 and the doctor prescribed Vascepa, do you agree 17 Q. Let me rephrase the hypothetical because I
18 that that prescription would be an off-label 18 understand and appreciate what you just said.
19 prescription? 19 Let's assume that the patient presents and the only
20 MR. STOLE: Objection to form. 20 information the doctor has is the triglyceride test
21 THE WITNESS: I can think of circumstances 21 and it's the very first triglyceride test. It was
22 in which the patient had a level above 500 and then 22 400. And the physician prescribes Vascepa.
23 went on a lipid lowering diet and exercise. Came 23 Do you agree that the labeling is not
24 in not taking Vascepa but gave the doctor that 24 encouraging that type of prescription?
25 history. Doctors understand that the ability to 25 MR. STOLE: Objection. Form. Incomplete

009
of 28C. PECK, M.D.
Page 97 Page 99
1 recommendation, but it's not -- it doesn't limit 1 case at this moment.

2 the doctor to a particular action. 2 Q. Okay. I think I understand your use of --
3 Q. I saw a statement to that effect in your 3 your opinions with regard to the use of the term
4 report and it confused me because the label doesn't 4 "should" in the labeling. But let me ask you --
5 really limit the doctor at all, right? 5 well, is it fair to say that when FDA uses the term
6 A. But it advises the doctor and it uses 6 "should" in a pharmaceutical label, it is leaving
7 various terminology, and I think the plain language 7 certain actions to the wide discretion of the
8 understanding of "should" is that it's a good idea 8 physician?
9 but the real world may or may not permit it. 9 A. Yes.
10 Q. And so there's a distinction between the 10 Q. And in your opinion when the labeling
11 first sentence of the indication and then the usage 11 leaves physicians with discretion on how to
12 considerations, right? The first sentence is 12 practice the approved Vascepa use, is the labeling
13 saying this is how you use the drug and then the 13 encouraging doctors to prescribe any specific
14 second sentence in the usage consideration is 14 method of treatment?
15 providing a further recommendation that isn't as 15 MR. STOLE: Objection. Form.
16 mandatory? 16 THE WITNESS: I would say yes.
17 MR. STOLE: Objection to form. 17 BY MR. KLEIN:
18 THE WITNESS: Well, I would interpret the 18 Q. And so in essence, are you saying that if
19 first sentence somewhat differently. 19 the label allows the doctor to use the discretion
20 BY MR. KLEIN: 20 to, for example, to for example use Diet A, Diet B,
21 Q. Okay. 21 Diet C or Diet D, it's encouraging the use of all
22 A. The first sentence defines the population 22 four diets?
23 of the patients that were included in the adequate 23 A. It's encouraging the doctor to use
24 and well controlled trial that supported the 24 discretion and use his best -- to make the decision
25 evidence of safety and effectiveness. So that is 25 in the best interest of the patient.
Page 98 Page 100
1 as I would say good guidance to the physician that 1 MR. KLEIN: How are we doing? Does anyone
2 the greatest expectation of benefit would be by 2 need a break? Are you doing okay?
3 treating patients who have this characteristic. 3 THE WITNESS: I could use a brief break.
4 Q. And then the next two paragraphs both use 4 MR. KLEIN: Why don't we take a brief
5 the term "should." This is providing a softer 5 break.
6 recommendation in your view; is that right? 6 THE VIDEOGRAPHER: Going off the record.
7 A. Yes. 7 The time is 11:17 a.m.
8 Q. Do drug labels ever say "must" perhaps in 8 (Recess taken from 11:17 a.m. to
9 a black box maybe? 9 11:30 a.m.)
10 A. Certainly a black box has a stronger 10 THE VIDEOGRAPHER: Back on the record.
11 impact. The physician would interpret that way. 11 The time is 11:30 a.m.
12 Q. Let's put aside the black box situation. 12 BY MR. KLEIN:
13 Did labels typically use the term "must" as opposed 13 Q. Dr. Peck, I assume you had no substantive
14 to "should"? 14 communications with counsel over the break?
15 A. You know, I expect so but I think we would 15 A. Did not.
16 have to look. 16 Q. I want to turn back to your report,
17 Q. Okay. 17 Exhibit 1, and direct you to Page 86.
18 A. There may be other information in the 18 A. 86.
19 label like numerical information that would lead 19 Q. Correct. And at the top of Page 86
20 the physician to consider this is a must. 20 there's a heading Roman Numeral X, "Vascepa's
21 Q. A drug-drug interaction for example? 21 labeling encourages, recommends and promotes
22 A. Drug interaction or this has not been 22 administration and use of Vascepa without a
23 studied in elderly patients. That's a very strong 23 concurrent lipid altering therapy or concomitant
24 indication that it's less certain. But this is, 24 statin therapy."
25 again, I haven't reviewed in the context of this 25 Do you see that?

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of 28C. PECK, M.D.
Page 101 Page 103
1 A. I do. 1 statin.
2 Q. And in Paragraph 2 of 9, in the middle of 2 Q. But is there anything in the label that
3 the paragraph there's a sentence that starts with 3 would encourage doctors either to use or not use a
4 "rather"? 4 statin because it's relevant to triglyceride
5 A. Yes. 5 levels?
6 Q. And then you say "The labeling is 6 A. You know, the drug is approved on the
7 instructing physicians that the drug can be used 7 basis of adequate and well controlled trial, the
8 safely and effectively with or without a statin." 8 MARINE trial which in the clinical study section
9 Do you see that? 9 contains information about the use and non-use. As
10 A. Yes, I do. 10 you know, 25 percent of patients in the trial were
11 Q. And it says it "Is therefore recommending 11 using a statin. There's no indication in the label
12 and encouraging both uses." 12 that there was any differential effects. That
13 Do you see that? 13 absence of information is not accidental, though,
14 A. Yes. 14 because FDA would have and did in fact analyze the
15 Q. Now, can you explain how in your opinion 15 data both ways; in other words, it selected out
16 the Vascepa label is encouraging doctors and 16 whether patients had a different safety or
17 patients to use Vascepa without a statin? And feel 17 effectiveness profile.
18 free to refer to the label if you want which is 18 So not finding any difference, it didn't
19 Exhibit 5. 19 provide a specific advisory in the level or
20 A. The question is how? 20 information in the label. So essentially it
21 Q. Yeah. What statements in the label in 21 teaches, encourages, recommends, promotes in the
22 your opinion are encouraging doctors and patients 22 words of Mr. Mathers in the label by not providing
23 to use Vascepa without a statin? 23 any additional information about that.
24 A. Well, as I've -- to begin, the indication 24 Q. So is the Vascepa label as a whole
25 and indications of usage make no mention of 25 teaching doctors that the decision whether to use a
Page 102 Page 104
1 statins. Meaning that FDA has considered this and 1 statin with Vascepa should not affect triglyceride
2 represents in the label that it is not an adjunct 2 levels?
3 to it or a supplement or to be used in combination 3 A. Well, there's no specific about that other
4 as a specific recommendation. 4 than the table and the data, but it's very clear
5 Q. Do you agree that the indication is silent 5 from that paragraph that precedes it and the table
6 as to whether the doctor should use a statin or 6 that FDA came to the conclusion that there is no
7 not? 7 reason to mention that particular issue. It
8 A. I think I just mentioned that that 8 certainly is aware that some patients will present
9 information is absent but that doesn't mean the 9 with hypertriglyceridemia who are taking a statin.
10 label is silent. 10 Q. Right.
11 Q. Well, the indication is silent, correct? 11 A. And there will be some who after treatment
12 A. Yeah. You know, under the understanding 12 with Vascepa may be candidates in the patient's
13 that there's no words in there, that's silence. 13 mind to add a statin. So FDA I think wisely and
14 Q. And -- but do you agree the label as a 14 within the information it had leaves it up to the
15 whole permits the use of Vascepa either with or 15 doctor, but it definitely includes encouragement to
16 without a statin, correct? 16 use it according to the doctor's discretion with a
17 A. The label as a whole teaches that the 17 statin or without a statin.
18 physician should use his or her discretion with 18 Q. Do you know whether statins are approved
19 respect to use with a statin or without a statin. 19 to reduce triglyceride levels?
20 Q. Does the label discuss whether using a 20 A. I don't think there was a specific
21 statin with Vascepa is relevant to reducing 21 indication for that for -- which drugs did you say?
22 triglyceride levels? 22 Q. Statins?
23 A. Well, there's information in the label in 23 A. Statins. I'm not aware of at this moment,
24 the clinical studies section that provides 24 but of course triglycerides are one of a handful of
25 information with respect to use or non-use of a 25 lipids that are related to the adverse reactions of

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Page 105 Page 107
1 a high lipid exposure, a high lipid concentration 1 of lipids. Definitely would want to be sure that
2 over a long period of time. 2 it didn't have an adverse affect on the treatment
3 Q. So when you read the Vascepa label as a 3 of triglyceridemia. So absent information in here
4 whole, do you see anything in the label that would 4 that would prohibit that, doctor would feel
5 encourage doctors to either use or not use a statin 5 comfortable for other reasons to add a statin or
6 with Vascepa to affect triglyceride levels? 6 continue a patient on a statin or not employ a
7 MR. STOLE: Objection to form. Asked and 7 statin during treatment with Vascepa.
8 answered. 8 Q. So putting aside drug-drug interaction
9 THE WITNESS: Well, the answer is yes. 9 concerns, there's nothing in the Vascepa label that
10 BY MR. KLEIN: 10 specifically encourages a doctor to either use or
11 Q. What are you referring to? 11 not use a statin to reduce triglyceride levels,
12 A. The clinical trial section. Look at the 12 correct?
13 table and you come to the conclusion that because 13 MR. STOLE: Objection to form.
14 of the absence of a -- having an indication in 14 THE WITNESS: I believe the label teaches
15 there that there was a differential effect on 15 that it encourages either/or.
16 triglyceride, FDA felt comfortable with the 16 BY MR. KLEIN:
17 analysis that lumped them both together. 17 Q. Would you say the -- what the label is
18 Q. There might be a disconnect between my 18 really doing, to use one of your terms, the label
19 question and your answer. First of all, the table 19 is agnostic as to whether Vascepa is used in a
20 you're referring to so we are on the same page is 20 patient who happens to also be taking a statin. Is
21 Table 2 in the label, right? 21 that a fair way to characterize the label?
22 A. Let me check. Yes. Yes. 22 MR. STOLE: Objection. Misstates
23 Q. And Table 2 does not distinguish 23 testimony.
24 triglyceride levels in patients taking a statin 24 THE WITNESS: Just repeat that, would you
25 from triglyceride levels in patients who are not on 25 please?
Page 106 Page 108
1 a statin, correct? 1 BY MR. KLEIN:

2 A. By absence of a finding that there was a 2 Q. Would you say the Vascepa label is
3 differential, a physician and FDA interpreted this 3 agnostic as to whether Vascepa is used in a patient
4 to be -- this is sufficient information to 4 who happens to also be taking a statin?
5 understand that a patient without a statin will 5 MR. STOLE: Objection. Form.
6 achieve this level of triglyceride reduction and 6 THE WITNESS: I think that the label
7 both taking a statin will achieve that. 7 encourages either/or.
8 Q. Right. So a doctor looking at Table 2 8 BY MR. KLEIN:
9 will reasonably understand that the use of a statin 9 Q. But when the label encouraging either/or,
10 is not going to have a material effect on how 10 the use of Vascepa either with or with a statin
11 Vascepa affects triglyceride levels, correct? 11 doesn't affect the effectiveness of Vascepa to
12 A. Yes. 12 reduce triglyceride levels, correct?
13 MR. STOLE: Objection to form. 13 MR. STOLE: Objection to form.
14 BY MR. KLEIN: 14 THE WITNESS: And that's a good thing.
15 Q. That's what I was getting at. 15 Yes.
16 And you understand that the decision a 16 BY MR. KLEIN:
17 doctor to use a statin with Vascepa would likely be 17 Q. So when you say the label encourages
18 based on concerns other than severe 18 either/or, you're really referring to a drug-drug
19 hypertriglyceridemia, correct? 19 interaction concern, right?
20 MR. STOLE: Objection to form. 20 MR. STOLE: Objection to form. Misstates
21 THE WITNESS: No. 21 testimony.
22 BY MR. KLEIN: 22 THE WITNESS: Well, a drug interaction can
23 Q. Can you explain that? 23 invoke a safety problem or it can invoke a efficacy
24 A. Because a doctor would -- a doctor would 24 problem. In this case the physician would be
25 understand that statins have an effect on a number 25 interested mostly in an adverse reaction on the

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Page 117 Page 119
1 FDA for Vascepa did not approve any 1 possible should -- the patient should be on a lipid
2 disease or condition other than to reduce 2 lowering diet.
3 triglyceride levels in adult patients with severe 3 But the reality is that the lipid lowering
4 hypertriglyceridemia; is that true? 4 diet are -- and diet and exercise regimens, which
5 A. As a general matter? 5 are also difficult to actually achieve in patients.
6 Q. Yes. 6 So "adjunct" in this setting means in addition to
7 A. Well, I don't know if I can answer that. 7 every best effort a physician can undertake to
8 Q. Well, in the Vascepa label? 8 induce the patients to do that. But it doesn't
9 A. If we're talking about Vascepa? 9 preclude Vascepa being used in a patient who just
10 Q. Yeah, I'm talking about Vascepa. 10 can't get there.
11 A. Is that what you mean? 11 BY MR. KLEIN:
12 Q. Yes, yes. Let me rephrase the question. 12 Q. Is the Vascepa label saying that the
13 For Vascepa, FDA did not approve any disease or 13 primary mode of therapy to reduce triglyceride
14 condition other than to reduce triglyceride levels 14 levels in adults with severe hypertriglyceridemia
15 in adult patients with severe hypertriglyceridemia; 15 is diet and exercise?
16 is that true? 16 MR. STOLE: Objection. Form.
17 A. That's the concise statement of the 17 THE WITNESS: No.
18 indication. 18 MR. KLEIN: Let me mark another exhibit.
19 Q. Right. So FDA has not approved Vascepa 19 (Exhibit 6 was marked for identification.)
20 for example to reduce LDLC, correct? 20 BY MR. KLEIN:
21 A. That's not included in the indication -- 21 Q. So I've handed you what has been marked as
22 Q. Right. 22 Exhibit 6. This is a copy of 21 CFR Section
23 A. -- for this drug. 23 201.57.
24 Q. Right. And for FDA has not approved 24 Are you familiar with this regulation?
25 Vascepa to address LDLC? 25 A. Generally speaking, yes.
Page 118 Page 120
1 MR. STOLE: Objection. Form. 1 Q. Can you turn to Page 4 of the document.
2 MR. KLEIN: Control LDLC, correct? 2 It's Bates labeled 18077.
3 MR. STOLE: Objection. Form. 3 A. Yes.
4 THE WITNESS: There is no separate 4 Q. If you look at the top, it says "This
5 indication, no separate -- Icosapent, 5 section," and we are talking about the indication
6 I-C-O-S-A-P-E-N-T ethyl. Approved concise 6 and usage section, right?
7 indication for anything other than 7 A. Yes.
8 hypertriglyceridemia. 8 Q. "Must including the following information
9 BY MR. KLEIN: 9 if the conditions listed are applicable. A, if the
10 Q. Right. Now the indication talks about how 10 drug is used for an indication only in conjunction
11 Vascepa is indicated as an adjunct to diet. 11 with a primary mode of therapy, e.g., diet,
12 Do you see that? 12 surgery, behavior changes or some other drug, the
13 A. Yes. 13 statement that the drug is indicated as an adjunct
14 Q. And what does the term "adjunct" mean in 14 to that mode of therapy."
15 that context? 15 Do you see that?
16 A. In combination with. 16 A. Yes.
17 Q. Is the indication saying that the Vascepa 17 Q. Is the Vascepa label in your opinion
18 is not the primary mode of therapy? Is that what 18 applying that regulation?
19 the term "adjunct" is referring to? 19 A. I believe so.
20 MR. STOLE: Objection. Form. 20 Q. Okay. And so under that regulation is the
21 THE WITNESS: Well, "adjunct" is further 21 primary mode of therapy in the Vascepa label diet?
22 explained in the usage and considerations where if 22 MR. STOLE: Objection to form.
23 the label states that the patient should be placed 23 THE WITNESS: It's the best effort that
24 on an appropriate lipid lowering diet. So this is 24 the physician and the patient can make to achieve a
25 FDA and the label teaching the physician that if 25 diet as specified under "shall be placed on an

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of 28C. PECK, M.D.
Page 121 Page 123
1 appropriate lipid lowering diet." 1 "clinical studies," right?

2 BY MR. KLEIN: 2 A. Yes, it is.
3 Q. So in essence, what the Vascepa label is 3 Q. And then if you go down a paragraph to
4 conveying is that Vascepa can help reduce 4 little I?
5 triglyceride levels in patients if they are 5 A. Yes.
6 following an appropriate diet; is that right? 6 Q. It says that "Any clinical study that is
7 MR. STOLE: Objection to form. 7 discussed in prescription drug labeling that
8 THE WITNESS: I believe that's a true 8 relates to an indication for or use of the drug
9 statement but it's not limited to situation where 9 must be adequately well controlled" as described in
10 the patient is not eating an appropriate lipid 10 another regulation," right?
11 lowering diet. 11 A. Yes.
12 BY MR. KLEIN: 12 Q. And then it says "Any clinical study must
13 Q. And let's take it one step at a time. Do 13 not imply or suggest indications or uses or dosing
14 you agree that the Vascepa label as a whole is not 14 regimens not stated in the indication and usage or
15 encouraging doctors to prescribe Vascepa regardless 15 dosage and administration section."
16 of the patient's diet? 16 Do you see that?
17 In other words, the label isn't 17 A. I do.
18 encouraging doctors to say "Take Vascepa. You 18 Q. So do you agree the clinical study section
19 don't have to worry about what you eat." 19 cannot expand the indications that are approved in
20 MR. STOLE: Objection. Form. 20 the indications and usage section?
21 THE WITNESS: I think so, yes. 21 A. Just the straight wording of this would
22 BY MR. KLEIN: 22 lead me to say yes.
23 Q. What you're saying is that in the real 23 Q. And the same question with regard to the
24 world patients may not follow an appropriate diet? 24 dosage administration section, information in the
25 A. Yes, that's true. 25 clinical study section is not supposed to imply or
Page 122 Page 124
1 Q. But from the labeling perspective, the 1 suggest a dosing regimen not stated in the dosage
2 drug is supposed to be used with an appropriate 2 and administration section, correct?
3 diet, correct? 3 A. Yes.
4 A. Correct. 4 Q. So the length of a clinical study reported
5 Q. Let's go back to the label which is 5 in the clinical study section is not supposed to
6 Exhibit 5 and talk about the clinical trials, 6 imply or suggest a particular dosing regimen that's
7 clinical study section which is Section 14. And 7 not stated in the dosage and administration
8 actually, you can keep out the -- let's look at 8 section, right?
9 them both at the same time to make sure we are on 9 MR. STOLE: Objection to form.
10 the same page. And if you go to Page 19 of Exhibit 10 THE WITNESS: Yes.
11 6. That's the regulation. 11 BY MR. KLEIN:
12 A. Okay. 12 Q. And so you know, I'm sure you're aware the
13 MR. STOLE: 19 of the document? 13 clinical study addressed in the Vascepa labeling
14 MR. KLEIN: Yeah, Page 19, Bates labeled 14 happened to be a 12-week study, right?
15 18092. 15 A. Yes.
16 Q. Are you with me? 16 Q. The clinical study section of the Vascepa
17 A. I am, yes. 17 labeling is not implying that Vascepa should be
18 Q. So on Page 19 of Exhibit 6 there is a 18 taken for 12 weeks, correct?
19 Subsection 15 that references 14 clinical studies. 19 A. Not correct.
20 Do you see that? 20 Q. Why is that not correct?
21 A. Yes. 21 A. The clinical study section as required
22 Q. It's kind of in the middle of the page? 22 under the regulation describes the study that
23 A. Yes, I do. 23 supported the indication with an adequate and well
24 Q. And that, the 14 clinical studies is 24 controlled trial. So absent a specific statement
25 referring to Section 14 of the labeling entitled 25 elsewhere in the label, particularly the

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of 28C. PECK, M.D.
Page 125 Page 127
1 indication, for a minimum or a maximum period of 1 second line therapy.

2 therapy, a physician would look at the label and 2 It's a very different level of teaching
3 say "Well, we know efficacy is achieved at 12 3 than the adjunct that we just discussed. So you
4 weeks. Let's go for at least 12 weeks." 4 asked about the, you know, purpose of the
5 Q. I don't mean to cut you off but I think I 5 limitations section. So that's a brief overview.
6 understand where you're going and that wasn't my 6 Q. So there are two limitations of use in the
7 yes. I'm not -- let me rephrase my question. Let 7 Vascepa indication, right?
8 me withdraw and rephrase. 8 A. Well.
9 MR. STOLE: Hang on a second. Are you 9 MR. STOLE: Hang on a second. Am I
10 done with your answer? 10 missing one?
11 THE WITNESS: Not really. But. 11 THE WITNESS: No, there are two.
12 MR. STOLE: Okay, continue. 12 BY MR. KLEIN:
13 BY MR. KLEIN: 13 Q. Two sentences?
14 Q. I'll withdraw the question because I think 14 A. There's two sentences.
15 my question was poor. 15 Q. Maybe you're pausing because the second
16 The fact that the clinical study reported 16 sentence addresses more than one thing.
17 in the clinical study section lasted 12 weeks is 17 A. Well, to be frank with you, this is
18 not implying that doctors when prescribing Vascepa 18 unusual to find a statement in limitations of use
19 should prescribe Vascepa only for a 12-week 19 with respect to what indications it hasn't been.
20 duration, correct? 20 Very uncommon. I was actually surprised to see it.
21 A. I would agree with that. 21 Often you find that elsewhere in the label that
22 Q. What you were getting at your answer is 22 "This has not been studied in patients with renal
23 that the clinical study section can inform a 23 failure so use with caution."
24 physician that Vascepa can be used for 12 weeks, 24 This I think is aimed at prohibiting
25 correct? 25 marketing actually and promotion for an important
Page 126 Page 128
1 A. That's correct. 1 indication that has not been supported by an

2 Q. It can be used for other durations as well 2 adequate and well controlled study data, so.
3 though? 3 Q. No. So in essence, the Vascepa indication
4 A. That's correct. 4 is teaching that Vascepa can reduce triglyceride
5 Q. I think we are on the same page. Okay. 5 levels in adult patients with severe
6 Lets go back to the indication section for 6 hypertriglyceridemia and the doctors may know that
7 a second. There's a third section in the 7 when patients have severe hypertriglyceridemia,
8 indication, "limitations of use," right? 8 that presents a risk of pancreatitis, but the
9 A. Yes. 9 doctors should not assume that FDA has actually
10 Q. What is the purpose of the limitations of 10 approved the drug to reduce the risk of
11 use portion of the indications and usage section? 11 pancreatitis; is that correct?
12 A. Well, it's to advise or to teach that in 12 A. Yes. That's a good articulation of that.
13 this case, certain information has not been 13 Q. And the same thing with regard to the
14 forthcoming that would permit a clear addition to 14 second limitation of use sentence. Doctors may
15 the indication that it's reduced risk of 15 understand that if you have severe
16 pancreatitis or that it has an effect on 16 hypertriglyceridemia, that can lead to
17 cardiovascular mortality or morbidity. But that's 17 cardiovascular mortality and morbidity, but FDA is
18 a pretty open-ended section. 18 not approving Vascepa to mitigate the risk of
19 FDA sometimes when it really does want -- 19 cardiovascular mortality or morbidity; is that
20 when it really does want to convey that a drug 20 correct?
21 should be used in a certain way, say, for example, 21 MR. STOLE: Objection. Form.
22 cancer chemotherapy; that if thinks that it wants 22 THE WITNESS: I think what FDA is doing
23 to instruct that this drug is new and not known to 23 here in this is a little advance regulation because
24 be any more effective than one that's already in 24 triglycerides are not the only lipid -- they are
25 the market, then this should be used only as a 25 not the only lipid that's been identified to be a

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of 28C. PECK, M.D.
Page 129 Page 131
1 risk factor for cardiovascular morbidity and 1 clinical study section includes information about a
2 mortality. And since Vascepa actually has some 2 beneficial effect on ApoB. So while the specific
3 effects on some of the other lipids, this is kind 3 indication of ApoB reduction is not included in the
4 of a volley over the deck that says "The clinical 4 indication, there is information in the label with
5 study section may imply that there's some benefits 5 respect to that potential benefit.
6 on some of the other lipids, but don't advertise on 6 BY MR. KLEIN:
7 this because that would be off-label promotion." 7 Q. Understood. But FDA did not approve an
8 That's how I read this. Having been the 8 indication for Vascepa to reduce ApoB, correct?
9 head of FDA Drug Center for six years, I've been 9 MR. STOLE: Objection. Form.
10 responsible for advertising and promotion 10 THE WITNESS: Not specifically. No.
11 regulation. And perhaps that's more than you 11 BY MR. KLEIN:
12 needed to know, but I think this will help us all 12 Q. And FDA did not approve Vascepa -- strike
13 understand what's going on here. 13 that.
14 BY MR. KLEIN: 14 FDA did not approve a specific indication
15 Q. So in the indication and usage section, 15 for Vascepa to reduce triglycerides by any
16 FDA is saying "Don't advertise this drug to reduce 16 particular amount, correct?
17 the risk of pancreatitis," correct? 17 MR. STOLE: Objection to form.
18 A. I think that's one of the outcomes of 18 THE WITNESS: Well, the MARINE trial, the
19 this, yes. 19 protocol that defined the MARINE trial included an
20 Q. And FDA is saying "Don't advertise Vascepa 20 outcome, the basis of which FDA made its decision
21 as reducing risks of cardiovascular mortality and 21 that they had an adequate support for this
22 morbidity," correct? 22 indication. That outcome including numerical goals
23 A. Well, and it's informing the physician 23 for the reduction of triglycerides. So that can be
24 that it has not -- it's not aware of or has 24 learned by reading the FDA report on that public
25 evaluated the data that persuades it that either of 25 information and it can be inferred by reading this
Page 130 Page 132
1 these two conditions are met. 1 table here.

2 Q. And FDA did not approve any indication to 2 BY MR. KLEIN:
3 reduce LDLC, correct, for Vascepa? 3 Q. Well, there's the protocol from MARINE
4 A. For Vascepa. 4 that you just referenced?
5 MR. STOLE: Objection to form. 5 A. Yes.
6 THE WITNESS: Not that I'm aware of. 6 Q. That portion is not in the Vascepa label,
7 BY MR. KLEIN: 7 correct?
8 Q. And FDA has not approved any Vascepa 8 MR. STOLE: Objection. Form.
9 indication to reduce non-HDLC, correct? 9 THE WITNESS: No, but the -- you can see
10 MR. STOLE: Objection. Form. 10 here that the change from baseline, there's a 27
11 THE WITNESS: Would you repeat that 11 percent change in the Vascepa arm and went up ten
12 question, please? 12 percent in the placebo arm. Started at 680. The
13 BY MR. KLEIN: 13 criterion for change was to be below 500. That was
14 Q. FDA has not approved any Vascepa 14 a statistically significant reduction.
15 indication to reduce non-HDLC? 15 So the -- there's a lot of information
16 A. Well, it's -- this is an approved 16 here that would guide the physician on what to
17 indication and a label that informs it. So there 17 expect. And so in that sense the label teaches a
18 is no information actually in this label with 18 lot of valuable qualitative information for the
19 respect to cardiovascular morbidity. So yes, I 19 physician.
20 would agree with that. 20 BY MR. KLEIN:
21 Q. Okay. And FDA did not approve Vascepa to 21 Q. Understood. But the indication for
22 reduce ApoB, correct? 22 Vascepa is not addressing a particular reduction of
23 MR. STOLE: Objection to form. 23 triglyceride levels, correct?
24 THE WITNESS: Well, it comes along with 24 MR. STOLE: Objection to form.
25 the territory on this one. That is to say the 25 THE WITNESS: Well, by implication it is.

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1 BY MR. KLEIN: 1 Q. In the middle of that paragraph you say

2 Q. What do you mean? 2 "Severe hypertriglyceridemia has a strong genetic
3 A. The indication is for patients that have 3 component associated with genetic defects that
4 greater than 500 milligrams per liter of 4 result in the inability to break down fatty acids
5 triglycerides. Greater than 500 is not a good 5 in the body."
6 thing. This was approved to treat that problem. 6 Do you see that?
7 So this plus the table and the clinical study 7 A. I do.
8 teaches the physician that it is likely that if 8 Q. And you're quoting the Vascepa medical
9 they use this drug appropriately in the right 9 review?
10 populations, that patients during therapy will have 10 A. Yes.
11 a triglyceride level less than 500. So it would be 11 Q. Does the label make any mention of a
12 -- it would not be correct that there's not 12 genetic component associated with severe
13 quantitative information about what to expect. 13 hypertriglyceridemia?
14 Q. So you read the Vascepa label as telling 14 A. I don't think so. No, I don't think so.
15 doctors that if the doctors use Vascepa as an 15 Q. And in Paragraph 198 -- oh, by the way.
16 adjunct, that could be sufficient to bring the 16 Do you -- with regard to genetic -- any genetic
17 patient below 500 milligrams per deciliter? 17 causes of severe hypertriglyceridemia, do you have
18 A. That's what the outcome of this trial 18 any knowledge of that independent of what you've
19 demonstrated. 19 read in the medical review?
20 Q. Now, you agree that the Vascepa labeling 20 A. No, I didn't.
21 would permit, for example, a patient with 1000 to 21 Q. If you go to Paragraph 198.
22 take Vascepa and diet and get down to 600? 22 MR. STOLE: Did you say 198?
23 A. Yes, I would. 23 MR. KLEIN: 198.
24 Q. And there's -- so the Vascepa label, the 24 Q. In the middle -- in the second sentence
25 Vascepa indication is not specifically teaching 25 you say "it," referring to severe
Page 134 Page 136
1 doctors that Vascepa plus diet will be sufficient 1 hypertriglyceridemia, "is a chronic condition."
2 to avoid severe hypertriglyceridemia, right? 2 Do you see that?
3 MR. STOLE: Objection to form. 3 A. Yes.
4 THE WITNESS: Yeah, I would agree with 4 Q. And you're citing the ATP 3 report in the
5 that statement at that level of precision, yes. 5 medical review?
6 MR. KLEIN: Why don't we take a break. 6 A. Yes.
7 THE VIDEOGRAPHER: This is the end of Disc 7 Q. Does the Vascepa label ever say that
8 Number 2, Volume 1 in the deposition of Carl C. 8 severe hypertriglyceridemia is a chronic condition?
9 Peck, MD. The time is 12:26 p.m. We are off the 9 A. No, but physicians would know that.
10 record. 10 Q. Do you know whether hypertriglyceridemia
11 (Luncheon recess was taken from 12:26 p.m. 11 is always a chronic condition?
12 to 1:10 p.m.) 12 A. No. It can be transient due to a drug
13 THE VIDEOGRAPHER: Back on the record. 13 interaction. You know, there may be some other
14 This is the beginning of Disc Number 3, Volume 1 in 14 transient states but --
15 the deposition of Carl C. Peck, MD. The time is 15 Q. Did you finish?
16 1:10 p.m. on July 1st, 2019. 16 A. Yes. Sorry to stop on a high note.
17 BY MR. KLEIN: 17 Q. No, I didn't know. I didn't want to
18 Q. Welcome back, Dr. Peck. I assume you had 18 interrupt you.
19 no substantive communications with counsel about 19 A. Yeah.
20 your testimony? 20 Q. Do you know whether hypertriglyceridemia
21 A. I did not. 21 can be caused by lifestyle choices, for example,
22 Q. Let's go back to Exhibit 1, your report. 22 poor diet and no exercise?
23 And I would like to direct you to Paragraph 117 on 23 A. I'm not aware that the level of
24 Page 43. 24 hypertriglyceridemia can dissipate or -- above 500
25 A. Yes. 25 does or does not.

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1 Q. And you mentioned drug interactions. What 1 Q. Is that necessarily true if the drug
2 do you mean by that as a potential cause of 2 approved by the FDA as an adjunct to some other
3 hypertriglyceridemia? 3 treatment?
4 A. I think the label actually identifies, 4 A. Generally, are you referring to generally?
5 makes a statement about that. That's what I 5 Q. Yes, just generally speaking.
6 thought when I answered this question but I'm not 6 A. I don't think I can answer generally but I
7 seeing it right this minute. 7 mean, you know, all depends. In hypertension, you
8 Q. I think that may be right. I'm not sure 8 know, first and second line therapies, I presume
9 it's in the label. 9 that first line has failed but -- or failed
10 A. Well, here's what I'm referring to. 10 partially. So anyway, it's very hard to answer
11 Medications that can exacerbate 11 that on a general basis.
12 hypertriglyceridemia. Beta blockers, thiazides and 12 Q. Fair enough. Let's go to Paragraph 191.
13 estrogens. 13 In the second line from the bottom, you say
14 Q. Where are you? 14 "Vascepa is approved for an indication and dosing
15 A. It's in the indications and usage. 15 regimen that is not limited in duration; thus,
16 Q. Oh, okay. 16 whether physician prescribed Vascepa for 12 weeks,
17 A. Yeah. 17 24 weeks or even just three weeks, any such use
18 Q. I see, I see. 18 would be within the scope of FDA's approval,"
19 Are you aware of other medications that 19 right?
20 are known to exacerbate hypertriglyceridemia? 20 A. Yes.
21 A. Not at this moment, no. 21 Q. And so the Vascepa indication is silent as
22 Q. And is the indicated use of Vascepa 22 to duration of treatment, correct?
23 limited to chronic use? 23 MR. STOLE: Objection to form.
24 A. No, I don't think so. 24 THE WITNESS: The concise indication does
25 Q. In Paragraph 199 of your report? 25 not include any limitation and the usage does not
Page 138 Page 140
1 A. Yes. 1 include any limitation with respect to duration of

2 Q. You say in the second sentence "A 2 therapy.
3 physician experienced in the treatment of 3 BY MR. KLEIN:
4 hypertriglyceridemia or other hyperlipidemia would 4 Q. Right. When you said -- what did you mean
5 understand that such lipid disorders often persist 5 by the concise --
6 if lipid lowering medication is withdrawn." 6 A. Well, I over-spoke. There's two locations
7 A. Yes. 7 in the label where the indication is articulated.
8 Q. And what's your basis for that statement? 8 One is in the highlights and I see what I just
9 A. FDA emphasized in the patient labeling the 9 stated would be true in the highlights as well as
10 importance of maintaining therapy with this 10 in the full prescribing information.
11 condition as long as the physician thinks it's 11 Q. Okay. I see. So neither the highlighted
12 important. So that's a tip-off to FDA's 12 indication nor the full prescribing indication
13 recognition. I just know this as a physician and a 13 limits the duration of use, correct?
14 reader. 14 A. That's correct.
15 Q. But your physician practice wasn't focused 15 Q. And same with regard to the dosage and
16 on using lipid lowering medications, right? 16 administration sections, neither section either in
17 A. No, it was not. I should say I have a 17 the highlights or the full prescribing information
18 longstanding interest in adherence with medication. 18 limits the duration of treatment, correct?
19 In other words, to the extent to which patients 19 A. I believe that's correct.
20 adhere to the regimen that the physician. And so 20 Q. And if FDA believed that Vascepa could
21 for drugs that are labeled without a limitation, I 21 only be safely administered for either a minimum or
22 would say typically there is an underlying 22 a maximum period, you would expect to see that in
23 assumption or basis, as in hypertension, for 23 at least a dosage and administration section,
24 example, that continued therapy is important for 24 correct?
25 the ultimate beneficial effect. 25 MR. STOLE: Objection. Form.

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Page 141 Page 143
1 THE WITNESS: I'm not sure I would limit 1 the various sections of the label that you just
2 it to the dosing administration. Any such 2 referenced and perhaps others, correct?
3 limitation would depend upon the importance, the 3 A. Yes.
4 level of seriousness of the absence of a beneficial 4 Q. And so, for example, in the Paragraph 191
5 effect or the development of a very serious adverse 5 that we read a moment ago you talked about how a
6 effect. 6 physician could prescribe Vascepa for 12, 24 or
7 BY MR. KLEIN: 7 three weeks?
8 Q. And so if FDA thought you should take 8 Do you remember that?
9 Vascepa for some minimum period of time or some 9 A. Yes, I do.
10 maximum period of time you would expect to see that 10 Q. So if the physician were to prescribe
11 in the labeling? 11 Vascepa, four grams a day, to patients with severe
12 A. Under the circumstances that I just 12 hypertriglyceridemia for 24 weeks, you would agree
13 described, yes. If it really matters with respect 13 that would fall within the scope of FDA approval,
14 to achieving efficacy. If it really mattered with 14 right?
15 respect to protecting the patient from an adverse 15 MR. STOLE: Objection. Form.
16 reaction. Then I give examples of both of those in 16 THE WITNESS: Yes.
17 my report. You would see it in at least one 17 BY MR. KLEIN:
18 location. In the case of opioid, opioids, it sits 18 Q. Because the label is implying that Vascepa
19 in the black box. 19 is suitable to be administered for that length of
20 Q. And there's no minimum or maximum period 20 time?
21 for using Vascepa anywhere in the Vascepa label, 21 A. It implies that it's suitable for an
22 correct? 22 indefinite period of time.
23 A. No, there's no specific statement about 23 Q. And same with regard to three weeks. If a
24 the minimum or maximum. 24 physician were to prescribe Vascepa, four grams per
25 Q. Do you agree that the Vascepa label leaves 25 day, with patients with severe hypertriglyceridemia
Page 142 Page 144
1 it up to the discretion of the doctor to determine 1 for only three weeks and then stop, would that fall
2 the duration of treatment? 2 within the scope of FDA approval?
3 A. I do. 3 A. If in the best interest of the patient the
4 Q. And do you believe that the Vascepa label 4 physician decided that three weeks was sufficient
5 is implicitly instructing doctors that the drug can 5 and there could be many reasons for that. An
6 be taken for long-term use? 6 allergy has arisen or it wasn't effective for that
7 A. Yes, I do. 7 patient or the patient is not taking the drug
8 Q. And you rely on the clinical study section 8 seriously. There's lots of reasons why a physician
9 for that opinion; is that right? 9 could come to that. Three weeks would not be a bad
10 A. I rely on the label as a whole. 10 time to check whether the drug was working or not.
11 Q. What sections of the label in particular? 11 So yes, I think that there's no advice, no teaching
12 A. Well, let's just begin with the 12 in the label that says stop at any time.
13 indications and usage. There's no limitation. So 13 Q. And so according to its labeling Vascepa
14 that's an indication that the FDA has determined 14 would be suitable for use of only three weeks or
15 that there is no upper bound. And same with the 15 six weeks or nine weeks, for example, correct?
16 dosage and administration. 16 MR. STOLE: Objection to the form.
17 The charge to patients that they take the 17 THE WITNESS: This is up to the physician.
18 drug for as long as the physician thinks is 18 The label leaves it to the discretion of the
19 important. These together and possibly more 19 physician. So you could name a thousand different
20 support what a physician would know coming into 20 durations and they would all be decisions that the
21 this, that hypertriglyceridemia is generally 21 physician could make for whatever reason that would
22 speaking a chronic condition. 22 not be inconsistent with the label.
23 Q. There's no explicit statement anywhere in 23 BY MR. KLEIN:
24 the label teaching doctors that they should use 24 Q. The label never says that Vascepa is safe
25 Vascepa long term? You're saying it's implied by 25 and effective only if administered for at least 12

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Page 145 Page 147
1 weeks, correct? 1 BY MR. KLEIN:

2 A. No. Not to my recollection. 2 Q. Do you agree that the Vascepa label
3 Q. Just to be clear, we had a double 3 doesn't express any duration preferences at all?
4 negative. You're agreeing with my statement, 4 A. Well, I think that the physician would
5 right? 5 know by reading the clinical trial section that
6 A. Could you repeat the statement, please? 6 since FDA approved the drug, based on evidence that
7 Q. Let me rephrase it. The Vascepa -- does 7 showed it's effective at 12 weeks, that that is a
8 the Vascepa label ever say that Vascepa is safe and 8 -- that's a good directive for the physician to
9 effective only if administered for at least 12 9 take another triglyceride level after 12 weeks and
10 weeks? 10 see if it's working.
11 A. And my answer should be no. 11 So I don't think the label is silent on
12 Q. Okay. Right. 12 duration entirely. There's a guidance in here land
13 And FDA did not approve Vascepa solely to 13 teaching. It's not coercive, it's advisory. But a
14 be used for at least 12 weeks, correct? 14 physician who knows how to read the label would
15 MR. STOLE: Objection. Form. 15 understand that it will definitely work at 12 weeks
16 THE WITNESS: FDA put no limitation on the 16 in most patients.
17 duration of the use. So if that speaks to your 17 Q. But to use a term you used a long time
18 question. 18 ago, the label is agnostic as to whether the doctor
19 BY MR. KLEIN: 19 prescribes it for three weeks, 12 weeks or 12
20 Q. Yeah, I think so. Let me give you a 20 years; is that right?
21 hypothetical. Let's say an obese patient presents 21 MR. STOLE: Objection. Form.
22 to the doctor with triglycerides of 510. First 22 THE WITNESS: Actually, I rather regret
23 test, no prior history, no family history. That's 23 that I introduced the word "agnostic."
24 all the information that's available. Okay. And 24 MR. KLEIN: Sorry.
25 the patient tells the doctor that he didn't like 25 THE WITNESS: That implies a sort of a
Page 146 Page 148
1 taking pills. 1 lack of faith in the religious sense.

2 The doctor prescribed diet and exercise 2 BY MR. KLEIN:
3 and Vascepa for two months. The doctor tells the 3 Q. Maybe that's the wrong term.
4 patient that if after two months, his triglycerides 4 A. Yeah. So it is not silent on the
5 go down to below 500, the patient can stop using 5 duration. Absence of a boundary, minimum or a
6 Vascepa but must continue the diet and exercise. 6 maximum, is a pretty broad statement implied to be
7 Would that be consistent with the FDA approved 7 sure. The 12-week demonstration of effectiveness
8 label? 8 is another piece of information. So if agnostic
9 MR. STOLE: Objection. Form. Incomplete 9 meant no information, that would work, but I think
10 hypothetical. 10 a better term is it is in the label and it
11 THE WITNESS: To the extent that I 11 instructs, teaches, recommends, promotes. That
12 understand the hypothetical, a physician who is 12 it's up to the physician but there's no boundary.
13 that -- faced with that situation could in fact ask 13 Q. In other words, the Vascepa labeling is
14 the patient to come back during that period of time 14 telling doctors you can use the drug for 12 weeks
15 to see what the benefit is and for various reasons 15 or longer if you want?
16 could stop, recommend stopping the medicine and 16 A. Yes.
17 then check again. So -- and that's not uncommon. 17 Q. But it's not saying you should. The label
18 Physicians are taught to monitor therapy. 18 is leaving it to the discretion of the doctor as to
19 But in this case, in this case I think 19 the duration for a particular patient; is that
20 that if a patient tells you right off the bat that 20 fair?
21 they don't like taking pills, that's a good signal 21 A. Yes. And that's how it should be. You
22 that they are not likely to take them in my study 22 don't want FDA managing your treatment, right? You
23 of adherence. But that aside, that's a 23 want your doctor to treat it, to manage it.
24 hypothetical that absent any other information 24 Q. Let's take a look at the label which is
25 could happen. 25 Exhibit 5 and I want to focus you on Section 6.

020
of 28C. PECK, M.D.
Page 149 Page 151
1 A. Yes. 1 that other --

2 Q. Adverse reactions? 2 A. No, I did not, and these are available for
3 A. Yes. 3 your inspection.
4 Q. You see there's a 6.1 and it says "Because 4 Q. I trust you. All right. Let's take a
5 clinical trials are conducted under widely varying 5 look at Table 2 which is a table entitled "Median
6 conditions, adverse reaction rates observed in the 6 baseline and percent change from baseline in lipid
7 clinical trials of a drug cannot be directly 7 parameters in patients with severe
8 compared to rates in the clinical trials of another 8 hypertriglyceridemia."
9 drug and may not reflect the rates observed in 9 A. Yes.
10 practice." 10 Q. And now the study is reporting median
11 Do you see that? 11 percent changes from baseline and placebo, right?
12 A. Yes. 12 A. Well, this table has more information than
13 Q. Is that standard FDA language? 13 just median change. It does have the actual
14 A. I don't really know for sure. It's not a 14 milligram per deciliter numbers. Column 2 and
15 surprising statement. 15 Column 4 are the actual numbers, percent changes in
16 Q. Why do you say that? 16 Column 3 and Column 6, and the difference between
17 A. Well, because of two things. First of 17 placebo and Vascepa with respect to -- that looks
18 all, most clinical trials that support an NDA are 18 like it is the -- looks like that's the percent
19 small relative to the overall populations that the 19 change. But that's the confidence interval and the
20 drug will be used in. So first approval of a new 20 difference.
21 drug is a sort of a preliminary estimate of the 21 Q. Let's put aside that last column, the
22 adverse reaction rate. So a controlled, highly 22 confidence interval for a second.
23 observed, so it's good information. In the life 23 A. Uh-huh.
24 cycle of a drug, the label will be modified often 24 Q. The other -- the baseline numbers, those
25 numerous times with the safety experience updated. 25 are median numbers, right?
Page 150 Page 152
1 The other thing is that it's adverse 1 A. Column 2 and Column 4 are median. Column
2 reaction rates in the practice of medicine is a 2 3 and Column -- no. Column 2 and Column 4 are
3 less confidence. It's not as accurate because it's 3 median, I believe, of the baseline, for example
4 not under controlled conditions. Not all the 4 triglyceride, the baseline and the -- actually, all
5 observations are reported. And so, you know, this 5 these shared the median concentrations of these
6 is a good safe harbor statement for FDA to make to 6 lipids baseline and then we see the percent change.
7 advise physicians that, you know, this information 7 So you could calculate the exact amounts. So what
8 is dynamic. And this is what we know at the moment 8 would be your question?
9 that we approved the actual label based on the 9 Q. The numbers in Columns 2 and 4 are
10 information known to us. 10 baseline -- I am sorry, are median numbers, right?
11 Q. Does FDA understand that effects seen in 11 MR. STOLE: Objection. Form.
12 clinical trials submitted to the agency may not 12 THE WITNESS: They are percent change in
13 necessarily reflect the range of effects observed 13 median.
14 in clinical practice? 14 BY MR. KLEIN:
15 A. Yes. 15 Q. Well, maybe I'm in the wrong column.
16 Q. Let's go to the Table 2 that we looked at 16 A. Percent change from baseline.
17 earlier. That's in the label Exhibit 5. 17 Q. Baseline numbers.
18 A. By the way, I have two copies of the 18 A. I think the baseline probably are medians.
19 labeled here. One that I brought with me and I 19 Q. That's my understanding. What does
20 meant to disclose that with you that's on a single 20 "median" mean?
21 page and it doesn't have the front page, but -- 21 A. Well, with a collection of numbers, median
22 Q. Try to use the exhibit just to make sure 22 would be a number if it exists that above which 50
23 -- I mean, it shouldn't matter but -- 23 of the values lie and below which 50 percent of the
24 A. Yeah, I will. 24 numbers lie. Sometimes the median doesn't actually
25 Q. But I see you didn't write anything on 25 exist because there's an odd number of subjects so

021
of 28C. PECK, M.D.
Page 153 Page 155
1 you have to take the average of the two that are 1 might have a different result?
2 competing for the median. 2 MR. STOLE: Objection. Form.
3 Q. And the median is different from a mean or 3 THE WITNESS: Well, this was evaluated by
4 average, right? 4 the medical reviewer. And since there was no
5 A. Sometimes -- well, yeah. Sometimes they 5 systematic difference between the two, FDA agreed,
6 can be the same, sometimes not. 6 then the physician would realize that they are --
7 Q. FDA in Table 2 is not suggesting that all 7 FDA does not consider there to be an expectation of
8 Vascepa patients will experience the median results 8 a difference. But as we point out, in fact in an
9 that are reported in the table, right? 9 individual patient monitored several times during
10 MR. STOLE: Hold on a second. Hold on. 10 therapy, you will very likely see differences among
11 Objection. Form. 11 those values. That's the nature of variability.
12 THE WITNESS: All patients? 12 BY MR. KLEIN:
13 BY MR. KLEIN: 13 Q. And the median baseline for the Vascepa
14 Q. Right. The FDA is not teaching doctors 14 group was 680. If for example you're treating a
15 that all patients are going to have the median 15 patient with 1,500, you may get a very different
16 effects that are reported in Table 2? 16 result, correct?
17 MR. STOLE: Objection. Form. 17 MR. STOLE: Objection. Form.
18 THE WITNESS: From a numbers point of view 18 THE WITNESS: Not necessarily. And I
19 which is what you're asking here, if you repeated 19 think I referred to the statistical review. And
20 this study,you might get something slightly 20 that's a very rich analysis that FDA undertook, and
21 different. If you did a survey of the patients out 21 one of the things that it did not discover was a
22 there in the practice who were taking drugs under 22 baseline effect on the outcome. So we would have
23 these same conditions, you might get a somewhat 23 to look at that stat report together to really
24 different value. So these are estimates based upon 24 answer your question.
25 the observations in this particular trial. 25 The first approximation says there is no
Page 154 Page 156
1 BY MR. KLEIN: 1 expectation that the percent change from baseline

2 Q. Right, but -- 2 would be any different between a 510 and a 1200.
3 A. This is a good approximation to what you 3 MR. STOLE: Can we take a quick ten-minute
4 should expect, but exact replication is not 4 break?
5 expected. 5 MR. KLEIN: Okay.
6 Q. Right. And so in taking the Table 2 data 6 THE VIDEOGRAPHER: Going off the record.
7 and applying it in a clinical setting where the 7 The time is 1:46 p.m.
8 doctor is treating an individual patient, the 8 (Recess taken from 1:46 p.m. to 1:48 p.m.)
9 doctor may see that for triglycerides, the median 9 THE VIDEOGRAPHER: Back on the record.
10 percent change with Vascepa was negative 27 10 The time is 1:48 p.m.
11 percent, but the doctor would understand that it 11 BY MR. KLEIN:
12 could -- that the percent change could be greater 12 Q. Okay. We were talking about Table 2. And
13 or less in an individual patient, correct? 13 just to recap Table 2, let's focus just on the
14 A. I would agree with that, yes. 14 triglyceride parameter for now. Is not teaching
15 Q. And the patient population that was tested 15 doctors that if they prescribe Vascepa according to
16 in the study underlying Table 2 had certain 16 the indication all patients will receive a negative
17 characteristics that may or may not be -- that may 17 27 percent change, correct?
18 or may not translate to an individual patient, 18 A. I agree.
19 correct? 19 Q. In fact if you go to the difference in the
20 A. Yes. That's true of all drugs and all 20 confidence interval you see variation from negative
21 approvals. 21 47 to negative 22, right?
22 Q. For example, most of the participants were 22 A. Yes.
23 white males, right? 23 Q. Now, and the same would be true with
24 A. Yes. 24 regard to the LDLC parameter. The Table 2 is not
25 Q. And maybe if you're treating a female you 25 teaching doctors that all patients will experience

022
of 28C. PECK, M.D.
Page 157 Page 159
1 a negative change in LDLC, correct? 1 Q. Do you know why the label does that?
2 A. That's correct. Focusing on your note. 2 A. Well, as I speculated before, FDA is more
3 You're noting the confidence interval? 3 concerned about off-label promotion. And perhaps,
4 Q. Right. 4 you know, this is just an unusual label in that
5 A. For triglycerides, there was an 5 respect to see this repeated twice.
6 expectation that 95 percent of the patients would 6 So since there's no cardiovascular
7 have a decrease of at least 22 percent, whereas the 7 mortality or morbidity or pancreatitis information
8 confidence level for LDLC teaches that it's 8 in the -- directly in the label, it's alerting the
9 unlikely that they'll be any change. 9 physician and the manufacturer actually that this
10 Q. We'll get to this in a bit. Now for LDLC, 10 is not a -- this is not an effect that FDA has
11 some patients may have an LDLC increase, right? 11 determined to be approvable. Not that there has
12 A. Yeah. 12 even been a request by the manufacturers for this
13 Q. For ApoB, for example, Table 12 is not 13 that FDA has approved.
14 teaching that all patients will have a decrease, 14 Q. So is FDA essentially saying that "We are
15 correct? 15 approving Vascepa to reduce triglycerides in
16 MR. STOLE: Objection. Form. 16 certain populations but we are not saying that
17 THE WITNESS: Well, from my reading, the 17 doing so will have a clinical effect?
18 confidence level of minus 14 to minus 8 doesn't 18 MR. STOLE: Objection to form.
19 include zero or a plus number. So if this is a 19 THE WITNESS: This is a fine point I would
20 reflection of the future, then 95 percent of 20 like to just bring up. FDA distinguishes between
21 patients ought to have a decrease. 21 clinical end points and surrogate end points. And
22 BY MR. KLEIN: 22 I'm using the second in a very specific manner.
23 Q. But five percent could increase; we don't 23 FDA defines a surrogate end point as an end point
24 know, right? 24 as a clinical trial in which there's a high
25 MR. STOLE: Objection to form. 25 expectation that it will yield a clinical benefit.
Page 158 Page 160
1 THE WITNESS: Two and a half percent. 1 In this case, triglyceride measurements
2 BY MR. KLEIN: 2 are a surrogate end point. They are not a clinical
3 Q. After the chart? 3 end point. But implicit in the FDA review and this
4 It says "Vascepa, four grams per day, 4 approval is based upon the expectation, not the
5 reduce median TG v LDL-C and ApoB levels from 5 proven but the expectation that it will reduce the
6 baseline relative placebo." Then it says "The 6 risk of pancreatitis.
7 reduction in TG observed with Vascepa was not 7 BY MR. KLEIN:
8 associated with elevations in LDLC levels relative 8 Q. But FDA did not have enough information to
9 to placebo." 9 go all the way and say "Take this drug to reduce
10 Do you see that? 10 the risk of pancreatitis"?
11 A. Yes. 11 MR. STOLE: Objection to form.
12 Q. So that statement is referring back to the 12 BY MR. KLEIN:
13 study results reported in Table 2, correct? 13 Q. Correct?
14 A. Yes. 14 A. Well, I expect that's true. I mean, I
15 Q. FDA is not ruling out that Vascepa may 15 don't know everything that was submitted by the
16 actually cause LDLC elevations in some patients, 16 sponsor in this case. But if they did submit
17 correct? 17 information on that, FDA obviously didn't approve a
18 MR. STOLE: Objection. Form. 18 label that included that. So if they did it was
19 THE WITNESS: That's correct. 19 insufficient.
20 BY MR. KLEIN: 20 Q. Let's go to another exhibit, and I
21 Q. Then the labeling repeats the limitations 21 apologize for its size but we are not going to go
22 of use that we saw in the indication section on 22 through every page, I promise.
23 pancreatitis and cardiovascular mortality and 23 MR. KLEIN: Sometimes counsel is
24 morbidity, right? 24 particular about completeness. So.
25 A. Yes. 25 (Exhibit 7 was marked for identification.)

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of 28C. PECK, M.D.
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1 Q. You reviewed the medical review, right? 1 Q. So this advertisement is talking about an
2 A. I did, yeah. 2 average. It says "Individual results may vary."
3 Q. And do you recall that the change in LDLC 3 Do you see that?
4 were not found to be statistically significant 4 A. Yes.
5 compared to placebo? 5 Q. Do you know why FDA -- or do you know if
6 MR. STOLE: Hang on a second. 6 that's a requirement from FDA to say that
7 Go ahead. 7 individual results may vary?
8 THE WITNESS: Well, not specifically, but 8 A. I doubt that that's a requirement. It is
9 we could be precise about that if you want to show 9 possible when FDA reviewed this ad that they
10 me the medical options report and we can look for 10 recommended that the company insert this.
11 it. 11 Q. Is that fairly typical when reported
12 BY MR. KLEIN: 12 average data in an advertisement?
13 Q. It is what it is so I'll move on. 13 A. I can't confirm or otherwise, but it's not
14 Suffice it to say that FDA did not find 14 surprising that FDA's advertising and promotion
15 sufficient evidence to approve a Vascepa indication 15 group wants to be sure there's accurate data and a
16 to avoid increases in LDLC levels, correct? 16 fair balance. In any case, it did not object to
17 MR. STOLE: Objection. Form. 17 this statement.
18 THE WITNESS: Well, this is not an 18 Q. Right. And it doesn't surprise you that
19 approval specifically for that in this table. 19 the advertisement says "individual result may vary"
20 Doesn't mean that they didn't look. And I don't 20 when referring to an average result, right?
21 even know whether the sponsor requested that. 21 A. That doesn't surprise me, no.
22 BY MR. KLEIN: 22 Q. By definition, if it's average, some are
23 Q. Let's go to another exhibit. 23 below average and some are above?
24 (Exhibit 9 was marked for identification.) 24 A. Yes, that would be true.
25 BY MR. KLEIN: 25 Q. And if a patient were to take four grams
Page 182 Page 184
1 Q. Doctor, you've been handed what has been 1 of Vascepa per day and experience an LDLC increase,
2 marked as Exhibit 9. This is labeled AMRN 3149773 2 that would still be consistent with the Vascepa
3 to 9774. 3 labeling, correct?
4 Do you recognize this advertisement? 4 A. Well, yes. Yes.
5 A. I do. 5 I mean, an increase can be a tiny increase
6 Q. This is one of the advertisements 6 or big increase. From what the label teaches it is
7 discussed in your report? 7 not likely to be a big increase.
8 A. Yes. 8 Q. If a patient were to take four grams of
9 Q. And in Footnote 1, or it's a cross, I 9 Vascepa per day and experience an ApoB increase,
10 guess. It says in this advertisement, "On average, 10 that would still be consistent with the Vascepa
11 along with diet changes, adults with very high 11 labeling, right?
12 triglycerides experienced a 33 percent reduction 12 A. Well, from what we know so far it would be
13 without raising LDLC versus placebo. Individual 13 highly unlikely.
14 results may vary." 14 Q. But you can't rule that out, right?
15 Do you see that? 15 A. Yeah, that's true. I mean, it's variation
16 A. Just give me a moment. 16 everywhere. And suppose there were very large
17 Q. Yeah, it's small. 17 excursion. That could happen even with the therapy
18 A. It's actually, yeah, okay. It's a second 18 with Vascepa if the patient violated, deviated from
19 tick in the footnote, right? 19 a lipid lowering diet and had himself a party with
20 Q. Right. There's a star, there's an 20 a bunch of hamburgers.
21 asterisk. 21 Q. But if a patient were to take four grams
22 A. Right, right. 22 of Vascepa per day and experience an ApoB increase,
23 Q. Then like a cross and then looks like a 23 you wouldn't say that that's completely different
24 double cross. 24 than what the label's contemplating, correct?
25 A. Okay. I see that. 25 MR. STOLE: Objection to form.

024
of 28C. PECK, M.D.
Page 185 Page 187
1 THE WITNESS: I think we have agreed that 1 interval.

2 there's a lot of variation in all these lipid 2 Q. I want to make sure because it's getting
3 parameters. The contribution I would like to make 3 late in the day that we are on the same page here,
4 to this understanding though is that there are many 4 because that footnote is referring to a 33 percent
5 parameters associated with these lipid levels 5 reduction in triglyceride but then it says "without
6 including diet and exercise and the drugs you're 6 raising LDLC."
7 taking. So yes, that could happen. 7 A. Uh-huh.
8 BY MR. KLEIN: 8 Q. So it's not saying on average there was a
9 Q. And the same with if a patient takes 9 reduction in LDLC, right?
10 Vascepa, four grams per day, and experiences a 10 A. Point taken.
11 non-LDLC increase, that would still be consistent 11 Q. And so what my question was getting at is
12 with the labeling, right? 12 this advertisement is not setting an expectation
13 A. Well, it would be unlikely. 13 that taking Vascepa will reduce LDLC as opposed to
14 Q. The advertising we just looked at is not 14 keep it constant, correct?
15 setting an expectation that Vascepa will reduce 15 MR. STOLE: Objection to form.
16 LDLC, correct? 16 THE WITNESS: To the extent I understand
17 MR. STOLE: Objection. Form. 17 your question, yes. This is not a statement that
18 THE WITNESS: You know, I think that would 18 includes the words "reduction."
19 be an interpretation that the physician looking at 19 MR. STOLE: I have a question. Are --
20 the label. 20 what's your timing? We have been going for almost
21 BY MR. KLEIN: 21 two hours with the anticipation that we were going
22 Q. Would it -- 22 to --
23 A. There's not a definite assertion. But 23 MR. KLEIN: Let's go off the record.
24 looking at the label I think a physician would 24 THE VIDEOGRAPHER: Going off the record.
25 conclude -- we are talking non-HDLC? 25 The time is 2:36 p.m.
Page 186 Page 188
1 Q. No, I switched. Sorry. Going back to 1 (Discussion was held off the record.)
2 that footnote we looked at. 2 THE VIDEOGRAPHER: Back on the record.
3 A. Oh. 3 The time is 2:36 p.m.
4 Q. Where it says "On average along with diet 4 MR. KLEIN: Thank you, Dr. Peck.
5 changes, adults with very high triglycerides 5 I have no further questions.
6 experienced a 32 percent reduction without raising 6 MR. STOLE: And I have no questions
7 LDLC versus placebo"? 7 either.
8 A. Yes. 8 THE REPORTER: Counsel on the phone?
9 Q. That footnote is not setting an 9 MS. FINKELSTEIN: I have no questions.
10 expectation that patients who would take Vascepa, 10 Thank you.
11 according to the indication their LDLC will go 11 THE VIDEOGRAPHER: This is the end of Disc
12 down, correct? 12 Number 3, Volume 1 and concludes the deposition of
13 MR. STOLE: Objection. Form. 13 Carl C. Peck, MD. The time is 2:37 p.m. on July
14 THE WITNESS: Well, I would say that's 14 1st, 2019 and we are off the record.
15 setting an expectation that there's a high 15 MR. KLEIN: Rough.
16 likelihood that that will go down. 16 MR. STOLE: Rough.
17 BY MR. KLEIN: 17 (Whereupon the deposition was concluded at
18 Q. Go down or remain constant? 18 2:37 p.m.)
19 A. Well, I mean, 33 percent. You see what's 19
20 absent from this is the range and that may be why 20
21 FDA may have said "Well, listen. Throw in the 21
22 phase 'individual results may vary.'" 22
23 But reading this advertisement, and this 23
24 is aimed at physicians, it's missing a little bit 24
25 of information with respect there's no confidence 25

025
1 DEPOSITION OFFICER'S CERTIFICATE
2 STATE OF NEVADA )
) ss.
3
6 I, LINDA VACCAREZZA, hereby certify:
7 I am a duly qualified Certified Shorthand
8 Reporter in the State of Nevada, holder of
9 Certificate Number CSR 10201 issued by the Certified
10 Court Reporters' Board of Nevada and which is in full
11 force and effect. (Fed. R. Civ. P. 28(a)(1))
12 I am authorized to administer oaths or
13 affirmations pursuant to Nevada Revised Statutes, Section
14 656.315 and prior to being examined, the witness was first
15 duly sworn by me. (Fed. R. Civ. P. 28(a)(1), 30(f)(1))
16 I am not a relative or employee or attorney
17 or counsel of any of the parties, nor am I a relative or
18 employee of such attorney or counsel, nor am I financially
19 interested in this action. (Fed. R. Civ. P. 28)
20 I am the deposition officer that stenographically
21 recorded the testimony in the foregoing deposition and
22 the foregoing transcript is a true record of the
23 testimony given by the witness. (Fed. R. Civ. P. 30(f)(1))
24 / / /
25 / / /
189
CARL C. PECK, M.D.

026
1 Before completion of the deposition, review of
2 the transcript [ ] was [XX] was not requested. If
3 requested, any changes made by the deponent (and
4 provided to the reporter) during the period allowed, are
5 appended hereto. (Fed. R. Civ. P. 30(e))
7 Dated: JULY 18, 2019
10
11 ______________________________
12
13
14
15
16
17
18
19
20
21
22
23
24
25
190
CARL C. PECK, M.D.

027
EXHIBIT 7
Jonathan I. Sheinberg, M.D., dated July 2, 2019
(FILED UNDER SEAL)

EXHIBIT 8
Declaration of Matthew Budoff, M.D.,
dated August 30, 2019

3
4 Tel.: (702) 948-8771
Fax: (702) 948-8773
6
7
11
13 Tel.: (202) 662-6000
Fax: (202) 662-6291

18

20
21
22 NJK)
23 v.
24 HIKMA PHARMACEUTICALS USA INC., et DECLARATION OF MATTHEW

al., BUDOFF, M.D.
25
Defendants.
26
27
001
1 I, Matthew Budoff, M.D., hereby declare as follows:

2 1. I have been retained by counsel for Plaintiffs Amarin Pharma Inc. and Amarin
3 Pharmaceuticals Ireland Limited (collectively, “Amarin”) to serve as a consultant and expert
4 witness in the above-captioned action. My experience and qualifications are discussed in
5 paragraphs 6–18 in my “Opening Expert Report of Matthew Budoff, M.D., Regarding Hikma’s
6 ANDA Product and Vascepa,” dated March 10, 2019. I make this Declaration in support of
7 Amarin’s Opposition to Defendants’ Motion for Summary Judgment of Noninfringement.
8 2. I have been asked by Amarin to provide expert testimony concerning infringement
9 of the asserted patents in the above-captioned action. Specifically, I have been asked to opine as
10 to whether Defendants Hikma Pharmaceuticals USA Inc. and Hikma Pharmaceuticals
11 International Ltd. (together, “Hikma”) and Defendants Dr. Reddy’s Laboratories, Inc. and Dr.
12 Reddy’s Laboratories, Ltd. (together, “DRL”) (collectively, “Defendants”) infringe the asserted
13 patents based on Defendants’ filing of Abbreviated New Drug Applications seeking approval for
14 generic versions of Amarin’s Vascepa®.
17 4. As an expert witness in the above-captioned action, I drafted two Opening Expert
18 Reports, which consisted of one report addressing infringement by Hikma and a second report
19 addressing infringement by DRL. The statements and opinions in my Opening Expert Report
20 addressing DRL’s infringement are the same in all material respects to the statements and opinions
21 in my Opening Expert Report addressing Hikma’s infringement.
22 5. In addition, as an expert witness in the above-captioned action, I drafted a single
23 Reply Expert Report that addressed infringement by both Hikma and DRL.
24 6. Confidential Exhibit 9 is a true and correct excerpted copy of my “Opening Expert
25 Report of Matthew Budoff, M.D., Regarding Hikma’s ANDA Product and Vascepa,” dated March
26 10, 2019 (“Opening Expert Report”).
27
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002
1 7. Confidential Exhibit 10 is a true, correct, and complete copy of my “Reply Expert

2 Report of Matthew Budoff, M.D., Regarding Defendants’ ANDA Products and Vascepa,” dated
3 June 10, 2019 (“Reply Expert Report”).
4 8. In preparing this declaration, I reviewed each of my expert reports and hereby
5 incorporate by reference my Opening Expert Reports and Reply Expert Report. In so doing, I stand
6 by the opinions expressed in my Opening Expert Reports and Reply Expert Report, and reaffirm
7 that these reports are true and accurate reflections of my opinions and that I believe the facts set
8 forth therein are true and correct.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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003
004
EXHIBIT 9
Excerpts from Opening Expert Report of
Matthew Budoff, M.D. Regarding
Hikma’s ANDA Product and Vascepa,
dated March 10, 2019
(FILED UNDER SEAL)

EXHIBIT 10
Reply Expert Report of Matthew Budoff, M.D.
Regarding Defendants’ ANDA Products and
Vascepa, dated June 10, 2019
(FILED UNDER SEAL)

EXHIBIT 11
Declaration of Carl C. Peck, M.D.,
dated August 30, 2019

3
4 Tel.: (702) 948-8771
Fax: (702) 948-8773
6
7
11
13 Tel.: (202) 662-6000
Fax: (202) 662-6291

18

20
21
22 NJK)
23 v.
24 HIKMA PHARMACEUTICALS USA INC., et DECLARATION OF CARL C. PECK,

al., M.D.
25
Defendants.
26
27
001
1 I, Carl C. Peck, M.D., hereby declare as follows:

2 1. I have been retained by counsel for Plaintiffs Amarin Pharma Inc. and Amarin
3 Pharmaceuticals Ireland Limited (collectively, “Amarin”) to serve as a consultant and expert
4 witness in the above-captioned action. My experience and qualifications are discussed in
5 paragraphs 7–18 in my “Reply Expert Report of Carl C. Peck, M.D.,” dated June 10, 2019.
6 2. I have been asked by Amarin to provide expert testimony concerning infringement
7 of the asserted patents in the above-captioned action. Specifically, I have been asked to respond to
8 the opinions of Defendants’ regulatory expert, Peter Mathers, and to opine as to whether
9 Defendants Hikma Pharmaceuticals USA Inc. and Hikma Pharmaceuticals International Ltd.
10 (together, “Hikma”) and Defendants Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories,
11 Ltd. (together, “DRL”) (collectively, “Defendants”) infringe the asserted patents based on
12 Defendants’ filing of Abbreviated New Drug Applications seeking approval for generic versions
13 of Amarin’s Vascepa®.
16 4. As an expert witness in the above-captioned action, I drafted a single Reply Expert
17 Report that addressed infringement by both Hikma and DRL.
18 5. Exhibit 12 is a true and correct excerpted copy of my “Reply Expert Report of Carl
19 C. Peck, M.D.,” dated June 10, 2019 (“Reply Expert Report”).
20 6. In preparing this declaration, I reviewed my expert report and hereby incorporate
21 by reference my Reply Expert Report. In so doing, I stand by the opinions expressed in my Reply
22 Expert Report, and reaffirm that this report is a true and accurate reflection of my opinions and
23 that I believe the facts set forth therein are true and correct.
24
25
26
27
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002
003
EXHIBIT 12
Excerpts from the Reply Expert Report of
Carl C. Peck, M.D., dated June 10, 2019
CONFIDENTIAL – SUBJECT TO DISCOVERY CONFIDENTIALITY ORDER
Nicholas J. Santoro (Nev. Bar No. 532)

SANTORO WHITMIRE, LTD.
Las Vegas, NV 89135
Tel: (702) 948-8771 / Fax: (702) 948-8773

Michael N. Kennedy (admitted pro hac vice)
Tel: (202) 662-6000 / Fax: (202) 662-6291
hpark@cov.com, jmoran@cov.com
Attorneys for Plaintiffs Amarin Pharma, Inc. and

UNITED STATES DISTRICT COURT

DISTRICT OF NEVADA
AMARIN PHARMA, INC. and AMARIN

PHARMACEUTICALS IRELAND LIMITED, CASE No.: 2:16-cv-02525-MMD-NJK
Plaintiffs, (Consolidated with

2:16-cv-02562-MMD-NJK)
v.
REPLY EXPERT REPORT OF
HIKMA PHARMACEUTICALS USA INC., CARL C. PECK, M.D.
et al.,
Defendants.
001
TABLE OF CONTENTS
Page(s)
I. INTRODUCTION .............................................................................................................. 1
II. QUALIFICATIONS AND BACKGROUND .................................................................... 3
A. Qualifications ................................................................................................................ 3
B. Prior Testimony ............................................................................................................ 8
C. Statement of Compensation .......................................................................................... 8
D. Materials Considered .................................................................................................... 9
III. OVERVIEW OF ASSERTED CLAIMS ............................................................................ 9
A. Duration ...................................................................................................................... 10
B. Concomitant / Concurrent Therapy ............................................................................ 11
C. Other Lipid Levels ...................................................................................................... 13
D. Western Diet ............................................................................................................... 17
IV. CLAIM CONSTRUCTIONS............................................................................................ 18
V. LEGAL STANDARDS .................................................................................................... 20
VI. SUMMARY OF OPINIONS ............................................................................................ 22
VII. THE FDA’S APPROVAL PROCESS .............................................................................. 25
A. BRIEF OVERVIEW OF THE FDA ........................................................................... 25
B. NEW DRUG APPLICATIONS .................................................................................. 25
C. THE FDA’S REVIEW OF LABELING..................................................................... 37
D. ABBREVIATED APPLICATIONS ........................................................................... 40
VIII. VASCEPA® AND ITS LABELING................................................................................. 43
A. BACKGROUND ON VASCEPA® ............................................................................ 43
B. OVERVIEW OF VASCEPA®’S LABELING ........................................................... 47
1. INDICATIONS AND USAGE ............................................................................. 48
2. DOSAGE AND ADMINISTRATION ................................................................. 52
3. CONTRAINDICATIONS .................................................................................... 54
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002
4. WARNINGS AND PRECAUTIONS ................................................................... 55
5. DRUG INTERACTIONS ..................................................................................... 56
6. CLINICAL PHARMACOLOGY ......................................................................... 58
7. CLINICAL STUDIES .......................................................................................... 61
8. PATIENT COUNSELING INFORMATION ...................................................... 66
IX. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® FOR 12 OR MORE WEEKS........... 69
A. The Vascepa® Labeling Informs and Instructs Prescribers that the Drug Is Safe and
Effective for Extended Use in Reducing Triglycerides in Patients with Severe
Hypertriglyceridemia. ................................................................................................. 70
B. The Vascepa® Labeling Encourages Physicians to Administer Vascepa® for 12 or

More Weeks. ............................................................................................................... 78
X. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® WITHOUT A CONCURRENT LIPID
ALTERING THERAPY OR CONCOMITANT STATIN THERAPY. .......................... 86
XI. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® TO REDUCE TRIGLYCERIDES IN
PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA WITHOUT ADVERSELY
AFFECTING LDL-C, APO B, OR NON-HDL-C LEVELS ........................................... 92
XII. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® IN PATIENTS WITH SEVERE
HYPERTRIGLYCERIDEMIA WHO CONSUME A WESTERN DIET...................... 102
XIII. CONCLUSION ............................................................................................................... 109
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003
I. INTRODUCTION
1. I, Carl C. Peck, M.D., have been asked by Plaintiffs Amarin Pharma, Inc. and
Amarin, Pharmaceuticals Ireland Limited (collectively, “Amarin”) to offer my opinions
responding to the Rebuttal Expert Report of Peter R. Mathers in this patent infringement action.
2. I understand that Amarin filed a lawsuit against Dr. Reddy’s Laboratories, Inc. and
Dr. Reddy’s Laboratories, Ltd. (collectively, “DRL”) and Hikma Pharmaceuticals USA Inc. and
Hikma Pharmaceuticals International Limited (collectively, “Hikma”) (together, “Defendants”)
for infringement of U.S. Patent No. 8,293,728, U.S. Patent No. 8,318,715, U.S. Patent No.
8,357,677, U.S. Patent No. 8,367,652, U.S. Patent No. 8,377,920, U.S. Patent No. 8,399,446, U.S.
Patent No. 8,415,335, U.S. Patent No. 8,426,399, U.S. Patent No. 8,431,560, U.S. Patent No.
8,440,650, U.S. Patent No. 8,518,929, U.S. Patent No. 8,524,698, U.S. Patent No. 8,546,372, and
U.S. Patent No. 8,617,594 (“the ’594 Patent”) (collectively, the “Asserted Patents”).
3. I understand that Amarin’s infringement allegations are based on Defendants’ filing
of Abbreviated New Drug Applications (“ANDAs”) with the U.S. Food and Drug Administration
(“FDA”) seeking approval to market generic versions of Amarin’s Vascepa® (icosapent ethyl)
capsules (“Defendants’ proposed ANDA Products”).
4. On May 10, 2019, Defendants served a Rebuttal Expert Report prepared by Peter
R. Mathers, who is a partner at the law firm of Kleinfeld, Kaplan, and Becker, LLP. Mr. Mathers’s
report addresses whether, based on his understanding of FDA regulations and guidance concerning
prescription drug labeling, “the Vascepa® label (and by extension, the proposed labeling for
Defendants’ ANDA products) specifically instructs, encourages, recommends, or promotes the use
004
of Vascepa®” in a manner consistent with four categories of limitations in the claims asserted by
Amarin.1 Amarin has asked that I offer my opinion in response to Mr. Mathers’s report.
5. Mr. Mathers represents in his report that, “[f]or purposes of this case, [he]
understand[s] that there are no material differences between Vascepa® and Defendants’ proposed
ANDA products, which are generic versions of Vascepa®.”2 Mr. Mathers further represents that
he “analyzed the current labeling for Vascepa®, as well as the proposed draft labeling for
Defendants’ ANDA products,” finding “that “[i]n all material respects, these three labels are
substantively identical.”3 Given these representations, though I discuss the Vascepa® labeling in
this report, my conclusions apply equally to Defendants’ proposed ANDA Products.
6. I reserve the right to provide testimony, whether at a hearing, in deposition, or
through declaration, that consists of, explains, elaborates upon, or provides background and
context regarding: (a) the opinions and information set forth in this report; (b) the testimony that I
might give in deposition or through declaration; (c) the testimony that other fact or expert witnesses
may give or have given at a hearing, in deposition, or through declaration; (d) additional opinions
that I form in response to reply expert reports, briefs, arguments, or other materials submitted by
or on behalf of any party to this action; (e) additional opinions relating to facts that come to light
after the date of this report; and/or (f) additional opinions in response to any arguments that
Defendants may assert on the issue of infringement or on the scope of the patent claims.
1
Rebuttal Expert Report of Peter R. Mathers, Case No. 2:16-cv-02525 (D. Nev. May 10,
2019) (hereinafter, “Mathers Rep.”) ¶¶ 43–46.
2
Id. ¶ 71.
3
Id.
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005
II. QUALIFICATIONS AND BACKGROUND
A. Qualifications
7. I am a board-certified physician in internal medicine and clinical pharmacology.4 I
attended the University of Kansas as both an undergraduate and medical student, receiving a
bachelor’s degree in mathematics and chemistry before earning my medical degree in 1968.
Between undergraduate and medical school, I received a Fulbright Grant and studied physical
chemistry at the Tecnisole Hochschule in Stuttgart, Germany. I completed my medical internship
at USA Tripler General Hospital in Honolulu, Hawaii in 1969, and my residency in internal
medicine at Letterman General Hospital in San Francisco, CA in 1972.
8. During my medical internship and internal medicine residency, I practiced
medicine full time, as well as sporadically thereafter until 1987, when I joined the FDA. My
patients during internship and residency comprised seriously ill American soldiers, who were
injured or exposed to tropical diseases while on duty in Vietnam. At the same time, I managed a
wide range of acute and chronic medical illnesses of civilian family members of active duty
personnel, and military retirees, including illnesses such as cancer, trauma, and other serious
conditions. After I began my research career in 1993, I regularly treated patients with chronic
4
“Clinical pharmacology” is “the study of drugs in humans.” As the American Society of
Clinical Pharmacology and Therapeutics (“ASCPT”) explains:
Clinical pharmacologists are physicians, pharmacists, and scientists whose focus is
developing and understanding new drug therapies. Clinical pharmacologists work in
a variety of settings in academia, industry and government. In the laboratory setting
they study biomarkers, pharmacokinetics, drug metabolism and genetics. In the
office setting they design and evaluate clinical trials, create and implement
regulation guidelines for drug use, and look at drug utilization on local and global
scales. In the clinical setting they work directly with patients, participate in
experimental studies, and investigate adverse reactions and interactions.
See ASCPT, What is Clinical Pharmacology? (AMRN-PEXP-0010617).
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006
medical conditions in 1-day per week clinics and with acute medical illnesses in emergency room
duties. Upon joining the faculty of the Uniformed Services University of the Health Sciences
(USUHS) in Bethesda, Maryland in 1980, I served as the attending physician each year on medical
service wards at the Walter Reed Army Medical Center and Naval National Medical Center. In
this capacity, I supervised internal medical residents and physician staff in the care of seriously ill
inpatients, often advising on the clinical pharmacology of drugs used in the patient’s management.
9. During my professional career as an internist and physician scientist, I have held
academic research and teaching positions at several institutions, including: Clinical Assistant
Professor and Adjunct Professor of Medicine and Bioengineering and Therapeutic Sciences at the
University of California, San Francisco (“UCSF”); Chief of the Division of Blood Research at the
Letterman Army Institute of Research; Professor and Director of the Division of Clinical
Pharmacology at the Uniformed Services University of the Health Sciences; and Professor of
Pharmacology at Georgetown University. Early in my career, as a practicing internist, I prescribed
many medicines to my patients, based in part upon knowledge and facts derived from FDA
approved drug labels. In my clinical research career, I designed, executed and analyzed numerous
clinical trials involving human volunteers. My use of FDA approved drugs in these trials,
alongside experimental medicines, was also informed by information gathered from relevant drug
labels. Findings in these trials contributed to drug labels when results were submitted to FDA.
10. I served in the U.S. Army Medical Corps and Medical Research and Development
Command from 1967 to 1990, achieving the rank of Colonel. From 1980 to 1987, I was assigned
as Consultant in Clinical Pharmacology to the Army Surgeon General. In 1990, I transferred to
the U.S. Public Health Service and held the rank of Rear Admiral and was appointed Assistant
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007
Surgeon General of the United States. In these roles, I advised the Surgeon General on the safety
of the nation’s drug supply for emergency use in military and civilian disaster situations.
11. I was named Director of the Center for Drug Evaluation and Research (“CDER”)
at the Food and Drug Administration (“FDA”) in 1987 and served in that position until 1993, when
I retired from government service after 26 years. CDER is the part of FDA responsible for
evaluating and approving new drugs (including the labeling of new drugs). As the Director of the
CDER, I supervised over 1,700 scientists, managers, and associated FDA staff. My
responsibilities included establishing and enforcing standards of guidance, review and approval or
rejection of new medical products, safety of all marketed products, and advertising and
promotional practices of drug manufacturers. Approval decisions always involved close attention
to the information in the approved drug label.
12. I have testified before Congress on numerous occasions and have explained FDA
policies and decisions to the public in advisory committee meetings, scientific conferences, and
press interviews. In my FDA position, I reviewed and commented on the sufficiency of the studies
that were being performed to support Investigational New Drug applications (“INDs”) and New
Drug Applications (“NDAs”), including clinical trials and bioequivalence. During my six years
at CDER, I reviewed, commented, or rendered decisions on drug labels relating to more than 500
INDs, NDAs, Abbreviated New Drug Applications (“ANDAs”), 505(b)(2) and Over the Counter
applications, policy documents, requests for drug information from Members of Congress and the
media, and Citizen Petitions. During my tenure at CDER, I also instituted major changes to the
drug-evaluation process, which resulted, in part, in the agency placing more emphasis on a drug’s
pharmacokinetic / pharmacodynamic profiles when evaluating such data for approval.
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13. In late 1993, I was appointed to the Honorary Boerhaave Professor at the University
of Leiden in the Netherlands, where I taught and researched human drug development and
regulation at the Leiden-Amsterdam Center for Drug Research. Following my sabbatical in
Europe, in 1994, I became Professor of Pharmacology and the Founding Director of the Center for
Drug Development Science (“CDDS”) at Georgetown University in Washington, D.C. In 2004,
the Center was transferred to UCSF, where I became the Director of the CDDS in the School of
Pharmacy and Professor in UCSF’s Department of Bioengineering and Therapeutic Sciences. In
2006, I retired from the directorship of CDDS. Since then, I have continued teaching at UCSF as
an Adjunct Professor. As an academic research, education, public policy, and technical assistance
center, CDDS permitted the continuation of my career-long study of scientific and regulatory
methods for evaluating the effectiveness and safety of new drugs.
14. I co-founded the UCSF-American (2007) and Chinese (2009) Courses in Drug
Development and Regulatory Science (“ACDRS, CCDRS”), which are Executive Masters level
courses in advanced drug development and regulation for experienced industry scientists and
regulatory agency scientists and reviewers. I served as a founding member of the Executive and
Planning Committees of the ACDRS, CCDRS. I also served as a member of the Advisory Board
for the European Center for Pharmaceutical Medicine. In addition, I served on the Advisory Board
for PharmaTrain and the Innovative New Medicines Initiative (“IMI”) Master of Pharmaceutical
Medicine degree program funded by the European Commission.
15. Throughout my professional career, I have published over 150 original scientific
papers as well as a book and several book chapters. Amongst my published papers are reports that
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009
focus on adequacy of drug labels,5 as well as drug advertising and promotion.6 For over 45 years,
I have also been an active journal reviewer for multiple scientific publications, including Clinical
Pharmacology and Therapeutics. I have served as a member of the Publications Committee of the
American Society for Clinical Pharmacology and Therapeutics (“ASCPT”), and I have reviewed
research manuscripts submitted for publication in journals sponsored by ASCPT. I served on the
ASCPT Board of Directors for many years prior to being elected President in 1998.
16. Since 2003, I have served as the Founder and Chairman of NDA Partners LLC,
which is an international consulting company that provides scientific and regulatory advice and
services to scientists and entrepreneurs in private industry, as well as to government agencies such
as the Department of Defense. NDA Partners assists companies in understanding and meeting the
FDA’s high scientific standards and requirements, and it supports various aspects of their
engagements with the FDA during the IND, NDA, and post-approval phases. Our services include
advising biotechnology firms and U.S. government agencies on clinical and bioequivalence study
designs as well as clinical trial analysis, interpretation, and communications with the FDA. While
at NDA Partners, I have personally consulted on more than 200 INDs, NDAs, and 505(b)(2)
5
ED Harvey, BE Harvey, AM Harvey, BH Rumack, CC Peck, AJ Atkinson, RL Woosley,
DR Abernethy, LR Cantilena: Assessment of clinical pharmacology information (CPI) in drug
labeling. Clin Pharmacol Thera 61(2): 166, 1997; Spyker DA, Harvey ED, Harvey BE, Harvey
AM, Rumack BH, Peck CC, Atkinson AJ, Woosley RL, Abernethy, Cantilena LR: Assessment
and reporting of clinical pharmacology information in drug labeling. Clin Pharmacol Thera
67(3):196-199, 2000; Cross, J, Lee, H, Westelinck, A, Nelson, J, Grudzinskas, C, Peck, C.
Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999.
Pharmacoepidemiology and Drug Safety 2002, 11 (6): 439-446; 85. Jolson, HM, Bosko, L, Peck,
CC. Clustering of Adverse Drug Events: Analysis of Risk Factors for Cerebellar Toxicity with
High-Dose Cytarabine. JNCI J Natl Cancer Inst FDA regulation of prescription drug advertising
(1992) 84 (7): 500-505; 110.
6
Peck CC, Rheinstein PH: "FDA Regulation of Prescription Drug Advertising" (editorial)
JAMA 264:18, pps. 2424-2425, 1990.
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010
applications, and helped companies to develop strategies for evaluating the clinical pharmacology,
safety, and effectiveness of new drugs in order to satisfy the high standards of the FDA. In order
to provide my clients with my best, fully informed counsel, I have kept up to date on FDA
regulations and procedures for provision of adequate drug labels. I have also served on numerous
Science Advisory Boards and a few Boards of Directors of biopharmaceutical companies.
17. My honors and awards include the Department of Army Research and Development
Award for contributions to the multi-center cooperative evaluations of the CPDA-1 blood
preservative system (1978), Army Meritorious Service Medal (1980), the Defense Superior
Service Medal (1988), the FDA Distinguished Career Service Award (1993), the FDA
Distinguished Alumnus Award (1999), and an Honorary Doctorate Degree from Uppsala
University in Sweden for “outstanding contributions to the science of drug development” (2002).
More recently, I was awarded the Henry W. Elliott Distinguished Service Award by the ASCPT
(2009), the ASCPT Gary Neil Prize for Innovation in Drug Development (2012), the ASCPT
Sheiner-Beal Pharmacometrics Award (2017), and the Gary Levy Memorial Lectureship (2018).
18. My qualifications are set out more fully in my curriculum vitae, which is attached
as Exhibit A to this Report.
B. Prior Testimony
19. Within the past four years, I have testified in the matters listed in Exhibit B.
C. Statement of Compensation
20. I am being paid $650.00 per hour for time spent consulting or testifying in this
matter, and $325.00 per hour for any non-productive travel time associated with this matter. My
compensation does not depend in any way on the outcome of this litigation or on the opinions or
conclusions that I express in this Report or in any subsequent testimony.
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011
84. The principal purpose of Phase 2b trials is to identify a safe, likely to prove
effective, dosage regimen(s) to employ in the Phase 3 program. Phase 2b trials also provide
resolution of other safety/effectiveness issues such as timing of treatment and further selection of
the target population for the medication.27
85. Phase 3. The Phase 3 trial program commonly comprises two or more large
randomized, blinded trials. That they are randomized means that treatments in the trials are
assigned to patients in a random fashion. That they are blinded means that during the trial, patients
and investigators are not made aware of the specific treatment selected for each patient in order to
prevent biasing trial execution, outcomes, or interpretation. Phase 3 trials aim to confirm the
effectiveness and safety of the to-be-marketed dosage regimen(s), as compared to placebo or
another effective treatment of patients with the target disease. They are conducted per a common
protocol that the FDA reviews in conjunction with the end-of-Phase 2 meeting with the sponsor.28
86. New Drug Application submission and review. After completion and analysis
of the results of Phase 3 trials, the entire database of chemistry, manufacturing, in vitro and animal
pharmacology and toxicology, and Phase 1, 2, and 3 trial results (raw data tables, case report forms,
27
See id. § 312.21(b) (“Phase 2 includes the controlled clinical studies conducted to
evaluate the effectiveness of the drug for a particular indication or indications in patients with the
disease or condition under study and to determine the common short-term side effects and risks
associated with the drug. Phase 2 studies are typically well-controlled, closely monitored, and
conducted in a relatively small number of patients[.]”)
28
See id. § 312.21(c) (“Phase 3 studies are expanded controlled and uncontrolled trials.
They are performed after preliminary evidence suggesting effectiveness of the drug has been
obtained, and are intended to gather the additional information about effectiveness and safety that
is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate
basis for physician labeling.”).
- 30 -
012
and clinical study reports) are incorporated in an NDA and submitted to FDA for review. FDA
regulations specify the required content and format of NDAs.29
87. Within 60 days of receipt of the NDA, a team of FDA scientists—including
chemists, basic and clinical pharmacologists, toxicologists, microbiologists, pharmacometricians,
statisticians and physicians—scan the NDA for completeness and reviewability, deciding whether
to accept the NDA for formal review.30 If accepted, the FDA team commences a thorough and
critical review of all aspects of the NDA, undertaking re-analyses of raw data, in order to
independently critique the sponsor’s findings of effectiveness and safety. Once the primary team
has concluded its review and recommends that the FDA take one of several actions, secondary
reviews are undertaken within the division and at the division director level. The final decision is
made after additional review by the Office Director in which the division resides.
88. FDA reviews an NDA in order to confirm that the evidence submitted is sufficient
to demonstrate safety and effectiveness, and also to ensure that the data submitted are complete
and accurate. The FDA’s review can take months or years and may involve several cycles of NDA
submission and FDA review, multiple requests by FDA for responses to questions and for more
data, and submissions of amendments to the NDA. As set forth more fully below, the FDA
carefully reviews the applicant’s proposed labeling as part of this process.
89. A new medicine must be found to be safe and effective when used in accordance
with the proposed labeling in order to be approved.31 Safety and efficacy for the approved
indications must be established by scientifically rigorous, well-controlled clinical studies.
29
See id. § 314.50.
30
See id. § 314.101(a), (d)–(e). See also generally FDA, Guidance for Industry: Refuse to
File: NDA and BLA Submissions to CDER (Draft) (Dec. 2017) (AMRN-PEXP-0010360–70).
31
See 21 U.S.C. § 355; 21 C.F.R. § 105.
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013
However, because all medicines have risks, FDA approval does not mean a medicine is absolutely
safe, or has no risks or side effects. Rather, FDA approval means that the FDA has determined
that the benefits of the product for the category of patients for whom the medicine is intended have
been shown in trials to outweigh the risks when used in accordance with the approved labeling.32
90. CDER is the part of the FDA that reviews NDAs. CDER employs more than 5,000
staff and is organized into several groups, called offices. One group is responsible for the review
of NDAs, another for the review of generic drug applications, and another for the review of “over-
the-counter” drugs. Additionally, there are offices and divisions concerned with compliance and
enforcement, the advertising and promotion of prescription drugs, the monitoring of adverse events
in marketed drugs, and research and management support.
91. CDER’s review of all NDAs is comprehensive and thorough. It is accomplished
by subject matter experts, well-versed in each aspect of the proposed medication. Upon
submission, each NDA is assigned to a particular reviewing division within one of the Offices of
New Drug Evaluation, such as the Office of Antimicrobial Products, Offices of Drug Evaluation
I-IV, and Office of Hematology and Oncology Drug Products.33 The component parts of the NDA
are distributed to reviewers trained in specific disciplines within each appropriate review division.
92. The Chemistry, Manufacturing, and Controls (“CMC”) portion of the NDA is
assigned to a team of Ph.D. chemists who review the product’s chemistry, formulation, and
stability, strength, purity and quality characteristics.34 The chemistry and manufacturing team also
32
See FDA, About FDA Product Approval (AMRN-PEXP-0009880); FDA, Development
& Approval Process (Drugs) (AMRN-PEXP-0010132–35).
33
See FDA, Office of New Drugs (AMRN-PEXP-0010395–97).
34
See generally FDA, CDER, Office of Pharmaceutical Science, Chemistry Review of
Question-based Review (QbR) Submissions (Nov. 18, 2014) (AMRN-PEXP-0010062–73).
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014
labeling may more briefly describe or refer to the topic,” FDA advises that multiple sections should
“not repeat the same content or level of detail.”105 Accordingly, FDA instructs applicants to
“identif[y], prioritize[], and locat[e]” the “clinical information pertinent to prescribing decisions
. . . in the labeling section that most appropriately communicates the type of information.”106
126. Because the information critical to a physician’s understanding of how to use the
drug safely and effectively is divided across several sections in any given labeling, FDA advises
that the “labeling should be considered in its entirety for individual prescribing decisions.”107
127. In the following subsections, I review eight sections of Vascepa®’s labeling to
illustrate the content and purpose of these sections under FDA regulations and agency guidance.
1. INDICATIONS AND USAGE
128. According to FDA Guidance, “[t]he primary role of the Indications and Usage
section of labeling is to enable health care practitioners to readily identify appropriate therapies
for patients by clearly communicating the drug’s approved indication(s).”108
129. To this end, the Indications and Usage section concisely comprises “the indication
and, as appropriate, any identified limitations of use.”109 This section must “identif[y] the disease,
condition, or symptom for which the drug is approved,”110 and list other important aspects of the
approved indication, such as whether the drug is approved for selected patient subgroups, is
105
Id.
106
Id.
107
FDA, Guidance for Industry: Indications and Usage Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format 2 (Draft) (July 2018)
(hereinafter, “FDA Guidance: Indications and Usage”) (AMRN-PEXP-010246).
108
Id.
109
Id. at 6 (AMRN-PEXP-10250).
110
Id. at 8 (AMRN-PEXP-10252); see also 21 C.F.R. § 201.57(c)(2).
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approved for use as an adjunct to another form of therapy, and whether any specific tests are needed
to identify patients in whom to use the drug.111 This section should also present separately from
the indication any “limitations of use,” which advise physicians that there is “reasonable concern
or uncertainty among FDA’s expert reviewers” as to whether is it advisable to use the drug under
particular circumstances or in a specific subgroup of patients.112
130. The Indications and Usage section generally does not state how long a drug should
be used. According to FDA Guidance, this section “generally” should not “limit duration of use
. . . unless such a limited duration is essential to ensure the safe and effective use of the drug.”113
The Indications and Usage section should, where applicable, note any “specific conditions” that
FDA believes “should be met before [a] drug is used on a long-term basis.”114
131. FDA Guidance includes several recommendations intended to make the Indications
and Usage section more accessible to, and useful for, health care practitioners. For instance, FDA
has explained that this section “should clearly communicate the scope of the approved indication,
including the population to which the determination of safety and effectiveness is applicable.”115
The Indications and Usage section also should “use terminology that is . . . understandable to health
care practitioners.”116 And it should be “concisely written to include [only] the information
111
FDA Guidance: Indications and Usage at 8–9 (AMRN-PEXP-0010252–53).
112
113
114
Id.
115
116
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016
necessary to clearly convey the use(s) for which the drug has been shown to be safe and effective,”
which will make it easier for health care practitioners to search electronic drug databases.117
132. Because FDA intends for the Indications and Usage section to be “concise,” it has
explained that “[o]ther sections of labeling” necessarily “provide essential details that enable safe
and effective use of a drug, and labeling should be considered in its entirety for individual
prescribing decisions.”118 For instance, the Indications and Usage section “is not intended to be a
description of the data supporting the determination of effectiveness[.]”119 Instead, “detailed
information about topics such as clinical studies and risks related to limitations of use will
generally be found elsewhere in the labeling.”120 The Clinical Studies section, for example,
provides a detailed description of the clinical studies “that facilitate [the prescriber’s]
understanding of how to use the drug safely and effectively.”121
133. In limited circumstances, FDA requires the Indications and Usage section to cross-
reference more detailed discussions in other sections of the labeling.122 For instance, FDA may
require a “limitation of use” to be “further described in (and cross-referenced to)” to another
section, like the Warnings and Precautions or Clinical Studies section.123
117
Id.
118
Id.
119
120
121
Id. at 14 (AMRN-PEXP-0010258) (quoting 21 C.F.R. § 201.57(c)(15)).
122
123
Id. at 10–11 (AMRN-PEXP-0010254–55).
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148. The Drug Interactions section of the Vascepa® labeling, reproduced below, advises
physicians to “monitor[] periodically” patients taking Vascepa® with drugs that affect coagulation,
because some studies have shown prolonged bleeding time with omega-3 fatty acids.149
6. CLINICAL PHARMACOLOGY
149. FDA recognizes that “[c]linical pharmacology information collected throughout a
drug’s life cycle can contribute to clinical decision making and may be appropriate for inclusion
in a drug’s labeling.”150 FDA also has opined that “optimal pharmacotherapy”—i.e., medical
treatment by means of pharmaceutical drugs—“is driven by an understanding of a drug’s clinical
pharmacology and the clinical context in which the drug will be used.”151
150. When reviewing an NDA, FDA thus “consider[s] what clinical pharmacology
information can be directly translated to prescribing decisions and provide specific
recommendations that should be included in relevant sections of the labeling.”152 These
recommendations can include “strategies for dose selection, therapeutic individualization, and
149
Vascepa® Labeling at 3 (AMRN03132170).
150
FDA, Guidance for Industry: Clinical Pharmacology Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format 2 (Dec. 2016) (hereinafter,
“FDA Guidance: Clinical Pharmacology”) (AMRN-PEXP-0010172).
151
Id.
152
Id.
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018
minimization of adverse reaction risk.”153 For some patient-care recommendations, FDA deems
it “appropriate” to provide prescribers with “more detailed supportive information,” to allow “the
healthcare provider to determine the relevance of the information for a given patient or clinical
scenario.”154 This added detail is “typically included” in the Clinical Pharmacology section, which
FDA advises should be written in a way that is “understandable to health care providers who may
not have specific expertise in clinical pharmacology.”155
151. By regulation, the Clinical Pharmacology section “must contain information
relating to the human clinical pharmacology and actions of the drug in humans.”156 This can
include information regarding the drug’s “mechanism of action” (i.e., how the drug works),
“pharmacodynamics” (i.e., the biochemical and physiologic effects of the drug), and
“pharmacokinetics” (i.e., how the drug is absorbed, distributed, metabolized, and excreted).157
152. The “Pharmacokinetics” subsection may include a “Drug Interactions Studies”
heading under which the labeling provides “detailed information that informs the actionable
recommendations in the Drug Interactions section of labeling.”158 This heading should “also
include study design information that may inform prescribing decisions (e.g., if a clinically
relevant difference in exposures between patients and healthy volunteers was observed . . . ).”159
153
Id.
154
Id.
155
Id.
156
21 C.F.R. § 201.57(c)(13)(i).
157
Id. § 201.57(c)(13)(i)(A)–(C).
158
FDA Guidance: Clinical Drug Interaction at 24–25 (AMRN-PEXP-0010162–63).
159
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019
153. The Clinical Pharmacology section of the Vascepa® labeling, reproduced in part
below, includes subsections on Vascepa®’s “Mechanism of Action” (12.1) and
“Pharmacokinetics” (12.3). The Pharmacokinetics subsection includes a “Drug-Drug
Interactions” heading, under which the labeling advises physicians that Vascepa® 4 g / day (the
approved daily dose) has been studied for “drug-drug interactions” with four medications,
including a statin (atorvastatin). The labeling reports that “no drug-drug interactions were
observed” in 26 healthy adult subjects who were co-administered the daily dose of Vascepa® and
80 mg / day of atorvastatin.160
* * *
* * *
160
Vascepa® Labeling at 5–6 (AMRN03132172–73).
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7. CLINICAL STUDIES
154. The Clinical Studies section “must discuss those clinical studies that facilitate an
understanding of how to use the drug safely and effectively.”161 “This is usually accomplished by
providing concise, accurate summaries of information from studies concerning a drug’s
effectiveness (and sometimes safety) that practitioners consider important to clinical decision
making.”162
155. To this end, the Clinical Studies section “must discuss” the “adequate and well-
controlled” studies “that support effectiveness for the labeled indication(s), including discussion
of study design, population, endpoints, and results.”163 “[T]he amount of detail” FDA requires to
“provide a useful description of a study and its results will depend on the indication, the trial
design, the understanding of the drug or drug class, and the extent to which the information adds
to an understanding of the clinical effects of the drug and how the drug should be used.”164 But
the “primary objective” is to concisely and accurately “summarize (1) the evidence supporting
effectiveness in the subjects who were studied, (2) the critical design aspects of the studies,
including the populations studied and endpoints measured, and (3) the important limitations of the
available evidence.”165 Because the studies described in this section may not “imply or suggest
indications or uses or dosing regimens not stated in the ‘Indications and Usage’ or ‘Dosage and
161
21 C.F.R. § 201.57(c)(15).
162
FDA, Guidance for Industry: Clinical Studies Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format 2 (Jan. 2006) (hereinafter,
“FDA Guidance: Clinical Studies”) (AMRN-PEXP-0010191).
163
21 C.F.R. § 201.57(c)(15), (15)(i).
164
FDA Guidance: Clinical Studies at 3 (AMRN-PEXP-0010192).
165
Id.
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021
Administration’ section,”166 a study should not be included in this section if it “impl[ies]
effectiveness for an unapproved indication, use or dosing regimen.”167 For the same reason, the
FDA’s decision to include information in the Clinical Studies section reflects a judgment that this
information facilitates a clinician’s safe and effective use of the product in accordance with the
approved indication, use, or dosing regimen.
156. FDA Guidance “recommend[s]” that the Clinical Studies section discuss several
“elements” when “describing the study design.”168 For instance, this section should describe the
“major design characteristics” of the study, including the “level of blinding,” “duration of the
study,” and the “method of allocation to treatment groups (e.g., randomization).”169 It also should
describe the dose and regimen for each arm and provide “[i]nformation about concomitant
therapies . . . to the extent it helps to understand the use of the study drug or its effects.”170 Finally,
this section should describe the study population and “identify those characteristics that are
important for understanding how to interpret and apply the study results,” such as “baseline values
of any clinically relevant variables important for understanding the treatment effect.”171
157. As for endpoints, this section should “present those endpoints that establish the
effectiveness of the drug or show the limitations of effectiveness.”172 “When . . . informative, the
166
21 C.F.R. § 201.57(c)(15)(i).
167
168
169
Id.
170
Id. at 6–7 (AMRN-PEXP-0010195–96).
171
172
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022
Clinical Studies section can also discuss other endpoints shown to be affected by the drug and
endpoints that might have been expected to be influenced by the drug, but were not.”173
158. The Clinical Studies section also should set out a “summary of the findings [that]
describe the clinical outcome of the treatment relative to the comparator (e.g., placebo or active)”
(i.e., the “treatment effect” of the drug).174 The treatment effect is generally “presented as a mean
or median result accompanied by a measure of uncertainty or distribution of results for the treated
groups.”175 The labeling “should usually” provide a confidence interval and p-value to describe
“the uncertainty of the treatment effect” and “the strength of the finding.”176
159. The Clinical Studies section of the Vascepa® labeling, reproduced in two parts
below, describes the design of the MARINE clinical study, which established effectiveness of
Vascepa® for its current approved indication (as an adjunct to diet to TGs among severely
hypertriglyceridemic patients). The opening paragraph of the section specifically describes the
major design characteristics of the study (“a randomized, placebo-controlled, double-blind,
parallel group study” that lasted “12 weeks”). It describes the dosing regimen (4 g per day) and
relevant concomitant therapies (25% of the patients were on concomitant statin therapy). And it
describes several characteristics of the study population, including that all patients were adults
with severe hypertriglyceridemia (baseline TGs ≥ 500 mg/dl), with median baseline TG, LDL-C,
and HDL-C levels of 684 mg/dl, 86 mg/dl, and 27 mg/dl, respectively.177
173
174
Id. at 7–8 (AMRN-PEXP-0010196–97).
175
176
Id.
177
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023
160. The Clinical Studies section of the Vascepa® labeling also identifies the “efficacy
endpoints” measured in the MARINE study and provides “baseline values of [these] clinically
relevant variables” to assist physicians in “understanding the treatment effect” of Vascepa® 4 g
per day.178 Table 2 (reproduced below) lists several “major lipoprotein lipid parameters” studied
in the severely hypertriglyceridemic patients—including TGs, LDL-C, Apo B, and Non-HDL-C—
and provides corresponding median baseline values for both the treatment and placebo groups.179
161. The Clinical Studies section also summarizes the study’s findings regarding
Vascepa®’s treatment effect. Table 2 reports the median percent change from baseline and
compared to placebo for each of the lipid parameters studied. For example, the table reports that
patients who received 4 g per day of Vascepa® experienced a median 27% reduction in TGs relative
to baseline and a 33% reduction compared to placebo, a statistically significant reduction with a
p-value < 0.001. These same patients also experienced the following lipid effects:
• Apo B: reduction of 4% from baseline and 9% compared to placebo (statistically

significant with a p-value < 0.05);
• LDL-C: reduction of 5% from baseline and 2% compared to placebo; and
178
179
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024
• Non-HDL-C: reduction of 8% from baseline and 18% compared to placebo.
Beneath Table 2, the labeling summarizes these findings, reporting, among other things, that 4 g
per day of Vascepa® “reduced median TG . . . and Apo B levels from baseline relative to placebo”
and that the “reduction in TG observed with Vascepa® was not associated with elevations in LDL-
C levels relative to placebo.”180 Table 2 and the textual summary are reproduced below.
180
Id.
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025
8. PATIENT COUNSELING INFORMATION
162. Unlike other sections of the labeling, the Patient Counseling Information section is
not intended to inform a physician’s prescribing decision. While, “[o]ther sections of the labeling
contain the detailed information used by prescribers to fully assess the risks and benefits of a drug
for an individual patient,” “[t]he intent of [this] section, is to identify topics for counseling
discussions between health care providers and patients after a prescribing decision has been
made.” 181 Accordingly, this section “summarizes the information that a health care provider
should convey to a patient (or caregiver when applicable) when a counseling discussion is taking
place (e.g., a physician prescribing a drug during an office visit . . . ).”182
163. The Patient Counseling Information section “must contain information necessary
for patients to use the drug safely and effectively.”183 For example, this section must advise
physicians to warn patients if “the concomitant use of other substances . . . may have harmful
additive effects.”184 Depending on the drug, FDA also might require a manufacturer to include in
this section information about adverse reactions or drug interactions or “other patient-focused
information relevant for providers to convey,” such as important dosing instructions or “unique
181
FDA, Guidance for Industry: Patient Counseling Information Section of Labeling for
Human Prescription Drug and Biological Products — Content and Format at 3 (Dec. 2014)
(hereinafter, “FDA Guidance: Patient Counseling Information”) (AMRN-PEXP-0010353)
(emphasis added)
182
183
21 C.F.R. § 201.57(c)(18).
184
Id.
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026
storage and handling instructions.”185 However, in keeping with the purpose of this section, it
“should generally not . . . include . . . [i]nformation that informs prescribing decisions.”186
164. The Patient Counseling Information section of the Vascepa® labeling, reproduced
below, recommends four topics for discussion with patients: (1) Vascepa® should be used with
caution in patients with fish or shellfish allergies; (2) Vascepa® does not displace diet and exercise;
(3) patients should not alter Vascepa® capsules; and (4) Vascepa® should be taken as prescribed.187
165. In addition to the Patient Counseling Information, Vascepa®’s package insert
includes the full text of the FDA-approved “Patient Information” that is directed to patients.188
Among other things, the Patient Information sheet (excerpted in part below) instructs patients to
“[t]ake VASCEPA exactly as your doctor tells you to take it” and to “not change your dose or stop
taking VASCEPA without talking to your doctor.” It informs patients that “your doctor may start
185
FDA Guidance: Patient Counseling Information at 4–8 (AMRN-PEXP-0010354–58).
186
187
188
See 21 C.F.R. § 201.57(c)(18).
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027
you on a diet that is low in saturated fat, cholesterol, carbohydrates, and low in added sugars before
giving you VASCEPA,” and if so, patients “should stay on this diet while taking VASCEPA.”
Finally, the Patient Information also advises patients that “your doctor may do blood tests to check
your triglyceride and other lipid levels while you take VASCEPA.”189
* * *
189
Vascepa® Labeling at 9–10 (AMRN03132176).
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028
IX. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® FOR 12 OR MORE WEEKS.
166. As I discussed in paragraphs 25–29 above, each of the Asserted Claims involves a
method of reducing triglycerides in a patient with severe hypertriglyceridemia (TGs ≥ 500 mg/dl)
by administering the claimed icosapent-ethyl pharmaceutical composition to the patient for a
specified period of time—depending on the claim, for either 12 weeks, about 12 weeks, at least 12
weeks, or at least about 12 weeks.
167. Mr. Mathers opines that “as a regulatory matter, FDA did not write or approve the
Vascepa® label to instruct, encourage, recommend, or promote the use of Vascepa® for a period
of 12 weeks.”190 He bases this conclusion on two interpretations: First, neither the Indications
and Usage nor the Dosage and Administration section of the Vascepa® labeling specify a duration
of treatment.191 Second, reading the Clinical Studies section to “imply or suggest” that physicians
should administer Vascepa® for 12 weeks would, in his view, violate FDA regulations.192
168. For the reasons discussed below, I disagree with Mr. Mathers’s conclusions. In
summary, the absence of a specific limitation of duration of use in any section of the labeling
required to list such limitations, instructs and informs physicians that FDA has determined that
Vascepa® is safe and effective for long-term use in reducing TGs in patients with severe
hypertriglyceridemia. Further, the Clinical Studies section of the labeling, which is intended to
facilitate a health care practitioner’s understanding of how to use Vascepa® safely and effectively,
encourages physicians to prescribe Vascepa® for 12 or more weeks by teaching them that a 12-
week course of Vascepa® was effective to reduce TGs in patients with severe hypertriglyceridemia.
190
Mathers Rep. ¶ 130.
191
See id. ¶¶ 131–141.
192
See id. ¶¶ 142–151.
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029
A. The Vascepa® Labeling Informs and Instructs Prescribers that the Drug Is
Safe and Effective for Extended Use in Reducing Triglycerides in Patients with
Severe Hypertriglyceridemia.
169. Mr. Mathers opines that, because the Indications and Usage and Dosage and
Administration sections of Vascepa®’s labeling are “silent with respect to the approved duration”
of treatment, FDA must have been “indifferent as to the duration of treatment” with Vascepa®.193
170. That is not accurate. Mr. Mathers is correct that neither the Indications and Usage
or Dosage and Administration sections expressly refer to a recommended duration of treatment.194
But the absence of a duration limitation from these sections of the Vascepa® labeling does not
suggest that the FDA was “indifferent” as to the duration of use of Vascepa®. The FDA’s
penetrating review of an NDA and any proposed labeling always involves consideration of whether
safety or efficacy concerns warrant limiting the minimum or maximum treatment length for a new
drug or specifying conditions that should be met before the drug is prescribed for long-term use.
If the FDA-approved labeling omits any such limitation, it is because the FDA determined that
physicians could administer the drug safely and effectively for an extended period of time.
171. This judgment is reflected in FDA regulations and guidance. If treatment were to
be terminated at a particular point (e.g., shorter duration or when a particular treatment goal is
reached), the labeling would so state. For instance, FDA regulations require the Indications and
Usage section or the Dosage and Administration section to include information regarding the
“appropriate” or “usual” duration of treatment when the FDA has determined that there is a reason
193
Id. ¶ 141.
194
Vascepa® Labeling (AMRN03132168–69).
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030
that “treatment duration should be limited.” 195 The Indications and Usage section also is required
to identify “specific conditions that should be met before the drug is used on a long-term basis.”196
172. FDA guidance clarifies that these sections should include a statement regarding
duration of use if the agency has concerns regarding the safety or efficacy of long-term use.197 For
example, FDA guidance states that the Indications and Usage section should include a “limitation
of use” if there are concerns about the “appropriate treatment duration . . . such as how long a drug
can safely be used or uncertainty about the risks and benefits of treatment beyond a certain period
(e.g., long-term cumulative toxicity)[.]”198 Similarly, FDA has advised applicants that the Dosage
and Administration section should include a duration-of-use statement “when duration of use
should be limited (e.g., because of lack of data on long-term use and a basis for concern about
toxicity associated with long-term use, cumulative toxicity, or tolerance)”, or “if it is known that
above a certain dose or beyond a certain duration of use, toxicity is increased to an extent that the
risk exceeds the benefit, that dose or duration must be identified (§ 201.57(c)(3)(i)(B)).”199
173. Absent such concerns, however, FDA advises applicants that (a) duration should
be omitted from these sections and (b) any information about the length of treatment in the clinical
studies should be discussed in the Clinical Studies section. For example, the FDA has explained
that “[i]t is generally not necessary to limit duration of use in the [Indications and Usage] section
unless such a limited duration is essential to ensure the safe and effective use of the drug.”200 In
195
21 C.F.R. § 201.57(c)(2)(i)(D), (c)(3)(i)(F).
196
Id. § 201.57(c)(2)(i)(F).
197
See FDA Guidance: Indications and Usage at 12 (AMRN-PEXP-0010256).
198
Id.
199
FDA Guidance: Dosage and Administration at 2 (AMRN-PEXP-0010233).
200
FDA Guidance: Indications and Usage at 13 (AMRN-PEXP-0010257).
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reserving a discussion of clinical-trial length for the Clinical Studies section, the FDA’s goal is to
avoid implying (mistakenly) that a drug that the agency has approved for treatment of a chronic
condition, or a condition that requires extended treatment, is approved only for short-term use.201
174. Relatedly, when FDA has specific concerns that a physician may need to terminate
a course of treatment earlier than intended because of safety or efficacy concerns, it requires the
labeling to call for appropriate monitoring. Specifically, FDA guidance advises that the Dosage
and Administration section “should provide information about any monitoring that should be done
to assess effectiveness, including . . . how to adjust dose based on results of monitoring [and] on
what basis to discontinue a drug because of apparent lack of effectiveness.”202 The guidance even
uses the example of a “lipid-lowering drug,” explaining that when such a drug requires ongoing
efficacy monitoring “the section should identify which lipids to monitor, when to monitor, and
how to adjust the dose based on lipid profile.”203 FDA guidance further explains that the Dosage
and Administration section “should identify any specific safety monitoring procedures that should
be implemented before initiating therapy . . . or during therapy to determine whether to stop a
drug” or “withhold or decrease the dose of a drug given repeatedly.”204
175. As noted above, neither the Indications and Usage section nor the Dosage and
Administration section of Vascepa®’s labeling identify an “appropriate duration of treatment,”
which informs physicians that FDA determined that there was no safety or efficacy reason that use
of Vascepa® to reduce TGs in patients with severe hypertriglyceridemia “should be limited” in
201
Id.
202
203
204
Id.
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032
duration.205 Nor does Vascepa®’s labeling impose any limitations on long-term use once therapy
is initiated or require any specific monitoring to ensure that Vascepa®, when used for an extended
period, remains safe and effective. Instead, the labeling makes clear to physicians that Vascepa®
is approved for, and may be safely and effectively used for, sustained reduction of triglycerides
over the long-term in patients with severe hypertriglyceridemia.
176. Mr. Mathers attempts to bolster his opinion by citing examples of FDA-approved
labeling that he says affirmatively “instruct” physicians to prescribe the corresponding drug for a
minimum period of time.206 But prescription drug labeling can encourage, recommend, and
promote administration of a drug in a particular manner, or under particular conditions, without
affirmatively “instruct[ing]” that physicians must do, or must avoid doing, something. As just
explained, for example, by stating that a drug is indicated for a particular treatment using a
particular dosing regimen, without limiting duration of use, FDA-approved labeling can teach
physicians that the drug may be used for as long as they deem in the best interests of their patient.
177. Moreover, each example cited by Mr. Mathers presents a situation quite different
from Vascepa®. As Mr. Mathers notes, OxyContin® is approved for “long-term opioid treatment,”
and the Dosage and Administration section of the drug’s labeling notes that it is to “be prescribed
only by healthcare professionals who are knowledgeable in the use of potent opioids for the
management of chronic pain.”207 The reason why FDA felt it necessary to specify duration of
treatment in OxyContin®’s labeling is spelled out in the many warnings and other statements in
the labeling about the risk and abuse potential of opioids like OxyContin®. The FDA-approved
205
See 21 C.F.R. § 201.57(c)(2)(i)(D), (c)(3)(i)(F).
206
See Mathers Rep. ¶¶ 135–140.
207
Mathers Rep. Ex. C at 5–6 (ICOSAPENT_DFNDT00015575–76).
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033
labeling emphasizes the need to limit use of OxyContin® to only those circumstances where the
drug is truly needed and to expressly avoid its use to treat “as an as-needed (prn) analgesic.”208
The OxyContin® labeling has no relevance to Vascepa® or any other TG-lowering medication.
178. Mr. Mathers also cites the labeling for Lovenox®, pointing out that the drug is
indicated for, among other things, the treatment of “acute deep vein thrombosis.”209 He also
emphasizes that the Lovenox® labeling advises physicians that the “average duration of
administration is 7 days.”210 What Mr. Mathers says about the Lovenox® labeling is correct, but
its implications are the opposite of what he implies. The use of “acute” in Lovenox®’s labeling
makes clear that the drug is not approved, and has not been found safe and effective, for long-term
treatment of deep vein thrombosis. In other words, FDA determined that it was necessary for safe
and effective use of the product to limit Lovenox®’s approval to a short-term (acute) condition.
Indeed, the labeling warns that Lovenox® places patients at increased risk of hemorrhage and
certain uses resulted in “long-term or permanent paralysis.”211
179. Contrast this with another drug, Eliquis®. Unlike Lovenox®, Eliquis® is indicated
for “treatment of deep vein thrombosis” generally, with no limitation to the “acute” form of that
condition.212 This conveys that FDA has approved Eliquis® (and deemed it safe and effective) for
long-term use in treating deep vein thrombosis—even though the Eliquis® labeling does not
specifically state that it is indicated for “long-term” use or treatment of a “chronic” condition. To
208
Id. at 5 (ICOSAPENT_DFNDT00015575).
209
Mathers Rep. ¶ 140 (emphasis added) (quoting Mathers Rep. Ex. G at 1, 3
(ICOSAPENT_DFNDT00015711, 15713)).
210
Id. (quoting Mathers Rep. Ex. G at 5 (ICOSAPENT_DFNDT00015715)).
211
See Mathers Rep. Ex. G at 9–14 (ICOSAPENT_DFNDT00015719–24).
212
Eliquis Labeling® at 4 (2019) (AMRN-PEXP-0009838).
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facilitate that use, the Eliquis® labeling describes (in Section 14.3) the clinical study supporting its
approval for treatment of deep vein thrombosis, including the duration of the study and relevant
study results.213
180. Mr. Mathers’s remaining examples involve drugs for which safety or efficacy
concerns led the FDA to limit duration of treatment and/or put conditions on long-term use.214
181. Lamisil®, for example, is prescribed for patients with fungal infections of the
nail.215 The Dosage and Administration section of the Lamisil® labeling states that it should be
used for either 6 weeks to treat a fingernail or for 12 weeks for the same infection in a toenail.216
These duration recommendations were keyed to both efficacy trials and safety concerns. They
conveyed to physicians that treatment should be limited to the 6 or 12 weeks necessary to cure this
hard-to-treat infection, because FDA was concerned the drug might cause hepatotoxicity (liver
failure) even in patients with no preexisting liver disease, concerns that prompted FDA to advise
both pre-therapy evaluation and monitoring of hepatic serum transaminases throughout therapy.217
182. Levaquin® is an antibiotic that, like Lamisil®, is approved for treatment of acute
infections (in this case, bacterial infections).218 The Indications and Usage and Dosage and
Administration sections of Levaquin®’s labeling recommend treatment regimens ranging from 3
213
See id. at 36–39 (AMRN-PEXP-0009870–73).
214
See Mathers Rep. ¶¶ 137–139. See also generally 21 C.F.R. § 201.57(c)(2)(i)(D),
(2)(i)(F), (3)(i)(F).
215
See Mathers Rep. ¶ 137.
216
Mathers Rep. Ex. D at 2 (ICOSAPENT_DFNDT00015618).
217
See, e.g., id. (instructing physicians to “evaluate patients for evidence of chronic or
active liver disease,” explaining Lamisil® is “contraindicated for patients with chronic or active
liver disease” and advising physicians to “perform liver function tests” before and during treatment
“because hepatotoxicity may occur in patients with and without preexisting liver disease”).
218
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(uncomplicated urinary tract infection) to 60 days (anthrax) based on infection type.219 These
limitations were based on efficacy trials220 and FDA’s concern that using Levaquin® for less than
the recommended course, or when a patient no longer has an infection, “may (1) decrease the
effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop
resistance and will not be treatable by LEVAQUIN® or other antibacterial drugs in the future.”221
Levaquin® also is associated with an extended list of safety concerns including musculoskeletal
adverse reactions and in patients with reduced renal (kidney) function.222
183. Finally, Fosamax® is prescribed to prevent bone fractures in patients with
osteoporosis.223 The Indications and Usage section of the Fosamax® labeling includes a limitation
of use recommending that physicians “consider drug discontinuation after 3 to 5 years of use” in
“[p]atients at low-risk for fracture.”224 The FDA required this limitation of use because clinical
studies had not established “[t]he optimal duration of use” of Fosamax®,225 and because
biophosphonates like Fosamax® posed significant safety risks, including femoral fractures and
osteonecrosis of the jaw, that could increase with continued exposure.226
219
Mathers Rep. Ex. E at 3–8 (ICOSAPENT_DFNDT00015632–37).
220
See, e.g., id. at 38–48 (ICOSAPENT_DFNDT00015667–77) (describing efficacy
studies of varying treatment regimens for various bacterial infections).
221
Id. at 50 (ICOSAPENT_DFNDT00015679); see also, e.g., id. at 15
(ICOSAPENT_DFNDT00015644) (“[p]rescribing LEVAQUIN® in the absence of a proven or
strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to
the patient and increases the risk of development of drug-resistant bacteria”).
222
See, e.g., id. at 9–17, 25, 27 (ICOSAPENT_DFNDT00015638-46, 15654, 15656).
223
Mathers Rep. ¶ 139; Mathers Rep. Ex. F at 2 (ICOSAPENT_DFNDT00015689).
224
Mathers Rep. Ex. F at 2 (ICOSAPENT_DFNDT00015689).
225
Id.
226
See generally Letter from Audrey Gassman, Deputy Director for Safety, FDA Ctr. for
Drug Evaluation and Research, to Elinor Chen, Director of Worldwide Regulatory Affairs, Merck
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184. I agree with Mr. Mathers that Vascepa® is materially different from each of the
examples he cites, but the conclusion he draws from those differences is mistaken. Vascepa®’s
Indications and Usage and Dosage and Administration sections do not specify a duration of use
because, unlike Mr. Mathers’s examples, there was no safety or efficacy issue that would have
required FDA to limit Vascepa®’s approval to an “acute” condition or a specific recommended
course of treatment. That contrast only highlights that, in the case of Vascepa®, the FDA has
determined that the drug is safe and effective for the long-term, sustained reduction of triglycerides
in patients with severe hypertriglyceridemia. The Vascepa® labeling thus instructs physicians that
the drug may be administered for as long as the drug is necessary, effective, and well-tolerated.
185. For the reasons discussed, it is my opinion that Vascepa®’s labeling (and
Defendants’ proposed ANDA labeling) instructs physicians that Vascepa® is safe and effective for
long-term use to reduce TGs in patients with severe hypertriglyceridemia and that the labeling thus
encourages, recommends, and promotes that Vascepa® be administered for as long as a physician
deems to be in the best interest of his or her patient.
Sharp & Dohme Corp., Supplement Approval and attached labeling (Jan. 25, 2011) (AMRN-
PEXP-0010512–40); Letter from Audrey Gassman, Deputy Director for Safety, FDA Ctr. for Drug
Evaluation and Research, to Elinor Chen, Director of Worldwide Regulatory Affairs, Merck Sharp
& Dohme Corp., Supplement Approval & Release REMS Requirement (July 1, 2011) (AMRN-
PEXP-0010509–11); Letter from Hylton V. Joffe, Director of the Division of Reproductive and
Urologic Products, FDA Ctr. for Drug Evaluation and Research, to Elinor Chen, Director of
Worldwide Regulatory Affairs, Merck Sharp & Dohme Corp., Supplement Approval (Apr. 19,
2013) (AMRN-PEXP-0010571–74); Letter from Christine P. Nguyen, Deputy Director for Safety,
FDA Ctr. for Drug Evaluation and Research, to Barbra Weiss, Sr. Scientist of Global Regulatory
Affairs, Merck Sharp & Dohme Corp., Supplement Approval and attached labeling (Apr. 8, 2015)
(AMRN-PEXP-0010541–70).
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B. The Vascepa® Labeling Encourages Physicians to Administer Vascepa® for

12 or More Weeks.
186. The Clinical Studies section of a prescription drug’s labeling is intended to
“facilitate” a health care practitioner’s “understanding of how to use the drug safely and
effectively.”227 Mr. Mathers recognizes this.228 He concedes, too, that the Clinical Studies section
of the Vascepa® labeling “suggests that Vascepa® can be safely and effectively administered to
patients for a period of 12 weeks.”229 Later in his report, he even admits that “a physician reading
the Clinical Studies section of the [Vascepa®] label would understand that Vascepa® was shown
to be effective in reducing triglycerides” after being administered for “12 weeks.”230
187. I agree with these statements, which acknowledge both the importance of the
Clinical Studies section to prescribing decisions and the specific lesson physicians learn from
reading that section of the Vascepa® labeling: The daily dose of Vascepa® (4 g / day) is effective
at reducing TGs in severely hypertriglyceridemic patients when administered for 12 weeks.231
188. Despite the concessions above, Mr. Mathers maintains that “the Clinical Studies
section is, by regulation, not intended to—and does not—instruct, encourage, recommend, or
promote using Vascepa® (and by extension, the proposed labeling for Defendants’ ANDA
products) for any specified period of time.”232 He appears to believe that, even if a physician
would understand from the Clinical Studies section that Vascepa® is safe and effective to reduce
227
21 C.F.R. § 201.57(c)(15).
228
Mathers Rep. ¶¶ 121, 144.
229
Id. ¶ 120.
230
Id. ¶ 143.
231
See Vascepa® Labeling at 6–7 (AMRN03132173–74).
232
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TGs when administered for 12 weeks, it “would be a violation of FDA regulations for the Clinical
Studies section to ‘imply or suggest’ that Vascepa® should be used or dosed for a period of 12
weeks,” because that would somehow either “alter the scope of FDA approval” or “imply or
suggest” an indication or dosing regimen not set out in the Indications and Usage or Dosing and
Administration sections.233 I disagree with Mr. Mathers’s apparent reasoning and his conclusion.
189. As I discussed above, neither the Indications and Usage nor the Dosage and
Administration sections of the Vascepa® labeling specify a duration of treatment. The Vascepa®
labeling also does not specify pre-conditions to long-term use or ongoing safety or efficacy
monitoring. The absence of such limitations instructs physicians that Vascepa® is safe, effective,
and FDA-approved for long-term use to reduce TGs in patients with severe hypertriglyceridemia.
190. But that is not the only information in the Vascepa® labeling that is relevant to the
duration of treatment. The Clinical Studies section specifically informs physicians that the daily
dose of Vascepa® (4 g / day) effectively reduced TGs in severely hypertriglyceridemic patients
when administered for 12 weeks. By showing that Vascepa® was effective when used for 12
weeks, the Clinical Studies section advises and encourages physicians, who know they may safely
use Vascepa® for an extended period of time, to prescribe the drug for at least 12 weeks (or longer).
191. The reality that the Clinical Studies section encourages, recommends, and promotes
administration of Vascepa® for 12 weeks or more does not violate FDA regulations, as Mr. Mathers
suggests. Encouraging physicians to prescribe Vascepa® for 12 weeks or more does not “alter the
scope” of FDA approval and neither “impl[ies] [n]or suggest[s]” a new indication or dosing
regimen. Vascepa® is approved for an indication and dosing regimen that is not limited in duration.
Thus whether a physician prescribes Vascepa® for 12 weeks, 24 weeks, or even just 3 weeks, any
233
Id. ¶¶ 122, 145.
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such use would be within the scope of FDA’s approval. In other words, because FDA approved
Vascepa® without specifying any minimum or maximum duration of use, use for any period of
time is consistent with the labeling. Indeed, Mr. Mathers elsewhere appears to concede as much,
agreeing that the prescriber’s decision to “reference” the Clinical Studies section when prescribing
Vascepa® for “12 weeks” falls “within the scope of the approved Indication.”234
192. To the extent that Mr. Mathers argues that the Clinical Studies section does not
formally “instruct” prescribers to administer Vascepa® for 12 weeks, that is a red herring. Even if
the Clinical Studies does not tell physicians that they must prescribe Vascepa® for at least 12
weeks, the Clinical Studies section can, and in Vascepa®’s case does, encourage, recommend, or
promote use of a drug for a particular period of time, by explaining that a particular course of
treatment proved safe and effective in the study that served as the basis for FDA’s approval. Put
another way, the goal of the Clinical Studies section is to facilitate (that is, recommend or
encourage) the safe and effective use of the product by describing both the conditions under which
the drug has been found safe and effective and the expected treatment effects. By describing
Vascepa®’s administration to severely hypertriglyceridemic patients over the course of 12 weeks,
and the treatment effects seen from that administration, the labeling is instructing clinicians that
treatment for 12 weeks is a safe and effective way of treating their severely hypertriglyceridemic
patients to accomplish those effects, and is thereby recommending and encouraging that use.235
193. Vascepa®’s package insert not only encourages physicians to prescribe Vascepa®
for 12 weeks or more, but also helps assure that patients will actually take it for as long as directed.
234
Id. ¶ 122.
235
Because the labeling does not describe stopping the treatment at 12 weeks, clinicians
reading the labeling would understand the labeling to be encouraging 12 or more weeks of
administration (that is, long-term, indefinite administration).
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As Mr. Mathers acknowledges, “FDA regulations require that drug labels include a Patient
Counseling Information section that ‘must contain information necessary for patients to use the
drug safely and effectively.’”236 The corresponding section of Vascepa®’s labeling advises
physicians to “[i]nstruct patients to take VASCEPA as prescribed.”237 And the accompanying
“Patient Information,” which is directed to patients, specifically instructs patients to “[t]ake
VASCEPA exactly as your doctor tells you to take it,” to “not change your dose or stop taking
VASCEPA without talking to your doctor.”238 Together, this counseling encourages patients to
take Vascepa® for as long as their doctor prescribes it.
194. Mr. Mathers also cites the FDA’s Medical Review of Vascepa® in the belief that it
“confirms that the length of the reported clinical study for Vascepa® is not intended to specifically
encourage a minimum treatment duration.”239 In his view, the label does not encourage use for a
minimum of 12 weeks because the FDA Medical Review suggests that treatment with Vascepa®
can be “successful” in fewer weeks.240 Mr. Mathers notes that FDA reviewers determined that, in
the MARINE study, Vascepa® 4 g per day reached its maximum TG reduction at 4 weeks, at which
point he claims the therapy was “successful” because (in at least some patients) it had reduced TG
levels below 500 mg/dl.241 And in his view, “[o]nce triglycerides are controlled below 500 mg/dL,
236
Mathers Rep. ¶ 126 (quoting 21 C.F.R. § 201.57(c)(18)).
237
238
239
240
Id. ¶¶ 149–150.
241
Id.
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which can occur within 12 weeks according to the clinical study discussed above, the label does
not encourage physicians to continue treatment with Vascepa® as a prophylactic measure.”242
195. I disagree for several reasons. First, Mr. Mathers misreads the Medical Review’s
statement—drawn from an excerpt of the Adult Treatment Panel (ATP III) practice guidelines of
the American College of Cardiology—that “[t]herapy is considered to be successful if TG is
lowered to < 500 mg/dl.”243 The relevant, full statement is:
For most persons with extremely high triglycerides, therapy can be

considered successful if it reduces serum triglycerides to < 500
mg/dl; often it is not possible to normalize triglycerides in these
persons.244
This is not saying that therapy is complete and thus should be discontinued as soon as a patient’s
TG levels dip below 500 mg/dl. Instead, the Medical Review (and ATP III Statement) indicates
that therapy is working, and should be continued, if a patient’s TG levels are brought and kept
below 500 mg/dl, and should not be discontinued as a failure because the patient’s TGs have not
been reduced all the way to near-normal levels. This statement reflects a recognition (widely
acknowledged in the field) that it is usually not possible to bring a severely hypertriglyceridemic
patients TGs down to normal levels (< 150 mg/dl). As a result, the treatment should not be viewed
as a failure (or the medicine stopped) merely because such patients cannot be brought to a normal
TG level. Instead, the treatment is successful (and should be maintained) if it is able to keep a
severely hypertriglyceridemic patient’s TGs below 500 mg/dl.
242
Id. ¶ 150.
243
Id. ¶ 149 (quoting Vascepa® Medical Review at 40, 49–51
(ICOSAPENT_DFNDT00015464, 15473–75)).
244
Vascepa® Medical Review at 40 (ICOSAPENT_DFNDT00015464) (quoting ATP III
Report at 3336 (AMRN00290109)).
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196. Indeed, the FDA medical reviewer specifically examined whether Vascepa® TG-
lowering effects were “persisten[t],” meaning the reduction could be sustained over the course of
treatment.245 In a section entitled “Persistence of Efficacy and/or Tolerance Effects,” the reviewer
noted that Amarin submitted data from an 40-week open-label extension of MARINE to FDA.
But the reviewer determined from the 12-week study itself sufficed to show that Vascepa®’s
efficacy was “persisten[t]” because, “the maximum TG-lowering effect of 4 g Vascepa occurred
by Week 4 and the effects were maintained throughout the [12-week] study.”246 This stood in
contrast to TG levels in the placebo and Vascepa 2 g per day groups, which fluctuated over the
course of the 12 weeks.247 It is noteworthy that FDA approved labeling for the product that set
forth the 12-week results and not the 4-week results—making clear that FDA approved Vascepa®
not simply for purposes of reducing a severely hypertriglyceridemic patient’s TGs to below 500
mg/dl, but rather for persistently reducing TGs in order to maintain that level.
197. If the approved indication for Vascepa® had been simply to achieve a TG level
below 500 mg/dl for severely hypertriglyceridemic patients, then FDA would have included in the
labeling the four-week point of maximum TG reduction. Indeed, if the FDA had determined that
Vascepa® had no additional benefit beyond 4 weeks, as Mr. Mathers suggests, FDA would have
required a statement to that effect in the labeling. Specifically, when “describing the dosage range
and duration, if it is known that a drug provides no additional benefit above a certain dose or
beyond a certain duration of use, that dose or duration must be identified” in the Dosage and
Administration section.248 Of course, the Vascepa® labeling contains no such duration
245
Vascepa® Medical Review at 67 (ICOSAPENT_DFNDT00015491).
246
Id. (emphasis added)
247
Id. at 67–68 (ICOSAPENT_DFNDT00015491–92).
248
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recommendation in the Dosage and Administration section (or any reference to the level of TG
reduction achieved at 4 weeks). The Medical Review’s focus, not just on the point of maximum
TG reduction at 4 weeks, but on Vascepa®’s ability to maintain TG reductions over the course of
the full study explains why the FDA determined that Vascepa®’s efficacy included the ability to
maintain persistent reductions in TGs and thus approved Vascepa® for that purpose.
198. The ATP III Report and the Medical Review thus acknowledge several things
known to practicing physicians and FDA reviewers: Severe hypertriglyceridemia poses significant
safety risks for patients. It is a chronic condition and TG levels in severely hypertriglyceridemic
patients often cannot be normalized. Thus, even if treatment is considered to be working when
such a patient’s TG levels are brought below 500 mg/dl, the treatment regimen should be continued
to prevent accumulation of TGs in the patient that might bring them back about 500 mg/dl.
199. Second, the FDA intends for physicians to read prescription labeling in its entirety
and to use it to make informed prescribing decisions in the context of their clinical experience and
the particular needs of the patient. A physician experienced in the treatment of
hypertriglyceridemia (or other hyperlipidemias) would understand that such lipid disorders often
persist if lipid-lowering medication is withdrawn. Knowing that, and knowing the grave health
risks associated with severe hypertriglyceridemia, a physician reading the Vascepa® labeling
would be encouraged to prescribe Vascepa® for an extended period (or for 12 weeks or more)
because the label indicates that extended use is safe, the Clinical Studies section shows treatment
lasting at least 12 weeks is effective, and the labeling does not suggest that Vascepa®’s beneficial
effect ceases after a certain period of use.
200. Third, even if a physician were concerned only with getting a patient’s TG levels
below 500 mg/dl, and not with maintaining that effect, the Medical Review shows that for some
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patients that goal may take longer than 12 weeks.249 Thus, even under Mr. Mathers’s reading of
the labeling (with which I disagree), the labeling would still encourage some physicians to treat
some patients for 12 or more weeks.
201. Fourth, the FDA’s Medical Review memorandum is not part of the prescription
drug labeling. There is no suggestion or statement in Vascepa®’s labeling that physicians should
prescribe Vascepa® for only 4 weeks, as opposed to the 12-week course of treatment shown by the
Clinical Studies section to have been effective in lowering TGs.
202. Finally, Mr. Mathers opines that, if a physician were to continue to administer
Vascepa® after a severely hypertriglyceridemic patient’s TGs dip below 500 mg/dl while on
Vascepa®, that would be an “off-label” use. I do not agree. Severe hypertriglyceridemia is a
chronic condition, the label instructs that Vascepa can safely be used to treat that condition for
extended periods, and the Clinical Studies section encourages administration for 12 or more weeks.
FDA would not consider chronic Vascepa® therapy of a patient who presented with chronic severe
hypertriglyceridemia, to be an off-label use.
Defendants’ proposed ANDA labeling) encourages, recommends, and promotes that Vascepa® be
administered to severely hypertriglyceridemic patients for 12 or more weeks to reduce TGs.
249
See Vascepa® Medical Review at 50 (ICOSAPENT_DFNDT00015474).
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X. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® WITHOUT A CONCURRENT
LIPID ALTERING THERAPY OR CONCOMITANT STATIN THERAPY.
204. As I discussed in paragraphs 30–32 above, the Asserted Claims from three
patents—the ’728, ’715, and ’335 Patents—involve methods of reducing triglycerides in a patient
with severe hypertriglyceridemia (TGs ≥ 500 mg/dl) by administering the claimed icosapent-ethyl
pharmaceutical composition to reduce triglycerides in a patient who is not on, or does not receive,
a concurrent/concomitant lipid-altering or statin therapy.
205. Specifically, the Asserted Claims from the ’728 Patent involve a method of
reducing TGs in a severely hypertriglyceridemic patient “who does not receive concurrent lipid
altering therapy,” while the ’715 Patent claims involve a method of reducing TGs by administering
the composition to a patient “who does not receive a concurrent lipid altering therapy.”250
Meanwhile, the Asserted Claims of the ’335 Patent require administration of the icosapent-ethyl
pharmaceutical composition to a patient “who is not on concomitant statin therapy.”251
206. I understand that the Court has construed the terms “concurrent/concomitant lipid
altering therapy” to mean “a medication to alter lipid levels in a subject whereby the medication
is administered concurrently/concomitantly with the administration of a pharmaceutical
composition comprising ethyl eicosapentaenoate.”252 Mr. Mathers represents that Dr. Matthew
Budoff has opined that a person of ordinary skill in the art would understand “lipid altering
therapy,” as used in the asserted claims, to refer to “medications like statins.”253 Like Mr. Mathers,
250
See supra ¶ 31.
251
See supra ¶ 32.
252
See supra ¶ 49.
253
Mathers Rep. ¶ 189 (quoting Opening Expert Report of M. Budoff, M.D. ¶ 103).
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209. As an initial matter, Mr. Mathers is wrong to talk about what the labeling “permits”
physicians to do: FDA does not regulate physicians or “permit” the practice of medicine. Instead,
the labeling is carefully constructed to instruct physicians on how to use the product safely and
effectively. In so doing, it is “recommending” ways to use the product in a safe and effective
fashion and “encouraging” the safe and effective use of the product. The labeling is thus not
“indifferent” as to whether the drug is prescribed with or without a statin. Rather, the labeling is
instructing physicians that the drug can be used safely and effectively with or without a statin. It
is therefore recommending and encouraging both uses. (Indeed, under Mr. Mathers’s erroneous
logic, the labeling would not be recommending or encouraging any use—since the labeling under
his theory would be “indifferent” as to administration with or without a statin and therefore could
not recommend or encourage either.)
210. Mr. Mathers also points to the Drug Interactions and Clinical Pharmacology
sections of the Vascepa® labeling, which he observes do not affirmatively “instruct against
concomitant use” of Vascepa® and statins.260 Instead, the Drug Interactions section advises only
of an adverse interaction with anticoagulants, and the Clinical Pharmacology section notes that
“no drug-drug interactions were observed” when the daily dose of Vascepa® (4 g) was
administered to 26 healthy adult subjects who were also taking 80 mg per day of atorvastatin, a
statin.261 Consistent with FDA regulations, these sections of the labeling inform physicians that
there are no significant drug-drug interactions or safety concerns associated with co-administration
of Vascepa® and statins.262
260
Id. ¶¶ 193–196.
261
See supra ¶¶ 0, 153 (citing Vascepa® Labeling (AMRN03132170, 72–73)).
262
See 21 C.F.R. § 201.57(a)(12), (c)(8)(i), (c)(13).
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211. That observation, however, does not justify Mr. Mathers’s conclusion. Mr. Mathers
appears to reason that, because Vascepa®’s labeling does not specifically warn against concurrent
use of Vascepa® and a statin—and indeed suggests concurrent use poses no drug-drug interaction
risks—the labeling cannot encourage administration of Vascepa® without a statin. In other words,
he appears to believe the only way for labeling to encourage use of Vascepa® alone is to explicitly
warn against combination therapy. That is not correct. The way that the labeling recommends
and encourages administration of Vascepa® alone (without a statin) is by instructing physicians
that this use is a safe and effective treatment for the approved indication.
212. The relevant question thus is not whether the Vascepa®’s label expressly instructs
against using Vascepa® with a statin, but whether it encourages, recommends, or promotes use
without a statin. Mr. Mathers does not answer that question. Nor does he acknowledge that
prescription drug labeling can encourage use of the approved drug without concurrent
administration of another medicine, for example, by showing that the drug is safe and effective
without co-administration of a drug often paired with other members of the same therapeutic class,
regardless of whether it affirmatively warns that co-administration of the drugs poses safety risks.
213. That is what the Vascepa® labeling does: It informs physicians that Vascepa® can
be used safely and effectively to reduce TGs without concurrent administration of a statin. Indeed,
the Clinical Studies section goes even further in recommending and encouraging administration of
Vascepa® alone, as it instructs physicians that the treatment effects of the drug do not themselves
require administration of a statin to address. Statins, as is well known, comprises a class of drug
that is indicated to reduce cholesterol levels. The Clinical Studies section teaches that Vascepa®
lowers TGs without adversely affecting other lipid levels in patients with severe
hypertriglyceridemia. For example, the labeling instructs that “[t]he reduction in TG observed
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with VASCEPA was not associated with elevations in LDL-C levels relative to placebo.”263
Indeed, the labeling reports that patients in the study who were treated for 12 weeks with Vascepa®
4 g / day experienced a median reduction from baseline in every “major lipoprotein lipid
parameter[]” listed in Table 2 (including LDL-C, Apo B, and Non-HDL-C).264 Because the
labeling teaches physicians that Vascepa®, without statins, will reduce TGs without adversely
affecting LDL-C, it also teaches there is no need in many cases for physicians to prescribe statins
alongside Vascepa®. The fact that Vascepa®’s labeling also reflects that it can be safely combined
with a statin does not change that it shows that Vascepa® is safe and effective on its own, without
any concurrent statin therapy.
214. It is consistent with FDA regulations and guidance that a prescribing physician
would glean such information from the Clinical Studies section when deciding what treatment
regimen to prescribe. Again, the purpose of the Clinical Studies section is to “facilitate an
understanding of how to use the drug safely and effectively.”265 And among the pieces of
information that FDA “consider[s] important to clinical decision making,” which it directs should
be included in the Clinical Studies section, is “[i]nformation about concomitant therapies” that
helps a physician “understand the use of the study drug or its effects.”266
215. Vascepa®’s ability to reduce TGs without a rise in LDL-C was also a point of focus
in FDA’s Medical Review. Specifically, the medical reviewer noted that, at the time Amarin
sought approval for Vascepa®, the “only currently available prescription omega-3 fatty acid
263
264
Id.
265
21 C.F.R. § 201.57(c)(15).
266
FDA Guidance: Clinical Studies at 2, 6–7 (AMRN-PEXP-0010191, 10195–96).
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049
of a statin, like the other conditions identified by Mr. Mathers,274 fall within the scope of the
approved use. In other words, because Vascepa® is approved without regard to concomitant use
of statins, it may, consistent with the approved indication, be administered either with or without
a concomitant statin, a fact Mr. Mathers appears to concede in the same paragraph of his report.275
The Clinical Studies section can, and in this case does, instruct, encourage, recommend, or promote
that the drug be prescribed to a subset of the conditions of use approved for Vascepa®.
administered to reduce triglycerides in patients with severe hypertriglyceridemia who are not on,
or do not receive, a concurrent/concomitant lipid-altering or statin therapy.
XI. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® TO REDUCE TRIGLYCERIDES
IN PATIENTS WITH SEVERE HYPERTRIGLYCERIDEMIA WITHOUT
ADVERSELY AFFECTING LDL-C, APO B, OR NON-HDL-C LEVELS
218. As I discussed in paragraphs 33–46 above, some of the Asserted Claims involve a
method of reducing triglycerides in a patient with severe hypertriglyceridemia (TGs ≥ 500 mg/dl)
by administering the claimed icosapent-ethyl pharmaceutical composition to reduce triglycerides
in the patient without adversely affecting the patient’s LDL-C, Apo B, and/or Non-HDL-C levels.
219. Some of the Asserted Claims involve administration of the claimed composition to
reduce TGs without increasing LDL-C, without increasing LDL-C by a certain amount, or while
274
See id. (discussing use of Vascepa® to treat patients who are not on statin therapy, who
have diabetes, who have TGs ≥ 750 mg/dl, and use of Vascepa® for a period of 12 weeks.)
275
See id. (acknowledging the decision whether to prescribe Vascepa® with or without a
statin is “within the discretion of the prescriber” and “within the scope of the approved
Indication”).
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reducing LDL-C.276 Other claims involve the use of the pharmaceutical composition to reduce
TGs while reducing or without increasing Apo B.277 Finally, Claim 8 of the ’715 Patent involves
a method of reducing TGs while reducing the patient’s Non-HDL-C levels by at least about 5%.278
220. Mr. Mathers’ opinion regarding these limitations proceeds in two parts. First, Mr.
Mathers opines that the Indications and Usage section of Vascepa®’s labeling does not encourage,
recommend, or promote use of Vascepa® to affect LDL-C, Apo B, or Non-HDL-C. Mr. Mathers
reasons that, in contrast to drugs like Lipitor® and Tricor®, Vascepa®’s indication does not mention
any lipid other than TGs. As a result, FDA did not approve use of Vascepa® to affect any lipid
level other than TGs,279 and “[p]rescribing Vascepa® with the intent to produce” any of the required
“effects [on LDL-C, Apo B, or non-HDL-C] would be an off-label” or “unapproved use.”280
Second, Mr. Mathers opines that the Clinical Studies section of Vascepa®’s labeling may not be
read as encouraging, recommending, or promoting use of Vascepa® to affect LDL-C, Apo B, or
Non-HDL-C, because the Clinical Studies section is not supposed to “imply or suggest”
indications or uses not set out in the Indications and Usage section.281
221. Mr. Mathers is correct that Vascepa®’s approved indication is as an adjunct to
reduce TGs in adult patients with severe hypertriglyceridemia (TGs ≥ 500 mg/dl).282 But the
relevant question is not, as Mr. Mathers suggests, whether the Indications and Usage section
276
See supra ¶¶ 34–40.
277
See supra ¶¶ 41–45.
278
See supra ¶ 46.
279
Mathers Rep. ¶¶ 169–175.
280
Id. ¶¶ 174, 176.
281
Id. ¶¶ 177–187.
282
See supra ¶ 134.
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encourages, recommends, or promotes use of Vascepa® to affect LDL-C, Apo B, or Non-HDL-C
levels alone. The correct question is whether the labeling as a whole teaches that Vascepa® is safe
and effective to reduce TGs in a patient with severe hypertriglyceridemia without adversely
affecting the patient’s LDL-C, Apo B, and/or Non-HDL-C levels. Mr. Mathers’s improperly
restrictive understanding of labeling disregards that other sections beyond the Indications and
Usage section, including the Clinical Studies section, are critical to answering that question.
222. As I noted previously, FDA intends for physicians to review the prescription drug
labeling in its entirety to understand how to use the drug safely and effectively in a patient who
exhibits the disease or condition listed in the indication.283 For example, because the Indications
and Usage section is intended to be concise, FDA guidance expressly advises that “[o]ther sections
of labeling . . . also provide essential details that enable safe and effective use of a drug, and
labeling should be considered in its entirety for individual prescribing decisions.”284
223. For example, in this instance, other sections of the labeling convey to physicians
the FDA’s judgment that understanding how Vascepa® affects a patient’s non-TG lipid levels is
necessary to safe and effective use of the drug to reduce TGs in severely hypertriglyceridemic
patients. Specifically, the Dosage and Administration section expressly instructs physicians to
“[a]ssess lipid levels before initiating therapy,” which encourages and recommends that physicians
consider the patient’s overall lipid profile when administering Vascepa®.285 FDA further
acknowledges the importance of understanding how Vascepa® affects non-TG lipid levels when,
283
See supra ¶ 105.
284
285
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in the Patient Information, it specifically advises patients that “[y]our doctor may do blood tests to
check your triglyceride and other lipid levels while you take VASCEPA.”286
224. The Clinical Studies section reinforces the importance of Vascepa®’s effects on
non-TG lipid levels to the safe and effective use of the drug. Every approved indication must be
based on substantial evidence of effectiveness derived from adequate and well-controlled
studies.287 But the Indications and Usage section of the labeling “is not intended to be a description
of the data supporting the determination of effectiveness.”288 Instead, the Clinical Studies section
must “describe the studies that support effectiveness for the labeled indication(s), including
discussion of study design, population, endpoints, and results.”289 By regulation, the express
purpose of the Clinical Studies section is thus to “facilitate an understanding of how to use the
drug safely and effectively.”290 In other words, the Clinical Studies section is intended to teach
physicians what effects and results they can expect or hope to achieve when they prescribe the
drug under the conditions of use incorporated into the approved indication.291
225. FDA’s approval of the Vascepa® labeling, including the Clinical Studies section,
represents the agency’s considered judgment that Vascepa®’s demonstrated effects on the other
lipid levels listed is important information for facilitating a physician’s proper use of the product
in a safe and effective manner to treat severely hypertriglyceridemic patients. Indeed, FDA
286
Id. at 9 (AMRN03132176).
287
21 C.F.R. § 201.57(c)(2)(iv).
288
289
21 C.F.R. § 201.57(c)(15).
290
Id.
291
See FDA Guidance: Clinical Studies at 3 (AMRN-PEXP-0010192) (explaining that
detail should be provided concerning a study establishing effectiveness if “the information adds to
an understanding of the clinical effects of the drug and how the drug should be used”).
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permitted inclusion of additional lipid parameters beyond TGs because they were considered
efficacy or safety endpoints or “clinically relevant variables important for understanding
[Vascepa®’s] treatment effect” when used in accordance with the approved conditions of use (i.e.,
as an adjunct to diet to reduce TGs in patients with severe hypertriglyceridemia).292
226. Physicians reading Vascepa®’s entire labeling, including the Clinical Studies
section, would thus understand (a) that they should be conscious, when prescribing Vascepa®, of
the patient’s overall lipid profile, (b) that Vascepa®’s effect (or lack of effect) on these other “major
lipoprotein lipid levels” are critical to understanding Vascepa®’s treatment effect, and how the
drug can be used safely and effectively for its approved indication (to reduce TGs in adult patients
with severe hypertriglyceridemia), and (c) that the approved dosage of Vascepa®, prescribed to
patients for a minimum of 12 weeks, reduces TGs without increasing (and indeed, while reducing)
LDL-C, Apo B, and Non-HDL-C relative to both baseline and placebo. Specifically, Table 2 notes
that patients treated with 4 g per day of Vascepa® for 12 weeks experienced:
• a 5% median reduction in LDL-C compared to baseline and 2% reduction compared

to placebo;
• a 4% median reduction in Apo-B compared to baseline and 9% reduction compared

to placebo (statistically significant with p value < 0.05); and
• an 8% median reduction in non-HDL-C compared to baseline and 18% reduction

compared to placebo.
After Table 2, the Clinical Studies section specifically summarizes relevant aspects of Vascepa®’s
treatment effect, advising physicians specifically that the daily dose of 4 g of Vascepa®, when
administered for 12 weeks, “reduced median TG . . . and Apo-B levels from baseline relative to
292
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placebo” and explained that “[t]he reduction in TG observed with VASCEPA was not associated
with elevations in LDL-C levels relative to placebo.”293
227. Physicians, who care about how medication will affect their patients, base their
intent and expectations in prescribing a medication upon these data. And a physician who
understands the whole label, and reads the Clinical Studies section, will in this case understand
that he can administer Vascepa® to effectively reduce TGs in severely hypertriglyceridemic
patients without adversely affecting these other lipid effects. Especially with respect to
Vascepa®’s lack of association with LDL-C increases, that presented a significant advancement in
the treatment of severe hypertriglyceridemia over the predecessor Lovaza®.294 Together, the
Dosage and Administration and Clinical Studies sections therefore instruct, encourage,
recommend, and promote that physicians administer Vascepa® to adult patients with severe
hypertriglyceridemia to reduce TGs with the added intent and expectation that the reduction in
TGs in these patients will not increase LDL-C, Apo B, or Non-HDL-C, or will indeed will be
associated with a reduction in these other lipid levels.
228. I do not agree with Mr. Mathers that it would violate FDA regulations for the
Clinical Studies section to encourage prescription of Vascepa® to reduce TGs without adversely
affecting LDL-C, Apo B, or Non-HDL-C. A physician who prescribes Vascepa® with the intent
to reduce TGs without increasing LDL-C, for example, is not engaging in an unapproved use,
because this use would meet all conditions of the approved use (i.e., adjunct to diet, severely
hypertriglyceridemic adult patient, to reduce TGs).
293
294
See supra ¶ 215.
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229. Moreover, administering Vascepa® is encouraged by and consistent with the
Clinical Studies section, and is clearly an on-label use. Administering Vascepa® to reduce TGs in
severely hypertriglyceridemic patients while intending to have the general “treatment effect”
described in the Clinical Studies section is not an off-label use. Indeed, if the results of the
MARINE study, which are reported in the Clinical Studies of Vascepa®’s labeling, “impl[ied] or
“suggest[ed]” an off-label use, the FDA would not have allowed Amarin to include them in the
labeling. FDA guidance explains that “[c]linical studies with results that imply effectiveness for
an unapproved indication, use, or dosing regimen” should not be included in the Clinical Studies
section.295 That the FDA allowed Amarin to include the results of this study and Vascepa®’s
effects on these other lipid parameters reflects the FDA’s judgment that these results are critical to
understanding Vascepa®’s treatment effect under the approved conditions of use, and that these
results thus facilitate an understanding of how to use the drug safely and effectively for its
approved indication.
230. That Amarin can advertise Vascepa®’s LDL-C benefits, when used to reduce TGs
in adult patients with severe hypertriglyceridemia, reflects that such advertising is consistent with
the FDA-approved labeling.296 FDA policy, articulated in FDA guidance, explains that it is
consistent with FDA-required labeling to advertise the effects of a drug when used in its approved
population for its approved indication. That guidance posed the question: “What are examples of
295
296
See, e.g., AMRN03149773–74 (Vascepa® print ad) AMRN0314719–23 (Vascepa DTC
TV story board); AMRN03160122–25 (letter from FDA Office of Prescription Drug Promotion
responding to Amarin’s submission of these ads, making a handful or recommendations re the
prominence of various information, but not raising any concerns about the ad’s highlighting of
Vascepa®’s LDL-C benefits when used consistent with the approved indication).
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the kinds of information that could be consistent with the FDA-required labeling for a product?”297
Among the information that FDA explained would be consistent with FDA-approved labeling298:
• “Information about the effects or use of a product in specific patient subgroups

that are included in its approved patient population…” (e.g., promotion of
Vascepa to severely hypertriglyceridemic patients who are vulnerable to
increasing LDL-C levels);
• “Information concerning the effects of a product on the patient for its FDA-
approved indication in its approved patient population…”. (e.g., severely
hypertriglyceridemic patients do not experience increases of LDL-C while
taking Vascepa); and
• “Information that provides additional context about the mechanism of action

described in the FDA-required labeling…” (e.g., severely hypertriglyceridemic
patients are not vulnerable to increases in LDL-C levels while taking Vascepa).
In contrast, FDA guidance cautions that it would be considered inconsistent with the FDA-required
labeling to advertise the use of the product (a) to treat an entirely different disease or condition;
(b) to treat patients not included within the approved patient population; (c) to treat a different
stage or severity of a condition; (d) without an adjunct therapy; (e) through a different route of
administration; or (f) in a different dosage strength, regimen, or form.299 None of those situations
apply here, because advertising about Vascepa®’s LDL-C benefits when used to reduce TGs in
severely hypertriglyceridemic adult patients, for example, still concern use of Vascepa® in the
approved form, for the approved patient population, and to treat the indicated condition.
297
FDA, Guidance for Industry: Medical Product Communications that Are Consistent
with the FDA-Required Labeling — Questions and Answers 8 (June 2018) (hereinafter, “FDA
Guidance: Medical Product Communications”) (AMRN-PEXP-0010336).
298
Id. at 9–10 (AMRN-PEXP-0010337–38).
299
Id. at 10–11 (AMRN-PEXP-0010338–39).
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231. Indeed, FDA guidance specifically acknowledges that “[a]dvertising and
promotion make frequent use of statements or data appearing in the Clinical Studies section.”300
FDA simply reminds companies that “any claim of effectiveness made in prescription drug
promotion . . . must be supported by substantial evidence (21 CFR 201.56(a)(3)) or substantial
clinical experience (see e.g., 21 CFR 202.1(e)(6)(i)).”301 In the case of promoting Vascepa®’s
ability to reduce TGs without increasing LDL-C, the evidence is clearly documented in the Clinical
Studies section of the Vascepa® labeling.
232. Victoza®, which is cited by Mr. Mathers, illustrates this point. Mr. Mathers
contrasts Victoza® with Saxenda®, noting that both “contain the same active ingredient but are
FDA-approved for different uses.”302 While Victoza®’s Clinical Studies section shows a reduction
in body weight, Victoza® is only indicated for treatment of diabetes,303 Saxenda® is specifically
approved for “chronic weight management.”304 Yet, consistent with the above description, the
maker of Victoza® advertises Victoza®’s “additional benefit of greater weight loss” compared to
two competitor drugs when used consistent with its approved use to treat diabetes.305
233. This is not to suggest that Amarin, consistent with the labeling, could advertise
Vascepa® solely to reduce LDL-C, Apo B, or Non-HDL-C, or that the maker of Victoza® could
advertise that drug solely for weight loss. It merely reflects that it is permissible, for example, to
300
301
Id.
302
303
Id.
304
Id. ¶ 182.
305
See NovoNordisk, Victoza® Provided an Additional Benefit of Greater Weight Loss in
2 Head-to-Head Trials (AMRN-PEXP-0010575–82).
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advertise that Victoza® has been shown to have additional weight loss benefits when used for its
approved indication—because such advertising is consistent with the FDA-approved labeling.
234. Finally, Mr. Mathers also points out the fact that Amarin previously sought, but did
not receive, FDA approval for a second indication to “reduce TG, non-HDL-C, Apo-B, [and] LDL-
C.”306 Mr. Mathers neglects what he acknowledged earlier in his report: this second proposed
indication was based on a different clinical study (the ANCHOR study) for a different indication
that the FDA rejected because it implied a cardiovascular benefit that the agency believed was
uncertain and unproven.307 In other words, the FDA’s refusal to approve the ANCHOR indication
signifies only that Vascepa® is not presently approved to reduce lipid levels for the specific purpose
of cardiovascular risk reduction, because, at that point, there was not substantial evidence showing
that TG-lowering agents such as Vascepa® actually improved cardiovascular outcomes.
235. Unlike the ANCHOR study and indication, the FDA clearly determined that the
endpoints and results concerning non-TG lipid levels in the principal study supporting establishing
effectiveness for the approved indication at issue in this case (the MARINE study) were
appropriate to include Vascepa®’s labeling. The FDA determined that an understanding of how
use of Vascepa® impacted these additional lipid levels in severely hypertriglyceridemic patients
was important to a physician’s clinical prescribing decisions and to facilitating the safe and
effective use of Vascepa® in patients with severe hypertriglyceridemia.
306
Mathers Rep. ¶ 175 (quoting FDA Briefing Document (AMRN03106518)).
307
See id. ¶¶ 83, 86.
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administered to severely hypertriglyceridemic patients to reduce TGs without adversely affecting
a patient’s LDL-C, Apo B, and/or Non-HDL-C levels.
XII. VASCEPA®’S LABELING ENCOURAGES, RECOMMENDS, AND PROMOTES

ADMINISTRATION AND USE OF VASCEPA® IN PATIENTS WITH SEVERE
HYPERTRIGLYCERIDEMIA WHO CONSUME A WESTERN DIET
237. As I discussed in paragraphs 47–48 above, five of the Asserted Claims involve a
method of reducing triglycerides in patients with severe hypertriglyceridemia (TGs ≥ 500 mg/dl)
who “consume a Western Diet.”
238. I understand the parties have agreed that “Western Diet” means “a diet consisting
of, by percentage of total calories, about 45% to about 50% carbohydrate, about 35% to about 40%
fat, and about 10% to 15% protein that may alternately or additionally be characterized by
relatively high intakes of red and processed meats, sweets, refined grains, and desserts.”308
239. Mr. Mathers represents that Dr. Budoff has opined that “the majority of [severely
hypertriglyceridemic] patients who take Vascepa or will take [Defendants’ ANDA products]
consume a Western diet before and during treatment.”309 Mr. Mathers does not contest that aspect
of Dr. Budoff’s opinion,310 and I accept it as true to the extent it is relevant to my opinion here.
240. Mr. Mathers opines that, “[a]s a regulatory matter, to the extent patients consume a
Western diet before and during treatment with Vascepa® this would constitute an off-label use.”311
And because, in his view, FDA-approved labeling cannot encourage, recommend, or promote an
308
See supra ¶ 0.
309
Mathers Rep. ¶ 154 (quoting Opening Expert Report of M. Budoff, M.D. ¶ 193 (Hikma),
¶ 194 (DRL)).
310
See generally id. ¶¶ 154–160.
311
Id. ¶ 155.
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(and thus remains on a Western diet) or to a patient who, despite counseling, subsequently returns
to a Western diet, without any need to monitor ongoing compliance with a given diet.
administered to severely hypertriglyceridemic patients who consume a Western diet.
XIII. CONCLUSION
256. As explained in the preceding sections, it is my opinion that Vascepa®’s FDA-
approved labeling instructs, encourages, recommends, and promotes the administration and use of
Vascepa® in ways that meet each of the four sets of limitations discussed in this Report. I therefore
disagree with the opinions expressed by Peter R. Mathers in his Rebuttal Report. Given Mr.
Mathers’s representations that the Defendants’ proposed ANDA labeling is materially identical to
Vascepa®’s FDA-approved labeling, my opinions apply equally to Defendants’ proposed labeling.
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EXHIBIT 13
Excerpts from the Rebuttal Expert Report of
Jonathan I. Sheinberg, M.D., F.A.C.C., on
Noninfringement of the Asserted Claims of the
Patents-in-Suit, dated May 10, 2019

DISTRICT OF NEVADA
AMARIN PHARMA, INC. and AMARIN Case No. 2:16-cv-02525-MMD-NJK

PHARMACEUTICALS IRELAND LIMITED
(Consolidated with 2:16-cv-02562-MMD-NJK)
Plaintiffs,
v.
Judge: Miranda M. Du
HIKMA PHARMACEUTICALS USA INC.
and HIKMA PHARMACEUTICALS
INTERNATIONAL LIMITED, CONFIDENTIAL
Defendants.
REBUTTAL EXPERT REPORT OF JONATHAN I. SHEINBERG, M.D., F.A.C.C.,

ON NONINFRINGEMENT OF THE ASSERTED CLAIMS OF THE PATENTS-IN-SUIT
001
TABLE OF CONTENTS
Page
I. INTRODUCTION .............................................................................................................. 1

II. BACKGROUND AND QUALIFICATIONS .................................................................... 2
III. LEGAL STANDARDS ...................................................................................................... 4
A. General principles ................................................................................................... 4
B. Induced infringement .............................................................................................. 5
C. Contributory infringement ...................................................................................... 6
IV. SUMMARY OF OPINIONS .............................................................................................. 7
V. THE ASSERTED PATENTS ........................................................................................... 10
A. The asserted claims ............................................................................................... 10
B. Level of ordinary skill in the art ........................................................................... 17
C. Claim construction ................................................................................................ 18
VI. VASCEPA® AND DEFENDANTS’ ANDA PRODUCTS............................................. 20
A. Summary of approved labeling ............................................................................. 21
1. Indications and usage ................................................................................ 21
2. Dosage and administration ........................................................................ 24
3. Drug-drug interactions .............................................................................. 26
4. Clinical studies .......................................................................................... 26
5. Patient information.................................................................................... 30
B. Underlying clinical data ........................................................................................ 31
C. Clinical guidelines and FDA review ..................................................................... 34
VII. DEFENDANTS WILL NOT INFRINGE THE ASSERTED CLAIMS .......................... 41
A. Defendants will not infringe any asserted claims because they will not
induce or contribute to using their ANDA products for at least 12 weeks. .......... 41
1. The product labels will not induce physicians to administer
Defendants’ ANDA products for at least 12 weeks. ................................. 41
2. Defendants will not contribute to the administration of their ANDA
products for at least 12 weeks. .................................................................. 49
B. Defendants will not infringe claims that require additional lipid effects.............. 52
1. Defendants will not infringe claims that require specific minimum
reductions in triglyceride levels. ............................................................... 52
a. The product labels will not induce physicians to administer
002
TABLE OF CONTENTS—continued
Page
Defendants’ ANDA product to achieve the specifically

claimed reductions in triglyceride levels. ..................................... 52
b. Defendants will not contribute to the administration of their
ANDA products to achieve the specifically claimed
reductions in triglyceride levels. ................................................... 55
2. Defendants will not infringe claims that require reducing or not
increasing LDL-C. .................................................................................... 58
Defendants’ ANDA product to reduce or avoid increasing
LDL-C levels. ............................................................................... 59
ANDA products to reduce or avoid increasing LDL-C. ............... 63
3. Defendants will not infringe claims that require reducing or not
increasing Apo B....................................................................................... 66
Defendants’ ANDA product to reduce or avoid increasing
Apo B levels. ................................................................................. 66
ANDA products to reduce or avoid increasing Apo B. ................ 69
4. Defendants will not infringe claims that require reducing HDL-C. ......... 71
Defendants’ ANDA product to reduce non-HDL-C levels........... 72
ANDA products to reduce non-HDL-C. ....................................... 75
C. Defendants will not infringe claims that limit the treated patient population....... 77
1. Defendants will not infringe claims that exclude the concomitant or
concurrent use of statins or lipid-altering therapy. ................................... 78
a. The product labels will not induce physicians to exclude co-
administration of statins or lipid-altering therapy. ........................ 78
b. Defendants will not contribute to the infringement of claims
that exclude the use of statins or lipid-altering therapy. ............... 81
2. Defendants will not infringe claims that require specific baseline
cholesterol levels....................................................................................... 84
a. The product labels will not induce physicians to treat patients
with the claimed baseline cholesterol levels. ................................ 84
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TABLE OF CONTENTS—continued
Page

that require specific baseline cholesterol levels. ........................... 88
3. Defendants will not infringe claims that require a Western diet. ............. 90
a. The product labels will not induce physicians to prescribe or
advise their patients to consume a Western diet. .......................... 91
that require patients to consume a Western diet. .......................... 95
VIII. CONCLUSION ................................................................................................................. 97
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I. INTRODUCTION
1. I, Jonathan I. Sheinberg, submit this rebuttal expert report on behalf of Hikma
Pharmaceuticals USA Inc., Hikma Pharmaceuticals International Limited, Dr. Reddy’s
Laboratories, Inc., and Dr. Reddy’s Laboratories, Ltd. (collectively, “Defendants”). I understand
that Defendants have filed Abbreviated New Drug Applications (“ANDAs”) with the FDA
seeking approval to market generic versions of Vascepa® (icosapent ethyl). I have been retained
by Defendants to provide my technical expertise and expert opinions regarding patents asserted
by Amarin Pharma, Inc. and Amarin Pharmaceuticals Ireland Limited (collectively, “Amarin”),
and to analyze and respond to certain opinions in the two Opening Expert Reports of Matthew
Budoff, M.D., dated March 10, 2019, regarding Hikma’s ANDA product and DRL’s ANDA
product, respectively (collectively, “Budoff Opening Rept.”).
2. I have formulated certain opinions about the patent claims asserted by Amarin and
the opinions of Dr. Budoff that are set forth in his opening reports. My opinions in connection
with this case are set forth in this report, and I expect to testify about them at trial if asked to do
so. The bases for my opinions include the documents and other materials cited in my reports, my
education, and my years of experience and research.
3. Many of the opinions set forth in this report are in rebuttal to opinions set forth in
Dr. Budoff’s opening reports. I disagree with many of the opinions set forth in Dr. Budoff’s
opening reports and identify many of those disagreements in this report. However, to the extent
that I do not comment on a specific opinion of Dr. Budoff’s, any such silence should not be
interpreted as an indication that I agree with his opinion.
4. I reserve the right to amend or supplement my opinions in light of evidence
presented by or on behalf of Amarin or its experts in this case, or in connection with additional
information that may be made available to me in the future.
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5. In addition to the information, materials and opinions discussed in my reports in
this case, I may use demonstrative exhibits at hearings and/or at trial to the extent they are useful
for explaining and understanding the opinions I set forth in this report.
6. I may also testify at trial about background scientific concepts related to my
opinions to the extent that is useful for understanding my opinions.
7. I have not testified by trial or deposition in the last four years.
8. My work on this case is being charged to Defendants at a rate of $600 per hour.
My compensation does not depend upon the ultimate outcome of this case.
II. BACKGROUND AND QUALIFICATIONS
9. I am a Board-certified cardiologist and Fellow of the American College of
Cardiology. I have an active clinical cardiology practice at the Baylor Scott & White Health
Medical Center in Austin, Texas. My practice focuses on invasive cardiology, general
cardiology, lipidology, and coronary disease and prevention.
10. In my clinical cardiology practice, I see and treat approximately 400 patients each
month. I regularly prescribe omega-3 fatty acids to my patients, including over-the-counter fish
oil products, Lovaza® (including its generic forms), and Vascepa®. I routinely treat patients for
hyperlipidemia, including for elevated triglycerides and cholesterol.
11. I earned my B.S. degree, cum laude, from Washington & Lee University in 1990.
I earned my M.D. degree, with honors, from the George Washington University School of
Medicine in 1994. I completed a rotating internship at Georgetown University and Fairfax
Hospital in 1995. I completed my residency in internal medicine at the U.S. Air Force Keesler
Medical Center in 1997. I completed my fellowship in cardiovascular disease at the Wilford
Hall U.S. Air Force Medical Center in 2000, and became certified in the treatment of
cardiovascular disease by the American Board of Internal Medicine.
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006
12. I have been a licensed cardiologist in the State of Ohio since November 2000 and
in the State of Texas since December 2003.
13. Prior to my current position at Baylor Scott & White Health, I was a cardiologist
at Jonathan I. Sheinberg, M.D., PLLC, d/b/a Cardiovascular Associates. Prior to that position, I
was a cardiologist at the Wright-Patterson Medical Center in Ohio. I was on active duty in the
U.S. Air Force and served as a Major and Flight Surgeon in the U.S. Air Force Medical Corps,
and was Director of the Cardiac Catheterization Laboratory.
14. I was a Professor of Medicine at the Uniformed University of Health Science
Department of Medicine from 1997 to 2004, and an Assistant Clinical Professor of Medicine,
Wright State University School of Medicine from 2000 to 2004.
15. I have been a principal investigator, assistant principal investigator, and sub-
investigator for multiple clinical trials on cardiovascular treatments and drug therapies.
16. I am the President and Chief Executive Officer of the Public Safety Cardiac
Foundation, a non-profit entity that promotes heart-disease awareness in the public safety arena.
The Foundation’s mission is to provide support and resources for identifying and treating the
earliest stages of coronary heart disease in First Responders.
17. I have been the Assistant Medical Director of Williamson County EMS for
tactical medicine. I currently oversee the tactical medical support for the Central Texas Regional
SWAT Team. I am also involved in cardiac research within the law enforcement community. I
am a member of the U.S. Department of Justice (“USDOJ”) Presidential Task Force on 21st
Century Policing and sit on the Community Oriented Policing Services Officer Safety and
Wellness Working Group. I am a member of the USDOJ Bureau of Justice Assistance, Institute
for Intergovernmental Research, under its Valor for Blue Program. In the course of my research,
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007
I developed the Cardiac Screening Initiative (“CSI”), an observational cohort study for
determining the prevalence of coronary disease in asymptomatic law enforcement officers. I am
also a frequent speaker throughout the United States and internationally on the development of
wellness and safety initiatives for public safety agencies.
18. Beyond my medical practice, I am a licensed Peace Officer for the State of Texas,
a Lieutenant of the Cedar Park Police Department, a reserve State Trooper for the Texas
Department of Public Safety, and have received a deputation as a Special Deputy United States
Marshal.
19. A summary of my education, experience, and publications is provided in my
curriculum vitae, a copy of which is attached to this report as Exhibit A.
20. The opinions expressed in this report are based on my personal knowledge and
experience in the field, as well as my review of materials pertinent to the issue of infringement of
the asserted patents. In addition to the materials cited in the text of this report, a list of the
materials that I reviewed in connection with this report is attached as Exhibit B.
III. LEGAL STANDARDS
21. In order to form my opinions in this report, counsel for Defendants have
explained to me certain legal standards that are not in my area of expertise. I have relied upon
these legal principles, as explained to me by counsel, in forming my opinions.
A. General principles
22. I understand that Amarin bears the burden of proving infringement by a
preponderance of the evidence. I understand that this means that Amarin must prove that
infringement is more likely than not to occur.
23. I understand that the patent claims at issue in this case are method-of-treatment
claims. I understand that evaluating whether such a patent claim is infringed is a two-step
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95. Apo B. Likewise, the MARINE data show that not all patients taking Vascepa®
experience a reduction in Apo B levels. In fact, in the third quartile of the 4 g treatment arm,
MARINE reported a 3.8% increase in Apo B levels at 12 weeks compared to baseline. (Id. at
AMRN00053695.) This means that an increase in Apo B levels was observed in at least 25% of
patients, and those patients’ Apo B levels increased by 3.8% or more. Again, for some patients,
MARINE reported even greater increases in Apo B—the maximum was 41% compared to
baseline. (Id. at AMRN00053698.) Thus, MARINE failed to show that Vascepa® reduces Apo
B levels for a substantial number of patients—i.e., at least a quarter or more.
96. Non-HDL-C. The MARINE data also show that not all patients experience a
reduction in non-HDL-C levels of at least 5%. In the third quartile of the 4 g treatment arm,
MARINE reported only a 0.1% decrease in non-HDL-C levels at 12 weeks compared to baseline.
(Id. at AMRN00053732.) This means that a reduction of no more than 0.1% in non-HDL-C
levels was observed in at least 25% of patients. The maximum change was an increase of 63%
in non-HDL-C compared to baseline. (Id. at AMRN00053739.) Thus, MARINE failed to show
that Vascepa® reduces non-HDL-C levels in a substantial number of patients—i.e., at least a
quarter or more.
97. These data on triglycerides, LDL-C, Apo B, and non-HDL-C confirm that not all
patients will experience the “median” changes reported in the “Clinical Studies” section of the
labels for Vascepa® and Defendants’ ANDA products. In fact, a substantial number of
patients—often a quarter or more—may experience significantly different effects.
C. Clinical guidelines and FDA review
98. One of the leading clinical guidelines for treating elevated triglycerides and
cholesterol is the National Cholesterol Education Program’s Adult Treatment Panes III (“ATP-
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III”)2, which Dr. Budoff relies on throughout his report. (E.g., Budoff Opening Rept. ¶¶ 56, 94
(Hikma); id. ¶¶ 55, 94 (DRL).) The FDA also relied on ATP-III in its medical review during the
approval process for Vascepa®. (E.g., Center for Drug Evaluation and Research, Appl. No.
202057Orig1s000, Medical Review(s) (2011) (“FDA Medical Review”) at 9.) Both ATP-III and
the FDA’s medical review reflect important background information that a POSA would
understand and bring to bear in using Vascepa® or Defendants’ ANDA products for their
indicated use of reducing triglycerides in patients with triglycerides of at least 500 mg/dL.
99. The FDA’s medical review for Vascepa® explains that “[a]ccording to the NCEP
ATP III, the first priority for persons with very high TG is to prevent acute pancreatitis.
Prevention of CHD [i.e., coronary heart disease] is a secondary priority in this population.”
(FDA Medical Review at 10; see also ATP-III at 3247.) “In addition to very low-fat diets and
increased physical activity, TG lowering drugs are usually required in persons with very high TG
to prevent acute pancreatitis.” (FDA Medical Review at 10; see also ATP-III at 3247.) The FDA
explained the implications of these treatment requirements for Vascepa® as follows:
The indication for Vascepa is for treatment of very high TG, >500
mg/dL. Patients with very high TG have a strong genetic
component to their disease and have an increased risk for acute
pancreatitis. Therefore, the primary goal for therapy is to lower
TG to prevent this complication. Therapy is considered to be
successful if TG is lowered to <500 mg/dL; often it is not possible
to normalize TG in these patients. Methods recommended by the
NCEP ATPIII to reduce the risk of acute pancreatitis include
discontinuation of drugs that raise TG, very low-fat diets, and TG-
lowering drugs such as fibrates or nicotinic acid. The NCEP
guidelines also state that omega-3 fatty acids are alternatives to
2
National Cholesterol Education Program, Nat’l Institute of Health, Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and treatment
of High Blood Cholesterol in Adults (Adult Treatment Panes III) Final Report, 106 CIRCULATION
3143–3421 (2002).
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fibrates or nicotinic acid for the treatment of hypertriglyceridemia,

particularly chylomicronemia.
(FDA Medical Review at 40-41; see also ATP-III at 3254, 3318.)
100. As these sources confirm, a POSA would understand that having triglyceride
levels of at least 500 mg/dL is not, by itself, necessarily a chronic condition requiring long-term
treatment with a triglyceride-lowering drug. Rather, it requires medical attention primarily
because of the acute risk of pancreatitis. Thus, once a patient’s triglyceride levels fall below 500
mg/dL, “[t]herapy is considered to be successful” for purposes of Vascepa®’s approved
indication. (FDA Medical Review at 40.) As the FDA recognized, “the NCEP ATPIII treatment
guidelines define treatment success as TG less than 500 mg/dL for patients with very high TG.”
(Id. at 49.) Moreover, while Vascepa® can help reduce a patient’s triglyceride levels quickly to
below 500 mg/dL, the primary therapies for maintaining healthy triglycerides levels in the long
term remain specialized “diets and increased physical activity.” (Id. at 10.)
101. The FDA’s medical review cites the MARINE data to confirm that when
combined with diet and exercise, Vascepa® rapidly reduces triglyceride levels to below 500
mg/dL. Indeed, “as shown in the figure below, the maximum TG-lowering effect of 4 g Vascepa
occurred by Week 4” during the course of the 12-week study. (Id. at 67.)
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information to instruct, advise, and encourage indefinite administration of [the] ANDA Product
so long as the medication is effective and well tolerated.” (Id.) I disagree.
116. The labeled indication for Vascepa® and Defendants’ ANDA products does not
“instruct, advise, and encourage indefinite administration” of the product “so long as the
medication is effective and well tolerated.” (Id.) Dr. Budoff does not cite any support for that
opinion. Again, the labeled indication simply states that Vascepa® and Defendants’ ANDA
products are indicated “as an adjunct to diet to reduce triglyceride (TG) levels in adult patients
with severe (≥500 mg/dL) hypertriglyceridemia.” (Hikma label at WWICO-NV-002835–36;
DRL label at DRLEEPA 0095595–96; Vascepa® label at 2.) That indication is silent about the
duration of treatment, and nothing else in the labels instructs a minimum duration either. Thus,
while the indication may permit indefinite administration, it does not specifically encourage use
for at least 12 weeks. This is in contrast to labels for other drugs that do instruct a minimum
duration of treatment, such as labels for antibiotics. (Mathers Rept. ¶¶ 131-40; see also, e.g.,
Lamisil® Label at 1 (Highlights of Prescribing Information); id. at 2 (Full Prescribing
Information); Levaquin® Label at 1 (Highlights of Prescribing Information); id. at 7-9 (Full
Prescribing Information); Lovenox® Label at 1 (Highlights of Prescribing Information); id. at 3
(Full Prescribing Information).)
117. Nor is there anything in the labels that states that having triglycerides of at least
500 mg/dL is necessarily a chronic disease requiring “indefinite” treatment. As discussed above,
for purposes of Vascepa®’s indication, “[t]herapy is considered to be successful if TG is lowered
to <500 mg/dL.” (FDA Medical Review at 40-41.) This is consistent with the ATP-III
guidelines that Dr. Budoff relies on, which “define treatment success as TG less than 500
mg/dL.” (Id. at 49 (citing ATP-III at 3336).) As discussed above, “treatment success” for
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purposes of the indication occurs in a much shorter time period than 12 weeks. When taken in
conjunction with a lipid-lowering diet, as required by the label, Vascepa® reduces triglyceride
levels below 500 mg/dL in only four weeks. (MARINE Study Report at AMRN00053670.) At
that point, “[t]herapy is considered to be successful.” (FDA Medical Review at 40-41.)
118. Dr. Budoff ignores that Vascepa® and Defendants’ ANDA products are indicated
only as “an adjunct to diet,” which is the primary therapy under the approved indication for
reducing triglycerides below 500 mg/dL. (Hikma label at WWICO-NV-002835–36; DRL label
at DRLEEPA 0095595–56; Vascepa® label at 2.) Some patients may be able to follow the
indication for Vascepa® and Defendants’ ANDA products and lower their triglyceride levels
below 500 mg/dL with a short course of the drug in conjunction with diet and exercise, and then
maintain such levels through diet and exercise alone.
119. To be clear, I generally do not prescribe Vascepa® for short-term treatment.
Instead, my general practice is to tell patients to take Vascepa® for an extended period, unless
they experience adverse events, cannot afford the treatment, or have difficulty swallowing the
pill (which is large). But this does not mean that when I prescribe Vascepa® according to the
indicated use, I always do so for at least 12 weeks of treatment. Instead, when Vascepa®
successfully reduces triglyceride levels below 500 mg/dL within 12 weeks (e.g., when the patient
returns for a follow-up visit within 12 weeks and triglyceride levels have fallen below 500
mg/dL), I may suggest that the patient continue the therapy for reasons unrelated to the
indication, e.g., to reduce cardiovascular risk. Because Vascepa® has minimal side effects, and
could potentially help patients reduce cardiovascular risk, I see no need to tell patients to stop the
treatment even after their triglyceride levels are maintained below 500 mg/dL. To the extent that
Vascepa® is being prescribed to reduce cardiovascular risk, however, that is an off-label use.
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120. Second, Dr. Budoff states that he “routinely prescribe[s] a minimum of twelve
weeks of treatment with Vascepa®” and usually instructs patients to take Vascepa® “until their
next follow-up appointment, generally four to six months after the initial appointment.” (Budoff
Opening Rept. ¶¶ 124 (Hikma), 125 (DRL).) Even accepting this prescribing practice, it does
not necessarily follow that it was induced by the product label. Indeed, Dr. Budoff does not cite
anything from the actual product labels that instructs such a course of treatment. If a physician
like Dr. Budoff decides to prescribe Vascepa® for 12 weeks or longer, it is not because anything
in the label instructed him to do so, or otherwise encouraged, recommended, or promoted that
duration of treatment. In fact, the prescription may not even relate to controlling triglycerides at
all. Again, the labels here are indifferent to the duration of treatment, which is within the
physician’s discretion. And, of course, physicians are entitled to use the drug for off-label uses.
121. Dr. Budoff ignores that many, if not most, uses of Vascepa® are off-label uses
that are not relevant to the approved indication on the labels. The labels themselves note that
Vascepa®
label at 9.) In my own clinical practice, I usually prescribe Vascepa® and other omega-3 fatty
acids products (such as Lovaza®) for reasons other than reducing triglycerides below 500
mg/dL. As Dr. Budoff acknowledges, Vascepa® has “been shown to lower cardiovascular risk
in patients who are also on statin therapy” in the REDUCE-IT trial. (Budoff Opening Rept.
¶¶ 66 (Hikma), 65 (DRL).) Unlike the approved use of reducing triglycerides below 500 mg/dL,
which takes only four weeks, reducing cardiovascular risk can take years. Indeed, the mean
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requires that patients to lower their lipids.
Vascepa® label at 2.) That
instruction, as discussed above, specifically encourages physicians to advise their patients not to
consume a “Western diet” as that term has been construed in this case.
273. I also disagree that “following the prescribing information for that indication will
lead to infringement of the claims.” (Budoff Opening Rept. ¶¶ 195 (Hikma), 196 (DRL).) Even
if physicians were to prescribe Vascepa® or Defendants’ ANDA products to patients who
consume a Western diet, that would not be the inevitable result of “following the prescribing
information,” which actually instructs the opposite. Even if the labels could be understood to
permit the use of the drug to treat patients who consume a Western diet (and they do not), the
labels still would not specifically encourage treating patients who consume a Western diet.
274. In sum, it is my opinion that Defendants will not induce or contribute to
infringement of asserted claims 15 and 17 of the ’728 patent; and claims 11, 15, and 18 of the
’715 patent, because Defendants’ actions in seeking approval for their ANDA products do not
meet the limitations in those asserted claims that require the patient being treated to consume a
Western diet.
VIII. CONCLUSION
275. In sum, for the reasons discussed above, it is my opinion that if Defendants’
ANDA products are approved and marketed, Defendants will not induce or contribute to
infringement of any of the asserted claims.
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I hereby declare that all of the statements made herein are true of my own knowledge and
that all statements made on information and belief are believed to be true; and further that these
statements were made with knowledge that willful false statements and the like so made are
punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States
Code.
Date:
Jonathan I. Sheinberg, M.D., F.A.C.C.
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016
EXHIBIT 14
FDA, Guidance for Industry:
Clinical Studies Section of Labeling for Human
Prescription Drug and Biological Products —
Content and Format (January 2006),
https://www.fda.gov/media/ 72140/download
(AMRN-PEXP-0010187–211)
Guidance for Industry
Clinical Studies Section of Labeling

for Human Prescription Drug and
Biological Products — Content and
Format
U.S. Department of Health and Human Services

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
Labeling
AMRN-PEXP-0010187
001
Contains Nonbinding Recommendations
Guidance for Industry
Clinical Studies Section of Labeling

for Human Prescription Drug and
Biological Products — Content and
Format
Copies of this guidance are available from:
Office of Training and Communications

Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
5600 Fishers Lane, Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm.
or
Office of Communication, Training, and

Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800.
(Internet) http://www.fda.gov/cber/guidelines.htm.
U.S. Department of Health and Human Services

Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
Labeling
AMRN-PEXP-0010188
002
TABLE OF CONTENTS
I. INTRODUCTION................................................................................................................. 1
II. IDENTIFYING STUDIES FOR INCLUSION IN THE CLINICAL STUDIES
SECTION....................................................................................................................................... 2
A. Studies To Include in the Clinical Studies Section...................................................................... 2
B. Studies Not To Include in the Clinical Studies Section............................................................... 3
III. DESCRIBING STUDIES IN THE CLINICAL STUDIES SECTION ............................ 3
A. General Principles.......................................................................................................................... 3
B. Describing the Study Design ......................................................................................................... 6
C. Summarizing Study Findings........................................................................................................ 7
D. Presenting Data for Different Types of Outcomes ...................................................................... 9
E. Implied Claims and Advertising and Promotional Considerations ........................................ 10
F. Updating the Clinical Studies Section ........................................................................................ 11
APPENDIX.................................................................................................................................. 12
INTRODUCTION....................................................................................................................... 12
GRAPHS...................................................................................................................................... 12
TABLES....................................................................................................................................... 22
AMRN-PEXP-0010189
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Guidance for Industry1
Clinical Studies Section of Labeling for Prescription Drug

and Biological Products — Content and Format
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I. INTRODUCTION
This guidance is intended to assist applicants in deciding (1) what studies should be included in
the CLINICAL STUDIES section of prescription drug2 labeling, (2) how to describe individual
studies, and (3) how to present study data, including presentation of data in graphs and tables.
This guidance is intended to make the CLINICAL STUDIES section of labeling, as described in
the final rule amending the requirements for the content and format of labeling for human
prescription drug and biological products (21 CFR 201.56 and 201.57),3 more useful, and to
promote consistency in the content and format of the section across drug product classes and
within drug classes and indications. This guidance also calls attention to the advertising and
promotional implications of data and statements contained in the CLINICAL STUDIES section.
The principal objective of labeling is to provide the information that is most useful to prescribers
in treating their patients. In some cases, making the information in the CLINICAL STUDIES
section of labeling more useful to prescribers could warrant significant departures from past
labeling practices.
FDA's guidance documents, including this guidance, do not establish legally enforceable
1
This guidance has been prepared by the Medical Policy Coordinating Committees in the Center for Drug
Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and
Drug Administration.
2
This guidance applies to drug products, including biological drug products. For purposes of this guidance, drug or
drug product will be used to refer to human prescription drug and biological products that are regulated as drugs.
3
See the final rule “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological
Products” published in the Federal Register in January 2006.
AMRN-PEXP-0010190
004
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. IDENTIFYING STUDIES FOR INCLUSION IN THE CLINICAL STUDIES

SECTION
The CLINICAL STUDIES section of labeling must discuss those clinical studies that facilitate
an understanding of how to use the drug safely and effectively (21 CFR 201.57(c)(15)). This is
usually accomplished by providing concise, accurate summaries of information from studies
concerning a drug’s effectiveness (and sometimes safety) that practitioners consider important to
clinical decision making. Generally, this should include information from the adequate and
well-controlled studies that demonstrate the effectiveness of the drug for its approved indication.
This section of the labeling is not intended to describe all available effectiveness data.
Additional studies that reach the same conclusion should be omitted or described briefly without
detail. If there are multiple studies that address the same effectiveness issue, the subset selected
for presentation should ordinarily reflect the overall conclusions derived from the database as a
whole (e.g., not suggest a larger treatment effect than the database as a whole).
A. Studies To Include in the Clinical Studies Section
The following are the types of adequate and well-controlled studies4 that should usually
be included in the CLINICAL STUDIES section.
1. Clinical studies that provide primary support for effectiveness
2. Clinical studies that provide other important information about a drug’s

effectiveness not furnished by the studies that provide primary support for
effectiveness, such as:
• Studies that suggest differential effects in population subsets (e.g., women vs.
men, presence or absence of concomitant illness or medications)
• Studies that suggest lack of effectiveness in a clinical situation or lack of
effect on a particular endpoint where the drug might have been expected to
work
• Studies that provide information relevant to dose selection or adjustment (e.g.,
dose-response studies or studies in nonresponders to a particular dose)
• Studies that provide information about the nature and size of the treatment
effect, particularly where the effect is small
3. Clinical studies that prospectively evaluate an important safety endpoint
4
See 21 CFR 314.126.
2
AMRN-PEXP-0010191
005
B. Studies Not To Include in the Clinical Studies Section
The following are the types of studies that should usually not be included in the
CLINICAL STUDIES section, unless they also meet one of the factors in II.A (above).
If an exception is made, the limitations of the study and the reasons for inclusion should
be stated.
1. Clinical studies with results that imply effectiveness for an unapproved

indication, use, or dosing regimen
2. Active control clinical studies that imply comparative effectiveness or safety

claims not supported by substantial evidence
3. Studies that are not adequate and well-controlled within the meaning of
21 CFR 314.126.
III. DESCRIBING STUDIES IN THE CLINICAL STUDIES SECTION
A. General Principles
1. Focus on Effectiveness Data
The primary objective of the CLINICAL STUDIES section is to summarize (1) the
evidence supporting effectiveness in the subjects who were studied, (2) the critical design
aspects of the studies, including the populations studied and endpoints measured, and (3)
the important limitations of the available evidence. Ordinarily, safety data are described
in the ADVERSE REACTIONS section. However, in some cases it may be appropriate
to present important information about safety in the CLINICAL STUDIES section (e.g.,
if the safety data are best understood when presented with a detailed study description or
in the context of effectiveness results). The section should also include safety data from
controlled studies specifically designed to evaluate a safety endpoint. If safety data are
presented in the CLINICAL STUDIES section, they must be cross-referenced in the
ADVERSE REACTIONS section and other sections, as appropriate (21 CFR
201.57(c)(15)(ii)).
2. Amount of Detail
In general, the amount of detail needed to provide a useful description of a study and its
results will depend on the indication, the trial design, the understanding of the drug or
drug class, and the extent to which the information adds to an understanding of the
clinical effects of the drug and how the drug should be used. The amount of detail
appropriate for a given study or dataset is inevitably a matter of judgment, but some
general principles can be described.
3
AMRN-PEXP-0010192
006
Ordinarily, applicants should include more detail when:
• The study responses measured are of critical health importance. In most cases, such
responses would be direct measures of a meaningful clinical outcome (e.g., mortality,
stroke, acute myocardial infarction rates, fracture rates, symptom alleviation, or
functional improvement), but could also include effects on important surrogate
endpoints (e.g., cholesterol or hemoglobin A1c).
• The study results demonstrate that a new agent offers a clear advantage over existing
therapy (see section III.A.4 for a discussion of comparative claims).
• The study results represent a significant advance in the treatment of a disease or

condition, or provide important information about a drug’s activities relative to its
therapeutic class.
• The study enrolled a very specific population or used a very specific concomitant
regimen, and the results may not be applicable to other populations.
• The study results are not what would be expected for that drug class and indication —
for example, when the study results demonstrate a particularly marginal response or a
response for which the clinical meaning or implications are unclear.
• The study uses an unfamiliar endpoint (e.g., a novel surrogate endpoint), or there are
important limitations and uncertainties associated with an endpoint.
Applicants should include less detail when:
• The new drug appears to have effects that are typical of its class.
• The magnitude of the effect on clinical endpoints measured in the study is not readily
translatable into effects in clinical practice. For example, exercise testing in a study
of heart failure can demonstrate effectiveness, but does not translate to a quantifiable
clinical outcome. Similarly, changes in HAM-D scores can be used to demonstrate
effectiveness of an antidepressant, but the results for a given study are population-
and probably site-specific, and thus, do not necessarily translate to a numerically
similar outcome in clinical practice.
In these cases, it could be useful to describe the study in general terms (e.g., population,
duration, endpoints measured, and qualitative outcome) without providing detailed
results.
3. Endpoints
The CLINICAL STUDIES section should present those endpoints that establish the
effectiveness of the drug or show the limitations of effectiveness. This includes
4
AMRN-PEXP-0010193
007
endpoints the Agency has accepted as evidence of effectiveness, or closely related

endpoints that may be more easily understood. When it would be informative, the
CLINICAL STUDIES section can also discuss other endpoints shown to be affected by
the drug and endpoints that might have been expected to be influenced by the drug, but
were not.
• Composite Endpoints:5 In general, the results for all components of a composite

endpoint should be presented. Presentation of all components reveals which
components are driving the result and which components may be unaffected, or even
adversely affected, by treatment with the drug. When there is a range of effects on
the components of a composite endpoint, selectively presenting only a single
component of the composite endpoint, or presenting only the change in the composite
endpoint, can be misleading. In most cases, discussion of a component of a
composite endpoint should be only descriptive (i.e., not be presented with statistical
analyses) unless the component has been assessed as a separate endpoint with a
prospectively defined hypothesis and analysis plan.
• Primary and Secondary Endpoints: The terms primary endpoint and secondary
endpoint are used so variably that they are rarely helpful. The appropriate inquiry is
whether there is a well-documented, statistically and clinically meaningful effect on a
prospectively defined endpoint, not whether the endpoint was identified as primary or
secondary.
• Closely Related Endpoints: If two or more endpoints are closely related and convey
essentially the same information, only one should generally be presented.
4. Comparative Data
If the effectiveness of a drug can be determined by comparison to placebo, data

comparing the effects of the drug to an active comparator should generally not be
included in labeling unless the data are adequate to support an explicit comparative claim
(either a superiority or similar effectiveness claim). For example, when describing a
clinical trial with three treatment arms (study drug, active control, and placebo) in which
the comparison of study drug to placebo yields important effectiveness information and
the active control was present only to confirm assay sensitivity, the identity of the active
control and the results from that arm should be omitted if those data are not adequate to
support a comparative claim and are not otherwise important to a clinician’s
understanding of the drug’s effect.
If effectiveness can be determined only by comparison to an active control (superiority or

non-inferiority trial) and the identity of the active comparator is important to a clinician’s
5
Note that composite endpoint refers to combined morbidity and mortality endpoints that could potentially be
evaluated separately, not to the separate components of standard evaluative scales (e.g., HAM-D for depression,
BPRS for schizophrenia, nasal symptoms score).
5
AMRN-PEXP-0010194
008
understanding of the drug’s effects, the active control data and identity of the comparator
should be included in labeling. In such cases, the labeling should make clear that no
comparative claim has been established (if it has not been) and should disclose any
limitations of the comparative data (e.g., if the comparator was administered in a
suboptimal or unapproved regimen).
An explicit claim of superior or similar effectiveness must be supported by substantial

evidence (21 CFR 201.56(a)(3)). For superiority claims, such evidence would include
adequate and well-controlled trials designed to establish superiority of one treatment over
another. For claims of similar effectiveness, such evidence would include adequate and
well-controlled trials designed to demonstrate that one treatment is not inferior to another
and that the difference between the two is not clinically significant. Thus, the non-
inferiority margin used would have to be smaller than the margin needed to merely
establish effectiveness. For example, a non-inferiority trial designed to show that a new
drug has at least 50 percent of the effect of the active control can provide adequate
evidence of effectiveness, but a 50 percent non-inferiority margin would ordinarily be too
large to support a claim of similar effectiveness. For each type of trial, the active control
should be used at an appropriate dose and regimen, generally the highest recommended
dose, and in an appropriate patient population. 6
B. Describing the Study Design
The following elements are recommended when describing the study design.
1. Major Design Characteristics
The major design characteristics should be identified, including level of blinding (e.g.,
double-blinded, partially blinded, open-label), type of controls (e.g., placebo, active,
historical), duration of the study, method of allocation to treatment groups (e.g.,
randomization), and use of a run-in period to identify potential responders or eliminate
placebo responders from subsequent phases of the study. Often, many of these factors
can be summarized in a phrase such as “randomized, double-blind, placebo-controlled
study.”
2. Treatment Arms
The dose, regimens, and any titration procedure should be identified for each trial arm.
3. Concomitant Therapy
Information about concomitant therapies should be included to the extent it helps to
6
International Conference on Harmonization (ICH) guidance E10 (Choice of Control Group and Related Issues in
Clinical Trials) considers fairness of comparisons intended to show superiority or equivalence of one treatment to
another. The guidance discusses how to design a trial that does not inappropriately favor one treatment over another
(see section on Fairness of Comparisons in ICH E10).
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understand the use of the study drug or its effects.
4. Study Population
The description of the study population should identify those characteristics that are
important for understanding how to interpret and apply the study results. The description
thus should identify important inclusion and exclusion criteria, the demographic
characteristics of the studied population, baseline values of any clinically relevant
variables important for understanding the treatment effect, and other characteristics of the
population that have important implications for the extent to which results can be
generalized. For example, the description should discuss enrollment factors that exclude
subjects prone to adverse effects, the age distribution of the study population, a baseline
value that results in a study population that is more or less sick than usual, or a study
population enriched by a study design that eliminates nonresponders.
5. Critical Endpoints
Endpoints critical to establishing effectiveness should be identified, and those that are not
commonly understood should be defined.
C. Summarizing Study Findings
When including a detailed summary of study findings (see section III.A.2 for a discussion
of when more detail is important), the following elements should be addressed to the
extent they contribute to practitioners’ understanding of drug effectiveness.
1. Disposition of Subjects
It is generally recommended that the discussion of disposition of subjects include the

following:
• The number of subjects enrolled
• The number of subjects completing the study
• The number of subjects discontinuing the study and the reasons for discontinuation
• For a study with a run-in period or other distinct phases, the number of subjects
entering each phase and the number of subjects not progressing to the next phase
2. Treatment Effect7
7
Treatment effect means the effect that can be attributed to the drug. It is typically derived from a comparison of
two prospectively identified treatment arms. Examples of such comparisons include differences in proportions of
patients achieving some treatment goal, differences in mean change from baseline, or hazard ratios.
7
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It is recommended that the summary of findings describe the clinical outcome of the
treatment relative to the comparator (e.g., placebo or active).
• Absolute vs. Relative Difference: When presenting differences between study

group and comparator, it is important to present the absolute difference between
treatment groups for the endpoint measured, as well as the relative difference (e.g.,
relative risk reduction or hazard ratio). For example, if mortality is 6 percent in one
study arm and 8 percent in the other, the absolute difference (2 percent) should be
presented along with the 25 percent relative risk reduction.
• Group Results and Individual Subject Data: In most cases, the treatment effect is
presented as a mean or median result accompanied by a measure of uncertainty or
distribution of results for the treated groups. However, providing individual subject
data for all treatment groups can be a useful alternative for describing the clinical
effect of a drug. This can be done by including a graphical presentation of the
distribution or cumulative distribution of responses among individual subjects (see
Appendix for examples of graphical methods for presenting individual subject data).
Individual data can also be presented as categorical outcomes (e.g., the proportion of
patients reaching a prospectively defined goal, such as systolic blood pressure of 120
mmHg).
• Combined Data: In certain situations, analyses of data combined from multiple

effectiveness studies can be useful for estimating the treatment effect. These analyses
should be included only when they are scientifically appropriate and better
characterize the treatment effect. Meta-analytic graphs (see Appendix) can be useful
for displaying confidence intervals from several studies.
• Uncertainty of Treatment Effect: A confidence interval and a p-value provide

complementary information, and both should usually be provided when describing
uncertainty of the treatment effect. A confidence interval provides a better numerical
description of the uncertainty of the treatment effect and provides some information
about its size. A p-value better conveys the strength of the finding (i.e., how likely it
is that the observed treatment effect is a chance finding). However, it is generally
better not to use a p-value alone.
3. Describing Results Within Treatment Groups
In controlled trials, the change from baseline in a treatment group is usually not by itself
informative. The comparison of the change from baseline between treatment groups is
critical for understanding the treatment effect. Therefore, results for both the study drug
and comparator should almost always be presented because the magnitude of the
treatment effect is conveyed by the comparison. Presentation of results for both study
drug and comparator is especially important for studies with large effects in the placebo
group, where presentation of results uncorrected for the placebo group response can be
highly misleading. When results from active control arms are discussed, a comparative
claim should not be implied where one is not supported. The relevant statistical
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AMRN-PEXP-0010197
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comparisons are those comparing the groups, not the comparison of the treated and
baseline value within a group.
For continuous data, the presentation of results within a treatment group should include,
where appropriate, information about the variability of individual subject responses
within the treatment group. This variability can be described with standard deviations
and illustrated with box plots (see Appendix for examples of graphical methods for
presenting results within treatment groups).
4. Demographic and Other Subgroups
The CLINICAL STUDIES section should include a summary statement about the results
of required explorations of treatment effects in age, gender, and racial subgroups (21
CFR 314.50(d)(5)(v)). The summary statement should report the findings of analyses
that had a reasonable ability to detect subgroup differences and should note when
analyses were not useful because of inadequate sample size. The following are examples
of appropriate summary statements.
• The database was not large enough to assess whether there were differences in effects
in age, gender, or race subgroups.
• Examination of age and gender subgroups did not identify differences in response to
(study drug) among these subgroups. There were too few African-American subjects
to adequately assess differences in effects in that population.
• Examination of age and gender subgroups suggested a larger treatment effect in

women (possibly resulting from the larger mg/kg dose in women), but no age-related
differences. There were too few African-American subjects to adequately assess
differences in effects in that population.
Compelling results from analyses of other subgroups of established interest should also
be presented, with a caution statement, where appropriate, about the inherent risks of
unplanned subgroup analyses.
D. Presenting Data for Different Types of Outcomes
Data on outcomes of treatment should be presented only if the outcome is of clinical

significance.
1. Categorical Outcomes (e.g., success or failure)
For categorical outcomes, the number (or percentage) of outcomes for randomized
subjects should be shown. For example, the total sample size for the treatment group, the
number of successes, the number of failures, and the number of unknown status should be
provided. Where informative, those subjects whose outcome status is unknown can be
further differentiated by including the number who dropped out due to adverse events,
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AMRN-PEXP-0010198
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the number who were lost to follow-up, or any other pertinent distinction. If only
percentages are reported, the denominator should be included.
2. Continuous Variables
For continuous variables, measures of central tendency (e.g., mean, median),

accompanied by a measure of distribution, are the usual methods for presenting data.
When means or medians are used, the number of subjects remaining in the study at each
time point should be provided. Because means or medians, even when accompanied by
descriptions of variability, may not adequately convey the variability of responses, it
might be useful to display individual responses (e.g., by graphical representation of the
cumulative distribution of responses — see Appendix). It is important to include the
baseline value when reporting any change (either numerical or percent change) from that
baseline.
3. Time-to-Event Endpoints
When time-to-event endpoints (e.g., mortality) are used, median or mean survival alone
is not usually an adequate descriptor. Survival curves (or event-free survival curves) and
hazard ratios are often effective ways to display such data. Data can also be summarized
at specific times (e.g., prevalence at 3, 6, 9, 12 months) or at specific event frequency
(e.g., time to 25 percent, 50 percent, and 75 percent prevalence of events). The number
of subjects evaluated at a given interval or frequency should be specified. Note again the
need to convey both absolute and relative difference (see III.C.2).
4. Graphs or Tables
Graphs and/or tables are often more effective than text alone in communicating study
results, and one or the other should be used when presenting study results in the
CLINICAL STUDIES section. See the Appendix for guidance on the use of graphs and
tables in the CLINICAL STUDIES section of labeling.
E. Implied Claims and Advertising and Promotional Considerations
The CLINICAL STUDIES section must not suggest or imply indications, uses or dosing
regimens not stated in the INDICATIONS AND USAGE or DOSAGE AND
ADMINISTRATION section (21 CFR 201.57(c)(15)(i)). Words or phrases that lack a
commonly understood meaning (e.g., imprecise quantitative terms), are not easily
defined, are vague, misleading, or promotional in tone should be avoided. Examples
include large or small (instead, use actual size or amount), well-designed (instead,
provide specifics about the study design), extensively studied (instead, provide specifics
about the database), rapid (instead, specify change/unit time), trend (instead, provide
specifics about the outcome), potent (instead, give the size of the effect), pivotal study
(instead, describe as major effectiveness study), and highly significant (instead, provide
the confidence interval).
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Advertising and promotion make frequent use of statements or data appearing in the
CLINICAL STUDIES section. Sponsors are reminded that any claim of effectiveness
made in prescription drug promotion, including comparative effectiveness, must be
supported by substantial evidence (21 CFR 201.56(a)(3)) or substantial clinical
experience (see e.g., 21 CFR 202.1(e)(6)(i)).
F. Updating the Clinical Studies Section
The CLINICAL STUDIES section must be updated when new information becomes
available (21 CFR 201.56(a)(2)) that causes the labeling to become inaccurate, false or
misleading. Such outdated information must be promptly revised or deleted.
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APPENDIX
Presenting Study Results in Tables and Graphs
INTRODUCTION
When clinical data are to be presented in some detail in the CLINICAL STUDIES section, tables
and graphs are often better than text alone because they can convey the desired information more
effectively. The following general principles should be applied to the use of tables and graphs:
• Depict study results clearly, fairly, and accurately.
• Do not repeat in accompanying text, information that would be clear from

viewing the table or graph, although the text can point out the most important data
presented. Often the statement, “Results are found in Table X,” is sufficient.
• Small tables can be embedded in the text. Do not place larger tables and graphs
next to any explanatory text.
• Use clear titles and clearly labeled axes to limit the need for any explanatory text.
GRAPHS
A. Common Uses of Graphs
• To present a large amount of data, such as individual

subject data points (e.g., distribution of responses)
• To show effects of treatment on major events or survival

over time (Kaplan-Meier curves)
• To illustrate changes over time
• To illustrate differences in magnitude of response,

particularly where more than two treatment groups are
being compared
• To convey dose-response information
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B. Graphs Most Commonly Used in the Description of Clinical Trial

Effectiveness Data
Histogram
Distribution of Responses
by Percent Change from Baseline and Treatment Group
Group A
Frequency
40
30
20
10
0
Group B
Frequency
40
30
20
10
0
-60 -50 -40 -30 -20 -10 0. 10 20 30
% Change from Baseline
A histogram illustrates results of a trial by presenting the number or percentage of

subjects (y-axis) exhibiting a given response (x-axis) over the whole response range.
13
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Bar Graph
Distribution of Responses by Response Category

60
Drug A
Percentage of Subjects
50
Drug B
40
30
20
10
0
0 1 2 3 4
Response Category
In a bar graph, the length of the bar (the y-axis) represents the group response for the
outcome variable or the percentage or frequency of subjects exhibiting a categorical
response. Similar graphs can be useful for comparing effects among subgroups. In this
case, the response would appear on the y-axis, with various subgroups on the x-axis. In
most cases, it is helpful to include error bars. A bar graph should not be used to illustrate
just a few numbers that could be summarized better in a table. Graphs in 3-D should be
avoided because the values for the bars are difficult to read. Stippling or other small
patterns in bars should also be avoided because the bars can be difficult to differentiate
after reduction or reproduction.
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Line Graph
Percent Change from Baseline by Week

and Treatment Group for Study 1
10
0
% Change from Baseline
-10
-20
-30
-40
-50
-60 Treatment:
Placebo (n=75)
-70 Low Dose (n=73)
High Dose (n=76)
0 1 2 4 6
Week
A line graph most often illustrates responses (y-axis) over time (x-axis) where each line
represents the data for a defined group of subjects (e.g., a treatment group, a subgroup).
It is helpful in some cases to include error bars and number of subjects remaining on
study treatment at each time point. Similar graphs can be used to show dose response
with response on the y-axis and dose on the x-axis.
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Survival Curve
Kaplan-Meier Survival Curve of Time to Event for Study 1
0.9
0.8
Proportion Surviving
0.7
0.6
0.5
0.4
0.3 Treatment:
Drug
0.2 Placebo
0.1
L.R.: p = 0.0012
0
12 24 36 48 60 72
Time to Event (Months)
A survival curve depicts time-to-event data for events like death or recurrence of
disease. Usually, Kaplan-Meier estimates of the proportion of patients surviving at any
time as a fraction of people still in the study at that point are plotted, but some survival
plots show the raw cumulative incidence rates as a fraction of patients randomized over
time.
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Scatter Plot
Endpoint Response Versus Baseline Response for Study 1

350
300
Endpoint Response
250
200
150
200 250 300 350
Baseline
A scatter plot shows the relationship between two (usually continuous) variables for
individual patients (e.g., response (y-axis) related to a baseline value (x-axis)).
17
AMRN-PEXP-0010206
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Boxplot
Boxplots of Response at Endpoint by Dose for Study 1
0
-20
-40
Change from Baseline
-60
-80
-100
-120
-140
-160
-180
-200
N= 38 N= 45 N= 38 N= 44 N= 42
5 10 20 40 80
Dose (mg)
A boxplot illustrates the distribution of data for a single group. Several plots in a single
graph are useful for comparing distributions. Boxes in this example represent the range
of values from the 25th percentile to the 75th percentile. The median may be
represented by a line or symbol. The definition for the length of the whiskers (lines
extending out from each end of the box) varies with software packages and should be
defined with the plot (e.g., the ends represent the 10th and 90th percentile).
18
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Cumulative Distribution Plot
Cumulative Distribution Plot of Change From Baseline for Study 1
Improvement No Improvement
100
90 DRUG B
80
70 DRUG A
60
Cumulative
50
40
30
20
10
0
-8 -6 -4 -2 0 +2 +4
Change from Baseline
This graph shows the percentage of subjects (y-axis) attaining a
change from baseline less than or equal to the value on the x-
axis. A curve that shifts to the left indicates a better response.
A cumulative distribution plot shows the percentage of subjects with a change value
equal to or less than the value on the x-axis. These distributions can be graphed using
connected points, bars, or steps. A cumulative distribution plot may need a footnote and
additional text in the body of the label describing how to read the graph. For example,
the following text could accompany the graph shown above: “Approximately 50% of
the patients in each group had a decrease of at least 2 mg/dL at endpoint.”
J:\!GUIDANC\5534fnl.doc 19
01/17/06
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Meta-Analytic Graph
Odds Ratios and 95% Confidence Intervals

For Each Study and for All Studies Combined
Favors Treatment A Favors Placebo
9 B
7 B
3 B
8 B
6 B
1 B
4 B
5 B
2 B
Overall B
0.05 0.1 0.2 0.5 1 2
Odds Ratio Plotted on Log Scale
A meta-analytic graph depicts summary results (usually a treatment difference or ratio) for
several studies (or centers) on one graph. The x-axis displays the difference or ratio with a
reference line at zero or one. The results are usually given with their variance or confidence
interval. This graph is useful for illustrating consistency or lack of consistency across studies.
Ordering the responses by magnitude or sample size enhances the visualization of the effects.
Similar displays can show results in demographic or other subsets (e.g., disease severity,
background therapy, country, or region) of a population.
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C. Features of a Good Graph
• Title: The title should include the name of the study, the type of data, the timepoint, and
important features of the patient population (e.g., intent-to-treat, evaluable, age range if
relevant). For ease of reading, the first letter of each word should be capitalized, not every
letter in the title.
• Axis Label/Title: Label each axis and include units of measurement.
• Ticks and Grids: Label selected ticks for each axis. A graph will appear less cluttered if
ticks face away from the graph and if grids are eliminated.
• Axis Scale: Ensure that the scale of measurement (generally the y-axis) does not exaggerate
the treatment effect or any other variable being measured (e.g., by interruptions). In general,
make the scales for like graphs consistent within the labeling.
• Symbols: Distinguish symbols by size, shape, or fill (e.g., open symbols for placebo and
closed symbols for treatment).
• Footnotes: Use a footnote if further information would be helpful to explain the content of
the graph (e.g., the meaning of a term used, the meaning of a symbol). Statements directly
interpreting the graph, however, should not be in a footnote, but in the text accompanying the
graph.
• Error Bars: Measures of variability or uncertainty are represented in graphs by error bars or
sometimes by shading. Make it clear from the graph which measure of variability is used to
define the error bars (e.g., standard deviation, standard error, percentiles). Accompany
treatment differences or ratios with confidence intervals.
• Legend: Ensure that the legend does not overpower the graph. Labels directly on the graph
are preferable to a legend.
• Sample Size: Including sample sizes for each group often helps the reader interpret the
graph. Sample sizes can be identified in text within the graph or in a small table just below
the graph.
• P-values: The text or a table accompanying the graph usually will include p-values when
describing the significance of the results, so it is generally not necessary or desirable to
include p-values in a graph. One exception may be the plot of Kaplan-Meier survival curves
where a p-value may be preferred to confidence bands and may enhance interpretation of the
graph.
• Additional Graph Descriptors: To aid in interpretation of the graph, show reference lines
for no change or no difference. Descriptors that denote change, such as an arrow labeled
“Improvement” may be useful to the reader.
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III. TABLES
A. Use of Tables
• To present simple, descriptive statistics such as medians, means, standard

deviations, and sample sizes by treatment group
• To present comparative statistics such as treatment differences, confidence

intervals, and p-values
• To summarize data from more than one effectiveness variable
• To present exact values, if that information is desirable
B. Features of a Good Table
• Title: Include the name of the study, the type of data, the timepoint, and
the patient population (intent-to-treat, evaluable). For ease of reading,
capitalize the first letter of each word, not every letter in the title.
• Units: Include the units of measurement for the data presented, either in
the title or column headings. When presenting percentages, it is helpful to
include the percent sign, particularly when several numbers are included
on one line (such as mean percentages and sample sizes). Only include
the number of digits after the decimal that are significant or meaningful.
• Sample Size: Include the sample size for each treatment group in the
table.
• Baseline Data: Include baseline data whenever applicable.
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APPENDIX A
Asserted Patent Claims
Appendix A: Asserted Patent Claims
‘728 Claims:
Claim 1: A method of reducing triglycerides in a subject having a

fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl who
does not receive concurrent lipid altering therapy comprising:
administering orally to the subject about 4 g per day of a pharmaceutical
composition comprising at least about 96%, by weight of all fatty acids
present, ethyl eicosapentaenoate, and substantially no docosahexaenoic
acid or its esters for a period of 12 weeks to effect a reduction in
triglycerides without substantially increasing LDL-C compared to a
second subject having a fasting baseline triglyceride level of 500 mg/dl
to about 1500 mg/dl who has not received the pharmaceutical
composition and a concurrent lipid altering therapy.
Claim 13: The method of claim 8, comprising administering to the

subject about 4 g of the pharmaceutical composition daily for the period
of 12 weeks to effect a reduction in fasting triglycerides of at least about
25%.
Claim 16: The method of claim 1, wherein no fatty acid of the

pharmaceutical composition, except for ethyl-EPA, comprises more than
about 0.6% by weight of all fatty acids combined.
1
‘715 Claims:
Claim 14: The method of claim 13 comprising administering to the

subject about 4 g per day of the pharmaceutical composition to effect a
statistically significant reduction in triglycerides and apolipoprotein B
without effecting a statistically significant increase of in the subject.
2
‘677 Claims

fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl
comprising: administering orally to the subject about 4 g per day of a
pharmaceutical composition comprising at least about 96%, by weight of
all fatty acids present, ethyl eicosapentaenoate and substantially no
docosahexaenoic acid or its esters for a period of at least about 12 weeks
to effect a reduction in triglycerides without substantially increasing
LDL-C compared to placebo control.

of at least about 12 weeks to effect a reduction in fasting triglycerides of
at least about 25% without substantially increasing LDL-C compared to
placebo control.

of at least about 12 weeks to effect a reduction in apolipoprotein B
compared to placebo control.
3
‘652 Claims

fasting baseline triglyceride level of 500 mg/dl to about 1500 mg/dl
comprising: administering orally to the subject about 4 g per day of a
pharmaceutical composition comprising at least about 96%, by weight of
all fatty acids present, ethyl eicosapentaenoate and substantially no
docosahexaenoic acid or its esters for a period of about 12 weeks to
effect a reduction in triglycerides without substantially increasing LDL-
C compared to baseline.
Claim 7: The method of claim 1, comprising administering to the 15

subject. about 4 g of the pharmaceutical composition daily for the period
of at least about 12 weeks to effect a reduction in fasting triglycerides of
at least about 25% without substantially increasing LDL-C compared to
baseline

subject. about 4 g of the pharmaceutical composition daily for the period
of at least about 12 weeks to effect a reduction in apolipoprotein B
compared to baseline.
4
‘560 Claims
Claim 4: The method of claim 1, wherein said administering effects a

reduction in fasting triglycerides of at least about 10% without
increasing LDL-C by more than 5% in the subject.
Claim 7: The method of claim 1, wherein said administration effects

increasing LDL-C in the subject.
Claim 17: The method of claim 11, wherein said administering effects
increasing LDL-C in the subject compared to placebo control.
5
‘929 Claims
Claim 1: A method of reducing triglycerides in a subject having fasting

triglycerides of at least 500 mg/dl comprising, orally administering to
the subject daily for at least about 12 weeks a pharmaceutical
composition comprising about 4 g of ethyl eicosapentaenoate and not
more than about 4% docosahexaenoic acid or its esters, by weight of all
fatty acids.
Claim 5: The method of claim 1, wherein 12 weeks of said daily

administration is effective to reduce apolipoprotein B in subjects who
have fasting triglycerides levels of at least 500 mg/dl.
6
APPENDIX B
Asserted Claims Describing Specific Effects on
TGs, LDL-C, and/or Apo B
Appendix B:
Asserted Claims Describing Specific Effects on TGs, LDL-C, and/or Apo B
Defendants’ Motion for Summary Judgment of Noninfringement seeks summary
adjudication of the fourteen asserted claims that “require specific effects on a patient’s blood
lipid levels.” Defs.’ Br. at 19; see generally Defs.’ Br. at 19–24; Amarin’s Opposition Br. at 20–
24, 29.
The table below lists the claim limitations to which Defendants’ Motion refers, and the
corresponding asserted claim(s) in which those claim limitations appear.
Claim Limitation Claim(s)

“to effect a reduction in fasting triglycerides ’728 Patent, Claim 13
of at least about 25%” ’652 Patent, Claim 7
“effects a reduction in fasting triglycerides of
’560 Patent, Claim 4
at least about 10%”
“effects reduction in fasting triglycerides of at
least about 20%”
“to effect a statistically significant reduction
in triglycerides”
’728 Patent, Claims 1, 13, and 16
“without substantially increasing LDL-C ’677 Patent, Claims 1 and 8
’652 Patent, Claims 1, 7, and 8
“without effecting a statistically significant
increase in LDL-C”
“without increasing LDL-C by more than 5%
in the subject”
“without increasing LDL-C” ’560 Patent, Claims 7 and 17
“to effect a statistically significant reduction
in . . . apolipoprotein B”
“to effect a reduction in apolipoprotein B”
“effective to reduce apolipoprotein B” ’929 Patent, Claim 5
001
2 I hereby certify that on August 30, 2019, I caused true and correct copy of APPENDIX
3 OF EXHIBITS AMARIN’S OPPOSITION TO DEFENDANTS’ MOTION FOR
4 SUMMARY JUDGMENT to be filed with the Clerk of the Court using the Court’s CM/ECF
5 system, and service was thereby effected electronically to the following counsel of record in this
6 matter and deposited for mailing in the U.S. Mail, postage prepaid and address to::
7 Wayne A. Shaffer Michael D. Rounds
8 LAXALT & NOMURA, LTD. Ryan James Cudnik
9790 Gateway Drive, Suite 200 Brownstein Hyatt Farber Schreck, LLP
9 Reno, NV 89521 5371 Kietzke Lane
Tel: (775) 322-1170 Reno, NV 89511
10 Email: wshaffer@laxalt-nomura.com Email: mrounds@bhfs.com,
rcudnik@bhfs.com
11 George C. Lombardi
12 WINSTON & STRAWN LLP Constance S. Huttner
35 W. Wacker Drive Frank D. Rodriguez
13 Chicago, IL 60601 Caroline Sun
Tel: (312) 558-5969 Beth Finkelstein
14 Email: glombard@winston.com James Barabas
Windels Marx Lane & Mittendorf, LLP
15 Charles B. Klein 1 Giralda Farms, First Floor
16 Claire A. Fundakowski Madison, New Jersey 07940
WINSTON & STRAWN LLP Email: chuttner@ windelsmarx.com
17 1700 K Street N.W. frodriguez@ windelsmarx.com
Washington, D.C. 20006 csun@ windelsmarx.com
18 Tel: (202) 282-5000 bfinkelstein@ windelsmarx.com
Email:cklein@winston.com, jbarabas@windelsmarx.com
19
cfundakowski@winston.com
20 Attorneys for Defendants Dr. Reddy’s
Eimeric Reig-Plessis Laboratories, Inc. and Dr. Reddy’s
21 WINSTON & STRAWN LLP Laboratories, Ltd
101 California Street
22 San Francisco, CA 94111
Tel: (415) 591-6808
23
Email: ereigplessis@winston.com
24
Attorneys for Defendants Hikma
25 Pharmaceuticals USA, Inc. and Hikma
Pharmaceuticals International Limited
26 /s/ Rachel Jenkins
27

4 Tel.: (702) 948-8771 / Fax: (702) 948-8773
7 Einar Stole (admitted pro hac vice)
Michael N. Kennedy (admitted pro hac vice)
8 Megan P. Keane (admitted pro hac vice)
9 Alaina M. Whitt (admitted pro hac vice)
10
11 COVINGTON & BURLING LLP
12 Washington, DC 20001
Tel.: (202) 662-6000 / Fax: (202) 662-6291
mkennedy@cov.com, mkeane@cov.com
14

17
18
19
20
Plaintiffs, (Consolidated with 2:16-cv-02562-MMD-NJK)
21
22 v. AMARIN’S MOTION FOR LEAVE TO

FILE AMARIN’S OPPOSITION TO
23 HIKMA PHARMACEUTICALS USA INC., et DEFENDANTS’ MOTION FOR
al., SUMMARY JUDGMENT AND EXHIBITS
24 UNDER SEAL
Defendants.
25
26
27
1 Pursuant to Local Rule IA 10-5 and the parties’ Stipulated Discovery Confidentiality Order
2 in the above-captioned action (ECF No. 69), Plaintiffs Amarin Pharma Inc. and Amarin
3 Pharmaceuticals Ireland Limited (collectively, “Amarin” or “Plaintiffs”) hereby move for leave to
4 file portions of Amarin’s Opposition to Defendants’ Motion for Summary Judgment, portions of
5 Exhibit 13, and the entirety of Exhibits 5, 7, 9, and 10 under seal. Amarin filed redacted and sealed
6 versions of these filings contemporaneously with this Motion. This Motion is based upon the
7 following Memorandum of Points and Authorities and any additional information the Court may
8 choose to consider.
9 MEMORANDUM OF POINTS AND AUTHORITIES
10 The Local Rules of Practice for the United States District Court for the District of Nevada,
11 LR IA 10-5, allow for papers to be filed with the Court under seal if those papers are accompanied by
12 a motion for leave to file those documents under seal. Under the Stipulated Discovery
13 Confidentiality Order in this case, “[a]ny party to this litigation … shall have the right to designate as
14 ‘Confidential Material’” any document or potion of any document that contain “trade secrets,
15 competitively-sensitive technical, marketing, financial, sales or other confidential business
16 information.” ECF No. 69 at 3. Courts have discretion in determining whether to seal records, and
17 will do so when the interests in non-disclosure outweigh those favoring public access. See, e.g.,
18 Kamakana v. City & Cty. of Honolulu, 447 F.3d 1172, 1179 (9th Cir. 2006).
19 Defendants Hikma Pharmaceuticals USA Inc., Hikma Pharmaceuticals International Limited,
20 Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd. (collectively, “Defendants”) have
21 moved for summary judgement of noninfringement. See ECF No. 236. Amarin’s Opposition to
22 Defendants’ Motion for Summary Judgment addresses infringement by Defendants, and includes
23 details of Defendants’ proposed generic pharmaceutical product. The redacted portions of Amarin’s
24 Opposition to Defendants’ Motion for Summary Judgment and accompanying exhibits should be
25 sealed because they reflect information Defendants have designated “Confidential” under the
26 Stipulated Confidentiality Order based on Defendants assertion that the information constitutes
27 competitively-sensitive technical and other confidential business information.
1
1 Exhibits 5 and 7 to Amarin’s Opposition to Defendants’ Motion for Summary Judgement are
2 excerpts of expert deposition transcripts that have been marked “Confidential” and that discuss
3 information Defendants have asserted constitutes competitively-sensitive information concerning
4 Defendants’ ANDA products. Exhibits 9, 10, and 13 include a full expert report and excerpts from
5 expert reports that have been marked “Confidential” and that discuss information Defendants have
6 asserted constitutes competitively-sensitive information concerning Defendants’ ANDA products.
7 For the reasons stated above, Amarin requests that the Court grant its Motion for leave to file
8 Amarin’s Opposition to Defendants’ Motion for Summary Judgment and Exhibits under seal.
9 DATED: August 30, 2019 Respectfully submitted,
10 /s/ Jason D. Smith
Nicholas J. Santoro (Nev. Bar No. 532)
11
13 Las Vegas, NV 89135
Tel: (702) 948-8771 / Fax: (702) 948-8773

19
22 Tel: (202) 662-6000 / Fax: (202) 662-6291
23
24 esonnenschein@cov.com, awhitt@cov.com,
hpark@cov.com, jmoran@cov.com
25
Attorneys for Plaintiffs Amarin Pharma, Inc.
26 and Amarin Pharmaceuticals Ireland Limited
27
2
2 I hereby certify that on August 30, 2019, I caused true and correct copy of AMARIN’S
3 MOTION FOR LEAVE TO FILE AMARIN’S OPPOSITION TO DEFENDANTS’
4 MOTION FOR SUMMARY JUDGMENT AND EXHIBITS UNDER SEAL to be filed with
5 the Clerk of the Court using the Court’s CM/ECF system, and service was thereby effected
6 electronically on the following counsel of record in this matter:
7 Laxalt & Nomura, Ltd.

Wayne A. Shaffer Email: wshaffer@laxalt-nomura.com
8 Winston & Strawn LLP
George C. Lombardi Email: glombard@winston.com
9 Charles B. Klein Email: cklein@winston.com
10 Claire A. Fundakowski Email: cfundakowski@winston.com
Eimeric Reig-Plessis Email: ereigplessis@winston.com
11
Attorneys for Defendants Hikma Pharmaceuticals USA, Inc. and Hikma Pharmaceuticals
12 International Limited
13
Brownstein Hyatt Farber Schreck, LLP
14 Michael D. Rounds Email: mrounds@bhfs.com
Ryan James Cudnik Email: rcudnik@bhfs.com
15 Windels Marx Lane & Mittendorf, LLP
Constance S. Huttner Email: chuttner@ windelsmarx.com
16 Frank D. Rodriguez Email: frodriguez@ windelsmarx.com
Caroline Sun Email: csun@windelsmarx.com
17
Beth Finkelstein Email: bfinkelstein@windelsmarx.com
18 James Barabas Email: jbarabas@windelsmarx.com
19 Attorneys for Defendants Dr. Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories, Ltd.
20
/s/ Rachel Jenkins
21
22
23
24
25
26
27

Amarin V Hikma 252-254

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Case 2:16-cv-02525-MMD-NJK Document 252 Filed 08/30/19 Page 1 of 38

1 Nicholas J. Santoro (Nev. Bar No. 532)

7 Christopher N. Sipes (admitted pro hac vice)

19 UNITED STATES DISTRICT COURT

22 Plaintiffs, (Consolidated with 2:16-cv-02562-MMD-

26 Defendants. ORAL ARGUMENT REQUESTED

2 I. INTRODUCTION AND FACTUAL BACKGROUND ...................................................... 1

17 B. Defendants’ Product Labels Will Induce Clinicians to Administer Their

26 VI. FACT ISSUES REMAIN FOR TRIAL ON AMARIN’S CONTRIBUTORY

A. Use of Defendants’ Generic Products For Less Than 12 Weeks Is Not a

3 Allergan Sales, LLC v. Sandoz, Inc.,

8 Aydin Corp. v. Loral Corp.,

16 First Nat’l Bank v. Cities Serv. Co.,

21 GlaxoSmithKline LLC v. Glenmark Pharm. Inc.,

26 Impax Labs., Inc. v. Actavis Labs. FL, Inc.,

Pernix Ireland Pain DAC v. Alvogen Malta Operations Ltd.,

4 Sanofi v. Watson Labs. Inc.,

9 Tyco Healthcare Grp. LP v. Biolitec, Inc.,

14 Wyeth v. Sandoz, Inc.,

20 21 C.F.R. § 201.57(c)(15) ..............................................................................................................17

21 21 C.F.R. § 314.92(a)(1) ............................................................................................................4, 16

27 Vascepa Label Vascepa Prescribing Information (2017) (Defs.’ Ex. 13)

1 I. INTRODUCTION AND FACTUAL BACKGROUND

10 Anyone who “actively induces infringement of a patent shall be liable as an infringer.” 35

12 The asserted patent claims describe a method of treating severe hypertriglyceridemia by

1 “Clinical Studies” sections in particular—as encouraging, suggesting, or recommending use of 4

12 BudoffTr. 194:12- 22; see also BudoffOpening Rept. ~23;

13 BudoffReply Rept. mJ 4<H55; Peck Rept. mJ 130, 170-75.

16 administration in the Indications and Usage section. Budoff Tr. 203:17- 19

20 Sheinberg Tr. 143:22- 25 (emphasis added). Amarin's clinical expe11 agrees

1 (“baseline”) levels. Budoff Tr. 93:23–25

18 Sheinberg Tr. 139:20–21, 141:20-24. Clinicians therefore

1 Sheinberg Rebuttal Rept. ~ 119 (Ex. 13); see

3 Sheinberg Tr. 135:3-1 5.

5 Budoff Tr. 111 :7- 25. That clinicians read the

9 therapy. Sheinberg Tr. 233: 18- 234:6

10 Sheinberg Tr. 139:21- 25 -

11 Budoff Tr. 114:24-25

12 Budoff Opening Rept. ~ 124-26;

18 read prescribing infmm ation in a vacumn, but

22 Budoff Reply Rept. ~ 37. In fact, this case has more

22 Budoff Tr. 200:23–201:1. Dr. Sheinberg agreed

24 Sheinberg Tr. 135:3–15.

19 — Content and Format, at 2 (January 2006), https://www.fda.gov/media/72140/download (Ex. 14)

1 1. Defendants Labels Will Induce Clinicians to Use Defendants’ Products to

8 effectively use the drug. Budoff Tr. 147:4–8

21 Reply Rept. ¶ 105. And as Dr. Sheinberg conceded,

22 Sheinberg Tr. 154:4–7.

25 Budoff Tr. 152:18–24

3 2. Defendants Labels Will Induce Clinicians to Use Defendants' Products to

8 5% reduction in LDL-C compared to baseline and a 2% reduction compm·ed to placebo control.

10 expect a 4% reduction in apo B compm·ed to baseline and a 9% reduction compm·ed to placebo

14 § 14. Expe11s on both sides agree with this reading.16

19 Defendants are inconect.

25 ascepa to they can

7 Sheinberg Tr. 188:20–189:2. Dr. Sheinberg agreed

13 Budoff Opening Rept. ¶ 147; Budoff Reply Rept. ¶ 116; Peck

21 clinicians will administer Defendants’ products as adjunctive monotherapy or in combination therapy

23 ; Peck Tr. 49:16–19,

2 2. A ny N oninfringing Use for Def endants' Products Is N ot "Substantial"

5 hypeltriglyceridemic patients, clinicians' intend "indefinite" treatment. See Section V.A.l. It is

24 Christopher N. Sipes (admitted pro hac vice)

Han Park (admitted pro hac vice)