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Paper 1

Date: May 21, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE

BEFORE THE PATENT TRIAL AND APPEAL BOARD

COALITION FOR AFFORDABLE DRUGS VII LLC,


Petitioner,
v.
POZEN INC.,
Patent Owner.

IPR2015-01241
Patent 6,926,907

PETITION FOR INTER PARTES REVIEW

IPR2015-01241
Patent 6,926,907
TABLE OF CONTENTS
I.

Introduction....................................................................................................1

II.

Mandatory Notices Per 37 C.F.R. 42.8 .....................................................1


A.

Real Party-In-Interest ............................................................................1

B.

Notice of Related Matters .....................................................................2

C.

Lead and Back-Up Counsel and Service Information ..........................3

III. Payment of Fees .............................................................................................3


IV.

V.

VI.

Requirements Per 37 C.F.R. 42.104 ..........................................................4


A.

Grounds for Standing ............................................................................4

B.

Identification of Challenge and Precise Relief Requested ....................4

C.

Evidence Relied Upon to Support the Challenge..................................5

Background ....................................................................................................5
A.

State of the Art ......................................................................................5

B.

Person of Ordinary Skill in the Art (POSA) .........................................9

Claim Construction .....................................................................................10


A.

Unit Dosage Form............................................................................10

B.

Acid Inhibitor ...................................................................................10

C.

Coordinated Release ........................................................................11

D.

All Remaining Terms ..........................................................................11

VII. Ground 1: Gimet in View of Chiverton Renders Obvious Claims


1, 7, 8, 12, 13, 22, and 23 ..............................................................................12
A.

A POSA Would Have Combined Chiverton with Gimet ...................12

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Patent 6,926,907
B.

Claim 1: ...............................................................................................12
1.

A pharmaceutical composition in unit dosage form


suitable for oral administration to a patient, comprising: .........12

2.

(a) an acid inhibitor present in an amount effective to


raise the gastric pH of said patient to at least 3.5 upon the
administration of one or more of said unit dosage forms; ........13

3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in


an amount effective to reduce or eliminate pain or
inflammation in said patient upon administration of one
or more of said unit dosage forms; ...........................................14

4.

and wherein said unit dosage form provides for


coordinated release such that: i) said NSAID is
surrounded by a coating that, upon ingestion of said unit
dosage form by said patient, prevents the release of
essentially any NSAID from said dosage form unless the
pH of the surrounding medium is 3.5 or higher; ......................14

5.

ii) at least a portion of said acid inhibitor is not


surrounded by an enteric coating and, upon ingestion of
said unit dosage form by said patient, is released
regardless of whether the pH of the surrounding medium
is below 3.5 or above 3.5. .........................................................15

C.

Claim 7: The pharmaceutical composition of claim 1, wherein


said NSAID is a cyclooxygenese-2 (COX-2) inhibitor. .....................17

D.

Claim 8: The pharmaceutical composition of claim 7, wherein


said COX-2 inhibitor is selected from the group consisting of
celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib,
parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and
NS398. .................................................................................................17

E.

Claim 12: .............................................................................................17


1.

The pharmaceutical composition of claim 1 wherein said


unit dosage form is a multilayer tablet comprising ..................17
ii

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Patent 6,926,907
2.

a single core and one or more layers outside of said


single core, wherein: .................................................................18

3.

i) said NSAID is present in said core;.......................................18

4.

ii) said coating that does not release said NSAID unless
the pH of the surrounding medium is 3.5 or higher
surrounds said core; and............................................................18

5.

iii) said acid inhibitor is in said one more layers outside


said core. ...................................................................................19

F.

Claim 13: The pharmaceutical composition of claim 12,


wherein said one or more layers outside of said core do not
contain NSAID and are not surrounded by an enteric coating. ..........19

G.

Claim 22: .............................................................................................19

H.

1.

A method of treating a patient for pain or inflammation,


comprising .................................................................................20

2.

administering to said patient the pharmaceutical


composition of any one of claims 1-14. ....................................20

Claim 23: The method of claim 22, wherein said pain or


inflammation is due to either osteoarthritis or rheumatoid
arthritis.................................................................................................20

VIII. Ground 2: Gimet in View of Goldman in Further View of


Remington Renders Obvious Claims 1-5 and 7-23...................................21
A.

A POSA Would Have Combined Goldman, Remington and


Gimet ...................................................................................................21

B.

Claim 1: ...............................................................................................22
1.

A pharmaceutical composition in unit dosage form


suitable for oral administration to a patient, comprising: .........22

2.

(a) an acid inhibitor present in an amount effective to


raise the gastric pH of said patient to at least 3.5 upon the

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administration of one or more of said unit dosage forms; ........22
3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in


an amount effective to reduce or eliminate pain or
inflammation in said patient upon administration of one
or more of said unit dosage forms; ...........................................23

4.

and wherein said unit dosage form provides for


coordinated release such that: i) said NSAID is
surrounded by a coating that, upon ingestion of said unit
dosage form by said patient, prevents the release of
essentially any NSAID from said dosage form unless the
pH of the surrounding medium is 3.5 or higher; ......................23

5.

ii) at least a portion of said acid inhibitor is not


surrounded by an enteric coating and, upon ingestion of
said unit dosage form by said patient, is released
regardless of whether the pH of the surrounding medium
is below 3.5 or above 3.5. .........................................................24

C.

Claim 2: The pharmaceutical composition of claim 1, wherein


said acid inhibitor is an H2 blocker.....................................................24

D.

Claim 3: The pharmaceutical composition of claim 2, wherein


said H2 blocker is selected from the group consisting of:
cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine;
loxtidine and famotidine......................................................................24

E.

Claim 4: The pharmaceutical composition of claim 3, wherein


said H2 blocker is famotidine, present in said unit dosage form
in an amount of between 5 mg and 100 mg. .......................................25

F.

Claim 5: The pharmaceutical composition of claim 1, wherein


said acid inhibitor is a proton pump inhibitor selected from the
group consisting of: omeprazole, esomeprazole, lansoprazole,
pantoprazole and rabeprazole. .............................................................26

G.

Claim 7: The pharmaceutical composition of claim 1, wherein


said NSAID is a cyclooxygenese-2 (COX-2) inhibitor. .....................26

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H.

Claim 8: The pharmaceutical composition of claim 7, wherein


said COX-2 inhibitor is selected from the group consisting of
celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib,
parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and
NS398. .................................................................................................26

I.

Claim 9: The pharmaceutical composition of claim 1, wherein


said NSAID is selected from the group consisting of: aspirin;
acetaminophen; ibuprofen; flurbiprofen; ketoprofen;
lornoxicam; naproxen; oxaprozin; etodolac; indomethacin;
ketorolac; and nabumetone..................................................................27

J.

Claim 10: The pharmaceutical composition of claim 9, wherein


said NSAID is naproxen present in an amount of between 50
mg and 1500 mg. .................................................................................27

K.

Claim 11: The pharmaceutical composition of claim 10,


wherein said naproxen is present in an amount of between 200
mg and 600 mg. ...................................................................................28

L.

Claim 12: .............................................................................................29

M.

1.

The pharmaceutical composition of claim 1 wherein said


unit dosage form is a multilayer tablet comprising ..................29

2.

a single core and one or more layers outside of said


single core, wherein: .................................................................29

3.

i) said NSAID is present in said core;.......................................29

4.

ii) said coating that does not release said NSAID unless
the pH of the surrounding medium is 3.5 or higher
surrounds said core; and............................................................29

5.

iii) said acid inhibitor is in said one more layers outside


said core. ...................................................................................29

Claim 13: The pharmaceutical composition of claim 12,


wherein said one or more layers outside of said core do not
contain NSAID and are not surrounded by an enteric coating. ..........29

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N.

Claim 14: .............................................................................................30


1.

The pharmaceutical composition of claim 13, wherein


said unit dosage form is a bilayer tablet having an outer
layer of said acid inhibitor and an inner core of said
NSAID and ................................................................................30

2.

wherein said outer layer of said tablet is surrounded by a


non-enteric film coating that releases said acid inhibitor
upon ingestion by patient. .........................................................31

O.

Claim 15: The pharmaceutical composition of any one of


claims 1 or 7-14, wherein said acid inhibitor is a proton pump
inhibitor. ..............................................................................................31

P.

Claim 16: .............................................................................................32

Q.

1.

The pharmaceutical composition of any one of claims 1214, wherein said acid inhibitor is a proton pump inhibitor
and .............................................................................................32

2.

wherein said coating surrounding said core does not


dissolve unless the pH of the surrounding medium is 4 or
greater........................................................................................33

Claim 17: .............................................................................................33


1.

The pharmaceutical composition of any one of claims 1214, wherein said acid inhibitor is a proton pump inhibitor
and .............................................................................................33

2.

wherein said coating surrounding said core does not


dissolve unless the pH of the surrounding medium is 5 or
greater........................................................................................34

R.

Claim 18: The pharmaceutical composition of any one of


claims 7-14, wherein said acid inhibitor is an H2 blocker. .................35

S.

Claim 19: .............................................................................................35


1.

The pharmaceutical composition of any one of claims 12vi

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Patent 6,926,907
14, wherein said acid inhibitor is an H2 blocker and ...............35
2.

T.

Claim 20: .............................................................................................36


1.

The pharmaceutical composition of any one of claims 1214, wherein said acid inhibitor is an H2 blocker and ...............37

2.

wherein said tablet has an inner core of said NSAID


surrounded by a barrier coating that dissolves at a rate
such that said NSAID is not released until the pH of the
surrounding medium is 5 or greater. .........................................37

U.

Claim 21: The pharmaceutical composition of claim 1, wherein


said unit dosage form is a capsule. ......................................................38

V.

Claim 22: .............................................................................................38

W.

IX.

wherein said tablet has an inner core of said NSAID


surrounded by a barrier coating that dissolves at a rate
such that said NSAID is not released until the pH of the
surrounding medium is 4 or greater. .........................................36

1.

A method of treating a patient for pain or inflammation,


comprising .................................................................................38

2.

administering to said patient the pharmaceutical


composition of any one of claims 1-14. ....................................39

Claim 23: The method of claim 22, wherein said pain or


inflammation is due to either osteoarthritis or rheumatoid
arthritis.................................................................................................39

Ground 3: Goldman in View of Remington in Further View of


Abe Renders Obvious Claims 1-5, 7-18, 21, and 22..................................39
A.

A POSA Would Have Combined Remington, Abe, and


Goldman ..............................................................................................39

B.

Claim 1: ...............................................................................................40
1.

A pharmaceutical composition in unit dosage form

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IPR2015-01241
Patent 6,926,907
suitable for oral administration to a patient, comprising: .........40
2.

(a) an acid inhibitor present in an amount effective to


raise the gastric pH of said patient to at least 3.5 upon the
administration of one or more of said unit dosage forms; ........40

3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in


an amount effective to reduce or eliminate pain or
inflammation in said patient upon administration of one
or more of said unit dosage forms; ...........................................41

4.

and wherein said unit dosage form provides for


coordinated release such that: i) said NSAID is
surrounded by a coating that, upon ingestion of said unit
dosage form by said patient, prevents the release of
essentially any NSAID from said dosage form unless the
pH of the surrounding medium is 3.5 or higher; ......................42

5.

ii) at least a portion of said acid inhibitor is not


surrounded by an enteric coating and, upon ingestion of
said unit dosage form by said patient, is released
regardless of whether the pH of the surrounding medium
is below 3.5 or above 3.5. .........................................................43

C.

Claim 2: The pharmaceutical composition of claim 1, wherein


said acid inhibitor is an H2 blocker.....................................................44

D.

Claim 3: The pharmaceutical composition of claim 2, wherein


said H2 blocker is selected from the group consisting of:
cimetidine; ranitidine; ebrotidine; pabutidine; lafutidine;
loxtidine and famotidine......................................................................44

E.

Claim 4: The pharmaceutical composition of claim 3, wherein


said H2 blocker is famotidine, present in said unit dosage form
in an amount of between 5 mg and 100 mg. .......................................45

F.

Claim 5: The pharmaceutical composition of claim 1, wherein


said acid inhibitor is a proton pump inhibitor selected from the
group consisting of: omeprazole, esomeprazole, lansoprazole,
pantoprazole and rabeprazole. .............................................................45
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G.

Claim 7: The pharmaceutical composition of claim 1, wherein


said NSAID is a cyclooxygenese-2 (COX-2) inhibitor. .....................45

H.

Claim 8: The pharmaceutical composition of claim 7, wherein


said COX-2 inhibitor is selected from the group consisting of
celecoxib; rofecoxib; meloxicam; piroxicam; valdecoxib,
parecoxib, etoricoxib, CS-502, JTE-522; L-745,337; and
NS398. .................................................................................................46

I.

Claim 9: The pharmaceutical composition of claim 1, wherein


said NSAID is selected from the group consisting of: aspirin;
acetaminophen; ibuprofen; flurbiprofen; ketoprofen;
lornoxicam; naproxen; oxaprozin; etodolac; indomethacin;
ketorolac; and nabumetone..................................................................46

J.

Claim 10: The pharmaceutical composition of claim 9, wherein


said NSAID is naproxen present in an amount of between 50
mg and 1500 mg. .................................................................................46

K.

Claim 11: The pharmaceutical composition of claim 10,


wherein said naproxen is present in an amount of between 200
mg and 600 mg. ...................................................................................47

L.

Claim 12: .............................................................................................47

M.

1.

The pharmaceutical composition of claim 1 wherein said


unit dosage form is a multilayer tablet comprising ..................47

2.

a single core and one or more layers outside of said


single core, wherein: .................................................................48

3.

i) said NSAID is present in said core;.......................................48

4.

ii) said coating that does not release said NSAID unless
the pH of the surrounding medium is 3.5 or higher
surrounds said core; and............................................................49

5.

iii) said acid inhibitor is in said one more layers outside


said core. ...................................................................................49

Claim 13: The pharmaceutical composition of claim 12,


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Patent 6,926,907
wherein said one or more layers outside of said core do not
contain NSAID and are not surrounded by an enteric coating. ..........50
N.

Claim 14: .............................................................................................51


1.

The pharmaceutical composition of claim 13, wherein


said unit dosage form is a bilayer tablet having an outer
layer of said acid inhibitor and an inner core of said
NSAID and ................................................................................51

2.

wherein said outer layer of said tablet is surrounded by a


non-enteric film coating that releases said acid inhibitor
upon ingestion by patient. .........................................................51

O.

Claim 15: The pharmaceutical composition of any one of


claims 1 or 7-14, wherein said acid inhibitor is a proton pump
inhibitor. ..............................................................................................52

P.

Claim 16: .............................................................................................52

Q.

R.

1.

The pharmaceutical composition of any one of claims 1214, wherein said acid inhibitor is a proton pump inhibitor
and .............................................................................................52

2.

wherein said coating surrounding said core does not


dissolve unless the pH of the surrounding medium is 4 or
greater........................................................................................53

Claim 17: .............................................................................................53


1.

The pharmaceutical composition of any one of claims 1214, wherein said acid inhibitor is a proton pump inhibitor
and .............................................................................................54

2.

wherein said coating surrounding said core does not


dissolve unless the pH of the surrounding medium is 5 or
greater........................................................................................54

Claim 18: The pharmaceutical composition of any one of


claims 7-14, wherein said acid inhibitor is an H2 blocker. .................54

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Patent 6,926,907

X.

S.

Claim 21: The pharmaceutical composition of claim 1, wherein


said unit dosage form is a capsule. ......................................................55

T.

Claim 22: .............................................................................................55


1.

A method of treating a patient for pain or inflammation,


comprising .................................................................................55

2.

administering to said patient the pharmaceutical


composition of any one of claims 1-14. ....................................55

Ground 4: Goldman in View of Remington in Further View of


Fitton Renders Obvious Claims 1, 5, and 6 ...............................................56
A.

A POSA Would Have Combined Remington, Fitton, and


Goldman ..............................................................................................56

B.

Claim 1: ...............................................................................................57
1.

A pharmaceutical composition in unit dosage form


suitable for oral administration to a patient, comprising: .........57

2.

(a) an acid inhibitor present in an amount effective to


raise the gastric pH of said patient to at least 3.5 upon the
administration of one or more of said unit dosage forms; ........57

3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in


an amount effective to reduce or eliminate pain or
inflammation in said patient upon administration of one
or more of said unit dosage forms; ...........................................58

4.

and wherein said unit dosage form provides for


coordinated release such that: i) said NSAID is
surrounded by a coating that, upon ingestion of said unit
dosage form by said patient, prevents the release of
essentially any NSAID from said dosage form unless the
pH of the surrounding medium is 3.5 or higher; ......................58

5.

ii) at least a portion of said acid inhibitor is not


surrounded by an enteric coating and, upon ingestion of
said unit dosage form by said patient, is released
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Patent 6,926,907
regardless of whether the pH of the surrounding medium
is below 3.5 or above 3.5. .........................................................59

XI.

C.

Claim 5: The pharmaceutical composition of claim 1, wherein


said acid inhibitor is a proton pump inhibitor selected from the
group consisting of: omeprazole, esomeprazole, lansoprazole,
pantoprazole and rabeprazole. .............................................................59

D.

Claim 6: The pharmaceutical composition of claim 5, wherein


said proton pump inhibitor is pantoprazole, present in said unit
dosage form in an amount of between 10 mg and 200 mg. ................60

Any Secondary Considerations of Nonobviousness Would Fail .............60

XII. Conclusion ....................................................................................................60

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TABLE OF AUTHORITIES
Statutes
35 U.S.C. 102(b) .................................................................................................4, 5
35 U.S.C. 103(a) .................................................................................................4, 5
35 U.S.C. 311-319 ................................................................................................1
Regulations
37 C.F.R. 42.8(b)(3) ...................................................................................................3
37 C.F.R. 42.10(b) ..................................................................................................3
37 C.F.R. 42.100 et seq. ..........................................................................................1
37 C.F.R. 42.104 .....................................................................................................4
37 C.F.R. 42.15(a)...................................................................................................4
37 C.F.R. 42.6(c) .....................................................................................................5
37 C.F.R. 42.63(e)...................................................................................................5
37 C.F.R. 42.8 .........................................................................................................1
37 C.F.R. 42.8(b)(1) ................................................................................................1
37 C.F.R. 42.8(b)(2) ................................................................................................2
37 C.F.R. 42.8(b)(4) ................................................................................................3

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EXHIBIT LIST

Exhibit No.

Description

1001

U.S. Patent No. 6,926,907 (the 907 Patent)

1002

File History of the 907 Patent

1003

Declaration of Leon Shargel, Ph.D., R.Ph.

1004

U.S. Patent No. 5,698,225 (Gimet)

1005

U.S. Patent No. 5,204,118 (Goldman)

1006

Remingtons Pharmaceutical Sciences, Alfonso R. Gennaro, et


al., Mack Publg Co., Seventeenth Edition, 1985 (Remington)

1007

Does Misoprostol Given as a Single Large Dose Improve its


Antisecretory Effect? S.G. Chiverton, et al., Aliment. Pharmacol.
Therap., Vol. 3 (1989) (Chiverton)

1008

U.S. Patent No. 4,757,060 (Lukacsko)

1009

The Mechanism of Action of Aspirin, J.R. Vane, et al., Pergamon


(2003)

1010

G.B. Patent No. 1211134

1011

Drug-Induced Peptic Ulcer Disease, Valerie Vella, Journal of the


Malta College of Pharmacy Practice (2005)

1012

Goodman & Gilmans The Pharmacological Basis of


Therapeutics, Joel G. Hardman, et al., McGraw-Hill Publg Co.,
Ninth Edition (1996)

1013

U.S. Patent No. 6,365,184 (Depui)

1014

Tagamet: The Discovery of Histamine H2-Receptor Antagonists,


SmithKlein Beecham Pharmas., Am. Chem. Soc. (Nov. 24, 1997)
xiv

IPR2015-01241
Patent 6,926,907

Exhibit No.

Description

1015

Inhibition of Gastric (H+ + K+)-ATPase by the Substituted


Benzimidazole Picoprazole, B. Wallmark, et al., Biochimica et
Biophysica Acta, Vol. 728, at 31-38 (1983)

1016

U.S. Patent No. 4,255,431

1017

Drug Discovery: Practices, Processes, and Perspectives, Jie Jack


Li, et al., John Wiley & Sons (Apr. 3, 2013)

1018

U.S. Patent App. Pub. 2002/0045184 (Chen)

1019

Management of NSAID-Related Gastrointestinal Mucosal Injury,


A.F. Barrison, et al., Inflammopharmacology 7(3), at 277-86 (1999)

1020

Prevention of NSAID-Induced Gastroduodenal Ulcers, A.


Rostom, et al., Cochrane Database of Systematic Reviews (2000)

1021

VIMOVO (Naproxen and Esomeprazole Magnesium) Tablets |


Horizon Pharma, http://www.horizonpharma.com/vimovo/ (last
visited May 9, 2015)

1022

Horizon Pharma plc 2014 Irish Statutory Accounts, Horizon


Pharma Public Limited Company (Apr. 9, 2015)

1023

Nov. 19, 2004 Amendment and Response Under 37 C.F.R. 1.116,


File History of the 907 Patent

1024

Pharmaceutical Companies Buy Rivals Drugs, Then Jack Up the


Prices, The Wall Street Journal (Apr. 26, 2015)

1025

Oct. 20, 2004 Final Office Action, File History of the 907 Patent

1026

Nov. 19, 2004 Request for Continued Examination, File History of


the 907 Patent

1027

Mar. 29, 2005 Notice of Allowance and Fee(s) Due, File History of
the 907 Patent

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Patent 6,926,907

Exhibit No.

Description

1028

Dec. 25, 2007 Certificate of Correction, File History of the 907


Patent

1029

Clinical Trial: Evaluation of Gastric Acid Suppression with Three


Doses of Immediate-Release Esomeprazole in the Fixed-Dose
Combination of PN 400 (Naproxen/Esomeprazole Magnesium)
Compared with
Naproxen 500 mg and Enteric-Coated Esomeprazole 20 mg: A
Randomized, Open-Label, Phase I Study in Healthy Volunteers,
Miner et al., Alim. Pharmacol. Ther., 32:414-424 (2010)
(Miner)

1030

Nexium 24HR Acid Reducer, 42 Capsules Walmart.com,


http://www.walmart.com/ip/Nexium-24HR-Acid-Reducer-42Capsules/35284453 (last visited May 9, 2015)

1031

Effects of Misoprostol on Gastric Acid and Mucus Secretion in


Man, Donald E. Wilson, et al., Digestive Diseases and Sciences,
Vol. 31, No. 2 (Feb. 1986)

1032

Misoprostol Versus Antacid Titration for Preventing Stress Ulcers


in Postoperative Surgical ICU Patients, Michael J. Zinner, MD, et
al., Ann. Surg., Vol. 210, No. 5 (Nov. 1989)

1033

COX-2 Inhibitors, Peter M. Brooks, et al., Australian Prescriber


(Feb. 1, 2000)

1034

Effect of Orally Administered Prostaglandin E2 and its 15-Methyl


Analogues on Gastric Secretion, Karim, et al., British Med.
Journal (Jan. 20, 1973)

1035

Effect of Increasing Gastric pH with Famotidine on the


Absorption and Oral Pharmacokinetics of the Inotropic Agent
Vesnarinone, B. Koneru, et al., J. Clin. Pharmacol. (1998)

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Patent 6,926,907

Exhibit No.

Description

1036

Twenty-Four-Hour Intragastric pH Profiles and Pharmacokinetics


Following Single and Repeated Oral Administration of the Proton
Pump Inhibitor Pantoprazole in Comparison to Omeprazole, M.
Hartmann, et al., Aliment Pharmacol. Ther. (Jan. 3, 1996)

1037

Effects of Famotidine on Gastric pH and Residual Volume in


Pediatric Surgery. J.S. Jahr, et al., Acta Aneasthesiol Scand.
(1991)

1038

Effect of Preanesthetic Famotidine on Gastric Volume and pH,


Takahiko Okuda, et al., Journal of Anesthesia, Vol. 2, Issue 1 (Mar.
1988)

1039

Effect of Oral and Intramuscular Famotidine on pH and Volume


of Gastric Contents, Kazuo Abe, M.D., et al., Anesth. Analg.
(1989) (Abe)

1040

High-Viscosity HPMC as a Film-Coating Agent, G. Maffione, et


al., Drug Dev. & Indus. Pharmacy (1993)

1041

Upper Gastrointestinal (GI) pH in Young, Healthy Men and


Women, Jennifer B. Dressman, et al., Pharmaceutical Research,
Vol. 7, No. 7, 756-761 (1990)

1042

FDA Response to Horizons Citizen Petition

1043

Notice of Final Determination, In re: Patent Term Extension for


U.S. Patent No. 6,143,771

1044

Prevention of the Gastrointestinal Adverse Effects of Nonsteroidal


Anti-Inflammatory Drugs, Gregor J.E. Brown, et al., Drug Safety
(6): 503-512 (December 21, 1999)

1045

Abolition by Omeprazole of Aspirin Induced Gastric Mucosal


Injury in Man, T K Daneshmend et al., Gut, Vol. 31, 514-517
(1990) (Daneshmend)

1046

U.S. Patent No. 6,319,519


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Patent 6,926,907

Exhibit No.

Description

1047

Shargel Walmart Receipts

1048

Pantoprazole A Review of its Pharmacological Properties and


Therapeutic Use in Acid-Related Disorders, A. Fitton, et al.,
Drugs, Vol. 51, Issue 3 (Mar. 1996) (Fitton)

1049

The Pathophysiological and Pharmacological Basis of Peptic


Ulcer Therapy, J. Freston, Toxicologic Pathology, Vol, 16, No. 2
(1988)

1050

Measurement of Gastrointestinal pH Profiles in Normal Ambulant


Human Subjects, D. F. Evans, et al., Gut, Vol. 29, 1035-1041
(1988) (Evans)

1051

Intragastric pH and Serum Gastrin During Administration of


Different Doses of Pantoprazole in Healthy Subjects, H. Koop, et
al., European Journal of Gastroenterology & Hepatology (Sept.
1996)

1052

Omeprazole: A Preliminary Review of Its Pharmacodynamic and


Pharmacokinetic Properties, and Therapeutic Potential in Peptic
Ulcer Disease and Zollinger- Ellison Syndrome, Clissold et al.,
Drugs, 32, 15-47 (1986) (Clissold)

1053

Development of an Oral Formulation of Omeprazole, Pilbrant


and Cederberg, Scand. J. Gastroenterol., 20(Suppl. 108):113-120
(1985) (Pilbrant)

1054

Effects of Single and Repeated Doses of Omeprazole in Gastric


Acid and Pepsin Secretion in Man, Howden et al., Gut, Vol. 25,
707-710 (1984) (Howden)

1055

Omeprazole: A Study of Its Inhibition of Gastric pH and Oral


Pharmacokinetics After Morning or Evening Dosage, Prichard et
al., Gastroenterol., 88:64-69 (1985) (Prichard)

xviii

IPR2015-01241
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Exhibit No.

Description

1056

The Effects of Oral Doses of Lansoprazole and Omeprazole on


Gastric pH, Tolman et al., J. Clin. Gastroenterol, 24(2):65-70
(1997) (Tolman)

1057

Horizons Citizen Petition (February 4, 2014)

xix

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I.

Introduction
The Coalition for Affordable Drugs VII LLC (CFAD or Petitioner)

respectfully requests inter partes review of claims 1-23 of U.S. Patent No.
6,926,907 (the 907 Patent) (Ex. 1001) in accordance with 35 U.S.C. 311-319
and 37 C.F.R. 42.100 et seq. The 907 Patent is assigned to Pozen Inc.
II.

Mandatory Notices Per 37 C.F.R. 42.8


A.

Real Party-In-Interest

Pursuant to 37 C.F.R. 42.8(b)(1), CFAD certifies that Coalition For


Affordable Drugs VII LLC; Hayman Credes Master Fund, L.P. (Credes);
Hayman Orange Fund SPC Portfolio A (HOF); Hayman Capital Master Fund,
L.P. (HCMF); Hayman Capital Management, L.P. (HCM); Hayman Offshore
Management, Inc. (HOM); Hayman Investments, L.L.C. (HI); nXn Partners,
LLC (nXnP); IP Navigation Group, LLC (IPNav); J Kyle Bass; and Erich
Spangenberg (collectively, RPI) are the real parties-in-interest. The RPI certify
the following: CFAD is a wholly owned subsidiary of Credes. Credes is a limited
partnership. HOF is a segregated portfolio company. HCMF is a limited
partnership. HCM is the general partner and investment manager of Credes and
HCMF. HCM is the investment manager of HOF. HOM is the administrative
general partner of Credes and HCMF. HI is the general partner of HCM. J Kyle
Bass is the sole member of HI and sole shareholder of HOM. CFAD, Credes,

IPR2015-01241
Patent 6,926,907
HOF, and HCMF act, directly or indirectly, through HCM as the general partner
and/or investment manager of Credes, HOF, and HCMF. nXnP is a paid
consultant to HCM. Erich Spangenberg is the Manager and majority member of
nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is the Manager and
majority member of IPNav. Other than HCM and J Kyle Bass in his capacity as
the Chief Investment Officer of HCM and nXnP and Erich Spangenberg in his
capacity as the Manager/CEO of nXnP, no other person (including any investor,
limited partner, or member or any other person in any of CFAD, Credes, HOF,
HCMF, HCM, HOM, HI, nXnP, or IPNav) has authority to direct or control (i) the
timing of, filing of, content of, or any decisions or other activities relating to this
petition or (ii) any timing, future filings, content of, or any decisions or other
activities relating to the future proceedings related to this petition. All of the costs
associated with this petition are expected to be borne by HCM, CFAD, Credes,
HOF, and/or HCMF.
B.

Notice of Related Matters

Per 37 C.F.R. 42.8(b)(2), CFAD is aware of the following judicial matters


involving the 907 Patent: (1) AstraZeneca AB v. Dr. Reddys Labs. Inc., 3:11-cv02317 (D.N.J.); (2) AstraZeneca AB v. Dr. Reddys Labs., Inc., 3:13-cv-00091
(D.N.J.); (3) AstraZeneca AB v. Watson Labs., Inc.- Florida, 3:13-cv-03038
(D.N.J.); and (4) AstraZeneca AB v. Mylan Pharmas., 3:13-cv-04022 (D.N.J.). In

IPR2015-01241
Patent 6,926,907
addition, CFAD is aware of the following judicial and administrative matters
involving patents related to the 907 Patent: (1) Dr. Reddys Labs., Inc. v. Pozen
Inc., IPR2015-00802 (P.T.A.B.); (2) Horizon Pharma, Inc. v. Actavis Labs. FL,
Inc., 3:15-cv-03322 (D.N.J.); (3) Horizon Pharma, Inc. v. Dr. Reddys Labs., Inc.,
3:15-cv-03324 (D.N.J.); (4) Horizon Pharma, Inc. v. Lupin Ltd., 3:15-cv-03326
(D.N.J.); and (5) Horizon Pharma, Inc., v. Mylan Pharmas., Inc. 3:15-cv-03327
(D.N.J.).
C.

Lead and Back-Up Counsel and Service Information

Per 37 C.F.R. 42.8(b)(3), CFAD designates counsel as follows:


Lead Counsel
Amy E. LaValle (Reg. No. 51,092)
alavalle@conleyrose.com
Postal and Hand-Delivery Address:
Conley Rose, P.C.
5601 Granite Parkway, Suite 500
Plano, Texas 75024
(972) 731-2288 (phone)
(972) 731-2289 (fax)

Back-Up Counsel
Jerry C. Harris, Jr. (Reg. No. 66,822)
jcharris@conleyrose.com
Rodney B. Carroll (Reg. No. 39,624)
rcarroll@conleyrose.com
Postal and Hand-Delivery Address:
Conley Rose, P.C.
5601 Granite Parkway, Suite 500
Plano, Texas 75024
(972) 731-2288 (phone)
(972) 731-2289 (fax)

Per 37 C.F.R. 42.8(b)(4), CFAD may be served at the above addresses for Lead
and Back-Up Counsel. CFAD consents to electronic service by e-mail. Per 37
C.F.R. 42.10(b), a Power of Attorney accompanies this Petition.
III.

Payment of Fees
The undersigned authorizes the Office to charge the fee required by 37 C.F.R.

IPR2015-01241
Patent 6,926,907
42.15(a) for this Petition to Deposit Account No. 50-1515.
IV.

Requirements Per 37 C.F.R. 42.104


A.

Grounds for Standing

CFAD certifies that the 907 Patent is available for inter partes review and that
CFAD is not barred or estopped from requesting inter partes review challenging
claims 1-23 of the 907 Patent on the grounds identified in this Petition.
B.

Identification of Challenge and Precise Relief Requested

Ground 1: CFAD challenges claims 1, 7, 8, 12, 13, 22, and 23 of the 907
Patent and seeks a ruling that those claims are unpatentable under 35 U.S.C.
103(a) as obvious over Gimet (Ex. 1004) in view Chiverton (Ex. 1007). Gimet
and Chiverton are available as prior art under 35 U.S.C. 102(b).
Ground 2: CFAD challenges claims 1-5 and 7-23 of the 907 Patent and seeks
a ruling that those claims are unpatentable under 35 U.S.C. 103(a) as obvious
over Gimet in view of Goldman (Ex. 1005) and in further view of Remington (Ex.
1006). Gimet, Goldman, and Remington are available as prior art under 35 U.S.C.
102(b).
Ground 3: CFAD challenges claims 1-17, 21, and 22 of the 907 Patent and
seeks a ruling that those claims are unpatentable under 35 U.S.C. 103(a) as
obvious over Goldman in view of Remington and in further view of Abe
(Ex. 1039). Goldman, Remington, and Abe are available as prior art under 35

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Patent 6,926,907
U.S.C. 102(b).
Ground 4: CFAD challenges claims 1, 5, and 6 of the 907 Patent and seeks a
ruling that those claims are unpatentable under 35 U.S.C. 103(a) as obvious over
Goldman in view of Remington and in further view Fitton (Ex. 1048). Goldman,
Remington, and Fitton are available as prior art under 35 U.S.C. 102(b).
C.

Evidence Relied Upon to Support the Challenge

CFAD relies upon the publications cited herein in support of Grounds 1-4.
CFAD also relies upon the Declaration of Leon Shargel, Ph.D., R.Ph. (Ex. 1003)
and the documents cited therein. Filed herewith are an Exhibit List and copies of
the references per 37 C.F.R. 42.63(e) and 37 C.F.R. 42.6(c).
V.

Background
A.

State of the Art

Non-steroidal anti-inflammatory drugs (NSAIDs) refer to a group of drugs that


reduce pain, inflammation, and fever. (Ex. 1003, 30.) Aspirin is one type of
NSAID. (Id.) Bayer first chemically synthesized aspirin in the 1890s and began
selling aspirin in 1899. (Id.) Since that time, aspirin has become the most widely
used medicine ever. (Id.) Syntex Corporation disclosed its synthesis of naproxen,
another NSAID, in 1968. (Id.) However, since at least 1971, NSAIDs like aspirin
and naproxen have been known to increase gastric acid production and, thus,
increase the incidence of gastric ulcers. (Id.)

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Acid inhibitors refer to a group of agents that reduce gastric acid secretion and
gastric acidity. (Ex. 1003, 31.) Prostaglandins, H2 blockers, and proton pump
inhibitors (PPIs) are all types of acid inhibitors. (Id.) Since at least 1973,
prostaglandins have been known to inhibit gastric acid production. (Id.) In 1996,
misoprostol, a prostaglandin, was known to inhibit gastric acid secretion and was
approved for the treatment of gastric ulcer disease induced by NSAIDs. (Id.) In
1970, it was discovered that cimetidine, an H2 blocker, inhibited gastric acid
production. (Id.) Similarly, in the early 1980s, it was discovered that picoprazole,
a PPI, inhibited gastric acid production. (Id.) Omeprazole, another PPI, and its
inhibition of gastric action production, also was discovered in the early 1980s.
(Id.) In 1987, a group led by Gunnel Sundn separated esomeprazole, which is the
enantiopure (S)-isomer of omeprazole. (Id.)
Although NSAIDs provide certain therapeutic benefits, their tendency to
increase the incidence of gastric ulcers may limit their use. (Ex. 1003, 34.) In
order to avoid such limitations, NSAIDs have been used with acid inhibitors at
least as early as 1986. (Id.) For decades before that time, doctors had
recommended that patients take over-the-counter gastric acid neutralizers like
Maalox along with NSAIDs. (Id.) The literature is replete with combination
therapies that include NSAIDs for their therapeutic effects of reducing pain and
inflammation with acid inhibitors to address the side effects of the NSAIDs. (Id.)
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However, administration of separate drugs causes various patient compliance
issuespatients may forget or get confused about when to take each drug or how
much to take. (See Chen (Ex. 1018); see also id.)
Acid inhibitors have been combined with NSAIDs in a single tablet at least as
early as 1986. (See, e.g., Lukacsko (Ex. 1008), col. 3 ll. 13-18; see also Ex. 1003,
36.) For example, Dupui discloses a single tablet comprising both an NSAID
and an acid inhibitor. (Dupui (Ex. 1013), col. 1 ll. 11-20, 45-54) Depui recognizes
that such single tablet is [t]he most promising solution to the problem of healing
and preventing NSAID associated upper gastrointestinal problems. (Id. at col. 1
ll. 45-54.) Furthermore, the single tablet addresses the issue of patient compliance.
(Id. at col. 2 ll. 32-41; see also Ex. 1003, 36.)
A combination of an NSAID and an acid inhibitor is just one example of what
is called a combination therapy. (Ex. 1003, 37.) Combination therapy usually
consists of two or more active ingredients combined into a single entity. (Id.)
Through marketing of patented combination drug products, the pharmaceutical
companies can increase their revenue greatly by decreasing or hindering the
consumers access to known, tested, safe, and affordable drugs. (Id.)
Vimovo is a prime example. Vimovo is a combination therapy of naproxen
and esomeprazole magnesium. (Ex. 1003, 39.) Vimovos ingredients,
naproxen and esomeprazole magnesium, are available separately as generic drug
7

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products. (Id. at 45-51) Pozens affiliates, including Horizon Pharma USA
(Horizon) and AstraZeneca AB (AstraZeneca), currently market and sell
Vimovo. Horizon admits that the active pharmaceutical ingredients (APIs) in
Vimovo have been on the market . . . for many years. (Horizon Pharma plc
2014 Irish Statutory Accounts (Ex. 1022) at 35.) For this reason, Horizon resorts
to sales tactics to convince physicians to prescribeand pharmacists to dispense
Vimovo:
Another key part of our commercial strategy is to encourage physicians to
have their patients agree to fill prescriptions through our PrescriptionsMade-Easy (PME) [mail-order] specialty pharmacy program . . . .
[P]rescriptions filled through our PME program are . . . less likely to be
subject to the efforts of traditional pharmacies to switch a physicians
intended prescription of our products to a generic or over the counter
brand.
(Ex. 1022 at 5.) Horizon admits that sales of Vimovo may suffer [i]f we are
unsuccessful in convincing physicians to complete prescriptions through our PME
program or otherwise provide prescribing instructions prohibiting the substitution
of . . . generic naproxen and branded Nexium (esomeprazole) as a substitute.
(Ex. 1022, at 17 (emphasis added).) This is a common strategy when APIs are not
themselves patent worthy. (Ex. 1003, 40.) Nonetheless, by virtue of obtaining
the 907 Patent, Pozen and its affiliates have succeeded, thus far, in extending a

IPR2015-01241
Patent 6,926,907
monopoly on a long-known combination that should be available to the public.
(Id.)
The rewards for such an extension are considerable. Indeed, on January 1,
2014, the first day Horizon sold Vimovo, Horizon increased the list price for 60
Vimovo tablets to $959.04, or $15.98 per tablet, a 597% increase. (Wall Street
Journal (Ex. 1024).) On January 1, 2015, Horizon again increased the list price for
60 tablets, this time to $1,678.32, or $27.97 per tablet. (Id.) Currently, Vimovo
can be purchased for $26.46 per tablet. (Ex. 1003, 41.) In contrast, a similar
dosage of the two APIs of Vimovoesomeprazole magnesium and naproxen
can be purchased without a prescription for under $1.00 total. (Id.) In other
words, for the same APIs, the public must pay 30-40 times more for Vimovo.
Despite this enormous pricing disparity, Horizon has announced that it may effect
further price increases for [Vimovo] in 2015 and future periods in response to
future market conditions. (Ex. 1022, at 17.)
B.

Person of Ordinary Skill in the Art (POSA)

The field of the 907 Patent is pharmacology. (Ex. 1003, 52-53.) A POSA
in that field at the time of the alleged invention of the 907 Patent, presumably
June 1, 2001, would have been a pharmacist, medical doctor, or pharmaceutical
scientist having a doctor of medicine degree, a doctor of pharmacy degree, or a
Ph.D. degree, or equivalent training or degree, and at least two years of practical

IPR2015-01241
Patent 6,926,907
experience or clinical research in pharmaceutical formulations. (Id.)
Alternatively, a POSA at the time of the alleged invention would have been a
pharmacologist or pharmacokineticist having a Ph.D. degree or equivalent training
or degree and at least two years of practical experience or clinical research in
pharmacology or pharmacokinetics. (Id.)
VI.

Claim Construction
A.

Unit Dosage Form

Claims 1, 4, 6, 12, 14, and 21 include the phrase unit dosage form. (Ex.
1001 col. 20 ll. 9-32, 39-41, 46-49, col. 21 ll. 1-10, 14-19, 39-40.) As issued,
claim 1 uses the phrase unit dose form, but corrects that phrase to unit dosage
form in a Certificate of Correction. (Id. at col. 20 l. 9; Certificate of Correction
(Ex. 1028) at 1.) The specification defines unit dosage form as a single entity
for drug administration. (Ex. 1001 col. 3 ll. 60-61.) Thus, the broadest
reasonable interpretation of unit dosage form in light of the specification of the
907 Patent means a single entity for drug administration. (Ex. 1003, 55.)
B.

Acid Inhibitor

Claims 1, 2, 5, 12, 14, 15, and 18 use the phrase acid inhibitor. (Ex. 1001
col. 20 ll. 12, 28, 34, 43, col. 21, ll. 9, 16, 18, 29.) The specification does not
explicitly define acid inhibitor but does state, [t]he term acid inhibitor refers
to agents that inhibit gastric acid secretion and increase gastric pH. (Ex. 1001 col.

10

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Patent 6,926,907
3 ll. 26-28.) In the context of claims 1, 2, 5, 12, 14, 15, and 18, as well as the
specification of the 907 Patent, the broadest reasonable interpretation of acid
inhibitor means an agent that hinders, prevents, or reduces the amount of gastric
acid. (Ex. 1003, 56.) Furthermore, under the broadest reasonable interpretation
in light of the specification of the 907 Patent, the acid inhibitor would include
prostaglandins, H2 blockers, and PPIs. (Id.)
C.

Coordinated Release

Claim 1 includes the phrase coordinated release. (Ex. 1001 col. 20 ll. 20-21.)
The specification equates a coordinated release with a sequential release:
All of the dosage forms are designed for oral delivery and provide for the
coordinated release of therapeutic agents, i.e., for the sequential release of
acid inhibitor followed by analgesic.
(Id. at col. 5 ll. 16-19.) Thus, the broadest reasonable interpretation of
coordinated release in light of the specification of the 907 Patent means
sequential release. (Ex. 1003, 57.)
D.

All Remaining Terms

Per 37 C.F.R. 42.100(b), all remaining terms in claims 1-23 should be given
[their] broadest reasonable construction in light of the specification.

11

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VII. Ground 1: Gimet in View of Chiverton Renders Obvious Claims 1, 7, 8,
12, 13, 22, and 23
A.

A POSA Would Have Combined Chiverton with Gimet

Gimet teaches a unit dosage form suitable for oral administration that
comprises an NSAID and an acid inhibitor (e.g. misoprostol), wherein the NSAID
is present in an enterically-coated core and the acid inhibitor is present in a mantle
coating surrounding the enterically-coated core. (Ex. 1003, 64.) In considering
the dosage and therapeutic effect upon administration of the acid inhibitor (e.g.,
misoprostol) present in the unit dosage form, a known method would be to look to
related literature studying the therapeutic effect of the particular drug (e.g.,
misoprostol) to provide predictable results related to administering the drug. (Id.)
Thus, a POSA would have been motivated to look to clinical studies showing
results of misoprostol on gastric acid pH such as those shown in Chiverton to
provide predictable results of an increase of gastric acid pH associated with the
administration of the known acid inhibitor, misoprostol. (Id.)
B.

Claim 1:

Gimet in view of Chiverton discloses each limitation of claim 1 as follows.


1.

A pharmaceutical composition in unit dosage form suitable for


oral administration to a patient, comprising:

Gimet discloses this limitation. (Ex. 1003, 66.) Specifically, Gimet discloses
[t]he invention herein is directed to a pharmaceutical composition which is a

12

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core/mantle tablet and [a] method of treating inflammation comprising orally
administering to a patient . . . . (Ex. 1004, col. 3 ll. 8-14, col. 12 ll. 41-44; Ex.
1003, 67-68.)
2.

(a) an acid inhibitor present in an amount effective to raise the


gastric pH of said patient to at least 3.5 upon the administration
of one or more of said unit dosage forms;

Gimet in view of Chiverton discloses this limitation. (Ex. 1003, 69.)


Specifically, Gimet discloses that [s]urrounding the core is a mantle coating
which consists of a prostaglandin. (Ex. 1004, col. 3 ll. 8-14; Ex. 1003, 70.)
Gimet also discloses that the prostaglandin can be administered for its beneficial
therapeutic value in preventing and or inhibiting the incidence of NSAID induced
ulcers. (Ex. 1004, col. 12 ll. 14-19; Ex. 1003, 70.) Gimet further discloses that
the prostaglandin can be misoprostol . . . in an amount from about 50 to about 500
mcg. (Ex. 1004, col. 6 l. 20; Ex. 1003, 70.)
Gimet provides a POSA with a rationale (e.g., a specific teaching, suggestion,
and motivation) for a combination therapy, coordinated release, oral unit dosage
form comprising a prostaglandin as an acid inhibitor, e.g., misoprostol from about
50 to about 500 mcg per dose, and an NSAID, e.g., piroxicam. (Ex. 1003, 7172.) A POSA would have understood that a gastric acid inhibitor would be
expected, upon administration, to have a therapeutic effect on gastric pH. (Ex.
1003, 72.) Furthermore, the POSA would have understood that the therapeutic

13

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effect on gastric pH for a dosage of from about 50 to about 500 mcg of misoprostol
could be readily determined by referencing prior art clinical studies such as
Chiverton. (Ex. 1003, 73.) Chiverton discloses that [m]isoprostol is a
prostaglandin E1 analogue that acts primarily through its antisecretory activity.
(Ex. 1007, at 404; Ex. 1003, 71.) Chiverton further discloses that misoprostol
can be dosed in an amount effective to raise gastric pH to at least 3.5. (Ex. 1007,
at 406, Fig. 2, Table 1; Ex. 1003, 71.) A POSA would have known that
misoprostol is a potent inhibitor of gastric acid secretion that can maintain
gastric pH at 4.0 or higher. (Ex. 1003, 74-75.)
3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in an


amount effective to reduce or eliminate pain or inflammation in
said patient upon administration of one or more of said unit
dosage forms;

Gimet discloses this limitation. (Ex. 1003, 76.) Specifically, Gimet discloses
[i]f the inner core is piroxicam, the piroxicam can be present in a therapeutically
acceptable amount. (Ex. 1004, col. 4 ll. 34-39; Ex. 1003, 77.) Gimet discloses
that piroxicam is an NSAID. (Ex. 1004, col. 6 ll. 26-27; Ex. 1003, 77.) Gimet
further discloses that [t]he composition . . . provides an ease of delivery of an
NSAID for its therapeutic value such as the alleviation of inflammation. (Ex.
1004, col. 12 ll. 9-14; Ex. 1003, 77.)
4.

and wherein said unit dosage form provides for coordinated


release such that: i) said NSAID is surrounded by a coating

14

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that, upon ingestion of said unit dosage form by said patient,
prevents the release of essentially any NSAID from said dosage
form unless the pH of the surrounding medium is 3.5 or higher;
Gimet discloses this limitation. (Ex. 1003, 78.) Specifically, Gimet discloses
a tablet 16 that includes an NSAID inner core 18 surrounded by an enteric coating
20, the latter of which aids in segregating the NSAID from the prostaglandin and
in directing the dissolution of the NSAID core in the lower G.I. tract as opposed to
the stomach. (Ex. 1004, col. 6 ll. 24-36, Fig. 2; Ex. 1003, 79.)
A POSA would understand that a typical purpose associated with enteric
coatings is to delay release of an enterically-coated drug until after the drug has
exited the stomach. Also, the POSA would know that a typical patient would have
a pH in the small intestine after exiting the stomach of greater than about 3.5. (Ex.
1003, 80.) Thus, the POSA would have a rationale and a reasonable expectation
of success in preparing a combination therapy, coordinated release, unit dosage
form having a delayed release component, for example an enterically-coated drug
(e.g., NSAID) to prevent the release of the drug from the dosage form unless the
pH of the surrounding medium (e.g., portions of the G.I. tract after exiting the
stomach) is 3.5 or higher. (Ex. 1003, 81-82.)
5.

ii) at least a portion of said acid inhibitor is not surrounded by


an enteric coating and, upon ingestion of said unit dosage form
by said patient, is released regardless of whether the pH of the
surrounding medium is below 3.5 or above 3.5.

Gimet discloses this limitation. (Ex. 1003, 83.) Specifically, Gimet discloses
15

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Patent 6,926,907
that the mantle 22 consist[s] of a prostaglandin, which is orally available. (Ex.
1004, col. 1 l. 66 col. 2 l. 3 and col. 6 ll. 24-44; Ex. 1003, 84.)

(Ex. 1004, Fig. 2.) There is nothing, including an enteric coating, surrounding the
prostaglandin. (Ex. 1003, 84.) This means that the prostaglandin (i.e., the acid
inhibitor) is released immediately due to its direct contact with stomach fluids.
(Ex. 1003, 85.) In contrast to enteric coatings, a POSA would have understood
that a given dosage form may employ an uncoated drug and/or a drug coated with
non-enteric coatings, and that, following administration, such formulations may
release their drug quickly upon contact with the surrounding medium (e.g., about
immediate release upon entering the stomach). (Ex. 1003, 86.) Thus, the POSA
would have a rationale and a reasonable expectation of success in preparing a
combination therapy unit dosage form having an immediate release component, for
example an uncoated drug (e.g., acid inhibitor) and/or drug coated with a nonenteric coating that releases regardless of the pH of the surrounding medium. (Ex.
1003, 87.)

16

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C.

Claim 7: The pharmaceutical composition of claim 1, wherein said


NSAID is a cyclooxygenese-2 (COX-2) inhibitor.

As discussed above, Gimet in view of Chiverton renders claim 1 obvious.


Gimet further discloses this limitation of claim 7. (Ex. 1003, 88.) Specifically,
Gimet discloses that the inner core is piroxicam. (Ex. 1004, col. 4 ll. 34-39; Ex.
1003, 89.) Gimet discloses that piroxicam is an NSAID. (Ex. 1004, col. 6 ll. 2627; Ex. 1003, 89.) Piroxicam is a COX-2 inhibitor. (Ex. 1003, 89.)
Furthermore, claim 8 indicates that piroxicam is a COX-2 inhibitor.
D.

Claim 8: The pharmaceutical composition of claim 7, wherein said


COX-2 inhibitor is selected from the group consisting of celecoxib;
rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib,
CS-502, JTE-522; L-745,337; and NS398.

As discussed above, Gimet in view of Chiverton renders claim 1 obvious, and


Gimet renders claim 7 obvious. Gimet further discloses this limitation of claim 8.
(Ex. 1003, 90.) Specifically, Gimet discloses that the inner core is piroxicam.
(Ex. 1004, col. 4 ll. 34-39; Ex. 1003, 91.)
E.

Claim 12:

As discussed above, Gimet in view of Chiverton renders claim 1 obvious.


Gimet further discloses each limitation of claim 12.
1.

The pharmaceutical composition of claim 1 wherein said unit


dosage form is a multilayer tablet comprising

Gimet discloses this limitation. (Ex. 1003, 93.) Specifically, Gimet discloses
that the pharmaceutical composition is a core/mantle tablet. (Ex. 1004, col. 3 ll. 817

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Patent 6,926,907
14; Ex. 1003, 94.)
2.

a single core and one or more layers outside of said single core,
wherein:

Gimet discloses this limitation. (Ex. 1003, 95.) Specifically, Gimet discloses
that [s]urrounding the coated inner core is a mantle 22 consisting of a
prostaglandin. (Ex. 1004, col. 6 ll. 24-44, Fig. 2; Ex. 1003, 96.)
3.

i) said NSAID is present in said core;

Gimet discloses this limitation. (Ex. 1003, 97.) Specifically, Gimet discloses
that the inner core is piroxicam. (Ex. 1004, col. 4 ll. 34-49; Ex. 1003, 98.)
4.

ii) said coating that does not release said NSAID unless the pH
of the surrounding medium is 3.5 or higher surrounds said
core; and

As discussed above with respect to claim 1, Gimet discloses this limitation.


(Ex. 1003, 99.) Specifically, Gimet discloses that the enteric coating aids in
segregating the NSAID from the prostaglandin and in directing the dissolution of
the NSAID core in the lower G.I. tract as opposed to the stomach. (Ex. 1004, col.
6 ll. 24-36; Ex. 1003, 100.)
A POSA would understand that a typical purpose associated with enteric
coatings is to delay release of an enterically-coated drug until after the drug has
exited the stomach. Also, the POSA would know that a typical patient would have
a pH in the small intestine after exiting the stomach of greater than about 3.5. (Ex.
1003, 101.) Thus, the POSA would have a rationale and a reasonable expectation
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of success in preparing a combination therapy, coordinated release, unit dosage
form having a delayed release component, for example an enterically-coated drug
(e.g., NSAID) to prevent the release of the drug from the dosage form unless the
pH of the surrounding medium (e.g., portions of the G.I. tract after exiting the
stomach) is 3.5 or higher. (Ex. 1003, 102.)
5.

iii) said acid inhibitor is in said one more layers outside said
core.

Gimet discloses this limitation. (Ex. 1003, 103.) Specifically, Gimet


discloses that [s]urrounding the coated inner core is a mantle 22 consisting of a
prostaglandin. (Ex. 1004, col. 6 ll. 24-44, Fig. 2; Ex. 1003, 104.)
F.

Claim 13: The pharmaceutical composition of claim 12, wherein said


one or more layers outside of said core do not contain NSAID and
are not surrounded by an enteric coating.

As discussed above, Gimet in view of Chiverton renders claim 1 obvious, and


Gimet discloses each limitation of claim 12. Gimet further discloses this limitation
of claim 13. (Ex. 1003, 105.) Specifically, Gimet discloses that the mantle 22
consist[s] of a prostaglandin, which is orally available. (Ex. 1004, col. 1 ll. 66
col. 2 l. 3 and col. 6 ll. 24-44; Ex. 1003, 106.) There is nothing, including an
enteric coating, surrounding the prostaglandin. (Ex. 1003, 106-07.)
G.

Claim 22:

Gimet in view of Chiverton discloses each limitation of claim 22.

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1.

A method of treating a patient for pain or inflammation,


comprising

Gimet discloses this limitation. (Ex. 1003, 109.) Specifically, Gimet


discloses [a] method of treating inflammation comprising orally administering to
a patient . . . . (Ex. 1004, 12 ll. 41-44; Ex. 1003, 110.)
2.

administering to said patient the pharmaceutical composition of


any one of claims 1-14.

Gimet discloses this limitation. (Ex. 1003, 111.) Specifically, Gimet


discloses [a] method of treating inflammation comprising orally administering to
a patient . . . . (Ex. 1004, 12 ll. 41-44; Ex. 1003, 112.) As discussed above,
Gimet in view of Chiverton discloses and renders obvious the pharmaceutical
composition of claim 1. (Ex. 1003, 112.)
H.

Claim 23: The method of claim 22, wherein said pain or


inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Gimet in view of Chiverton renders claim 22 obvious.


Gimet further discloses this limitation of claim 23. (Ex. 1003, 113.)
Specifically, Gimet discloses that [n]onsteroidal anti-inflammatory drugs
(NSAIDs) . . . have long been recognized as having high therapeutic value
especially for the treatment of inflammatory conditions such as . . . osteoarthritis
(OA) and rheumatoid arthritis (RA). (Ex. 1004, col. 1 ll. 18-23.) Gimet further
discloses piroxicam be administered in a single daily dose of 20 mg for
rheumatoid arthritis and osteoarthritis. (Ex. 1004, col. 4 ll. 34-39; Ex. 1003,
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114.)
VIII. Ground 2: Gimet in View of Goldman in Further View of Remington
Renders Obvious Claims 1-5 and 7-23
A.

A POSA Would Have Combined Goldman, Remington and Gimet

Both Gimet and Goldman are directed to pharmaceutical compositions


comprising an NSAID and an acid inhibitor, and a POSA tasked with formulating
an NSAID/acid inhibitor combination therapy would have considered their
collective teachings on the subject. (Ex. 1003, 117.) For example, the POSA
would have substituted the NSAIDs and acid inhibitors in Gimet for other known
NSAIDs and acid inhibitors in Goldman to obtain predictable results; alternatively,
it would have been obvious to try Goldmans NSAIDs and acid inhibitors with
Gimets tablets; alternatively, Gimet has a teaching, suggestion, or motivation to
be combined with Goldman. (Id.) A POSA would have substituted Gimets
prostaglandin with Goldmans H2 blockers or PPIs to obtain predictable results of
inhibiting gastric acid, particularly since Gimet discloses that [w]hile
prostaglandins are beneficial compounds and have found therapeutic usage,
prostaglandins are generally considered highly unstable. (Ex. 1004, col. 1 ll. 5153; Ex. 1003, 119.) Goldman discloses acid inhibitors other than the unstable
prostaglandins, namely H2 blockers and PPIs, that are more efficacious. (Ex.
1005, col. 5 ll. 64-65; Ex. 1003, 119.) Moreover, a POSA would have
substituted Gimets NSAID, diclofenac, with Goldmans NSAID, naproxen, to
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obtain the predictable analgesic effect of said NSAIDs. (Ex. 1003, 120.) It
would have been obvious for a POSA to choose from those identified solutions and
have a reasonable expectation of success in treating pain, inflammation, and other
symptoms with an NSAID while preventing or reducing the undesirable side
effects of the NSAID. (Ex. 1003, 121.) Furthermore, Goldman provides the
POSA with a specific teaching, suggestion, and motivation to look to conventional
techniques for preparing medicament tablets as set forth in Remington and further
incorporates by reference the disclosure of Remington (Ex. 1005, 122.), thereby
providing a design incentive to prepare or improve tablets via known techniques
including enteric and non-enteric coatings to yield predictable results. (Ex. 1005,
col. 6 ll. 26-33; Ex. 1006, at 1604, 1633; Ex. 1003, 122.)
B.

Claim 1:

Gimet in view of Goldman in further view of Remington discloses each


limitation of claim 1.
1.

A pharmaceutical composition in unit dosage form suitable for


oral administration to a patient, comprising:

Gimet discloses this limitation. (Ground 1 at VII(B)(1); Ex. 1003, 124-26.)


2.

(a) an acid inhibitor present in an amount effective to raise the


gastric pH of said patient to at least 3.5 upon the administration
of one or more of said unit dosage forms;

Gimet discloses this limitation. (Ground 1 at VII(B)(2); Ex. 1003, 127-28.)


A POSA would know that a typical patient would have a pH in the stomach in a
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range of from about 1.5 to about 3.5, and the POSA would know that the typical
therapeutic effect of known acid inhibitors is to increase the gastric pH of the
patient following administration thereof. (Ex. 1003, 130.) Thus, the POSA
would have a rationale and reasonable expectation of success in preparing a
combination therapy unit dosage form having an effective amount of a known acid
inhibitor to raise the gastric pH of a patient to at least 3.5 upon the administration
of one or more unit dosage forms containing the known acid inhibitor. (Ex. 1003,
131.) Further, due to the claim language of one or more of said unit dosage
forms, multiple dosage forms may be administered to achieve the desired effect.
(Ex. 1003, 133.) Thus, the POSA would have a rationale and a reasonable
expectation of success in providing the appropriate dose, including administration
of multiple dosage forms, as needed, to raise the pH to a desired level consistent
with pharmacological effects associated with the known acid inhibitor. (Id.)
3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in an


amount effective to reduce or eliminate pain or inflammation in
said patient upon administration of one or more of said unit
dosage forms;

Gimet discloses this limitation. (Ground 1 at VII(B)(3); Ex. 1003, 134-35.)


4.

and wherein said unit dosage form provides for coordinated


release such that: i) said NSAID is surrounded by a coating
that, upon ingestion of said unit dosage form by said patient,
prevents the release of essentially any NSAID from said dosage
form unless the pH of the surrounding medium is 3.5 or higher;

Gimet discloses this limitation. (Ground 1 at VII(B)(4); Ex. 1003, 136-41.)


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5.

ii) at least a portion of said acid inhibitor is not surrounded by


an enteric coating and, upon ingestion of said unit dosage form
by said patient, is released regardless of whether the pH of the
surrounding medium is below 3.5 or above 3.5.

Gimet discloses this limitation. (Ground 1 at VII(B)(5); Ex. 1003, 142-46.)


C.

Claim 2: The pharmaceutical composition of claim 1, wherein said


acid inhibitor is an H2 blocker.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious. Gimet in view of Goldman further discloses this
limitation of claim 2. (Ex. 1003, 147.) Specifically, Goldman discloses a
composition containing an H2 blocker such as famotidine. (Ex. 1005, col. 5 ll. 2530; Ex. 1003, 148.) A POSA would have been motivated to combine Goldman
with Gimet as described above. (Ex. 1003, 149.) Furthermore, a POSA would
have been motivated to replace Gimets prostaglandin with Goldmans H2 blocker
because doing so would be a substitution of one known element for another to
obtain predictable results. (Ex. 1003, 150.)
D.

Claim 3: The pharmaceutical composition of claim 2, wherein said


H2 blocker is selected from the group consisting of: cimetidine;
ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and
famotidine.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious, and Gimet in view of Goldman renders claim 2 obvious.
Gimet in view of Goldman further discloses this limitation of claim 3. (Ex. 1003,
151.) Specifically, Goldman discloses a composition containing an H2 blocker
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such as famotidine. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 152.) A POSA would
have been motivated to combine Goldman with Gimet as described above. (Ex.
1003, 154.) Furthermore, a POSA would have been motivated to replace
Gimets prostaglandin with Goldmans famotidine because doing so would be a
substitution of one known element for another to obtain predictable results. (Ex.
1003, 155.)
E.

Claim 4: The pharmaceutical composition of claim 3, wherein said


H2 blocker is famotidine, present in said unit dosage form in an
amount of between 5 mg and 100 mg.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious, and Gimet in view of Goldman renders claims 2 and 3
obvious. Gimet in view of Goldman further discloses this limitation of claim 4.
(Ex. 1003, 156.) Specifically, Goldman discloses a composition containing an
H2 blocker such as famotidine from 5 to 40 mg per dose. (Ex. 1005, col. 5 ll.
25-30; Ex. 1003, 157.) A POSA would have been motivated to combine
Goldman with Gimet as described above. (Ex. 1003, 158.) Furthermore, a
POSA would have been motivated to replace Gimets prostaglandin with
Goldmans famotidine in the disclosed amount because doing so would be a
substitution of one known element for another to obtain predictable results and
because, as shown in Goldman, 5 mg to 40 mg was a known therapeutic dosage
range for famotidine. (Ex. 1003, 159.)

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F.

Claim 5: The pharmaceutical composition of claim 1, wherein said


acid inhibitor is a proton pump inhibitor selected from the group
consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole
and rabeprazole.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious. Gimet in view of Goldman further discloses this
limitation of claim 5. (Ex. 1003, 160.) Specifically, Goldman discloses a
composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll. 29-31; Ex.
1003, 161.) A POSA would have been motivated to combine Goldman with
Gimet as described above. (Ex. 1003, 163.) Furthermore, a POSA would have
been motivated to replace Gimets prostaglandin with Goldmans PPI omeprazole
because doing so would be a substitution of one known element for another to
obtain predictable results. (Ex. 1003, 164.)
G.

Claim 7: The pharmaceutical composition of claim 1, wherein said


NSAID is a cyclooxygenese-2 (COX-2) inhibitor.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious. Gimet further discloses this limitation of claim 7.
(Ground 1 at VII(C); Ex. 1003, 165-66.)
H.

Claim 8: The pharmaceutical composition of claim 7, wherein said


COX-2 inhibitor is selected from the group consisting of celecoxib;
rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib,
CS-502, JTE-522; L-745,337; and NS398.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1 and 7 obvious. Gimet further discloses this limitation of claim 8.
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(Ground 1 at VII(D); Ex. 1003, 167-69.)
I.

Claim 9: The pharmaceutical composition of claim 1, wherein said


NSAID is selected from the group consisting of: aspirin;
acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam;
naproxen; oxaprozin; etodolac; indomethacin; ketorolac; and
nabumetone.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious. Gimet in view of Goldman further discloses this
limitation of claim 9. (Ex. 1003, 170.) Specifically, Goldman discloses a
composition containing an NSAID such as naproxen. (Ex. 1005, col. 5 ll. 17-20;
Ex. 1003, 171.) A POSA would have been motivated to combine Goldman with
Gimet as described above. (Ex. 1003, 173.) Furthermore, a POSA would have
been motivated to replace Gimets NSAID with Goldmans NSAID, naproxen,
because doing so would be a substitution of one known element for another to
obtain predictable results. (Ex. 1003, 173-74.)
J.

Claim 10: The pharmaceutical composition of claim 9, wherein said


NSAID is naproxen present in an amount of between 50 mg and
1500 mg.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious, and Gimet in view of Goldman renders claim 9 obvious.
Gimet in view of Goldman further discloses this limitation of claim 10. (Ex. 1003,
175.) Specifically, Goldman discloses a composition containing an NSAID such
as naproxen from 200 to 500 mg per dose. (Ex. 1005, col. 5 ll. 17-20; Ex. 1003,

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176.) A POSA would have been motivated to combine Goldman with Gimet as
described above. (Ex. 1003, 177.) Furthermore, a POSA would have been
motivated to replace Gimets NSAID with Goldmans NSAID, naproxen, in the
disclosed amount because doing so would be a substitution of one known element
for another to obtain predictable results and because, as shown in Goldman, 200
mg to 500 mg was a known therapeutic dosage range for naproxen. (Ex. 1003,
178.)
K.

Claim 11: The pharmaceutical composition of claim 10, wherein said


naproxen is present in an amount of between 200 mg and 600 mg.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious, and Gimet in view of Goldman renders claims 9 and 10
obvious. Gimet in view of Goldman further discloses this limitation of claim 11.
(Ex. 1003, 179.) Specifically, Goldman discloses a composition containing an
NSAID such as naproxen from 200 to 500 mg per dose. (Ex. 1005, col. 5 ll. 1720; Ex. 1003, 180.) A POSA would have been motivated to combine Goldman
with Gimet as described above. (Ex. 1003, 181.) Furthermore, a POSA would
have been motivated to replace Gimets NSAID with Goldmans NSAID,
naproxen, in the disclosed amount because doing so would be a substitution of one
known element for another to obtain predictable results and because, as shown in
Goldman, 200 mg to 500 mg was a known therapeutic dosage range for naproxen.

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(Ex. 1003, 182.)
L.

Claim 12:

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious. Gimet further discloses each limitation of claim 12.
1.

The pharmaceutical composition of claim 1 wherein said unit


dosage form is a multilayer tablet comprising

Gimet discloses this limitation. (Ground 1 at VII(E)(1); Ex. 1003, 184-85.)


2.

a single core and one or more layers outside of said single core,
wherein:

Gimet discloses this limitation. (Ground 1 at VII(E)(2); Ex. 1003, 186-87.)


3.

i) said NSAID is present in said core;

Gimet discloses this limitation. (Ground 1 at VII(E)(3); Ex. 1003, 188-89.)


4.

ii) said coating that does not release said NSAID unless the pH
of the surrounding medium is 3.5 or higher surrounds said
core; and

Gimet discloses this limitation. (Ground 1 at VII(E)(4); Ex. 1003, 190-94.)


5.

iii) said acid inhibitor is in said one more layers outside said
core.

Gimet discloses this limitation. (Ground 1 at VII(E)(5); Ex. 1003, 195-96.)


M.

Claim 13: The pharmaceutical composition of claim 12, wherein said


one or more layers outside of said core do not contain NSAID and
are not surrounded by an enteric coating.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1 and 12 obvious. Gimet further discloses this limitation of claim

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13. (Ground 1 at VII(F); Ex. 1003, 197-99.)
N.

Claim 14:

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1, 12, and 13 obvious. Gimet in view of Remington further
discloses each limitation of claim 14.
1.

The pharmaceutical composition of claim 13, wherein said unit


dosage form is a bilayer tablet having an outer layer of said
acid inhibitor and an inner core of said NSAID and

Remington discloses this limitation. (Ex. 1003, 201.) Specifically,


Remington discloses various conventional techniques for preparing medicament
tablets or caplets. (Ex. 1006, at 1603-32; Ex. 1003, 202.) Remington discloses
that the tablets can be used to give a simple repeat-action effect where
unprotected drug coated over the enteric coat is released in the stomach, while the
remainder, being protected by the coating, is released further down the
gastrointestinal tract. (Ex. 1006, at 1637; Ex. 1003, 202.) A POSA would
understand Remingtons quoted description to refer to a bilayer tablet. (Ex. 1003,
203.) A POSA faced with a common task such as manufacturing a combination
therapy oral dosage form comprising known ingredients would have a rationale
(e.g. motivation) and a reasonable expectation of success in consulting one or more
reputable reference publications, such as Remington, providing conventional
techniques to perform the task. (Ex. 1003, 204.) Furthermore, Goldman

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provides a POSA with a rationale, e.g., a specific teaching, suggestion and
motivation, to look to conventional techniques for preparing medicament tablets as
set forth in Remington and further incorporates by reference the disclosure of
Remington. (Ex. 1003, 202.)
2.

wherein said outer layer of said tablet is surrounded by a nonenteric film coating that releases said acid inhibitor upon
ingestion by patient.

Remington discloses this limitation. (Ex. 1003, 205.) Specifically,


Remington discloses that the tablets can include film coating that imparts the
same general characteristics as sugar coating, namely to protect the drug from its
surrounding environment and increase the ease by means of which the product
can be ingested. (Ex. 1006, at 1604; Ex. 1003, 206.) Furthermore, a POSA
would understand Remingtons cited description to refer to a non-enteric film
coating that releases said acid inhibitor upon ingestion by the patient. (Ex. 1003,
207.) In addition, a POSA would have been motivated to prepare Gimets tablets
as described in Remington for the reasons described above, including to protect
Gimets tablets from the environment. (Ex. 1003, 208.)
O.

Claim 15: The pharmaceutical composition of any one of claims 1 or


7-14, wherein said acid inhibitor is a proton pump inhibitor.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious, and Gimet in view of Goldman renders claim 9 obvious.
Gimet in view of Goldman further discloses this limitation of claim 15. (Ex. 1003,
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209.) Specifically, Goldman discloses a composition containing a PPI such as
omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 210.) A POSA would have
been motivated to combine Goldman with Gimet as described above. (Ex. 1003,
211.) Furthermore, a POSA would have been motivated to replace Gimets
prostaglandin with Goldmans PPI because doing so would be a substitution of one
known element for another to obtain predictable results. (Ex. 1003, 212.)
P.

Claim 16:

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1 and 12 obvious. Gimet in view of Goldman and in further view of
Remington further discloses each limitation of claim 16.
1.

The pharmaceutical composition of any one of claims 12-14,


wherein said acid inhibitor is a proton pump inhibitor and

Goldman discloses this limitation. (Ex. 1003, 214.) Specifically, Goldman


discloses a composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll.
9-31; Ex. 1003, 215.) A POSA would have been motivated to combine Goldman
with Gimet as described above. (Ex. 1003, 216.) Furthermore, a POSA would
have been motivated to replace Gimets prostaglandin with Goldmans PPI
because doing so would be a substitution of one known element for another to
obtain predictable results. (Ex. 1003, 217.)

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2.

wherein said coating surrounding said core does not dissolve


unless the pH of the surrounding medium is 4 or greater.

Remington discloses this limitation. (Ex. 1003, 218.) Specifically,


Remington discloses the following:
By definition, enteric coatings are those which remain intact in the stomach
. . . to delay the release of drugs which . . . may cause nausea or bleeding
by irritating the gastric mucosa . . . Thus, many modern enteric coatings are
those which remain undissociated in the low pH environment of the
stomach, but readily ionize when the pH rises to about 4 or 5.
(Ex. 1006, at 1637; Ex. 1003, 219.) A POSA would understand this to mean that
enteric coating surrounding the NSAID does not ionize until it is subjected to an
environment having a pH of about 4 or 5. (Ex. 1003, 220.) Furthermore, a
POSA would have been motivated to prepare Gimets tablets as described in order
to allow release of the acid inhibitor in the small intestine, where acid inhibitors are
more effectively absorbed. (Ex. 1003, 221-22.)
Q.

Claim 17:

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1 and 12 obvious. Gimet in view of Goldman and in further view of
Remington further discloses each limitation of claim 17.
1.

The pharmaceutical composition of any one of claims 12-14,


wherein said acid inhibitor is a proton pump inhibitor and

Goldman discloses this limitation. (Ex. 1003, 224.) Specifically, Goldman

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discloses a composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll.
9-31; Ex. 1003, 225.) A POSA would have been motivated to combine Goldman
with Gimet as described above. (Ex. 1003, 226.) Furthermore, a POSA would
have been motivated to replace Gimets prostaglandin with Goldmans PPI
because doing so would be a substitution of one known element for another to
obtain predictable results. (Ex. 1003, 227.)
2.

wherein said coating surrounding said core does not dissolve


unless the pH of the surrounding medium is 5 or greater.

Remington discloses this limitation. (Ex. 1003, 228.) Specifically,


Remington discloses the following:
By definition, enteric coatings are those which remain intact in the stomach
. . . to delay the release of drugs which . . . may cause nausea or bleeding
by irritating the gastric mucosa . . . Thus, many modern enteric coatings are
those which remain undissociated in the low pH environment of the
stomach, but readily ionize when the pH rises to about 4 or 5.
(Ex. 1006, at 1637; Ex. 1003, 229.) A POSA would understand this to mean that
enteric coating surrounding the NSAID does not ionize until it is subjected to an
environment having a pH of 5. (Ex. 1003, 230.) Furthermore, a POSA would
have been motivated to prepare Gimets tablets as described in order to allow
release of the acid inhibitor in the small intestine, where acid inhibitors are more
effectively absorbed. (Ex. 1003, 231-32.)

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R.

Claim 18: The pharmaceutical composition of any one of claims 714, wherein said acid inhibitor is an H2 blocker.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious, and Gimet in view of Goldman renders claim 9 obvious.
Gimet in view of Goldman further discloses this limitation of claim 18. (Ex. 1003,
233.) Specifically, Goldman discloses a composition containing an H2 blocker
such as famotidine. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 234.) A POSA would
have been motivated to combine Goldman with Gimet as described above. (Ex.
1003, 235.) Furthermore, a POSA would have been motivated to replace
Gimets prostaglandin with Goldmans H2 blocker because doing so would be a
substitution of one known element for another to obtain predictable results. (Ex.
1003, 236.)
S.

Claim 19:

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1 and 12 obvious. Gimet in view of Goldman further discloses each
limitation of claim 19.
1.

The pharmaceutical composition of any one of claims 12-14,


wherein said acid inhibitor is an H2 blocker and

Goldman discloses this limitation. (Ex. 1003, 238.) Specifically, Goldman


discloses a composition containing an H2 blocker such as famotidine or a PPI such
as omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 239.) A POSA would have

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been motivated to combine Goldman with Gimet as described above. (Ex. 1003,
240.) Furthermore, a POSA would have been motivated to replace Gimets
prostaglandin with Goldmans H2 blocker because doing so would be a
substitution of one known element for another to obtain predictable results. (Ex.
1003, 241.)
2.

wherein said tablet has an inner core of said NSAID


surrounded by a barrier coating that dissolves at a rate such
that said NSAID is not released until the pH of the surrounding
medium is 4 or greater.

Gimet discloses this limitation. (Ex. 1003, 242.) Specifically, Gimet


discloses a tablet 24 consist[ing] of an inner core 26 comprising an NSAID and
[s]urrounding the core 26 is an undercoat 28 . . . [that] can be any suitable coating
material and preferably is HPMC. (Ex. 1004, col. 6 ll. 45-54; Ex. 1003, 243.)
A POSA would have understood that the timed-release provided by an HPMC
coating would give Gimets unit dose, as modified by Goldman, enough time to
travel far enough along the G.I. tract so as to reach the small intestine, where the
pH of the surrounding medium would be 4 or greater. (Ex. 1003, 244.) Thus,
Gimets NSAID would not be released until the pH of the surrounding medium
was 4 or greater. (Ex. 1003, 245-47.)
T.

Claim 20:

As discussed above, Gimet in view of Goldman in further view of Remington


renders claims 1 and 12 obvious. Gimet in view of Goldman further discloses each
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limitation of claim 20.
1.

The pharmaceutical composition of any one of claims 12-14,


wherein said acid inhibitor is an H2 blocker and

Goldman discloses this limitation. (Ex. 1003, 249.) Specifically, Goldman


discloses a composition containing an H2 blocker such as famotidine or a PPI such
as omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 250.) A POSA would have
been motivated to combine Goldman with Gimet as described above. (Ex. 1003,
251.) Furthermore, a POSA would have been motivated to replace Gimets
prostaglandin with Goldmans H2 blocker because doing so would be a
substitution of one known element for another to obtain predictable results. (Ex.
1003, 252.)
2.

wherein said tablet has an inner core of said NSAID


surrounded by a barrier coating that dissolves at a rate such
that said NSAID is not released until the pH of the surrounding
medium is 5 or greater.

Gimet discloses this limitation. (Ex. 1003, 253.) Specifically, Gimet


discloses a tablet 24 consist[ing] of an inner core 26 comprising an NSAID and
[s]urrounding the core 26 is an undercoat 28 . . . [that] can be any suitable coating
material and preferably is HPMC. (Ex. 1004, col. 6 ll. 45-54; Ex. 1003, 254.)
A POSA would have understood that the timed-release provided by an HPMC
coating would give Gimets unit dose, as modified by Goldman, enough time to
travel far enough along the G.I. tract so as to reach the small intestine, where the

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pH of the surrounding medium would be 5 or greater. (Ex. 1003, 255.) Thus,
Gimets NSAID would not be released until the pH of the surrounding medium
was 5 or greater. (Ex. 1003, 256-58.)
U.

Claim 21: The pharmaceutical composition of claim 1, wherein said


unit dosage form is a capsule.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 1 obvious. Gimet in view of Goldman further discloses this
limitation of claim 21. (Ex. 1003, 259.) Specifically, Goldman discloses
[v]arious other dosage forms can be applied herein such as a filled gelatin
capsule. (Ex. 1005, col. 7 ll. 57-59; Ex. 1003, 260.) A POSA would have been
motivated to combine Goldman with Gimet as described above. (Ex. 1003, 261.)
Furthermore, a POSA would have been motivated to replace Gimets tablets with
Goldmans capsules because doing so would be a substitution of one known
element for another to obtain predictable results. (Ex. 1003, 262.)
V.

Claim 22:

Gimet in view of Goldman in further view of Remington discloses each


limitation of claim 22 as follows.
1.

A method of treating a patient for pain or inflammation,


comprising

Gimet discloses this limitation. (Ground 1 at VII(G)(1); Ex. 1003, 264-65.)

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2.

administering to said patient the pharmaceutical composition of


any one of claims 1-14.

Gimet discloses this limitation. (Ground 1 at VII(G)(2); Ex. 1003, 266-67.)


W.

Claim 23: The method of claim 22, wherein said pain or


inflammation is due to either osteoarthritis or rheumatoid arthritis.

As discussed above, Gimet in view of Goldman in further view of Remington


renders claim 22 obvious. Gimet further discloses this limitation of claim 23.
(Ground 1 at VII(H); Ex. 1003, 268-270.)
IX.

Ground 3: Goldman in View of Remington in Further View of Abe


Renders Obvious Claims 1-5, 7-18, 21, and 22
A.

A POSA Would Have Combined Remington, Abe, and Goldman

Goldman teaches a unit dosage form suitable for oral administration that
comprises an NSAID and an acid inhibitor (e.g., an H2 receptor blocker such as
famotidine). (Ex. 1003, 273.) In considering the dosage and therapeutic effect
upon administration of the acid inhibitor (e.g., famotidine) present in the unit
dosage forms of Goldman, a known method would be to look to related literature
studying the therapeutic effect of the particular drug (e.g., famotidine) to provide
predictable results related to selecting and administering the drug. (Ex. 1003,
274.) Thus, a POSA would have been motivated to look to clinical studies
showing results of famotidine on gastric acid pH such as those shown in Abe to
provide predictable results of an increase in gastric acid pH associated with the
administration of the known acid inhibitor, famotidine. (Ex. 1003, 275.)
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Furthermore, Goldman provides the POSA with a specific teaching,
suggestion, and motivation to look to conventional techniques for preparing
medicament tablets as set forth in Remington and further incorporates by reference
the disclosure of Remington, thereby providing a design incentive to prepare or
improve tablets via known techniques including enteric and non-enteric coatings to
yield predictable results. (Ex. 1005, col. 6 ll. 26-33; Ex. 1006, at 1604, 1633; Ex.
1003, 276.)
B.

Claim 1:

Goldman in view of Remington in further view of Abe discloses each


limitation of claim 1.
1.

A pharmaceutical composition in unit dosage form suitable for


oral administration to a patient, comprising:

Goldman discloses this limitation. (Ex. 1003, 278.) Specifically, Goldman


discloses the oral administration of one tablet of [a] pharmaceutical composition.
(Ex. 1005, col. 8 ll. 4-7; Ex. 1003, 279.)
2.

(a) an acid inhibitor present in an amount effective to raise the


gastric pH of said patient to at least 3.5 upon the administration
of one or more of said unit dosage forms;

Goldman in view of Abe discloses this limitation. (Ex. 1003, 281.)


Specifically, Goldman discloses a composition containing an H2 blocker such as
famotidine or a PPI such as omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003,
282.) Accordingly, Goldman provides a POSA with a rationale, e.g., a specific
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teaching, suggestion and motivation, for a combination therapy oral unit dosage
form comprising an H2 receptor blocking drug as an acid inhibitor, for example
famotidine from 5 to 40 mg per dose. (Ex. 1003, 283.) The POSA would
understand that a gastric acid inhibitor would be expected upon administration to
have a therapeutic effect on gastric pH. (Ex. 1003, 284.) Furthermore, the
POSA would understand that the therapeutic effect on gastric pH for the 5 to 40
mg of famotidine could be readily determined by referencing prior art clinical
studies such as Abe. (Ex. 1003, 285.)
Abe discloses that famotidine can be dosed in an amount effective to raise
gastric pH to at least 3.5. (Ex. 1039, at 541-43, Table 2, Ex. 1003, 286.) Abe
further discloses that [t]he mean gastric pH in the famotidine-treated groups was
in the range of 5.7-7.2, which indicates that the drug effectively decreased gastric
secretion. (Ex. 1039, at 543, Ex. 1003, 287-88.)
3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in an


amount effective to reduce or eliminate pain or inflammation in
said patient upon administration of one or more of said unit
dosage forms;

Goldman discloses this limitation. (Ex. 1003, 289.) Specifically, Goldman


discloses a composition containing one of several NSAIDs, which are
commonly used for the treatment of pain and inflammation. (Ex. 1005, col. 4 ll.
28-30, col. 5 ll. 9-23; Ex. 1003, 290.)

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4.

and wherein said unit dosage form provides for coordinated


release such that: i) said NSAID is surrounded by a coating
that, upon ingestion of said unit dosage form by said patient,
prevents the release of essentially any NSAID from said dosage
form unless the pH of the surrounding medium is 3.5 or higher;

Goldman in view of Remington discloses this limitation. (Ex. 1003, 291.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington (Ex. 1006), which Goldman incorporates by reference. (Ex. 1005, col.
6 ll. 26-33; Ex. 1003, 292.) Goldman provides the following:
Various conventional techniques for preparing medicament tablets or
caplets can be employed as would be known to those skilled in the art as is
disclosed for example by [Remington]. The disclosure of this reference is
hereby incorporated herein by reference.
(Ex. 1005, col. 6 ll. 26-33.) A POSA faced with a common task such as
manufacturing a combination therapy oral dosage form comprising known
ingredients would have a rationale (e.g., motivation) and a reasonable expectation
of success in consulting one or more reputable reference publications such as
Remington providing conventional techniques to perform the task. (Ex. 1003,
293.) Furthermore, Goldman provides a POSA with a rationale, e.g., a specific
teaching, suggestion and motivation, to look to conventional techniques for
preparing medicament tablets as set forth in Remington and further incorporates by
reference the disclosure of Remington. (Ex. 1003, 294.) Remington expressly
discloses the following:
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By definition, enteric coatings are those which remain intact in the stomach
. . . to delay the release of drugs which . . . may cause nausea or bleeding
by irritating the gastric mucosa . . . Thus, many modern enteric coatings are
those which remain undissociated in the low pH environment of the
stomach, but readily ionize when the pH rises to about 4 or 5.
(Ex. 1006, at 1637.) Thus, Remington teaches that the acid inhibitor of Goldman
is released first in the low pH of the stomach and that the release of the NSAID
does not occur until after the enteric coating has ionized at a pH of about 4 or 5.
(Ex. 1006, at 1637; Ex. 1003, 296-97.)
5.

ii) at least a portion of said acid inhibitor is not surrounded by


an enteric coating and, upon ingestion of said unit dosage form
by said patient, is released regardless of whether the pH of the
surrounding medium is below 3.5 or above 3.5.

Goldman in view of Remington discloses this limitation. (Ex. 1003, 298.)


As discussed above, Goldman incorporates Remington by reference. (Ex. 1005,
col. 6 ll. 26-33; Ex. 1003, 299.) Remington discloses that unprotected drug
coated over the enteric coat is released in the stomach, while the remainder, being
protected by the coating, is released further down the gastrointestinal tract. (Ex.
1006, at 1637; Ex. 1003, 300.) In contrast to enteric coatings, a POSA would
have understood that a given dosage form may employ an uncoated drug and/or a
drug coated with non-enteric coatings, and that, following administration, such
formulations may release their drug quickly upon contact with the surrounding

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medium (e.g., about immediate release upon entering the stomach). (Ex. 1003,
301.) Thus, the POSA would have a rationale and a reasonable expectation of
success in preparing a combination therapy unit dosage form having an immediate
release component, for example an uncoated drug (e.g., acid inhibitor) and/or drug
coated with a non-enteric coating that releases regardless of the pH of the
surrounding medium. (Ex. 1003, 302.)
C.

Claim 2: The pharmaceutical composition of claim 1, wherein said


acid inhibitor is an H2 blocker.

As discussed above, Goldman in view of Remington in further view of Abe


renders claim 1 obvious. Goldman further discloses this limitation of claim 2.
(Ex. 1003, 303.) Specifically, Goldman discloses a composition containing an
H2 blocker such as famotidine. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 303.)
D.

Claim 3: The pharmaceutical composition of claim 2, wherein said


H2 blocker is selected from the group consisting of: cimetidine;
ranitidine; ebrotidine; pabutidine; lafutidine; loxtidine and
famotidine.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 2 obvious. Goldman further discloses this limitation of claim
3. (Ex. 1003, 304.) Specifically, Goldman discloses a composition containing an
H2 blocker such as famotidine. (Ex. 1005, col. 5 ll. 25-30; Ex. 1003, 304.)

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E.

Claim 4: The pharmaceutical composition of claim 3, wherein said


H2 blocker is famotidine, present in said unit dosage form in an
amount of between 5 mg and 100 mg.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1, 2, and 3 obvious. Goldman further discloses this limitation of
claim 4. (Ex. 1003, 306.) Specifically, Goldman discloses a composition
containing an H2 blocker such as famotidine from 5 to 40 mg per dose. (Ex.
1005, col. 5 ll. 25-30; Ex. 1003, 307.)
F.

Claim 5: The pharmaceutical composition of claim 1, wherein said


acid inhibitor is a proton pump inhibitor selected from the group
consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole
and rabeprazole.

As discussed above, Goldman in view of Remington in further view of Abe


renders claim 1 obvious. Goldman further discloses this limitation of claim 5.
(Ex. 1003, 308.) Specifically, Goldman discloses a composition containing a PPI
such as omeprazole. (Ex. 1005, col. 5 ll. 29-31; Ex. 1003, 309.)
G.

Claim 7: The pharmaceutical composition of claim 1, wherein said


NSAID is a cyclooxygenese-2 (COX-2) inhibitor.

As discussed above, Goldman in view of Remington in further view of Abe


renders claim 1 obvious. Goldman further discloses this limitation of claim 7.
(Ex. 1003, 311.) Specifically, Goldman discloses a composition containing an
NSAID such as piroxicam. (Ex. 1005, col. 5 ll. 22-24; Ex. 1003, 312.)
Piroxicam is a COX-2 inhibitor. (Ex. 1003, 313.) Furthermore, claim 8 indicates

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that piroxicam is a COX-2 inhibitor.
H.

Claim 8: The pharmaceutical composition of claim 7, wherein said


COX-2 inhibitor is selected from the group consisting of celecoxib;
rofecoxib; meloxicam; piroxicam; valdecoxib, parecoxib, etoricoxib,
CS-502, JTE-522; L-745,337; and NS398.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 7 obvious. Goldman further discloses this limitation of claim
8. (Ex. 1003, 314.) Specifically, Goldman discloses a composition containing an
NSAID such as piroxicam. (Ex. 1005, col. 5 ll. 22-24; Ex. 1003, 315.)
I.

Claim 9: The pharmaceutical composition of claim 1, wherein said


NSAID is selected from the group consisting of: aspirin;
acetaminophen; ibuprofen; flurbiprofen; ketoprofen; lornoxicam;
naproxen; oxaprozin; etodolac; indomethacin; ketorolac; and
nabumetone.

As discussed above, Goldman in view of Remington in further view of Abe


renders claim 1 obvious. Goldman further discloses this limitation of claim 9.
(Ex. 1003, 317.) Specifically, Goldman discloses a composition containing an
NSAID such as naproxen. (Ex. 1005, col. 5 ll. 17-20; Ex. 1003, 318.)
J.

Claim 10: The pharmaceutical composition of claim 9, wherein said


NSAID is naproxen present in an amount of between 50 mg and
1500 mg.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 9 obvious. Goldman further discloses this limitation of claim
10. (Ex. 1003, 320.) Specifically, Goldman discloses a composition containing
an NSAID such as naproxen from 200 to 500 mg per dose. (Ex. 1005, col. 5 ll.
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17-20; Ex. 1003, 321.)
K.

Claim 11: The pharmaceutical composition of claim 10, wherein said


naproxen is present in an amount of between 200 mg and 600 mg.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1, 9, and 10 obvious. Goldman further discloses this limitation of
claim 11. (Ex. 1003, 322.) Specifically, Goldman discloses a composition
containing an NSAID such as naproxen from 200 to 500 mg per dose. (Ex.
1005, col. 5 ll. 17-20; Ex. 1003, 323.)
L.

Claim 12:

As discussed above, Goldman in view of Remington in further view of Abe


renders claim 1 obvious. Goldman in view of Remington further discloses each
limitation of claim 12.
1.

The pharmaceutical composition of claim 1 wherein said unit


dosage form is a multilayer tablet comprising

Goldman in view of Remington discloses this limitation. (Ex. 1003, 325.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 26-33;
Ex. 1003, 326.) Remington discloses that the tablets can be used to give a
simple repeat-action effect where unprotected drug coated over the enteric coat is
released in the stomach, while the remainder, being protected by the coating, is
released further down the gastrointestinal tract. (Ex. 1006, at 1637; Ex. 1003,

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327.)
2.

a single core and one or more layers outside of said single core,
wherein:

Goldman in view of Remington discloses this limitation. (Ex. 1003, 328.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 26-33;
Ex. 1003, 329.) Remington discloses that the tablets can be used to give a
simple repeat-action effect where unprotected drug coated over the enteric coat is
released in the stomach, while the remainder, being protected by the coating, is
released further down the gastrointestinal tract. (Ex. 1006, at 1637; Ex. 1003,
330.) Thus, Remingtons cited description refers to the disclosed remainder of the
drug being the claimed single core and the disclosed unprotected drug being the
claimed one or more layers outside of said single core. (Ex. 1003, 331.)
3.

i) said NSAID is present in said core;

Goldman in view of Remington discloses this limitation. (Ex. 1003, 332.)


Specifically, Goldman discloses that the tablets can include an NSAID and be
prepared as described in Remington, which Goldman incorporates by reference.
(Ex. 1005, col. 6 ll. 9-33; Ex. 1003, 333.) Remington discloses that the tablets
can contain an inner, protected drug (for example, aspirin, an NSAID), which is
covered by an enteric coating and then an outer, unprotected drug. (Ex. 1006, at
1637; Ex. 1003, 334.) Thus, Remingtons cited description refers to the
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disclosed remainder of the drug being the claimed NSAID present in said core.
(Ex. 1003, 335.)
4.

ii) said coating that does not release said NSAID unless the pH
of the surrounding medium is 3.5 or higher surrounds said
core; and

Goldman in view of Remington discloses this limitation. (Ex. 1003, 336.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 26-33;
Ex. 1003, 337.) Remington discloses the following:
By definition, enteric coatings are those which remain intact in the stomach
. . . to delay the release of drugs which . . . may cause nausea or bleeding
by irritating the gastric mucosa . . . Thus, many modern enteric coatings are
those which remain undissociated in the low pH environment of the
stomach, but readily ionize when the pH rises to about 4 or 5.
(Ex. 1006, at 1637.) Thus, Remington teaches that the acid inhibitor of Goldman
is released first in the low pH of the stomach and that the release of the NSAID
does not occur until after the enteric coating has ionized at a pH of about 4 or 5.
(Ex. 1006, at 1637; Ex. 1003, 338-40.)
5.

iii) said acid inhibitor is in said one more layers outside said
core.

Goldman in view of Remington discloses this limitation. (Ex. 1003, 341.)


Specifically, Goldman discloses that the tablets can include an H2 blocker or a PPI,
i.e., an acid inhibitor, Ex. 1005, col. 5 ll. 9-31, and be prepared as described in
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Remington, which Goldman incorporates by reference. (Ex. 1005, col. 5 ll. 9-31;
Ex. 1003, 342.) Remington discloses that the tablets can contain an outer,
unprotected drug. (Ex. 1006, at 1637; Ex. 1003, 343.) Thus, Remingtons cited
description refers to the disclosed unprotected drug being the claimed acid
inhibitor in said one more layers outside said core. (Ex. 1003, 344.)
M.

Claim 13: The pharmaceutical composition of claim 12, wherein said


one or more layers outside of said core do not contain NSAID and
are not surrounded by an enteric coating.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 12 obvious. Goldman in view of Remington further discloses
this limitation of claim 13. (Ex. 1003, 345.) Specifically, Goldman discloses
that the tablets can include an NSAID and be prepared as described in Remington,
which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 9-33; Ex. 1003,
346.) Remington discloses that the tablets can contain an inner, protected drug (for
example, aspirin, an NSAID), which is covered by an enteric coating and then an
outer, unprotected drug. (Ex. 1006, at 1637; Ex. 1003, 347.) Goldman further
discloses that the tablets can include an H2 blocker or a PPI. (Ex. 1005, col. 5 ll.
9-31; Ex. 1003, 348.) Because the NSAID is the inner, protected drug, the H2
blocker or PPI would be the outer, unprotected drug and thus in the claimed one
more layer outside of said core. (Ex. 1003, 349.) Nowhere does Goldman
indicate that the disclosed outer, unprotected drug contains an NSAID. (Ex. 1003,

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350.) Also, because the outer drug is unprotected, it can be deemed not to be
surrounded by an enteric coating. (Ex. 1003, 351.)
N.

Claim 14:

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1, 12, and 13 obvious. Goldman in view of Remington further
discloses each limitation of claim 14.
1.

The pharmaceutical composition of claim 13, wherein said unit


dosage form is a bilayer tablet having an outer layer of said
acid inhibitor and an inner core of said NSAID and

Goldman in view of Remington discloses this limitation. (Ex. 1003, 354.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 9-33;
Ex. 1003, 355.) Remington discloses that the tablets can be used to give a
simple repeat-action effect where unprotected drug coated over the enteric coat is
released in the stomach, while the remainder, being protected by the coating, is
released further down the gastrointestinal tract. (Ex. 1006, at 1637; Ex. 1003,
356.) Thus, Remingtons cited description refers to a bilayer tablet. (Ex. 1003,
357-59.)
2.

wherein said outer layer of said tablet is surrounded by a nonenteric film coating that releases said acid inhibitor upon
ingestion by patient.

Goldman in view of Remington discloses this limitation. (Ex. 1003, 360.)

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Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 26-33;
Ex. 1003, 361.) Remington discloses that the tablets can include film coating
that imparts the same general characteristics as sugar coating, namely to protect
the drug from its surrounding environment and increase the ease by means of
which the product can be ingested. (Ex. 1006, at 1604, 1633; Ex. 1003, 362.)
Thus, Remingtons cited description refers to a non-enteric film coating that
releases said acid inhibitor upon ingestion by the patient. (Ex. 1003, 363-65.)
O.

Claim 15: The pharmaceutical composition of any one of claims 1 or


7-14, wherein said acid inhibitor is a proton pump inhibitor.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 9 obvious. Goldman further discloses this limitation of claim
15. (Ex. 1003, 366.) Specifically, Goldman discloses a composition containing a
PPI such as omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003, 367.)
P.

Claim 16:

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 12 obvious. Goldman in view of Remington further discloses
each limitation of claim 16.
1.

The pharmaceutical composition of any one of claims 12-14,


wherein said acid inhibitor is a proton pump inhibitor and

Goldman discloses this limitation. (Ex. 1003, 369.) Specifically, Goldman

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discloses a composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll.
9-31; Ex. 1003, 370.)
2.

wherein said coating surrounding said core does not dissolve


unless the pH of the surrounding medium is 4 or greater.

Goldman in view of Remington discloses this limitation. (Ex. 1003, 371.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 26-33;
Ex. 1003, 372.) Remington discloses the following:
By definition, enteric coatings are those which remain intact in the stomach
. . . to delay the release of drugs which . . . may cause nausea or bleeding
by irritating the gastric mucosa . . . Thus, many modern enteric coatings are
those which remain undissociated in the low pH environment of the
stomach, but readily ionize when the pH rises to about 4 or 5.
(Ex. 1006, at 1637; Ex. 1003, 373.) Thus, Remington teaches that an enteric
coating surrounding the core could be employed which does not dissolve until the
pH in the GI tract is 5. (Ex. 1003, 373-75.)
Q.

Claim 17:

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 12 obvious. Goldman further discloses each limitation of
claim 17.

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1.

The pharmaceutical composition of any one of claims 12-14,


wherein said acid inhibitor is a proton pump inhibitor and

Goldman discloses this limitation. (Ex. 1003, 377.) Specifically, Goldman


discloses a composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll.
9-31; Ex. 1003, 378.)
2.

wherein said coating surrounding said core does not dissolve


unless the pH of the surrounding medium is 5 or greater.

Goldman in view of Remington discloses this limitation. (Ex. 1003, 379.)


Specifically, Goldman discloses that the tablets can be prepared as described in
Remington, which Goldman incorporates by reference. (Ex. 1005, col. 6 ll. 26-33;
Ex. 1003, 380.) Remington discloses the following:
By definition, enteric coatings are those which remain intact in the stomach
. . . to delay the release of drugs which . . . may cause nausea or bleeding
by irritating the gastric mucosa . . . Thus, many modern enteric coatings are
those which remain undissociated in the low pH environment of the
stomach, but readily ionize when the pH rises to about 4 or 5.
(Ex. 1006, at 1637; Ex. 1003, 381.) Thus, Remington teaches that an enteric
coating surrounding the core could be employed which does not dissolve until the
pH in the GI tract is 5. (Ex. 1003, 382-83.)
R.

Claim 18: The pharmaceutical composition of any one of claims 714, wherein said acid inhibitor is an H2 blocker.

As discussed above, Goldman in view of Remington in further view of Abe


renders claims 1 and 9 obvious. Goldman further discloses this limitation of claim
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18. (Ex. 1003, 384.) Specifically, Goldman discloses a composition containing
an H2 blocker such as famotidine or a PPI such as omeprazole. (Ex. 1005, col. 5
ll. 9-31; Ex. 1003, 385.)
S.

Claim 21: The pharmaceutical composition of claim 1, wherein said


unit dosage form is a capsule.

As discussed above, Goldman in view of Remington in further view of Abe


renders claim 1 obvious. Goldman further discloses this limitation of claim 21.
(Ex. 1003, 386.) Specifically, Goldman discloses [v]arious other dosage forms
can be applied herein such as a filled gelatin capsule. (Ex. 1005, col. 7 ll. 57-59;
Ex. 1003, 387.)
T.

Claim 22:

Goldman discloses each limitation of claim 22 as follows.


1.

A method of treating a patient for pain or inflammation,


comprising

Goldman discloses this limitation. (Ex. 1003, 389.) Specifically, Goldman


discloses [a] method of treating the symptoms of overindulgence and [t]he
symptoms of overindulgence include . . . abdominal pain. (Ex. 1005, col. 1 ll. 2736; Ex. 1003, 390.)
2.

administering to said patient the pharmaceutical composition of


any one of claims 1-14.

Goldman discloses this limitation. (Ex. 1003, 391.) Specifically, Goldman


discloses [a] method of treating the symptoms of overindulgence . . . comprising
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administering to a patient suffering from the symptoms of over- overindulgence a
combination pharmaceutical composition comprising a therapeutically effective
amount of an analgesic and a gastric acid inhibiting effective amount of a proton
pump inhibitor wherein the therapeutically effective amount of analgesic is . . .
naproxen from 200 to 500 mg per dose . . . in combination with an effective
amount of a proton pump inhibitor selected from the group consisting of
omeprazole from 60 to 500 mg per dose . . . . (Ex. 1005, col. 9 ll. 6-27; Ex. 1003,
392.)
X.

Ground 4: Goldman in View of Remington in Further View of Fitton


Renders Obvious Claims 1, 5, and 6
A.

A POSA Would Have Combined Remington, Fitton, and Goldman

Goldman teaches a unit dosage form suitable for oral administration that
comprises an NSAID and an acid inhibitor (e.g., a PPI such as omeprazole). In
evaluating performance of the dosage form, a POSA would have been motivated to
look to clinical studies showing results of omeprazole on gastric acid pH such as
those shown in Fitton. (Ex. 1003, 395-96.) In considering Fittons clinical
studies, a POSA also would have seen comparative results (e.g., a comparison of
omeprazole and pantoprazole) that provide a motivation and reasonable
expectation of success to substitute pantoprazole for omeprazole in the
formulations of Goldman. (Ex. 1003, 397.) Furthermore, as noted previously for
Ground 3, the POSA further would have been motivated to employ conventional
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techniques for preparing medicament tablets as set forth in Remington. (Ex. 1003,
398.)
B.

Claim 1:

Goldman in view of Remington in further view of Fitton discloses each


limitation of claim 1.
1.

A pharmaceutical composition in unit dosage form suitable for


oral administration to a patient, comprising:

Goldman discloses this limitation. (Ground 3 at IX(B)(1); Ex. 1003, 40002.)


2.

(a) an acid inhibitor present in an amount effective to raise the


gastric pH of said patient to at least 3.5 upon the administration
of one or more of said unit dosage forms;

Goldman in view of Fitton discloses this limitation. (Ex. 1003, 403.)


Specifically, Goldman discloses a composition containing an H2 blocker such as
famotidine or a PPI such as omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex. 1003,
404.) Accordingly, Goldman provides the POSA with a rationale (e.g., a specific
teaching, suggestion and motivation) for a combination therapy oral unit dosage
form comprising a proton pump inhibitor (PPI) as an acid inhibitor, for example
omeprazole from 60 to 500 mg per dose. (Ex. 1003, 405.) The POSA would
recognize that PPIs are a well-known class of drugs that provide gastric acid
inhibiting efficacy, and therefore the POSA would have a rationale (e.g.,
motivation) and a reasonable expectation of success in substituting individual
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compounds within the PPI class in a given formulation. Further, the POSA tasked
with evaluating and selecting individual compounds from the known drug class
(e.g., PPIs) would be readily motivated to reference prior art clinical studies such
as Fitton. (Ex. 1003, 406-07.) Fitton discloses that 40 mg of omeprazole would
raise the median 24h intragastric pH to 4.0. Ex. 1048, at 467,Table I; Ex. 1003,
408.) Thus, a POSA would have understood that increasing the dose to 60 mg of
omeprazole would raise the median 24h intragastric pH to 4.0 or higher. (Ex.
1048, at 467,Table I; Ex. 1003, 409-10.)
3.

(b) a non-steroidal anti-inflammatory drug (NSAID) in an


amount effective to reduce or eliminate pain or inflammation in
said patient upon administration of one or more of said unit
dosage forms;

Goldman discloses this limitation. (Ground 3 at IX(B)(3); Ex. 1003, 41112.)


4.

and wherein said unit dosage form provides for coordinated


release such that: i) said NSAID is surrounded by a coating
that, upon ingestion of said unit dosage form by said patient,
prevents the release of essentially any NSAID from said dosage
form unless the pH of the surrounding medium is 3.5 or higher;

Goldman in view of Remington discloses this limitation. (Ground 3 at


IX(B)(4); Ex. 1003, 413-419.)

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5.

ii) at least a portion of said acid inhibitor is not surrounded by


an enteric coating and, upon ingestion of said unit dosage form
by said patient, is released regardless of whether the pH of the
surrounding medium is below 3.5 or above 3.5.

Goldman in view of Remington discloses this limitation. (Ground 3 at


IX(B)(5); Ex. 1003, 420-24.)
C.

Claim 5: The pharmaceutical composition of claim 1, wherein said


acid inhibitor is a proton pump inhibitor selected from the group
consisting of: omeprazole, esomeprazole, lansoprazole, pantoprazole
and rabeprazole.

As discussed above, Goldman in view of Remington in further view of Fitton


renders claim 1 obvious. Goldman in view of Fitton further discloses this
limitation of claim 5. (Ex. 1003, 425.) Specifically, Goldman discloses a
composition containing a PPI such as omeprazole. (Ex. 1005, col. 5 ll. 9-31; Ex.
1003, 426.) Goldman in view of Fitton also discloses this limitation of claim 5.
(Ex. 1003, 428.) Specifically, Fitton discloses that [p]antoprazole. . . is an
irreversible proton pump inhibitor. (Ex. 1048, at 465; Ex. 1003, 429.) Goldman
provides a POSA with a rationale (e.g., a specific teaching, suggestion and
motivation) for a combination therapy oral unit dosage form comprising a proton
pump inhibitor (PPI) as an acid inhibitor, for example omeprazole from 60 to 500
mg per dose. (Ex. 1003, 430.) The POSA would have recognized that PPIs are a
well-known class of drugs that provide gastric acid inhibiting efficacy, and
therefore the POSA would have a motivation and a reasonable expectation of

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Patent 6,926,907
success in substituting individual compounds within the PPI class in a given
formulation. (Ex. 1003, 431.) Further, the POSA tasked with evaluating and
selecting individual compounds from the known drug class (e.g., PPIs) would be
motivated to reference prior art clinical studies such as Fitton. (Ex. 1003, 432.)
D.

Claim 6: The pharmaceutical composition of claim 5, wherein said


proton pump inhibitor is pantoprazole, present in said unit dosage
form in an amount of between 10 mg and 200 mg.

As discussed above, Goldman in view of Remington in further view of Fitton


renders claims 1 and 5 obvious. Goldman in view of Fitton further discloses this
limitation of claim 6. (Ex. 1003, 433.) Specifically, Fitton discloses that
[p]antoprazole. . . is an irreversible proton pump inhibitor. (Ex. 1048, at 465;
Ex. 1003, 434.) Fitton further discloses that [o]ral pantoprazole 40mg appears
to be more effective than omeprazole 20mg and as effective as omeprazole 40mg
in inhibiting gastric acid secretion in healthy volunteers. (Ex. 1048, at 462; Ex.
1003, 435-37.)
XI.

Any Secondary Considerations of Nonobviousness Would Fail


CFAD is unaware of any evidence of secondary considerations of

nonobviousness in this case. (Ex. 1003, 439-48.)


XII. Conclusion
CFAD respectfully requests that the Board institute an Inter Partes Review of
claims 1-23 on the grounds set forth above.

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Date: May 21, 2015

Respectfully submitted,

/Amy E. LaValle/
Amy E. LaValle (Reg. No. 51,092)
Jerry C. Harris, Jr. (Reg. No. 66,822)
Rodney B. Carroll (Reg. No. 39,624)
Conley Rose, P.C.
5601 Granite Parkway, Suite 500
Plano, Texas 75024
(972) 731-2288 (phone)
(972) 731-2289 (fax)
alavalle@conleyrose.com
jcharris@conleyrose.com
rcarroll@conleyrose.com
Counsel for Petitioner
Coalition for Affordable Drugs VII LLC

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CERTIFICATE OF SERVICE
Pursuant to 37 C.F.R. 42.6(e), I hereby certify that on May 21, 2015 a copy
of the foregoing PETITION FOR INTER PARTES REVIEW was provided via
FedEx, overnight delivery, to the Patent Owner by serving the correspondence
address of record for the 907 Patent:
Steven L. Highlander
Parker Highlander PLLC
1120 South Capital of Texas Highway
Bldg. 1, Suite 200
Austin, Texas 78746

Date: May 21, 2015

/Amy E. LaValle/
Lead Counsel for Petitioner
Coalition for Affordable Drugs VII LLC

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