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Paper No.

______
Filed: September 2, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
___________________
COALITION FOR AFFORDABLE DRUGS (ADROCA) LLC
PETITIONER
V.
ACORDA THERAPEUTICS, INC.
PATENT OWNER
___________________
CASE NO.: UNASSIGNED
PATENT NO. 8,007,826
FILED: DECEMBER 13, 2004
ISSUED: AUGUST 30, 2011
INVENTORS: ANDREW R. BLIGHT, RON COHEN
TITLE: SUSTAINED RELEASE AMINOPYRIDINE COMPOSITION
___________________
PETITION FOR INTER PARTES REVIEW
OF U.S. PATENT NO. 8,007,826

Patent No. 8,007,826
TABLE OF CONTENTS
I.

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

II.

Grounds for Standing (37 C.F.R. § 42.104(a)) ................................................1

III.

Mandatory Notices (37 C.F.R. § 42.8) ............................................................1

A. Real Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) ...........................................1
B. Related Judicial and Administrative Matters (37 C.F.R. §
42.8(b)(2)) ......................................................................................................2
C. Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)) and Service
Information (37 C.F.R. § 42.8(b)(4)) .............................................................3
IV.

Payment of Fees (37 C.F.R. § 42.15(a) and § 42.103) ....................................4

V.

Identification of Challenge ..............................................................................4
A. Overview of U.S. Patent No. 8,007,826 .........................................................4
1.

The ’826 Patent Specification ....................................................................4

2.

The ’826 Claims .........................................................................................5

3.

Prosecution History of the ’826 Patent ......................................................7

B. Effective Priority Date of the ’826 Patent Claims .......................................11
C.

Level of Ordinary Skill in the Art ................................................................19

D. Claim Construction of Challenged Claims...................................................20
1.
E.

“to improve walking”...............................................................................21
Statement of Precise Relief Requested for Each Claim
Challenged ....................................................................................................21

1.

Claims for Which Review is Requested ..................................................21

2.

Statutory Grounds of Challenge ..............................................................21
i

Patent No. 8,007,826
Overview of the State of the Art and Prior Art References .........................22

F.

VI.

1.

History of 4-AP and State of the Art of the ’826 Patent..........................22

2.

The S-1 (Ex. 1003) ...................................................................................23

3.

Hayes (Ex. 1005) .....................................................................................28

Detailed Explanation of the Challenge ..........................................................30

A. 35 U.S.C. § 325(d) should not bar the petition ............................................30
1.

The present Petition presents a combination of art not
previously before the Office....................................................................30

2.

The present Petition presents grounds not previously addressed
by the P.T.A.B. ........................................................................................31

B.

Ground 1: Claims 1–3, 5–8, and 10–41 are obvious in light of the
S-1 in view of Hayes and the knowledge of a POSA. ..................................33
1.

Independent claims 1, 6, 11, 17, 31, and 36–37 are obvious in
light of the S-1 and Hayes combination and the knowledge of
a POSA. ...................................................................................................34
a. The S-1 and Hayes teach a method of “orally administering”
to a “human multiple sclerosis patient” a “sustained release
composition” of “10 milligrams of 4-aminopyridine” “twice
daily” (all independent claims). .............................................................35
b. The S-1 and Hayes teach administering the sustained release
4-AP composition “to improve walking” and for “increasing
walking speed” (all independent claims). ..............................................40
c. The S-1 and Hayes combination teaches the pharmacokinetic
limitations of all independent claims. ....................................................42
d. The S-1 and Hayes combination teaches administering 4-AP
for “for a day” followed by “maintaining administration;” “at
least two weeks;” and “greater than two weeks” (all
independent claims) ...............................................................................45
ii

.....51 d.....................57 VIII......54 f....... 32-35 and 38–41 are obvious in light of the S-1 in view of Hayes and the knowledge of a POSA........... Dependent claims 2–3........ 32........ and 10–41 .............. ......................................... 16. 38.....................007................................................ 18.. The S-1 and Hayes combination teaches administration of 4AP “without a… period of 4-aminopyridine titration” (claim 6).......................... ....... 12-16.................. and 40)..............56 VII.....48 2. The S-1 and Hayes combination teaches “[BID] administration or administration at 12-hour intervals” (claims 14....... 19............................. The S-1 and Hayes combination teaches the presence of a “pharmaceutically acceptable excipient” along with the 4-AP (claims 11 and 17)...................... and 38. 10.......................... The S-1 and Hayes combination teaches “the sustained release composition is a tablet” (claims 22.. 33 and 39.... The S-1 and Hayes combination teaches or suggests the “maintaining” and “time” periods of claims 20... and 12).......................53 e.............. 27..................................... 8........................ 28.. 15...................................................................... The S-1 and Hayes combination teaches “the sustained release composition further comprises a pharmaceutically acceptable excipient” (claims 5 and 10)........................ .. Any secondary considerations are insufficient to overcome the obviousness of Claims 1–3. 34........ 5............ and 41)..................................60 iii ............................ .......... ............................. Conclusion..............Patent No..... 5–8.. ...... 35...... 22–25...... 32.............. 8.................................................49 a...... .......................................... The S-1 and Hayes combination teaches “an increase in walking speed is obtained” (claims 2 and 7) and “an improvement in lower extremity muscle strength” (claims 3...49 b. 18-30..........50 c............826 e............... 7–8.............47 f. The S-1 and Hayes combination teaches the pharmacokinetic limitations of claims 13.. ... 29–30..................

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LEXIS 27435 (N................... Cir............ Dist................... Eagle Mfg...... Inc........ 2007)......... 506 F.............. Far-Mar-Co......C. 1994) .................. 772 F. Cir... Vermeer Mfg.T. 2015).............. v...............Patent No........................ Par Pharm. 642 F........ v....... Inc......S......................................... 2012). 1985)..C.. 2002)... 2012)............... § 119(e)(1) .... §§ 311–19 ............................A......13 Zenon Envtl..S.. Premier Election Solutions.......19 Santarus. 28 35 U... 698 F............ Ohio Sept.. 2003 U...3d 1374 (Fed.... v. Cir..............................1 vi ........ v.......24 Waldemar Link v..... 94 F............................. Paper 13 (P.S..... Cir... 32 F....... Cir...S.........3d 1370 (Fed..... 21.........42 Sentry Prot...S. Inc............ 24 35 U................. 2011)............ Prods.. 298 F.19 Statutes 35 U..........C. 21. Case IPR2014-01203...................... v....................826 New Railhead Mfg........ Osteonics Corp..... § 102(a) . January 25...... 2003 WL 25539702.........2d 1570 (Fed......2d 687 (Fed.............................. Filter Corp............................. 2003) ...................27 Tyco Healthcare Grp..............3d 1344 (Fed...............007........ 1:01-cv-2240... v............. 12.... L.... Inc....... 15 Ralston Purina Co....21 35 U.............L.... LP v. 36.................. Cir.....C... § 103 ......... § 102(b) ......C............3d 1370 (Fed...... 777 F.......... Mut.............. Co........................C............. 38 Tyler Refrig..................11 35 U.. Magna Electronics....26 Valeo North America.. No. 13..........3d 1290 (Fed........S.... 23. Inc..................... U... Inc..D....... Co.............. v........................... 30.. 8........................................... Corp.... Pharm......31 Voter Verified.......... Cir............B................. et al.. v....................... Inc............. Kysor Indus..............3d 556 (Fed...... Cir.................S..... 1985)........ Co............

...007......R...........F.....100 .. 8..........1 vii ...........826 Regulations 37 C..............Patent No................. §§ 42............................

Provisional Patent Application No.826 (filed Dec.826 Prosecution History (“’826 prosecution history”) – Part 1 Exhibit 1003 Acorda Therapeutics. 11. no. 8. 60/528. PlaceboControlled. 2004) (“’894 Provisional”) Exhibit 1008 Masterson et al.894 (filed Apr.007.. no. 2003-186 (Sept.Patent No.S.007. 2.540. The Effect of 4-Aminopyridine on the Clinical Signs in Multiple Sclerosis: A Randomized. 9. Formulations and Their Use in the Treatment of Neurological Diseases (filed Oct. Neurol. 30.826 TABLE OF EXHIBITS Exhibit No. 2004) (issued Aug. 24. Patent No.938. Quantitative Assessment of Sustained Release 4Aminopyridine for Symptomatic Treatment of Multiple Sclerosis.S. Registration Statement Under the Securities Act of 1933 (Form S-1) (Sept. 13.txt (“S-1 Registration Statement”) Exhibit 1005 Keith C. M. Blight & Ron Cohen. Inc. 5.. 8.. 8.S. 48 Neurol. Cross-over Study.gov/news/digest/dig093003... et al. 2003) (“S-1”) Exhibit 1004 Rules and Related Matters. Hayes et al. Pharmacokinetic Studies of Single and Multiple Oral Doses of Fampridine-SR (Sustained-Release 4Aminopyridine) in Patients With Chronic Spinal Cord Injury. 26 Clinical Neuropharmacology.. 4. 2003). 2011) (“the ’826 Patent”) Exhibit 1002 Relevant excerpts of U.760 (filed Dec. at 353–62 (1983) (“Jones”) Exhibit 1011 Harriët van Diemen. 60/560. available at http://www. Jones et al. Effects of 4-Aminopyridine in Patients with Multiple Sclerosis.. Description Exhibit 1001 Andrew R. 30. 1994) (“Masterson”) Exhibit 1009 Schwid et al. 1997) (“Schwid”) Exhibit 1010 Richard E. 1992) (“van Diemen”) viii . Provisional Patent Application No. at 185–92 (“Hayes”) Exhibit 1006 U. at 123–30 (Aug. 2003) (“’760 Provisional”) Exhibit 1007 U.sec.S. 2003. U. 60 J. 32 Annals Neurol.S. 26. no.007. at 817–21 (Apr. 4.D. Double-Blind. Patent No.. U. Sci. Patent No.

Placebo-Controlled Double-Blinded Dose Ranging Study of Fampridine-SR in Multiple Sclerosis.org/pub_releases/200207/pn-atb062802. 11. 4-Aminopyridine Improves Clinical Signs In Multiple Sclerosis. Davis...”) Exhibit 1017 C. Stefoski. at 1136–39 (“Polman”) Exhibit 1013 D. Nat. 18–21.. 2000. 4-Aminipyridine is Superior to 3..biospace. 2003) Exhibit 1020 Goodman et al. at 186–92 (Feb. Sep. Description Exhibit 1012 Chris H. Baltimore. 27 Annals Neurol. 1994. Orally Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis. M. poster presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). no.com/company_profile.D.4. Fampridine Acorda Therapeutics.php Exhibit 1019 Acorda Therapeutics Company Profile. at 71–77 (1987) (“Stefoski”) Exhibit 1014 Floyd A.eurekalert. 11.D. Abstract.aspx?CompanyId=100 704 (last updated May 9. 1990) (“Davis”) Exhibit 1015 Types of MS. 2.007.Patent No. 8.nationalmssociety. Acorda Therapeutics Begins Phase 3 Trials of Fampridine-SR for Chronic Spinal Cord Injury. no. no. Biospace. 2002. http://www... Darlington. M. Nov. PhD et al. 1. http://www. http://www. 3.826 Exhibit No.” 21 Annals Neurol. 2002). Nov. MD. Polman. MD (“Goodman”) ix . et al. American Association for the Advancement of Science (AAAS) EurekAlert! (July 1. et al. 51 Archives Neurol. 2015) (“NMSS”) Exhibit 1016 Declaration of Scott Bennett (“Bennett Decl. at 375–79 Exhibit 1018 Porter Novelli. Multiple Sclerosis Soc’y.diaminopyridine in the Treatment of Patients with Multiple Sclerosis. 1 Current Opinions in Investigational Drugs.org/What-is-MS/Types-of-MS (last visited Aug. no..

html -texts/html/epc/2010/e/ar54. Espacenet Brochure. Pleasure.epo. M. (2). Ph. no. filed with the EPO. Description Exhibit 1021 European Patent Convention art..D. 8. Attachment 7 Exhibit 1037 Bennett Decl.html (“EPC Art. European Patent No.D. Oct. Attachment 4 Exhibit 1034 Bennett Decl.epo.S. & Stephen C. 2000). Attachment 3 Exhibit 1033 Bennett Decl.D. 1 732 548 B9. available at http://www. Attachment 1 Exhibit 1031 Bennett Decl. Attachment 9 x .703 (B2) (“Espacenet 703 Data”) Exhibit 1029 CV of Scott Bennett Exhibit 1030 Bennett Decl. Attachment 2 Exhibit 1032 Bennett Decl. 5. Pleasure. (“Pleasure Decl.826 Exhibit No. (“Pleasure CV”) Exhibit 1025 European Patent No. 2004 (“Acorda EP Brief”) Exhibit 1027 European Patent Office.Patent No. 54”) Exhibit 1022 Fred D.pdf (“Espacenet Brochure”) Exhibit 1028 Espacenet Bibliographic Data for US Patent No.. M.. 199 (as amended Nov.org/projects/babylon/eponet. http://documents. Ph. September 16. M. Lublin. Reingold Ph. 8. 1065 U.T.nsf/0/4E8744EB 66E8F944C12577D600598EEF/$File/espacenet_brochure_en. 54(1).org/law-practice/legaltexts/html/epc/2010/e/ar54. 1996) (“Lublin”) Exhibit 1023 Declaration of Samuel J. 29. 4.440.N. 1 732 548 (B9) (“EP 548”) Exhibit 1026 Excerpts from Proprietor’s Response to Opponents’ Appeals. Attachment 5 Exhibit 1035 Bennett Decl. Attachment 6 Exhibit 1036 Bennett Decl. Attachment 8 Exhibit 1038 Bennett Decl. Defining the Clinical Course of Multiple Sclerosis: Results of an International Survey.”) Exhibit 1024 CV of Samuel J.007. at 907–11 (Apr. 46 Neurology.D. 1973.D.D.

S. 1994. 1054 Neurology No. U.S.D. at 1430–38 (Nov.. 2000) Exhibit 1041 Timed 25-Foot Walk (T25-FW). 2001 Exhibit 1040 Christian Confavreux. 15. 60/528. Nat’l Multiple Sclerosis Soc’y Website. Double-Blind.org/ForProfessionals/Researchers/Resources-for-Researchers/ClinicalStudy-Measures/Timed-25-Foot-Walk-(T25-FW) (last visited Aug. Bever.593 (filed Dec. et al. 8. Concentration-Controlled. Jun. Patent No. Crossover Trial.826 Prosecution History – Subpart 2 (“’826 prosecution history”) – Part 2 xi .826 Exhibit No. Provisional Patent Application No. J. (“Polli CV”) Exhibit 1043 Pleasure Decl. Provisional Patent Application No. 2452–61.. Relapses and Progression of Disability in Multiple Sclerosis.592 (filed Dec.. Description Exhibit 1039 Stephen L. 11. The Effects of 4-Aminopyridine in Multiple Sclerosis Patients: Results of a Randomized. Patent No. 31. 60/528.D. Harrison’s Principles of Internal Medicine.T. Blight & Ron Cohen.D. 15th ed. PlaceboControlled. 16. Med.Patent No.007. 20. 8. Hauser. (“Polli Decl. no. 343 New Eng.”) Exhibit 1050 Relevant excerpts of U.. at 1054– 59 (“Bever”) Exhibit 1048 Andrew R.nationalmssociety. & Donald E.S. 44. Goodkin. http://www. 2003) (“’592 Provisional”) Exhibit 1045 U. M. 8. 2005) (issued Jan. 2015) Exhibit 1042 CV of James Polli. 11.S.437 (filed Apr. 8. 2013) (“the ’437 Patent”) Exhibit 1049 Declaration of James Polli.D. 2003) (“’593 Provisional”) Exhibit 1046 Orange Book Listing for ’826 Patent (“Orange Book”) Exhibit 1047 C. M.354. et al. Attachment 2 (Claim Charts for the ’826 Patent) Exhibit 1044 U. M.007. and Polli Decl. Jr. Ph.D. Ph.

Kyle Bass. Patent No. The RPI hereby certify the following information: CFAD is a wholly owned subsidiary of Credes. J. Hayman Credes Master Fund. Inc. (Credes). L.826 (the “’826 Patent”) (Ex. L.007. L.8(b)(1). § 42. LLC (nXnP). Hayman Capital Master Fund.Patent No. and Erich Spangenberg are the real parties in interest (collectively.P. §§ 42.104(a)) Pursuant to 37 C.L.F. 1001) in accordance with 35 U. (HCM). IP Navigation Group. requests an Inter Partes Review (“IPR”) of claims 1–3.P. Hayman Investments.R. § 42. 8.F. RPI).C. §§ 311–19 and 37 C. nXn Partners. § 42.P. Credes is a limited partnership.F. the “Challenged Claims”) of U.F. § 42.R. HCMF is a limited partnership. L. 5–8.826 I.C. Petitioner certifies that the ’826 Patent is available for IPR and that Petitioner is not barred or estopped from requesting IPR challenging the claims of the ’826 Patent on the grounds identified in this Petition. Hayman Offshore Management.8(b)(1)) Pursuant to 37 C. GROUNDS FOR STANDING (37 C.R.F. LLC (IPNav).S.R. II. (HOM). INTRODUCTION Petitioner Coalition For Affordable Drugs (ADROCA) LLC (“CFAD”). A.007. and 10–41 (collectively. (HCMF).104(a). 8.100 et seq. Petitioner certifies that Coalition For Affordable Drugs (ADROCA) LLC (CFAD).R. MANDATORY NOTICES (37 C.8) Real Parties-in-Interest (37 C. HCM is the general partner and investment manager of Credes 1 .S. Hayman Capital Management. (HI).R.F. § 42. III.

No. future filings. limited partner. content of.). Inc. no other person (including any investor. HOM is the administrative general partner of Credes and HCMF.5% member of nXnP. nXnP is a paid consultant to HCM.Patent No. No. 2 . Inc. Inc. Kyle Bass in his capacity as the Chief Investment Officer of HCM and nXnP and Erich Spangenberg in his capacity as the Manager of nXnP.8(b)(2). CFAD. All costs associated with this Petition will be borne by HCM. Kyle Bass is the sole member of HI and sole shareholder of HOM. Petitioner states that the ’826 Patent has been the subject of the following lawsuits: Acorda Therapeutics. nXnP or IPNav) has authority to direct or control (i) the timing of. Del). J. directly or indirectly. Acorda Therapeutics. § 42.826 and HCMF. Erich Spangenberg is 98. v. Other than HCM and J. Credes. CFAD.R. or any decisions or other activities relating to this Petition or (ii) any timing.F.Va. content of. Mylan Pharms.D. Credes.R. 8. HCM. Inc. and HCMF act. Mylan.W..5% member of IPNav.8(b)(2)) Pursuant to 37 C. v. IPNav is a paid consultant to nXnP. Acorda Therapeutics. Related Judicial and Administrative Matters (37 C. § 42. HI. 1:14-cv-00935 (D. HCMF. B. HI is the general partner of HCM. or member or any other person in any of CFAD. v. Erich Spangenberg is the 98. Accord and Intas.F.007. filing of. through HCM as the general partner and/or investment manager of Credes and HCMF. 1:14-cv-00139 (N. Credes and/or HCMF. or any decisions or other activities relating to the future proceedings related to this Petition. HOM.

007. 1:14-cv-00909 (D. No. Acorda Therapeutics. 8.S. Inc. Dallas.S. Alkem.663. 8. Actavis. No. Acorda Therapeutics. Patent No. 1:14-cv-00917 (D. 3 . Ste. Patent No. No. Inc. 8.). Del. Spires. and its parent U. Parvathi Kota.685. v. Aurobindo.F.122.).R.com. Patent No.8(b)(3)) and Service Information (37 C. Del. v.com and of Skiermont Puckett LLP.354.). Simultaneously with this Petition. the Board issued decisions denying institution for both petitions. Roxane. Acorda Therapeutics. and on February 27. 1:14-cv-00932 (D.440.). Lead and Back-Up Counsel (37 C. On August 24.8(b)(4)) Lead counsel is Sarah E. 8. Del.685. 8. 8. No.703.007. Petitioner filed IPR2015-00817 seeking inter partes review of U. Acorda Therapeutics. Acorda Therapeutics. C. P: 214-978-6600 / F: 214-978-6601. Acorda Therapeutics. 65.).Patent No.). Petitioner consents to electronic service at 826ADROCA@skiermontpuckett. Inc. 1:14-cv-00955 (D. 4800W. Inc. No. § 42. Texas 75201. Inc. v. 1:14-cv-00941 (D. the child of the presently challenged ’826 Patent. § 42. Patent No. v.F. In addition to the related judicial matters. Skiermont (pro hac vice requested)— all at 826ADROCA@skiermontpuckett.663. Del.). and Paul J. Petitioner filed IPR2015-00720 seeking inter partes review of U. Apotex.826. Patent No. Del. No. Inc. and U. Petitioner is seeking IPR of: U. Reg. 2015.826 No. v. Back-up counsel are Dr. Del. on February 10. Del.S. v. 1:14-cv00882 (D.501.S. 2200 Ross Ave.437. No. 61. Teva. Reg. 2015. 1:14-cv-00922 (D. 2015.S. No.R.

and Provisional App. §§ 42. Provisional App.” (Ex. No. filed Dec. 1) The underlying application.826 The ’826 Patent is titled “Sustained Release Aminopyridine Composition. Patent No. 8. 1023 ¶ 40. the Office is authorized to charge such fees to Deposit Account No.F. filed Apr. PAYMENT OF FEES (37 C.15(A) AND § 42.R.894. 2004 (the “’894 Provisional”).007. 13. 60/560. No. 8. No.” and the extended release version is known as “SR 4-AP” and “fampridine-SR.007. 2003. (Id. filed Dec. If any additional fees are due during this proceeding. 11. IDENTIFICATION OF CHALLENGE A. V. 60/528.760.S. U.F.828 (the “’828 application”) was filed Dec. 2004.592.) The ’828 application claims priority to Provisional App.) 4 . 60/528. (Id. Provisional App.826 IV. 2 4-aminopyridine is also known as “4-AP” and “fampridine. 60/528.593.15(a) and 42.) 1.R. No. 1001-1.” (Ex. 2003. Overview of U. 9. 11. § 42. The ’826 Patent Specification The ’826 Patent describes methods of administering l0 mg of a sustained release oral dosage form of 4-aminopyridine (“4-AP”) 2 twice daily to patients with 1 All references to Exhibit pin-cites are to the Bates-labeled page number.103(a). filed Dec. 2003.103) The required fees are submitted herewith in accordance with 37 C. Any overpayment or refund of fees may also be deposited in this Deposit Account. Patent App. No. 11.Patent No. 506293. 11/010.S.

0 to 3. 36.007.0 to 3. said method comprising: orally administering to the human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a day. 8:5–17. 6. a CavSS of 15 ng/ml to 35 ng/ml. 17. and improve lower extremity muscle strength. maintaining administration of 4-aminopyridine by orally administering to said human a sustained release composition of 10 milligrams of 4-aminopyridine twice daily for a time period of at least two weeks.2 hours after administration. (Id. Claim 1 is representative and copied below: A method for maintaining a therapeutically effective concentration of 4-aminopyridine in order to improve walking in a human with multiple sclerosis in need thereof.826 multiple sclerosis (“MS”) to improve walking. at 6:27–29. 31. at 27:17–30. of which claims 1. and 37 are independent claims. increase walking speed. and a mean Tmax from about 1 to about 6 hours. 5–8.5. 8. Claims 1–3.Patent No.5 and a CavSS of 15 ng/ml to 35 ng/ml are obtained in the human. and thereafter. at 7:29–40. (Id. 25:59–60.) The ’826 Patent further describes administering 4-AP to obtain an in-vivo CmaxSS:CminSS ratio of 1.) 5 . 11. and from about 2 to about 5.) 2. The ’826 Claims The ’826 Patent has 41 claims. and 10–41 are challenged in this petition. whereby an in vivo 4-aminopyridine CmaxSS:CminSS ratio of 1. (Id.

8. claims 12 and 14–16 depend from claim 11. at 27:41–57.0 to 3.” respectively.Patent No. claims 7–8.” (Id. (Id. 5.” claim 6 merely requires administration for a day followed by an undefined maintenance period.” and claims 31 and 37 merely require administration for “greater than two weeks. claims 1. 17. and 23–29 depend from claim 6.5 and a CavSS of 15 ng/ml to 35 ng/ml. 6. claims 11 and 17 require administration for one day followed by maintenance of “greater than two weeks. and 36 also require that the administration results in a CmaxSS:CminSS ratio of 1. (Id. 6 .” (Id. at 27:17–30:21.) Claim 11 further requires the presence of an “excipient” along with the 4-AP in the sustained release composition.) Claims 1 and 36 further require that the administration occur for one day followed by maintenance of “at least two weeks.826 Each of the independent claims requires a method of orally administering 10 mg of sustained release 4-AP twice daily in a human with multiple sclerosis. while claim 17 further requires an “agent” such as an “excipient” and/or an “active ingredient.” and “about 2 to about 5.007. 17.” (Id. while claims 31 and 37 require that administration results in a mean Tmax of “about 1 to about 6 hours. and 18–22 depend from claim 1.) Claims 1. 6.) Dependent claims 2–3. 11. (Id. 13.) In addition. 11.) Claim 6 also prohibits a period of 4-AP “titration” before or after the administration. at 28:1–50. 10. and 36 require that the method is to “improve walking” while claims 31 and 37 require that the method is for “increasing walking speed.2 hours.

the applicant petitioned to have Sean Cunningham removed as an inventor. claims 32–35 depend from claim 31. -56–57. Prosecution History of the ’826 Patent The ’826 Patent was filed as the ’828 application on Dec.) The challenged dependent claims contain certain additional limitations that are discussed below in Section VI.) Subsequently. (Id.) Of the 23 originally filed claims. at 27:31–30:21.) The PTO granted the petition to remove Cunningham as an inventor. 1002-2–3. 3. and based on the USPTO’s final patent term adjustment calculation.S. 1002. 100258–59. (Id.) The ’828 application was filed with original inventors Andrew R. 1046-1.) The applicant petitioned to have the application reviewed without a Declaration by Cunningham because “diligent efforts to locate Sean Cunningham in order to execute the Declaration were unsuccessful. (Ex. passim. (Ex.) According to the FDA’s “Orange Book”. the ’826 Patent expires in 2027.) The ’826 file history is over 2. 8. Blight and Sean Cunningham.Patent No. in greater detail. rendering the first petition moot.000 pages and references over 430 U. -123. 2008 in response to a restriction 7 . (Id. 2004. the applicant cancelled claims 12–14 and withdrew Claims 1–8 and 18–23 on May 21. 1050.2. -35. (Ex. (See Exs.826 claim 30 depends from claim 17. 1001-1. 13.B. (Ex.” (Id.007. and claims 38–41 depend from claim 37.) The applicant later added Ron Cohen as an inventor. and foreign patents and non-patent literature documents.

1002-26–27.) The applicant also submitted declarations by Andrew R. -95–112. (Ex. (Ex. (Id. 1005). and added claims 42–47.) The Examiner also rejected claims 9–11 and 15–17 as obvious over Masterson (Ex.) The Examiner noted that “[a]ccording to one study in Hayes et al. 1002-28–30. -120–132. amended claims 30–33 and 39–40. (Id.826 requirement. 1002-45–49. but rejected all claims as obvious over Masterson. -25. 8. 1009).) The Examiner then issued a Final Office Action withdrawing the Hayes anticipation rejection and the original Masterson rejection. 1002-27. Hayes et al admit that fampridine is potentially a valuable treatment for multiple sclerosis.007. -73–94. (Id. (Id. 10–25 mg of fampridine was administered twice daily for one week to 16 patients with chronic spinal cord injury” and “[i]n addition. applicant filed a Request for Continued Examination cancelling claims 1–47 and adding new claims 48–69. 1008).) 8 . and Schwid (Ex.) The Examiner then rejected remaining claims 9–11 and 15– 17 as anticipated by Hayes (Ex.) The applicant responded by amending Claim 9 and adding Claims 24–41. applicant canceled claims 1–29 and 36–38. 1002-60–64.) After another Examiner interview. Hayes. (Ex.) After an interview with the Examiner discussing Masterson. Blight and David Lawrence attempting to distinguish Masterson and purporting to support secondary considerations of non-obviousness.Patent No. (Ex.” (Ex.

Neither the Sabella nor Medori declarations anywhere mention a period of treatment that is two weeks or greater.” (Ex. and (3) Masterson. -214. 1002-133–39. or a mean Tmax. 1011). Cmax.Patent No.) Additionally. predictable solutions. 199– 263. (Ex.) After another Examiner interview. -291–884. (Ex. Rosella Medori and Lauren Sabella in support of its allegations of secondary considerations of nonobviousness. the Medori declaration described: Biogen’s interest in obtaining…rights to…the ‘828 application was based on the following longstanding and well-known needs that were met by Ampyra®…: 9 . 8. the applicant submitted an amendment introducing independent claims requiring 4-AP administration for “at least two weeks. “the claimed invention is nonobvious.) The applicant also submitted declarations by Dr.826 The Examiner issued a non-final Office Action rejecting all claims over (1) van Diemen et al. the applicant argued that.” (Id. and the art did not contain a finite number of identified. Cmin. (Id.) Specifically. and Bever.007. because the requisite predictability is lacking: the claimed invention is not composed of a combination of elements that yields predictable results. such as CavSS. 1047).” (Id. -251–52. (Ex. van Diemen. (2) van Diemen and Bever et al.) The Medori declaration addressed the applicant’s allegations of “secondary considerations of long-felt but unsolved need and failure of others. nor do the declarations anywhere mention the claimed pharmacokinetic parameters. 1002-175–77.

(Id.826 (a) It was an effective MS treatment. (e) It was effective to treat all four forms of MS.’” (Id. the Examiner issued a Notice of Allowance. and the effects are noticeable by patients and physicians.) Additionally. the applicants directed the Examiner to the previously-filed Blight declaration. stating that “because the prior art taught much higher dosages of 4aminopyridine and lacked the predictability to whereby an improvement in 10 . (b) It met the…need for any MS treatment to improve walking. –261. the Sabella declaration alleged “evidence of the nonobviousness of the claimed invention. (c) Its onset of action can be rapid. -256–57. -252.…Sanofi noted that the ‘[d]ata on Nerispirdine in improving the ability to walk in multiple sclerosis patients…did not support progression to Phase III trials. -259. 2010. which alleges that “There are at least two surprising results from our work: (i) a 10 mg dose is as effective as a 20 mg dose and (ii) no dose escalation was required to have a well-tolerated and meaningful clinical result. 8. establishing that it achieved commercial success.) Following two additional interviews.” (Id.) Finally. (d) It was an orally administered MS treatment.007.Patent No. as measured by sales and other factors.) The Medori declaration also alleged that “[a]n example of the failure by others…is the drug Nerispirdine…in a Press Release dated April 29.” (Id. based on its merits rather than undue marketing efforts.

and 40–41 is no earlier than the ’828 application’s filing date: December 13.) B. 60/528. 1044). 1007).S. 2003 (Ex. filed on Dec.760. § 119(e)(1) (pre-AIA version) (“An application for patent filed…by an inventor or inventors named in the provisional application. or any filing date that could have been be accorded by the 2003 Provisionals. as though filed on the date of the provisional application…”) (emphasis added).826 walking could be obtained with the instant dosage. 60/528. The 11 . See 35 U. Provisional App. 5–8.” (Ex. it cannot render obvious the claimed method. 13. For a host of reasons. none of the claims of the ’826 Patent can claim priority to any of the 2003 Provisionals because the ’826 Patent does not share a common inventor with the 2003 Provisionals—a statutory requirement for claiming the benefit of priority from a provisional.592. filed on Dec. 11. 1050-386–420. 2003 (Ex.593.) Nevertheless. 60/528.C. filed on Dec. 10–32. As an initial matter. No. as well as: Provisional App.007. filed on Dec. 8. the challenged claims are not entitled to the benefit of the ’894 Provisional’s filing date.Patent No. (Ex. 11. 2004. No. which claims priority to the ’894 Provisional (Ex. 1006). No. 34–38. as to such invention. Effective Priority Date of the ’826 Patent Claims The ’826 Patent matured from the ’828 application. 1045) (hereinafter the “2003 Provisionals”). 11. shall have the same effect. 2004. the priority date of claims 1–3. and Provisional App. 1001-1. 2003 (Ex.

1294–96 (Fed. (Ex. § 112 ¶1.. 2002) (“for the non-provisional utility application to be afforded the priority date of the provisional application. 1045-1.. Co.L. L. (Ex. To satisfy written description.826 2003 Provisionals all list Sean Cunningham as the sole inventor. 1002-56–58. applicant removed Mr.C. 10–32.C. Ex. and 40–41 are not entitled to the benefit of the ’894 Provisional’s filing date. Cir.3d at 129496. New Railhead. 298 F. Ex. 1006-1. Vermeer Mfg. v. 5–8. a POSA must immediately discern that the ’894 Provisional “necessarily discloses” the ’826 Patent’s claim limitations from the four corners of the ’894 Provisional at the time it was filed. The application that issued as the ’826 Patent does not share a common inventor to the 2003 Provisionals. 8. Cunningham as an inventor on the application during prosecution of the application that ultimately issued as the ’826 Patent. Additionally. claims 1–3. 1044-1. 34–38.S. because the challenged claims can only receive the benefit of the ’894 Provisional’s filing date if its disclosure satisfies the requirements of 35 U. It is not enough that a POSA could speculate as to modifications to the ’894 Provisional’s disclosure that the inventor might have envisioned but failed to disclose—and it is not even 12 . See New Railhead Mfg.Patent No. the two applications must share at least once common inventor”). 298 F.3d 1290. and so cannot claim priority to them.) However.) When the applicant removed Cunningham—the sole inventor of the 2003 Provisionals—it forfeited any claim of priority to them by statute.007. Id.

3d 1565. Waldemar Link v. 1277 (Fed. 34–38. 10. See also Lockwood v. 107 F. it must contain an equivalent description of the claimed subject matter based on an examination of the ’894 Provisional’s words.007.. Cir.Patent No. and diagrams. or improving lower extremity muscle strength by administering 10 mg 4-AP for a one or two-week treatment period.” “at least two weeks. and 27–29 do not require a specific dosing “time period.3d 1267. at 1296.. In re Huston. 2002).3d at 1572. Claims 6– 8. Cir. increasing walking speed. 30–32. 8. The ’894 Provisional nowhere discloses a method of improving walking. Example 11 of the ’894 Provisional 13 . structures. 1994). 558–59 (Fed. 1571–72 (Fed. 11–20.g. Id. 107 F. claims 1–3.826 enough if such limitations are obvious from the ’894 Provisional’s disclosure.” other than the initial twice-daily dosing of SR 4-AP “for a day” and “maintaining administration” for an unspecified period thereafter. 22–25.3d 556. Osteonics Corp. American Airlines. Lockwood. Nor does the ’894 Provisional disclose dosages of 10 mg sustained release 4-AP twice daily for an unspecified period of time (e. and 40–41 each require that 10 mg 4-AP be administered twice daily or every 12 hours.” or “more than” or “greater than two weeks” (the “one-to-two week limitations”). and the claimed “time period” for the treatment is “at least a week. 32 F. 308 F. Though the ’894 Provisional need not use the exact words of later-filed claims. more than a day) in which efficacy is demonstrated. First. figures. 5. Cir. 1997).

” (Ex.) Example 11 discloses data collected at Visit 4 (end of upward titration period) and not again until Visit 7. 20 mg) to improve walking in MS patients—and that is the only disclosure in the ’894 Provisional where 10 mg SR 4-AP is administered twice daily to treat MS patients. parallel-group study…designed in accordance with the Figure entitled Example 11 Study Design. (Ex. (Ex. 1007-50. a POSA would understand that Visit 7 occurred no earlier than week 4 of the 12-week treatment period. 1023 ¶ 42. Example 11 of the ’894 Provisional discloses a “double-blind.) Example 11. 20 week. -56. based on the placement of Visit 7 in the 12-week treatment period figure. However.) However. and does not disclose improvement of walking or lower extremity function 14 .) The Study Design discloses the following time periods: “2-week placebo run-in”. placebocontrolled. “2-week upward titration (10/15 mg bid or placebo)”.” (Ex. does not disclose any data for the first 2 weeks of the 12-week treatment period. therefore. “12-week stable treatment period”.) The ’894 Provisional does not disclose when Visit 7 occurred. (Id.Patent No. that disclosure of a 12week “treatment period” to improve walking in MS patients does not adequately disclose to a POSA that the challenged claims’ abbreviated dosing periods were necessarily present from the ’894 Provisional’s disclosure. 8. 1007-56.826 describes administering 4-AP during a 12-week “treatment period” at 3 different doses (10 mg. 1007-56 (emphasis added). and “2-week post treatment follow-up.007. “1-week downward titration”. 15 mg.

this disclosure is not a full.” (Ex.) A POSA would have inferred from such non-disclosure that “the applicant either collected no data after the first one or two weeks of the treatment period. two weeks.007. 8.) However. 1023 ¶ 45.” (Id. (Ex.) As a result.. one week. concise. In fact. upon reviewing the ’894 Provisional. the ’894 Provisional is silent as to precise method of performing the “upward titration (10/15 mg bid or placebo)” for two weeks. Ex.) New Railhead. ¶ 44. clear.Patent No. more than two weeks)—and “a POSA would not immediately discern that the ’894 Provisional necessarily disclosed the abbreviated treatment period limitations based on reviewing the ’894 Provisional.) Specifically: 15 .3d at 1294–96.” (Id. 298 F. (Id.826 after the first two weeks of this treatment period.e. or the applicant collected data but did not disclose it because such data did not show improved walking or lower extremity function. and exact disclosure of the challenged claims’ abbreviated treatment periods (i. Nor does Example 11’s two-week upward-titration period prior to the stable 12-week “treatment” period support the lesser treatment period limitations of the challenged claims. 1007-56. “a POSA would have understood from experience that the ‘2-week upward titration’ period refers to a standard phrase in the industry that describes the time period during which a dose is introduced and gradually increased to ensure the patient does not have an adverse reaction to the medication. one day. ¶ 43. 1023 ¶47.

) As a result.) This added description is conspicuously absent from the ’894 Provisional’s disclosure of the upward titration period of Example 11. 1007. Nothing in Example 11 suggests that the different treatment groups took different dosages during the upward titration period—instead. a POSA would have understood this disclosure to mean that the “2-week upward titration” period involved administering SR 4-AP BID at a dose of 10 mg for some portion of the 2-week period.) Further support for this proposition can be found in actions taken by the applicant in its related ’437 patent. 1048 at 18:20–35. which also claims priority to the ‘894 Provisional. passim. Example 5 of the ’437 patent – which corresponds to Example 8 of the ’826 Patent – adds at least 15 lines of text to explain the particular dosing parameters of the upward-titration period.826 The figure entitled “Example 11 Study Design” ambiguously alludes to “2-week upward titration (10/15 mg bid or placebo)” without further explanation.) At best.007. (Ex. to ensure patients do not have an adverse reaction. following by an upward dose of 15 mg for the remaining portion of the 2-week period. (Ex. 1023 ¶ 48. the upward titration period of Example 11 does not disclose to a POSA that the abbreviated dosing time period limitations of the challenged claims were necessarily present from the ’894 Provisional’s disclosure. the ‘’894 Provisional shows that each treatment group (other than the placebo group) received the same 10/15 mg bid upward titration. 8. 1007-56 (emphasis added).Patent No. (Ex. because those 16 . (See Ex.

” (Ex. following by at least two weeks.) Lockwood.. Inc. original claims 1–2 of the ’894 Provisional do not satisfy § 112 ¶1 for the challenged claims. 1023 ¶ 53.5 ng/ml for 10 mg BID dosing. are not disclosed by the original claims based on a POSA’s evaluation of the disclosure as a whole. (Ex. 10–30 and 36 all require the pharmacokinetic range of CavSS of 15 ng/ml to 35 ng/ml in MS patients receiving 10 mg 4-AP BID. 107 F. (Ex.3d 1336. 8. Likewise. 5–8. 1007 at 45. two weeks or more than two weeks—not merely for some undiscernible portion of the two-week upward titration period.) See Ariad Pharms. one week. claims 1–3. however. 2010) (en banc).) 17 .) Therefore.. 1007-52.3d at 1571–72.1 ng/ml to 26. Eli Lilly & Co. Second.Patent No.007. 1349–1351 (Fed. ¶ 50. merely discloses ranges encompassing a CavSS of 15. 598 F.826 claims require administering the same dose of 10 mg 4-AP for one day. those claims “do not disclose to a POSA that the abbreviated treatment period limitations were necessarily present— because such limitations. (Id. Moreover. By contrast. because those claims are entirely open-ended with respect to dosing duration—and those claims are also not specifically limited to 10 mg SR 4-AP dosing (those claims are directed to “about 10 to about 15 milligrams”). Cir. v. (Id. or their equivalents. the only pharmacokinetic ranges disclosed in the ’894 Provisional are in Table 7. the upward titration period of the ’894 Provisional nowhere discloses administering 10 mg 4-AP for one day.) That table.

” (Ex.. “a POSA would not have immediately discerned that the ’894 Provisional necessarily disclosed the full scope of the claimed CavSS ranges. The written support for the claimed CavSS ranges found in the ’826 Patent (Ex. v. Thus.P. and 36 claim up to 35 ng/ml—while the ’894 Provisional does not disclose at least the upper range of 26. 1007 at 45. In re Lukach. at the time of the ’894 Provisional.A. all require a CmaxSS:CminSS ratio of 1. 442 F.3. e. 1259 (Fed.6 ng/ml–35 ng/ml—those claims of the ’826 Patent cannot claim priority to the ’894 Provisional.C.3–4.007. 10–30.. in addition to previously discussed claims 1–3. 5–8.3d 1247. 1970) (explaining “a single embodiment” is less likely to support a claimed range broader than the embodiment when claims are directed to physiological activity rather than more predictable mechanical or electrical arts). Cf.0” based on a “single example” in the priority application disclosing a “Mw/Mn ratio of 2.). and 29–30.g. Genentech.0 to 3. 1108 (C. Claims 32 and 38.5. 17.6”). In re Fisher. 1023. But Table 7 of the ’894 Provisional only disclose a CmaxSS:CminSS ratio of 1. 57 C.A. See.Patent No. 1971) (patentee not entitled to an earlier application’s filing date for a claimed Mw/Mn ratio ranging “from 2. 969 (C.g. 8.0 to 3. 1001 at 7:55–8:43) is absent from the ’894 Provisional.2d 967. e. Inc. (Ex. Chiron Corp. 2004) (claims broader than the specification lack written description or enablement where disclosure lacks a specific and useful teaching commensurate with claim scope).P.) 18 . 20–26.C. 14.826 Because all claimed ranges for claims 1–3.P. 5–8. See.A. Cir. 1099.. ¶ 54.C. 363 F.

passim. 10–14. 10–14. v. Inc. 2004. (Ex. while the ’894 Provisional does not disclose the ratio range of 1.2.. and 40–41 are entitled to a priority date that is no earlier than December 13. 10–32. 772 F..826 Because all claimed ranges for claims 1–3. at 1039–40 (Fed. 506 F. claims 1–3. 1007. Frank. v. Cir.Patent No. or Ph. 52 F. 19 . 5–8. Far-Mar-Co. 34–38.” “between 20% and 40%.” or “in the range of 20%–30%”). 5–8. 1378 (Fed.0–1.D. 8.0.g. Ralston Purina Co. Eiselstein v.D. 1575–76 (Fed.007. 5–8. Cir. 1985) (parent application disclosing 25%–27% water in soybean mixture does not support broader claims to “at least 20%.S. in neuroscience or a related field with an understanding of pharmacokinetics and at least some experience in providing drug 3 The Provisional purports to incorporate by reference certain documents that cannot provide the missing disclosure because they do not identify where the incorporated material is found. Level of Ordinary Skill in the Art A POSA as of April 9. U.. e. C. See. 20–26. 17. Filter Corp. Cir.3d 1035.. 3 For all of the foregoing reasons.) See Zenon Envtl. and 29–30 of the ’826 Patent are not entitled to claim priority to the ’894 Provisional. 17. at least claims 1–3. 1995) (specification describing nickel content of 45%–50% does not support broader claim for 50% to 60%). 2004—the earliest possible priority date for the ’826 Patent—“would have an M. 20–26.2d 1570. and 29–30 claim a CmaxSS:CminSS ratio beginning at 1. 2007).3d 1370.

The broadest reasonable construction of claim language is not one that permits any reading.S. LLC. or at least 5 years of experience in formulating oral sustained release pharmaceutical drug products. with access to a person having an advanced degree (M. of Sci. for purposes of this IPR only. 20 .R.D. 1023 ¶ 16. Acad. Claim Construction of Challenged Claims A claim subject to IPR receives the “broadest reasonable construction in light of the specification of the patent in which it appears. Petitioner accepts. § 42.” (Id.” but also take advantage of “specialized skills of others on the team.” In re Am. that the claim terms of the ’826 Patent are presumed to take on the ordinary and customary meaning that they would have to a POSA.Patent No. specifically oral sustained release formulations. Ctr..” (Ex. Cir. 1364 (Fed. or Ph. see In re Cuozzo Speed Techs. 778 F..826 therapy to MS patients.100(b).F.” 37 C. ¶ 17) D. Cir.) “A POSA may work as part of a multi-disciplinary team and draw upon not only his or her own skills.3d 1271. 367 F.007. Unless otherwise noted. but instead is one that must be made “in light of the specification as it would be interpreted by one of ordinary skill in the art. Tech. 8. 2015). 2004) (quotation omitted).3d 1359.) in pharmaceutics or pharmaceutical formulation. 1279 (Fed.

S. 2. §§ 102(a) and (b) or 103.S. (See Exs. § 103: Ground Proposed Rejections for the ’826 Patent 1 Claims 1–3.) Claims 1–3. 5–8. and 10–41 are obvious under 35 U.) E. Statutory Grounds of Challenge Petitioner requests IPR of the ’826 Patent claims 1–3. and the obviousness combination for the sole ground in this petition was not the basis of any rejection in any Office Action. Claims for Which Review is Requested Petitioner requests IPR under 35 U.C. § 311 of claims 1–3.S. 5–8. each of which is prior art to the ’826 Patent under 35 U.007. 1050.Patent No.C. 1023 ¶ 57. § 103 in light of the S-1 in view of Hayes 21 Exhibit Number(s) 1003. and cancellation of these 39 claims as unpatentable. The S-1 was not cited by the applicant or otherwise introduced to the Examiner during the ’826 Patent prosecution. and 10–41 of the ’826 Patent. 5– 8. 1005 .826 1. passim.C.S. and 10–41 in view of the following references. 5–8. and 10–41 are unpatentable under 35 U. 1002. Statement of Precise Relief Requested for Each Claim Challenged 1. “to improve walking” The phrase “to improve walking” means “to quantifiably make better a patient’s ability to walk.C. 8.” (Ex.

Patent No. 8,007,826
F.

Overview of the State of the Art and Prior Art References
1.

History of 4-AP and State of the Art of the ’826 Patent

The ’826 Patent does not claim the 4-AP compound. (Ex. 1001, passim.)
Nor does it claim to have pioneered the use of 4-AP to treat MS patients. (Id.) The
’826 Patent does not even claim that the oral administration of 10 mg 4-AP BID to
MS patients or the use of sustained release 4-AP are novel, because those teachings
were known in the art. (See, e.g., Ex. 1003; Ex. 1005; Ex. 1020.) Instead, the ’826
Patent claims methods of administering 4-AP BID to MS patients for certain time
periods to attain therapeutic objectives such as improving walking. By at least
April 2004—prior to the earliest possible priority date for the ’826 Patent—a
POSA would have known to apply the claimed methods to achieve those
objectives.
By April 2004, a POSA would have known that MS is a chronic disease that
causes problems with walking and lower extremity muscle function on an ongoing
basis, and especially as the disease progresses over time. (Ex. 1023 ¶ 26.) As a
result, “[a]mong the therapeutic objectives of a POSA seeking to treat MS patients
with 4-AP prior to April 2004,” were to improve walking, increase walking speed,
and increase lower extremity muscle strength and tone. (Id. ¶ 27.) By 1987,
researchers had measured neurological changes resulting from administering 7–35
mg of 4-AP in 1–5 mg doses every 10–60 minutes, with “motor function (power,

22

Patent No. 8,007,826
coordination, gait)” in 5 out of 12 patients improving “within minutes of drug
injection at doses as low as 2 mg.” (Ex. 1013-1.) In 1990, Davis et al. administered
10–25 mg 4-AP (total doses per individual) to MS patients and observed marked
improvements in motor functions, including gait, in doses as low as 10 mg.
(Ex. 1014-1.) Polman also found that “4-Aminopyridine was more effective than
3,4-diaminopyridine, especially for ambulation” in patients with MS. (Ex. 1012-3.)
Thus, by April 2004, a POSA would have known to use 10 mg 4-AP to improve
lower extremity function in MS patients.
Moreover, van Diemen taught administering 4-AP to treat MS disability for
at least two weeks, with an efficacy analysis performed only in patients who
completed “at least two weeks” of treatment. (Ex. 1011-2–3.) van Diemen further
teaches a significant effect of 4-AP on the mean Expanded Disability Status Scale
score after 2, 6, and 12 weeks of treatment. (See id. at Table 1.)
2.

The S-1 (Ex. 1003)

The S-1 constitutes prior art under 35 U.S.C. §§ 102(a) and (b) because it
was published at least as early as September 30, 2003—more than one year before
the earliest effective filing date of December 13, 2004 (for claims without
provisional priority). (Ex. 1004-9; see generally, Ex. 1003.) Even assuming
arguendo that the priority date is December 11, 2003 or April 9, 2004, the S-1

23

Patent No. 8,007,826
would still qualify as prior art against all claims under 35 U.S.C. § 102(a). The S-1
was not art of record during the ’826 Patent’s prosecution. (See Ex. 1001-1–10.)
A reference is a “printed publication” if it was “available to the extent that
persons interested and ordinarily skilled in the subject matter or art[,] exercising
reasonable diligence, can locate it.” Voter Verified, Inc. v. Premier Election
Solutions, Inc., 698 F.3d 1374, 1380 (Fed. Cir. 2012) (quotation omitted). The
touchstone is access. If the S-1 was accessible to interested persons skilled in the
art “it is unnecessary to show that anyone actually inspected the reference.” In re
Lister, 583 F.3d 1307, 1314 (Fed. Cir. 2009). See also Constant v. Advanced
Micro-Devices, Inc., 848 F.2d 1560, 1569 (Fed. Cir. 1988) (holding if publication
is accessible, “there is no requirement to show that particular members of the
public actually received the information.”).
As early as 2000, a POSA would have known that Acorda was investigating
fampridine [4-AP] “for the potential treatment of spinal cord injuries and multiple
sclerosis.” (Ex. 1017-1.) This had received attention in prominent publications in
the field as well as general news sources from 2002 until the date of the S-1 filing.
(See id; Ex. 1018-1 (“[f]ampridine-SR is also in Phase 2 clinical trials to evaluate
safety and efficacy in the treatment of symptoms associated with multiple sclerosis
(MS).”); Ex. 1019-1 (“[t]he Company’s lead product, Fampridine-SR, is in Phase 3
clinical trials for chronic SCI and Phase 2 for MS.”).) Based on such information, a
24

007. Analysis.”) “Included in these disclosures is the S-1 form. 848 F. and Retrieval) system.) The S-1 HTML properties establish that.” (Ex. on 26 September 2003 and filed it on 25 .2.” (Id.) “By law.Patent No. including the S-1 form.) See Constant. these public filings have been available online in the SEC’s EDGAR (Electronic Data Gathering.S.” (Id.” (Ex.2d at 1569 (“Evidence of routine business practice can be sufficient to prove that a reference was made accessible before a critical date. ¶¶ 59–60. “and would have been motivated to keep apprised of Acorda’s research and studies conducted with 4-AP in 2003. ¶ 12 n. companies in the United States making an initial public offer of stock must file certain forms with the U. which contains basic business and financial information about the issuer. 1023. Securities and Exchange Commission (SEC). A POSA would therefore monitor and seek information about such studies by looking for and accessing statements and publications by researchers and companies conducting such studies.” which endeavors to make the filings publicly available within “a matter of minutes.826 POSA would have been motivated to consult information—particularly public filings such as the S-1—relating to Acorda’s research. A POSA interested in researching and treating MS would have known that Acorda is active in the field of SR 4-AP research to treat patients with MS.) “Since 1996. 8. “[t]he SEC received the Acorda Therapeutics filing. 1016 ¶ 11. ¶ 11. including Acorda’s research and disclosures.

¶¶ 4. 1026.)5 In its EPO brief.4 Specifically. Cir. 2014. 777 F. 1732548 (B9) (“EP ’548”) (Ex. 1004-9. telling you if similar patents have been claimed in other countries. Tyler Refrig. which provided instructions to the public for obtaining a printed copy of the S-1 publication via mail. 1026 ¶ 5.Patent No.826 29 September 2003. ¶¶ 14–15. (Ex.” (Ex. Acorda repeatedly admitted that the S1 was prior art to EP ’548 (See e. 1985) (collecting 4 The European Patent Office’s “Espacenet” search tool provides access to “patent family information. 5. 690 (Fed.19.) Lest there be any doubt. 6. 2003.g. 16. e.g. Annex A.6. further establishes its public availability. (Ex. (Id.39. 1028.) Espacenet’s bibliographic data for the ’826 patent states it was “also published as” Acorda’s “EP1732548 (B9). 1025). ¶ 14.) 5 The S-1 is document C27 in the EPO appeal. 6..” (Ex. and countered an argument that the S-1 (the “C27” reference) anticipates EP ’548’s claims. See. v.) 26 . Kysor Indus.27.) The Federal Circuit has held that a patentee’s admissions of a reference’s prior art status is “clear and convincing evidence” that the reference is prior art. 2003 SEC Registration Statement. id. Corp.) Thus. 8..) The September 30.007. on Sept. (Ex. No. 1027-2. and that admission is binding here. Acorda responded to an appeal opposing European Pat.61. the S-1 was available to a POSA interested in reviewing information regarding Acorda Therapeutics. Acorda has admitted that the S-1 is prior art to the ’826 Patent’s European counterpart with the same claimed priority date. by at least September 30.2d 687..” (Id.

S. 1126.D. the EPO standards for writings as prior art are comparable to the U.826 authority). 30. 8. 1996) (finding public use admissions from foreign patent proceedings admissible in the U. The S-1 describes clinical trials conducted using a sustained-release (“SR”) composition of 4-AP. 27 .. LEXIS 27435.S. the S-1 is a prior art printed publication to the challenged claims. Mich. The reference teaches the effectiveness of the 10–25 mg BID dosing range. e. Supp..6 See. Dist.) The S-1 described using sustained-release fampridine in an MS Phase II clinical trial: 6 For purposes of Acorda’s admissions. under FRE 801(d)(2)). 1021-1 (“everything made available to the public by means of a written… description …before the date of filing of the European patent application.D.”). v. Gentex Corp. 1003-37.Patent No.. 1134–35 (W. 2003) (collecting authority and finding “[s]everal other cases have held that statements made by a patentee during foreign patent proceedings can constitute admissions”). 2003 U. 918 F. *32–33 (N. v. requirements for prior art printed publications. Prods. stating that “clinical trials indicated that there was evidence of increasing dose-response through the range of 10 to 25 mg twice a day. possibly being offset by increased side effects. (See Ex. No.g. Ohio Sept. Eagle Mfg. Sentry Prot. Donnelly Corp. Thus.” (Ex.007. 2003 WL 25539702. but that evidence of increasing efficacy at doses higher than 25 mg twice a day was limited. 1:01-cv-2240. The fact that the admissions occurred during EPO proceedings does not negate Acorda’s admissions. Co.S.

emphasis added. 3.” Id. -37. MS-F201. The clinical trial is also designed to compare three doses of 10. as explained in more detail below.007. was designed. The MS-F201 Phase II trial “demonstrated that doses up to 25 mg twice a day were well tolerated. Hayes (Ex.) In that study.Patent No.) The S-1 also discussed a previously conducted Phase II study.826 The current late Phase II clinical trial. and to assess their relative safety and efficacy over a treatment period of 12 weeks. twice per day. 8.) The S-1 disclosures teach nearly all claim limitations. MS-F202.S. §§ 102(a) or (b) to all claims because it was published and accessible by September 2003 (Ex. (Id. and 11 subjects were given placebo over the same period. 1016 ¶¶ 16-21) in 28 . to provide pivotal data for support of an NDA for the use of fampridine-SR in MS. and were associated with statistically significant improvements in walking speed and leg muscle strength” and that “[m]ost of the improvement in strength and walking speed was apparent within the first three weeks of the Fampridine-SR treatment. (Id. “a total of 25 subjects received fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight weeks of treatment. 1005) Hayes constitutes prior art under 35 U. at doses from 10 to 25 mg twice a day. which was completed in 2001. after extensive consultation with a panel of expert MS neurologists and with the FDA.” (Id. 15 and 20 mg.C. The primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk.

) The data for 10 mg BID showed a CavSS (average plasma concentration at steady state) of 20. (Ex. 8. -3.5 ng/mL (accounting for error). 7. 1002-222. The applicant cited Hayes as factual prior art evidence supporting its claimed pharmacokinetic ranges. 2004. 15 mg. (Ex. a tmax 29 . -5. 2003 or April 9. 1005-1. -2.007. and 25 mg.7) ng/mL—a range of 15.) Figure 1 provides release profile information for the drug.” (Ex. § 102(a).” (Ex.) Even assuming arguendo a priority date of December 11.S. (Id. for claims not entitled to provisional priority. 20 mg. and Table 3 provides pharmacokinetic data.Patent No. 1005-1.C. 1005. Clinical Neuropharmacology—more than one year before the earliest effective filing date of December 13.) The doses in each study were 10 mg. (Id.) Hayes reported that “[s]teady state was achieved by day 5…after twice-daily administration” and recorded pharmacokinetic data in relation to the plasma concentration of the drug. 2004. (Id. incomplete SCI.) It presents the results of two studies “conducted to determine the pharmacokinetics and safety profile of an oral. 10–25 mg) [1] administered as a single dose…and [2] twice daily for 1 week…in patients with chronic.1 ng/mL to 26. Hayes would still be prior art against all claims under 35 U.) Dose administrations occurred every 12 hours. (Id.8 (± 5.) Hayes notes that “[c]linical trials have confirmed that administration of fampridine [4-AP] results in symptomatic improvements in patients with SCI and multiple sclerosis.826 the peer-reviewed journal. sustained-release (SR) formulation of fampridine (fampridine-SR. -4.

7–3. The present Petition presents a combination of art not previously before the Office.007..) Moreover. 1050. 1002-26. and reject the petition or request because. § 325(d) provides that for institution. Chimei Innolux Corp.3 when accounting for error. (Id. 7. 35 U. the same or substantially the same prior art or arguments previously were presented to the Office. v.S. “the Director may take into account whether.. § 325(d) should not foreclose this Petition. (Ex.T.g. -5. See e.) Because these prior art references and associated arguments differ from those previously presented to the Office. 8.) VI. that rejection was an anticipation reference. passim.Patent No. § 325(d) should not bar the petition 35 U.3—a range of 1. slip op. DETAILED EXPLANATION OF THE CHALLENGE A.C. the primary reference that is combined with Hayes in the present petition—the S-1—was not previously presented to the Office during prosecution. (See Exs.” 1.7 ± 1.S. April 24.C.7 hours (accounting for error).826 of 10 mg SR 4-AP is 2. Here. 2013) (Paper 10) (rejecting PO’s 325(d) argument because during prosecution the examiner did not consider 30 .S.B. 1002.3–4. Semiconductor Energy Lab.0 hours—a range of 1.C. at 8 (P. although the Examiner rejected the ’828 application based on Hayes.A. Case IPR2013-00066. 35 U. and a CmaxSS:CminSS ratio of 2. in contrast to the obviousness combination presented in this Petition.

T. and noting that ex parte proceedings differ from adversarial nature of IPRs). 8.A.. et al. reexamination. Inc. v. Case IPR2015-00483. or in a previous IPR proceeding).T. See.A.g. The present Petition presents grounds not previously addressed by the P. January 25..826 substantially the same arguments presented in the petition). Case IPR2014-01235. Case IPR2014-01203.B.B. 2.B. December 22. at 911 (P.T. Inc. 2015) (Paper 10) (rejecting PO’s 325(d) argument because there was no evidence the examiner considered the disclosures cited in the petition.A.A.T.. e. 2014) (Paper 12) (rejecting PO’s 325(d) argument because the specific obviousness combination in the petition were not considered during prosecution. Steuben Foods. that Petition relied on the S-1 in combination with different prior art references for which the P. at 6-7 (P. July 15. Nestle USA. at 14-15 (P.A.) This Petition presents obviousness combinations not previously presented in any other petition.B. Paper 12. 31 . Parallel Networks Licensing. slip op..T. 2015) (Paper 13) (rejecting PO’s 325(d) argument because the combination of prior art and arguments presented in the petition were not the same or substantially the same as presented in a previous petition). Magna Electronics.Patent No. slip op. Although the Petitioner previously filed a Petition for IPR related to the ’826 Patent.B. slip op. Inc. found insufficient evidence of printed publication status. v. v.007. Microsoft Corp. Inc. (IPR2015-00817. Valeo North America.

Motorola Mobility v. See. Thus.B. Chicago Mercantile Exchange v.A.T. March 27. the P.’s views of the present obviousness challenge. Intellectual Ventures.B.g.T.B. July 16. 2015) (Paper 10) (rejecting PO’s 325(d) argument that Petitioner “should not get a second chance” “when it already tried.A. slip op.826 Importantly. at 15-16 (P. also did not reach the merits of the previous prior art obviousness combinations in denying institution of Petitioner’ prior challenge to the ’826 patent—nor did the prior decision reach the issue of whether the S-1 is a printed publication. the prior art combination in the present Petition is also presented in simultaneously filed Petitions against two other Acorda patents (the ’703 and ’437 patents). which Petitioner is challenging for the first time. slip op.T. at 38-40 (P. 2015) (Paper 9) (rejecting PO’s 325(d) argument alleging petitioner’s “piecemeal attacks” in filing new challenges making arguments “it could have raised before” and “attempting to cure the deficiencies” the Board identified in a prior decision because prior decision “did not reach the merits” of the challenge. the present Petition does not have the benefit of the P. and because Petitioner presented different invalidity grounds than prior petition). Moreover. As a result. Case CBM2015-00005. 8. 5th Market. Acorda will not be unduly burdened by responding to the same prior art combination presented 32 .B..007.Patent No.T.A. Case CBM2015-00061. e.A. and failed” because in prior denial of institution “[the prior decision] did not reach the merits of Petitioner’s arguments”).

(Ex.A. 5–8.) In particular. May 1.) The particular relevance of the Hayes teachings to the pending claims was explicitly acknowledged by the applicants during prosecution of the ’826 Patent. at 10-11 (P..) A POSA would have been motivated to combine the S-1 with common knowledge and publications like Hayes—which focuses on the same 10 mg BID doses of SR 4-AP oral tablets disclosed in the S-1—“to further understand and apply the methods disclosed in the S-1 to treat patients suffering from MS and its associated conditions. e.B. Each of claims 1–3.T. Allure Energy. Inc.007. v. 157. Inc.Patent No.826 here. Nest Labs. 2015) (Paper 6) (rejecting PO’s 325(d) argument because addressing petition’s arguments would not be unduly burdensome for the PO and the petition’s grounds were not redundant with previous petition). ¶ 66. B. 1002151–52. 5–8.g. ¶ 67.) 33 . Case IPR 2015-00181.” (Id. and 10–41 are obvious in light of the S-1 in view of Hayes and the knowledge of a POSA. 8. See. “[a] POSA considering the effectiveness of the clinical trials disclosed in the S-1 implementing oral low-dose SR 4-AP twice daily would have been motivated to look to the teachings of Hayes—disclosing the use of the same oral low-dose SR 4-AP—in an effort to achieve effective blood plasma pharmacokinetics. 1023 ¶¶ 63–124. and 10–41 would have been obvious to a POSA over the S-1 in view of Hayes and a POSA’s common knowledge. slip op.. (Ex.” (Id. Ground 1: Claims 1–3.

and 36 require that the method is to “improve walking” while claims 31 and 37 require that the method is for “increasing walking speed. Each of the independent claims requires a method of orally administering 10 mg of sustained release 4-AP twice daily in a human with multiple sclerosis.” (Id.” (Id. 31. at 27:17–30:21.826 1.007.0 to 3. while claim 17 further requires an “agent” such as an “excipient” and/or an “active ingredient. Independent claims 1. and 36–37 are obvious in light of the S-1 and Hayes combination and the knowledge of a POSA. 17.” and “about 2 to about 5. 6.) Claims 1. 6. 11.) 34 .” claim 6 merely requires administration for a day followed by a maintenance period.5 and a CavSS of 15 ng/ml to 35 ng/ml. while claims 11 and 17 require administration for one day followed by maintenance of “greater than two weeks. at 27:41–57. 11.” (Id.2 hours. 6. at 28:1–50. 17.Patent No.) In addition. 8. (Id.” respectively. (Id.” and claims 31 and 37 merely require administration for “greater than two weeks.) Claims 1 and 36 further require that the administration occur for one day followed by maintenance of “at least two weeks. while claims 31 and 37 require that administration results in a mean Tmax of “about 1 to about 6 hours. 17. claims 1. and 36 also require that the administration results in a CmaxSS:CminSS ratio of 1.) Claim 11 further requires the presence of an “excipient” along with the 4-AP in the sustained release composition.) Claim 6 also prohibits a period of 4-AP titration before or after the administration. (Id. 11.

1023 ¶¶ 60–63. (Id. MS-F201…was designed to determine the optimal dose level of Fampridine-SR and to evaluate possible ways in which to measure the effect of the drug on symptoms of the disease. 1003-34 (“We have a worldwide exclusive license from Elan to its patent for the sustained release formulation of aminopyridines.) To do so. and a POSA would have understood.” (Ex. suitable for twice daily dosing.826 a. oral tablet formulation of fampridine. (Ex. (Ex. all with the intended outcome of improving lower-extremity function. the S-1 describes research into “Fampridine-SR.Patent No. Specifically. Ex. 1003-34 (emphasis added). timed walking. 1023 ¶ 40. The S-1 and Hayes teach a method of “orally administering” to a “human multiple sclerosis patient” a “sustained release composition” of “10 milligrams of 4-aminopyridine” “twice daily” (all independent claims).) The S-1 discloses that the “Phase 2 clinical trial of Fampridine-SR in Multiple Sclerosis.) The S-1 also discloses the details of multiple clinical trials in which Fampridine-SR was administered to patients suffering from MS.007. or SR 4AP.) The S-1 teaches all of these limitations. 1003-37 (emphasis added). 8. [which] is a sustained release.) The S-1 confirms. Each of the independent claims requires a method of orally administering 10 mg of sustained release 4-AP twice daily in a human with multiple sclerosis. at 27:17–30:21. including motor strength. and self-reported fatigue. that Fampridine-SR is another name for sustained release 4-aminopyridine. which includes fampridine”).” (Ex. “subjects 35 .

The 4-AP dosing during the first 3 weeks of treatment was 10–25 mg twice per day. 642 F.. 8. 1371–72 (Fed. (Id. -37 (emphasis added).) Significantly. (emphasis added). “A POSA considering the teachings disclosed in the S-1 as clinical trial MS-F201 would have understood that low-dose SR 4-AP could be orally administered to MS patients for a short period of time (e.g. Cir. MS-F201. wherein patients exhibited improvements in walking strength and speed within the first 3 weeks.. several weeks) to achieve an improvement in lower extremity strength and walking speed.Patent No.” (Id.) Further. in which MS patients received 4-AP twice a day orally for 8 weeks.” (Ex. Co. at doses from 10 to 25 mg twice a day. LP v. ¶ 86.826 received Fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight weeks of treatment.” and “demonstrated that doses up to 25 mg twice a day…were associated with statistically significant improvements in walking speed and leg muscle strength. Pharm. “[m]ost of the improvement in strength and walking speed was apparent within the first three weeks of the Fampridine-SR treatment. 2011) (“physicians 36 .007. Mut.” (Id. 1023 ¶ 118. the S-1 disclosed the results of a completed clinical trial.) In sum. common knowledge available at the time would have motivated a POSA to seek similar teachings in which lower doses of 4-AP could be administered to achieve efficacious results.) See Tyco Healthcare Grp.3d 1370.

e. 1003-37 (emphasis added). 10 mg) of 4-AP at each administration step.” (Id. -37 (emphasis added).3d 1325.” (Id. The primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk. twice a day…over a treatment period of 12 weeks” means that 10 mg of Fampridine-SR was administered twice per day to a first patient group for 12 weeks. Cir. as here. 1023 ¶ 79. 1023 ¶ 81.) See In re Peterson.007.7 and to assess their relative safety and efficacy over a treatment period of 12 weeks.” (Ex. the S-1 discloses a second “Phase 2 clinical trial. 15. 15. and 20 mg. 2003) (“[W]hen. MS-F202. the claimed ranges are completely 7 “A POSA would have understood that the MS-F202 comparison in the S-1 of “three doses of 10.) 37 .826 always seek to prescribe the lowest effective dose of any medication”). -37. hence receiving the same amount (i. twice per day.” (Ex. The S-1 provides exactly that teaching.) According to the S-1.) In light of this disclosure that the 10 mg dose described for MS-F202 was chosen following the conclusion of the MS-F201 trial “designed to determine the optimal dose level of Fampridine-SR. 315 F. Ex. this trial was “designed to compare three doses of 10. [that] was designed…to provide pivotal data for support of an NDA for the use of Fampridine-SR in MS. Following the MS-F201 trial.Patent No. and 20 mg. 1329–30 (Fed.” the ’826 Patent’s claimed point of novelty over the prior art—its 10 mg dose—“would have been obvious to a POSA. 8.

it is not inventive to discover the optimum or workable ranges by routine experimentation. 1003-37 (emphasis added). 8. 642 F.” (Ex. and 20 mg) of this trial to be successful in treating lower extremity motor dysfunction.Patent No.” particularly in the case of “patients sensitive to the side effects of” the medication).) “Based on these statements of intent to rely on this clinical data for NDA submission and drug label indications. characterized by weakness and walking impairment. 456 (CCPA 1955)). 15.”).007. LP. Moreover. Cir. Inc.) See Tyco Healthcare Grp. 1295 (Fed. the [obviousness] conclusion is even more compelling than in cases of mere overlap. the S-1 further discloses that the data from the MS-F202 trial was intended “to support an indication for the treatment of lower extremity motor dysfunction..” (Ex. a POSA would have reasonably expected all doses (10.3d 1289. 220 F.826 encompassed by the prior art. and particularly with respect to improving 38 .’”) (quoting In re Aller.3d at 1371–72 (affirming summary judgment of invalidity on the basis that it would have been obvious to administer a medication at the lowest disclosed efficacious range since “physicians always seek to prescribe the lowest effective dose of any medication. In re Applied Materials.2d 454. 692 F. Such is the case here because it is a basic precept in the field of medicine that “a POSA would have been motivated to try to use the lowest effective dose to minimize side effects. 1023 ¶ 29. 2012) (“‘[W]here the general conditions of a claim are disclosed in the prior art.

1382–83 (Fed.” (Ex. 1005-2 (emphasis added).” (Id.3d 1375. 2012) (affirming invalidity over a published clinical protocol “designed to obtain data for submission to regulatory agencies” and so in “an advanced stage of testing designed to secure regulatory approval” in light of Manual of Patent Examining Procedure § 2107. 20 mg. each given for 1 week) of fampridine-SR.” (Ex.826 walking and walking speed.007.) As the bold typeface above indicates. 677 F. Hayes also teaches “a sustained-release tablet formulation of fampridine (fampridine-SR). 8. [Patent & Trademark] Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility”). Cir. 15 mg. twice daily. 1023 ¶ 93. and “examine[s] multiple oral doses (10 mg.03’s statement that.Patent No. “if an applicant has initiated human clinical trials for a therapeutic product or process. In addition. the S-1—in combination with Hayes— discloses limitations common to all of the independent claims: 1) orally 39 .) Hayes further discloses that “[c]linical trials have confirmed that administration of fampridine results in symptomatic improvements in patients with SCI and multiple sclerosis. and 25 mg. -1.) See In re Montgomery.

1023 ¶¶ 75–89.) See In re Montgomery.) The S-1 disclosure of Fampridine-SR clinical trials “to support an indication for the treatment of lower extremity motor dysfunction. at 27:17–30:21. 4) of 10 mg 4-aminopyridine 5) twice daily. 1023 ¶ 88. the above limitations of the independent claims would have been obvious to a POSA in light of the S-1 and Hayes. 677 F. The S-1 and Hayes teach administering the sustained release 4AP composition “to improve walking” and for “increasing walking speed” (all independent claims). to determine the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. Claims 1. (Ex.” (Id. Thus. including motor strength. and the S-1 confirms. [and] timed walking” satisfies each of these limitations.826 administering. that these Phase 2 MS clinical trials were conducted in ‘human multiple sclerosis patient[s] in need’” of treatment.” measuring “an improvement in average walking speed” and “the effect of the drug on symptoms of the disease. (Ex. 6. (Ex.007. 3) a sustained release composition. 8. characterized by weakness and walking impairment. 11. Ex.3d at 1382–83.”). 1003-45 (“Human clinical trials…: Phase 2: The drug is administered to a limited subject population to identify possible adverse effects and safety risks. 8 “A POSA would have understood.Patent No. 17.) b. 1003–37 (emphasis added). and 36 require that the method is to “improve walking” while claims 31 and 37 require that the method is for “increasing walking speed. 2) to a human 8 multiple sclerosis patient in need thereof.) 40 .

” (Id.) “Applying this knowledge to the S-1. called the Multiple Sclerosis Functional Composite Score. is indicative of not just walking speed. 35.) In particular.) The T25-FW “is part of a standardized set of neurological tests.007. and involves timing the subject completing a 25 foot walk. [they] found clear differences in the pattern of response between Fampridine-SR and placebo-treated subjects.) The researchers additionally found that “the Fampridine-SR treated group showed a marked tendency for improvement in speed. used as a primary measure of improvement in the studies disclosed in the S-1. and looked at the improvement in walking speed between the baseline period and the average over the first four treatment weeks. 37. MSFC.) In one clinical trial. a POSA would have concluded—based on a reasonable expectation—that the administration of 10 mg BID of sustained release 4-AP in the reference resulted in the claimed improved walking and increased walking speed. the S-1 teaches that “[t]he primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk” (“T25-FW”). when the researchers “examined the measurements from individual subjects. -37. (Id.” 41 .826 The S-1 is replete with observations that the administration of the fampridine sustained-release formulation resulted in “improvement in walking speed. (Ex. but also other aspects of walking.Patent No.” (Id. 1003–30.) A patient’s score on the T25-FW. 1023 ¶ 97.” (Id.” (Ex. 8. 33.

applicant’s basis for patentability relied squarely on the known “pharmacokinetics of SR 4-AP. 1002–222. 8. 694 F. Inc.) c.) During examination. 11. (See Exs. 6..2 hours. 1002.. (Id.”) (citation omitted).) The applicants further admitted that “[Hayes] at 42 . 17. Claims 1.” respectively. passim.007. See also Santarus. these claims would have been obvious to a POSA in light of the S-1 and Hayes. The S-1 and Hayes combination teaches the pharmacokinetic limitations of all independent claims.” (Ex. In fact.826 (Id.) Therefore. 2012) (affirming obviousness because “an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations.” and “about 2 to about 5. ¶ 98.3d 1344. 1050. while claims 31 and 37 require that administration results in a mean Tmax of “about 1 to about 6 hours. (Id.0 to 3. Cir. and 36 also require that the administration results in a CmaxSS:CminSS ratio of 1. the applicants cited “[t]he pharmacokinetics of SR 4-AP reported by [Hayes]” as being reliable data points for demonstrating the in vivo pharmacokinetics recited in the claims of the ’826 Patent. Inc. 1354 (Fed. Par Pharm. the applicant conceded as much during the prosecution of the ’826 Patent. (Id. To hold otherwise would allow any formulation — no matter how obvious — to become patentable merely by testing and claiming an inherent property.) Specifically.Patent No.5 and a CavSS of 15 ng/ml to 35 ng/ml. at 27:17–30:21.) Each of these pharmacokinetic limitations is obvious over the combination of the S-1 and Hayes. v.

3–4.) Dr.3 53. 20 mg BID and 25 mg BID SR 4-AP: 10 mg BID 15 mg BID 20 mg BID 25 mg BID CavSS 20.0±7. 1023 ¶ 108. applicants admitted that “[o]ne of ordinary skill would expect the same pharmacokinetics in MS patients as in patients with spinal cord injury. 1049 ¶ 47.5 CminSS 14.’” (Ex.3 9 During prosecution. Ex. Polli agree.7 31.4±9.8±5.8 (+5. which is largely renally cleared. Ex. 191 teaches that in patients with spinal cord injury 9 CavSS.0 41.7) in Hayes for 10 mg BID administration of 4-AP falls squarely within the claimed range of ‘CavSS of about 15 ng/ml to about 35 ng/ml.4±9.1 27.Patent No.007.) Additionally.) By acknowledging the reliability of the pharmacokinetic data reported in Hayes. CmaxSS. 1002-222.2 39. “[t]he reported Cavss of 20. because these disabilities were and are not expected to affect metabolism of half-life of 4-AP. and CminSS (in ng/ml) were as follows.4 23.5±9. 1049 ¶ 35.3±10. Ex.3±14.3±14. (Ex. Pleasure and Dr.826 Table 3 on p. for 10 mg BID. 8.3 53.2 39. “the reported 2.5 (Id. 1023 ¶ 108. 1023 ¶ 113. 15 mg BID.3±15.3 (1.) 43 .7 31. In particular. the applicant essentially admitted that the pharmacokinetic limitations recited in the ’826 Patent claims are obvious in view of the prior art.2 CmaxSS 20.8±5. 1049 ¶ 35.” (Ex.0±4. Ex.0±7.

4).’” (Ex.) 10 Hayes reports a CmaxSS of 32. Ex. whereas the range of the ratios—23.7 ± 1.) Table 3 of Hayes additionally discloses a 2. 1023 ¶ 113.4 and 41. Ex.” (Ex.) 44 . and “Hayes discloses that ‘[s]teady state was achieved by day 5 (4 days of fampridine-SR dosing) after twice-daily administration of fampridine-SR. Ex.826 when accounting for error) CmaxSS:CminSS ratio10 in Hayes for 10 mg BID administration of 4-AP falls squarely within the claimed range of ‘CmaxSS:CminSS ratio of 1.’” (Ex.11 (Ex.3:18.3. Ex.4 (so from 9.Patent No.007. 1049 ¶ 49. and Tmax were all measured at steady state.9 (so from 23. 1023 ¶ 111.0 ± 4.2 ± 8. 1049 ¶ 38.2:14. 1005-4.6—results in a CmaxSS:CminSS ratio range of 1.) A POSA also would have known that “the 10 mg BID sustained release 4AP disclosed in the S-1 would have the same pharmacokinetics as both Hayes” and the claimed methods. 1049 ¶ 36. Ex.3. 1023 ¶ 109.0 is 2.2 hours.1) and a CminSS of 14.3–4.0 to 3. Ex. which falls within the claimed ranges of “about 1 to about 6 hours” and “about 2 to about 5.1:9. 8.0 hour tmax for 10 mg BID administration of 4-AP. 11 Although the S-1 teaches administration of 10 mg BID SR 4-AP for twelve weeks and Hayes teaches administration of 10 mg BID SR 4-AP for 6 ½ days. a POSA would have understood that the pharmacokinetics for the two administrations would have been the same because the CavSS.6–18. 1005-7. 1049 ¶ 48. The ratio of 32.5. CmaxSS:CminSS ratio.3–41. 1023 ¶ 113.

3–4. Ex. 692 F. The S-1 and Hayes combination teaches administering 4-AP for “for a day” followed by “maintaining administration. 1023 ¶ 102.” “at least two weeks. and • the tmax for 10 mg BID sustained release 4-AP was 2.) See In re Applied Materials.1–26.” and “greater than two weeks” (all independent claims) Claims 1 and 36 further require that the administration occur for one day followed by maintenance of “at least two weeks. This knowledge of a POSA would have rendered obvious the pharmacokinetic limitations of the independent claims when combining the teachings of Hayes with the 10 mg BID dosing regimen of sustained release 4-AP described in the S-1. 1049 ¶¶ 47–49.0 hour—a range of 1. 1049 ¶ 29. 8. • the CmaxSS:CminSS ratio of 10 mg BID sustained release 4-AP at steady state was 2.007.3d at 1295.7 when accounting for error.5 when accounting for error.826 Thus.Patent No.” claim 6 merely requires administration “for a day” followed by a undefined maintenance period.7—a range of 15. d. Ex. (Ex. as demonstrated by Table 3 of Hayes.7–3. 1023 ¶¶ 114.7 ± 1. while Steady state refers to the situation where the overall intake of a drug is fairly in dynamic equilibrium with its elimination.3 when accounting for error).) 45 . Inc. (Ex..8±5.3 (1. a POSA would have known that • the CavSS of 10 mg BID sustained release 4-AP at steady state was 20.

) The S-1 discloses a “Phase 2 clinical trial.007. In re Montgomery.) 46 . this trial was “designed to compare three doses of 10.” See In re Applied Materials.”) (quotation omitted).. these limitations of independent claims 1. (Ex. twice per day. MS-F202. 1003-37 (emphasis added).” (Ex. Therefore. [that] was designed…to provide pivotal data for support of an NDA for the use of Fampridine-SR in MS. 1001 at 27:17–30:21.” (Id.3d at 1295 (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art. 11.) The S-1 disclosure of a “treatment period of 12 weeks” meets the open-ended limitations of 1) administration for a day followed by maintenance of “at least two weeks. 1023 ¶¶ 119–20.” and claims 31 and 37 require administration for “greater than two weeks. and 36–37 would have been obvious to a POSA in light of the S-1 disclosure and Hayes.” 2) administration for a day followed by a maintenance period.Patent No. 8. 6. 17. 15. 677 F.826 claims 11 and 17 require administration for one day followed by maintenance of “greater than two weeks.” (Ex. 692 F.) According to the S-1. Inc. and to assess their relative safety and efficacy over a treatment period of 12 weeks. 3) administration for a day followed by maintenance of “greater than two weeks. 31. -37 (emphasis added). and 20 mg.” and 4) administration for “greater than two weeks.3d at 1382–83.

1003-37 (emphasis added).’ a POSA would have understood that the MS-F201 10 mg dose did not include any form of titration. 1023 ¶ 121.Patent No. this trial was “designed to compare three doses of 10.) Thus. and to assess their relative safety and efficacy over a treatment period of 12 weeks.” (Ex.826 e.) According to the S-1. MS-F201” which “was designed to determine the optimal dose level of Fampridine-SR” and during which “[a] total of 25 subjects received Fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight weeks of treatment. including before or after the treatment period.” (Id. 1003-37 (emphasis added). (Id.) By contrast. 15. in contrast to the absence of a disclosure of any form of titration in the MS-F202 trial ‘designed to compare three doses of 10. [that] was designed…to provide pivotal data for support of an NDA for the use of Fampridine-SR in MS.” (Ex. twice per day.007. the S-1 also discloses “a doubleblind Phase 2 clinical trial of Fampridine-SR in Multiple Sclerosis. the additional limitation of independent claim 6 of the ’826 Patent would have been obvious to a POSA in light of the S-1 and Hayes. MS-F202.) 47 . and 20 mg. and 20 mg. ¶ 122. 8. -37 (emphasis added). for at least the foregoing reasons.) “In light of the S-1’s disclosure of dose titration in the MSF201 trial. The S-1 discloses a “Phase 2 clinical trial. 15.” (Ex. twice per day. The S-1 and Hayes combination teaches administration of 4-AP “without a… period of 4-aminopyridine titration” (claim 6).

suitable for twice daily dosing.” (Ex. oral tablet formulation of fampridine.Patent No. 1049 ¶ 52.826 f.” (Ex. (Ex.) 48 . for at least the foregoing reasons. 1049 ¶ 51 (emphasis added). the additional limitation of independent claims 11 and 17 of the ’826 Patent would have been obvious to a POSA in light of the S-1 and Hayes.007. 1023 ¶¶ 123–24. Polli has noted that “by definition. 1003-34 (emphasis added). is a sustained release. The S-1 and Hayes combination teaches the presence of a “pharmaceutically acceptable excipient” along with the 4-AP (claims 11 and 17). “Fampridine-SR. As noted above. (Ex. a sustained release formulation contains at least one pharmaceutically acceptable excipient in addition to the active pharmaceutical ingredient (4-aminopyridine). 8. Ex.) Dr. This would have to be so in order for the formulation to function as a sustained release composition as intended. Claims 11 and 17 further require the presence of pharmaceutically acceptable excipient (and/or an additional active agent (claim 17)) along with the 4-AP.) Thus.) The S-1 implicitly teaches a composition comprising “one or more pharmaceutically acceptable excipients” because the 4-AP composition disclosed therein—fampridine SR—comprises a sustained release composition. 1001 at 28:1–50.

1001 at 27:31–32. at 27:60–61. the S-1 discloses Fampridine-SR clinical trials “to support an indication for the treatment of lower extremity motor dysfunction.Patent No. but depends from claim 6. 32-35 and 38–41 are obvious in light of the S-1 in view of Hayes and the knowledge of a POSA. 5.) Claim 7 has the same requirement.1. and requires “an improvement in lower extremity muscle strength.007. but depend from claims 6 and 11. (Id. Claim 2 depends from claim 1.” as in claims 2 and 7.. 18-30. 7–8.” (Ex. 28:19–20. 10. at 27:33–34. (Ex.) Claims 8 and 12 have the same requirement.826 2.” and measuring “the effect of the drug on symptoms of the disease. 8. or would have been obvious to a POSA in further view of Hayes and/or the common knowledge in the field. characterized by weakness. 12-16. 8. The S-1 and Hayes combination teaches “an increase in walking speed is obtained” (claims 2 and 7) and “an improvement in lower extremity muscle strength” (claims 3. 49 .A. As noted above.) a. Dependent claims 2–3. at 27:58–59. and 12).” (Id.b. respectively. Each element of the dependent claims is disclosed in the S-1. 1023 ¶¶ 125–77. and requires that “an increase in walking speed is obtained.) As discussed with respect to the independent claims in Section VI.) Claim 3 depends from claim 1. The dependent claims fail to add any non-obvious limitations. (Id. the S-1 teaches administration of 10 mg BID sustained release 4-AP so that “an increase in walking speed is obtained.

Patent No. 8.007. a POSA would have found it obvious to apply the methods disclosed in the S-1 and Hayes to achieve these additional elements of claims 3.) Thus.) Claim 10 has the same requirement. The S-1 and Hayes combination teaches “the sustained release composition further comprises a pharmaceutically acceptable excipient” (claims 5 and 10). (Id.” (Ex. (Id.3d at 1382–83.) Thus. 1003-37 (emphasis added). a POSA would have found it obvious to 50 .) See In re Montgomery. Claim 5 depends from claim 1. the S-1’s disclosure of treating lower extremity motor dysfunction.” (Ex. (Id. a “POSA would understand that a sustained release formulation contains at least one pharmaceutically acceptable excipient in addition to the active pharmaceutical ingredient (4aminopyridine).” (Ex. at 27:65–67. 1049 ¶ 51. ¶ 135.) A POSA would have understood “weakness” here to refer at least to muscle strength as lower extremity weakness in an MS patient implies deficient muscle strength.A. characterized by weakness. and requiring that “the sustained release composition further comprises a pharmaceutically acceptable excipient.f. Dr.. 8. but depends from claim 6. 677 F. upon reading the S-1 and Hayes.) As discussed with respect to the independent claims in Section VI. and 12. (Ex. 1023 ¶ 132. ¶¶ 131–34. b. 1001 at 27:38–40. Polli testifies that.826 including motor strength. implies an indication directed to an improvement in muscle strength.1.) Therefore.

29: 9–11. requiring that “an in vivo CmaxSS:CminSS ratio of 2. 51 . (Ex. 32.1. at 28:54–56.2. but depends from claim 37.) Claim 16 depends from claim 11. requiring that “an in vivo CmaxSS:CminSS ratio of 1.) Claim 15 depends from claim 11.A.) 12 As discussed with respect to the independent claims in Section VI. respectively. (Id. 27. 29:6–8. respectively.) Thus. Hayes discloses the CavSS for 10 mg BID sustained release 4-AP at steady state.. at 28:26–28.) Claims 19 and 28 have the same requirement.” (Id.0 to 3.A. at 28:29– 31.” which is discussed in section VI. (Id. and so inherently discloses the step of determining this CavSS.) Claim 38 has the same requirement. 1023 ¶ 149. at 30: 22–25. (Id.” (Id. Claim 13 depends from claim 1. and 38.c.5. 15. 28.826 apply the methods disclosed in the S-1 and Hayes to achieve these additional elements of claims 5 and 10. administration or administration at 12-hour intervals.0 to 3. below.d.007. 8.5 to 3.0 and a CavSS of 15 ng/ml to 35 ng/ml are obtained. but depend from claims 1 and 6. 16.. at 28:51–53.) Claim 32 depends from claim 31. 18.i.” (Id. a 12 Claims 32 and 38 also require “b. but depend from claims 1 and 6. The S-1 and Hayes combination teaches the pharmacokinetic limitations of claims 13. requiring “a step of determining the CmaxSS:CminSS ratio or the CavSS” (Ex.d. c. and requires “an in vivo CmaxSS:CminSS ratio of 1. 19.) Claims 18 and 27 have the same requirement. at 29:24–27.0 and a CavSS of 15 ng/ml to 35 ng/ml are obtained. 1001 at 38:21–22.Patent No.

) This knowledge would have rendered obvious the additional pharmacokinetic limitations of the claims when combining the teachings of Hayes with the 10 mg BID dosing regimen of sustained release 4AP described in the S-1. 18. which falls squarely within the claimed range of “CavSS of about 15 ng/ml to about 35 ng/ml. 67.3 (1.3 when accounting for error) for 10 mg BID administration of 4-AP.007. and 28. 692 F. 8.. (Ex. 18–19. 1049 ¶ 36..826 POSA would have found it obvious to apply the methods disclosed in the S-1 and Hayes to achieve these additional elements of claim 13. which also falls squarely within the claimed “CmaxSS:CminSS ratio of 1.) See In re Applied Materials. Also as discussed with respect to the independent claims in Section VI.” of claims 15–16..0 to 3.0 to 3.5” of claims 16.0” of claims 15.3–4.1. Hayes discloses a Cavss of 20.A. 1049 ¶¶ 65–67. (Ex. 52 . and the claimed “CmaxSS:CminSS ratio of 1.0 to 3. 19. Hayes discloses a CmaxSS:CminSS ratio of 2.5” of claims 32 and 38.) Additionally. Inc.7) for 10 mg BID administration of 4-AP. (Ex. (Id. the claimed “CmaxSS:CminSS ratio of 2.) As discussed above. 1005-7. 1049 ¶¶ 65.Patent No. 27.c. Ex.8 (+5.3d at 1295. and 27–28. a POSA also would have known that the S-1’s 10 mg BID sustained release 4-AP would have the same pharmacokinetics as both Hayes and the claimed methods.

Ex..5. but depend from claim 31.A. 32. (Ex. 38.c.) Claims 38 and 41 also have the same requirement. The S-1 and Hayes combination teaches “[BID] administration or administration at 12-hour intervals” (claims 14. twice per day” is about every 12 hours. above. the S-1 discloses that the administration of Fampridine SR to spinal cord injury patients “every 12 hours produced peak concentrations of Fampridine-SR.” (Ex.0 to 3. 1003-37.” (Ex. because researchers can standardize their administration of a drug by using the 12-hour mark” as the designated dosing time. 53 .007. 1003-36. 8. a POSA would have known that the most preferable administration of the S-1’s dosings “10. 13 As noted above. and 41.” as discussed in Section VI. 32–34. 32. 1001 at 28: 23–25. Claim 14 depends from claim 11. and requires “b. 1023 ¶ 158. at 29: 24–27.d. and 41 alternatively require.) 13 Claims 32 and 38 also require “an in vivo CmaxSS:CminSS ratio of 1. (Ex.) Indeed. (Ex. and 41). 1003-37. 15. but depend from claim 37. 38. 1023 ¶ 158. 38. (Id. 35.) The spacing of doses at 12 hour intervals is even more important and “likely to occur in a clinical trial setting such as that disclosed in the S-1. 32. as claims 14. the S-1 teaches BID (twice daily dosing) of SR 4-AP.Patent No. 35.) In addition.826 d. 35. and 20 mg [4-AP].2. thus meeting the limitations of claims 14.i.) Claims 32 and 35 have the same requirement. administration or administration at 12-hour intervals.

(Id. 1023 ¶ 159. at 28: 64–65. 15. 8.” (Id. and requires “maintaining [10 mg BID administration of sustained release 4-AP] for a period of at least a week.007. and 54 .” (Ex. Claim 20 depends from claim 1.) Claim 33 depends from claim 31. 22–25.826 Additionally. but depends from claim 6.) Claim 23 depends from claim 6. 32. and requires “maintaining [10 mg BID administration of sustained release 4-AP] for a period of more than two weeks. and requires “maintaining [10 mg BID administration of sustained release 4-AP] for a period of at least two weeks. (Id. at 28:59–61. 35.) Claim 21 depends from claim 1. 33 and 39. (Ex. and 41 would have been obvious over the S-1 in view of Hayes. 20.) Claim 24 depends from claim 6. but depends from claim 6. at approximately 8:00 AM and 8:00 PM.) e.Patent No. and 25 mg) twice daily for 6 consecutive days …[and] were asked to take their medication at 12-hour intervals. at 28:66–67. 1005-2–3 (emphasis added).) Claim 26 has the same requirement.) Thus.” (Ex. 38.) Claim 25 has the same requirement.” (Id.” (Id. the additional limitations of claims 14. The S-1 and Hayes combination teaches or suggests the “maintaining” and “time” periods of claims 20. 1001 at 28:57–58. at 29:3–5. Hayes discloses a study in which patients “received doses of orally administered fampridine-SR tablets at each dose level (10. and requires “maintaining [10 mg BID administration of sustained release 4-AP] for a period of more than twelve weeks. at 29:1–2.

and 20 mg..007. twice daily.) Claim 39 has the same requirement. 677 F. and to assess their relative safety and efficacy over a treatment period of 12 weeks. 15. 1003-37.1.. 2) “maintaining for a period of at least a week” as in claim 23. 692 F. 3) “maintaining for a period of at least two weeks” as in claim 24. Hayes also teaches “a sustained-release tablet formulation of fampridine (fampridine-SR).) The S-1 disclosure of a “treatment period of 12 weeks” meets the open-ended limitations of 1) “maintaining for a period of more than two weeks” as in claims 20 and 25.” (Id.A. this trial was “designed to compare three doses of 10. [that] was designed…to provide pivotal data for support of an NDA for the use of Fampridine-SR in MS.” 55 . 1023 ¶¶ 167–70. -37 (emphasis added). In re Montgomery. MS-F202. (Id. Inc.826 requires that “said time period is twelve weeks. 8. twice per day.”) (quotation omitted).) According to the S-1. 20 mg. but depends from claim 37. (Ex. each given for 1 week) of fampridine-SR.d. and 25 mg. Therefore. and “examine[s] multiple oral doses (10 mg. the S-1 discloses a “Phase 2 clinical trial.” (Ex. See In re Applied Materials.3d at 1295 (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art. 15 mg.) As discussed in Section VI. at 30:26–27.” (Id. these claims would have been obvious to a POSA in light of the S-1 disclosure.Patent No. at 29:28–29. and 4) “said time period is twelve weeks” as in claims 33 and 39.3d at 1382–83.) In addition.

30:28–29. and 40 all have the same requirement. 1023 ¶ 171. stating that “Fampridine-SR. 34. 1001 at 28:62–63. 1023 ¶ 171. -1. (Id. (Ex.) The S-1 discloses the “said sustained release composition is a tablet” limitations of claims 22. 34.” (Ex. As noted by Dr. for the foregoing reasons.) The limitation “maintaining for a period of more than twelve weeks” as in claims 21 and 26 would also have been obvious to a POSA considering the 12week stable dosing regimen of 10 mg SR 4-AP twice daily.) Hayes also discloses this limitation. and as such may require treatment for more than a 12 week period. 29–30. 34. and 37. at 29:12–15. 31.” (Ex. 29–30.) Hayes further discloses that “[c]linical trials have confirmed that administration of fampridine results in symptomatic improvements in patients with SCI and multiple sclerosis. and 40). contained in a sustained release tablet form. stating that “a sustained-release tablet formulation of fampridine (fampridine-SR) has been 56 . The S-1 and Hayes combination teaches “the sustained release composition is a tablet” (claims 22. (Ex. 30–31.) f. a POSA would understand that MS is a chronic condition. Claim 22 depends from claim 1. and requires that “the sustained release composition is a tablet.007.) Claims 29–30. respectively.) Thus.Patent No. these claim limitations would have been obvious to a POSA in light of the S-1 and Hayes.” (Id. Pleasure. but depend from claims 6. is an oral. 17. 1005-2 (emphasis added). 8. 100329 (emphasis added).826 (Ex. small molecule drug. and 40.

-219. The Blight Declaration data is consistent with the expected dose-benefit correlation. The crux of the secondary considerations discussed in the declarations was “[t]he fact that use of the twice daily 10 mg sustained release composition was as effective in treating multiple sclerosis as the 20 mg sustained release composition.” (Ex. 8.) The declarants argued that this result was surprising because “[t]he working paradigm prior to the present invention was that since there appeared to be a dose-benefit correlation for many of 4-AP’s clinical benefits. 1023 ¶ 179. (Ex. was quite surprising and unexpected. AND 10–41 During prosecution of the ’826 Patent. as much 4-AP was to be given as possible.) For example.007.” (Ex. the results described are neither unexpected nor surprising in view of the disclosures in the prior art that render the treatment methods obvious. (Id. the applicant submitted declarations stating that the claimed inventions were nonobvious in light of secondary considerations.) VII. (Ex. 1023 ¶ 177. improvement in walking did increase with 57 .826 developed. ¶ 180.) Thus.” (Id. However.) First. the declarants’ assertion that the results were unexpected is incorrect. these declarations fail to overcome the particularly strong evidence of obviousness presented above. 1005-2.Patent No. 5–8. 1002-80. yet without the side effects of the larger dose.) However. these additional claim limitations would have been obvious to a POSA in light of the S-1 and Hayes. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT TO OVERCOME THE OBVIOUSNESS OF CLAIMS 1–3.

The court described the unexpected result—the lack of a percent increase in the prevalence of side effects—as constituting “only a difference in degree from the prior art results” rather than a “difference in kind. Moreover. is particularly instructive. 2014). Cir. LP v. Id. Even though the increase was not statistically significant. (Id. any “evidence of superior efficacy does nothing to undercut the showing that there was a reasonable expectation of success with the [10 mg BID] dose.3d 1326. and it remains the only drug approved for this purpose… Moreover. albeit in small increments (1–2 percentage points).) The Federal Circuit’s opinion in Galderma Labs.007. even if the level of success may have turned out to be somewhat greater than would have been expected. Here. Tolmar Inc. 748 F. Second. In that case. the court found unexpected results insufficient for nonobviousness. 8.” Hoffmann-La Roche Inc. the Medori declaration touts Ampyra’s approval as “the first FDAapproved drug for improving walking in patients with MS.Patent No. 737 F.” Id. the applicant’s argument regarding the lack of significant improvement from one dose to another is a difference in degree. 1334 (Fed.826 the dosage. 739 (Fed. and where the dosage difference was slight to begin with—a mere 5 to 10 mg compared with studies in which up to 50–60 mg of 4-AP had been administered—such small increases would be expected.3d 731. the FDA approval of Ampyra® was the first approval for an MS drug without any restriction on the subtype of MS for 58 . Cir. v.. Apotex Inc. 2013). it showed an upward trend.

1385 (Fed.) The S-1 and Hayes disclose the claimed dosing of 10 mg BID.Patent No.) However. none of the declarations establish a nexus between the alleged secondary considerations and the particular limitations of the challenged patent claims..” which failed to enter Phase III clinical trials. 8. Third.) Nor was there evidence that any long-felt need allegedly solved by Ampyra was due to these treatment periods.3d 1376. none of the claims of the ’826 Patent require that a covered drug be an MS treatment effective to treat all four forms (subtypes) of MS—or any specific subtype at all. 1002-73–87. Cir. (See Exs. like “Nerispirdine. -636. none of the declarations attribute such treatment periods to the success of 4-AP. 1050-1–385.826 which it is indicated. v.”) (quotation omitted). 291–499. Ex. 780 F. so there is no nexus to the merits of the claimed invention. Although the claims also require certain treatment periods ranging from a day and an unspecified maintenance period to a period of twelve weeks (which the S-1 also discloses). Kennametal.) The Medori declaration points to other MS drugs. there is no showing that an “at least two weeks” regimen of 10 mg sustained release 4-AP or the pharmacokinetic parameters recited in the claims were—or 59 .) However. (See id. (Id. Ingersoll Cutting Tool Co. 1050-69–70. 2015) (affirming obviousness where “[T]he offered secondary consideration actually results from something other than what is both claimed and novel in the claim. (See id. Inc.” (Ex.007.

8. 726 F. Bayer Healthcare Pharms. although secondary considerations must be taken into account.. 60 . VIII. 5–8.826. Cir.3d 1286.826 could have been—the particular elements that rendered Ampyra successful where other MS drugs failed.. CONCLUSION Thus. Patent No. including purported evidence of unexpected results from the claimed drug combinations).Patent No. Cir. the Federal Circuit has repeatedly held that even relevant secondary considerations supported by substantial evidence may not dislodge the primary conclusion of obviousness. Watson Pharms.007.. 1293 (Fed. Where a strong prima facie obviousness showing exists. Fourth. e.g. See. Inc. Petitioner respectfully requests inter partes review of claims 1–3.440. v. Sandoz Inc. they do not control the obviousness conclusion. Allergan Inc.S. 2013) (proffered evidence of secondary considerations “d[id] not overcome the express teachings of multiple references”).3d 1369. 1376 (Fed. Inc. 2013) (finding claims directed to drug combinations and methods of treating glaucoma obvious and rejecting proffered secondary considerations. 713 F. and 10–41 of U. v. 8.

No. Parvathi Kota (Reg. 4800W Dallas. 61. Texas 75201 P: 214-978-6600/F: 214-978-6621 Back-Up Counsel for Petitioner 61 . Spires/ Sarah E. Skiermont (pro hac vice requested) SKIERMONT PUCKETT LLP 2200 Ross Ave. No. Spires (Reg. /Sarah E. 2015 Dr. 65. 4800W Dallas.007. 8. Texas 75201 P: 214-978-6600/F: 214-978-6601 Lead Counsel for Petitioner September 2.Patent No. Ste. Ste.826 Respectfully submitted.122) Paul J.501) SKIERMONT PUCKETT LLP 2200 Ross Ave.

overnight delivery. was served via FedEx. upon the following: AcordaJD Jones Day 222 East 41st Street New York. a copy of this Petition for Inter Partes Review of U.007. 420 Saw Mill River Road Ardsley. NY 10502 Date: September 2. 8.826 CERTIFICATE OF SERVICE I hereby certify that on September 3.826. including all exhibits. NY 10017 Anthony Michael Acorda Therapeutics. Patent No.Patent No. 2015. Spires/ . 8. 2015 /Sarah E.007.S. Inc.