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Paper No.

___
Filed: September 3, 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. 8,354,437
FILED: APRIL 8, 2005
ISSUED: JANUARY 15, 2013
INVENTORS: ANDREW R. BLIGHT, RON COHEN
TITLE: METHOD OF USING SUSTAINED RELEASE AMINOPYRIDINE
COMPOSITIONS
___________________
PETITION FOR INTER PARTES REVIEW
OF U.S. PATENT NO. 8,354,437

Patent No. 8,354,437
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 the U.S. Patent No. 8,354,437 ..........................................4
1.

The ’437 Patent Specification .....................................................4

2.

The ’437 Patent Claims ...............................................................5

3.

Summary of ’437 Patent Prosecution History ............................6

B.

Effective Priority Date of the ’437 Patent Claims ..............................11

C.

Level of Ordinary Skill in the Art .......................................................18

D.

Claim Construction of Challenged Claims .........................................18
1.

“improving walking” ................................................................19

2.

“treating walking disability” .....................................................19

3.

“for a time period of at least two weeks, wherein said
10 milligrams of 4-aminopyridine twice daily are the
only doses of 4-aminopyridine administered to said
patient during said time period”................................................19
i

Patent No. 8,354,437
4.
E.

“initiating treatment” ................................................................20

Statement of Precise Relief Requested for Each Claim
Challenged ...........................................................................................20
1.

Claims for Which Review is Requested ...................................20

2.

Statutory Grounds of Challenge................................................20

F. Overview of the State of the Art and Prior Art References .......................21

VI.

1.

4-AP History and State of the Art at the Time of the
’437 Patent ................................................................................21

2.

The Acorda S-1 (Ex. 1003) .......................................................24

3.

Hayes (Ex. 1005).......................................................................29

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

Ground 1: Claims 1–21 and 26–40 are obvious in light of
the S-1 in view of the knowledge of a POSA......................................30
1.

Independent Claims 1–4, 32–35, and 38 Are Obvious .............31
a.

The Acorda S-1 teaches “orally administering
to” “a human multiple sclerosis patient in need
thereof” “a sustained release composition of 10
milligrams of 4-aminopyridine” either “twice
daily” or “every 12 hours” “for a time period
of at least two weeks,” wherein the claimed
doses “are the only doses of 4-aminopyridine
administered” during that time period. ...........................31

b. The S-1 teaches “increasing walking speed,”
“improving walking,” “treating walking
disability,” “improving lower extremity muscle
tone,” or “improving lower extremity muscle
strength” ..........................................................................38

ii

........... Dependent claims 13–17 are obvious because the methods wherein “twice daily is about every 12 hours” were obvious based on Acorda S-1 and the knowledge of one of ordinary skill in the art ..... Dependent Claims 5–8 are obvious because the Acorda S-1 discloses a time period comprising twelve weeks for the claimed methods .... 8...... and 40 are Obvious because the Acorda S-1 teaches a time period of “twelve weeks”.............................. Dependent claims 18–21 are obvious because the Acorda S-1 discloses a sustained-release composition is a tablet . Dependent Claims 28-31 are obvious because the Acorda S-1 in combination with common knowledge teaches patients with “relapsing remitting multiple sclerosis”......................................................45 g....................................46 iii .......... 26–31.......... . Dependent claims 9–12 are obvious because the Acorda S-1 teaches “initiating treatment” with 4-aminopyridine............44 f.....................354............................Patent No..................... .......................41 a......43 e................... 37................. Dependent claims 26 and 27 are obvious because the Acorda-S1 teaches “measuring walking speed” and “lower extremity muscle strength” .............. 36–37............. Dependent Claims 36.................42 c.....................46 h...................................43 d......................... Dependent Claims 5–21. Dependent Claim 39 is Obvious because the Acorda S-1 teaches administration of 10 mg 4AP “every twelve hours” ............41 b.... and 39–40 Are Obvious over the Acorda S-1 and Ordinary Knowledge of the Art......437 2.................................................

.......... ... The S-1 and Hayes combination teaches that sustained release 4-AP “provides a release profile to obtain a CavSS of about 15 ng/ml to about 35 ng/ml” (claims 22–25)............................ 18-25................. .... 8............. The S-1 and Hayes combination teaches “twice daily is about every 12 hours” (claims 13–17.....48 3...................... 32-35...................Patent No.............. 39 are obvious in light of the Acorda S-1 in view of Hayes and the knowledge of a person of ordinary skill in the art.........47 2.. Ground 2: Claims 13-17.46 1............... 32–35......................... and 39).......... The S-1 and Hayes combination teaches “wherein said sustained release composition is a tablet” (claims 18–21).............52 VIII. .................49 VII...............................437 B.................354.................................... Any Secondary Considerations are Insufficient to Overcome the Obviousness of the Claims ....................... Conclusion ..........56 iv ...............................................

...............D..3d 1035 (Fed........ Cir.......28 Eiselstein v... Cir.......... 220 F...................... Acad... Frank............. v........... 1126 (W............. v.. Inc............ LP v. 1988).3d 1341 (Fed............... 8...................... Genentech..... Apotex Inc............................................... 726 F......... 2013)....... Cir.... Inc...437 TABLE OF AUTHORITIES Cases Allergan Inc........56 Bayer Schering Pharma AG v........ v..................2d 454 (CCPA 1955) ..3d 1336 (Fed.................... 598 F. 575 F.........3d 1359 (Fed. Inc............ Watson Pharms.......................... 778 F....... v........................ Cir..................3d 1326 (Fed........ 367 F....45 Chiron Corp.... 1995) .....34 In re Am........ Mich.........54 In re Aller........ 1996) ............ 52 F..................... Gentex Corp........ LLC......16 Bayer Healthcare Pharms............................................ 737 F...........354.......................... 2009)...................... Inc. Cir......Patent No................... Supp..... Ctr..3d 1369 (Fed..... 2015). of Sci........ 363 F..... Cir.... 2010)........17 Galderma Labs. Cir........ Cir............................ 26 Donnelly Corp........16 Constant v.......... 2004) ..... 713 F........... 53.............. 918 F..................................... Advanced Micro-Devices.... Cir.. Sandoz Inc..................... Cir... 2013)................. 2004)......... Inc. v...................... 24..3d 731 (Fed................. v. 2014)........ Eli Lilly & Co......2d 1560 (Fed.... 54 Hoffmann-La Roche Inc..... Tech..18 v ................... Inc................... Barr Labs..................3d 1247 (Fed............ 848 F...............56 Ariad Pharms............. 2013)... Cir..................3d 1271 (Fed......19 In re Cuozzo Speed Techs.....3d 1286 (Fed..... Tolmar Inc.... 748 F........

............. Inc............ 1985).................... 398 (2007) ................................... 2002). Cir.....S.27 Tyler Refrig..... No... v........................ Cir......... Osteonics Corp............................... v.. 35.............. 41 In re Peterson. L...D................... Co........ Prods................................ 2003 WL 25539702.... 1:01-cv-2240.............. Premier Election Solutions. 12.24 Waldemar Link v....Patent No.... 587 F........... v. Corp... Cir...... 16 New Railhead Mfg......52 Lockwood v... v.... Eagle Mfg........ Kysor Indus............437 In re Lister.............2d 967 (C.. 2003)........ 30...............354.......3d 1324 (Fed.............. 2009)............... 772 F.. 2009) ......... 14 Perfect Web Techs...................... 8............... Inc... 583 F.............2d 687 (Fed....... Inc...... 2012)..................... 2003 U.............41 Ralston Purina Co...........3d 1307 (Fed.17 In re Montgomery......................3d 556 (Fed.... 315 F...... Cir.........2d 1570 (Fed......17 Sentry Prot.............. LEXIS 27435 (N......... 107 F................................ Inc............P.54 KSR Int’l Co.....3d 1375 (Fed... Cir........... v........ Cir...... InfoUSA... 1994). v. 2015)................ Dist...........3d 1376 (Fed. Ingersoll Cutting Tool Co....... 2012).3d 1325 (Fed.................. 12.........................C.......... Cir..34 Kennametal. v........ 1997).......... Ohio Sept......................... 2003) . Far-Mar-Co................................................................A.. Teleflex Inc..S................................3d 1565 (Fed... 442 F. Cir....... 1971) ....... 298 F... 1985).......C...................... Vermeer Mfg.................. Co.....12 vi ......... 38...3d 1374 (Fed.....24 In re Lukach..... American Airlines.L.. Cir...............27 Voter Verified.. v... 777 F.................. Inc.. 550 U........................ 32 F. Cir.............. Cir..3d 1290 (Fed.......................... 780 F....................... 698 F...... 677 F.......................

................ § 42.........F.................15(A)............................ Inc........................................................F.........................................................R............................................................... § 311 ........................ § 42..................Patent No........................................................C.1 Rules Manual of Patent Examining Procedure § 2107................................... Cir...C......437 Zenon Envtl.....................................................................................S............................R.............................F...............................................S. § 112 ............................... .....S................................100 .... § 42....3d 1370 (Fed.........................F.. § 42. §§ 42.............................................. § 42.............03 .R...C......103(a).......................103 ...................8(b)(1) ....................... 8........8 ......................F...1 37 C............. §§ 42...................3 37 C................................................ § 103 ..............................22 35 U...........R.................................F...........................13 35 U.....104(a)..........8(b)(4) .17 Statutes 35 U.....................R........................ § 42...4 37 C...22 35 U...............R.1 37 C.....R............R...4 vii ...... v.......................... § 42............................................. Filter Corp.. §§ 311–19 ............1 37 C............ 506 F..R...................8(b)(2) .........................1 37 C.............................. U....354.........35 Regulations 37 C..F.................. § 42.......................100 et seq.............S............4 37 C...F.. 2007).............................R..............F.............F........................................................C...................... 42...........................R.............................2 37 C..F.................................3 37 C.....................................1 37 C........S........8(b)(3) ...

at 115–25 (“Juarez”) Exhibit 1007 U.540.txt (“S-1 Registration Statement”) Exhibit 1005 Keith C. no.gov/news/digest/dig093003. 1994) (“Masterson”) Exhibit 1009 Schwid et al. 1992) (“van Diemen”) viii . 216 Int’l J.437 TABLE OF EXHIBITS Exhibit No.354. 8. available at http://www. 2003). Pharmacokinetic Studies of Single and Multiple Oral Doses of Fampridine-SR (Sustained-Release 4Aminopyridine) in Patients With Chronic Spinal Cord Injury. 2013) (“the ’437 Patent”) Exhibit 1002 Relevant excerpts of U. 4. 60/560. 2005) (issued Jan. 1997) (“Schwid”) Exhibit 1010 Richard E.938. Blight & Ron Cohen. Inc.sec.Patent No. 9. Patent No. Registration Statement Under the Securities Act of 1933 (Form S-1) (Sept.354.S. U. 60 J.. M. PlaceboControlled. 26 Clinical Neuropharmacology. 2003) (“S-1”) Exhibit 1004 Rules and Related Matters..437 Prosecution History (“’437 prosecution history”) – Part 1 Exhibit 1003 Acorda Therapeutics. Effects of 4-Aminopyridine in Patients with Multiple Sclerosis. 2003-186 (Sept. 2004) (“the Provisional”) Exhibit 1008 Masterson et al. Formulations and Their Use in the Treatment of Neurological Diseases (filed Oct. Sci. 24. 15.354.894 (filed Apr.. 26. Double-Blind. no. Hayes et al. Jones et al. 48 Neurol. et al. at 185–192 (2003) (“Hayes”) Exhibit 1006 Haydee Juárez et al.. 2001.. 32 Annals Neurol. 2. at 817–21 (Apr. Patent No. at 123–30 (Aug..S.. 8. no.. 4.437 (filed April 8. Description Exhibit 1001 Andrew R. Patent No. Influence of Admixed Carboxymethylcellulose on Release of 4-Aminopyridine from Hydroxypropyl Methylcellulose Matrix Tablets.. Cross-over Study. 5.. Neurol. 8. The Effect of 4-Aminopyridine on the Clinical Signs in Multiple Sclerosis: A Randomized.D. Pharm. Provisional Patent Application No. Quantitative Assessment of Sustained Release 4Aminopyridine for Symptomatic Treatment of Multiple Sclerosis.S. 30.S. U. at 353–62 (1983) Exhibit 1011 Harriët van Diemen.

2.biospace..”) Exhibit 1017 C. Darlington. 18–21. 1994) (“Polman”) Exhibit 1013 D. Placebo-Controlled Double-Blinded Dose Ranging Study of Fampridine-SR in Multiple Sclerosis.D. Orally Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis. Nat. American Association for the Advancement of Science (AAAS) EurekAlert! (July 1.354.eurekalert..437 Exhibit No. et al.org/pub_releases/200207/pn-atb062802. no. 1 Current Opinions in Investigational Drugs. 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). 3. Ph. Fampridine Acorda Therapeutics. Description Exhibit 1012 Chris H. at 375–79 Exhibit 1018 Porter Novelli. Neurol. Biospace.4-Diaminopyridine in the Treatment of Patients With Multiple Sclerosis.com/company_profile.php Exhibit 1019 Acorda Therapeutics Company Profile. M.D. 1990) Exhibit 1015 Types of MS. 11. Baltimore. 4-Aminopyridine Improves Clinical Signs In Multiple Sclerosis. et al. at 1136–39 (Nov..D. 2015) (“NMSS”) Exhibit 1016 Declaration of Scott Bennett (“Bennett Decl. at 71–77 (1987) Exhibit 1014 Floyd A. Davis. Abstract. no. 27 Annals Neurol. Multiple Sclerosis Soc’y. Stefoski. http://www. 2002). Sep..Patent No. Nov. http://www.aspx?CompanyId=100 704 (last updated May 9. no. no. 4-Aminopyridine Is Superior to 3.nationalmssociety.. 8.. Acorda Therapeutics Begins Phase 3 Trials of Fampridine-SR for Chronic Spinal Cord Injury.. MD (“Goodman”) ix .” 21 Annals Neurol. et al. M. M.org/What-is-MS/Types-of-MS (last visited Aug. 51 Arch. Polman. at 186–92 (Feb. 2003) Exhibit 1020 Goodman et al. 2002.D. http://www. 2000. 1.. 11.

epo. 8.437 Exhibit No. M. Attachment 1 Exhibit 1031 Bennett Decl.354. M.”) Exhibit 1024 CV of Samuel J. Pleasure. European Patent No. Description Exhibit 1021 European Patent Convention art. 54(1). 5. Attachment 3 Exhibit 1033 Bennett Decl.354.D. Attachment 5 Exhibit 1035 Bennett Decl. Ph.pdf (“Espacenet Brochure”) Exhibit 1028 Espacenet Bibliographic Data for US Patent No. 2452–61. 1065 U. 1 732 548 B9. Attachment 4 Exhibit 1034 Bennett Decl..N. Attachment 9 Exhibit 1039 Stephen L. (“Pleasure CV”) Exhibit 1025 European Patent No. Attachment 6 Exhibit 1036 Bennett Decl. Harrison’s Principles of Internal Medicine. available at http://www.org/law-practice/legaltexts/html/epc/2010/e/ar54. 2000).D. September 16. 15th ed.html -texts/html/epc/2010/e/ar54. Hauser. no. 8. 199 (as amended Nov. Espacenet Brochure.D. (2)..T. Reingold Ph. Goodkin. Pleasure. 29. 2004 (“Acorda EP Brief”) Exhibit 1027 European Patent Office.. M.437 Exhibit 1029 CV of Scott Bennett Exhibit 1030 Bennett Decl. Defining the Clinical Course of Multiple Sclerosis: Results of an International Survey.html (“EPC Art. at 907–11 (Apr. 4. & Donald E. 1 732 548 (B9) (“EP 548”) Exhibit 1026 Excerpts from Proprietor’s Response to Opponents’ Appeals. Ph. Attachment 8 Exhibit 1038 Bennett Decl.D. 46 Neurology.D.Patent No. http://documents. 1973. 2001 x . Lublin. 54”) Exhibit 1022 Fred D. 1996) Exhibit 1023 Declaration of Samuel J.S. M. (“Pleasure Decl.D. filed with the EPO.org/projects/babylon/eponet.nsf/0/4E8744EB 66E8F944C12577D600598EEF/$File/espacenet_brochure_en.D. Attachment 2 Exhibit 1032 Bennett Decl. Attachment 7 Exhibit 1037 Bennett Decl. & Stephen C. Oct.epo.

Nat’l Multiple Sclerosis Soc’y Website. (“Polli CV”) Exhibit 1046 Relevant excerpts of U. Med. 8. James Polli. Description Exhibit 1040 Christian Confavreux. at 1430–38 (Nov.437 Exhibit No. Ph.nationalmssociety.354.437 Prosecution History (“’437 prosecution history”) – Part 4 Exhibit 1049 Relevant excerpts of U. 2015) Exhibit 1042 RESERVED Exhibit 1043 Pleasure Decl.D. and Polli Decl. 2000) Exhibit 1041 Timed 25-Foot Walk (T25-FW).354.S.S.S. Patent No.S.. 8.437 Prosecution History (“’437 prosecution history”) – Part 5 Exhibit 1050 Relevant excerpts of U. Ph.354. 8.D. 8.org/ForProfessionals/Researchers/Resources-for-Researchers/ClinicalStudy-Measures/Timed-25-Foot-Walk-(T25-FW) (last visited Aug.354. 343 New Eng. Relapses and Progression of Disability in Multiple Sclerosis. Patent No.354. Patent No. (“Polli Decl. 16. 8. J. 20.Patent No.”) Exhibit 1045 CV of Dr.354. Patent No.D.S. no. http://www.437 Prosecution History (“’437 prosecution history”) – Part 6 xi . M. Attachment 2 (Claim Charts for the ’437 Patent) Exhibit 1044 Declaration of Dr. 31. Patent No. James Polli.437 Prosecution History (“’437 prosecution history”) – Part 3 Exhibit 1048 Relevant excerpts of U. 8. et al.437 Prosecution History (“’437 prosecution history”) – Part 2 Exhibit 1047 Relevant excerpts of U.

F. § 42.100 et seq. (Credes). L. The RPI hereby certify the following information: CFAD is a wholly owned subsidiary of Credes. Petitioner certifies that the ’437 patent is available for IPR. II.R. (HOM). (HCM).R. HI is 1 .F. and that Petitioner is not barred or estopped from requesting IPR challenging the claims of the ’437 patent on the grounds identified in this Petition. § 42. Inc.437 (the “’437 patent”) (Ex. HOM is the administrative general partner of Credes and HCMF. Hayman Credes Master Fund. §§ 42.F. IP Navigation Group. § 42.P. Hayman Capital Management. Hayman Capital Master Fund.354. HCMF is a limited partnership.P.Patent No. Hayman Investments.437 I.R.C.R.F.F. L. L. MANDATORY NOTICES (37 C. LLC (nXnP). (HCMF).C.R. 8.S. § 42.R.8) A. J. Patent No. nXn Partners. Kyle Bass. § 42. GROUNDS FOR STANDING (37 C. III. HCM is the general partner and investment manager of Credes and HCMF.354. LLC (IPNav).S. INTRODUCTION Petitioner Coalition For Affordable Drugs ADROCA LLC (“CFAD”) requests an Inter Partes Review (“IPR”) of claims 1–40 of U. Real Parties-in-Interest (37 C.104(a).L. (HI). Credes is a limited partnership. 1001) in accordance with 35 U. and Erich Spangenberg are the real parties in interest (collectively RPI). Hayman Offshore Management. §§ 311–19 and 37 C.8(b)(1)) Pursuant to 37 C. 8. L.F.104(a)) Pursuant to 37 C. Petitioner certifies that Coalition For Affordable Drugs (ADROCA) LLC (CFAD).P.8(b)(1).

Credes and/or HCMF. 22. No.. future filings.354. 1-14-cv-00139 (N. W. nXnP or IPNav) has authority to direct or control (i) the timing of. Del. Sun Pharm. CFAD. filed Aug. Petitioner states that the ’437 Patent has been the subject of the following lawsuits: Acorda Therapeutics. v. no other person (including any investor. 8. Apotex Corp. Inc. 2015). v. HCM. Related Judicial and Administrative Matters (37 C. HOM. Other than HCM and J. Inc. 1-15-cv-00391 (D.D. through HCM as the general partner and/or investment manager of Credes and HCMF.. HCMF. J. § 42. filed May 15. Erich Spangenberg is 98. Acorda Therapeutics. nXnP is a paid consultant to HCM. content of. § 42.5% member of nXnP.F. limited partner. Credes. v. Credes. Inc.8(b)(2). No.Patent No.5% member of IPNav. or member or any other person in any of CFAD. filing of.8(b)(2)) Pursuant to 37 C. 2014). Acorda Therapeutics.437 the general partner of HCM. directly or indirectly. No. Erich Spangenberg is the 98. Va. Kyle Bass is the sole member of HI and sole shareholder of HOM. content of. All costs associated with this Petition will be borne by HCM. 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.. Inc. or any decisions or other activities relating to this Petition or (ii) any timing. and HCMF act. IPNav is a paid consultant to nXnP. HI.R.F. Indus. or any decisions or other activities relating to the future proceedings related to this Petition. Mylan Pharm. CFAD. 1-14-cv-00955 2 .R. B.

No. Mylan Inc. Acorda Therapeutics. Petitioner filed IPR2015-00720 seeking inter partes review of U. Back–up counsel are Dr. 1-14-00922 (D. 2014).S. Petitioner is seeking IPR of U. filed July 17.. § 42.S. Patent No. 440. v. Simultaneously with this Petition. Del. Del. Acorda Therapeutics. filed July 18. Accord Healthcare Inc. Ltd. USA. filed July 10. FL Inc. Spires. Acorda Therapeutics. 8.703—a continuation of the presently challenged ’437 patent.8(b)(3)) and Service Information (37 C.501. Inc. Parvathi Kota. On August 24. 2015.685. Inc. 1-14-cv-00935 (D. Inc. No. Teva Pharm. 2014). 8. No. No. Reg.S. Lead and Back-Up Counsel (37 C. filed July 16. Inc. No.S. Acorda Therapeutics. Roxane Labs. Inc. Aurobindo Pharma Ltd. C. 2014.. 8.826. v. Inc. Patent No.685.F. Del. Acorda Therapeutics. 8. 2015. 2015. § 42. the Board issued decisions denying institution for both petitions. Inc.R. 2014). Del. and Acorda Therapeutics. and U. In addition to the related judicial matters. 1-14-cv-0082 (D. No.007. filed July 14. 2014). 2014). Petitioner filed IPR2015-00817 seeking inter partes review of U..R. v. v. No.S..Patent No.F. filed July 15. v. Inc. Alkem Labs. and its child U. and on February 27. No. Del.007. filed July 11. 61.354. Patent No. 1-14-00917 (D. Patent No. v.. Skiermont (pro hac vice requested)— 3 . Inc. 2014).437 (D. 65. 1-14-cv-00909 (D. Patent No.122 and Paul J. v.663.. Del. Del. filed July 7.. 8. No. Reg. Actavis Labs. Acorda Therapeutics. 1-14-cv-00941 (D.8(b)(4)) Lead counsel is Sarah E. 2014). 1-14-cv-00932 (D. Del.826. on February 10.663.

Patent No. Ste. Petitioner consents to electronic service at ADROCA473IPR1@skiermontpuckett.S.” (Ex. 4800W.F.354. 2200 Ross Ave.) The application.103(a). 2005. The ’437 Patent Specification The ’437 patent describes methods of administering 10 mg of a sustained release oral dosage form of 4-aminopyridine (“SR 4-AP” or “fampridine-SR”) twice daily to patients with multiple sclerosis (“MS”) in order to improve certain aspects of lower extremity function.354. No. IDENTIFICATION OF CHALLENGE A. 506293.437 The ’437 Patent is titled “Methods of Using Sustained Release Aminopyridine Compositions. U. 2004.F. 60/560.R.437 all at ADROCA437IPR1@skiermontpuckett. § 42. 1001 at 1.S.894 (the “Provisional”). If any additional fees are due during this proceeding. 11/102. 8. V. 8. Dallas.15(a) and 42. (Id.559 (the “’559 application”). IV. No. filed on Apr. Texas 75201. 8.15(A) AND § 42. (Id. and claims priority to Provisional App.com. Patent App. at 3:57-4:24) The specification discusses 4 .com and of Skiermont Puckett LLP. Any overpayment or refund of fees may also be deposited in this Deposit Account.R.103) The required fees are submitted herewith in accordance with 37 C. 9.) 1. P: 214-978-6600 / F: 214-9786601. the Office is authorized to charge such fees to Deposit Account No. Overview of the U. PAYMENT OF FEES (37 C. §§ 42. was filed on Apr.Patent No.

(Id. at 7:34-8:10.) While the claims also recite limitations relating to “improving walking” (see.” (Id.354. at 12:11-27. claim 2) and “treating walking disability” (see. Each of the nine independent claims describes a method 5 .) In particular. Alzheimer’s disease. e. the use of the Timed 25 Foot Walk – “a quantitative measure of lower extremity function…[in which] subjects were instructed to use whatever ambulation aids they normally use and to walk as quickly as they could from one end to the other end of a clearly marked 25-foot course” – is disclosed. of which claims 1–4. such as increasing walking speed and improving lower extremity muscle tone and strength. at 2:21-24.. and 38 are independent claims. at 3:57-4:24. 32–35.) The inventors describe the composition as “formulated to avoid large peaks in initial release of the aminopyridine” (Id. (Id.) The specification also discusses embodiments of the invention targeted at various therapeutic goals of treatment.) 2.Patent No. e. and ALS. (Id. multiple sclerosis. at 18:53-60..g. 8. for example. (Id. at 3:43-46) and list certain pharmacokinetic parameters achieved by the drug according to dosage. the specification is silent on what is encompassed by these terms beyond improvement in walking speed and lower extremity muscle function. spinal cord injury. claim 38). The ’437 Patent Claims The ’437 patent has 40 claims.437 the use of this pharmaceutical composition for “the effective treatment of various diseases.g.

38) or “at about every 12 hours” (claims 32–35). 35). the “said 10 milligrams of 4-aminopyridine” at the specified frequency “are the only doses of 4-aminopyridine administered to said patient. • “improving walking” (claims 2.437 comprising “orally administering to [a human multiple sclerosis patient] a sustained release composition of 10 milligrams of 4-aminopyridine. e. id. 34). and • “treating walking disability” (claim 38).” (See.500 pages and references over 400 U. at claim 1.559 (’559 Application) on April 8. Summary of ’437 Patent Prosecution History The ’437 patent was filed as Application No. The additional limitations of the challenged dependent claims are discussed below in Section VI..) The administration of the composition is either “twice daily” (claims 1–4.g.g.. id. 8. 2005. and foreign patents and non-patent literature 6 . and for each claim. • “improving lower extremity muscle strength” (claim 4.) The only other limitations of the nine independent claims consist of certain therapeutic objectives of the treatment method: • “increasing walking speed” (claims 1. 1001 at Cover. e. 3. 32).Patent No.354..) The ’437 patent file history is over 2. (Ex. 33). • “improving lower extremity muscle tone” (claim 3. 11/102. at claim 1.for a time period of at least two weeks…” (See.S..

and cancelled claims 17–20. First.” (Id.354. 1002-1–2 1. 8. None of the prior art references relied on in the present Petition formed the basis of any Examiner rejection during prosecution of the ’559 Application.” “improving lower extremity muscle tone. 1 All references to Exhibit hyphenated pin-cites are to the Exhibit’s Bates-labeled page number. (Id. 7. they were rejected as unpatentable in view of the prior art combination of Masterson (Ex.Patent No. the patentee’s submitted claims were rejected at least four times because they were obvious. -3.” or “improving lower extremity muscle strength. -21–25. (Id.) The Examiner issued a restriction requirement requiring the Applicant to elect either Group I (claims 1–16) or Group II (17-20) of the as-filed claims for further prosecution.437 documents. -16-20. 7 . claims 1.” (Ex. claim 17. which were generally directed to “administering to a patient with multiple sclerosis” “a sustained release aminopyridine composition twice daily…less than about 15 milligrams” for “increasing walking speed.) Applicant elected Group I.) Original claims 17–20 were generally directed to “methods of selecting individuals based on responsiveness to treatment.) Over the course of the ensuing prosecution history. The originally filed ’559 Application included original claims 1–16. 12.

) The Examiner also pointed out the obviousness of claims drawn to dosage ranges in view of the prior art. 79–85. this 8 .” (Id. the prior art relied upon by the Examiner “fail[ed] to teach or suggest to one skilled in the art that administration of a twice daily dose of less than about 15 mg of sustained release aminopyridine would be effective in increasing walking speed or improving lower extremity muscle tone…” (Id. In response to this rejection. In particular. in view of Schwid showing “improved in walking speed and lower extremity muscle tone and strength” in patients with MS receiving this formulation. inter alia. noting that the dose optimization argued by the applicants was obvious. attempting to overcome the Examiner’s rejection by asserting that the results of using SR 4-AP at “doses much lower than those expected at the time of the invention” were “surprising and unexpected. (Id. 8.Patent No. -54.) Next. 1009). the applicants argued that the claims were distinguishable over Schwid and Masterson because.437 1008) and Schwid (Ex. (Id.) However. -63–68. -46. rendered the submitted claims obvious. the Examiner maintained the rejection. Id. the Examiner noted that Masterson taught “a method of treating multiple sclerosis comprising administering a controlled administration of [4-AP] that can maintain therapeutically effective blood levels over a period of 12 hours….354. -34–36.” and.) However. the applicants cancelled their original claims and submitted new ones.

354. the applicants also submitted several declarations asserting that secondary considerations – specifically. -181–86. as well as Davis et al. (Id. among other things.) Finally. too.Patent No.) In support of these new claims. 2011 – almost six years after the prosecution of the patent commenced – the applicants cancelled all claims submitted to date (a total of 52 claims) and submitted a new set of claims (claims 53–92). 8. however. Applicant submitted limitations directed to particular functional pharmacokinetic parameters. included the further limitation that the 4AP composition be administered for “at least two weeks” for all claims. (Id. -140–49.) The Examiner. -105–15. -94. on March 17. -183–84. the applicants once again amended their claims and sought to overcome the rejection by arguing that the prior art cited by the Examiner did not disclose the efficacy of a sustained-release 10 mg formulation. maintained her rejection based on obviousness. (Id. 1014). (Ex. (Id. was unsuccessful – the claims were once again rejected in view of the prior art previously cited by the Examiner. (Id. which disclosed MS patients “who displayed greater improvements in motor function” with treatment of 10 mg of 4-AP in comparison to the placebo group. (Id. (Id. 156–65.437 attempt.) The Examiner also found the applicants’ arguments with respect to unexpected results unpersuasive. 90–96.) For certain dependent claims. unexpected 9 .) These new claims.) Subsequently.

354.e. i.) Dr. (Ex. Medori alleging longfelt but unsolved needs: Ampyra® met the long-felt but unsolved needs for an MS treatment effective to improve walking.Patent No. -211–18.. (Id. (Id. the higher the dose. … Ampyra® was the first FDA-approved drug indicated for improving walking in patients with MS.. for an orally administered MS treatment. long-felt but unmet need.) The applicants also submitted a declaration from Dr. 8.. -218) (citations omitted. the surprising results…show that there was no greater therapeutic benefit associated with higher dosages of SR 4-AP in the 10 to 20 mg BID range with respect to improving walking or lower extremity muscle strength. Medori’s declaration further included alleged failures by others: 10 .. 1002-212. the applicants submitted a declaration from Dr. the greater the therapeutic benefit. and commercial success – overcame any apparent obviousness of the claims. and for an MS treatment effective to treat all four forms (subtypes) of MS. Blight—one of the listed inventors of the ’437 patent—setting forth allegedly surprising results: Dr. Blight then explains that the surprising and unexpected results obtained with respect to lower extremity muscle function…at about the time…that there was a dose-benefit correlation for 4-AP’s clinical effects.) In particular. Contrary to this understanding.437 results. which is a lower extremity function.

By December 31.about 10% of the total U. 1001 at Cover. 1007-2. Nevertheless. 2010 through September 30.Patent No. 38.) B. the “Provisional”). 8. -213 (citation omitted). Nerispirdine is a prime example of such a failure by others. the applicants submitted a declaration from Ms. MS patient base-had taken Ampyra®.354. Sabella alleging commercial success of their product: From its launch on March 1. 18–35. 11 . (Id. Ampyra® achieved over $85 million in sales. at least claims 1–4. which like Ampyra…was evaluated in a Phase II clinical trial to improve walking ability in MS patients. However.… In the 13 weeks post launch of Ampyra®. 2004 (Ex. 2010. 9– 16. Additional failures by others to meet the long-felt needs met by Ampyra® also include the prior failures to provide a drug that can treat all 4 of the MS subtypes. Thus.S.000 MS patients. and 39 are not entitled to the benefit of the Provisional’s filing date. Medori describes in her Declaration the drug Nerispirdine. -215 (citations omitted).) The claims were allowed and the patent issued on January 15. filed April 9. about 40.437 Dr. 2010. clinical development of Nerispirdine was discontinued. (Id. Effective Priority Date of the ’437 Patent Claims The ’437 Patent claims the benefit of the ‘894 Provisional application. it achieved approximately 30% of newly written prescriptions by the physician group to whom it was marketed (id).) Finally. 2013 (Ex. since the data did not support progression to a Phase III trial.

See also Lockwood v.3d 1290.. 38.C. 32 F.3d at 1572. it must contain an equivalent description of the claimed subject matter based on an examination of the Provisional’s words. Id. 107 F. To satisfy written description.3d 556. First. 558–59 (Fed. Cir.354. at 1296.. L. claims 1–4. 1997). 1571–72 (Fed.. and the claimed “time period” 12 . 1294–96 (Fed. and 39 each require that 10 mg of 4-AP be administered either twice daily or every 12 hours.Patent No. Waldemar Link v. Co. American Airlines. 18–35.3d 1565. a POSA must immediately discern that the Provisional “necessarily discloses” the ’437 Patent’s claim limitations from the four corners of the Provisional at the time is was filed—it is not enough that a POSA could speculate as to modifications to the Provisional’s disclosure that the inventor might have envisioned but failed to disclose—and it is not even enough if such limitations are obvious from the Provisional’s disclosure. 2002). Lockwood. 298 F. figures. Vermeer Mfg. structures. 1994). 2005. v. and diagrams. Though the Provisional need not use the exact words of later-filed claims. 107 F.L. New Railhead Mfg. For a host of reasons.437 The priority date for those claims is the ’559 application’s filing date: April 8. § 112 ¶ 1. Osteonics Corp. 9–16.C. The ’437 Patent’s challenged claims can only receive the benefit of the Provisional’s filing date if its disclosure satisfies the requirements of 35 U. the Provisional fails to provide adequate written description for the challenged claims.S. Cir. 8. Cir.

” Example 11 of the Provisional describes administering 4-AP during a 12-week “treatment period” at 3 different doses (10 mg.437 for the treatment method be “at least two weeks.” (Ex. “2-week upward titration (10/15 mg bid or placebo)”. emphasis added.) The Provisional nowhere discloses a method of improving any lower extremity function by administering 10 mg 4-AP for “at least two weeks.) The Study Design discloses the following time periods: “2-week placebo run-in”.) However. 1007-56. 15 mg. (Ex. 20 week. 8. 1007-56. based on the placement of Visit 7 in the 12-week treatment period figure. 20 mg) to improve lower extremity function in MS patients—and that is the only disclosure in the Provisional where 10 mg 4-AP is administered twice daily to MS patients. and “2-week post treatment follow-up. “12-week stable treatment period”. parallelgroup study…designed in accordance with the Figure entitled Example 11 Study Design. a POSA would 13 . “1-week downward titration”.” (Ex. placebo-controlled.” (the “two-week limitation”) (Ex. The Provisional does not disclose when Visit 7 occurred. the disclosure of a 12-week “treatment period” to improve lower extremity function in MS patients does not adequately disclose to a person of ordinary skill in the art that the challenged claims’ two-week limitations were necessarily present from the Provisional’s disclosure. 1007-50. Example 11 discloses a “double-blind. However.Patent No. 1001 at claims.354.) Example 11 discloses data collected at Visit 4 (end of upward titration period) and not again until Visit 7.

(Ex.354. Nor does Example 11’s two-week upward-titration period prior to the stable 12-week “treatment” period support the claimed two-week limitations in the challenged claims. therefore. ¶ 43.) However.3d at 1294–96. does not disclose any data for the first two weeks of the 12-week treatment period. “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 14 . 1023 ¶ 41. and exact disclosure of the challenged claims’ two-week limitations—and “a POSA would not immediately discern that the Provisional necessarily disclosed the two-week limitations based on reviewing the Provisional.437 understand that Visit 7 occurred no earlier than week 4 of the 12-week treatment period. the Provisional is silent as to precise method of performing “upward titration (10/15 mg bid or placebo)” for two weeks. In fact. clear. concise. (Ex. (Id. or the applicant collected data but did not disclose it because such data did not show lower extremity function improvement. 298 F. 1023 ¶ 46.) Example 11.” (Id.” (Id. 8.) See also New Railhead. ¶ 42. this disclosure is not a full. and does not disclose improvement of lower extremity function after the first two weeks of this treatment period.Patent No. upon reviewing the Provisional.) As a result.) A POSA “would have inferred from such non-disclosure that the applicant either collected no data after the first two weeks of the treatment period.

¶ 44.) As a result. 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.) At best. Those claims also require 15 . 1007-56.” (Id. following by an upward dose of 15 mg for the remaining portion of the 2-week period. to ensure patients do not have an adverse reaction. because those claims require administration of 10 mg 4-AP—not 10/15 mg 4-AP. Ex. ¶ 47. Nothing in Example 11 suggests that different treatment groups took different dosages during the upward titration period.437 introduced and gradually increased to ensure the patient does not have an adverse reaction to the medication.) Specifically: The figure entitled “Example 11 Study Design” ambiguously alludes to “2-week upward titration (10/15 mg bid or placebo)” without further explanation. And the applicant essentially acknowledges the Provisional’s failure to disclose the upward titration method of Example 11 because it added at least 15 lines of text to the ’437 Patent to explain the dosing parameters of the upward-titration period (Ex. 8. 1007-56. that explanation is different from how a person of ordinary skill in the art at the time the Provisional was filed would have understood the Example 11 Study Design. (Id.354. (Ex.Patent No. As noted. the “upward titration period of Example 11 does not disclose to a POSA that the two-week limitations of the independent claims of the ’437 patent (and their dependent claims that include the two-week limitations) were necessarily present from the Provisional’s disclosure. 1001 at 18:20–36).

) Because all claimed ranges for claims 22–25 claim up to 35 ng/ml—while the Provisional does not disclose at least the upper range of 26.) Lockwood. 107 F. See.. which only discloses CavSS ranges of 15. because those claims are entirely open-ended with respect to duration of dosing. 8. 1007-52. claims 22-25 are not supported by the Provisional because they require a CavSS range of 15 ng/ml to 35 ng/ml in MS patients receiving 10 mg 4-AP BID.Patent No. or their equivalents. (Ex. 363 F. Inc. e.3d 1336.” (Id. 2004) (claims 16 . from the perspective of a POSA such claims “do not disclose to a POSA that the two-week limitation was necessarily present—because such limitations. v. 1007-45. followed by an upward dose of 15 mg—as suggested by Example 11’s disclosure. 1259 (Fed. 2010) (en banc). By contrast. the only CavSS ranges disclosed in the Provisional are in Table 7. (Ex..3d 1247.354. Chiron Corp.) Therefore.5 ng/ml. Cir.1 ng/ml to 26.3d at 1571-72. are not disclosed by the original claims based on a POSA’s evaluation of the disclosure as a whole.437 administering the same dose for at least two weeks—not merely for some undiscernible portion of the two-week upward titration period. Genentech.. original claims 1–2 of the Provisional do not satisfy § 112 for the challenged claims.) See Ariad Pharms. v. 1023 ¶¶ 48. 1349–51 (Fed. Eli Lilly & Co. Cir. 598 F. Inc. Second.6 ng/ml–35 ng/ml— claims 22-25 of the ’437 Patent cannot claim priority to the Provisional. Likewise.g.” (Ex..

772 F. Cir. Eiselstein v.C. 52 F.” (Ex. 1971) (patentee not entitled to an earlier application’s filing date for a claimed Mw/Mn ratio ranging “from 2.354. 1023. Cir. Cir. 442 F. Inc.A.6”). ¶ 49.0” based on a “single example” in the priority application disclosing a “Mw/Mn ratio of 2.Patent No. Frank. 1575–76 (Fed. thus “a POSA would not have immediately discerned that the Provisional necessarily disclosed the full scope of the claimed CavSS ranges. The written support for the claimed CavSS ranges found in the ’437 Patent (Ex. 1378 (Fed. Far-Mar-Co. Ralston Purina Co.3d 1370.. 1040 (Fed..2d 1570. 1995) (disclosed range of 45% to 55% does not provide written description for claimed range of 50% to 60%). (Ex. Filter Corp. passim. 1985) (parent application disclosing 25%–27% water does not support broader claims “in the range of 20%–30%”).3d 1035. 1007.2d 967. U. 506 F.0 to 3.)2 2 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.P. 1001 at 7:57–63) is absent from the Provisional. 969 (C. 2007). v. v..437 broader than the specification lack written description where disclosure lacks a specific and useful teaching commensurate with claim scope). 17 .) See Zenon Envtl. In re Lukach. 8.S.

1023 ¶ 17. with access to a person having an advanced degree (M. 8.F. 778 F. see In re Cuozzo Speed Techs. 1044 ¶ 14. 2004—the earliest possible priority date for the ’437 patent—“would have an M. but instead is one that must be made “in light of the specification as it 18 .” but also “take advantage of specialized skills of others on the team.354.R. 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. and 39 are entitled to a priority date that is no earlier than April 8.D. 1023 ¶ 16. C.) D..) “A POSA may work as part of a multi-disciplinary team and draw upon not only his or her own skills. 2015). in neuroscience or a related field with an understanding of pharmacokinetics and at least some experience in providing drug therapy to MS patients. at least claims 1–4.3d 1271.Patent No. § 42.” (Ex.100(b). Ex. Cir. Level of Ordinary Skill in the Art A person of ordinary skill in the art (“POSA”) as of April 9. 9–16.D.” 37 C. The broadest reasonable construction of claim language is not one that permits any reading. Ex. 1279 (Fed.D. or Ph.) in pharmaceutics or pharmaceutical formulation.437 For all of the foregoing reasons.S. 18–35. 2005. 1044 ¶ 13. specifically oral sustained release formulations. LLC. or Ph.” (Ex. or at least 5 years of experience in formulating oral sustained release pharmaceutical drug products. 38.

367 F. for purposes of this IPR only. “improving walking” The phrase “improving walking” means “to quantifiably make better a patient’s ability to walk.354. that the claim terms of the ’437 patent are presumed to take on the ordinary and customary meaning that they would have to a POSA.) 2.” (Ex. 8. 1023 ¶ 52. 1364 (Fed. Petitioner accepts. 1023 ¶ 56. Acad.) 3. 1. Tech. 1023 ¶ 54. of Sci. wherein said 10 milligrams of 4-aminopyridine twice daily are the only doses of 4-aminopyridine administered to said patient during said time period” The phrase “for a time period of at least two weeks. 2004) (quotation omitted)..” (Ex. Cir.Patent No. Unless otherwise noted.437 would be interpreted by one of ordinary skill in the art.” (Ex. “treating walking disability” The phrase “treating walking disability” means “to relieve or cure abnormalities in a patient’s walking. wherein said 10 milligrams of 4-aminopyridine twice daily are the only doses of 4-aminopyridine administered to said patient during said time period” means “a treatment period equal to or greater than 14 days in which a stable dose of only 10 mg of 4-AP is administered twice daily. including slow speed and impaired lower extremity motor function. Ctr.3d 1359.” In re Am. “for a time period of at least two weeks.) 19 .

437 4. 18–25.S. 39 are obvious under 35 U. “initiating treatment” The phrase “initiating treatment” means “beginning administration of a therapeutic agent or drug. (See Exs.S.S. § 311 of claims 1–40 of the ’437 patent.C.) Claims 1–40 are unpatentable under 35 U.C.C. 1002. 1046-1050. 1001 at 11:40–44. and cancellation of these 40 claims as unpatentable.C. 2. Ex. Statutory Grounds of Challenge Petitioner requests IPR of the ’437 patent claims 1–40 in view of the following references. The S-1 was not cited by the applicant or otherwise introduced to the Examiner during the ’437 patent prosecution. Statement of Precise Relief Requested for Each Claim Challenged 1.) E.Patent No. 8. § 103 in light of 20 1003 and 1005 .354.” (Ex. Claims for Which Review is Requested Petitioner requests IPR under 35 U. passim. and the Examiner did not rely on any of the prior art in the following chart as the basis of any rejection in any Office Action. §103: Ground 1 Proposed Rejections for the ’437 Patent Claims 1–21 and 26–40 are obvious under Exhibit Number(s) 1003 35 U. 32–35.S. §§ 102(a) and (b) or 103.S. 1023 ¶ 58. each of which is prior art to the ’437 patent under 35 U.C. § 103 in view of the S-1 2 Claims 13–17.

Ex. because those teachings were known in the art. 1011. 2004—the earliest possible priority date for the ’437 Patent—a POSA would have known to apply the claimed methods to achieve those objectives. 1003. F.) By the 1990s. researchers have shown the effectiveness of 4-AP treatment in MS patients—“an inflammatory demyelinating disease featuring selective destruction of the central nervous system (CNS) myelin.) Nor does it claim to have pioneered the use of 4-AP to treat MS patients.” (Ex. For over 30 years. the ’437 Patent claims methods of administering 4-AP BID to MS patients for a time period to attain therapeutic objectives such as improving walking. 1012. 1020. 1023 ¶ 18. Ex. passim. (See. 8. 1005. 4-AP History and State of the Art at the Time of the ’437 Patent The ’437 Patent does not claim the 4-AP compound. 1001.) And by 21 . By at least April 9. (Id.437 S-1 in view of Hayes..g.) The ’437 Patent does not even claim that the oral administration of 10 mg 4-AP (or less than 15 mg) BID to MS patients or the use of sustained release 4-AP are novel.354. Ex.) Instead.Patent No. (See generally. Ex. e. (Ex. The pharmacological properties of 4-AP have been studied for decades. Ex. researchers conducted double-blind studies evaluating the effectiveness of oral 4-AP administration in MS patients. Overview of the State of the Art and Prior Art References 1. 1010-2.

. and especially as the disease progresses over time.g. 1012-3. 10 mg) 4-AP to improve lower extremity function in MS patients. Ex. coordination.” (Ex.) Thus. (Ex. especially for ambulation” in patients with MS. including gait. 1014-1. 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. 1013-1. (Ex. 1023 ¶ 26. e. by April 2004. a POSA would have known to use less than 15 mg (e. (Ex. 1008.4-diaminopyridine. increase walking speed. and increase lower extremity muscle strength and tone. ¶ 27.354.. with “motor function (power.) In 1990.) By April 2004. passim. were to improve walking.437 1991.) Polman also found that “4-Aminopyridine was more effective than 3. researchers had measured neurological changes from 7–35 mg of 4-AP in 1–5 mg doses administered every 10–60 minutes. relapsing-progressive.) By 1987. (See.) As a result. 8. 22 . in doses as low as 10 mg. administered 10–25 mg 4-AP (total doses per individual) to MS patients and observed marked improvements in motor functions. among the therapeutic objectives of a POSA “seeking to treat MS patients with 4-AP prior to April 2004. By 1996. Davis et al.” (Id.Patent No. the National Multiple Sclerosis Society (“NMSS”) had introduced four disease categories for MS: relapsing-remitting.g. gait)” in 5 out of 12 patients improving “within minutes of drug injection at doses as low as 2 mg. it was even known in the art that sustained-release oral compositions of 4AP were effective in treating MS.

van Diemen taught administering 4-AP to treat MS disability for at least two weeks. (See id. while minimizing adverse effects. Pharm.437 primary-progressive. and to sustain treatment for a period of time of at least two weeks to maintain the benefits from treatment. Tyco Healthcare Grp.) Relapsing-remitting MS is the most common form of MS.. 1011-2–3. 8. 1022-2.) For example. (Ex. (Ex. with an efficacy analysis performed only in patients who completed “at least two weeks” of treatment.3d 1370. 10 mg BID) would be effective in achieving the treatment objectives for an MS patient.Patent No. Mut. affecting 85% of patients. 642 F. and 12 weeks of treatment. LP v. 1371–72 (Fed. (Ex. Ex. Co. 6. and secondary-progressive.) 23 . 2011). Therefore.g. because all four disease states require continuous treatment to maintain the benefits of the drug over time. 1015-1. 1023 ¶¶ 28–29. a POSA would be motivated to combine the elements of the prior art showing that an oral sustained-release tablet of 4-AP at a low dose (e. 1023 ¶¶ 21–22. Cir.) It is a basic precept in medicine that “physicians always seek to prescribe the lowest effective dose of any medication” to minimize side effects. (Ex. (Ex.) van Diemen further teaches a statistically significant estimated effect of 4-AP on the mean EDSS score after 2. at Table 1.. 1023 ¶ 28.) A typical MS treatment regimen would almost certainly extend for at least two weeks or even months.354.

a POSA would have known that Acorda was investigating fampridine [4-AP] “for the potential treatment of spinal cord injuries and multiple 24 . Premier Election Solutions. Cir. (See Exs.. Cir.. Inc.C. If the S-1 was accessible to interested persons skilled in the art “it is unnecessary to show that anyone actually inspected the reference.3d 1374. 1569 (Fed. 2004. the S-1 would still qualify as prior art against all claims under 35 U. 1003) The S-1 constitutes prior art under 35 U.S. The touchstone is access. The S-1 was not art of record during the ’437 patent prosecution. 1003.2d 1560. “there is no requirement to show that particular members of the public actually received the information.354. 1046–50. 698 F. See also Constant v. Inc.] exercising reasonable diligence. see generally. As early as 2000. 2005 (for claims without provisional priority). Inc. 1380 (Fed. Ex. The Acorda S-1 (Ex.Patent No. 8.) Even assuming arguendo that the priority date is April 9.” Voter Verified. 2003—more than one year before the earliest effective filing date of April 8. § 102(a). 2009). 1314 (Fed.437 2. v. §§ 102(a) and (b) because it was publicly available at least as early as September 30.S.3d 1307.”). Advanced Micro-Devices. 2012) (quotation omitted). can locate it. 848 F.” In re Lister. (Ex. 1004-9.C. Cir.) 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[. 1002. 583 F. 1988) (holding if publication is accessible.

1017-1.”). companies in the United States making an initial public offer of stock must file certain forms with the U.354. these public filings have been available online in the SEC’s EDGAR (Electronic Data Gathering. 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.” (Ex.S.Patent No. 1016 ¶ 11.437 sclerosis.) “By law. Securities and Exchange Commission (SEC). 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). ¶¶ 60.”).) Based on such information. 1019-1 (“[t]he Company’s lead product. 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. Fampridine-SR. “and would have been motivated to keep apprised of Acorda’s research and studies conducted with 4-AP in 2003. and Retrieval) system. including Acorda’s research and disclosures. (See id. 1023. 8.” which endeavors to make the filings publicly available within “a matter of 25 .” (Ex.” (Ex.) 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. is in Phase 3 clinical trials for chronic SCI and Phase 2 for MS. a POSA would have been motivated to consult information—particularly public filings such as the S-1—relating to Acorda’s research. Ex. Analysis.) “Since 1996.

which contains basic business and financial information about the issuer. 8. (Id. telling you if similar patents have been claimed in other countries.) The S-1 HTML properties establish that. (Ex.”) “Included in these disclosures is the S-1 form. Acorda 3 The EPO’s “Espacenet” search tool provides access to “patent family information.2) See Constant.” (Id. 2003 SEC Registration Statement.” (Ex. on 26 September 2003 and filed it on 29 September 2003. on September 16.354.) Espacenet’s bibliographic data for the ’437 patent states it was “also published as” Acorda’s opposed “EP1732548 (B9)” patent. including the S-1 form. (Ex.) 26 . by at least September 30. 1027-2.” (Id. and that admission is binding here.) Lest there be any doubt. 1004-9. 2014. 1028.437 minutes. ¶ 14–15) Thus.) The September 30.” (Id. “[t]he SEC received the Acorda Therapeutics filing.3 Specifically. ¶¶ 12. ¶ 11. Acorda has admitted that the S-1 is prior art to a European counterpart of the ’437 patent with the same priority date. 15. n.Patent No. 2003. further establishes its public availability. the S-1 was available to a POSA interested in reviewing information regarding Acorda Therapeutics. 848 F.2d at 1569 (“Evidence of routine business practice can be sufficient to prove that a reference was made accessible before a critical date. which provided instructions to the public for obtaining a printed copy of the S-1 publication via mail.

LEXIS 27435. Annex A. 5 See.. The fact that the admissions occurred during EPO proceedings does not negate Acorda’s admissions. (Ex. 6. (Ex. 4 The S-1 is document C27 in the EPO appeal. Acorda repeatedly admitted that the S-1 was prior art to EP ’548 (See e. 1:01-cv-2240. Kysor Indus. Prods. Cir.D.g.. 1025). ¶¶ 4. 690 (Fed.g.) 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.. 5. Eagle Mfg.g.354.)4 In its EPO brief.27. e. id. 30. 8. Gentex Corp. Dist. 2003) (collecting authority and finding “[s]everal other cases have held that statements made by a patentee during foreign patent proceedings can constitute admissions”).S. 1026.6... Ohio Sept. at *32–33 (N. Sentry Prot. v.Patent No. 777 F. See. 1985) (collecting authority). ¶ 5.2d 687.) 5 For purposes of Acorda’s admissions.. requirements for prior art printed publications. 1026. the EPO standards for writings as prior art are comparable to the U. 1021-1 (“everything made available to the public by means of a written… description …before the date of filing of the European patent application. 2003 U. Corp. v. 27 .. No. Donnelly Corp. 6. (See Ex.S.19. and countered an opponent’s argument that the S-1 (the “C27” reference) anticipates EP ’548’s claims. 2003 WL 25539702. v. Tyler Refrig.”). e.61. Co.39.437 responded to an appeal opposing its European Patent No. 1732548 (B9) (“EP ’548”) (Ex.

The S-1 describes clinical trials conducted using a sustained-release (“SR”) composition of 4-AP. 1996) (finding public use admissions from foreign patent proceedings admissible in U. the S-1 is a prior art printed publication to the challenged claims.354. but that evidence of increasing efficacy at doses higher than 25 mg twice a day was limited. 1003-37. stating that “clinical trials indicated that there was evidence of increasing dose-response through the range of 10 to 25 mg twice a day. 8. -33. and to assess their relative safety and efficacy over a treatment period of 12 weeks.) The Acorda S-1 also discussed a previously conducted Phase II study. was designed. 15 and 20 mg. (Id. twice per day.S. Thus.) The S-1 described using sustained-release fampridine in an MS Phase II clinical trial: The current late Phase II clinical trial. after extensive consultation with a panel of expert MS neurologists and with the FDA. proceedings under FRE 801(d)(2)).” (Ex. MS-F202. Mich. to provide pivotal data for support of an NDA for the use of fampridine-SR in MS. The primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk. The reference teaches the effectiveness of the 10–25 mg BID dosing range. Supp.D. -37.Patent No. The clinical trial is also designed to compare three doses of 10. emphasis added.) In that study. (Id.437 918 F. MSF201. 1126. possibly being offset by increased side effects. “a total of 25 subjects received fampridine-SR in doses increasing from 10 mg to 40 mg twice per day 28 . 1134–35 (W. which was completed in 2001.

Hayes was not the basis of any Examiner rejection during the ’437 Patent prosecution.437 over eight weeks of treatment. § 102(a). priority date. the applicant cited Hayes as prior art evidence supporting its claimed pharmacokinetic ranges. 1005. at doses from 10 to 25 mg twice a day. 1005) Hayes constitutes prior art under 35 U.) Rather.) Even assuming arguendo an April 9.C. 8. for claims not entitled to provisional priority.Patent No. 1002.) The S-1 disclosures teach nearly all claim limitations. 3. passim. as explained in more detail below. (Ex.” (Id. 1046-1050. 2004. and 11 subjects were given placebo over the same period. (Ex. 2005. Clinical Neuropharmacology—more than one year before the earliest effective filing date of April 8. 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. §§ 102(a) or (b) to all claims because it was published and accessible by September 2003 (Ex. 1002-205.) The Hayes reference teaches that “[c]linical trials have confirmed that administration of fampridine [4-AP] results in symptomatic improvements in 29 .C.354.S. 1016 ¶¶ 16–21) in the peer-reviewed journal. Hayes would still be prior art against all claims under 35 U. (Exs.) The MS-F201 Phase II trial “demonstrated that doses up to 25 mg twice a day were well tolerated.” (Id.S. Hayes (Ex.

) The data for 10 mg BID showed a CavSS (average plasma concentration at steady state) of 20. e. 8.g. 15 mg.7) ng/mL – a range of 15. (See.) Dose administrations occurred every twelve hours.) A POSA 30 . and 25 mg.” (Id.1 ng/mL to 26. (Id. Ground 1: Claims 1–21 and 26–40 are obvious in light of the S-1 in view of the knowledge of a POSA.) Table 3 provides pharmacokinetic data measured at various points in the multiple-dose study. The combination of the S-1 with common knowledge available to a POSA teaches each limitation of the challenged claims.. 20 mg.5 ng/mL (accounting for error). would have been motivated to consult the S-1 in order to keep apprised of Acorda’s clinical research activities investigating the use of sustainedrelease formulations of fampridine in MS patients.” (Ex. 10-25 mg) [1] administered as a single dose…and [2] twice daily for 1 week…in patients with chronic.8 (±5.Patent No. -1. -3) The doses in each study were 10 mg. sustained-release (SR) formulation of fampridine (fampridine-SR. One of ordinary skill in the art.) It presents the results of two studies “conducted to determine the pharmacokinetics and safety profile of an oral.) VI. incomplete SCI. Ex. (Id. (Id. 1017.437 patients with SCI and multiple sclerosis. 1005-1. prior to 2004. -2. (Id. -5–7. (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. DETAILED EXPLANATION OF THE CHALLENGE A.354. -4.

Patent No.) 1. 1023 ¶ 39. and 38 Are Obvious a. while minimizing adverse side effects. 1023 ¶¶ 2. Ex. (Id. The Acorda S-1 teaches “orally administering to” “a human multiple sclerosis patient in need thereof” “a sustained release composition of 10 milligrams of 4-aminopyridine” either “twice daily” or “every 12 hours” “for a time period of at least two weeks. that Fampridine-SR is another name for sustained release 4-aminopyridine. 36.) The S-1 confirms. oral tablet formulation of fampridine. The Patent Owner cannot reasonably dispute that the Acorda S-1 teaches “orally administering to” “a human multiple sclerosis patient in need thereof” “a sustained release composition of 10 milligrams of 4-aminopyridine. [which] is a sustained release.” wherein the claimed doses “are the only doses of 4-aminopyridine administered” during that time period. 100334. or SR 4-AP. 48. which includes fampridine”). (Ex. Independent Claims 1–4.354. 8. The S-1 describes research into “Fampridine-SR.” (Ex.) The S-1 also discloses the details of multiple clinical trials in which Fampridine-SR 31 .437 would then have been motivated to combine the disclosure of the S-1 with common knowledge in the field to arrive at low-dose methods for improving lowerextremity functions associated with MS. 32–35. (“We have a worldwide exclusive license from Elan to its patent for the sustained release formulation of aminopyridines.” as required by all of the independent claims. and a POSA would have understood.

” (Id. -37 (emphasis added).Patent No.437 was administered to patients suffering from MS.) In sum. wherein patients exhibited improvements in walking strength and speed within the first 3 weeks.) To do so.” (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. -37 (emphasis added). 1003-37–39.” and “demonstrated that doses up to 25 mg twice a day…were associated with statistically significant improvements in walking speed and leg muscle strength. all with the intended outcome of improving lower-extremity function.” (Id. 8. “subjects received Fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight weeks of treatment. (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 32 . (Ex. “[m]ost of the improvement in strength and walking speed was apparent within the first three weeks of the Fampridine-SR treatment. timed walking. at doses from 10 to 25 mg twice a day. MS-F201.354.) Significantly. in which MS patients received 4-AP twice a day orally for 8 weeks. including motor strength.) The S-1 discloses that the “Phase 2 clinical trial of Fampridine-SR in Multiple Sclerosis. the S-1 disclosed the results of a completed clinical trial. and self-reported fatigue. The 4-AP dosing during the first 3 weeks of treatment was 10–25 mg twice per day.

¶ 94. Following the MS-F201 trial. twice per day.) See Tyco Healthcare Grp. 8.437 administered to MS patients for a short period of time (e. [that] was designed…to provide pivotal data for support of an NDA for the use of Fampridine-SR in MS. 642 F.Patent No.” (Ex. and to assess their relative safety and efficacy over a treatment period of 12 weeks. this trial was initiated early in 2003 and was “designed to compare three doses of 10.) “In light of this disclosure that a stable 10 mg dose was chosen for MS-F202 following the conclusion of the MS-F201 trial ‘designed to determine the optimal 33 .354. and 20 mg. 15.. would have motivated a POSA to try the lowdose 10 mg SR 4-AP based on a reasonable likelihood that such a dose would be successful at improving lower extremity functions of MS patients” (Id. MS-F202.” (Id. a POSA would seek to administer the lowest efficacious dose for safety reasons. and “the S-1 and a POSA’s knowledge of MS and SR 4-AP literature reviewed above in paragraphs 18-35. the S-1 discloses a second “Phase 2 clinical trial. two weeks) to achieve an improvement in lower extremity strength and walking speed.) According to the S-1.” (Ex. 1023 ¶ 92.g. -37 (emphasis added). The S-1 provides exactly that teaching. LP. 1003-37 (emphasis added).) The primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk.) Further.” (Id.3d at 1371–72 (“physicians always seek to prescribe the lowest effective dose of any medication”).

it is not inventive to discover the optimum or workable ranges by routine experimentation.3d 1289.3d 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. 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. 220 F. Cir. 2003) (“[W]hen. 1295 (Fed. ¶ 71. 1329–30 (Fed. as here. 100337 (emphasis added). 315 F.2d 454. 1023. 642 F. quoting Ex. Moreover.) See In re Peterson. 8.” (Ex. 692 F. 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. “[t]he current late Phase II 34 .” particularly in the case of “patients sensitive to the side effects of” the medication). LP. characterized by weakness and walking impairment. 1003-37.354.’ the ’437 patent’s claimed point of novelty over the prior art—its 10 mg dose—would have been obvious to a POSA. 456 (CCPA 1955)). 2012) (“‘[W]here the general conditions of a claim are disclosed in the prior art.437 dose level of Fampridine-SR. In re Applied Materials.) The S-1 further disclosed that.Patent No.” (Ex.”). Inc. the [obviousness] conclusion is even more compelling than in cases of mere overlap. 1023 ¶ 29.) See Tyco Healthcare Grp.3d 1325.” (Ex.’”) (quoting In re Aller. the claimed ranges are completely encompassed by the prior art. Cir..

) See In re Montgomery. Cir. and therefore triggers the Office’s presumption of a reasonable expectation of success—which the Federal Circuit has found dispositive for obviousness.3d 1375. and particularly with respect to improving lower extremity muscle strength and walking speed. emphasis added. after extensive consultation with a panel of expert MS neurologists and with the FDA. Further. The S-1 establishes this fact based two human clinical trials. a POSA would reasonably expect all doses (10. 677 F. both of the clinical trials described in the reference involved twice daily dosing.” and reasoning that.) “Based on these statements of intent to rely on this clinical data for NDA submission and drug label indications. 1023 ¶ 81. 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”) (emphasis added).437 clinical trial.354. 15. 100337.Patent No. “if an applicant has initiated human clinical trials for a therapeutic product or process. to provide pivotal data for support of an NDA for the use of fampridine-SR in MS.” (Ex. (Ex. including for the 10 mg dose. 1382–83 (Fed. as is explicit in the S-1. the limitation of independent claims 1–4 and 38 that requires 35 . MS-F202.” (Id. was designed. -33.) Therefore. 2012) (affirming invalidity over a published clinical protocol “designed to obtain data for submission to regulatory agencies. and 20 mg) of this trial to be successful in treating lower extremity motor dysfunction.

1003-45 (“Human clinical trials…: Phase 2: The drug is administered to a limited subject population to identify possible adverse effects and safety risks.) “Because it is common knowledge that a day is 24 hours. independent claims 32–35 require that the SR 4-AP be administered “every 12 hours. As the bold typeface above indicates.” (Ex. 1001 at claims. it would have been obvious to a person of ordinary skill in the art to administer the 10 mg at the 12 hour mark to ensure evenly spaced. (See Ex. 1001 at claims. the S-1 discloses the administration of Fampridine SR to spinal cord injury patients occurred twice daily “every 12 hours produced peak concentrations of Fampridine-SR. Ex. twice daily dosing.) Indeed. the S-1 explicitly discloses claim limitations common to claims 1-4.Patent No.354. 1023 ¶ 67.) Similarly.” (Ex.” (Ex. 8. 1023 ¶ 76. that these Phase 2 clinical trials for MS were conducted in ‘human multiple sclerosis patient[s] in need’ of treatment. and half of a day is 12 hours.” (Ex.437 “twice daily” administration was disclosed in the S-1. and 38: 1) orally administering to 2) a human 6 multiple sclerosis patient in need thereof 3) a sustained release 6 “A POSA would have understood. to determine the efficacy of the product for 36 . and the S-1 confirms. 1003-36 (emphasis added)). 32-35.

32–35. 1003-37.) With respect to the final limitation of claims 1–4. Cir.437 composition of 10 milligrams of 4-aminopyridine. the requirement that the specified doses be the only doses of 4-AP given to the treated patient. 8. 15. and 38. all other administrations of that medication are suspended or avoided. 2012) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.. 12 weeks). (Ex. any data concerning the safety or efficacy would be subjected to a variety of confounding factors and would be essentially useless in the field as evidence.) According to the common knowledge of a POSA.354.”). 1023 ¶ 64. or 5) every 12 hours.Patent No. 692 F.e. (Ex. See In re Applied Materials.3d 1289. 1295 (Fed. “in order to test a particular dose of a medication. Inc. and 20 mg. 6) for a time period of at least two weeks (i. in clinical trials such as the ones described in the S-1. a POSA would have understood that the MS-F202 comparison in the S-1 of “three doses of 10.) 37 . specific targeted diseases and to determine dosage tolerance and optimal dosage.”) (quotation omitted). 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. either 4) twice daily..” (Ex. If additional medication had been given.

characterized by weakness and walking impairment.) Hence. and 38.Patent No.) See In re Montgomery. 1003-37 (emphasis added).) Claim 38 requires “treating walking disability. [and] timed walking” satisfies the additional limitations of claims 1–4.” “improving lower extremity muscle tone.437 1023 ¶ 73. 8.” (Id. 32–35.” (Id. (Ex.” and measuring “an improvement in average walking speed” and “the effect of the drug on symptoms of the disease. 677 F.” (Id. The S-1 teaches “increasing walking speed.” or “improving lower extremity muscle strength” Claims 1 and 32 additionally contain the requirement of “increasing walking speed.” “treating walking disability.) Claims 3 and 34 require “improving lower extremity muscle tone.) Claims 4 and 35 require “improving lower extremity muscle strength. The S-1 is replete with the researchers’ observations that the administration of the sustained-release formulation of fampridine resulted in “improvement in 38 . (Id. ¶ 72. 1001 at claims.354. including motor strength. the specified doses of 4-AP “were the only doses of 4-AP received by study participants” during treatment and this claim limitation was obvious.) Claims 2 and 33 require “improving walking.) The S-1 disclosure of Fampridine-SR clinical trials “to support an indication for the treatment of lower extremity motor dysfunction.” (Ex.) b.3d at 1382–83.” (Id.” “improving walking.

8.” (Ex. and looked at the improvement in walking speed between the baseline period and the average over the first four treatment weeks.g.” (Id. 1023 ¶¶ 65. used as a primary measure of improvement in the studies 39 . -37. MSFC.437 walking speed. 1001 at 12:11–27. 37. 35.” (Id. called the Multiple Sclerosis Functional Composite Score. 80–85.. and involves timing the subject completing a 25 foot walk.” (Ex.) The T25-FW “is part of a standardized set of neurological tests.) In particular. [they] found clear differences in the pattern of response between Fampridine-SR and placebo-treated subjects. 33.354. (Ex. the specification is silent on what is encompassed by these terms beyond improvement in walking speed and lower extremity muscle function. with respect to the limitations “improving walking” (claims 2 and 33) and “treating walking disability” (see. when the researchers “examined the measurements from individual subjects.) The researchers additionally found that “the Fampridine-SR treated group showed a marked tendency for improvement in speed.) Applying this knowledge to the S-1.) As noted above.Patent No. 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 claims 1 and 32’s “increasing 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’). e.) A patient’s score on the T25-FW.” (Id. claim 38).” (Id. 1003-30.) In one clinical trial.

but also other aspects of walking. the S-1’s disclosure of treating lower extremity motor dysfunction.” and measuring “the effect of the drug on symptoms of the disease. 1003-37 (emphasis added).) Muscle tone.” satisfying claims 3 and 34. (Id.354. respectively.” (Ex. (Ex. (Ex. (Id. a POSA would understand that teachings from the S-1 related to “treatment of lower extremity muscle function” (discussed below) and “increasing walking speed” also meet the requirement of “improving walking” and “treating walking disability” recited in claims 2 and 33. (Id.) In light of this disclosure in the S-1. ¶¶ 86–87. (Id. a POSA would have found 40 . and as discussed above. as a POSA would have known. 8. refers to a muscle’s resistance to passive stretch during a resting state. and claim 38.) In addition. 1023 ¶¶ 65.) Thus. is indicative of not just walking speed. characterized by weakness. (Id. implies an indication directed to improvements in muscle strength and muscle tone. characterized by weakness. including motor strength.) A POSA would have understood “weakness” in this context to refer to both muscle strength and tone. it would be obvious to a POSA that such improvements would naturally also improve “lower extremity muscle tone.) Thus. ¶ 87. 86–87.437 disclosed in the S-1.Patent No.) Therefore. 1023 ¶ 84. the S-1 discloses Fampridine-SR clinical trials “to support an indication for the treatment of lower extremity motor dysfunction.) Lower extremity weakness in an MS patient implies both deficient muscle tone and strength. ¶ 85.

354. InfoUSA.3d at 1382–83. 8. respectively) further define the time period of “at least two weeks” of the independent claims to be “12 weeks. Thus. 26–31. As described herein. and common sense of the person of ordinary skill. 2009) (“KSR expanded the sources of information for a properly flexible obviousness inquiry to include … the background knowledge. Dependent Claims 5–8 are obvious because the Acorda S-1 discloses a time period comprising twelve weeks for the claimed methods Claims 5–8 (dependent on claims 1–4.”). Inc. 4. v. 2004 in view of the Acorda S-1. In re Montgomery. 677 F. 34. 1329 (Fed. each limitation of the dependent claims is disclosed in the Acorda S-1.Patent No. and 35. creativity. a.3d 1324.) See Perfect Web Techs. Cir. (Id..” The Acorda S-1 explicitly teaches a twelve-week time period for treatment: “[t]he 41 . 36–37.. or would have been obvious to a skilled artisan in light of common knowledge in the field of the invention. Inc. Dependent Claims 5–21. and 39–40 Are Obvious over the Acorda S-1 and Ordinary Knowledge of the Art The dependent claims of the ’437 patent fail to add any limitations that would not have been obvious to one of ordinary skill in the art prior to the date of the invention.437 it obvious to apply the methods disclosed in the S-1 to achieve the additional limitations of claims 3. 587 F. 2. all of the limitations of the independent claims of the ’437 patent would have been obvious to a person of ordinary skill in the art prior to April 9.

) Because the S-1 discloses initiating treatment of MS patients in the MS-F202 trial by administering to the patient doses of 10 mg BID of fampridine-SR. Dependent claims 9–12 are obvious because the Acorda S-1 teaches “initiating treatment” with 4-aminopyridine.) 42 . b. the additional limitations of claims 9–12 would have been obvious in light of the S-1 disclosure.) Therefore. respectively) require that the claimed methods of orally administering the sustained release composition twice daily further comprise “initiating treatment of said patient with 4-aminopyridine. (Ex. 1023 ¶ 58. and 20 mg. (Ex. Claims 9-12 (dependent on claims 1–4.Patent No. a person of ordinary skill in the art would have understood this to mean that patients initiated treatment with a 10 mg BID dose as indicated.) Thus. 15. the 12 week time period for administering 10 mg BID of a 4-AP was known in the art in view of the S-1.437 clinical trial is also designed to compare three doses of 10. 1023 ¶¶ 95–96. 1003-37. twice per day. and to assess their relative safety and efficacy over a treatment period of 12 weeks. 8.354.” A skilled artisan would have understood that “initiating treatment” refers to administering a therapeutic agent or drug to a patient. (Id.” (Ex.

1023 ¶¶ 99–100. a person of ordinary skill in the art would have found this claim limitation obvious in view of the Acorda S-1 disclosure.) As described above in Section VI.) 43 . for those same reasons.) The Acorda S-1 explicitly discloses the limitations of these claims. (Ex. 1023 ¶¶ 97–98.” the S1 reference expressly states that doses (including the 10 mg dose) were given to patients “twice per day.) d. small molecule drug. 1003-37.a. Dependent claims 13–17 are obvious because the methods wherein “twice daily is about every 12 hours” were obvious based on Acorda S-1 and the knowledge of one of ordinary skill in the art Claims 13-17. Thus. claims 18–21 would have been obvious to a POSA in light of the S-1.354.” (Ex. contained in a sustained release tablet form. 1003-29 (emphasis added). Dependent claims 18–21 are obvious because the Acorda S-1 discloses a sustained-release composition is a tablet Claims 18-21. stating that “Fampridine-SR is an oral. specify that the “sustained-release composition” is a “tablet. which depend on claims 1–5 respectively (of which claim 5 depends on claim 1). (Ex.” (Ex. 1001 at claims.” (Ex. further define “twice daily” as “about every 12 hours. which depend on claims 1–4 respectively.) Therefore.1.437 c. 8.Patent No. claims 13–17 are invalid as obvious.

” as required by independent claims 1 and 4.Patent No.) Therefore. 1023 ¶¶ 102–103. the Acorda S-1 explicitly discusses measurements taken to assess these two parameters: The Timed 25 Foot Walk is part of a standardized set of neurological tests. “[i]n order to ascertain whether there is improvement in walking speed and muscle strength. Dependent claims 26 and 27 are obvious because the AcordaS1 teaches “measuring walking speed” and “lower extremity muscle strength” Claims 26 and 27. and involves timing the subject completing a 25 foot walk. these additional limitations would have been obvious to one of ordinary skill in the art from claims 1 and 4. We plan to use these measurements to support an indication for the treatment of lower extremity motor dysfunction. “measurement of those aspects is necessary. As an initial matter. above.) 44 . a POSA would understand from basic knowledge of the art that. claims 26 and 27 would have been obvious to a POSA in view of the S-1. MSFC. dependent on claims 1 and 4 respectively.437 e. (Ex. require that “walking speed” and “lower extremity muscle strength” be measured as an additional step to the claimed methods. called the Multiple Sclerosis Functional Composite Score. characterized by weakness and walking impairment. 8.) Additionally. (Ex. 1023 ¶ 102. For reasons similar to those discussed previously. 1003-37.354.” (Ex.

S.. 575 F. 1023 ¶ 105. a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.Patent No. at 421). 8. Barr Labs. 2009) (“‘When there is a design need or market pressure to solve a problem and there are a finite number of identified. A POSA in 2003 would have known that relapsing remitting MS. 1023 ¶ 106. This additional limitation would have been obvious to a POSA. predictable solutions. Cir. dependent on claims 1–4. contain the additional claim limitation that the MS patient undergoing treatment “has relapsing remitting” MS. was the most common type of MS among patients at the time of diagnosis.) See Bayer Schering Pharma AG v.. respectively. Dependent Claims 28-31 are obvious because the Acorda S-1 in combination with common knowledge teaches patients with “relapsing remitting multiple sclerosis” Claim 28-31..3d 1341.437 f. The descriptions of clinical trials on MS patients contained in the Acorda S1 do not further classify the type of MS affecting the study subjects.’”) (quoting KSR Int’l Co. or teach away from treating any particular subtype. 1347 (Fed. Inc. (Ex. 1022. it is likely the product not of innovation but of ordinary skill and common sense.) And because the S-1 does not specify which MS subtype it is intended to treat. (Ex. 550 U. characterized by clearly defined attacks of worsening neurologic function followed by remission. a POSA would have been motivated to utilize the S-1’s disclosed methods to treat relapsing remitting MS patients.354. Ex. 45 . If this leads to the anticipated success.

Patent No. 8,354,437
Thus, claims 28-31 would have been obvious to a POSA having common
knowledge in view of the S-1. (Ex. 1023 ¶¶ 104–06.)
g. Dependent Claim 39 is Obvious because the Acorda S-1
teaches administration of 10 mg 4-AP “every twelve hours”
Claim 39, which depends on claim 38, additionally requires that the 10 mg
SR 4-AP be administered “every twelve hours.” For the reasons discussed above in
Section VI.A.1.a., this limitation, too, would have been obvious to a POSA
considering the S-1.
h. Dependent Claims 36, 37, and 40 are Obvious because the
Acorda S-1 teaches a time period of “twelve weeks”.
Claim 36 (dependent on 32), claim 37 (dependent on claim 33), and claim
40 (dependent on claim 39, which is dependent on claim 38) further require the
treatment period to be “12 weeks.” As described above in Section VI.A.2.a., this
claim limitation was expressly disclosed in the Acorda S-1. (See Ex. 1003-37.)
Accordingly, claims 36, 37 and 40 would have been obvious to a POSA in view of
the S-1.
B.

Ground 2: Claims 13-17, 18-25, 32-35, 39 are obvious in light of
the Acorda S-1 in view of Hayes and the knowledge of a person of
ordinary skill in the art.

Dependent claims 13–17, 18–25, and 39 and independent claims 32–35 are
obvious for at least the reasons described with respect to Ground 1.

46

Patent No. 8,354,437
Each of these would also have been obvious to a POSA over the S-1 in
further view of Hayes and common knowledge available to a POSA. (Ex. 1023 ¶¶
107-128; Ex. 1044 ¶¶ 38, 41, 44.) 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.” (Ex. 1023 ¶¶ 109–11; Ex. 1044
¶¶ 22–24.) In particular, “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.” (Ex. 1023 ¶ 111.) The particular relevance of the Hayes
teachings to the pending claims was explicitly acknowledged by the applicant
during prosecution of the ’437 Patent. (Ex. 1002-204–06.)
1.

The S-1 and Hayes combination teaches “twice daily is
about every 12 hours” (claims 13–17, 32–35, and 39).

Claims 13-17 depends from claims 1–5, claims 32–35 are independent, and
claim 39 depends from claim 38—as described above in Section VI.A with respect
to Ground 1. Each of these claims requires that the 4-AP be administered “about
every 12 hours.” (Ex. 1001 at claims.)

47

Patent No. 8,354,437
“A POSA would have known that the most preferable administration of the
dosings ‘10, 15, and 20 mg [4-AP], twice per day’ described in the S-1 is about
every 12 hours.” (Ex. 1003-37; Ex. 1023 ¶ 125; Ex. 1044 ¶ 38.) “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, because researchers can standardize
their administration of a drug by using the 12-hour mark” as the designated dosing
time. (Ex. 1023 ¶ 125; Ex. 1044 ¶ 39.) Indeed, 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. 1003-36.)
Additionally, Hayes discloses a study in which patients “received doses of
orally administered fampridine-SR tablets at each dose level (10, 15, 20, and 25
mg) twice daily for 6 consecutive days … [and] were asked to take their
medication at 12-hour intervals, at approximately 8:00 AM and 8:00 PM.” (Ex.
1005-2–3 (emphasis added).) Thus, claims 13–17, 32–35, and 39 would have been
obvious over the S-1 in view of Hayes. (Ex. 1023 ¶¶ 97-98; Ex. 1044 ¶ 38.)
2.

The S-1 and Hayes combination teaches “wherein said
sustained release composition is a tablet” (claims 18–21).

Each of dependent claims 18–21, which depend on claims 1–4, respectively,
requires that “said sustained release composition is a tablet.” (Ex. 1001 at claims.)
As explained above, the S-1 discloses the “said sustained release
composition is a tablet” limitations of claims 18–21, stating that “Fampridine-SR,
48

In fact. 1001 at claims.) Hayes also discloses this limitation. 1003-29 (emphasis added). 1044 ¶ 54. the applicant conceded as much during the prosecution of the ’437 patent. contained in a sustained release tablet form.” (Ex.Patent No. the applicant 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 ’437 patent.) “Thus.437 is an oral. The S-1 and Hayes combination teaches that sustained release 4-AP “provides a release profile to obtain a CavSS of about 15 ng/ml to about 35 ng/ml” (claims 22–25). these claims would have been obvious to a POSA in light of the S-1 and Hayes.) The combination of S-1 and Hayes discloses the pharmacokinetic ranges recited in dependent claims 22-–. 8.) Specifically. applicant’s basis for patentability relied squarely on the known “pharmacokinetics of SR 4-AP.” (Ex.354.) The applicant further admitted that “[Hayes] at Table 3 on p.” (Ex. Dependent claims 22–25 of the ’437 patent require that the 10 mg 4-AP sustained-release tablet “exhibit a release profile to obtain a Cavss of about 15 ng/ml to about 35 ng/ml. (Id. 1002-205. 1005-2. 1023 ¶ 100. During examination.” (Ex. Ex. small molecule drug.) 3. 191 49 . stating that “a sustained-release tablet formulation of fampridine (fampridine-SR) has been developed.” (Ex.

437 teaches that in patients with spinal cord injury 7 CavSS. 1044 ¶ 33. 1023 ¶ 120.) Drs. 20 mg BID and 25 mg BID SR 4AP:” CavSS 10 mg BID 15 mg BID 20 mg BID 25 mg BID 20.354. the applicant essentially admitted that the pharmacokinetic limitations recited in the claims of the ’437 patent are obvious in view of the prior art.4±9. Pleasure and Polli agree.” (Ex. and CminSS (in ng/ml) were as follows.3 53. because these disabilities were and are not expected to affect metabolism of half-life of 4-AP. CmaxSS. (Ex.8 (+5. Ex. the reported Cavss of 20. In particular.5 (Id.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.) 50 .” A POSA also would have known that the 10 mg BID sustained release 4-AP disclosed in the S-1 would have the same pharmacokinetics as both Hayes and the 7 During prosecution.2 39.7 31.) By acknowledging the reliability of the pharmacokinetic data points reported in Hayes. -205–06. 15 mg BID. 8.8±5. for 10 mg BID. 1002-205. the applicant admitted that “[o]ne of ordinary skill would expect the same pharmacokinetics in MS patients as in patients with spinal cord injury.3±14. which is largely renally cleared.Patent No.0±7.

due to overall intake of a drug being equal to drug elimination. because there are overall increasing or decreasing levels of drug in the system.) “Steady state refers to the pharmacokinetic situation where the drug plasma profile is the same. Prior to that point. 1044 ¶ 33.” (Ex. Ex. a POSA would have understood that the pharmacokinetics for the two administrations would have been the same because the CavSS was measured at steady state.Patent No. 1023 ¶ 115. (Id. and 20 mg BID doses. as they provide guidance regarding the clinical effects of 10.354. 1044 ¶ 28. as well as the plasma concentrations resulting from those dosages. 1005-4.) A POSA looking to optimize a stable dose regimen of sustained release 4-AP would have been motivated to look to both the S-1 and Hayes. Ex. Ex. Ex. 8 (Ex. resulting in stable treatment efficacy of 4-AP. respectively. (Ex. 1044 ¶ 42. and Hayes discloses that “[s]teady state was achieved by day 5 (4 days of fampridineSR dosing) after twice-daily administration of fampridine-SR. 1023 ¶ 121. 15.437 claimed invention.) 51 . 1044 ¶ 35. 1023 ¶ 127. ¶ 110. Ex.) A POSA would find further motivation to combine the references to assess the safety of sustained release 4-AP. any observed efficacy could correspondingly change. 1044 ¶ 42. 8. Ex. 1003-37 (“The clinical trial is 8 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.” (Ex.

v.S.7—a range of 15. 1005-2 (“This paper describes 2 open-label. 692 F. single-center studies designed to examine the pharmacokinetics and safety profile of fampridine-SR”. Thus.437 also designed to compare three doses of 10. (Ex. 1044 ¶ 44.) See In re Applied Materials. 398. Ex. and 20 mg.5 when accounting for error—“rendering obvious the pharmacokinetic limitations of claims 22-25 when combining the teachings of Hayes with the 10 mg BID dosing regimen of sustained release 4-AP described in the S-1.) See KSR Int’l Co. 15. and to assess their relative safety and efficacy”) (emphasis added). 8. VII. 420 (2007) (holding that “any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the limitations in the manner claimed”).. However.1–26. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT TO OVERCOME THE OBVIOUSNESS OF THE CLAIMS During prosecution of the ’437 patent. these declarations fail to overcome the particularly strong evidence of obviousness presented above. 1023 ¶ 118.8±5. as demonstrated by Table 3 of Hayes. Ex.. Inc. the applicant submitted declarations stating that the claimed inventions were nonobvious in light of secondary considerations.).354.) (emphasis added. twice per day. 52 . a POSA would have known that the CavSS of 10 mg sustained release 4-AP at steady state was 20. Teleflex Inc.Patent No. 550 U.3d at 1295.

.354. the declarants’ assertion that the results were unexpected is incorrect. the higher the dose the greater the therapeutic benefit. 1002217–18. Tolmar Inc. is particularly instructive. albeit in small increments (1–2 percentage points). (Ex. 737 F.437 The crux of the secondary considerations discussed in the declarations was “that there were no notable differences among the 10 mg BID. 8.Patent No. (See Ex. 1002-217.) However. Cir.” (Id.e. the results described are neither unexpected nor surprising in view of the disclosures in the prior art that render the treatment methods obvious. The court found 53 .) The declarants argued that this result was surprising because of an “understanding in the field…that there was a dose-benefit correlation for 4-AP’s clinical effects. (Ex. The Blight Declaration data is consistent with the expected dose-benefit correlation.3d 731. 1023 ¶¶ 131–32. improvement in walking did increase with the dosage.) Even though the increase was not statistically significant.) For example. LP v. i. 15 mg BID.” (Ex. it showed an upward trend.) First. and 20 mg BID treatment groups with respect to improving walking” and this “comparable efficacy of the 10 mg BID dosage of SR 4-AP as compared to the 15 mg and 20 mg BID dosages…is surprising and unexpected. 2013). (Id. 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. 739 (Fed.) The Federal Circuit’s opinion in Galderma Labs. 1023 ¶ 132. -218.

780 F.” (Ex. 1385 (Fed. 748 F.” Hoffmann-La Roche Inc.Patent No. Here. Cir.” Id.437 unexpected results insufficient for nonobviousness.3d 1376.. the Medori declaration touts Ampyra’s approval as “an MS treatment effective to treat all four forms (subtypes) of MS…Ampyra® was the first FDA-approved drug indicated for improving walking in patients with MS. the applicant’s argument regarding the lack of significant improvement from one dose to another is a difference in degree.) However. 1334 (Fed. Inc. By contrast. Ingersoll Cutting Tool Co. Any “evidence of superior efficacy does nothing to undercut the showing that there was a reasonable expectation of success with the [] dose. Kennametal. v. none of the claims of the ’437 patent require that a covered drug be an MS treatment effective to treat all four forms (subtypes) of MS. and it remains the only drug approved for this purpose. Apotex Inc. 8. 2014). v. even if the level of success may have turned out to be somewhat greater than would have been expected. Cir.3d 1326. the only subtype required by only two of the patent’s 52 claims is the most common subtype—relapsing remitting multiple sclerosis. Second.354. 1002-212.. 2015) (affirming obviousness where “[t]he offered secondary consideration actually results from something other 54 . because the unexpected result—the lack of a percent increase in the prevalence of side effects—constituted “only a difference in degree from the prior art results” rather than a “difference in kind.

) The Medori declaration points to other MS drugs.”) (quotation omitted). (Id..354.” which failed to enter Phase III clinical trials. 1002.) Nor was there evidence that any long-felt need allegedly solved by Ampyra was due to treatment for at least 2 weeks. See. Inc. 8. Watson Pharms. (See id.437 than what is both claimed and novel in the claim. 713 55 . Although the claims also require a treatment period of at least two weeks (which the S-1 also discloses). Where a strong prima facie obviousness showing exists. 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 could have been—the particular elements that explained Ampyra’s alleged success where other MS drugs failed. none of the declarations attribute a treatment period of at least two weeks to the success of 4-AP. Inc. so there is no nexus to the merits of the claimed invention.) However.g. v. Third.) The S-1 and Hayes disclose the claimed dosing of 10 mg BID. Bayer Healthcare Pharms. 1046–50. Fourth.Patent No. although secondary considerations must be taken into account. (See Exs. they do not control obviousness. like “Nerispirdine. (See id. none of the declarations establish a nexus between the alleged secondary considerations and the particular limitations of the challenged claims. e. the Federal Circuit repeatedly finds even relevant secondary considerations supported by substantial evidence may not dislodge the primary conclusion of obviousness.. -213.

3d 1286. Parvathi Kota (Reg.. 4800W Dallas. 8. Ste. Sandoz Inc. Allergan Inc. v.3d 1369. 4800W Dallas.437. Texas 75201 P: 214-978-6600/F: 214-978-6621 Back-Up Counsel for Petitioner 56 . Spires (Reg. VIII. 1376 (Fed. 65. Spires/ Sarah E.122) Paul J. 61. 2015 /Sarah E. 726 F. CONCLUSION Petitioner respectfully requests IPR of claims 1–40 of U. 8. Ste. September 3. Cir. Respectfully submitted. Patent No. Skiermont (pro hac vice requested) SKIERMONT PUCKETT LLP 2200 Ross Ave. Texas 75201 P: 214-978-6600/F: 214-978-6601 Lead Counsel for Petitioner Dr. 1293 (Fed.354. 2013) (proffered evidence of secondary considerations “d[id] not overcome the express teachings of multiple references”).S. No. 2013) (rejecting proffered secondary considerations. Cir.437 F. No.501) SKIERMONT PUCKETT LLP 2200 Ross Ave.354. including purported evidence of unexpected results from the claimed drug combinations).Patent No.

420 Saw Mill River Road Ardsley. NY 10017 Anthony Michael Acorda Therapeutics. overnight delivery.437 CERTIFICATE OF SERVICE I certify that on September 3.354. upon the following: AcordaJD Jones Day 222 East 41st Street New York. 8.S. 2015 /Sarah E. NY 10502 Date: September 3. including all exhibits was served via FedEx. Inc. 8.354. Patent No.Patent No.437. a copy of this Petition for Inter Partes Review of U. 2015. Spires/ .