Bass Petition at Acorda

Paper No.
______
Filed: September 2, 2015
UNITED STATES PATENT AND TRADEMARK OFFICE

____________________
BEFORE THE PATENT TRIAL AND APPEAL BOARD
___________________
COALITION FOR AFFORDABLE DRUGS (ADROCA) LLC
PETITIONER
V.
ACORDA THERAPEUTICS, INC.
PATENT OWNER
___________________
CASE NO.: UNASSIGNED
PATENT NO. 8,663,685
FILED: JULY 20, 2011
ISSUED: MARCH 4, 2014
INVENTORS: ANDREW R. BLIGHT, RON COHEN
TITLE: SUSTAINED RELEASE AMINOPYRIDINE COMPOSITION
___________________
PETITION FOR INTER PARTES REVIEW
OF U.S. PATENT NO. 8,663,685
Patent No. 8,663,685

TABLE OF CONTENTS
I.
Introduction ........................................................................................................1
II.
Grounds for Standing (37 C.F.R. 42.104(a)) ..................................................1
III. Mandatory Notices (37 C.F.R. 42.8) ...............................................................1

A.
Real Parties-in-Interest (37 C.F.R. 42.8(b)(1)) ..................................1
B.
Related Judicial and Administrative Matters (37 C.F.R.

42.8(b)(2)) .............................................................................................2
C.
Lead and Back-Up Counsel (37 C.F.R. 42.8(b)(3)) and

Service Information (37 C.F.R. 42.8(b)(4)) .......................................3
IV. Payment of Fees (37 C.F.R. 42.15(a) and 42.103) ......................................4

V. Identification of Challenge .................................................................................4
A.
Overview of U.S. Patent No. 8,663,685 ................................................4

1.
The 685 Patent Specification .....................................................5
2.
The 685 Claims ..........................................................................5
3.
Prosecution History of the 685 Patent .......................................7
4.
Summary of Selected Prosecution History of the

Parent 826 Patent .......................................................................8
B.
Effective Priority Date of the 685 Patent Claims ..............................12
C.
Level of Ordinary Skill in the Art .......................................................20
D.
Claim Construction of Challenged Claims .........................................20

1.
release profile ........................................................................21
2.
matrix .....................................................................................21
3.
improving walking ................................................................21

E.
F.
Statement of Precise Relief Requested for Each Claim

Challenged ...........................................................................................21
1.
Claims for Which Review is Requested ...................................21
2.
Statutory Grounds of Challenge................................................22
Overview of the State of the Art and Prior Art References ................22
1.
History of 4-AP and State of the Art at the Time of

the 685 Patent ..........................................................................22
2.
The S-1 (Ex. 1003) ....................................................................25
3.
Hayes (Ex. 1005).......................................................................30
4.
Juarez (Ex. 1006) ......................................................................31
VI. Detailed Explanation of the Challenge ............................................................32

A.
B.
35 U.S.C. 325(d) should not bar the petition ...................................32

1.
The present Petition presents a combination of art not

previously before the Office. ....................................................32
2.
The present Petition presents grounds not previously

addressed by the PTAB .............................................................33
Ground 1: Claims 1 and 8 are obvious in light of the S-1 in

view of the knowledge of a POSA. .....................................................35
1.
Independent claim 1 is obvious in light of the S-1

disclosure and the knowledge of a POSA.................................36
2.
Dependent claim 8 is obvious in light of the S-1 and a

POSAs knowledge. ..................................................................41
a.
The S-1 teaches b.i.d. (BID) administration of

SR 4-AP, including at 12 hour intervals (claim
8) .....................................................................................42
ii

C.
D.
Ground 2: Claims 25 are obvious over the S-1 in view of

Hayes and the knowledge of a POSA. ................................................43
1.
The S-1 and Hayes combination teaches a mean Tmax

in a range of about 2 to about 6 hours after SR 4-AP
administration (claim 2). ...........................................................43
2.
The S-1 and Hayes combination teaches a release

profile extending over at least 6 hours and at least
about 12 hours (claims 3 and 4). .............................................46
3.
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
(claim 5). ...................................................................................47
Ground 3: Claims 1, 6 and 7 are obvious in light of the S-1

in view of Juarez and the knowledge of a POSA. ..............................50
1.
The S-1 and Juarez combination teaches SR 4-AP

compositions comprising excipients, as well as
methods for controlling the release rate of the 4-AP
by dispersing it in a rate of release controlling
polymer such as a matrix in which the 4-AP is
homogenously dispersed (claims 1 and 67). .......................51
VII. Any secondary considerations are insufficient to overcome the

obviousness of Claims 18 ............................................................................54
VIII. Conclusion .....................................................................................................58
iii

TABLE OF AUTHORITIES
Cases
Allergan Inc. v. Sandoz Inc.,
726 F.3d 1286 (Fed. Cir. 2013)............................................................................57
Ariad Pharms., Inc. v. Eli Lilly & Co.,
598 F.3d 1336 (Fed. Cir. 2010) (en banc)............................................................18
Bayer Healthcare Pharms. Inc. v. Watson Pharms. Inc.,
713 F.3d 1369 (Fed. Cir. 2013)............................................................................57
Chicago Mercantile Exchange v. 5th Market,
Case CBM2015-00061, PH9 (P.T.A.B. July 16, 2015) .......................................34
Chimei Innolux Corp. v. Semiconductor Energy Lab.,
Case IPR2013-00066, PN10 (P.T.A.B. Apr. 24, 2013) .......................................33
Chiron Corp. v. Genetech, Inc.,
363 F.3d 1247 (Fed. Cir. 2004)............................................................................19
Constant v. Advanced Micro-Devices, Inc.,
848 F.2d 1560 (Fed. Cir. 1988)..................................................................... 25, 27
Donnelly Corp. v. Gentex Corp.,
918 F. Supp. 1126 (W.D. Mich. 1996) ................................................................29
Ex parte Gelles,
22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992) .................................................54
Galderma Labs. LP v. Tolmar Inc.
737 F.3d 731 (Fed. Cir. 2013)..............................................................................55
Hoffmann-La Roche Inc. v. Apotex Inc.,
748 F.3d 1326 (Fed. Cir. 2014)............................................................................56
In re Aller,
220 F.2d 454 (CCPA 1955) .................................................................................39
In re Am. Acad. of Sci. Tech. Ctr.,
367 F.3d 1359 (Fed. Cir. 2004) ............................................................................21
iv

In re Applied Materials, Inc.,
692 F.3d 1289 (Fed. Cir. 2012).................................................................... passim
In re Cuozzo Speed Techs., LLC,
778 F.3d 1271 (Fed. Cir. 2015)............................................................................20
In re Fisher,
57 C.C.P.A. 1099 (C.C.P.A. 1970) ......................................................................19
In re Huston,
308 F.3d 1267 (Fed. Cir. 2002)............................................................................14
In re Lister,
583 F.3d 1307 (Fed. Cir. 2009)............................................................................25
In re Lukach,
442 F.2d 967 (C.C.P.A. 1971) .............................................................................19
In re Montgomery,
677 F.3d 1375 (Fed. Cir. 2012)............................................................................39
In re Peterson,
315 F.3d 1325 (Fed. Cir. 2003)............................................................................38
Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
780 F.3d 1376 (Fed. Cir. 2015)............................................................................56
KSR Intl Co. v. Teleflex Inc.,
550 U.S. 398 (2007) .............................................................................................49
Leapfrog Enterprises Inc. v. Fisher-Price Inc.,
485 F.3d 1157 (Fed. Cir. 2007)............................................................................57
LizardTech v. Earth Res. Mapping, Inc.,
424 F.3d 1336 (Fed. Cir. 2005)............................................................................19
Lockwood v. American Airlines,
107 F.3d 1565 (Fed. Cir. 1997)..................................................................... 14, 18
Microsoft Corp. v. Parallel Networks Licensing,
Case IPR2015-00483, PN10 (P.T.A.B. July 15, 2015) .......................................33

Motorola Mobility v. Intellectual Ventures,
Case CBM2015-00005, PN10 (P.T.A.B. Mar. 27, 2015) ....................................34
Nest Labs, Inc. v. Allure Energy, Inc.,
Case IPR 2015-00181, PN6 (P.T.A.B. May 1, 2015) ..........................................35
Nestle USA, Inc. v. Steuben Foods, Inc.,
Case IPR2014-01235, PN12 (P.T.A.B. Dec. 22, 2014).......................................33
New Railhead Mfg., L.L.C. v. Vermeer Mfg. Co.,
298 F.3d 1290 (Fed. Cir. 2002)............................................................... 13, 14, 16
Santarus, Inc. v. Par Pharm., Inc.,
94 F.3d 1344 (Fed. Cir. 2012)................................................................. 44, 46, 48
Sentry Prot. Prods. v. Eagle Mfg. Co.,
No. 1:01-cv-2240, 2003 WL 25539702, 2003 U.S. Dist. LEXIS 27435
(N.D. Ohio Sept. 30, 2003) ..................................................................................28
Tyco Healthcare Grp. LP,
642 F.3d 1370................................................................................................ 37, 39
Tyler Refrig. v. Kysor Indus. Corp.,
777 F.2d 687 (Fed. Cir. 1985)..............................................................................28
Valeo North America, Inc., et al. v. Magna Electronics, Inc.,
Case IPR2014-01203, PN13 (P.T.A.B. Jan. 25, 2015) ........................................33
Waldemar Link v. Osteonics Corp.,
32 F.3d 556 (Fed. Cir. 1994)................................................................................14
Zenon Envtl., Inc. v. U.S. Filter Corp.,
506 F.3d 1370 (Fed. Cir. 2007)............................................................................20
Statutes
35 U.S.C. 102(a) ............................................................................................ 25, 30
35 U.S.C. 102(b) ...................................................................................... 25, 30, 31
35 U.S.C. 103 ........................................................................................................22
vi

35 U.S.C. 112 ........................................................................................................14
35 U.S.C. 119(e)(1) ...............................................................................................13
35 U.S.C. 311 ........................................................................................................21
35 U.S.C. 325(d) ...................................................................................................32
35 U.S.C. 31119 ..................................................................................................1
Rules
37 C.F.R. 42.100 .....................................................................................................1
37 C.F.R. 42.103 .....................................................................................................4
37 C.F.R. 42.104(a).................................................................................................1
37 C.F.R. 42.15(a)...................................................................................................4
37 C.F.R. 42.8(b)(1) ................................................................................................1
37 C.F.R. 42.8(b)(2) ................................................................................................2
37 C.F.R. 42.8(b)(3) ................................................................................................3
37 C.F.R. 42.8(b)(4) ................................................................................................3
Fed. R. Evid. 801(d)(2) ............................................................................................29
vii
TABLE OF EXHIBITS
Exhibit No.
Description
Exhibit 1001
Andrew R. Blight & Ron Cohen, U.S. Patent No. 8,663,685 (filed
Jun. 20, 2011) (issued Mar. 4, 2014) (the 826 Patent)
Exhibit 1002
Relevant excerpts of U.S. Patent No. 8,663,685 Prosecution

History (685 prosecution history)
Exhibit 1003
Acorda Therapeutics, Inc., Registration Statement Under the

Securities Act of 1933 (Form S-1) (Sept. 26, 2003) (S-1)
Exhibit 1004
Rules and Related Matters, 2003-186 (Sept, 30, 2003), available at

http://www.sec.gov/news/digest/dig093003.txt (S-1 Registration
Statement)
Exhibit 1005
Keith C. Hayes et al., Pharmacokinetic Studies of Single and

Multiple Oral Doses of Fampridine-SR (Sustained-Release 4Aminopyridine) in Patients With Chronic Spinal Cord Injury, 26
Clinical Neuropharmacology, no. 4, 2003, at 18592 (Hayes)
Exhibit 1006
Haydee Jurez et al., Influence of Admixed

Carboxymethylcellulose on Release of 4-Aminopyridine from
Hydroxypropyl Methylcellulose Matrix Tablets, 216 Intl J.
Pharm., 2001, at 11525 (Juarez)
Exhibit 1007
U.S. Provisional Patent Application No. 60/560,894 (filed Apr. 9,

2004) (894 Provisional)
Exhibit 1008
Masterson et al., U.S. Patent No. 5,540,938, Formulations and

Their Use in the Treatment of Neurological Diseases (filed
Oct. 24, 1994) (Masterson)
Exhibit 1009
Schwid et al., Quantitative Assessment of Sustained Release 4Aminopyridine for Symptomatic Treatment of Multiple Sclerosis,
48 Neurol., no. 4, at 81721 (Apr. 1997) (Schwid)
Exhibit 1010
Richard E. Jones et al., Effects of 4-Aminopyridine in Patients with

Multiple Sclerosis, 60 J. Neurol. Sci. at 35362 (1983) (Jones)
viii

Exhibit No.
Description
Exhibit 1011
Harrit van Diemen, M.D. et al., The Effect of 4-Aminopyridine on

the Clinical Signs in Multiple Sclerosis: A Randomized, PlaceboControlled, Double-Blind, Cross-over Study, 32 Annals Neurol.,
no. 2, at 12330 (Aug. 1992) (van Diemen)
Exhibit 1012
Chris H. Polman, MD, PhD et al., 4-Aminipyridine is Superior to

3,4,diaminopyridine in the Treatment of Patients with Multiple
Sclerosis, 51 Archives Neurol., no. 11, Nov. 1994, at 113639
(Polman)
Exhibit 1013
D. Stefoski, MD, et al., 4-Aminopyridine Improves Clinical Signs

In Multiple Sclerosis, 21 Annals Neurol., no. 1, Jan. 1987, at 71
77 (Stefoski)
Exhibit 1014
Floyd A. Davis, M.D. et al., Orally Administered 4-Aminopyridine

Improves Clinical Signs in Multiple Sclerosis, 27 Annals Neurol.,
no. 2, at 18692 (Feb. 1990) (Davis)
Exhibit 1015
Types of MS, Nat. Multiple Sclerosis Socy,

http://www.nationalmssociety.org/What-is-MS/Types-of-MS (last
visited Aug. 11, 2015) (NMSS)
Exhibit 1016
Declaration of Scott Bennett (Bennett Decl.)
Exhibit 1017
C. Darlington, Abstract, Fampridine Acorda Therapeutics,

1 Current Opinions in Investigational Drugs, no. 3, Nov. 2000, at
37579
Exhibit 1018
Porter Novelli, Acorda Therapeutics Begins Phase 3 Trials of

Fampridine-SR for Chronic Spinal Cord Injury, American
Association for the Advancement of Science (AAAS) EurekAlert!
(July 1, 2002), http://www.eurekalert.org/pub_releases/200207/pn-atb062802.php
Exhibit 1019
Acorda Therapeutics Company Profile, Biospace,

http://www.biospace.com/company_profile.aspx?CompanyId=100
704 (last updated May 9, 2003)
ix

Exhibit No.
Description
Exhibit 1020
Goodman et al., Placebo-Controlled Double-Blinded Dose

Ranging Study of Fampridine-SR in Multiple Sclerosis, 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), Sep. 1821, 2002,
Baltimore, MD (Goodman)
Exhibit 1021
European Patent Convention art. 54(1), (2), Oct. 5, 1973, 1065

U.N.T.S. 199 (as amended Nov. 29, 2000), available at
http://www.epo.org/law-practice/legaltexts/html/epc/2010/e/ar54.html -texts/html/epc/2010/e/ar54.html
(EPC Art. 54)
Exhibit 1022
Fred D. Lublin, Stephen C. Reingold, Defining the clinical course

of multiple sclerosis: Results of an international survey, 46
Neurology, no. 4, April 1996, at 907911 (Lublin)
Exhibit 1023
Declaration of Samuel J. Pleasure, M.D., Ph.D. (Pleasure Decl.)
Exhibit 1024
CV of Samuel J. Pleasure, M.D., Ph.D. (Pleasure CV)
Exhibit 1025
European Patent No. 1 732 548 (B9) (EP 548)
Exhibit 1026
Excerpts from Proprietors Response to Opponents Appeals,

European Patent No. 1 732 548 B9, filed with the EPO, September
16, 2004 (Acorda EP Brief)
Exhibit 1027
European Patent Office, Espacenet Brochure,

http://documents.epo.org/projects/babylon/eponet.nsf/0/4E8744EB
66E8F944C12577D600598EEF/$File/espacenet_brochure_en.pdf
(Espacenet Brochure)
Exhibit 1028
Espacenet Bibliographic Data for US Patent No. 8,440,703 (B2)

(Espacenet 703 Data)
Exhibit 1029
CV of Scott Bennett
Exhibit 1030
Bennett Decl. Attachment 1

Exhibit No.
Description
Exhibit 1031
Exhibit 1032
Exhibit 1033
Exhibit 1034
Exhibit 1035
Exhibit 1036
Exhibit 1037
Exhibit 1038
Exhibit 1039
Stephen L. Hauser, M.D. & Donald E. Goodkin, Harrisons

Principles of Internal Medicine, 245261, 15th ed. 2001
Exhibit 1040
Christian Confavreux, M.D. et al, Relapses and Progression of

Disability in Multiple Sclerosis, 343 New Eng. J. Med., no. 20, at
143038 (Nov. 16, 2000)
Exhibit 1041
Timed 25-Foot Walk (T25-FW), Natl Multiple Sclerosis Socy

Website, http://www.nationalmssociety.org/ForProfessionals/Researchers/Resources-for-Researchers/ClinicalStudy-Measures/Timed-25-Foot-Walk-(T25-FW) (last visited
Aug. 31, 2015)
Exhibit 1042
U.S. Provisional Patent Application No. 60/528,760 (filed Dec. 11,

Exhibit 1043
Claim Charts for the 685 Patent
Exhibit 1044

Exhibit 1045

xi

Exhibit No.
Description
Exhibit 1046
Orange Book Listing for 826 Patent (Orange Book)
Exhibit 1047
C.T. Bever, Jr., MD, et al., The effects of 4-aminopyridine in

multiple sclerosis patients: Results of a randomized, placebocontrolled, double-blind, concentration-controlled, crossover trial,
1054 Neurology No. 44, Jun. 1994, at 1054 59 (Bever)
Exhibit 1048
Apr. 8, 2005) (issued Jan. 15, 2013) (the 437 Patent)
Exhibit 1049

History (826 prosecution history)
Exhibit 1050
Dec. 13, 2004) (issued Aug. 30, 2011) (the 826 Patent)
Exhibit 1051
Declaration of James Polli, Ph.D. (Polli Decl.)
Exhibit 1052
CV of James Polli (Polli CV)
Exhibit 1053

History Part 2 (826 prosecution history)
xii

I.
INTRODUCTION
Petitioner Coalition For Affordable Drugs (ADROCA) LLC (CFAD),
requests an Inter Partes Review (IPR) of claims 18 (collectively, the

Challenged Claims) of U.S. Patent No. 8,663,685 (the 685 Patent) (Ex. 1001)
in accordance with 35 U.S.C. 31119 and 37 C.F.R. 42.100 et seq.
II.
GROUNDS FOR STANDING (37 C.F.R. 42.104(a))

Pursuant to 37 C.F.R. 42.104(a), Petitioner certifies that the 685 Patent is
available for IPR and that Petitioner is not barred or estopped from requesting IPR
challenging the claims of the 685 Patent on the grounds identified in this Petition.
III.
A.
MANDATORY NOTICES (37 C.F.R. 42.8)

Real Parties-in-Interest (37 C.F.R. 42.8(b)(1))
Pursuant to 37 C.F.R. 42.8(b)(1), Petitioner certifies that Coalition For
Affordable Drugs (ADROCA) LLC, Hayman Credes Master Fund, L.P.

(Credes), Hayman Orange Fund SPC Portfolio A (HOF), Hayman Capital
Master Fund, L.P. (HCMF), Hayman Capital Management, L.P. (HCM),
Hayman Offshore Management, Inc. (HOM), Hayman Investments, L.L.C.
(HI), J. Kyle Bass, and Erich Spangenberg are the real parties in interest
(collectively RPI). The RPI hereby certify the following information: CFAD is a
wholly owned subsidiary of Credes. Credes is a limited partnership. HOF is a
segregated portfolio company. HCMF is a limited partnership. HCM is the general
partner and investment manager of Credes and HCMF. HCM is the investment
1

manager of HOF. HOM is the administrative general partner of Credes and HCMF.
HI is the general partner of HCM. J. Kyle Bass is the sole member of HI and the
sole shareholder of HOM. CFAD, Credes, HOF and HCMF act, directly or
indirectly, through HCM as the general partner and/or investment manager of
Credes, HOF and HCMF. nXnP is a paid consultant to HCM. Erich Spangenberg is
98.5% member of nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is
the 98.5% member of IPNav. Other than J. Kyle Bass in his capacity of the Chief
Investment Officer of HCM, and nXnP and Erich Spangenberg in his capacity as
the Manager/CEO of nXnP, no other person (including any investor, limited
partner, or member or any other person in any of CFAD, Credes, HOF, HCMF,
HCM, HOM, HI, nXnP or IPNav) has authority to direct or control (i) the timing
of, filing of, content of, or any decisions or other activities relating to this petition
or (ii) any timing, future filings, content of, or any decisions or other activities
relating to the future proceedings related to this Petition. All of the costs associated
with this petition will be borne by HCM, CFAD, Credes, HOF and/or HCM.
B.
Related Judicial and Administrative Matters (37 C.F.R. 42.8(b)(2))

Pursuant to 37 C.F.R. 42.8(b)(2), Petitioner states that the 685 Patent has
been the subject of the following lawsuits: Acorda Therapeutics, Inc. v. Sun
Pharm. Indus., No. 1-15-cv-00391 (D. Del. filed May 15, 2015); Acorda
Therapeutics, Inc. v. Mylan Pharm. Inc., No. 1-14-cv-00139 (N.D. W. Va. filed
2

Aug. 22, 2014); Acorda Therapeutics, Inc. v. Apotex Corp., No. 1-14-cv-00955
(D. Del. filed July 18, 2014); Acorda Therapeutics, Inc. v. Teva Pharm. USA, Inc.,
No. 1-14-cv-00941 (D. Del. filed July 17, 2014); Acorda Therapeutics, Inc. v.
Mylan Inc., No. 1-14-cv-00935 (D. Del. filed July 16, 2014); Acorda Therapeutics,
Inc. v. Accord Healthcare Inc., No. 1-14-cv-00932 (D. Del. filed July 15, 2014);
Acorda Therapeutics, Inc. v. Roxane Labs., Inc., No. 1-14-00922 (D. Del. filed
July 14, 2014; Acorda Therapeutics, Inc. v. Alkem Labs. Ltd, No. 1-14-00917 (D.
Del. filed July 11, 2014); Acorda Therapeutics, Inc. v. Aurobindo Pharma Ltd.,
No. 1-14-cv-00909 (D. Del. filed July 10, 2014); and Acorda Therapeutics, Inc. v.
Actavis Labs. FL Inc., No. 1-14-cv-0082 (D. Del. filed July 7, 2014). In addition to
the related judicial matters, on February 10, 2015, Petitioner filed IPR2015-00720
seeking inter partes review of U.S. Patent No. 8,663,685, and on February 27,
2015, Petitioner filed IPR2015-00817 seeking inter partes review of U.S. Patent
No. 8,007,826. On August 24, 2015, the Board issued decisions denying institution
for both petitions. Simultaneously with this Petition, Petitioner is seeking IPR of:
U.S. Patent No. 8,440,703, and its parent U.S. Patent No. 8,354,437; and U.S.
Patent No. 8,007,826, the parent of the presently challenged 685 Patent.
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))
Lead counsel is Sarah E. Spires, Reg. No. 61,501. Back-up counsel are Dr.
Parvathi Kota, Reg. No. 65,122, and Paul J. Skiermont (pro hac vice requested)
3

all at 685ADROCA@skiermontpuckett.com and of Skiermont Puckett LLP, 2200
Ross Ave. Ste. 4800W, Dallas, Texas 75201, P: 214-978-6600 / F: 214-978-6601.
Petitioner consents to electronic service at 685ADROCA@skiermontpuckett.com.
IV.
PAYMENT OF FEES (37 C.F.R. 42.15(A) AND 42.103)

The required fees are submitted herewith in accordance with 37 C.F.R.
42.15(a) and 42.103(a). If any additional fees are due during this proceeding,
the Office is authorized to charge such fees to Deposit Account No. 506293. Any
overpayment or refund of fees may also be deposited in this Deposit Account.
V.
IDENTIFICATION OF CHALLENGE
A.
Overview of U.S. Patent No. 8,663,685

The 685 Patent is titled Sustained Release Aminopyridine Composition.
(Ex. 1001-1. 1) The underlying application, U.S. Patent App. No. 13/187,158 (the
158 application) was filed Jul. 20, 2011. (Id.) The 158 application is a
continuation of U.S. Patent App. No. 11/010,828 (the 828 application), filed
Dec. 13, 2004 (now U.S. Patent No. 8,007,826) (the 826 patent), which claims
priority to Provisional App. No. 60/560,894, filed Apr. 9, 2004 (the 894
Provisional), as well as Provisional App. No. 60/528,760, filed Dec. 11, 2003;
Provisional App. No. 60/528,592, filed Dec. 11, 2003; and Provisional App. No.
60/528,593, filed Dec. 11, 2003. (Id.)
All references to Exhibit pin-cites are to the Bates-labeled page number.

4

1.
The 685 Patent Specification
The 685 Patent describes methods of administering l0 mg of a sustained

release oral dosage form of 4-aminopyridine (4-AP) 2 twice daily to patients with
multiple sclerosis (MS) to improve walking, increase walking speed, and
improve lower extremity muscle strength. (Id. at 7:3445, 25:6364.) The 685
Patent further describes administering 4-AP to obtain an in-vivo CmaxSS:CminSS ratio
of 1.0 to 3.5, a CavSS of 15 ng/ml to 35 ng/ml, and a mean Tmax from about 1 to
about 6 hours, and from about 2 to about 5.2 hours after administration. (Id. at
6:3133.)
2.
The 685 Claims
The 685 Patent has 8 claims, with claim 1 being the sole independent claim.
Claims 18 are challenged in this petition.
Independent claim 1 recites:
A method of improving walking speed in a human multiple sclerosis
patient in need thereof comprising orally administering to said patient
a sustained release composition of 10 milligrams of 4-aminopyridine
twice daily for a time period of at least two weeks, wherein the
sustained release composition further comprises one or more
pharmaceutically acceptable excipients.
4-aminopyridine is also known as 4-AP and fampridine, and the extended
release version is known as SR 4-AP and fampridine-SR. (Ex. 1023 40.)

5

(Id. at 27:2228.)
Dependent claims 28 each ultimately depend directly or indirectly from
claim 1, and contain the following additional limitations:
said sustained release composition provides a mean Tmax in a range of about
2 to about 6 hours after administration of the sustained release composition to the

patient (claim 2);
the sustained release composition is capable of providing a release
profile of the 4-aminopyridine extending over at least 6 hours or over at least 12

hours (claims 3 and 4);
the sustained release composition provides an average plasma
concentration at steady state in humans in the range of about 15 ng/ml to about 35

ng/ml (claim 5);
the 4-aminopyridine is dispersed in a rate of release controlling polymer
(claim 6);
the sustained release composition comprises a matrix in which the 4-
aminopyridine is homogenously dispersed that is suitable for controlling the rate of

release of the 4-aminopyridine (claim 7); and
the step of administering comprises b.i.d. administering or administering at
12 hour intervals (claim 8).

(Id. at 28:127.)
6

3.
Prosecution History of the 685 Patent
The as-filed 158 application included 23 original claims. (Ex. 1002-3). In a

preliminary amendment, applicants cancelled all 23 of its original claims, and
added 10 new claims all directed to methods of improving walking in MS patients.
(Id. -34.)
In the first Office Action, the Examiner rejected the pending claims for
double patenting in view of claims in applicants 826 patent, copending
application No. 11/102,559 (now the 437 patent), copending application No.
13/410,388, and the copending 969 application (now the 703 patent). (Id. -41
45.) In response, applicant filed four terminal disclaimers against the identified
patent and applications. (Id. -5051.) A Notice of Allowance then issued, stating
that claims 2433 are methods of use claims, corresponding to the methods of use
claims which ha[ve] been found to be novel and unobvious and ha[ve] been
allowed and issued in the 826 patent. (Id. -6364)
The applicant then cancelled claims 32 and 33 and filed a petition to
withdraw the application from issuance and a Request for Continued Examination
to submit a fourth IDS with 12 additional references to the Examiner. (Id. -70, 85
89) In response, the Examiner again issued a Notice of Allowance, stating that the
newly submitted references do not teach nor provide adequate motivation to
arrive at the instantly claimed methods. (Id. -99101.) An updated Notice of
7

Allowance then issued to reflect applicants amendment canceling pending claims
32 and 33. (Id. -10406.)
After an Examiner interview, the applicants again filed a petition to
withdraw the application from issuance and a Request for Continued Examination
to submit a fifth IDS with 13 additional references for consideration, which
included the submission of the S-1 for the very first time. (Id. -10714.) In
response, the Examiner again issued a Notice of Allowance, stating that the newly
submitted references do not teach nor provide adequate motivation to arrive at the
instantly claimed methods. (Id. -12022.) The 685 patent issued on March 2,
2014. The Examiner never entered a substantive rejection against any of the
pending claims and no prior art was cited by the Examiner during the prosecution
of the 685 patent in any Office Action. (See Ex. 1001.)
4.
Summary of Selected Prosecution History of the Parent 826

Patent
The 826 Patent was filed as the 828 application on Dec. 13, 2004.
(Ex. 1050-1.) According to the FDAs Orange Book, and based on the USPTOs
final patent term adjustment calculation, the 826 Patent expires in 2027.
(Ex. 1046-1.) The 826 patent file history is over 2,000 pages and references over
430 U.S. and foreign patents and non-patent literature documents. (See Exs. 1049,
1053, passim.)

The 828 application was filed with original inventors Andrew R. Blight and
Sean Cunningham. (Ex. 1049-23.) The applicant petitioned to have the
application reviewed without a Declaration by Cunningham because diligent
efforts to locate Sean Cunningham in order to execute the Declaration were
unsuccessful. (Id. -35.) Subsequently, the applicant petitioned to have Sean
Cunningham removed as an inventor. (Id. -5657.) The PTO granted the petition to
remove Cunningham as an inventor, rendering the first petition moot. (Id. -5859.)
The applicant later added Ron Cohen as an inventor. (Id. -123.)
Of the 23 originally filed claims, the applicant cancelled claims 1214 and
withdrew Claims 18 and 1823 on May 21, 2008 in response to a restriction
requirement. (Id. -25.) The Examiner then rejected remaining claims 911 and 15
17 as anticipated by Hayes (Ex. 1005). (Ex. 1049-2627.) The Examiner noted that
[a]ccording to one study in Hayes et al, 1025 mg of fampridine was administered
twice daily for one week to 16 patients with chronic spinal cord injury and [i]n
addition, Hayes et al admit that fampridine is potentially a valuable treatment for
multiple sclerosis. (Id.-27.) The Examiner also rejected claims 911 and 1517 as
obvious over Masterson (Ex. 1008). (Id.-2830.)
The applicant responded by amending Claim 9 and adding Claims 2441.
(Id.-4549.) After an interview with the Examiner discussing Masterson, Hayes,
and Schwid (Ex. 1009), applicant canceled claims 129 and 3638, amended
9

claims 3033 and 3940, and added claims 4247. (Ex. 1049-6064.) The
applicant also submitted declarations by Andrew R. Blight and David Lawrence
attempting to distinguish Masterson and purporting to support secondary
considerations of non-obviousness. (Id. -7394.)
The Examiner then issued a Final Office Action withdrawing the Hayes
anticipation rejection and the original Masterson rejection, but rejected all claims
as obvious over Masterson. (Id. -95112.) After another Examiner interview,
applicant filed a Request for Continued Examination cancelling claims 147 and
adding new claims 4869. (Id. -12032.)
The Examiner issued a non-final Office Action rejecting all claims over (1)
van Diemen et al. (Ex. 1011), (2) van Diemen and Bever et al. (Ex. 1047), and (3)
Masterson, van Diemen, and Bever. (Ex. 1049-13339.) After another Examiner
interview, the applicant submitted an amendment introducing independent claims
requiring 4-AP administration for at least two weeks. (Id. -17577, 199263.)
Additionally, the applicant argued that, the claimed invention is nonobvious,
because the requisite predictability is lacking: the claimed invention is not
composed of a combination of elements that yields predictable results, and the art
did not contain a finite number of identified, predictable solutions. (Id. -214.) The
applicant also submitted declarations by Dr. Rosella Medori and Lauren Sabella in
support of its allegations of secondary considerations of nonobviousness.
10

Neither the Sabella nor Medori declarations anywhere mention a period of
treatment that is two weeks or greater; nor do the declarations anywhere mention
the claimed pharmacokinetic parameters, such as CavSS, Cmax, Cmin, or a mean Tmax.
(Id. -291499, Ex. 1053-1-385.) The Medori declaration addressed the applicants
allegations of secondary considerations of long-felt but unsolved need and failure
of others. (Ex. 1049-25152.) Specifically, the Medori declaration described:
Biogens interest in obtainingrights tothe 828 application was
based on the following longstanding and well-known needs that were
met by Ampyra:
(a) It was an effective MS treatment.
(b) It met theneed for any MS treatment to improve walking.
(c) Its onset of action can be rapid, and the effects are noticeable by
patients and physicians.
(d) It was an orally administered MS treatment.
(e) It was effective to treat all four forms of MS.
(Id. -252.) The Medori declaration also alleged that [a]n example of the failure by
othersis the drug Nerispirdinein a Press Release dated April 29,
2010,Sanofi noted that the [d]ata on Nerispirdine in improving the ability to
walk in multiple sclerosis patientsdid not support progression to Phase III
trials. (Id. -25657.)
Additionally, the Sabella declaration alleged evidence of the
nonobviousness of the claimed invention, establishing that it achieved commercial
11

success, as measured by sales and other factors, based on its merits rather than
undue marketing efforts. (Id. -259.)
Finally, the applicants directed the Examiner to the previously-filed Blight
declaration, which alleges that There are at least two surprising results from our
work: (i) a 10 mg dose is as effective as a 20 mg dose and (ii) no dose escalation
was required to have a well-tolerated and meaningful clinical result. (Id. -261.)
Following two additional interviews, the Examiner issued a Notice of
Allowance, stating that because the prior art taught much higher dosages of 4aminopyridine and lacked the predictability to whereby an improvement in
walking could be obtained with the instant dosage, it cannot render obvious the
claimed method. (Ex. 1053-386420.)
B.
Effective Priority Date of the 685 Patent Claims

The 158 Application is a continuation of the 828 application, filed Dec. 13,
2004 (now the 826 patent), which claims priority to the 894 Provisional
(Ex. 1007), as well as: Provisional App. No. 60/528,760, filed on Dec. 11, 2003
(Ex. 1042); Provisional App. No. 60/528,592, filed on Dec. 11, 2003 (Ex. 1044);
and Provisional App. No. 60/528,593, filed on Dec. 11, 2003 (Ex. 1045)
(hereinafter the 2003 Provisionals). (Ex. 1001-1.) Nevertheless, the challenged
claims are not entitled to the benefit of the 894 Provisionals filing date, or any
filing date that could have been be accorded by the 2003 Provisionals. For a host of
12

reasons, the priority date of claims 18 is no earlier than the 828 applications
filing date: December 13, 2004.
As an initial matter, none of the claims of the 685 Patent can claim priority
to any of the 2003 Provisionals because the 685 Patent does not share a common
inventor with the 2003 Provisionalsa statutory requirement for claiming the
benefit of priority. See 35 U.S.C. 119(e)(1) (pre-AIA version) (An application
for patent filedby an inventor or inventors named in the provisional
application, shall have the same effect, as to such invention, as though filed on the
date of the provisional application) (emphasis added). The 2003 Provisionals
all list Sean Cunningham as the sole inventor. (Ex. 1042-1; Ex. 1044-1; Ex. 10451.) However, applicant removed Mr. Cunningham as an inventor on the application
during prosecution of the application that ultimately issued as the 685 Patent.
(Ex. 1049-5658.) When the applicant removed Cunninghamthe sole inventor of
the 2003 Provisionalsit forfeited any claim of priority to them by statute. The
application that issued as the 685 Patent does not share a common inventor to the
2003 Provisionals, and so cannot claim priority to them. See New Railhead Mfg.,
L.L.C. v. Vermeer Mfg. Co., 298 F.3d 1290, 129496 (Fed. Cir. 2002) (for the
non-provisional utility application to be afforded the priority date of the
provisional application, the two applications must share at least once common
inventor).
13

Additionally, claims 18 are not entitled to the benefit of the 894
Provisionals filing date, because the challenged claims can only receive the
benefit of the 894 Provisionals filing date if its disclosure satisfies the
requirements of 35 U.S.C. 112 1. New Railhead, 298 F.3d at 129496. To
satisfy written description, a POSA must immediately discern that the 894
Provisional necessarily discloses the 685 Patents claim limitations from the
four corners of the 894 Provisional at the time it was filed. Id. It is not enough that
a POSA could speculate as to modifications to the 894 Provisionals disclosure
that the inventor might have envisioned but failed to discloseand it is not even
enough if such limitations are obvious from the 894 Provisionals disclosure. Id.
at 1296. See also Lockwood v. American Airlines, 107 F.3d 1565, 157172 (Fed.
Cir. 1997); Waldemar Link v. Osteonics Corp., 32 F.3d 556, 55859 (Fed. Cir.
1994); In re Huston, 308 F.3d 1267, 1277 (Fed. Cir. 2002). Though the 894
Provisional need not use the exact words of later-filed claims, it must contain an
equivalent description of the claimed subject matter based on an examination of
the 894 Provisionals words, structures, figures, and diagrams. Lockwood, 107
F.3d at 1572.
First, claims 18 each require that 10 mg 4-AP be administered twice daily
or every 12 hours, for at least two weeks, (the two week limitations) for
improving walking. The 894 Provisional nowhere discloses a method of
14

improving walking by administering 10 mg 4-AP for a two-week treatment period.
Example 11 of the 894 Provisional describes administering 4-AP during a 12week treatment period at 3 different doses (10 mg, 15 mg, 20 mg) to improve
walking in MS patientsand that is the only disclosure in the 894 Provisional
where 10 mg SR 4-AP is administered twice daily to treat MS patients. (Ex. 100756.) However, that disclosure of a 12-week treatment period to improve walking
in MS patients does not adequately disclose to a POSA that the challenged claims
two-week dosing periods were necessarily present from the 894 Provisionals
disclosure.
Example 11 of the 894 Provisional discloses a double-blind, placebocontrolled, 20 week, parallel-group studydesigned in accordance with the Figure
entitled Example 11 Study Design. (Ex. 1007-50.) The Study Design discloses the
following time periods: 2-week placebo run-in; 2-week upward titration (10/15
mg bid or placebo); 12-week stable treatment period; 1-week downward
titration; and 2-week post treatment follow-up. (Ex. 1007-56 (emphasis
added).) Example 11 discloses data collected at Visit 4 (end of upward titration
period) and not again until Visit 7. (Id. -56.) The 894 Provisional does not disclose
when Visit 7 occurred. However, based on the placement of Visit 7 in the 12-week
treatment period figure, a POSA would understand that Visit 7 occurred no earlier
than week 4 of the 12-week treatment period. (Ex. 1023 42.) Example 11,
15

therefore, does not disclose any data for the first 2 weeks of the 12-week
treatment period, and does not disclose improvement of walking or lower
extremity function after the first two weeks of this treatment period. (Id. 43.) 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, or the applicant
collected data but did not disclose it because such data did not show improved
walking or lower extremity function. (Id. 44.) As a result, this disclosure is not a
full, clear, concise, and exact disclosure of the challenged claims two-week
treatment periodand a POSA would not immediately discern that the 894
Provisional necessarily disclosed the two-week treatment period limitations of
claims 1-8 based on reviewing the 894 Provisional. (Id. 44.) New Railhead, 298
F.3d at 129496.
Nor does Example 11s two-week upward-titration period prior to the stable
12-week treatment period support the two-week treatment period limitations of
the challenged claims. In fact, the 894 Provisional is silent as to precise method of
performing the upward titration (10/15 mg bid or placebo) for two weeks.
(Ex. 1023 47.) However, upon reviewing the 894 Provisional, 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
16

dose is introduced and gradually increased to ensure the patient does not have an
adverse reaction to the medication. (Ex. 1023 45; Ex. 1007-56.) Specifically:
The figure entitled Example 11 Study Design ambiguously alludes
to 2-week upward titration (10/15 mg bid or placebo) without
further explanation. (Ex. 1007-56 (emphasis added).) At best, 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, 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. Nothing in
Example 11 suggests that the different treatment groups took different
dosages during the upward titration periodinstead, the 894
Provisional shows that each treatment group (other than the placebo
group) received the same 10/15 mg bid upward titration.
(Id. 48.)
Further support for this proposition can be found in actions taken by the
applicant in its related 437 patent, which also claims priority to the 894
Provisional. Example 5 of the 437 patent which corresponds to Example 8 of the
685 Patent adds at least 15 lines of text to explain the particular dosing
parameters of the upward-titration period. (See Ex. 1048 at 18:2035.) This added
description is conspicuously absent from the 894 Provisionals disclosure of the
upward titration period of Example 11. (Ex. 1007, passim.)
17

As a result, the upward titration period of Example 11 does not disclose to a
POSA that the two-week dosing time period limitations of the challenged claims
were necessarily present from the 894 Provisionals disclosure, because those
claims require administering 10 mg 4-AP for at least two weeksnot merely for
some undiscernible portion of the two-week upward titration period. (Id. 50.)
Lockwood, 107 F.3d at 157172.
Likewise, original claims 12 of the 894 Provisional do not satisfy 112 1
for the challenged claims, because those claims are entirely open-ended with
respect to dosing durationand those claims are also not specifically limited to 10
mg SR 4-AP dosing. (Ex. 1007-52.) Therefore, such claims do not disclose to a
POSA that the two-week treatment period limitations were necessarily present
because such limitations, or their equivalents, are not disclosed by the original
claims based on a POSAs evaluation of the disclosure as a whole. (Ex. 1023
52.) See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 13491351 (Fed.
Cir. 2010) (en banc).
Second, claim 5 requires the pharmacokinetic range of CavSS of 15 ng/ml to
35 ng/ml in MS patients receiving 10 mg 4-AP BID. By contrast, the only
pharmacokinetic ranges disclosed in the 894 Provisional are in Table 7. (Ex. 1007
at 45.) That table, however, merely discloses ranges encompassing a CavSS of 15.1
ng/ml to 26.5 ng/ml for 10 mg BID dosing. (Id.) Because the claimed range for
18

claim 5 claims up to 35 ng/mlwhile the 894 Provisional does not disclose at
least the upper range of 26.6 ng/ml35 ng/mlclaim 5 of the 685 Patent cannot
claim priority to the 894 Provisional. See, e.g., Chiron Corp. v. Genetech, Inc.,
363 F.3d 1247, 1259 (Fed. Cir. 2004) (claims broader than the specification lack
written description or enablement where disclosure lacks a specific and useful
teaching commensurate with claim scope). The written support for the claimed
CavSS ranges found in the 685 Patent (Ex. 1001 at 7:608:47) is absent from the
894 Provisional. Thus, at the time of the 894 Provisional, a POSA would not
have immediately discerned that the 894 Provisional necessarily disclosed the full
scope of the claimed CavSS range. (Ex. 1023 53.). See, e.g., In re Lukach, 442
F.2d 967, 969 (C.C.P.A. 1971) (patentee not entitled to an earlier applications
filing date for a claimed Mw/Mn ratio ranging from 2.0 to 3.0 based on a single
example in the priority application disclosing a Mw/Mn ratio of 2.6). Cf. In re
Fisher, 57 C.C.P.A. 1099, 1108 (C.C.P.A. 1970) (explaining a single
embodiment is less likely to support a claimed range broader than the
embodiment when claims are directed to physiological activity rather than more
predictable mechanical or electrical arts).3
The Provisional purports to incorporate by reference certain documents that
cannot provide the missing disclosure because they do not identify where the
19

For all of the foregoing reasons, claims 18 are entitled to a priority date that
is no earlier than December 13, 2004.
C.
Level of Ordinary Skill in the Art

A POSA as of April 9, 2004the earliest possible priority date for the 685
Patentwould have an M.D. or Ph.D. in neuroscience or a related field with an

understanding of pharmacokinetics and at least some experience in providing drug
therapy to MS patients, with access to a person having an advanced degree (M.S.
or Ph.D.) in pharmaceutics or pharmaceutical formulation, specifically oral
sustained release formulations, or at least 5 years of experience in formulating oral
sustained release pharmaceutical drug products. (Ex. 1023 16.) A POSA may
work as part of a multi-disciplinary team and draw upon not only his or her own
skills, but also take advantage of specialized skills of others on the team. (Id.
17).
D.
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. 37 C.F.R. 42.100(b);

see In re Cuozzo Speed Techs., LLC, 778 F.3d 1271, 1279 (Fed. Cir. 2015). The
broadest reasonable construction of claim language is not one that permits any
incorporated material is found. (Ex. 1007, passim.) See Zenon Envtl., Inc. v. U.S.
Filter Corp., 506 F.3d 1370, 1378 (Fed. Cir. 2007).
20

reading, but instead is one that must be made in light of the specification as it
would be interpreted by one of ordinary skill in the art. In re Am. Acad. of Sci.
Tech. Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004) (quotation omitted).
Unless otherwise noted, Petitioner accepts, for purposes of this IPR only,
that the claim terms of the 685 Patent are presumed to take on the ordinary and
customary meaning that they would have to a POSA.
1.
release profile
The term release profile means a concentration of a drug in a patients

plasma over time. (Ex. 1023 56; see Ex. 1001 at 16:611.)
2.
matrix
The term matrix means a composition which provides for a sustained

release of a drug into the plasma of a patient. (Ex. 1023 58; see Ex. 1001 at
12:2025.)
3.
improving walking
The phrase improving walking means to quantifiably make better a

patients ability to walk. (Ex. 1023 60.)
E.
Statement of Precise Relief Requested for Each Claim Challenged

1.
Claims for Which Review is Requested
Petitioner requests IPR under 35 U.S.C. 311 of claims 18 of the 685

Patent, and cancellation of these 8 claims as unpatentable.
21

2.
Statutory Grounds of Challenge
Petitioner requests IPR of the 685 Patent claims 18 in view of the

following references, each of which is prior art to the 685 Patent under 35 U.S.C.
102(a) and (b) or 103. 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. (See Ex. 1002.)
Claims 18 are unpatentable under 35 U.S.C. 103:
Ground Proposed Rejections for the 685 Patent
1
Claims 1 and 8 are obvious under 35 U.S.C. 103
Exhibit
Number(s)
1003
in light of the S-1

2
Claims 25 are obvious under 35 U.S.C. 103
1003, 1005
over the S-1 in view of Hayes

3
Claims 1 and 67 are obvious under 35 U.S.C.
1003, 1006
103 over the S-1 in view of Juarez

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

1.
History of 4-AP and State of the Art at the Time of the 685
Patent
The 685 Patent does not claim the 4-AP compound. (Ex. 1001, passim.)
Nor does it claim to have pioneered the use of 4-AP to treat MS patients. (Id.) The
685 Patent does not even claim that the oral administration of 10 mg 4-AP BID to
MS patients or the use of sustained release 4-AP are novel, because those teachings
were known in the art. (See, e.g., Ex. 1003; Ex. 1005; Ex. 1020.) Instead, the 685
22

Patent claims methods of administering 4-AP BID to MS patients for at least two
weeks to attain the therapeutic objective of improving walking. By at least April 9,
2004prior to the earliest possible priority date for the 685 Patenta POSA
would have known to apply the claimed methods to achieve those objectives.
The pharmacological properties of 4-AP have been studied for decades. For
over 30 years, researchers have shown the effectiveness of 4-AP treatment in MS
patientsan inflammatory demyelinating disease featuring selective destruction
of the central nervous system (CNS) myelin. (Ex. 1023 3033; Ex. 1010-354.)
By the 1990s, researchers conducted double-blind studies evaluating the
effectiveness of oral 4-AP administration in MS patients. (See generally, Ex. 1011;
1012.) And by 1991, it was even known in the art that sustained-release oral
compositions of 4-AP were effective in treating MS. (See, e.g., Ex. 1008, passim.)
By April 2004, a POSA would have known that MS is a long-lasting,
chronic disease, with patients experiencing problems walking on an ongoing basis,
and especially as the disease progresses over time. (Ex. 1023 26.) As a result,
among the therapeutic objectives of a POSA seeking to treat MS patients with 4AP prior to April 2004, was to alleviate walking diability, improve walking,
increase walking speed, and increase lower extremity muscle strength and improve
tone. (Id. 27.) By 1987, researchers had measured neurological changes
resulting from administering 735 mg of 4-AP in 15 mg doses every 1060
23

minutes, with motor function (power, coordination, gait) in 5 out of 12 patients
improving within minutes of drug injection at doses as low as 2 mg. (Ex. 10131.) In 1990, Davis et al. administered 1025 mg 4-AP (total doses per individual)
to MS patients and observed marked improvements in motor functions, including
gait, in doses as low as 10 mg. (Ex. 1014-1.) Polman also found that 4Aminopyridine was more effective than 3,4-diaminopyridine, especially for
ambulation in patients with MS. (Ex. 1012-3.) Thus, by April 2004, a POSA
would have known to use 10 mg 4-AP to improve lower extremity function in MS
patients.
By 1996, researchers had introduced four disease categories for MS:
relapsing-remitting, relapsing-progressive, primary-progressive, and secondaryprogressive. (Ex. 1023 2122; Ex. 1022-2.) Relapsing-remitting MS is the most
common form, affecting 85% of patients. (Ex. 1015-1.) A typical MS treatment
regimen would almost certainly extend for at least two weeks or even months,
because all four disease states require continuous treatment to maintain the benefits
of the drug over time. (Ex. 1023 28.) For example, van Diemen taught
administering 4-AP to treat MS disability for at least two weeks, with an efficacy
analysis performed only in patients who completed at least two weeks of
treatment. (Ex. 1011-23.) van Diemen further teaches a significant effect of 4-AP
24

on the mean Expanded Disability Status Scale score after 2, 6, and 12 weeks of
treatment. (See id. at Table 1.)
2.
The S-1 (Ex. 1003)
The S-1 constitutes prior art under 35 U.S.C. 102(a) and (b) because it
was published at least as early as September 30, 2003more than one year before
the earliest effective filing date of December 13, 2004. (Ex. 1004-9; see generally,
Ex. 1003.) Even assuming arguendo that the priority date is December 11, 2003 or
April 9, 2004, the S-1 would still qualify as prior art against all claims under 35
U.S.C. 102(a). The S-1 was introduced only after initial issuance during the 685
Patents prosecution. (See Ex. 1002-110.)
A reference is a printed publication if it was available to the extent that
persons interested and ordinarily skilled in the subject matter or art[,] exercising
reasonable diligence, can locate it. Voter Verified, Inc. v. Premier Election
Solutions, Inc., 698 F.3d 1374, 1380 (Fed. Cir. 2012) (quotation omitted). The
touchstone is access. If the S-1 was accessible to interested persons skilled in the
art it is unnecessary to show that anyone actually inspected the reference. In re
Lister, 583 F.3d 1307, 1314 (Fed. Cir. 2009). See also Constant v. Advanced
Micro-Devices, Inc., 848 F.2d 1560, 1569 (Fed. Cir. 1988) (holding if publication
is accessible, there is no requirement to show that particular members of the
public actually received the information.).
25

As early as 2000, a POSA would have known that Acorda was investigating
fampridine [4-AP] for the potential treatment of spinal cord injuries and multiple
sclerosis. (Ex. 1017-1.) This had received attention in prominent publications in
the field as well as general news sources from 2002 until the date of the S-1 filing.
(See id; Ex. 1018-1 ([f]ampridine-SR is also in Phase 2 clinical trials to evaluate
safety and efficacy in the treatment of symptoms associated with multiple sclerosis
(MS).); Ex. 1019-1 ([t]he Companys lead product, Fampridine-SR, is in Phase 3
clinical trials for chronic SCI and Phase 2 for MS.).) Based on such information, a
POSA would have been motivated to consult informationparticularly public
filings such as the S-1relating to Acordas research. A POSA interested in
researching and treating MS would have known that Acorda is active in the field of
SR 4-AP research to treat patients with MS, and would have been motivated to
keep apprised of Acordas research and studies conducted with 4-AP in 2004. 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, including Acordas research and disclosures. (Ex. 1023,
6263.)
By law, companies in the United States making an initial public offer of
stock must file certain forms with the U.S. Securities and Exchange Commission
(SEC). (Ex. 1016 11.) Since 1996, these public filings have been available
26

online in the SECs EDGAR (Electronic Data Gathering, Analysis, and Retrieval)
system, which endeavors to make the filings publicly available within a matter of
minutes. (Id. 12 n.2.) See Constant, 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.) Included in these disclosures is the S-1 form, which
contains basic business and financial information about the issuer. (Id. 11.)
The S-1 HTML properties establish that, [t]he SEC received the Acorda
Therapeutics filing, including the S-1 form, on 26 September 2003 and filed it on
29 September 2003. (Id. 14.) Thus, by at least September 30, 2003, the S-1 was
available to a POSA interested in reviewing information regarding Acorda
Therapeutics. (Id. 1415.) See also Constant, 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.) The September 30, 2003 SEC Registration
Statement, which provided instructions to the public for obtaining a printed copy of
the S-1 publication via mail, further establishes its public availability. (Ex. 1004-9.)
Lest there be any doubt, Acorda has admitted that the S-1 is prior art to the
European counterpart of the 685 parentthe 826 patentclaiming the same
priority date, and that admission is binding here.4 Specifically, on Sept. 16, 2014,
4
The European Patent Offices Espacenet search tool provides access to patent
family information, telling you if similar patents have been claimed in other
27

Acorda responded to an appeal opposing European Pat. No. 1732548 (B9) (EP
548) (Ex. 1025), and countered an argument that the S-1 (the C27 reference)
anticipates EP 548s claims. (Ex. 1026 5.19.)5 In its EPO brief, Acorda
repeatedly admitted that the S-1 was prior art to EP 548 (See e.g., id. 4.6, 5.27,
6.39, 6.61.) The Federal Circuit has held that a patentees admission of a
references prior art status is clear and convincing evidence that the reference is
prior art. See, e.g., Tyler Refrig. v. Kysor Indus. Corp., 777 F.2d 687, 690 (Fed.
Cir. 1985) (collecting authority). The fact that the admissions occurred during EPO
proceedings does not negate Acordas admissions.6 See, e.g., Sentry Prot. Prods. v.
Eagle Mfg. Co., No. 1:01-cv-2240, 2003 WL 25539702, 2003 U.S. Dist. LEXIS
27435, *3233 (N.D. Ohio Sept. 30, 2003) (collecting authority and finding
[s]everal other cases have held that statements made by a patentee during foreign
patent proceedings can constitute admissions); Donnelly Corp. v. Gentex Corp.,
countries. (Ex. 1027-2.) Espacenets bibliographic data for the 826 patent states
it was also published as Acordas EP1732548 (B9). (Ex. 1028.)
5
The S-1 is document C27 in the EPO appeal. (Ex. 1026, Annex A.)
For purposes of Acordas admissions, the EPO standards for writings as prior art
are comparable to the U.S. requirements for prior art printed publications. (See
Ex. 1021-1 (everything made available to the public by means of a written
description before the date of filing of the European patent application.).
28

918 F. Supp. 1126, 113435 (W.D. Mich. 1996) (finding public use admissions
from foreign patent proceedings admissible in the U.S. under FRE 801(d)(2)).
Thus, the S-1 is a prior art printed publication to the challenged claims.
The S-1 describes clinical trials conducted using a sustained-release (SR)
composition of 4-AP. The reference teaches the effectiveness of the 1025 mg BID
dosing range, stating that clinical trials indicated that there was evidence of
increasing dose-response through the range of 10 to 25 mg twice a day, but that
evidence of increasing efficacy at doses higher than 25 mg twice a day was limited,
possibly being offset by increased side effects. (Ex. 1003-37.) The S-1 described
using sustained-release fampridine in an MS Phase II clinical trial:
The current late Phase II clinical trial, MS-F202, was designed, after
extensive consultation with a panel of expert MS neurologists and
with the FDA, to provide pivotal data for support of an NDA for the
use of fampridine-SR in MS. The clinical trial is also designed to
compare three doses of 10, 15 and 20 mg, twice per day, and to
assess their relative safety and efficacy over a treatment period of
12 weeks. The primary endpoint of the study is an improvement in
average walking speed using the Timed 25 Foot Walk.
(Id. -37, emphasis added.)
The S-1 also discussed a previously conducted Phase II study, MS-F201,
which was completed in 2001. (Id.) In that study, a total of 25 subjects received
fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight
29

weeks of treatment, and 11 subjects were given placebo over the same period. Id.
The MS-F201 Phase II trial demonstrated that doses up to 25 mg twice a day were
well tolerated, 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, at doses from 10 to 25 mg twice a day. (Id.) The S-1
disclosures teach nearly all claim limitations, as explained in more detail below.
3.
Hayes (Ex. 1005)
Hayes constitutes prior art under 35 U.S.C. 102(a) or (b) to all claims
because it was published and accessible by August 2003 (Ex. 1016 1621) in
the peer-reviewed journal, Clinical Neuropharmacologymore than one year
before the earliest effective filing date of December 13, 2004. (Ex. 1005.) Even
assuming arguendo a priority date of December 11, 2003 or April 9, 2004, Hayes
would still be prior art against all claims under 35 U.S.C. 102(a). In prosecuting
the 685 parentthe 826 patentthe applicant cited Hayes as factual prior art
evidence supporting its claimed pharmacokinetic ranges. (Ex. 1049-222.)
Hayes notes that [c]linical trials have confirmed that administration of
fampridine [4-AP] results in symptomatic improvements in patients with SCI and
multiple sclerosis. (Ex. 1005-1.) It presents the results of two studies conducted
to determine the pharmacokinetics and safety profile of an oral, sustained-release
30

(SR) formulation of fampridine (fampridine-SR, 1025 mg) [1] administered as a
single doseand [2] twice daily for 1 weekin patients with chronic, incomplete
SCI. (Ex. 1005-1.) Dose administrations occurred every 12 hours. (Id. -3.) The
doses in each study were 10 mg, 15 mg, 20 mg, and 25 mg. (Id. -2.)
Hayes reported that [s]teady state was achieved by day 5after twice-daily
administration and recorded pharmacokinetic data in relation to the plasma
concentration of the drug. (Id. -4.) Figure 1 provides release profile information for
the drug, and Table 3 provides pharmacokinetic data. (Id. -5, 7.) The data for 10
mg BID showed a CavSS (average plasma concentration at steady state) of 20.8
( 5.7) ng/mLa range of 15.1 ng/mL to 26.5 ng/mL (accounting for error), a tmax
of 10 mg SR 4-AP is 2.7 1.0 hoursa range of 1.73.7 hours (accounting for
error), and a release profile of 24 hours. (Id. -5, 7.)
4.
Juarez (Ex. 1006)
Juarez constitutes prior art under 35 U.S.C. 102(b) regardless of priority

date, because it was published in the Intl J. of Pharm. in 2001, which is more than
one year before April 9, 2004. (Ex. 1006-1.) Juarez was not the basis of any
Examiner rejection during the 703 prosecution. (Ex. 1002, passim.)
Juarez teaches the preparation of an oral tablet comprising 4-AP and a rate
of release controlling polymer. (Ex. 1006-13.) Juarez also discloses a sustained
release 4-AP composition formulated as a matrix with the polymer hydroxypropyl
31

methylcellulose (HPMC). (Ex. 1006-23.) Juarez further discloses that the
purpose of this HPMC matrix is to prolong delivery with zero-order kinetics to
maintain a constant in vivo plasma drug concentration, and with this to maintain a
constant pharmacological effect. (Id. -2.) In addition, Juarez teaches the
preparation of oral sustained release tablets comprising 4-AP and excipients such
as Metolose (an HPMC) and lactose monohydrate. (Id. -23.)
VI.
DETAILED EXPLANATION OF THE CHALLENGE
A.
35 U.S.C. 325(d) should not bar the petition

35 U.S.C. 325(d) provides that for institution, the Director may take into
account whether, and reject the petition or request because, the same or
substantially the same prior art or arguments previously were presented to the
Office.
1.
The present Petition presents a combination of art not previously

before the Office.
Here, although the Examiner rejected the 828 application of the 685 parent
based on Hayes, that rejection was an anticipation reference, in contrast to the
obviousness combination presented in this Petition. (Ex. 1002-26.) Moreover, the
primary reference that is combined with Hayes in the present petitionthe S-1
was not previously presented to the Office. (See Exs. 1002, 1053, passim.) Because
these prior art references and associated arguments differ from those previously
presented to the Office, 35 U.S.C. 325(d) should not foreclose this Petition. See
32

e.g., Chimei Innolux Corp. v. Semiconductor Energy Lab., Case IPR2013-00066,
slip op. at 8 (PTAB April 24, 2013) (Paper 10) (rejecting POs 325(d) argument
because during prosecution the examiner did not consider substantially the same
arguments presented in the petition); Microsoft Corp. v. Parallel Networks
Licensing, Case IPR2015-00483, slip op. at 1415 (PTAB July 15, 2015) (Paper
10) (rejecting POs 325(d) argument because there was no evidence the examiner
considered the disclosures cited in the petition, and noting that ex parte
proceedings differ from adversarial nature of IPRs).
2.
The present Petition presents grounds not previously addressed

by the PTAB
Although the Petitioner previously filed a Petition for IPR related to the 685
Patent, that Petition relied on the S-1 in combination with different prior art
references for which the PTAB found insufficient evidence of printed publication
status. (IPR2015-00817, Paper 12.) This Petition presents obviousness
combinations not previously presented in any other petition. See, e.g., Nestle USA,
Inc. v. Steuben Foods, Inc., Case IPR2014-01235, slip op. at 67 (PTAB December
22, 2014) (Paper 12) (rejecting POs 325(d) argument because the specific
obviousness combination in the petition were not considered during prosecution,
reexamination, or in a previous IPR proceeding); Valeo North America, Inc., et al.
v. Magna Electronics, Inc., Case IPR2014-01203, slip op. at 911 (PTAB January
25, 2015) (Paper 13) (rejecting POs 325(d) argument because the combination of
33

prior art and arguments presented in the petition were not the same or substantially
the same as presented in a previous petition).
Importantly, the PTAB also did not reach the merits of the previous prior
obviousness combinations in denying institution of that Petitionnor did the prior
decision reach the issue of whether the S-1 is a printed publication. As a result, the
present Petition does not have the benefit of the P.T.A.B.s views of the present
obviousness challenge. See, e.g., Chicago Mercantile Exchange v. 5th Market,
Case CBM2015-00061, slip op. at 3840 (PTAB July 16, 2015) (Paper 9)
(rejecting POs 325(d) argument alleging petitioners piecemeal attacks in filing
new challenges making arguments it could have raised before and attempting to
cure the deficiencies the Board identified in prior decision because prior decision
did not reach the merits of the challenge, and because Petitioner presented
different invalidity grounds than prior petition); Motorola Mobility v. Intellectual
Ventures, Case CBM2015-00005, slip op. at 1516 (PTAB March 27, 2015) (Paper
10) (rejecting POs 325(d) argument that Petitioner should not get a second
chance when it already tried, and failed, to do so because in prior denial of
institution [the prior decision] did not reach the merits of Petitioners
arguments).
Moreover, the prior art combination in the present Petition is also presented
in simultaneously filed Petitions against two other Acorda patents (the 703 and
34

437 patents) which Petitioner is challenging for the first time. Thus, Acorda will
not be unduly burdened by responding to the prior art combination presented here.
See, e.g., Nest Labs, Inc. v. Allure Energy, Inc., Case IPR 2015-00181, slip op. at
1011 (PTAB May 1, 2015) (Paper 6) (rejecting POs 325(d) argument because
addressing petitions arguments would not be unduly burdensome for the PO and
the petitions grounds were not redundant with previous petition).
B.
Ground 1: Claims 1 and 8 are obvious in light of the S-1 in view of

the knowledge of a POSA.
Independent claim 1 recites:
A method of improving walking speed in a human multiple sclerosis
patient in need thereof comprising orally administering to said patient
a sustained release composition of 10 milligrams of 4-aminopyridine
twice daily for a time period of at least two weeks, wherein the
sustained release composition further comprises one or more
pharmaceutically acceptable excipients.
(Ex. 1001 at 27:2228.)

The combination of the S-1 with common knowledge available to a POSA
teaches each element of the challenged claims. A POSA would have been
motivated to combine the S-1 with common knowledge in an effort to arrive at
low-dose methods for improving lower-extremity functions associated with MS,
while minimizing adverse side effects. (Ex. 1023 68.)
35

1.
Independent claim 1 is obvious in light of the S-1 disclosure and

The S-1 teaches or suggests every limitation of claim 1. The S-1 describes
research into Fampridine-SR, [which] is a sustained release, oral tablet
formulation of fampridine, suitable for twice daily dosing. (Ex. 1003-34
(emphasis added).) The S-1 confirms, and a POSA would have understood, that
Fampridine-SR is another name for sustained release 4-aminopyridine, or SR 4AP. (Ex. 1003-34 (We have a worldwide exclusive license from Elan to its patent
for the sustained release formulation of aminopyridines, which includes
fampridine); Ex. 1023 40.) The S-1 also discloses the details of multiple clinical
trials in which Fampridine-SR was administered to patients suffering from MS, all
with the intended outcome of improving lower-extremity function. (Id. 70, 80
81.)
The S-1 discloses that the Phase 2 clinical trial of Fampridine-SR in
Multiple Sclerosis, MS-F201was 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, including motor strength, timed walking, and
self-reported fatigue. (Ex. 1003-37 (emphasis added).) To do so, subjects
received Fampridine-SR in doses increasing from 10 mg to 40 mg twice per day
over eight weeks of treatment, and demonstrated that doses up to 25 mg twice a
daywere associated with statistically significant improvements in walking
36

speed and leg muscle strength. (Id. -37 (emphasis added).) Significantly,
[m]ost of the improvement in strength and walking speed was apparent
within the first three weeks of the Fampridine-SR treatment, at doses from 10 to
25 mg twice a day. (Id. (emphasis added).)
In sum, the S-1 disclosed the results of a completed clinical trial, MS-F201,
in which MS patients received 4-AP twice a day orally for 8 weeks, wherein
patients exhibited improvements in walking strength and speed within the first 3
weeks. The 4-AP dosing during the first 3 weeks of treatment was 1025 mg twice
per day. A POSA considering the teachings disclosed in the S-1 as clinical trial
MS-F201 would have understood that low-dose SR 4-AP could be orally
administered to MS patients for a short period of time (e.g., several weeks) to
achieve an improvement in lower extremity strength and walking speed. (Ex.
1023 92.) Further, common knowledge available at the time would have
motivated a POSA to seek similar teachings in which lower doses of 4-AP could
be administered to achieve efficacious results. (Id. 94.) See Tyco Healthcare
Grp. LP, 642 F.3d 1370 at 137172 (physicians always seek to prescribe the
lowest effective dose of any medication). The S-1 provides exactly that teaching.
Following the MS-F201 trial, the S-1 discloses a second Phase 2 clinical
trial, MS-F202, [that] was designedto provide pivotal data for support of an
NDA for the use of Fampridine-SR in MS. (Ex. 1003-37 (emphasis added).)
37

According to the S-1, this trial was initiated early in 2003, and was designed to
compare three doses of 10, 15, and 20 mg, twice per day, 7 and to assess their
relative safety and efficacy over a treatment period of 12 weeks. The primary
endpoint of the study is an improvement in average walking speed using the
Timed 25 Foot Walk. (Id. -37 (emphasis added).) In light of this disclosure that a
stable 10 mg dose was chosen for MS-F202 following the conclusion of the MSF201 trial designed to determine the optimal dose level of Fampridine-SR, the
685 Patents claimed point of novelty over the prior artits 10 mg dosewould
have been obvious to a POSA. (Ex. 1023 76; Id. -37.) See In re Peterson, 315
F.3d 1325, 132930 (Fed. Cir. 2003) ([W]hen, as here, the claimed ranges are
completely encompassed by the prior art, the [obviousness] conclusion is even
more compelling than in cases of mere overlap.); In re Applied Materials, Inc.,
692 F.3d 1289, 1295 (Fed. Cir. 2012) ([W]here the general conditions of a claim
are disclosed in the prior art, it is not inventive to discover the optimum or
workable ranges by routine experimentation.) (quoting In re Aller, 220 F.2d 454,
7
A POSA would have understood that the MS-F202 comparison in the S-1 of
three doses of 10, 15, and 20 mg, twice a dayover 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; hence receiving the same amount (i.e. 10 mg) of
4-AP at each administration step. (Ex. 1023 74.)
38

456 (CCPA 1955)). 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. (Ex. 1023 94.) See Tyco Healthcare
Grp. LP, 642 F.3d at 137172 (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, particularly in the case of patients sensitive to
the side effects of the medication).
Moreover, 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, characterized by weakness and walking impairment. (Ex. 100337 (emphasis added).) Based on these statements of intent to rely on this clinical
data for NDA submission and drug label indications, a POSA would have
reasonably expected all doses (10, 15, and 20 mg) of this trial to be successful in
treating lower extremity motor dysfunction, and particularly with respect to
improving lower extremity muscle strength and walking speed. (Ex. 1023 82
(emphasis added).) See In re Montgomery, 677 F.3d 1375, 138283 (Fed. Cir.
2012) (affirming invalidity over a published clinical protocol designed to obtain
data for submission to regulatory agencies and so in an advanced stage of testing
designed to secure regulatory approval in light of Manual of Patent Examining
39

Procedure 2107.03s statement that, if an applicant has initiated human clinical
trials for a therapeutic product or process, [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).
Finally, the S-1 implicitly teaches a composition comprising one or more
pharmaceutically acceptable excipients because the 4-AP composition disclosed
thereinfampridine SRcomprises a sustained release composition. As noted
above, Fampridine-SR, is a sustained release, oral tablet formulation of
fampridine, suitable for twice daily dosing. (Ex. 1003-34 (emphasis added).) Dr.
Polli has noted that by definition, a sustained release formulation contains at
least one pharmaceutically acceptable excipient in addition to the active
pharmaceutical ingredient (4-aminopyridine). This would have to be so in order for
the formulation to function as a sustained release composition as intended.
(Ex. 1051 41 (emphasis added).)
As the bold typeface above indicates, the S-1 explicitly or implicitly
discloses every element in claim 1: 1) improving walking (e.g., increasing walking
speed); 2) in a human 8 multiple sclerosis patient in need thereof; 3) comprising
8
A POSA would have understood, and the S-1 confirms, that these Phase 2 clinical
trials for MS were conducted in human multiple sclerosis patient[s] in need of

treatment. (Ex. 1023 71; Ex. 1003-45 (Human clinical trials: Phase 2: The
40

orally administering to said patient; 4) 10 mg; 5) of a sustained release composition
of 4-aminopyridine (Fampridine-SR); 6) twice daily; 7) for a time period of at least
two weeks (i.e., 12 weeks); 8) wherein the composition further comprises one or
more pharmaceutically acceptable excipients. See In re Applied Materials, Inc.,
692 F.3d at 1295 (A prima facie case of obviousness typically exists when the
ranges of a claimed composition overlap the ranges disclosed in the prior art.)
(quotation omitted). (Ex. 1023 69.)
Thus, for at least the foregoing reasons, claim 1 of the 685 Patent would
have been obvious to a POSA in light of the S-1. (Id.)
2.
Dependent claim 8 is obvious in light of the S-1 and a POSAs

knowledge.
Dependent claim 8 fails to add any non-obvious limitations. Each element of

claim 8 is disclosed in the S-1, or would have been obvious to a POSA in light of
the common knowledge in the field.
drug is administered to a limited subject population to identify possible adverse

effects and safety risks, to determine the efficacy of the product for specific
targeted diseases and to determine dosage tolerance and optimal dosage.).)
41

a.
The S-1 teaches b.i.d. (BID) administration of SR 4-AP,

including at 12 hour intervals (claim 8)
Claim 8 depends from claim 1 and further recites the step of administering
comprises b.i.d. administering or administering at 12 hour intervals. (Ex. 1001 at
28:2527.)
As noted above with respect to claim 1, the S-1 teaches 10, 15, and 20 mg
[4-AP], twice per day, thus meeting the BID (twice daily dosing) limitation
recited in claim 8. (Ex. 1003-37.) Additionally, 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. 1023 99.) 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 100.) 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.) For those
reasons, the limitations set forth in claim 8 would have been obvious to a POSA
over the S-1. (Ex. 1023 101.)
42

C.
Ground 2: Claims 25 are obvious over the S-1 in view of Hayes and
The pharmacokinetic limitations set forth in claims 25 are obvious over the
S-1 in view of Hayes, as supported by common knowledge.

A POSA would have been motivated to combine the S-1 with common
knowledge and publications like Hayeswhich focuses on the same 10 mg BID
doses of SR 4-AP oral tablets disclosed in the S-1to further understand and
apply the methods disclosed in the S-1 to treat patients suffering from MS and its
associated conditions. (Id. 106.) 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
Hayesdisclosing the use of the same oral low-dose SR 4-APin an effort to
achieve effective blood plasma pharmacokinetics. (Id.) The particular relevance
of the Hayes teachings to the pending claims was explicitly acknowledged by the
applicants during prosecution of the 685 parentthe 826 Patent. (Ex. 1049-151
52, 157.)
1.
The S-1 and Hayes combination teaches a mean Tmax in a range of

about 2 to about 6 hours after SR 4-AP administration (claim 2).
Claim 2 depends from claim 1 and further requires that said sustained
release composition provides a mean Tmax in a range of about 2 to about 6 hours
43

after administration of the sustained release composition to the patient. (Ex. 1001
at 28:24.)
Claim 2 is obvious over the S-1 in view of Hayes, which discloses the steady
state tmax pharmacokinetic ranges for sustained release 4-A. See Santarus, Inc. v.
Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012) (affirming obviousness
because an obvious formulation cannot become nonobvious simply by
administering it to a patient and claiming the resulting serum concentrations. To
hold otherwise would allow any formulation no matter how obvious to
become patentable merely by testing and claiming an inherent property.) (citation
omitted).
During prosecution of the parent 826 patent, the applicants acknowledged
that the teachings of Hayes accurately depict known pharmacokinetic parameters
for 10 mg dosing of SR 4-AP twice daily. (Ex. 1049-151.)
In Table 3 of Hayes, for 10 mg BID sustained release 4-AP, Hayes teaches
that the tmax is 2.7 1.0 hours. (Ex. 1005-7.) 9 A tmax of 2.7 hours falls within the
9
During prosecution of the 826 Patent, applicants admitted that [o]ne of ordinary
skill would expect the same pharmacokinetics in MS patients as in patients with

spinal cord injury, because these disabilities were and are not expected to affect
metabolism of half-life of 4-AP, which is largely renally cleared. (Ex. 1049-151.)
Drs. Pleasure and Polli agree. (Ex. 1023 117; Ex. 1051 35.)
44

claimed range of about 2 to about 6 hours. Thus, the combination of the S-1 and
Hayes meets the pharmacokinetic limitation of claim 2. 10
In addition, 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 claimed invention at steady state. (Ex. 1023 118; Ex. 1051 36.)
This knowledge of a POSA would have rendered obvious to a POSA the
pharmacokinetic limitation of claim 2 when combining the teachings of Hayes
with the 10 mg BID dosing regimen of sustained release 4-AP described in the S-1.
10
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 days, a

POSA would have understood that the pharmacokinetics for the two
administrations would have been the same because the Tmax was measured at
steady state, and Hayes discloses that [s]teady state was achieved by day 5 (4 days
of fampridine-SR dosing) after twice-daily administration of fampridine-SR.
(Ex. 1005-4; Ex. 1023 119; Ex. 1051 37.) Steady state refers to the situation
where the overall intake of a drug is fairly in dynamic equilibrium with its
elimination. (Ex. 1023 110.) Similarly, a POSA would have understood that the
CavSS occurs at steady state, and so would also have occurred identically during
both the S-1 and shorter Hayes administrations. (Id. 118.)
45

(Ex. 1023 126; Ex. 1051 44.) See In re Applied Materials, Inc., 692 F.3d at
1295.
2.
The S-1 and Hayes combination teaches a release profile

extending over at least 6 hours and at least about 12 hours
(claims 3 and 4).
Claim 3 depends from claim 2, and claim 4 depends from claim 3, with
those claims additionally requiring that the sustained release composition is
capable of providing a release profile of the 4-aminopyridine extending over at
least 6 hours or over at least about 12 hours, respectively. (Ex. 1001 at 28:5
13.)
For reasons similar to those stated above with respect to the Tmax
pharmacokinetic parameter, Hayes discloses the steady state release profile recited
in claims 3 and 4, such that those claims are obvious over the S-1 in view of
Hayes. See Santarus, Inc., 694 F.3d at 1354.
Specifically, Hayes discloses in Figure 1 B, copied below, that a 10 mg BID
dose of SR 4-AP has a release profile (as defined in Section V.D.2.) extending over
24 hours:
46
(Ex. 1005-5.) Thus, according to Figure 1 of Hayes, a POSA would have known
that the release profile of the 10 mg sustained release 4-AP described in the S-1
and Hayes extends over 24 hours, rendering obvious the additional
pharmacokinetic limitations of claims 3 and 4 when combining the teachings of
Hayes with the 10 mg BID dosing regimen of sustained release 4-AP in the S-1.
(Ex. 1023 127; Ex. 1051 48.) See In re Applied Materials, Inc., 692 F.3d at
1295.
3.
The S-1 and Hayes combination teaches that sustained release 4AP provides a release profile to obtain a CavSS of about 15 ng/ml
to about 35 ng/ml (claim 5).
Claim 5 depends from claim 1 and additionally requires that the sustained
release composition provides an average plasma concentration at steady state in
humans in the range of about 15 ng/ml to about 35 ng/ml. (Ex. 1001 at 28:1417.)
47

For reasons similar to those stated above with respect to the Tmax and release
profile pharmacokinetic parameter, Hayes discloses the steady state CavSS
pharmacokinetic range recited in claim 5, such that that claim is obvious over the
S-1 in view of Hayes. See Santarus, Inc., 694 F.3d at 1354.
During examination of the parent 826 patent, the applicants basis for
patentability relied squarely on the known pharmacokinetics of SR 4-AP.
(Ex. 1049222.) Specifically, the applicants cited [t]he pharmacokinetics of SR 4AP reported by [Hayes] as being reliable data points for demonstrating the in vivo
pharmacokinetics recited in the claims of the 826 patent. (Id.) The applicants
further admitted that [Hayes] at Table 3 on p. 191 teaches that in patients with
spinal cord injury CavSS, CmaxSS, and CminSS (in ng/ml) were as follows, for 10 mg
BID, 15 mg BID, 20 mg BID and 25 mg BID SR 4-AP:
10 mg BID
15 mg BID
20 mg BID
25 mg BID
CavSS
20.85.7
31.07.2
39.49.3
53.314.5
CminSS
14.04.4
23.59.1
27.310.0
41.315.2
CmaxSS
20.85.7
31.07.2
39.49.3
53.314.5
(Id.) By acknowledging the reliability of the pharmacokinetic data reported in

Hayes, the applicant essentially admitted that the pharmacokinetic limitations
recited in the 826 patentand related 685 Patent claimsare obvious in view of
the prior art.
48

In particular, the reported CavSS of 20.8 (+5.7) in Hayes for 10 mg BID
administration of 4-AP falls within the claimed range of CavSS of about 15 ng/ml
to about 35 ng/ml.
In addition, 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 claimed invention at steady state. (Ex. 1023 118.) 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, as they provide guidance
regarding the clinical effects of 10, 15, and 20 mg BID doses, as well as the plasma
concentrations resulting from those doses, respectively. (Id. 105.) A POSA would
find further motivation to combine the references to assess the safety of sustained
release 4-AP. (Id.; Ex. 1003-37 (The clinical trial is also designed to compare
three doses of 10, 15, and 20 mg, twice per day, and to assess their relative safety
and efficacy) (emphasis added); Ex. 1005-2 (This paper describes 2 open-label,
single-center studies designed to examine the pharmacokinetics and safety profile
of fampridine-SR.).) See KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 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
elements in the manner claimed).
49

Consequently, as demonstrated by Table 3 of Hayes, a POSA would have
known that the CavSS of 10 mg sustained release 4-AP at steady state was
20.85.7a range of 15.126.5 when accounting for errorrendering obvious the
full pharmacokinetic range of claim 5 when combining the teachings of Hayes
with the 10 mg BID dosing regimen of sustained release 4-AP described in the S-1.
(Ex. 1023 128.) See In re Applied Materials, Inc., 692 F.3d at 1295.
D.
Ground 3: Claims 1, 6 and 7 are obvious in light of the S-1 in view of

Juarez and the knowledge of a POSA.
As discussed above in Ground 1, claim 1 recites a method of improving
walking in a human multiple sclerosis patient in need thereof comprising orally

administering to said patient a sustained release composition of 4-aminopyridine
wherein the sustained release composition further comprises one or more
pharmaceutically acceptable excipients. (Ex. 1001 at 27:2228 (emphasis added).)
Claim 6 depends from claim 1 and further requires that the 4-aminopyridine is
dispersed in a rate of release controlling polymer. (Ex. 1001 at 28:1819
(emphasis added).) Claim 7 depends from claim 1 and further requires that the
sustained release composition comprises a matrix in which the 4-aminopyridine is
homogenously dispersed that is suitable for controlling the rate of release of the 4aminopyridine. (Ex. 1001 at 28:2024 (emphasis added).) Claims 1, 6, and 7 are
obvious over the S-1 in view of Juarez.
50

A POSA would have been motivated to combine the S-1 with common
knowledge and publications like Juarezwhich focuses on optimizing the same
SR 4-AP oral tablets disclosed in the S-1 in an effort to further understand and
apply the methods disclosed in the S-1 to treat patients suffering from MS and its
associated conditions. (Ex. 1023 129; Ex. 1051 25.)
1.
The S-1 and Juarez combination teaches SR 4-AP compositions

comprising excipients, as well as methods for controlling the
release rate of the 4-AP by dispersing it in a rate of release
controlling polymer such as a matrix in which the 4-AP is
homogenously dispersed (claims 1 and 67).
As explained above with respect to Ground 1, the S-1 implicitly teaches a

composition comprising one or more pharmaceutically acceptable excipients as
in claim 1, because the 4-AP composition disclosed thereinfampridine SR
comprises a sustained release composition. Indeed, Fampridine-SR, is a sustained
release, oral tablet formulation of fampridine, suitable for twice daily dosing.
(Ex. 1003-34 (emphasis added).) Dr. Polli attests that by definition, a sustained
release formulation contains at least one pharmaceutically acceptable excipient in
addition to the active pharmaceutical ingredient (4-aminopyridine). This would
have to be so in order for the formulation to function as a sustained release
composition as intended. (Ex. 1051 41.) The opinions of Dr. Polli are further
verified by Juarez, which described certain SR 4-AP oral compositions in which 4-
51

AP was combined with excipients such as Metolose (HPMC) and lactose
monohydrate. (Ex. 1006-23.)
Further, a POSA reading the S-1 would have known that one of the methods
available to control the rate of release of a drug, such as would be necessary for the
sustained release 4-AP disclosed in the S-1, would be the use of a hydrophilic
polymer-formed matrix to control rate of release as in claims 6 and 7. (Ex. 1023
135; Ex. 1051 56.) A POSA also would have known that, for such a matrix to
function properly, the drug whose release rate was being controlled should be
homogenously dispersed in this matrix, as in claim 7. (Ex. 1023 136; Ex. 1051
57.)
Juarez discloses this claimed polymeric matrix. (Ex. 1006-13.) A POSA
working with a sustained release form of 4-AP, as disclosed in S-1, would have
been motivated to look to Juarez, because Juarez teaches how to use a polymerformed matrix to provide a sustained-release composition of 4-AP that could
maintain desirable in vivo plasma concentrations and thus a constant
pharmacological effect for the 4-AP composition. (Ex. 1023 131; Ex. 1051 59.)
See KSR Intl Co., 550 U.S. at 420.
Specifically, Juarez teaches the preparation of an oral tablet comprising 4aminopyridine and a rate of release controlling polymer as required by claim 6.
(Ex. 1006-12.) Juarez indicates that [t]ablets of the model drug 4-aminopyridine
52

with hydroxypropyl methylcellulose [HPMC] were prepared with different
proportions of polymer content. (Id. -1.) Juarez further discloses that the purpose
of this HPMC matrix is for controlling the release of soluble drugs from solid
dosage forms, and to prolong delivery with zero-order kinetics to maintain a
constant in vivo plasma drug concentration, and with this to maintain a constant
pharmacological effect, as in claims 6 and 7. (Id. -12.)
A POSA would have understood that Juarez teaches that 4-aminopyridine
could be readily and easily formulated into a useful rate of release controlling
polymer, more commonly known as a sustained release composition, using
universally known compounds such as HPMC. (Ex. 1051 64; Ex. 1023 144.)
Juarez additionally teaches that, to form the matrix:
Ten grams of each different formula were prepared by gently mixing
in a mortar the corresponding proportions of 4-aminopyridine and
HPMC for 20 min. Each mixture was moistened with 2 ml of distilled
water, kneaded for 5 min and sifted using a sieve number 12. The
resulting granulations were dried at 40oC for 3 h in beds with a
thickness up to 5 mm.
(Ex. 1006-3.) A POSA would have understood that these mixing instructions
would result in the 4-AP being homogenously dispersed in the matrix, such that the
matrix is suitable for controlling the release rate of the 4-aminopyridine as in
claim 7. (Ex. 1023 145; Ex. 1051 65.)
53

Therefore, for at least the foregoing reasons, claims 1 and 67 would have
been obvious to a POSA over the S-1 in view of Juarez. (Ex. 1023 134, 144
45.)
VII. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT TO
OVERCOME THE OBVIOUSNESS OF CLAIMS 18
The applicants submitted no evidence showing secondary considerations of
non-obviousness during prosecution of the 685 patent. (See Ex. 1002.) The
applicant has the burden of establishing the existence and sufficiency of such
secondary considerations, as well the burden of establishing nexus commensurate
with the claims. See Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. &
Inter. 1992). They did not do so during prosecution of the challenged claimsand
did not even do so during prosecution of the parent 826 patent when the applicants
attempted to put forth evidence of secondary considerations in support of claims
not challenged here.
The crux of the purported secondary considerations raised in declarations
applicant submitted in the 826 parent patent prosecution history was [t]he fact
that use of the twice daily 10 mg sustained release composition was as effective in
treating multiple sclerosis as the 20 mg sustained release composition, yet without
the side effects of the larger dose, was quite surprising and unexpected. (Ex.
1049-80.) The declarants argued that this result was surprising because [t]he
working paradigm prior to the present invention was that since there appeared to be
54

a dose-benefit correlation for many of 4-APs clinical benefits, as much 4-AP was
to be given as possible. (Id. -219.) However, the results described are neither
unexpected nor surprising in view of the disclosures in the prior art that render the
treatment methods obvious. (Ex. 1023 148.)
First, the declarants assertion that the results were unexpected is incorrect.
The Blight Declaration data is consistent with the expected dose-benefit
correlation. (Id. 149.) For example, improvement in walking did increase with
the dosage, albeit in small increments (12 percentage points). Even though the
increase was not statistically significant, it showed an upward trend, and where the
dosage difference was slight to begin witha mere 5 to 10 mg compared with
studies in which up to 5060 mg of 4-AP had been administeredsuch small
increases would be expected. (Id. 149.) The Federal Circuits opinion in
Galderma Labs. LP v. Tolmar Inc. is particularly instructive. 737 F.3d 731, 739
(Fed. Cir. 2013). In that case, the court found unexpected results insufficient for
nonobviousness. Id. The court described the unexpected resultthe lack of a
percent increase in the prevalence of side effectsas constituting only a
difference in degree from the prior art results rather than a difference in kind.
Id. Here, the applicants argument regarding the lack of significant improvement
from one dose to another is a difference in degree. Moreover, any evidence of
superior efficacy does nothing to undercut the showing that there was a reasonable
55

expectation of success with the [10 mg BID] dose, even if the level of success may
have turned out to be somewhat greater than would have been expected.
Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1334 (Fed. Cir. 2014).
Second, the Medori declaration touts Ampyras approval as the first FDAapproved drug for improving walking in patients with MS, and it remains the only
drug approved for this purpose Moreover, the FDA approval of Ampyra was
the first approval for an MS drug without any restriction on the subtype of MS for
which it is indicated. (Ex. 1053-6970.) However, none of the claims of the 826
patent require that a covered drug be an MS treatment effective to treat all four
forms (subtypes) of MSor any specific subtype at all. Kennametal, Inc. v.
Ingersoll Cutting Tool Co., 780 F.3d 1376, 1385 (Fed. Cir. 2015) (affirming
obviousness where [T]he offered secondary consideration actually results from
something other than what is both claimed and novel in the claim, so there is no
nexus to the merits of the claimed invention.) (quotation omitted).
Third, none of the declarations establish a nexus between the alleged
secondary considerations and the particular limitations of the challenged patent
claims. (See Ex. 1049-7387, 291-499, Ex. 1053-65385.) The S-1 and Hayes
disclose the claimed dosing of 10 mg BID. Although the claims also require certain
treatment periods ranging from a day and an unspecified maintenance period to a
period of twelve weeks (which the S-1 also discloses), none of the declarations
56

attribute such treatment periods to the success of 4-AP. (See id.) Nor was there
evidence that any long-felt need allegedly solved by Ampyra was due to these
treatment periods. (See id.) The Medori declaration points to other MS drugs, like
Nerispirdine, which failed to enter Phase III clinical trials. (Ex. 1053-137.)
However, 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
wereor could have beenthe particular elements that rendered Ampyra
successful where other MS drugs failed.
Fourth, although secondary considerations must be taken into account, they
do not control the obviousness conclusion. Where a strong prima facie obviousness
showing exists, the Federal Circuit has repeatedly held that even relevant
secondary considerations supported by substantial evidence may not dislodge the
primary conclusion of obviousness. See, e.g., Bayer Healthcare Pharms. Inc. v.
Watson Pharms. Inc., 713 F.3d 1369, 1376 (Fed. Cir. 2013) (proffered evidence of
secondary considerations d[id] not overcome the express teachings of multiple
references); Allergan Inc. v. Sandoz Inc., 726 F.3d 1286, 1293 (Fed. Cir. 2013)
(finding claims directed to drug combinations and methods of treating glaucoma
obvious and rejecting proffered secondary considerations, including purported
evidence of unexpected results from the claimed drug combinations).
57

In any event, the Examiner of the parent patent did not cite, rely on, or even
mention secondary considerations as a factor for issuing the parent claims. (See
Ex. 1049.) Thus, the burden is on the Patent Owner to come forward with such
evidence in the event trial is instituted, and it is not Petitioners burden to address
potential secondary considerations where no evidence or nexus was put forth
during prosecution of the challenged claims, and when the Examiner of the parent
application did not make any findings related to secondary considerations.
VIII. CONCLUSION
Thus, Petitioner respectfully requests inter partes review of claims 18 of
U.S. Patent No. 8,663,685.
Respectfully submitted,
September 2, 2015
/Sarah E. Spires/
Sarah E. Spires (Reg. No. 61,501)
SKIERMONT PUCKETT LLP
2200 Ross Ave. Ste. 4800W
Dallas, Texas 75201
P: 214-978-6600/F: 214-978-6601
Lead Counsel for Petitioner
Dr. Parvathi Kota (Reg. No. 65,122)

Paul J. Skiermont (pro hac vice requested)
SKIERMONT PUCKETT LLP
2200 Ross Ave. Ste. 4800W
Dallas, Texas 75201
P: 214-978-6600/F: 214-978-6621
Back-Up Counsel for Petitioner
58

CERTIFICATE OF SERVICE
I hereby certify that on September 3, 2015, a copy of this Petition for Inter
Partes Review of U.S. Patent No. 8,663,685, including all exhibits, was served via
FedEx, overnight delivery, upon the following:
AcordaJD
Jones Day
222 East 41st Street
New York, NY 10017
Anthony Michael
Acorda Therapeutics, Inc.
420 Saw Mill River Road
Ardsley, NY 10502
Date: September 2, 2015
/Sarah E. Spires/

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Paper No.

UNITED STATES PATENT AND TRADEMARK OFFICE

Patent No. 8,663,685

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

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

Real Parties-in-Interest (37 C.F.R. 42.8(b)(1)) ..................................1

Related Judicial and Administrative Matters (37 C.F.R.

Lead and Back-Up Counsel (37 C.F.R. 42.8(b)(3)) and

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

Overview of U.S. Patent No. 8,663,685 ................................................4

The 685 Patent Specification .....................................................5

The 685 Claims ..........................................................................5

Prosecution History of the 685 Patent .......................................7

Summary of Selected Prosecution History of the

Effective Priority Date of the 685 Patent Claims ..............................12

Level of Ordinary Skill in the Art .......................................................20

Claim Construction of Challenged Claims .........................................20

release profile ........................................................................21

improving walking ................................................................21

Patent No. 8,663,685

Statement of Precise Relief Requested for Each Claim

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

Statutory Grounds of Challenge................................................22

History of 4-AP and State of the Art at the Time of

The S-1 (Ex. 1003) ....................................................................25

Hayes (Ex. 1005).......................................................................30

Juarez (Ex. 1006) ......................................................................31

VI. Detailed Explanation of the Challenge ............................................................32

35 U.S.C. 325(d) should not bar the petition ...................................32

The present Petition presents a combination of art not

The present Petition presents grounds not previously

Ground 1: Claims 1 and 8 are obvious in light of the S-1 in

Independent claim 1 is obvious in light of the S-1

Dependent claim 8 is obvious in light of the S-1 and a

The S-1 teaches b.i.d. (BID) administration of

Patent No. 8,663,685

Ground 2: Claims 25 are obvious over the S-1 in view of

The S-1 and Hayes combination teaches a mean Tmax

The S-1 and Hayes combination teaches a release

The S-1 and Hayes combination teaches that

Ground 3: Claims 1, 6 and 7 are obvious in light of the S-1

The S-1 and Juarez combination teaches SR 4-AP

VII. Any secondary considerations are insufficient to overcome the

Patent No. 8,663,685

Patent No. 8,663,685

Patent No. 8,663,685

Patent No. 8,663,685

Patent No. 8,663,685

Relevant excerpts of U.S. Patent No. 8,663,685 Prosecution

Acorda Therapeutics, Inc., Registration Statement Under the

Rules and Related Matters, 2003-186 (Sept, 30, 2003), available at

Keith C. Hayes et al., Pharmacokinetic Studies of Single and

Haydee Jurez et al., Influence of Admixed

U.S. Provisional Patent Application No. 60/560,894 (filed Apr. 9,

Masterson et al., U.S. Patent No. 5,540,938, Formulations and

Richard E. Jones et al., Effects of 4-Aminopyridine in Patients with

Patent No. 8,663,685

Harrit van Diemen, M.D. et al., The Effect of 4-Aminopyridine on

Chris H. Polman, MD, PhD et al., 4-Aminipyridine is Superior to

D. Stefoski, MD, et al., 4-Aminopyridine Improves Clinical Signs

Floyd A. Davis, M.D. et al., Orally Administered 4-Aminopyridine

Types of MS, Nat. Multiple Sclerosis Socy,

Declaration of Scott Bennett (Bennett Decl.)