Anda di halaman 1dari 80

Filed: November 2, 2016

UNITED STATES PATENT AND TRADEMARK OFFICE


BEFORE THE PATENT TRIAL AND APPEAL BOARD

MYLAN PHARMACEUTICALS INC.


Petitioner,
v.
YEDA RESEARCH & DEVELOPMENT CO., LTD.
Patent Owner.
Patent No. 9,155,776

PETITION FOR INTER PARTES REVIEW OF


U.S. PATENT NO. 9,155,776

TABLE OF CONTENTS
Page
I.

INTRODUCTION ..........................................................................................1

II.

MANDATORY NOTICES (37 C.F.R. 42.8) ..............................................2


A.

Real Party-in-Interest ( 42.8(b)(1)) ....................................................2

B.

Related Matters ( 42.8(b)(2)) .............................................................2


1.

Identification of Counsel (37 C.F.R. 42.8(b)(3)) and


Service Information ( 42.8(b)(4)) ............................................4

2.

Service Information (37 C.F.R. 42.8(b)(4)) ............................4

III.

GROUNDS FOR STANDING AND PROCEDURAL STATEMENT ........ 5

IV.

IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE


PRECISE RELIEF REQUESTED .................................................................5

V.

THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW ............ 6

VI.

STATEMENT OF REASONS FOR THE RELIEF REQUESTED .............. 6


A.

Summary of the Argument ...................................................................6

B.

Background ..........................................................................................9
1.

Background of the 776 Patent ..................................................9

2.

Unpatentability of the 250, 413, and 302 Patents ................13

3.

The Post-Grant Review of the 776 Patent and the


Boards Adoption of Patent Owners Arguments on
Claim Scope .............................................................................15

C.

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

D.

Claim Construction.............................................................................19
1.

E.

The Reduced Severity Recitations Should Be Construed


to Encompass Improved Tolerability .......................................19

Patents and Printed Publications Relied on in This Petition ..............25


1.

Pinchasi (Ex. 1004) ..................................................................25

2.

SBOA (Ex. 1006) .....................................................................26

3.

Flechter 2002A (Ex. 1005) ......................................................27

4.

Caon .........................................................................................29
-i-

TABLE OF CONTENTS
(continued)
5.
F.

G.

H.

I.

J.

Prior Art Informing the General Knowledge of the


Ordinarily-Skilled Artisan .......................................................30

Summary of Petitioners Obviousness Positions ...............................31


1.

The Law of Obviousness .........................................................31

2.

The Prior Art Renders the Claims Obvious .............................32

Ground 1: All Claims of the 776 Patent Were Unpatentable as


Obvious Over Pinchasi and Flechter 2002A ......................................36
1.

Independent Claim 1 Was Obvious Over Pinchasi and


Flechter 2002A.........................................................................36

2.

Independent Claim 5 Was Obvious Over Pinchasi and


Flechter 2002A.........................................................................44

3.

Independent Claim 12 Was Obvious Over Pinchasi and


Flechter 2002A.........................................................................47

4.

Independent Claim 16 Was Obvious Over Pinchasi and


Flechter 2002A.........................................................................49

5.

Dependent Claims 3-4, 6-11, 13-15, and 17-30 Were


Obvious Over Pinchasi and Flechter 2002A............................50

Ground 2: All Claims of the 776 Patent Were Unpatentable as


Obvious Over Pinchasi and the SBOA ..............................................52
1.

Independent Claims 1, 5, 12, and 16 Were Obvious Over


Pinchasi and the SBOA ............................................................52

2.

Dependent Claims 2-4, 6-11, 13-15, and 17-30 Were


Obvious Over Pinchasi and the SBOA ....................................53

Ground 3: All Claims of the 776 Patent Are Unpatentable as


Obvious Over Pinchasi, Flechter 2002A, and Caon ..........................54
1.

Independent Claims 1, 5, 12, and 16 Were Obvious Over


Pinchasi, Flechter 2002A, and Caon ........................................54

2.

Dependent Claims 3-4, 6-11, 13-15, and 17-30 Were


Obvious Over Pinchasi, Flechter 2002A, and Caon ................56

Ground 4: All Claims of the 776 Patent Are Unpatentable as


Obvious Over Pinchasi, the SBOA, and Caon ...................................57
- ii -

TABLE OF CONTENTS
(continued)

K.

1.

Independent Claims 1, 5, 12, and 16 Were Obvious Over


Pinchasi, the SBOA, and Caon ................................................57

2.

Dependent Claims 3-4, 6-11, 13-15, and 17-30 Were


Obvious Over Pinchasi, the SBOA, and Caon ........................58

Any Secondary Considerations Fail to Overcome the Showing


of Obviousness ...................................................................................59
1.

The Methods Recited in the 776 Patent Produced No


Relevant Unexpected Results ..................................................59

2.

The 776 Patent Satisfied No Long-Felt But Unmet Need ......61

3.

No Mechanism of Action Theory Would Have Taught


Away From Less Frequent Dosing ..........................................62

4.

Copying By Generic Drug Makers Is Irrelevant......................62

VII. CONCLUSION.............................................................................................63

- iii -

TABLE OF AUTHORITIES
Page
CASES
Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
713 F.3d 1369 (Fed. Cir. 2013) ..........................................................................62
Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
246 F.3d 1368 (Fed. Cir. 2001) ..........................................................................45
Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
752 F.3d 967 (Fed. Cir. 2014) ......................................................................59, 60
Cuozzo Speed Techs., LLC v. Lee,
136 S. Ct. 2131 (2016) ........................................................................................19
Galderma Labs., L.P. v. Tolmar, Inc.,
737 F.3d 731 (Fed. Cir. 2013) ............................................................................62
Graham v. John Deere Co.,
383 U.S. 1 (1966) ................................................................................................31
Hoffmann-La Roche Inc. v. Apotex Inc.,
748 F.3d 1326 (Fed. Cir. 2014) ....................................................................31, 60
In re PepperBall Techs., Inc.,
469 F. Appx 878 (Fed. Cir. 2012) .....................................................................61
In re Skoll,
523 F.2d 1392 (C.C.P.A. 1975) ..........................................................................60
Iron Grip Barbell Co. v. USA Sports, Inc.,
392 F.3d 1317 (Fed. Cir. 2004) ..........................................................................61
KSR Intl Co. v. Teleflex Inc.,
550 U.S. 398 (2007) ............................................................................................31
New Hampshire v. Maine,
532 U.S. 742 (2001) ............................................................................................24
Pfizer, Inc. v. Apotex, Inc.,
480 F.3d 1348 (Fed. Cir. 2007) ....................................................................32, 59
- iv -

TABLE OF AUTHORITIES
(continued)
SanDisk Corp. v. Memorex Prods., Inc.,
415 F.3d 1278 (Fed. Cir. 2005) ..........................................................................24
SkinMedica, Inc. v. Histogen Inc.,
727 F.3d 1187 (Fed. Cir. 2013) ..........................................................................44
Warner Chilcott Co. v. Teva Pharms. USA, Inc.,
594 F. Appx. 630 (Fed. Cir. 2014) ....................................................................32
STATUTES
35 U.S.C. 102(b) ..............................................................................................27, 29
35 U.S.C. 103(a) ...................................................................................................31
REGULATIONS
37 C.F.R. 42.100(b) ..............................................................................................19

-v-

LIST OF EXHIBITS

EXHIBIT NO.

DESCRIPTION

1001

U.S. Patent No. 9,155,776

1002

Image File Wrapper For U.S. Patent No. 9,155,776 from Public
PAIR

1003

Declaration of Dr. Ari Green M.D.

1004

Irit Pinchasi: International Publication No. WO 2007/081975


(published July 19, 2007) (Pinchasi)

1005

Flechter et al., Copolymer 1 (Glatiramer Acetate) in Relapsing


Forms of Multiple Sclerosis: Open Multicenter Study of
Alternate-Day Administration. 25:1 CLINICAL
NEUROPHARMACOLOGY, 11-15 (2002) (Flechter 2002A)

1006

Affidavit of Marlene S. Bobka dated December 9, 2014; John J.


Jessop, Review and Evaluation of Pharmacology Toxicology
Data Original NDA Review (1996) (attached as Exhibit A)
(the SBOA)

1007

Caon et al., Randomized, Prospective, Rater-Blinded, Four


Year Pilot Study to Compare the Effect of Daily Versus Every
Other Day Glatiramer Acetate 20 mg Subcutaneous Injections
in RRMS, 72:11(3) NEUROLOGY, A317 (2009) (Caon 2009)

1008

Final Written Decision, IPR2015-00643 (Paper No. 85)

1009

Final Written Decision, IPR2015-00644 (Paper No. 86)

1010

Final Written Decision, IPR2015-00830 (Paper No. 80)

1011

Decision, PGR2016-00010 (Paper No. 9)

1012

Petition for Post-Grant Review, PGR2016-00010 (Paper No. 2)


- vi -

LIST OF EXHIBITS
(continued)
EXHIBIT NO.

DESCRIPTION

1013

Yedas Patent Owner Preliminary Response, PGR2016-00010


(Paper No. 7)

1014

Decision, Institution of Inter Partes Review, IPR2015-00643


(Paper No. 13)

1015

Decision, Institution of Inter Partes Review, IPR2015-00644


(Paper No. 14)

1016

Decision, Institution of Inter Partes Review, IPR2015-00830


(Paper No. 8)

1017

Yedas Preliminary Patent Owner Response,


IPR2015-00643 (Paper No. 11)

1018

Yedas Patent Owner Response, IPR2015-00643 (Paper No.


26)

1019

Second Amended Complaint, In re Copaxone 40 mg


Consolidated Cases, No. 1:14-cv-01171-GMS (D. Del.) (ECF
No. 115)

1020

Plaintiffs Opening Claim Construction Brief, In re Copaxone


40 mg Consolidated Cases, No. 1:14-cv-01171-GMS (D. Del.)
(ECF No. 91)

1021

Stipulation, In re Copaxone 40 mg Consolidated Cases, No.


1:14-cv-01171-GMS (D. Del.) (ECF No. 194)

1022

Order Construing the Terms of U.S. Patent Nos. 8,232,250,


8,399,413, 8,969,302, and 9,155,776, In re Copaxone 40 mg
Consolidated Cases, No. 1:14-cv-01171-GMS (D. Del.) (ECF
No. 214)

1023

Excerpts of Trial Transcripts, In Re Copaxone 40 mg


Consolidated Cases, No. 1:14-cv-01171-GMS (D. Del.)
- vii -

LIST OF EXHIBITS
(continued)
EXHIBIT NO.

DESCRIPTION

1024

U.S. Patent No. 8,232,250

1025

U.S. Patent No. 8,399,413

1026

U.S. Patent No. 8,969,302

1027

Affidavit of Marlene S. Bobka dated January 5, 2015; 1996


FDA Meeting Agenda minutes from the Peripheral and Central
Nervous System Drug Advisory Committee (dated September
19, 1996)

1028

Johnson et al., Copolymer 1 reduces relapse rate and improves


disability in relapsing-remitting multiple sclerosis,
NEUROLOGY 45:1268-76 (1995)

1029

Ge et al., Glatiramer acetate (Copaxone) treatment in


relapsing-remitting MS, Quantitative MR assessment, NEUROL.
54:813-17 (February 2000)

1030

Jacobs et al. Intramuscular interferon beta-1a therapy initiated


during a first demyelinating event in multiple sclerosis NEW
ENGL. J. MED 343:898-904 (2000) (Jacobs)

1031

Comi et al., European/Canadian multicenter, double-blind,


randomized, placebo-controlled study of the effects of
glatiramer acetate on magnetic resonance imaging-measured
disease activity and burden in patients with relapsing multiple
sclerosis, ANNALS NEUROL. 49:290-297 (2001)

1032

Copaxone U.S. Product Label (Feb. 2009)

1033

U.S. Patent Application No. 61/274,687

1034

Frohman, Multiple Sclerosis - The Plaque and its Pathogenesis,


NEW ENGLAND J. MED. 354:942-55 (2006)

- viii -

LIST OF EXHIBITS
(continued)
EXHIBIT NO.

DESCRIPTION

1035

Miller, The Importance of Early Diagnosis of Multiple


Sclerosis, J. MANAGED CARE PHARMACY 10:S4-S11 (June
2004)

1036

Haines et al., Linkage of the MHC to familial multiple sclerosis


suggests genetic heterogeneity. The multiple sclerosis genetics
group, HUM. MOL. GENET. 7:1229-34 (1998)

1037

Rich et al., Stepped-care approach to treating MS: A managed


care treatment algorithm, J. MANAGED CARE PHARM.
10(3)(Suppl. S-b):S26-S32 (June 2004)

1038

Bakshi et al., Imaging of multiple sclerosis: Role in


neurotherapeutics, J. AM. SOC. EXPER. NEUROTHERAPEUTICS
2:277-303 (April 2005)

1039

Pelidou et al., Multiple sclerosis presented as clinically isolated


syndrome: the need for early diagnosis and treatment, THER.
CLIN. RISK MANAGEMENT 4:627-30 (June 2008)

1040

Stuart, Clinical management of multiple sclerosis: The


treatment paradigm and issues of patient management, J.
MANAGED CARE PHARMACY 10(3)(Suppl. S-b):S19-S25 (June
2004)

1041

AVONEX Product Label (2006)

1042

BETASERON Product Label (October 2003)

1043

REBIF Product Label (June 2005)

1044

EXTAVIA Product Label (2009)

1045

TYSABRI Product Label (October 2008)

1046

Edgar et al., Lipoatrophy in patients with multiple sclerosis on


glatiramer acetate, CANADIAN J. NEUROL. Sci. 31:58-63 (2004)
- ix -

LIST OF EXHIBITS
(continued)
EXHIBIT NO.

DESCRIPTION

1047

Soares et al., Localized panniculitis secondary to subcutaneous


glatiramer acetate injections for the treatment of multiple
sclerosis: a clinicopathologic and immunohistochemical study,
J. AM. ACAD. DERM. 55:968-74 (2006)

1048

Klauer and Zettl, Compliance, adherence and the treatment of


multiple sclerosis, J. NEUROL. 255 [Suppl. 6]:87-92 (2008)

1049

Evelyn V. McBride, Second International Multiple Sclerosis


Week INTL J. MS CARE 4:85 (2002)

1050

Devonshire et al. The Global Adherence Project - A multicentre


observational study on adherence to disease-modifying
therapies in patients suffering from relapsing-remitting
multiple sclerosis, MULTIPLE SCLEROSIS 12:S1 (P316) (2006)

1051

Boissel and Nony, Using pharmacokinetic-pharmacodynamic


relationships to predict the effect of poor compliance, CLIN.
PHARMACOL. 41:1-6 (2002)

1052

COPAXONE, https://scamparoo.wordpress.com/2008/04/11/mstherapies-copaxone/ (dated April 11, 2008 (accessed February


5, 2015))

1053

Khan et al., Randomized, prospective, rater-blinded, four-year,


pilot study to compare the effect of daily versus every-other-day
glatiramer acetate 20 mg subcutaneous injections in relapsingremitting multiple sclerosis, 14 MULTIPLE SCLEROSIS, S296
(2008) (Khan 2008)

1054

Flechter et al., Comparison of glatiramer acetate (Copaxone)


and interferon -1b (Betaferon) in multiple sclerosis patients:
an open-label 2-year follow up, 197 JOURNAL OF THE
NEUROLOGICAL SCIENCES, 51-55 (2002). (Flechter 2002B)

-x-

LIST OF EXHIBITS
(continued)
EXHIBIT NO.

DESCRIPTION

1055

Khan, et al., Glatiramer acetate 20mg subcutaneous twice weekly versus daily injections: results of a pilot, prospective,
randomised, and rater-blinded clinical and MRI 2-year study in
relapsing-remitting multiple sclerosis, MULTIPLE SCLEROSIS
2009; 15:S151-S269, S249-S250 (2009)

1056

Cohen et al., Randomized, double-blind, dose-comparison


study of glatiramer acetate in relapsing-remitting MS, 68:12
NEUROLOGY, 939-44 (2007) (Cohen 2007)

1057

Comi et al., Results from a phase III, 1-year, Randomized,


Double-blind, Parallel-Group, Dose-Comparison Study with
Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis,
14 MULT. SCLER., S299-S301 (2008)

1058

Teva Provides Update on Forte Trial, Jerusalem, Israel


(July 7, 2008)

1059

Wolinsky, Glatiramer acetate for the treatment of multiple


sclerosis, EXPERT OPINION ON PHARMACOTHERAPY, 5(4):875891 (2004) (Wolinsky 2004)

1060

DiPiro et al., Introduction to pharmacokinetics and


pharmacodynamics, in CONCEPTS IN CLINICAL
PHARMACODYNAMICS (5th ed. 2010)

1061

FDA GUIDANCE FOR INDUSTRY - STATISTICAL APPROACHES TO


ESTABLISHING BIOEQUIVALENCE (2001)

1062

Tevas Shared Solutions How to Prepare for Your Injection,


http://www.copaxone.com/injection-assistance/preparing-yourinjection.html (last visited Mar. 7, 2016)

- xi -

LIST OF EXHIBITS
(continued)
EXHIBIT NO.

DESCRIPTION

1063

Orange book: Approved Drug Products with Therapeutic


Equivalence Evaluations,
http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew
.cfm?Appl_No=020622&Product_No=003&table1=OB_Rx
(accessed February 5, 2015)

1064

Schrempf et al., Glatiramer Acetate: Mechanisms of Action In


Multiple Sclerosis, 6 Autoimmun. Rev. 469 (2007)

1065

Ziemssen, Neuroprotection and Glatiramer Acetate: The


Possible Role in the Treatment of Multiple Sclerosis, in
FRONTIERS IN CLINICAL NEUROSCIENCE 111-134 (L. Vcsei ed.,
2004)

1066

Weber et al., Mechanism of Action of Glatiramer Acetate in


Treatment of Multiple Sclerosis, NEUROTHERAPEUTICS,
4(4):647-653 (2007)

1067

Meiner et al., Copolymer 1 in relapsing-remitting multiple


sclerosis: a multi-centre trial, in FRONTIERS IN MULTIPLE
SCLEROSIS: CLINICAL RESEARCH AND THERAPY (Oded
Abramsky and Haim Ovadia, eds., 1997) (Meiner 1997)

- xii -

TABLE OF ABBREVIATIONS
Abbreviations

Every-other-day .................................................................................................. EOD


Expanded disability status scale......................................................................... EDSS
Glatiramer acetate .................................................................................................. GA
Immediate post injection reactions .....................................................................IPIRs
Injection related adverse events ........................................................................ IRAEs
Injection site reactions ......................................................................................... ISRs
Inter partes review ................................................................................................ IPR
Multiple sclerosis ................................................................................................... MS
Patent Trial and Appeal Board ........................................................................... Board
Person of ordinary skill in the art ...................................................................... POSA
Post-grant review ................................................................................................. PGR
Relapsing-remitting multiple sclerosis .............................................................RRMS
Subcutaneous ................................................................................................. SC / s.c.
Three-times-per-week .......................................................................................... TIW
U.S. Food and Drug Administration ....................................................................FDA
U.S. Patent and Trademark Office .................................................................. USPTO
U.S. Patent No. 8,232,250....................................................................the 250 patent
U.S. Patent No. 8,399,413....................................................................the 413 patent
U.S. Patent No. 8,399,514....................................................................the 514 patent
- xiii -

TABLE OF ABBREVIATIONS
(continued)
U.S. Patent No. 8,969,302....................................................................the 302 patent
U.S. Patent No. 9,155,776....................................................................the 776 patent
U.S. Patent No. 9,402,874....................................................................the 874 patent
U.S. Provisional Application No. 61/274,687 ............... the 687 priority application

- xiv -

I.

INTRODUCTION
U.S. Patent No. 9,155,776 (the 776 patent) claims a dosing regimen for

the drug glatiramer acetate (GA) to be used for the treatment of multiple
sclerosis (MS).

The prior art has long recognized that GA is a safe and

efficacious treatment for MS. Traditionally GA was prescribed as a 20 mg daily


injection. The 776 patent claims a dosing regimen in which twice as much GA
(40 mg) is administered about half as often (three-times-per-week, or TIW). Not
only were GA and its use to treat MS well known, but the prior art also disclosed a
40 mg dose of GA administered every-other-day (EOD) to treat MSa regimen
virtually identical to that claimed in the 776 patent.
The 776 patent is Patent Owners fourth of five patents claiming the 40 mg
TIW GA dosing regimen.

In final written decisions issued in August and

September 2016, the Board held all claims of the first three patents unpatentable as
obvious.1 The 776 patent fares no betterit adds nothing patentable to the 250,
413 and 302 patents. Patent Owner is expected to contend that the 776 patent is
somehow different because it claims reduced severity of certain adverse events
as a result of using the claimed dosing regimen as compared to daily GA dosing.
1

The first three patents are U.S. Patent Nos. 8,232,250 (the 250 patent),

8,399,413 (the 413 patent), and 8,969,302 (the 302 patent). The fifth patent
is U.S. Patent No. 9,402,874 (the 874 patent) and just issued on August 2, 2016.

-1-

But Patent Owner has already declared that the disclosure of improved
tolerability with the TIW dosing regimena characteristic expressly claimed in
the earlier 250 and 413 patents and deemed unpatentable by the Boardalso
discloses the reduced severity elements. The reduced severity elements recited
in the 776 patent thus cannot rescue the unpatentable matter claimed in the 413,
250, and 302 patents.
II.

MANDATORY NOTICES (37 C.F.R. 42.8)


A.

REAL PARTY-IN-INTEREST ( 42.8(b)(1))

The real parties-in-interest for Petitioner are Mylan Pharmaceuticals Inc.,


Mylan Inc., Mylan N.V. and Mylan Teoranta (Mylan).
B.

RELATED MATTERS ( 42.8(b)(2))

Petitioner is not aware of any reexamination certificates or pending


prosecution concerning the 776 patent.
Petitioner is a defendant in the following litigations involving four patents in
the same family, the 250 patent, 413 patent, 302 patent, and the 776 patent:
Teva Pharms. USA, Inc. v. Mylan Pharms. Inc., No. 14-01278 (D. Del.); and
Teva Pharms. USA, Inc. v. Mylan Pharms. Inc., No. 14-00167 (N.D.W. Va.).
Other pending litigations involving these same four patents include:
Teva Pharms. USA, Inc. v. Sandoz, Inc., No. 14-cv-01171 (D. Del.);
Teva Pharms. USA, Inc. v. Dr. Reddys Labs., No. 14-cv-01172 (D. Del.);

-2-

Teva Pharms. USA, Inc. v. Dr. Reddys Labs., No. 14-cv-05672 (D.N.J.);
Teva Pharms. USA, Inc. v. Synthon Pharms. Inc., No. 14-cv-01419 (D.
Del.);
Teva Pharms. USA, Inc. v. Synthon Pharms. Inc., No. 14-cv-00975
(M.D.N.C.); and
Teva Pharms. USA, Inc. v. Amneal Pharms., LLC, No. 15-cv-00124 (D.
Del.).
The litigations in the District of Delaware have been consolidated as In re
Copaxone 40 mg Consolidated Cases, No. 14-cv-01171 (D. Del.). Trial was held
on the 250, 413, 302 and 776 patents between September 26, 2016 and October
6, 2016 and the Courts decision is pending.
Inter partes reviews of the 250, 413, and 302 patents were instituted, and
all claims of the 250, 413, and 302 patents were found to be unpatentable for
obviousness on two independent grounds. Ex. 1008-1010 (IPR2015-00643, Paper
No. 85 (250 patent); IPR2015-00644, Paper No. 86 (413 patent); IPR201500830, Paper No. 80 (302 patent)). Patent Owner has requested reconsideration of
the Boards decisions in all three cases. The Board has not yet ruled on those
requests.
Petitioner previously petitioned for PGR of the 776 patent.

Ex. 1012

(PGR2016-00010, Paper No. 2). The Board did not institute review, determining

-3-

that the 776 patent is a pre-AIA patent based on Patent Owners representation
that improved tolerability of injection site reactions (ISRs) and post-injection
reactions discloses reduced severity. Ex. 1011 (PGR2016-00010, Paper No. 9)
at 9-10.
The 874 patent and Application No. 15/148, 215 are in the same family as
the 776 patent.
1.

Identification of Counsel (37 C.F.R. 42.8(b)(3)) and


Service Information ( 42.8(b)(4))

Lead Counsel
Brandon M. White
(Reg. No. 52,354)
PERKINS COIE LLP
700 13th St., NW, Suite 600
Washington, DC 20005
BMWhite@PerkinsCoie.com
Tel: (202) 654-6200
Fax: (202) 654-9681
Back-Up Counsel
Jeffrey W. Guise
(Reg. No. 34,613)
Wilson Sonsini Goodrich & Rosati
650 Page Mill Road
Palo Alto, CA 94304
jguise@wsgr.com
Tel: (858) 350-2307
Fax: (858) 350-2399
2.

Back-Up Counsel
Emily Greb
(Reg. No. 68,244)
PERKINS COIE LLP
1 East Main Street, Suite 201
Madison, WI 53703-5118
EGreb@PerkinsCoie.com
Tel: (608) 663-7494
Fax: (608) 283-4494
Back-Up Counsel
Lorelei P. Westin
(Reg. No. 52,353)
Wilson Sonsini Goodrich & Rosati
12235 El Camino Real
Suite 200
San Diego, CA 92130
lwestin@wsgr.com
Tel: (858) 350-2225
Fax: (858) 350-2399

Service Information (37 C.F.R. 42.8(b)(4))

Please direct all correspondence to lead counsel and back-up counsel at the
contact information above. Petitioner consents to service by electronic mail at

-4-

bmwhite@perkinscoie.com,
egreb@perkinscoie.com,
jguise@wsgr.com, and
lwestin@wsgr.com.
III.

GROUNDS FOR STANDING AND PROCEDURAL STATEMENT


As required by 37 C.F.R. 42.104(a), Petitioner certifies that the 776 patent

is available for inter partes review and that the Petitioner is not barred or estopped
from requesting inter partes review on the grounds identified herein.
Petitioner was first served with a complaint asserting the 776 patent on
November 10, 2015 (the Second Amended Complaint in Civil Action No. 14-cv1171 (D. Del.)). Ex. 1019. Accordingly, the one-year time period set forth in 35
U.S.C. 315(b) does not bar the present Petition.
IV.

IDENTIFICATION OF CHALLENGE AND STATEMENT OF THE


PRECISE RELIEF REQUESTED
Petitioner requests inter partes review and cancellation of claims 1-30 of the

776 patent under pre-AIA 35 U.S.C. 103, as set forth herein. Petitioners
detailed statement of the reasons for the relief requested is set forth below in the
section titled Statement of Reasons for Relief Requested. In accordance with 37
C.F.R. 42.6(c), copies of the exhibits are filed herewith. In addition, this petition
is accompanied by the Declaration of Ari Green, M.D., M.C.R. (Ex. 1003).

-5-

The challenged claims of the 776 patent are generally directed to methods
of treating relapsing-remitting multiple sclerosis (RRMS) by administering three
injections per week of GA in a 40 mg dose. Claims 1-30 of the 776 patent are
unpatentable based on the following grounds:
Ground 1: Claims 1-30 were obvious over Pinchasi in view of Flechter
2002A.
Ground 2: Claims 1-30 were obvious over Pinchasi in view of the SBOA.
Ground 3: Claims 1-30 were obvious over Pinchasi in view of Flechter
2002A and Caon.
Ground 4: Claims 1-30 were obvious over Pinchasi in view of the SBOA
and Caon.
V.

THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW


A petition for inter partes review must demonstrate a reasonable likelihood

that the petitioner would prevail with respect to at least 1 of the claims challenged
in the petition. 35 U.S.C. 314(a). This Petition meets this threshold.
VI.

STATEMENT OF REASONS FOR THE RELIEF REQUESTED


A.

SUMMARY OF THE ARGUMENT

Glatiramer acetate (GA) was first patented as copolymer-1 in 1974 as U.S.


Patent No. 3,849,550 (the 550 patent).

In the 1980s, Yeda partnered with Teva

to develop GA as a treatment for, inter alia, RRMS and commercially market GA


under the brand name, Copaxone. The FDA first approved Copaxone for use in
-6-

treating MS in the U.S. in 1996 as a 20 mg daily subcutaneous injection regimen.


In the 1990s, following the expiration of the 550 patent and in preparation for the
U.S. launch of 20 mg Copaxone, Teva sought additional U.S. patent protection
and received patents on the GA compound and on methods of making and using it.
In 2013, with the last of these patents covering Tevas 20 mg daily dosage form
nearing expiration, Teva sought FDA approval of a 40 mg TIW Copaxone
product. Upon receiving FDA approval, Teva began to switch patients from the
old, 20 mg daily product to its recently-approved 40 mg TIW Copaxone product.
The 776 patent is Patent Owners fourth patent covering the 40 mg TIW
dosing regimen. All claims of the first three patentsthe 250, 413, and 302
patentswere previously held unpatentable in IPR proceedings on two grounds:
obviousness over Pinchasi in view of Flechter 2002A, and obviousness over
Pinchasi in view of the SBOA. Exs. 1008-1010 (IPR2015-00643, Paper No. 85;
IPR2015-00644, Paper No. 86; IPR2015-00830, Paper No. 80). Those same two
grounds, and two additional ones, are presented herein.
All four patents share the same specification. Like the 250, 413, and 302
patents, the 776 patent is generally directed to a low frequency glatiramer acetate
therapy for treating a human patient suffering from RRMS. Ex. 1001 at Title,
Abstract, col. 2, ll. 48-50. Also like the 250, 413, and 302 patents, the claims of

-7-

the 776 patent recite a method of administering 40 mg GA TIW to treat MS. Ex.
1001 at claims 1-30.
But before the earliest possible priority date (August 20, 2009), low
frequency GA dosage forms were well known in the art. As explained in detail
below, a 2007 Teva patent application to Pinchasi (Ex. 1004)the closest prior
art to the 250, 413, and 302 patentstaught the administration of a 40 mg
dosage of GA EOD. Ex. 1008 at 26; Ex. 1009 at 26; Ex. 1010 at 24; see also Ex.
1003 109-117. A number of other prior art references taught that administering
GA EOD is similarly efficacious to daily administration and improves patient
compliance and adherence by improving the tolerability of GA treatment. Ex.
1003 at 118, 127, 142-147 . The prior art also disclosed that the 40 mg dose
may improve efficacy over the 20 mg dose without increasing adverse effects. Ex.
1003 at 110-114.
The 776 patents claims recite only one element not expressly recited in the
250, 413, or 302 patents claims. Each of the 776 patents independent claims
requires that the treatment method induces reduced severity of injection site
reactions (ISRs) relative to administration of 20 mg GA daily (the reduced
severity element). Ex. 1001 at claims 1, 5, 12, and 16. Based on the Boards
prior decisions, the reduced severity element was obvious. In denying institution
of PGR on the 776 patent, the Board adopted Patent Owners argument that

-8-

disclosure of a 40 mg TIW regimen that improves the tolerability of GA treatment


discloses the reduced severity element. Accepting the Boards prior findings as
correct, as Petitioner must here, means that the 776 patents claims to reduced
severity clearly encompass claims to improved tolerability in the 250 and 413
patents. Ex. 1003 43-51. Because the Board has already held obvious all
claims of the 250 and 413 patentsincluding the claims to improved
tolerabilitythe Board should reach the same result here. The 776 patents
claims were obvious.
B.

BACKGROUND
1.

Background of the 776 Patent


a.

The 776 Patent

The 776 patent issued October 13, 2015 from an application filed five
months earlier, on May 22, 2015. That application was a continuation of earlier
applications, and claimed the benefit of related application numbers 13/770,677
(now the 302 patent) and 12/806,684 (now the 413 patent), which in turn claimed
the benefit of U.S. Provisional Application Nos. 61/337,612 and 61/274,687 (the
687 priority application). The 776 patents earliest possible priority date is
August 20, 2009.
The 776 patent issued with 30 claims directed to the 40 mg TIW dosing
regimen, with added limitations on reducing the severity and/or frequency of ISRs

-9-

and/or immediate post-injection reactions (IPIRs) associated with administration


of GA.
Claims 1, 5, 12, and 16 are the only independent claims. All claims recite a
single stepadministration of one subcutaneous injection of 1 ml of a
pharmaceutical composition comprising 40 mg of glatiramer acetate on only each
of three days during each week of treatment with at least one day without a
subcutaneous injection of the pharmaceutical composition between each day on
which there is a subcutaneous injection. Ex. 1001. The claims also include
limitations directed to presence of the GA in a prefilled syringe, the presence of
mannitol in the pharmaceutical composition, and the pharmaceutical composition
having a pH in the range of 5.5 to 7.0. Id.
Independent claim 1 of the 776 patent further recites [a] method of treating
a human patient suffering from a relapsing form of multiple sclerosis, while
inducing reduced severity of injection site reactions in the human patient relative to
administration of 20 mg of glatiramer acetate s.c. daily, . . . so as to thereby treat
the human patient with reduced severity of injection site reactions relative to
administration of 20 mg glatiramer acetate s.c. daily. Ex. 1001 at col. 16, ll. 3550.
Independent claim 5 recites a similar method, but recites in the preamble that
the method exhibits one of four listed treatment effects: (1) reducing the

- 10 -

frequency of relapses by 30% or more as compared to placebo in a human


population, (2) reducing brain atrophy, (3) reducing the cumulative number of
enhancing lesions on T1-weighted images, or (4) reducing the level of disability
as measured by EDSS Score. Id. at col. 16, l. 61 - col. 17, l. 19.
Independent claim 12 recites a similar method to claim 1 and includes
additional recitations directed to improving the tolerability of glatiramer acetate
treatment of a human patient suffering from a relapsing form of multiple sclerosis,
the treatment being as effective as administration of 20 mg of glatiramer acetate
s.c. daily, and treat[ing] the human patient as effectively as by administration of
20 mg of glatiramer acetate s.c. daily. Id. at col. 17, ll. 37-54.
Independent claim 16 recites a method similar to claims 1 and 5, and
includes additional recitations directed to improving the tolerability of glatiramer
acetate therapy [and] reducing the frequency of relapses, reducing brain atrophy,
reducing the cumulative number of enhancing lesions on T1-weighted images, or
reducing the level of disability as measured by EDSS Score, of a human patient
suffering from a relapsing form of multiple sclerosis as effectively as
administration of 20 mg of glatiramer acetate s.c. daily. Id. at col. 17, l. 65-col.
18, l. 22.
The dependent claims recite limitations directed to treating human patients
who have not received prior GA therapy (claims 3-4, 10-11, 14-15, and 25-30),

- 11 -

various improved treatment effects relative to placebo or 20 mg GA daily


(claims 6-8 and 17-20), and inducing reduced frequency and severity of ISRs and
immediate post-injection reaction (IPIRs) relative to 20 mg GA daily (claims 2,
9, 13, and 21-24).
The 776 patent acknowledges that treating MS patients with GA was not
new. Id. at col. 2, ll. 18-47. GA had been known for years to be a safe and
effective treatment for MS and had been FDA approved as a 20 mg daily injection
therapy for MS patients since 1996. Id.
b.

The Prosecution of the 776 Patent

The 776 patent was filed as a Track One application. Despite the pending
IPRs on its parent patents, the 776 patent issued less than five months after it was
filed. The Examiner issued only a single rejection based on nonstatutory double
patenting over claims 1-12 of the 302 patent, claims 1-20 of the 250 patent, and
claims 1-20 of the 413 patentall claims the Board has now found unpatentable.
Ex. 1002 at 259-67. In the rejection, the Examiner stated that [a]lthough the
claims at issue are not identical, they are not patentably distinct from each other
because the patent claims fully encompass the subject matter of the pending
claims. Id. at 265 2. Rather than dispute the rejection or the Examiners
characterization of claim scope, the applicant responded by filing a terminal
disclaimer. Id. at 188-90. The examiner then allowed all claims. Id. at 30-36.

- 12 -

2.

Unpatentability of the 250, 413, and 302 Patents

The 776 patentand several of its family members, including the 250,
413, and 302 patentsclaim priority to the 687 priority application, filed on
August 20, 2009. Like the 776 patent, the 250, 413, and 302 patents all relate
to [a] method of alleviating a symptom of relapsing-remitting multiple sclerosis
using low frequency glatiramer acetate therapy, i.e., administering 40 mg GA
TIW to treat MS. Ex. 1024-1026 at Abstract, Title. The 250 patent additionally
claims, e.g., methods of reducing the frequency of ISRs or IPIRs relative to 20 mg
GA daily, Ex. 1024, claims 14, 16, 17; treating GA-nave patients, id. at claim 13;
increasing the tolerability of GA treatment, id. at claim 15; and reducing relapse
rate, brain atrophy, enhancing lesions, and EDSS-scored disability, id. at claims 1,
4, 5-7, 10-11, 19. The 413 patent additionally claims a specific formulation (i.e., a
prefilled syringe for self-administration with a mannitol excipient, where the pH is
between 5.5 and 7.0), Ex. 1025 at claims 12-13, 19-20; certain clinical benefits of
administering 40 mg GA TIW including reducing the frequency of relapses, id. at
claims 19, 20; and reducing the frequency of IPIRs or ISRs relative to
administration of 20 mg daily, id. at claim 7. The 302 patent additionally claims
administration on specific days of the week. Ex. 1026 at claims 4, 5, 11.
The Board granted inter partes review and held unpatentable all claims of
the 250, 413, and 302 patents on two grounds: obviousness over Pinchasi (Ex.

- 13 -

1004) and Flechter 2002A (Ex. 1005) and obviousness over Pinchasi and the
SBOA (Ex. 1006). Ex. 1008-1010. Throughout its decisions, the Board credited
the testimony of Petitioners expert, Dr. Ari Green. See, e.g., Ex. 1008 at 10-13,
15-23, 26, 32, 34. The Board found that Pinchasi taught a method for alleviating a
symptom in an RRMS patient wherein the symptom is frequency of relapses, and
the patient is administered one subcutaneous injection of 40 mg GA EOD (i.e.,
seven administrations in a two-week period, as compared to the patents claims to
six administrations within the same two-week period). Ex. 1008 at 9-10; Ex. 1009
at 11-14; Ex. 1010 at 11-13. The Board further found that a POSA would have
been motivated to modify the method of treatment from EOD to TIW to increase
patient compliance, without fearing an increase in side effects or decrease in
efficacy. Ex. 1008 at 10-21, 31-33; Ex. 1009 at 11-23, 31-33; Ex. 1010 at 13-21,
28-30. The Board agreed that a POSA would have had a reasonable expectation of
success because the claimed regimen administered 120 mg GA per week, which
was within the dosing range known to be therapeutically effective, and nearly
identical to the FDA-approved 20 mg daily dosing regimen of 140 mg per week.
Ex. 1008 at 20-21; see also Ex. 1009 at 20-22; Ex. 1010 at 17-20.
The Board likewise found obvious the patents claimed treatment parameters
and effects. Claimed treatment effectssuch as reducing relapses, brain atrophy,
enhancing lesions, and EDSS-scored disabilitywere well-known beneficial

- 14 -

effects resulting from, and are the natural results of, the administration of a firstline therapy, such as GA. Ex. 1008 at 22 (internal quotations omitted). Likewise,
the 413 patents nave patient claimthe claimed method of treatment wherein
the patient has not received glatiramer acetate therapy prior to initiation of the
subcutaneous injections, (Ex. 1025) claim 6was obvious over Pinchasi and the
prior art, Ex. 1009 at 23-24, as were claims to specific excipients and pH, id. at 1113, 23-24. And ultimately, the Board found obvious purported improvements to
tolerability, because a POSA would have had a reason to switch patients treated
with GA from dosing 20 mg daily to 40 mg three times over a period of seven
days, and would have known that doing so would increase the tolerability of GA
treatment. Ex. 1008 at 24; see also Ex. 1010 at 27-28.
Patent Owner has requested rehearing of the Boards decisions in all three
inter partes review proceedings. The Board has not yet ruled on those requests.
3.

The Post-Grant Review of the 776 Patent and the Boards


Adoption of Patent Owners Arguments on Claim Scope

Petitioner previously requested PGR of the 776 patent, arguing inter alia
that the 776 patents claims were not entitled to an August 20, 2009 priority date
and that all claims lacked written description. Based on the later priority date it
advocated, Petitioner also argued that the claims were anticipated or obvious over a
2015 McKeage reference. Ex. 1012 at 52-65.

- 15 -

On priority and written description, Petitioner contended that the claimed


reduced severity differs from improved tolerability and reduced frequency,
and that this distinct concept lacked support in the specification or priority
applications. In responding to Petitioners PGR petition, Patent Owner stated that
the reduced severity recitations in the claims are supported by a claim in the 687
priority application to improved tolerability and that the claims of the 776 patent
were not patentably distinct from the now-unpatentable claims of the 302 patent.2
Ex. 1013.
Patent Owner stated:
Tolerability in the patent was specifically defined to include an
improvement in severity. At p.16, ll. 28-31, the 687 Application
states As used herein tolerability relates to the level of discomfort
associated with the GA treatment. Tolerability is associated with the
frequency and severity of post-injection reactions and injection site
reactions.

Thus, a POSA would understand [a method of

increasing the tolerability of GA treatment] as describing the


reduction of severity of post-injection reactions and injections site
reactions.
Ex. 1013 at 29 (emphasis added).
2

The 687 priority application and 776 patent employ the same definition of

tolerability. Compare Ex. 1033 at 18, l. 28 - 19, l. 2 with Ex. 1001 at col. 7, ll.
38-42.

- 16 -

Indeed, Patent Owner made not just one, but several such statements
explicitly equating increased tolerability of treatment with a corresponding
reduction in severity of ISRs and IPIRs. See, e.g., Ex. 1013 at 41 (A POSA
would have understood from the inclusion of these measures of tolerability in
Example 1 that the example was directed to a method for reducing the severity of
injection site reactions and immediate post injection reactions.); id. at 30 ([T]he
disclosure in the claims of the 687 Application and other ancestor Applications of
the 776 patent of methods of increasing tolerability . . . includes a reduction in the
severity of injection site reactions and thus provides additional written description
support for the claims of the 776 patent.); id. at 37-38 (These disclosures
describe a method of increasing the tolerability of GA treatment, i.e., improving
the frequency and severity of injection site reactions.). Patent Owner also made
clear that the improve[ment in] tolerability of 40 mg TIW was as compared to 20
mg daily. See, e.g., id. at 38 (A POSA reviewing the specification, therefore,
would understand that the described increase in tolerability is necessarily relative
to administration of 20 mg of GA daily.); id. at 28 (increasing tolerability
relative to a 20 mg/day subcutaneous dose of GA).
In other words, Patent Owner consistently argued in the PGR that disclosure
of any improvement in the tolerability of GA treatment describes a reduction in
ISR severity. Ex. 1003 43-51. Thus, under Patent Owners own interpretation

- 17 -

of the 776 patents reduced severity claims, a prior art teaching of improved
tolerability teaches a reduction in severity of ISRs and IPIRs.
The Board denied institution of the PGR. See Ex. 1011. In its denial, the
Board largely adopted Patent Owners interpretation of reduced ISR and IPIRs
severity as encompassing an improvement in the tolerability of GA treatment. The
Board agreed with Patent Owner that claim 10 of the 687 priority application
which discloses increasing the tolerability of GA treatmentdiscloses the claimed
reduced severity of ISRs and IPIRs. Id. at 9-10. The Board also noted that, in
prosecution, the Examiner had issued a statutory double patenting rejection over
the 302 patents claims to improved tolerability. Id. at 7-8 (Furthermore, as
noted by Patent Owner, the Examiner found in rejecting the claims for
obviousness-type double patenting over the 302 patent that the claims of the
application that matured into the 776 patent were fully disclosed in the 302
patent and is covered by that patent.). Rather than attempt to overcome the
rejections substance, Patent Owner filed a terminal disclaimer. The Examiner also
applied a pre-AIA effective filing date to the 776 patent during prosecution. Id. at
10. The Board therefore determined that the Petition had not set forth sufficient
evidence to deny Patent Owner the August 20, 2009 priority date. Id. at 9-10.
Accordingly, the Board did not address Petitioners written description,
anticipation, or obviousness arguments.

- 18 -

C.

LEVEL OF ORDINARY SKILL IN THE ART

For purposes of these proceedings, Petitioner accepts and applies the


Boards definition from the IPR2015-00643, -0644, and -0830 proceedings.
Namely, the POSA would have had (1) several years of experience in the
pharmaceutical industry or in practicing medicine; (2) experience with the
administration or formulation of therapeutic agents, dosing schedules and
frequencies, and drug developmental study and design; (3) a Ph.D. in
pharmacology or an M.D. with experience in clinical pharmacology, and
(4) knowledge of, and experience with, both MS and GA.

Ex. 1014 at 8-9; Ex.

1015 at 5, Ex. 1016 at 5.


D.

CLAIM CONSTRUCTION

The claims of the 776 patent are presumed to take on the broadest
reasonable construction in light of the specification of the patent in which it
appears. 37 C.F.R. 42.100(b); see also Cuozzo Speed Techs., LLC v. Lee, 136 S.
Ct. 2131, 2142-46 (2016).
1.

The Reduced Severity Recitations Should Be Construed to


Encompass Improved Tolerability

All claims include a recitation that the claimed method reduces the severity
of injection site reactions and/or immediate post injection reactions compared to
the 20 mg daily regimen (the reduced severity terms).

- 19 -

The Board should construe these terms to encompass improving the


tolerability of GA treatment. In the PGR of the 776 patent, the Board held that a
priority applications disclosure of a regimen that increases the tolerability of GA
treatment provides written description support for the reduced severity terms. In so
holding, the Board adopted an interpretation of the reduced severity terms
advocated by Patent Owner. Therefore, the Board should hold hereconsistent
with its interpretation in the PGRthat the broadest reasonable construction of the
reduced severity terms encompasses improved tolerability.
a.

The Board Has Already Construed Reduced Severity


to Encompass Improved Tolerability

One basis for Petitioners PGR petition was that the 776 patents claims
lack written description for the claim term reduced severity of injection site
reactions relative to administration of 20 mg glatiramer acetate s.c. daily.
In response to the petition and to avoid institution of the PGR, Patent Owner
argued that the reduced severity terms were adequately supported in the
specification and ancestor applications. Specifically, Patent Owner asserted that a
parent patent application to which the 776 patent claimed priority, the 687
application, included a claim that reads:
10. A method of increasing the tolerability of GA treatment in a
human patient suffering from relapsing-remitting multiple sclerosis or
a patient who has experienced a first clinical episode and is
- 20 -

determined to be at high risk of developing clinically definite multiple


sclerosis which comprises reducing the frequency of subcutaneous
injections

of

pharmaceutical

composition

comprising

therapeutically effective dose of glatiramer acetate to three times over


a period of seven days with at least one day between every injection.
Ex. 1033 at 38 (claim 10) (emphasis added).
Claim 10 of the 687 priority application recites a method of increasing
tolerability. Claim 10 nowhere uses the term severity, and it never expressly
refers to a reduction in ISR or IPIR severity. Increasing the tolerability of GA
treatment is the only descriptive content of claim 10 apart from administering a
therapeutically effective dose of GA TIW. Nonetheless, to avoid institution of
Petitioners PGR, Patent Owner asserted that a POSA would understand Claim 10
[above] as describing the reduction of severity of post-injection reactions and
injections site reactions. Ex. 10013 (PGR2016-00010, Paper No. 7) at 29.
The Board accepted Patent Owners arguments and declined to institute
Petitioners PGR. Specifically, the Board credited Patent Owners argument that
the 687 application included claim 10, which was directed to a method of
increasing the tolerability of GA treatment. Ex. 1011 (PGR2016-00010, Paper
No. 9) at 9. The Board also referenced Patent Owners contentions that [a] POSA
would understand that claim 10 of the 687 application, read in light of the

- 21 -

specification, is referring to a method of increasing tolerability relative to the 20


mg/day subcutaneous dose of GA, and that [t]olerability in the patent was
specifically defined to include an improvement in severity. Id. at 9-10. The
Board concluded that Patent Owner met [its] burden [of production] by pointing
to the Examiners findings as to the effective filing date of the 776 patent during
prosecution, as well as by pointing to supporting disclosures in the original priority
application. Id. at 10.
The Board therefore adopted Patent Owners argument and held that the
broadest reasonable interpretation of the reduced severity terms encompasses
increasing the tolerability of GA treatment. Ex. 1003 43-51. Patent Owner
must now face the consequences of pursuing the broader interpretation of reduced
severitythe reduced severity limitations are obvious. To the extent that Patent
Owner may criticize Petitioner for advocating for a different construction of the
reduced severity terms here than it urged in the PGR, in which it advocated that the
reduced severity terms were more limited, Patent Owners complaints are
without rational basis. 3 The Board has already interpreted these terms contrary to
3

Petitioner has taken that position in parallel district court litigation, and also

argued that the reduced severity terms were indefinite because a POSA would not
know how to measure severity.

The district court has yet to make any

determinations affecting these issues. In claim construction, the Court accepted the

- 22 -

Petitioners proposed construction in the PGR when it found that reduced severity
is encompassed in increased tolerability. Petitioner therefore submits that the
Board should simply adhere to its prior holding that disclosure of increasing the
tolerability of GA treatment also discloses the reduced ISR and IPIR severity
claimed in the 776 patent.
In sum, to construe the reduced severity terms, the Board need look no
further than its decision denying institution of PGR on the 776 patent. According
to that decision, disclosure of a regimen that increases the tolerability of GA
treatment must include the reduced ISR severity claimed in the 776 patent.
b.

Patent Owner is Judicially Estopped from Arguing


for a Narrower Construction of the Reduced Severity
Terms

Even if the Board does not find its PGR decision binding or persuasive, the
statements Patent Owner made to the Board during the PGR proceedings judicially

parties agreement that the reduced severity terms limit the claims and that
severity means the intensity of a patients ISRs and/or IPIRs (a construction that
did not resolve the dispute over whether disclosure of improved tolerability
discloses the reduced severity terms). See Ex. 1021. Moreover, the District Court
does not follow the broadest reasonable construction rule in construing patent
claims.

- 23 -

estop Patent Owner from seeking a construction of the reduced severity terms that
does not encompass increased tolerability.
Judicial estoppel is an equitable doctrine that prevents a litigant from
perverting the judicial process by, after urging and prevailing on a particular
position in one litigation, urging a contrary position in a subsequent proceeding
or at a later phase of the same proceedingagainst one who relied on the earlier
position. SanDisk Corp. v. Memorex Prods., Inc., 415 F.3d 1278, 1290 (Fed. Cir.
2005). Three factors have firmly tip[ped] the balance of equities in favor of
applying judicial estoppel: (1) the partys later position is clearly inconsistent
with its earlier position; (2) the party succeeded in persuading a court to adopt the
earlier position in the earlier proceeding (particularly where there is a risk of
inconsistent determinations or a possible perception of one of the courts being
misled); and (3) the party seeking to assert an inconsistent position would
derive an unfair advantage or impose an unfair detriment on the opposing party if
not estopped. New Hampshire v. Maine, 532 U.S. 742, 750-51 (2001).
All three factors are clearly met here. Patent Owners 776 PGR preliminary
response took firm positions on claim construction and the prosecution history.
The Board relied on those statements in interpreting tolerability and severity
and ultimately in denying institution of PGR on the 776 patent. Should Patent
Owner deviate from the positions taken in its PGR preliminary response on the

- 24 -

same patent, Patent Owner would derive an unfair benefit, prejudice Petitioner, and
risk the Board issuing inconsistent opinions. Therefore, Patent Owner is bound by
its previous statements in the 776 PGR preliminary response (Ex. 1013) that an
increase in the tolerability of GA treatment necessarily includes a reduction in the
severity of ISRs and IPIRs.
E.

PATENTS AND PRINTED PUBLICATIONS RELIED ON IN THIS PETITION

Petitioner relies on the following patents and printed publications:


1.

Pinchasi (Ex. 1004)

Pinchasi discloses methods of alleviating symptoms of a patient suffering


from RRMS by subcutaneously administering a pharmaceutical composition
comprising 40 mg of GA, optionally in a prefilled syringe with mannitol and a pH
in the range of 5.5 to 7.0. See, e.g., Ex. 1004 at 6, ll. 2-8, 9, ll. 2-15, 20-26, 10, l.
28-11, l. 1, 14, ll. 21-23; Ex. 1003 73-74. Certain embodiments involve daily
administration of this dosage, while other embodiments involve EOD
administration. See, e.g., Ex. 1004 at 9, ll. 2-15, 10, l. 26-11, l. 22. Pinchasi
discusses experimental data demonstrating that daily injection of 40 mg (280 mg
GA weekly) was safe and therapeutically effective. See, e.g., Ex. 1003 73-74.
Pinchasis data is also reported in the Cohen 2007 article (Ex. 1056) in Neurology,
a preeminent peer-reviewed journal in the field of neurology, which would have
led a POSA to consider the data especially persuasive and credible. Ex. 1003

- 25 -

89-91, 111.

Pinchasi discloses that treating patients with its daily and EOD

embodiments has beneficial effects on their symptoms, including reducing the


frequency of relapses and mean cumulative number of Gd-enhancing lesions in T1weighted images in patients brains. See, e.g., Ex. 1004 at 6, ll. 2-8, 10, ll. 2-16, 17
(Tables 1 and 2), 18 (Table 3), 29 (Figure 4); Ex. 1003 109, 155-156. Pinchasi
noted that daily administration of 40 mg GA was well tolerated and showed
improved efficacy as compared to 20 mg daily, yet was not accompanied by a
corresponding increase of adverse reactions which would be expected upon a
doubling of the administered dose. Ex. 1004 at 20, ll. 8-14; Ex. 1003 114-117.
The Board previously characterized Pinchasi as the closest prior art to the 250,
413, and 302 family member patents. Ex. 1008 at 26; Ex. 1009 at 26; Ex. 1010 at
24.
2.

SBOA (Ex. 1006)

In 1996, the FDA reviewed Tevas new drug application (NDA) for 20 mg
daily Copaxone. That reviewthe SBOAwas disclosed to Mylan (and so
publicly available) more than one year prior to the earliest possible priority date of
the 776 patent. In the SBOA, the FDA reviewer questioned:
In light of the fact that Copolymer-1 is most likely acting as a peptide
vaccine, it is unclear to me why it is necessary to inject the drug on a
daily basis. This dosing regimen seems like it would subject the
patient to an excessive amount of discomfort if it is not necessary to

- 26 -

maintain efficacy. Furthermore, if there should be a problem in


humans with saturation of the clearance mechanism, thus increasing
the amount of intact drug in the systemic circulation over time, this
problem might be lessened with intermittent rather than daily
administration. I would recommend that the Sponsor evaluate the
necessity of daily s.c. injections as opposed to more infrequent
intermittent administration of the drug.
Ex. 1006 at 252 (emphasis added).

The SBOA therefore demonstrated the

desirability of less frequent GA injections and would have motivated skilled


artisans to pursue less frequent GA dosing. See Ex. 1003 at 124, 186-187.
The SBOA was publically available at least as of July 17, 2007. Ex. 1006,
M. Bobka Affidavit (demonstrating availability to the public more than one year
before the priority date); see also Ex. 1008 at 9; Ex. 1009 at 10; Ex. 1010 at 10.
The Board previously agreed. See, e.g., Ex. 1008 at 9; Ex. 1009 at 10-11; Ex. 1010
at 10-11; Ex. 1014 at 9-10. As the SBOA was publically available as a printed
publication more than one year before the 776 patents earliest possible priority
date (see Ex. 1006), it qualifies as prior art to the 776 patent at least under preAIA 35 U.S.C. 102(b).
3.

Flechter 2002A (Ex. 1005)

Flechter 2002A discloses EOD treatment of RRMS with 20 mg of GA. Ex.


1003 75; Ex. 1005 at Abstract. In the study, RRMS patients were switched from
daily administration of 20 mg to EOD administration of 20 mg. Ex. 1005 at 1-2.
- 27 -

The relapse rate and Expanded Disability Status Scale (EDSS) score were
measured. Id. Using those endpoints, Flechter 2002A found similar efficacy rates
with 20 mg daily and 20 mg EOD treatment. 4 Id. at 5. Moreover, Flechter
2002As results indicated increased tolerability and compliance for patients treated
with less frequent dosing60.3% of patients treated with EOD dosing completed
two years of treatment while only 39.7% of patients receiving daily treatment
completed two years of treatment. Id. at 5.
4

In Table 5 Flechter 2002A reports a mean relapse rate in the first 2 years of

treatment with EOD treatment of .56 (+/- 1.02). Ex. 1005 at 4. In that same table,
Flechter 2002A reports data from the underlying Meiner 1997 study for patients
that received daily treatment.

See Ex. 1067.

Flechter 2002A reports the

annualized rate from the Meiner 1997 paper over two years of 0.30 (+/- 0.5). Ex.
1005 at 4. The Meiner relapse rate is annualized (relapse rate per year), whereas
the Flechter 2002A relapse rate is not (relapse rate over two years). Ex. 1067 at 78; Ex. 1005 at 3. Accordingly, as the paper reports, Flechter 2002A and Meiner
1997 show similar relapse rates between the 20 mg daily and 20 mg EOD
regimens. Ex. 1003 n. 1. The Board previously agreed with Petitioner on this
issue in the prior IPRs, finding that Patent Owner misinterpreted the data in Table
5 of Flechter in arguing that less frequent dosing would decrease efficacy. Ex.
1008 at 26.

- 28 -

Given the similar efficacy of daily and EOD dosing,

Flechter 2002A

suggested that 20 mg of Copolymer 1 on alternate days already has a maximal


effect, and daily injections are unnecessary. Id. at 5. Therefore, Flechter 2002A
stated that:
It is possible that the biologic effect of Copolymer 1 is not doserelated but is related to the exposure of the immune system to its
presence by the continuity of administering the drug with
rechallenging the immune system, thus making daily injections
unnecessary.
Id. Thus, Flechter 2002A taught a safe, efficacious, and more tolerable EOD
dosage of GA for MS patients. Ex. 1003 75-76, 118.
As Flechter 2002A was published in 2002, more than one year before the
776 patents earliest possible priority date, it qualifies as prior art to the 776
patent at least under pre-AIA 35 U.S.C. 102(b).
4.

Caon

Caon was published in March 2009, prior to the earliest possible priority
date of the 776 patent.
Caon is a meeting abstract describing the results of a 4-year, randomized,
rater-blinded study of 20 mg GA administered daily and EOD. Caon noted that
there were no difference[s] in relapse rate, disease progression, or any MRI
outcome between the EOD and daily treatment groups. Ex. 1007. Caon also

- 29 -

found that after 2 years of therapy all patients that had been administered daily
injections chose to switch to EOD injections. Id. Moreover, Caon stated that
[i]njection related lipoatrophy was significantly less in the [EOD] group. Id.
Caon also stated that [i]n vitro GA-proliferative responses and Th1/Th2 cytokine
expression did not differ between the two groups at any time point after
randomization. Id.
Caon concluded that GA 20 mg [subcutaneous] administered [daily] or
[EOD] may be equally effective in RRMS. Id.; Ex. 1003 79-81.
5.

Prior Art Informing the General Knowledge of the


Ordinarily-Skilled Artisan

In addition to the prior art discussed above, the declaration of Dr. Green
addresses additional prior art showing the POSAs general knowledge as of the
priority date. These additional publications confirm that a POSA would have
recognized that reducing the number of GA injections in a 7-day period would
increase patient adherence, compliance, and tolerability. See, e.g., Ex. 1003
117-130; Ex. 1007, 1053. The additional publications also confirm that as of the
priority date a POSA would have reasonably expected that EOD dosing would
have equivalent efficacy to daily dosing. See Ex. 1003 108-128; see also Ex.
1005 at 1; Ex. 1056 at 3-6; Ex. 1008 at 16-21; Ex. 1009 at 14-23; Ex. 1010 at 1421; Ex. 1053.

- 30 -

F.

SUMMARY OF PETITIONERS OBVIOUSNESS POSITIONS


1.

The Law of Obviousness

A patent claim is unpatentably obvious if an alleged infringer proves that the


differences between the claimed subject matter and the prior art are such that the
subject matter as a whole would have been obvious at the time of invention to a
person having ordinary skill in the art. 35 U.S.C. 103(a) (2006). Obviousness is
ultimately a question of law premised on underlying issues of fact, including:
(1) the scope and content of the prior art; (2) the level of ordinary skill in the
pertinent art; (3) the differences between the claimed invention and the prior art;
and (4) secondary considerations such as commercial success, long-felt need, and
the failure of others. KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 427 (2007);
Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966).
The Federal Circuit has frequently invalidated as obvious patents that seek to
claim modified dosing protocols for prior art drugs. For example, in Hoffmann-La
Roche Inc. v. Apotex Inc., 748 F.3d 1326 (Fed. Cir. 2014), the Federal Circuit
invalidated as obvious patents claiming modified dosing protocols for a
pharmaceutical product. The court noted that [c]onclusive proof of efficacy is not
necessary to show obviousness, and held that the claimed dosing regimen in the
invalidated patents was obvious to try: There was a need to solve the problem of
patient compliance by looking to less-frequent dosing regimens. Id. at 1331-32.

- 31 -

Indeed, the expectation of success need only be reasonable, not absolute. Pfizer,
Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Similarly, in Warner
Chilcott Co. v. Teva Pharms. USA, Inc., 594 F. Appx. 630, 635 (Fed. Cir. 2014),
the Federal Circuit found in another dosing regimen case that [a]s longer dosing
intervals suit patient convenience and compliance, the prior art therefore provided
express motivation to pursue a monthly dosing regimen.
2.

The Prior Art Renders the Claims Obvious

Pinchasi is practically anticipatorythe claimed regimen requires three 40


mg GA injections every week, and Pinchasi discloses three 40 mg GA injections
one week, and four the next.

The only difference between Pinchasi and the

claimed regimen is thus one dose every two weeks. Ex. 1003 131-132.
Modifying Pinchasi to remove this single dose every two weeks would have
been obvious to a POSA. It was well-known in the art that a TIW dosing schedule
was uniquely preferable, as it allowed patients to inject on the same three days
each week. Ex. 1003 131-132; Ex. 1008 at 15. Such a schedule was more
convenient and easier to remember than an EOD schedule, thus improving patient
compliance. Ex. 1003 129-130. In addition, as confirmed by the SBOA,
patients were known to prefer fewer injections, not only because patients dislike
painful injections, but also because GA induced injection-related adverse events,

- 32 -

such as ISRs and IPIRs. Ex. 1003 121-127, 142-147; Ex. 1008 at 13. POSAs
would have therefore been highly motivated to reduce injection frequency.
POSAs would also have held a reasonable expectation that a 40 mg TIW
regimen would be efficacious. POSAs would have considered Pinchasis 40 mg
EOD regimen to be therapeutically identical to the claimed regimenthe
difference between the two regimens is minor in light of standard interpatient
variability. Ex. 1003 131-134. Further, GA was known to be a forgiving drug,
as patients could take doses late or even miss doses entirely without compromising
efficacy. Id.; Ex. 1008 at 15-16. Indeed, Flechter 2002A confirmed in a study of a
20 mg EOD regimen that less frequent dosing is similarly efficacious. Ex. 1003
118; Ex. 1008 at 16-17, 20, 26, 32.
The Pinchasi, Flechter 2002A, and SBOA references, along with the prior
art which formed a POSAs background knowledge, demonstrates that, prior to
2009, POSAs had extensive interest in reducing the frequency of GA dosing to
improve patient convenience and reduce ISRs. Prior art studies established at least
the following foundational facts, which would have motivated POSAs to
administer 40 mg of GA TIW with a reasonable expectation of success:
Patients strongly preferred dosing schedules for GA treatment that required
less frequent injections; see Ex. 1003 127 (discussing Khan 2008 (Ex.
1053) and Caon (Ex. 1007)) (in study of daily vs. EOD 20 mg Copaxone

- 33 -

injections, [a]fter 2 years, all patients in the [daily] group opted to switch to
[EOD]);
Patient adherence and compliance for chronic therapies, a serious concern in
the art, is improved with less frequent and more convenient dosing
protocols; see, e.g., Ex. 1053 (noting that [t]here is considerable interest in
alternate dosing regimens of GA in RRMS. Daily SC injectable therapy can
be challenging for long-term patient compliance.); Ex. 1003 125;
EOD dosing is likely as effective as daily dosing. See, e.g., Exs. 1005, 1007,
1053; Ex. 1003 118, 122, 127;
Administering 40 mg GA daily was well-tolerated and effective. See, e.g.,
Ex. 1004 at 20, ll. 8-14; Ex. 1056 at Abstract (Glatiramer Acetate (GA) 40
mg was safe and well tolerated. The overall efficacy results suggested that a
40-mg dose of GA may be more effective than the currently approved 20-mg
daily dose in reducing MRI activity and clinical relapses.); Ex. 1003 111;
Administering 40 mg daily (by subcutaneous injection) created no safety or
tolerability concerns as compared to the daily administration of 20 mg GA.
See, e.g., Ex. 1004 at 20, ll. 8-14 (The increased efficacy observed with 40
mg/day GA . . . is not accompanied by a corresponding increase of adverse
reactions which would be expected upon a doubling of the administered
dose.); Ex. 1003 114;

- 34 -

The total weekly dose administered by the claimed regimen (120 mg) is
nearly identical to the FDA-approved 20 mg daily regimen (140 mg) and
falls within a range of total weekly doses known to be efficacious (70 mg to
280 mg), as shown in the below chart:

Figure 1. Copaxone prior art average total weekly dosing regimens. See Ex. 1003
134-135; Ex. 1008 at 15-16 (crediting Dr. Greens explanation of the range of
efficacious doses in the prior art and the forgiving nature of GA).
Further, the reduced severity limitations were obvious. Based on Patent
Owners prior statements and the Boards prior findings, disclosure of improved
tolerability discloses the reduced severity limitations. See supra Section VI.D.1;
Ex. 1003 43-51. And disclosure of improved tolerability was obviousindeed,
- 35 -

as explained above, improving the tolerability of GA treatment formed part of the


POSAs motivation to pursue the claimed regimen.

Ex. 1003 140-147.

Moreover, Patent Owner stated in the PGR that if a patient experiences a


reduction in frequency of a severe injection-related adverse event (e.g.,
lipoatrophy, or the destruction of tissue around an injection site), a POSA would
view that as a reduction in severity of an adverse event. Ex. 1013 at 14. But
Caon explicitly disclosed that patients on less frequent dosing experienced
lipoatrophy less frequently than patients on a 20 mg daily dose. Ex. 1007. The
reduced severity limitations are thus further obvious in view of Caon. Ex. 1003
200-213.
Finally, the dependent claims add nothing patentable to the obvious
independent claims. The dependent claims all recite obvious improvements in
ISRs and IPIRs resulting from less frequent administration, the characteristic that
the patient is GA-nave, or well-known treatment effects that are the inevitable
result of administering an efficacious MS medication. All of these limitations were
expressly disclosed in Pinchasi or were elementary knowledge to any skilled
artisan. Ex. 1003 178-184.

- 36 -

G.

GROUND 1: ALL CLAIMS OF THE 776 PATENT WERE


UNPATENTABLE AS OBVIOUS OVER PINCHASI AND FLECHTER 2002A
1.

Independent Claim 1 Was Obvious Over Pinchasi and


Flechter 2002A

Claim 1 recites the following elements:


a preamble explaining that the method is for treating a human patient
suffering from a relapsing form of multiple sclerosis;
a single step of administering one subcutaneous injection of 1 ml of a
pharmaceutical composition comprising 40 mg of glatiramer acetate on only
each of three days during each week of treatment with at least one day
without a subcutaneous injection of the pharmaceutical composition between
each day on which there is a subcutaneous injection;
components of formulation, including that the composition is in a prefilled
syringe, includes mannitol, and has a pH in the range of 5.5 to 7.0; and
duplicative recitations in the preamble and in the concluding statement of
intended use that the method results in reduced severity of injection site
reactions relative to administration of 20 mg of glatiramer acetate s.c. daily.
Ex. 1001 at claim 1.
GA is used to treat relapsing MS: As a threshold matter, Petitioner does not
concede that the preamble of claim 1 is limiting. Regardless, Pinchasi expressly
discloses the preamble of claim 1.

- 37 -

Pinchasi discloses a method of treating a human patient suffering from


relapsing-remitting MSby definition a relapsing form of multiple sclerosis.
Ex. 1004 at 9, ll. 2-4. Pinchasi discloses that the method can be used to alleviate a
symptom of a relapsing form of multiple sclerosis in a human patient, id. at 11, ll.
26-27, and that [i]n yet another embodiment, the relapsing form of multiple
sclerosis is relapsing-remitting multiple sclerosis, id. at 9, ll. 12-13; Ex. 1003
109.
The 40 mg TIW regimen: The Board has previously found that Pinchasi in
view of Flechter 2002A renders obvious the claimed 40 mg TIW regimen. See,
e.g., Ex. 1008 at 31-33. Pinchasi discloses a 40 mg EOD regimen. Ex. 1004 at 9,
ll. 2-11 (teaching periodically administering . . . a single dose of a pharmaceutical
composition comprising 40 mg of [GA] and stating that the periodic
administration is every other day in one embodiment). Such a regimen involves
three doses one week and four the next. That is extremely close prior artthe
difference between Pinchasi and the claimed regimen is one dose every two weeks.
In fact, given standard variability between patients, a POSA would consider
Pinchasi and the claimed regimen to be therapeutically equivalent. Ex. 1003
131- 134.
A POSA would also have been motivated to modify the EOD dosing
regimen disclosed in Pinchasi to remove one injection every two weeks. A TIW

- 38 -

regimen provides a more convenient and predictable dosing schedule than EOD
dosingallowing the patient to medicate on the same days of each week (e.g. M,
W, F)improving patient adherence, an important consideration in the treatment
of chronic conditions. Ex. 1003 129-130. Less frequent dosing would also have
been expected to reduce injection-related adverse events like ISRs and IPIRs,
further improving convenience and tolerability. Ex. 1003 145, 163-170.
Patent Owner may assert, as it did in the prior IPRs, that the FORTE trial
teaches away from a 40 mg dose because it found that a 40 mg daily dose does not
have superior efficacy to the 20 mg daily dose. But, as the Board previously
found, such an argument is not persuasive. Ex. 1008 at 12. [N]othing in FORTE
criticizes, discredits, or discourages the use of 40 mg of GA, so FORTE does not
teach away from the use of 40 mg of GA. Id. Indeed, FORTE demonstrated that
the 40 mg dose was equally effective and well-tolerated as the 20 mg dose, and
results suggested that the 40 mg dose may have a more rapid onset of action. Ex.
1057 at 1; Ex. 1003 92-94, 113, 167.
In addition to the clinical motivations, by 2009 there was an industryrecognized motivation to launch a new dosing regimen product to achieve further
marketplace exclusivity. By 2009, prior art 20 mg Copaxone had been on the
market for more than a decade and faced competition from less frequently injected
competitor products, oral therapies, and looming expiration of the 20 mg

- 39 -

Copaxone patents.

For example, since at least 2002, the competing Rebif

product was on the market and injected TIW. Ex. 1003 60, 129. The 776
patent did not contribute an inventive dosing regimen, but insteadin an attempt
to gain further market exclusivityadopted a predictably safe and effective
regimen that met the market pressures to offer a less frequent dosing regimen with
improved tolerability.
A POSA would also have had a reasonable expectation of success in
removing one dose every two weeks from the regimen disclosed in Pinchasi.
Flechter 2002A disclosed that a 20 mg EOD regimen was similarly efficacious to
20 mg daily. Ex. 1003 118; Ex. 1005 at Abstract, 4 (20 mg EOD slightly better
than 20 mg daily, with a slightly improved relapse rate and fewer adverse events),
5 (20 mg EOD is safe, well tolerated, and probably as effective as 20 mg daily
in reducing relapse rate and slowing neurologic deterioration). Flechter 2002A
disclosed that 20 mg daily and 20 mg EOD both demonstrated very few relapses,
and that disease severity was reduced by the same degree. Ex. 1005 at 5; Ex.
1003 118.

Flechter 2002A concluded that daily administration was likely

unnecessary to efficacy. Ex. 1005 at 5; Ex. 1003 118.


Moreover, a POSA would have recognized that the dosage amount of 120
mg in a 7-day period (i.e., three 40 mg injections in a 7-day period) fell squarely
within the safe and effective ranges established by Pinchasi and Flechter 2002A,

- 40 -

and other prior art references (supra Section VI.F.2.b at Figure 1); Ex. 1003 134.
Flechter 2002A disclosed that an average of 70 mg per week (20 mg EOD) is safe
and effective, and Pinchasi disclosed that the range of safe and effective doses
stretches at least to 280 mg per week (40 mg daily). The claimed regimen is 120
mg per week, not only within the range established by Pinchasi and Flechter
2002A, but also nearly identical to the FDA-approved 20 mg daily dose (140 mg
per week). A POSA also knew that GA was a forgiving drug, meaning it was
expected to have similar efficacy even with fluctuations in dosing schedule (e.g.,
taking a dose late, skipping a dose). Ex. 1003 132-134; see also Ex. 1008 at 1516 (crediting Dr. Greens testimony that an ordinary artisan would have
considered GA to be a forgiving drug.); supra Section VI.F.2 at Figure 1.
Based on these teachings, a POSA would have recognized that (1) reducing
the frequency of injections is desirable to improve patient adherence and
tolerability, (2) 40 mg dosing TIW would provide the same therapeutic profile with
the potential for a substantially improved safety and tolerability profile compared
to 20 mg daily dosing, and (3) 40 mg was a logical dosage choice for investigating
TIW administration because it kept the total weekly dose (120 mg) roughly
equivalent to Copaxones approved weekly dose (140 mg) and well within GAs
forgiving range. Ex. 1003 134; supra Section VI.F.2 at Figure 1. It would have

- 41 -

therefore been obvious for a POSA to modify Pinchasis 40 mg EOD regimen to


provide the desirable 40 mg TIW dosing schedule. Ex. 1003 108-136.
The formulation and delivery elements: Claim 1 further recites a GA
pharmaceutical composition in a prefilled syringe, and wherein the
pharmaceutical composition further comprises mannitol and has a pH in the range
5.5 to 7.0. Pinchasi explicitly discloses each of the following elements:
(1) Pinchasi discloses that the pharmaceutical composition is in a prefilled
syringe and is self-administered by the patient. Ex. 1004 at 9, ll. 24-26; Ex.
1003 137-139.
(2) Pinchasi discloses that the composition of 40 mg GA for injection is a
solution containing [a] dose of 40 mg of the drug substance and 40 mg of
Mannitol USP in 1 mL sterilized water for injection. Ex. 1004 at 14, ll. 2123, Example 1; Ex. 1003 137.
(3) Pinchasi further discloses that its pharmaceutical formulations have a pH
between 5.5 and 7.0. Ex. 1004 at 9, ll. 21-23 ([i]n an embodiment, the
pharmaceutical composition has a pH in the range of 5.5 to 7.0); Ex. 1003
137.
Accordingly, Pinchasi discloses each of the above-listed formulation and
delivery elements. Ex. 1003 137-139.

- 42 -

Pinchasi in view of Flechter 2002A discloses improved tolerabilityand


therefore reduced severity of ISRsas compared to 20 mg GA s.c. daily: Claim
1 twice recites that the method of treatment induces reduced severity of injection
site reactions [in the human patient] relative to administration of 20 mg of
glatiramer acetate s.c. daily. Ex. 1001 at col. 16, ll. 36-38, 48-50. To the extent
this recitation is a limitation, it was obvious.
The Board has previously determined that as of the priority date, a POSA
would have known that decreasing the number of injections a patient must endure
would increase the tolerability of GA treatment. See Ex. 1008 at 13-15, 23-24.
Pinchasi and the prior art suggested that less frequent administration of GA would
improve tolerability. Ex. 1003 142-146; see also Ex. 1008 at 23. Flechter
2002A disclosed that nearly twice as many patients completed two years of
treatment on EOD treatment compared to daily treatment, suggesting patients
found EOD treatment more tolerable. Ex. 1005 at Table 5. Moreover, Khan and
Caon likewise reported that all patients given a choice in their study between daily
and EOD dosing chose EOD dosing.
And by Patent Owners own statements to the Board and the Boards prior
findings, an increase in tolerability discloses the claimed reduced severity. See Ex.
1013 at 29 ([A] POSA would understand [the 687 Priority Applications claim to
a method of increasing the tolerability of GA treatment] as describing the

- 43 -

reduction of severity of post-injection reactions and injections [sic] site


reactions.).
Accordingly, claim 1s reduced severity of injection site reactions relative
to administration of 20 mg of glatiramer acetate s.c. daily was obvious over
Pinchasi and Flechter 2002A.
2.

Independent Claim 5 Was Obvious Over Pinchasi and


Flechter 2002A

Claim 5 recites the same method as claim 1, but adds in the preamble that the
method induces one or more of the following treatment effects:
(1) reducing frequency of relapses by 30% or more as compared to placebo
in a human population,
(2) reducing the cumulative number of enhancing lesions on T1-weighted
images,
(3) reducing brain atrophy, or
(4) reducing the level of disability as measured by EDSS Score.
For the same reasons as stated in Section VI.G.1, supra, claim 5 was obvious
over Pinchasi and Flechter 2002A. As to the four treatment effects, to the extent
the Board finds them limiting, they are recited using the disjunctive or, meaning
a prior art teaching of any one of the four endpoints discloses the limitation.
SkinMedica, Inc. v. Histogen Inc., 727 F.3d 1187, 1199 (Fed. Cir. 2013) (The
disjunctive or plainly designates that a series describes alternatives.).
- 44 -

Regardless, as explained below, Pinchasi and the prior art render obvious each of
the four treatment effects. See Ex. 1003 149-159.
As an initial matter, these treatment effects should be construed as nonlimiting. The treatment effects do not alter the claimed methodthey merely
express the intended result of administering 40 mg GA TIW as claimed. See, e.g.,
Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1375 (Fed. Cir.
2001).
Should the terms be construed as limiting, all four treatment effects were
obvious over the prior art.
Reduction in relapses by 30% or more as compared to placebo: Pinchasi
expressly discloses that its method reduces the frequency of relapses in patients
suffering from RRMS. See, e.g., Ex. 1004 at 9, ll. 2-15. A POSA would have also
known that the prior art 20 mg daily regimen reduced relapses by 30% over
placebo. Ex. 1003 150-152. For example, Comi found that the mean relapse
rate was 33% lower in [20 mg daily] than in the placebo arm. Ex. 1031 at 5, see
also id. at Abstract. Because the prior art would have given a POSA a reasonable
expectation that the claimed regimen would be similarly efficacious to the 20 mg
daily regimen, see supra Section VI.G.1 and infra Section VI.G.3, the claimed
30% reduction in relapse rate would have been obvious.

- 45 -

Reducing brain atrophy: A POSA as of the priority date would have


understood that successfully treating a patient with a first-line therapy such as GA
naturally results in a reduction in brain atrophy. Ex. 1003 157 (citing Ex. 1029).
Patent Owner does not allege that its methods were the first to reduce brain
atrophythe patent merely states that [t]reatment with 40 mg s.c. GA three times
weekly is at least as effective as 20 mg s.c. GA daily administration at reducing
brain atrophy. Ex. 1001 at col. 14, ll. 1-5. Thus, because a POSA would have
expected the claimed regimen to be efficacious, the reduction in brain atrophy was
obvious over Pinchasi and Flechter 2002A. Ex. 1003 157-159.
Enhancing lesions on T-1 weighted images: Pinchasi expressly discloses
that treatment of 40 mg GA daily reduced the total number of Gd-enhancing
lesions on T1-weighted images at month 3 and at months 7, 8, and 9 as compared
to treatment with 20 mg GA daily. Ex. 1004 at 15, ll.16-21, 17. Claim 5s
reduction in the cumulative number of enhancing lesions on T1-weighted images
was thus obvious over Pinchasi and Flechter 2002A. Ex. 1003 155-156, 158159.
EDSS-measured disability: Likewise, a POSA as of the priority date would
have known that the claimed reduction in level of disability as measured by EDSS
Score is the natural result of successful GA treatment. Patent Owner does not
allege that its methods were the first to reduce EDSS scorethe patent merely

- 46 -

states that [t]reatment with 40 mg s.c. GA three times weekly is at least as


effective as 20 mg s.c. GA daily administration at reducing the change . . . in EDSS
Score. Ex. 1001 at col. 15, ll. 23-27. Indeed, EDSS is a standard scale used to
measure disability progression in MS patients, so any efficacious treatment is
expected to improve EDSS score. Thus, the claimed EDSS score reduction was
obvious. Ex. 1003 155-159.
The four treatment effectsonly one of which need be disclosed to support
a finding of unpatentabilitywere thus all obvious over Pinchasi in view of
Flechter 2002A. See id.
3.

Independent Claim 12 Was Obvious Over Pinchasi and


Flechter 2002A

Independent claim 12 recites the same method as claim 1, but explicitly


recites that (1) the tolerability of 40 mg GA TIW is improved as compared to 20
mg GA daily, and (2) the 40 mg GA TIW treatment method is as effective[] as
20 mg daily. Both of these elements were obvious over Pinchasi and the prior art.
Improving the tolerability of GA treatment: Petitioner does not concede that
the preamble of claim 12 is limiting.

Nonetheless, as explained supra

Section VI.G.1, a POSA would have known that the 40 mg TIW regimen would
improve tolerability over the 20 mg daily regimena conclusion already reached
by the Board.

In addition, a POSA would understand that decreasing the

- 47 -

frequency of injections decreases the frequency of injection-related adverse events,


such as ISRs and IPIRs. Ex. 1003 163-167.
As effective as 20 mg GA daily:

A POSA would have reasonably

expected a 40 mg TIW regimen to be as effective as the 20 mg daily regimen.


Ex. 1003 172-175.
The prior art taught that 40 mg GA was safe, effective, and well-tolerated,
and that EOD dosing (with 20 mg) was also safe, effective, and well-tolerated.
Indeed, nothing in the prior art taught that 40 mg TIW had diminished efficacy as
compared to 20 mg dailyquite the opposite. For example, Pinchasi recognized
that administration of glatiramer acetate at a dose of 40 mg/day significantly
improves efficacy [as compared to 20 mg daily] but does not have a corresponding
increase in adverse reactions experienced by the patient. Ex. 1004 at 5, ll. 11-14.
Indeed, Pinchasi disclosed that 40 mg GA daily showed improvements in the
cumulative number of T1 and T2 Gd-enhancing lesions and confirmed relapses as
compared to 20 mg daily, id. at 17-18, 20, and further taught that positive results
could be similarly expected of EOD administration, id. at 10, ll. 18-21; Ex. 1003 at
109-110, 174. Cohen likewise disclosed that 20 mg and 40 mg both showed
similar safety profiles and efficacy (i.e., decreased relapse rates), with the latter
show[ing] a trend favoring GA 40 mg and a faster onset of action. Ex. 1056 at
3-6.

- 48 -

A POSA understood that the total weekly dose for 40 mg TIW (120 mg) was
similar to the total weekly dose for the FDA-approved 20 mg daily regimen (140
mg), and that both values were squarely within the therapeutically effective GA
dosing range of 70 mg per week (Flechter 2002A) to 280 mg per week (Pinchasi).
Ex. 1003 134, 174; see also Ex. 1008 at 20-21. A POSA would have expected a
similar weekly dose of GA to provide a similar safety, efficacy, and tolerability
profile. Ex. 1003 109-110, 134-135, 171-174. Thus, in view of Pinchasi and
Flechter 2002A, it would have been obvious to a POSA that 40 mg TIW would be
at least as effective as 20 mg daily. Ex. 1003 172-175. Patent Owners
recitation that 40 mg GA TIW is as effective as 20 mg GA daily does not render
claim 12 patentable.
4.

Independent Claim 16 Was Obvious Over Pinchasi and


Flechter 2002A

Independent claim 16 recites the same elements as claims 5 and 12, but only
claims that the frequency of relapses is reduced (without requiring the reduction to
be at least 30%).
Accordingly, for at least the reasons discussed previously in Sections
VI.G.2-3, Pinchasi in view of Flechter 200A renders claim 16 obvious. Ex. 1003
176-177.

- 49 -

5.

Dependent Claims 3-4, 6-11, 13-15, and 17-30 Were Obvious


Over Pinchasi and Flechter 2002A

Dependent Claims 3-4, 10-11, 14-15, and 25-30: Dependent claims 3 and 4
ultimately depend from claim 1, claims 10-11 ultimately depend from claim 5,
claims 14-15 ultimately depend from claim 12, and claims 25-30 ultimately depend
from claim 16.

These eleven claims all recite that the claimed method is

administered to a human patient that has not received glatiramer acetate therapy
prior to initiation of the treatment (the nave patient claims). Ex. 1001 at col.
16, l. 55-col. 19, l. 3.
Pinchasi in view of Flechter 2002A teaches this limitation. Ex. 1003 178179. A POSA would have understood that, as a first-line therapy for RRMS in
August 2009, GA would have been available and used to treat all MS patients,
including those who had not previously received GA (or any) therapy. Ex. 1003
179; see also Ex. 1008 at 21-23; Ex. 1007, 1053 (treatment-nave studies).
Dependent claims 6-8, and 17-20: Dependent claims 6-8 depend from
independent claim 5. Dependent claims 7-8 individually recite treatment effects
already recited in claim 5, and dependent claim 6 recites a combination of two:
reduction in brain atrophy and a 30% or more decrease in relapses as compared to
placebo. Dependent claims 17-20, which ultimately depend from claim 16, recite
a reduction in individual treatment effects as effectively as 20 mg daily
(collectively the treatment effect claims).
- 50 -

For the reasons stated supra in Section VI.G.2, the claimed treatment effects
(relapses, brain atrophy, enhanced lesions, and EDSS score) were taught by
Pinchasi in view of Flechter 2002A. Flechter 2002A also discloses that GA 20 mg
EOD is safe, well tolerated, and probably as effective as 20 mg daily in
reducing relapse rate and slowing neurologic deterioration. Ex. 1005 at 5; Ex.
1003 118, 149-159, 180-183.
Knowing that 40 mg TIW and 20 mg daily have similar weekly doses and
are expected to be effective, a POSA would thus reasonably expect 40 mg TIW to
exhibit reductions in relapse rate, brain atrophy, enhancing lesions, and EDSSscored disability at least as effectively as 20 mg daily. Ex. 1003 149-159,
180-183. Claims 6-8 and 17-20 were thus obvious over Pinchasi in view of
Flechter 2002A.
Claims 2, 9, 13, 21-24: Claim 2 depends from claim 1, claim 9 depends
from claim 5, claim 13 depends from claim 12, and claims 21-24 ultimately depend
from claim 16 (collectively the ISR and IPIR reduction claims). Whereas the
independent claims recite a reduction in the severity of ISRs relative to 20 mg
daily, and independent claims 12 and 16 recite a general improvement in
tolerability, these dependent claims also recite a reduction in frequency of ISRs
and IPIRs and the severity of IPIRs. This further limitation is likewise obvious in
view of Pinchasi. As explained above in Section VI.G.1, a POSA would know that

- 51 -

one of the reasons a 40 mg TIW regimen increases tolerability is because a less


frequently administered regimen results in fewer ISRs and IPIRs.

Ex. 1003

117-122, 140-147, 160-170, 184. And as discussed throughout this Petition,


disclosure of improved tolerability discloses reduced severity. For these reasons,
and those given above in Sections VI.G.1-4, claims 2, 9, 13, and 21-24 were
obvious Pinchasi and Flechter 2002A.
H.

GROUND 2: ALL CLAIMS OF THE 776 PATENT WERE


UNPATENTABLE AS OBVIOUS OVER PINCHASI AND THE SBOA
1.

Independent Claims 1, 5, 12, and 16 Were Obvious Over


Pinchasi and the SBOA

As explained above, all limitations of independent claims 1, 5, 12, and 16


were obvious over Pinchasi in view of Flechter 2002A. For all of the same
reasons, they were obvious in view of the SBOA. Comments made during the
FDA review process for the 20 mg daily product amplify the desire for less
frequent dosing, and demonstrate that skilled artisans appreciated less frequent
dosings benefits. In the SBOA, the FDA reviewer explicitly recommend[ed]
that the Sponsor evaluate the necessity of daily s.c. injections as opposed to more
infrequent intermittent administration of the drug because the daily dosing
regimen seems like it would subject the patient to an excessive amount of
discomfort if it is not necessary to maintain efficacy.
Ex. 1006 at 252.

- 52 -

The SBOA thus notes that more frequent injections subject the patient to
discomfort, indicating that reducing the frequency of injections is generally
desirable. The FDA reviewer also recommended that Teva evaluate the necessity
of daily s.c. injections. See Ex. 1006 at 252; Ex. 1003 186-187; see also Ex.
1008 at 13. In view all of the reasons above and for these additional reasons,
claims 1, 5, 12, and 16 were obvious over Pinchasi in view of the SBOA.
2.

Dependent Claims 2-4, 6-11, 13-15, and 17-30 Were Obvious


Over Pinchasi and the SBOA

Dependent Claims 3-4, 10-11, 14-15, and 25-30: These nave patient
claims depend alternatively from independent claims 1, 5, 12, or 16. For the
reasons stated supra in Section VI.G.5, these claims were likewise obvious over
Pinchasi in view of the SBOA.
Claims 6-8 and 17-20: These treatment effect claims ultimately depend
from independent claims 5 and 16, respectively. For the reasons stated supra in
Section VI.G.2, improved treatment effects (relapses, brain atrophy, enhanced
lesions, and EDSS score) were taught by Pinchasi in view of the prior art. Claims
6-8 and 17-20 were thus obvious over Pinchasi in view of the SBOA.
Claims 2, 9, 13, 21-24: Claim 2 depends from claim 1, claim 9 depends
from claim 5, claim 13 depends from claim 12, and claims 20-24 ultimately depend
from claim 16. Whereas the independent claims recite a reduction in the severity
of ISRs relative to 20 mg daily, these dependent claims also recite a reduction in
- 53 -

frequency of ISRs and IPIRs and the severity of IPIRs. The SBOA explains that
less frequent injections reduce patient discomfort. Ex. 1006 at 252; Ex. 1003
198. Moreover, as detailed above in Section VI.G.5, these dependent claims
were also obvious over Pinchasi in view of Flechter 2002A. For these reasons, and
those given above in Sections VI.G.1-4 and VI.H.1, claims 2, 9, 13, and 21-24
were obvious over Pinchasi and the SBOA.
I.

GROUND 3: ALL CLAIMS OF THE 776 PATENT ARE UNPATENTABLE


AS OBVIOUS OVER PINCHASI, FLECHTER 2002A, AND CAON
1.

Independent Claims 1, 5, 12, and 16 Were Obvious Over


Pinchasi, Flechter 2002A, and Caon

As above, all limitations of independent claims 1, 5, 12, and 16 were


obvious over Pinchasi in view of Flechter 2002A. However, to the extent not fully
rendered obvious by the Pinchasi and Flechter 2002A combination, the reduced
severity recitations of the 776 patent are also disclosed in the Caon reference.
In the PGR concerning the 776 patent, Patent Owner took the position that
if a patient experiences a reduction in frequency of a severe injection-related
adverse event (e.g. lipoatrophy, or the destruction of tissue around an injection
site), a POSA would view that as a reduction in severity of an adverse event. Ex.
1013 at 14 (emphasis added). A reduction in the frequency of lipoatrophy (to
which Patent Owner expressly refers as a severe injection-related adverse event)
with less frequent than daily dosing was disclosed in the Caon reference. See Ex.

- 54 -

1007; Ex. 1003 201-202.

Caon reports on the results of a four-year,

randomized, rater-blinded study of 20 mg GA daily and 20 mg EOD. Ex. 1007.


Among other positive results, Caon discloses that the 20 mg EOD regimen
significantly reduced the frequency of lipoatrophy compared to the 20 mg daily
regimen. Id. ([i]njection related lipoatrophy was significantly less in the [EOD]
group.).
In addition, for the reasons explained supra in Section VI.G.1, a POSA
would have known that fewer injections would result in fewer ISRs. And in
particular, nothing in the prior art indicates that serious ISRs would not also
decrease in frequency with less frequent dosing. If anything, Caon suggests that
less frequent dosing also reduces the frequency of lipoatrophy just like any other
ISR. Ex. 1003 202-203. Indeed, as explained above, the prior art contemplates
generally that IRAEs decrease in frequency with less frequent dosing. Ex. 1003
164-166. This teaching comports with common knowledgefewer injections
mean fewer opportunities to have an injection-related reaction of any kind. Ex.
1003 164, 204. Accordingly, the Board in the IPR concerning the 413 patent
held that the prior art appears to contradict Dr. Foxs [Patent Owners experts]
conclusion that the prior art suggests that 40 mg of GA would be associated with
more injection site reactions. Ex. 1009 at 24.

- 55 -

Therefore, based on at least Caon, a POSA would have expected a 40 mg


TIW regimen to induce fewer severe ISRs (such as Patent Owners example of
lipoatrophy), which Patent Owner asserts equates to reduced ISR severity as
claimed in the 776 patent.
2.

Dependent Claims 3-4, 6-11, 13-15, and 17-30 Were Obvious


Over Pinchasi, Flechter 2002A, and Caon

Dependent Claims 3-4, 10-11, 14-15, and 25-30: These nave patient
claims depend alternatively from independent claims 1, 5, 12, or 16. For the
reasons stated supra in Section VI.G.5, these claims were likewise obvious over
Pinchasi in view of Flechter 2002A and Caon.
Claims 6-8 and 17-20: These treatment effect claims ultimately depend
from independent claims 5 and 16, respectively.

Improved treatment effects

(relapses, brain atrophy, enhanced lesions, and EDSS score) were taught by
Pinchasi in view of the prior art, as well as by Flechter 2002A as detailed supra in
Section VI.G.2. Moreover, Caon taught that 20 mg EOD resulted in no difference
in the relapse rate, disease progression, or any MRI outcome, which would be
evident in endpoints such as brain atrophy measurements, T1-weighted images,
and EDSS score. Ex. 1007; Ex. 1003 209. Claims 6-8 and 17-20 were thus
obvious over Pinchasi in view of Flechter 2002A and Caon.
Claims 2, 9, 13, 21-24: These ISR and IPIR reduction claims ultimately
depend from independent claims 1, 5, 12, or 16, respectively.
- 56 -

Whereas the

independent claims recite a reduction in the severity of ISRs relative to 20 mg


daily, these dependent claims also recite a reduction in frequency of ISRs and
IPIRs and the severity of IPIRs. As detailed above in Section VI.G.5, these
dependent claims are also obvious. Caon also discloses that following two years of
treatment with daily injections all of the patients chose to switch to EOD dosing,
which indicates improved tolerability and thus reduced severity and/or frequency
of ISRs and IPIRs.

Id.; Ex. 1003 211.

Moreover, Caon discloses that

[i]njection related lipoatrophy was significantly less in the [EOD] group,


indicating reduced frequency of ISRs and IPIRs, and improved tolerabilityand
thus reduced severityof ISRs and IPIRs. Ex. 1007; Ex. 1003 211-212.
Claims 2, 9, 13, and 21-24 were thus likewise obvious over Pinchasi in view of
Flechter 2002A and Caon.
J.

GROUND 4: ALL CLAIMS OF THE 776 PATENT ARE UNPATENTABLE


AS OBVIOUS OVER PINCHASI, THE SBOA, AND CAON
1.

Independent Claims 1, 5, 12, and 16 Were Obvious Over


Pinchasi, the SBOA, and Caon

As above, all limitations of independent claims 1, 5, 12, and 16 were


obvious over Pinchasi in view of the SBOA. However, to the extent not fully
rendered obvious by the Pinchasi and the SBOA, the reduced severity recitations of
the 776 patent are also disclosed in the Caon reference, as detailed above in
Section VI.I.1.

- 57 -

2.

Dependent Claims 3-4, 6-11, 13-15, and 17-30 Were Obvious


Over Pinchasi, the SBOA, and Caon

Dependent Claims 3-4, 10-11, 14-15, and 25-30: These nave patient
claims depend alternatively from independent claims 1, 5, 12, or 16. For the
reasons stated supra in Section VI.G.5, these claims were likewise obvious over
Pinchasi in view of the SBOA and Caon.
Claims 6-8 and 17-20: These treatment effect claims ultimately depend
from independent claims 5 and 16, respectively. For the reasons stated supra in
Section VI.G.2, improved treatment effects (relapses, brain atrophy, enhanced
lesions, and EDSS score) were taught by Pinchasi in view of the prior art and are
disclosed in Caon. Claims 6-8 and 17-20 were thus obvious over Pinchasi in view
of the SBOA and Caon.
Claims 2, 9, 13, 21-24: These ISR and IPIR reduction claims ultimately
depend from independent claims 1, 5, 12, or 16, respectively.

Whereas the

independent claims recite a reduction in the severity of ISRs relative to 20 mg


daily, these dependent claims also recite a reduction in frequency of ISRs and
IPIRs and the severity of IPIRs. As detailed above in Section VI.H.2, these
dependent claims were taught by Pinchasi, the SBOA and Caon. Claims 2, 9, 13,
and 21-24 were thus likewise obvious over Pinchasi in view of the SBOA and
Caon.

- 58 -

K.

ANY SECONDARY CONSIDERATIONS FAIL


SHOWING OF OBVIOUSNESS

TO

OVERCOME

THE

To counter the overwhelming evidence that all claims of the 776 patent
were obvious, Patent Owner may try to rely on secondary considerations of
nonobviousness, despite no showing of such secondary considerations in the
patent. Any such evidence would be insufficient to overcome the strong [case]
of obviousness here. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372 (Fed. Cir.
2007). Moreover, to establish the required nexus, any evidence of secondary
considerations must be unique to a 40 mg TIW regimen over the nearly identical
40 mg EOD regimen disclosed in Pinchasi. See Bristol-Myers Squibb Co. v. Teva
Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (explaining that evidence
must show that there is a difference between the results obtained and the closest
prior art). Ex. 1003 234-235. Nonetheless, Petitioner preliminarily addresses
some secondary considerations Patent Owner may raise, and reserves the right to
respond to any arguments by Patent Owner asserted in this proceeding.
1.

The Methods Recited in the 776 Patent Produced No


Relevant Unexpected Results

The 776 patent makes no claim that the methods recited in its claims
achieve any unexpected result. Quite to the contrary, the best the 776 patent could
claim is that its methods are at least as effective as the prior art. Ex. 1001 at col.
13, l. 46-col. 15, l. 50. And even these statements are unsupported by any data in

- 59 -

the 776 patent. Nonetheless, in view of the extensive disclosures in the prior art
as discussed in this Petition, the efficacy and tolerability of a 40 mg TIW regimen
as recited in the 776 patents claims is not surprising, and is certainly not
unexpected. Ex. 1003 216-221. In particular, a TIW dosing schedule possesses
no unexpected properties over an EOD dosing schedule, which is identical save for
one less dose every two weeks.

And while unexpected results may suggest

nonobviousness, expected results suggest obviousness. In re Skoll, 523 F.2d 1392,


1397 (C.C.P.A. 1975).
Even assuming that the methods claimed in the 776 patent have
unexpected properties, they d[o] not upset an already established motivation to
treat patients with glatiramer acetate based on [its] expected properties. BristolMyers Squibb, 752 F.3d at 976. As discussed throughout this Petition, a POSA
would have been motivated to treat patients with 40 mg injections of GA TIW with
a reasonable expectation that it would alleviate symptoms of RRMS and would be
well tolerated with fewer side effects.

Thus, any evidence of [the claimed

methods] superior efficacy does nothing to undercut the showing that there was a
reasonable expectation of success . . . , even if the level of success may have turned
out to be somewhat greater than would have been expected. Hoffmann-La Roche,
748 F.3d at 1334.

- 60 -

Finally, to the extent Patent Owner shows any unexpected efficacy or


tolerability, these would be differences in degree, not in kind. Ex. 1003 221.
Any such showing would thus fail to serve as evidence of nonobviousness. See
Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004)
(explaining that, to be unexpected, results must be different in kind and not
merely in degree from the results of the prior art. (quoting In re Huang, 100 F.3d
135, 139 (Fed. Cir. 1996))).
2.

The 776 Patent Satisfied No Long-Felt But Unmet Need

Patent Owner may also claim that there was a long-felt but unmet need for a
method of treating patients suffering from MS with less frequent injections and
that the 776 patent met that need. Yet, if there was any long-felt need, it was met
long ago by Pinchasi, among other references. Ex. 1003 222-225. Therefore,
others had previously solved any long-felt need alleged to be met by the
claims of the 776 patent. See In re PepperBall Techs., Inc., 469 F. Appx 878,
882-883 (Fed. Cir. 2012) (nonprec.). Moreover, it is irrelevant that, as of the
priority date, no one else had made and commercialized a method of treatment as
in the 776 patent. Because the 776 patent recites methods of using GA, a
compound that was covered by other U.S. patents at the priority date, no entity
other than the Patent Owner could have successfully brought [the claimed

- 61 -

methods] to market. Galderma Labs., L.P. v. Tolmar, Inc., 737 F.3d 731, 740
(Fed. Cir. 2013).
3.

No Mechanism of Action Theory Would Have Taught Away


From Less Frequent Dosing

To the extent Patent Owner asserts that a theory of GAs mechanism of


action would have taught away from less frequent dosing, any such argument
contradicts the extensive prior art interest in, and exploration of, less frequent
dosing. Ex. 1003 226-233. The promising results of prior art clinical studies
would have superseded any theoretical understanding of GAs mechanism of
action. Ex. 1003 229-230. Moreover, in 2009and in fact still to this day
GAs mechanism of action was unknown, with many competing theories in the
literature. Ex. 1003 238.
4.

Copying By Generic Drug Makers Is Irrelevant

Finally, to the extent Patent Owner argues that Petitioner and other generic
drug companies seek to copy the invention of the 776 patent by commercializing
generic versions of glatiramer acetate, this too fails to support non-obviousness.
As copying is required for FDA approval of generic drugs, any evidence of
copying in the [generic drug] context is not probative of nonobviousness. Bayer
Healthcare Pharms., Inc. v. Watson Pharms., Inc., 713 F.3d 1369, 1377 (Fed. Cir.
2013).

- 62 -

VII. CONCLUSION
For the foregoing reasons, Petitioner respectfully requests that the Board
institute trial and cancel all claims of the 776 Patent.
Respectfully submitted,
PERKINS COIE LLP
Dated: November 2, 2016

By:

/s/ Brandon M. White


Brandon M. White
Reg. No. 52,354

- 63 -

CERTIFICATE OF COMPLIANCE WITH TYPE-VOLUME LIMITATION


This Petition complies with the type-volume limitation of 37 C.F.R.
42.24(a)(1) because this Petition contains 13,996 words, as determined by the
word-count function of Microsoft Word, excluding the parts of the Petition
exempted by Rule (i.e., a table of contents, a table of authorities, mandatory
notices under 37 C.F.R. 42.8, a certificate of service or word count, or appendix
of exhibits or claim listing).
Date: November 2, 2016
/s/ Brandon M. White
Brandon M. White
Counsel for Petitioner
Pharmaceuticals Inc.

- 64 -

Mylan

CERTIFICATE OF SERVICE
Pursuant to 37 C.F.R. 42.6(e) and 42.105, I certify that I caused to be
served a true and correct copy of the foregoing: Petition for Inter Partes Review of
U.S. Patent No. 9,155,776, including Exhibits 1001-1067 and Petitioners power of
attorney, by Federal Express Next Business Day Delivery on this day on the Patent
Owners correspondence address of record for the subject patent as follows:
COOPER & DUNHAM, LLP
30 Rockefeller Plaza
20th Floor
New York, NY 10112
and by Federal Express on this day on the Patent Owner of record for the subject
patent as follows:
Yeda Research & Development Co., Ltd.
Chief Intellectual Property Officer
Weizmann Institute of Science
Herzl Street, No. 2
Rehovot, 76100
Israel
Dated: November 2, 2016

/s/ Brandon M. White


Brandon M. White
Registration No. 52,354
Perkins Coie LLP
700 13th St., NW, Suite 600
Washington, D.C. 20005
Telephone: (202) 654-6206
E-mail: bmwhite@perkinscoie.com

- 65 -