IN THE UNITED STATES PATENT AND TRADEMARK OFFICE …fishpostgrant.com/wp-content/uploads/IPR2015-00864.pdfPharmaceuticals USA, Inc., Zydus Pharmaceuticals USA, Inc., and Cadila Healthcare

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE _____________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD

_____________________

Accord Healthcare Inc., USA, Accord Healthcare, Inc., Intas Pharmaceuticals Ltd., Amneal Pharmaceuticals LLC, Amneal

Pharmaceuticals of New York, LLC, Amneal Pharmaceuticals Co. India Pvt. Ltd., Apotex Corp., Apotex Inc., Dr. Reddy’s Laboratories, Ltd., Dr.

Reddy’s Laboratories, Inc., Glenmark Generics Inc., USA, Glenmark Generics Ltd., Glenmark Pharmaceuticals Ltd., Panacea Biotec Ltd., Sun

Pharma Global FZE, Teva Pharmaceuticals USA, Inc., Zydus Pharmaceuticals USA, Inc., and Cadila Healthcare Ltd.

Petitioners

v.

Daiichi Sankyo Company, Limited Patent Owner

U.S. Patent No. 8,404,703 to Asai et al.

Issue Date: March 26, 2013 Title: Medicinal Compositions Containing Aspirin

_____________________

Inter Partes Review No.: IPR2015-00864 _____________________

Petition for Inter Partes Review of U.S. Patent No. 8,404,703 Under 35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123

Mail Stop "PATENT BOARD" Patent Trial and Appeal Board U.S. Patent and Trademark Office P.O. Box 1450 Alexandria, VA 22313-1450

Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-00864)

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TABLE OF CONTENTS

Petitioners’ Exhibit List ......................................................................................... v

I. INTRODUCTION ........................................................................................ 1

II. OVERVIEW .................................................................................................. 1

III. THE ’703 PATENT ...................................................................................... 5

IV. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS ............................................................................................. 7

V. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) .................................. 7

A. Each real party-in-interest (37 C.F.R. § 42.8(b)(1)) ............................. 7

B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 8

1. Judicial matters involving the ’703 patent ................................. 8

2. Administrative matters ............................................................... 8

C. Designation of lead and back-up counsel (37 C.F.R. § 42.8(b)(3)) ............................................................................................. 8

D. Notice of service information (37 C.F.R. § 42.8(b)(4)) ...................... 10

VI. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE REASONS THEREFOR (37 C.F.R. § 42.22(a)) ............................ 10

VII. THE ’703 PATENT AND CLAIM CONSTRUCTION .......................... 10

VIII. PERSON OF SKILL IN THE ART (“POSA”) ....................................... 11

IX. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ........... 11

X. BACKGROUND ......................................................................................... 12

A. The antiplatelet aggregation benefits of thienopyridine derivatives—including prasugrel—were well known. ........................ 13


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B. The benefits of combining aspirin with thienopyridine derivatives were well known. .............................................................. 15

XI. ANALYSIS OF GROUNDS FOR TRIAL ............................................... 17

A. The challenged claims would have been obvious in view of WO ’500 alone. ................................................................................... 17

1. Independent claims 1, 3, 7, 14, 20, and 24 .............................. 18

2. Dependent challenged claims .................................................. 25

B. The challenged claims would have been obvious over any of the combinations of (i) Bernat in view of Asai, (ii) Bernat in view of Koike, and (iii) WO ’500 in view of Bernat, Asai, and Koike. ........................................................................................... 29

1. Independent claims 1, 3, 7, 14, 20, and 24 .............................. 29

2. Dependent claims 8, 12, 18, and 22 ......................................... 32

3. Dependent claims 2, 4, 9, 15, 21, and 25 ................................. 33

4. Dependent claim 5 ................................................................... 34

5. Dependent claim 6 ................................................................... 34

6. Dependent claims 10, 17, and 27 ............................................. 35

7. Dependent claims 11, 13, and 19 ............................................. 36

8. Dependent claims 16 and 26 .................................................... 37

C. Objective indicia of obviousness and nonobviousness ....................... 37

1. Near-simultaneous invention by different inventors confirms the obviousness of the claimed subject matter........................................................................................ 38

2. The bases cited by the examiner for allowing the claims do not support a finding that the ʼ703 patent’s claims are valid. ....................................................................... 40


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3. The other “unexpected results” asserted by Daiichi also fail to rebut the strong showing that the claimed combination therapy is obvious. .............................................. 46

4. No evidence of copying can overcome the showing of obviousness. ............................................................................. 54

5. No evidence of commercial success can overcome the showing of obviousness. .......................................................... 55

6. No long-felt need ..................................................................... 55

XII. CONCLUSION ........................................................................................... 56


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Petitioners’ Exhibit List

Exhibit #

Description

1001 Asai et al., U.S. Patent No. 8,404,703 B2, “Medicinal Compositions Containing Aspirin” (“the ʼ703 patent”)

1002 Declaration of Jack Hirsh, MD, in Support of Petition for Inter Partes Review (“Hirsh Decl.)

1003 International Patent Application Publication No. WO 99/65500 (“WO ʼ500”)

1004 U.S. Patent No. 6,509,348 to Ogletree (“Ogletree”)

1005 Leon, M.B. et al., “A Clinical Trial Comparing Three Antithrombotic-Drug Regimens After Coronary Artery Stenting,” N. Engl. J. Med. ,339:1665-1671 (1998) (“Leon”)

1006 U.S. Patent No. 5,989,578 (“Bernat”)

1007 Uchiyama, S. et al., “Combination Therapy With Low-Dose Aspirin And Ticlopidine In Cerebral Ischemia,” Stroke, 20:1643-47 (1989) (“Uchiyama”)

1008 Herbert, J.M. et al., “The Antiaggregating and Antithrombotic Activity of Clopidogrel is Potentiated by Aspirin in Several Experimental Models in the Rabbit,” Thromb. Haetomost., 80:512-18 (1998) (“Herbert”)

1009 Moshfegh, K. et al., “Antiplatelet Effects of Clopidogrel Compared with Aspirin After Myocardial Infarction: Enhance Inhibitory Effects of Combination Therapy,” Journal of the American College Cardiology, 36, 699 705 (2000) (“Moshfegh”)

1010 Asai, F. et al., “CS-747, a new platelet ADP receptor antagonist," Ann. Rep. Sankyo Res. Lab., 51:1-44 (1999) (“Asai”)


vi

Exhibit #

Description

1011 Sugidachi, A. et al., “The in vivo Pharmacological Profile of CS-747, a Novel Antiplatelet Agent with Platelet ADP Receptor Antagonist Properties,” Br. J. Pharmacal., 209:1439-46 (April 2000) (“Sugidachi”)

1012 U.S. Patent No. 5,288,726 to Koike (“Koike”)

1013 Mehta, S.R. et al., CURE Study Investigators “The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Programme: Rationale, Design and Baseline Characteristics Including a Meta Analysis of the Effects of Thienopyridines in Vascular Disease” Eur. Heart Journal, 21 (24):2033 2041 (December 1, 2000) (the “CURE study”)

1014 Rupprecht, H.J. et al., “Comparison of Antiplatelet Effects of Aspirin, Ticlopidine, or Their Combination After Stent Implantation” Circulation , 97:1046 1052 (1998) (“Rupprecht”)

1015 U.S. Patent No. 4,080,447 to Amselem (“Amselem”)

1016 Mishkel, G.J. et al., “Clopidogrel as Adjunctive Antiplatelet Therapy During Coronary Stenting,” J. Am. Coll. Cardiol., 34 (7):1884 1890 (1999) (“Mishkel”)

1017 Muller, C. et al., “A Randomized Comparison of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin After the Placement of Coronary Artery Stents,” Circulation, 101:590 593 (Feb. 2000) (“Muller”)

1018 Moussa, I. et al., “Effectiveness of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin in Preventing Stent Thrombosis After Coronary Stent Implantation,” Circulation, 99:2364 2366 (1999) (“Moussa”)

1019 Harker, L.A. et al., “Clopidogrel Inhibition of Stent, Graft, and Vascular Thrombogenesis with Antithrombotic Enhancement by Aspirin in Nonhuman Primates,” Circulation, 98:2461 2469 (1998) (“Harker”)


vii

Exhibit #

Description

1020 Bertrand, M.E. et al., “Double Blind Study of the Safety of Clopidogrel with and without a Loading Dose in Combination with Aspirin Compared with Ticlopidine in Combination with Aspirin After Coronary Stenting: The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS),” Circulation, 102(6):624 629 (2000) (“Bertrand”)

1021 Patrono et al., “Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects,” Chest, 114:470S-488S (1998) (“Patrono”)

1022 May 1, 2009 Office Action (excerpt from the prosecution history of the ’703 patent)

1023 May 26, 2011 Office Action (excerpt from the prosecution history of the ’703 patent)

1024 Nov. 25, 2011 Declaration Under 37 C.F.R § 1.131 (excerpt from the prosecution history of the ’703 patent)

1025 Nov. 25, 2011 Declaration Under 37 C.F.R. § 1.132 of Dr. Paul A. Gurbel (excerpt from the prosecution history of the ’703 patent) (“Gurbel Decl.”)

1026 Feb. 5, 2013 Notice of Allowance (excerpt from the prosecution history of the ’703 patent)

1027 Wiviott et al., “Prasugrel versus clopidogrel in patients with acute coronary syndromes,” 357 (20) N Engl J Med. 2001-15 (Nov. 15, 2007) (“Wiviott I”)

1028 Kaul and Diamond, “Trial and Error: How to Avoid Commonly Encountered Limitations of Published Clinical Trials,” 55 (5) JACC 415-27 (2010) (“Kaul”)

1029 Erlinge et al., 52(24) JACC 1968-1977 (2008) (“Erlinge”)


viii

Exhibit #

Description

1030 Chan, N.C., et al., “Role of phenotypic and genetic testing in managing clopidogrel therapy,” Blood, 124(5):689-699 (2014) (“Chan”)

1031 Jakubowski, J., et al., “Prasugrel: A Novel Thienopyridine Antiplatelet Agent. A Review of Preclinical and Clinical Studies and the Mechanistic Basis for Its Distinct Antiplatelet Profile,” Cardiovascular Drug Reviews, 25(4):357–74 (2007) (“Jakubowski”)

1032 Schomig et al, “A randomized comparison of antiplatelet and anticoagulant therapy after placement of coronary-artery stents,” N. Engl J. Med., 334:1084-1089 (1996)

1033 Urban et al, “Randomized evaluation of anticoagulation versus anti-platelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS),” Circulation, 98:2126-2132 (1998)

1034 July 12, 2012 Amendment and Response (excerpt from the prosecution history of the ’703 patent)

1035 Wiviott SD, et al., “Randomized Comparison of Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y12 Antagonist With Clopidogrel in Percutaneous Coronary Intervention: Results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)—TIMI 26 Trial,” Circulation, 111:3366-3373 (2005) (“Wiviott II”)

1036 Gurbel et al., “Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity,” Circulation, 107:2908-2913 (2003) (“Gurbel”).


ix

Exhibit #

Description

1037 Jernberg et al., “Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease,” European Heart Journal, 27:1166-1173 (2006) (“Jernberg”).

1038 Brandt, J., et al., “A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation,” Am. Heart J., 153(1):66.e9-16 (2007) (“Brandt”).

1039 Serebruany VL., et al., “Variability in platelet responsiveness to clopidogrel among 544 individuals,” J. Am. Coll. Cardiol., 45(2): 246-251 (2005) (“Serebruany”).

1040 Van De Graaff et al., “Variable Interindividual Responses To Antiplatelet Therapies—Do They Exist, Can We Measure Them, And Are They Clinically Relevant?” Heart Drug, 1(1):35-43 (2001) (“Van De Graaff”)

1041 Farrell et al., “The Lack Of Augmentation By Aspirin Of Inhibition Of Platelet Reactivity By Ticlopidine,” Am. J. Cardiol., 83; 770-774 (1999) (“Farrell”)

1042 Mar. 30, 2012 Office Action (excerpt from the prosecution history of the ’703 patent)

1043 Liang et al., “Active Metabolite Concentration Of Clopidogrel In Patients Taking Different Doses Of Aspirin: Results Of The Interaction Trial,” J. Thrombosis and Haemostasis, 13(3): 347-352 (2015) (“Liang”)

1044 Niitsu, et al., “Pharmacology of CS-747 (Prasugrel, LY640315), a Novel, Potent Antiplatelet Agent with in Vivo P2Y12 Receptor Antagonist Activity,” Semin Thromb Hemost., 31(2):184-94 (2005) (“Niitsu”)


x

Exhibit #

Description

1045 Office of Surveillance and Epidemiology (OSE), FDA, “Background Package for Advisory Committee NDA 22-307” (Jan. 8, 2009) (“OSE Rept.”)

1046 Labeling for Effient® (prasugrel) (rev. Nov. 2013)

1047 Labeling for Plavix® (clopidogrel) (rev. Dec. 2013)

I. INTRODUCTION

Accord Healthcare Inc., USA, Accord Healthcare, Inc., Intas

Pharmaceuticals Ltd., Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of

New York, LLC, Amneal Pharmaceuticals Co. India Pvt. Ltd., Apotex Corp.,

Apotex Inc., Dr. Reddy’s Laboratories, Ltd., Dr. Reddy’s Laboratories, Inc.,

Glenmark Generics Inc., USA, Glenmark Generics Ltd., Glenmark

Pharmaceuticals Ltd., Panacea Biotec Ltd., Sun Pharma Global FZE, Teva

Pharmaceuticals USA, Inc., Zydus Pharmaceuticals USA, Inc., and Cadila

Healthcare Ltd. (collectively, “Petitioners”) petition for Inter Partes Review,

seeking cancellation of claims 1-27 (“challenged claims”) of U.S. Patent No.

8,404,703 to Asai et al. (“the ’703 patent”) (EX1001), which is owned by Daiichi

Sankyo Company, Limited (“Daiichi” or “Patent Owner”).

II. OVERVIEW

The challenged claims of the ’703 patent are directed to methods for treating

diseases that are caused in part by blood platelet aggregation (blood clotting) by

administering a combination of prasugrel and aspirin—two drugs that, at the time

of the alleged invention, were each known to disrupt platelet aggregation, but

through separate and independent mechanisms of action.

Prasugrel is in the family of drugs known as “thienopyridine derivatives.”

Prior to the filing of the ’703 patent, the only other known thienopyridine


2

derivatives in clinical use were clopidogrel and ticlopidine. It had also been

established that these thienopyridine derivatives were not created equal.

Clopidogrel was many times more effective than ticlopidine in inhibiting platelet

aggregation, and prasugrel had been demonstrated to be 10 times more effective

than clopidogrel and some 100 times as effective as ticlopidine. Indeed, the

ʼ703 patent concedes that prasugrel was known to be “potent.” (EX1001 at 1:34.)

Prior to the application for the ’703 patent, aspirin was also known to inhibit

platelet aggregation, but by a different mechanism of action than the mechanism

used by thienopyridine derivatives to inhibit platelet aggregation. Taking

advantage of these different mechanisms of action, it had also been demonstrated

that ticlopidine and clopidogrel were even more effective in inhibiting platelet

aggregation when combined with aspirin than when taken alone.

Thus, the question presented by this petition is whether it was a patentable

invention to take the existing combinations of thienopyridine derivatives

(clopidogrel or ticlopidine) with aspirin, and substitute the next-generation

thienopyridine derivative—prasugrel—for the clopidogrel or the ticlopidine.

The answer is no.

Petitioners will demonstrate that the claims of the ’703 patent represent the

epitome of obviousness under 35 U.S.C. § 103(a). The prior art indisputably

established the existence, efficacy, and safety of two thienopyridine derivatives


3

(clopidogrel and ticlopidine) combined with aspirin. The prior art also established,

and the ’703 patent itself concedes, that only one other thienopyridine derivative—

prasugrel—had been studied and shown to be more potent than the other two

thienopyridine derivatives in terms of effectiveness.

Accordingly, it would have been obvious to one of ordinary skill as of the

invention date of the ’703 patent to substitute prasugrel for one of the other two

thienopyridine derivatives in combination with aspirin. Not only would such a

person of ordinary skill have had a reasonable expectation of success; the

expectation would have been that a combination of prasugrel and aspirin would

have been better than the known combinations of clopidogrel with aspirin and

ticlopidine with aspirin. At a minimum, the superior efficacy of prasugrel relative

to clopidogrel and ticlopidine would have been an enormous incentive to make the

substitution and arrive at the methods now claimed by the Patent Owner.

Indeed, during prosecution, the Patent Office rejected the claims by

recognizing that the claims of the ʼ703 patent were prima facie obvious—a finding

it never retracted. The Patent Owner only overcame that finding by asserting that

the combination therapy of prasugrel and aspirin produces “unexpected results.”

But the Patent Owner’s assertions of unexpected results are both legally and

factually flawed, and do not support non-obviousness of the claims. As Petitioners

will show, the alleged “unexpected results” were entirely expected and wholly


4

unrelated to the claimed invention. In any event, the teachings of the prior art in

this case are so overwhelming that they cannot be overcome by secondary

considerations. Furthermore, another entity disclosed the same alleged invention

in a patent application filed just months before the Japanese application to which

the ’703 patent claims priority—evidence of near-simultaneous invention that

further supports the obviousness of the claims.

The Patent Owner in this case has no more right to withdraw from the public

domain the combination of prasugrel and aspirin than did the patent owner in Novo

Nordisk A/S v. Caraco Pharm. Labs., Ltd., 719 F.3d 1346 (Fed. Cir. 2013). There,

as here, “the closest prior art was combination therapy” using two drugs that were

“well known in the art to produce beneficial and even synergistic results.” Id. at

1351. There, as here, the patentee merely replaced one of the drugs in the prior art

combination with a newer drug that was “known as … having a similar mechanism

of action.” Id. As the Federal Circuit confirmed, these facts “set forth a prima

facie case that it was obvious to try [the claimed] combination therapy,” and “the

results of the claimed combination therapy said by [the patentee] to be unexpected

and unexplainable were, to the contrary, expected and explainable.” Id. at 1351,

1354 (quotation omitted).

Nor can this case be distinguished from Richardson-Vicks, Inc. v. Upjohn

Co., 122 F.3d 1476 (Fed. Cir. 1997), where the prior art included similar


5

“combinations” of pseudoephedrine with aspirin and pseudoephedrine with

acetaminophen, and the patentee had claimed the combination of pseudoephedrine

with ibuprofen. As the Federal Circuit held, even “substantial evidence” of

“unexpected results” could “not overcome the … evidence that the subject matter

sought to patented is obvious.” Id. at 1484.

It can truly be said in this case that the substitution of prasugrel for

clopidogrel or ticlopidine in therapies that also employ aspirin was “no more

ingenious than selecting the last piece to put into the last opening in a jig-saw

puzzle. It is not invention.” Sinclair & Carroll Co. v. Interchemical Corp., 325

U.S. 327, 335 (1945). Because it “‘simply arranges old elements with each

performing the same function it had been known to perform’ and yields no more

than one would expect from such an arrangement, the combination is obvious.”

KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 417 (2007) (citation omitted).

III. THE ’703 PATENT

The ’703 patent issued on March 26, 2013, from U.S. Appl. No. 11/520,168.

(EX1001.) The patent states on its face that it is a division of U.S. Application

Serial No. 10/600,266, filed on June 20, 2003, which in turn is a continuation of

PCT/JP01/11201, filed on December 20, 2001. (Id.) The PCT application claimed

the benefit of priority from foreign patent application JP 2000-392983, filed on

December 25, 2000. (Id.)


6

The independent challenged claims (claims 1, 3, 7, 14, 20, and 24) are

generally directed to methods for inhibiting, preventing, or reducing

thrombogenesis, platelet aggregation, or thrombotic symptoms associated with

cardiovascular disease by administering prasugrel and aspirin, along with

pharmaceutically acceptable excipients. (EX1001 at 6:21-301; 6:33-40; 6:50-59;

7:10-19; 7:33-8:8; 8:17-26.) The challenged dependent claims limit the claimed

methods with respect to requiring pharmacologically effective amounts of the

active ingredients (claims 8, 18, 22), requiring the hydrochloride salt of prasugrel

(claims 2, 4, 9, 15, 21, and 25), requiring that the human is a patient undergoing

angioplasty or stent therapy (claims 5, 10, 17, 27), requiring that the disease caused

by thrombus or embolus is selected from the group consisting of various

cardiovascular disorders (claim 6), or that the human have a cardiovascular

disorder (claims 16 and 26).

The ’703 patent admits that 2-acetoxy-5-(α-cyclopropylcarbonyl-2-

fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, which is prasugrel, had been

known for many years to have “potent inhibitory activity against platelet

aggregation.” (Id. at 1:31-35; 2:5-25.) The specification also admits that aspirin

1 Citations are as follows: X:YY-ZZ (col:lines; patent); X:Y:Z (page:col:para;

journal article); X:Y (page:para; journal article).


7

was “well known to have an inhibiting activity against platelet aggregation,

although the activity is low.” (Id. at 1:35-37.) The purported invention of the ’703

patent is administering the combination of these two known medications, prasugrel

and aspirin, for inhibiting platelet aggregation—the same purpose for which they

were each already known to be useful.

IV. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS

Petitioners certify that (1) the ’703 patent is available for IPR; and (2)

Petitioners are not barred or estopped from requesting IPR of any claim of the ’703

patent on the grounds identified herein. The required fee is paid through the Patent

Review Processing System. The Office is authorized to charge fee deficiencies

and credit overpayments to Deposit Acct. No. 50-1814.

V. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))

A. Each real party-in-interest (37 C.F.R. § 42.8(b)(1))

Petitioners certify that Accord Healthcare Inc., USA, Accord Healthcare,

Inc., Intas Pharmaceuticals Ltd., Amneal Pharmaceuticals LLC, Amneal

Pharmaceuticals of New York, LLC, Amneal Pharmaceuticals Co. India Pvt. Ltd.,

Apotex Corp., Apotex Inc., Dr. Reddy’s Laboratories, Ltd., Dr. Reddy’s

Laboratories, Inc., Glenmark Generics Inc., USA, Glenmark Generics Ltd.,

Glenmark Pharmaceuticals Ltd., Panacea Biotec Ltd., Sun Pharma Global FZE,

Sun Pharmaceutical Industries, Ltd., Teva Pharmaceuticals USA, Inc., Teva


8

Pharmaceutical Industries, Ltd., Zydus Pharmaceuticals USA, Inc., and Cadila

Healthcare Ltd. are real parties-in-interest.

B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))

1. Judicial matters involving the ’703 patent

The ’703 patent is asserted in the consolidated action styled Eli Lilly and

Co., et al. v. Accord Healthcare, Inc., et al., No. 14-cv-00389-SEB-TAB, filed

March 12, 2014, in the United States District for the Southern District of Indiana.

2. Administrative matters

Petitioners have filed concurrently with this Petition, a Petition for Inter

Partes Review of U.S. Patent No. 8,569,325 (“the ’325 patent”), which issued on

October 29, 2013, and claims priority to the same applications as the ’703 patent.

C. Designation of lead and back-up counsel (37 C.F.R. § 42.8(b)(3))

Lead Counsel Back-Up Counsel

Samuel S. Park (Reg. #59,656)

Email: [email protected]

WINSTON & STRAWN LLP

35 W. Wacker Drive

Chicago, IL 60601

Telephone: (312) 558-7931

Fax: (312) 558-5700

John K. Hsu (Reg. #45,563)


WINSTON & STRAWN LLP

1700 K Street NW

Washington, D.C. 20006-3817

Telephone: (202) 282-5000

Fax: (202) 282-5100


9

Back-Up Counsel Back-Up Counsel

Patrick C. Gallagher (Reg. #63,407)


DUANE MORRIS LLP

190 South LaSalle Street

Chicago, Illinois 60611

Telephone: (312) 499-6759

Fax: (312) 276-8786

William L. Mentlik (Reg. #27,108)


LERNER, DAVID, LITTENBERG,

KRUMHOLZ & MENTLIK, LLP

600 South Avenue West

Westfield, NJ 07090

Telephone: (908) 654-5000

Fax: (908) 654-7866

Back-Up Counsel Back-Up Counsel

Azadeh S. Kokabi (Reg. # 58,902)


SUGHRUE MION PLLC

2100 Pennsylvania Avenue

Washington, D.C. 20037-3213

Telephone: (202) 293-7060

Fax: (202) 293-7860

Steven J. Moore (Reg. #35,959)


John Winterle (Reg. #57,276)


Hans-Peter Hoffman

(Reg. #37,352)


Alan Gardner (Reg. #69,495)



10

KELLEY DRYE & WARREN

400 Atlantic Street, 13th Floor

Stamford, CT 06901

Telephone: (203) 351-8020

Fax: (202) 293-7860

D. Notice of service information (37 C.F.R. § 42.8(b)(4))

Please direct all correspondence to lead counsel at the above address.

Petitioners consent to email service at the above-listed email addresses of lead and

back-up counsel.

VI. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE REASONS THEREFOR (37 C.F.R. § 42.22(a))

Petitioners request IPR and cancellation of claims 1-27 of the ’703 patent. A

detailed statement of the reasons for the relief requested is set forth in Section IX.

VII. THE ’703 PATENT AND CLAIM CONSTRUCTION

In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be

given their broadest reasonable interpretation in light of the specification of the

’703 patent. Under this standard, Petitioners submit that the terms of the

challenged claims should be given their plain and ordinary meaning in light of the

specification, and no terms or phrases require specific construction.


11

VIII. PERSON OF SKILL IN THE ART (“POSA”)

As explained in the Declaration of Jack Hirsh, M.D., a POSA with respect to

the ʼ703 patent would include a person who has a Ph.D., or M.D. who has had

several years of training or experience in the treatment of, or research and

development of treatments for, cardiovascular diseases, cardiovascular conditions,

or intervention cardiology. (EX1002 ¶ 28.) This person would regularly peruse

the literature of cardiology and thrombosis research and would know how to use

library resources to obtain more information about areas being researched. (Id.) In

addition, the POSA would know how to evaluate potential drug therapies for their

in vitro and in vivo activity. Although this POSA might not actually be trained to

set up or to carry out those biological assays, that POSA would know how to

obtain such results from a qualified commercial testing laboratory, either within or

outside the POSA’s organization, or through a collaboration with a colleague

elsewhere. (Id.)

IX. IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))

IPR of claims 1-27 of the ’703 patent is requested on the grounds for

unpatentability listed below. Per 37 C.F.R. § 42.6(d), copies of the references are

filed herewith. In support of the proposed grounds for unpatentability, this Petition

includes the declaration of a technical expert, Dr. Hirsh (EX1002), explaining what

the art would have conveyed to a POSA. Dr. Hirsh is an expert in the field of


12

hematology and thrombosis research. (Id. ¶¶ 1-22.)

References Basis Claims Challenged

WO ’500 (EX1003) § 103 All challenged claims

Bernat (EX1006) in view of

Asai (EX1010)

§ 103 All challenged claims

Bernat (EX1006) in view of

Koike (EX1012)


WO ʼ500 (EX1003) in view of

Bernat (EX1006), Asai (EX1010),

and Koike (EX1012)


X. BACKGROUND

As discussed in greater depth below, a POSA at the time of the invention

claimed in the ʼ703 patent would have known from the prior art that thienopyridine

derivatives were useful in preventing or treating diseases caused by thrombus of

embolus, and that their usefulness for such treatment was enhanced by combining

them with aspirin. A POSA would also have known that prasugrel was superior to

ticlopidine or clopidogrel—the only other thienopyridine derivatives that had been

clinically shown to be effective for treating diseases caused by thrombus and

embolus, particularly when combined with aspirin.


13

A. The antiplatelet aggregation benefits of thienopyridine derivatives—including prasugrel—were well known.

The prior art demonstrates that a POSA would have known that

thienopyridine derivatives such as ticlopidine, clopidogrel, and prasugrel were

beneficial in treating cardiovascular disorders and that all three drugs have

antiplatelet aggregation activity. (EX1002 ¶¶ 55-68.) The structural similarities of

these three compounds are all directly compared below:

Ticlopidine Clopidogrel Prasugrel

(Id. ¶ 57.)

These thienopyridine derivatives were well known to have antiplatelet

aggregation activity and to be beneficial in inhibiting thrombus formation. (Id.

¶ 58.) For example, Bernat disclosed that both ticlopidine and clopidogrel are

antithrombotic agents that are useful in treating various cardiovascular disorders in

humans such as the thromboembolic disorders associated with the atherosclerosis

or with diabetes such as unstable angina, restenosis following angioplasty, or

during the use of aortocoronary bypasses. (EX1006 at 1:35- 2:65, cls. 9-12, cls.

23-25.) Bernat also teaches that clopidogrel is 10 to 50 times more effective than


14

ticlopidine. (Id. at 2:34-36.)

International Patent Application Publication No. WO 99/65500 (“WO ’500”)

discloses methods for preventing and treating a range of cardiovascular disorders,

including diseases involving platelet aggregation and thrombus formation by

administering an ADP-receptor blocking antiplatelet agent and an antihypertensive

agent, optionally with aspirin. (EX1003 at 4:4-13, 9:1-2, 10:20-22, 14:9-11.) WO

’500 discloses that the ADP-receptor antiplatelet agent according to the invention

includes “clopidogrel, ticlopidine, and the like.” (Id. at 3:33-35).

Similarly, Uchiyama, Herbert, Moshfegh, the CURE study, Rupprecht, and

Amselem all teach the anti-aggregating and antithrombotic activity of ticlopidine

and/or clopidogrel. (EX1007 at 1643-45; EX1008 at 512, 514-517; EX1009 at

699, 701-05; EX1013 at 2033; EX1014 at 1046, 1051-52; EX1015 at 1:25-39, 6:9-

15, cl. 1.) Other references, including Mishkel, Müller, Moussa, Harker, and

Bertrand, similarly teach the use of ticlopidine and/or clopidogrel in connection

with stenting. (EX1016 at 1884, 1890; EX1017 at 590, 592-93; EX1018 at 2364-

66; EX1019 at 2461, 2467-68; EX1020 at 624, 628.)

Asai disclosed prasugrel (referred to as “CS-747”) and taught that it has

antiplatelet aggregation activity and is 100 times more potent than ticlopidine, and

10-fold efficacy superiority over clopidogrel. (EX1010 at 10-13.) Asai

demonstrated that prasugrel is rapidly and well absorbed after oral administration.


15

(Id.; see also id. at 38-41.) Moreover, Asai found that prasugrel has a fast onset,

long duration, and caused no abnormal changes in the safety parameters for any

study group. (Id.; see also id. at 22, 38-43.)

Asai and Sugidachi both teach that prasugrel has the same mechanism of

action but is better than clopidogrel in inhibiting ADP-induced platelet aggregation

and thrombus formation. (EX1010 at 10-22; EX1011 at 1444-45.) Sugidachi also

echoed Asai’s findings regarding prasugrel’s superior potency, faster onset, longer

duration, and comparable side effect profile. (EX1011 at 1439, 1444-45.) Asai

and Sugidachi also both teach that prasugrel has a similar clinical benefit/bleeding

risk ratio as compared to clopidogrel. (EX1010 at 16; EX1011 at 1445.) Other

references available at the time show that prasugrel was known (e.g., EX1012,

Koike) and that it has superior activity and/or safety profile to that of ticlopidine or

clopidogrel. (EX1002, Hirsh Decl. ¶¶ 61, 86-92.)

B. The benefits of combining aspirin with thienopyridine derivatives were well known.

Aspirin’s antithrombotic properties result from a separate biochemical

mechanism that is independent of the mechanism of thienopyridine derivatives

such as ticlopidine, clopidogrel, and prasugrel. (EX1002 ¶¶ 62-63.) The

antithrombotic action of acetylsalicylic acid (i.e., aspirin) is mainly due to

inhibition of platelet function by the irreversible acetylation of the cyclooxygenase

(COX) enzyme COX-1, which is located mainly in blood platelets, and COX-2, the


16

inducible form, which is located mainly in the vascular endothelium. (Id.)

Thienopyridine derivatives were known to be more efficacious when

combined with aspirin. (id. ¶¶ 64-67; e.g., EX1005, Leon at 1669.) The prior art

taught that the combination of “aspirin and ticlopidine,” which was shown to have

an additive effect, “should be considered for the prevention of the serious

complication of stent thrombosis.” (EX1005, Leon at 1665.) When clopidogrel

was introduced as the next-generation thienopyridine after ticlopidine, it was

obvious to substitute clopidogrel for ticlopidine in the known combination therapy

of ticlopidine and aspirin. (See EX1002, Hirsh Decl. ¶ 104.) This new

combination produced even greater benefits. Indeed, as taught in Bernat, it was

shown that an antiplatelet effect occurred in patients receiving the combination

therapy of clopidogrel and aspirin that was greater than the antiplatelet effect of

either drug in monotherapy. (E.g., EX1006, Bernat at 5:18-20, 2:48-54, 5:32-60,

5:57-6:15, Tbl. 1, Tbl. 2; EX1002, Hirsh Decl. ¶¶ 72-80.)

Thus, the prior art favorably demonstrates the use of the two earlier

thienopyridine derivatives—ticlopidine and clopidogrel—in combination with

aspirin, and that combination treatment with the later thienopyridine derivative—

clopidogrel—was more effective than monotherapy using either drug alone.

Accordingly, once prasugrel was identified as the next-generation thienopyridine

after clopidogrel, it would have been expected that substituting prasugrel for


17

clopidogrel in combination therapy with aspirin would produce the same greater-

than-additive improvement in effectiveness that had been obtained with

clopidogrel and aspirin. (EX1002 ¶¶ 66, 104, 145.)

Indeed, the inventors of the ʼ703 patent later admitted that they were

motivated to evaluate the combination of aspirin and prasugrel precisely because of

the known benefits of combining clopidogrel and aspirin. (EX1044, Niitsu at 187

(“Clinically, combined treatment of aspirin plus clopidogrel has shown additive

efficacy in preventing thrombotic disorders. Therefore, evaluation of [prasugrel]

included the study of the effects of [prasugrel] in combination with aspirin….”).)

As shown in this Petition, a POSA would have had that same motivation.

XI. ANALYSIS OF GROUNDS FOR TRIAL

As Petitioners explain below, each of the challenged claims would have

been obvious over (a) WO ʼ500 (EX1003) alone; (b) Bernat (EX1006) in view of

Asai (EX1010); (c) Bernat (EX1006) in view of Koike (EX1012) and (d), WO

ʼ500 in view of Bernat (EX1006), Asai (EX1010), and Koike (EX1012).

Furthermore, the secondary consideration of near-simultaneous invention supports

a finding of obviousness, and no other secondary considerations weigh against it.

A. The challenged claims would have been obvious in view of WO ’500 alone.

As noted above, WO ʼ500 was published on December 23, 1999, and thus

qualifies as prior art to the ʼ703 patent under 35 U.S.C. § 102(b). (EX1003.)


18

It would have been obvious to a POSA in view of the teachings of WO ’500

alone to combine prasugrel with aspirin to treat cardiovascular diseases by

inhibiting or reducing thrombogenesis and platelet aggregation, as specifically

claimed in each claim of the ʼ703 patent.

1. Independent claims 1, 3, 7, 14, 20, and 24

Independent claim 1 of the ’703 patent claims a method for treatment of a

disease caused by thrombus or embolus consisting of administering (i) prasugrel or

a pharmaceutically acceptable salt thereof, (ii) aspirin, and (iii) one or more

pharmaceutically acceptable excipients, wherein the prasugrel and aspirin are

administered in pharmacologically effective amounts to a human in need of

reduction of thrombogenesis or reduction of platelet aggregation. (EX1001, cl. 1.)

WO ’500 discloses using a combination of an ADP-receptor blocking

antiplatelet drug and an antihypertensive drug, and optionally aspirin, to treat

“diseases involved with platelet aggregation, thrombus formation and ischemic

events, in that the combination may provide additional antiplatelet aggregation,

anti-ischemic and anti-thrombus effects over that which may be obtained using

each of the components of the combination alone.” (EX1003 at 4:4-13, 9:1-2.)

WO ’500 also contains examples of inhibiting platelet aggregation and thrombus

formation. (Id. at Example 3, Example 4.) Further, WO ’500 teaches that such


19

treatments can be provided to humans. (Id. at 3:22-28.) Thus, the preamble and

“wherein” clause of claim 1 of the ʼ703 patent are expressly disclosed in WO ’500.

With respect to the compounds used to prevent and treat the various

cardiovascular disorders, WO ’500 defines the term “ADP receptor blocking

antiplatelet drug” as “drugs which inhibit ADP-induced platelet aggregation via

platelet ADP-receptor blocking including clopidogrel and/or ticlopidine and do not

include drugs such as aspirin which inhibit platelet inhibition by other

mechanisms.” (Id. at 4:23-28.) WO ’500 further discloses that the ADP-receptor

blocking antiplatelet agent according to the invention included “clopidogrel,

ticlopidine and the like.” (Id. at 3:33-35 (emphasis added).)

As Dr. Hirsh explains, thienopyridines were well known “ADP-receptor

blocking antiplatelet drugs” at the time of the alleged invention in the ʼ703 patent,

and prasugrel was the only known thienopyridine other than clopidogrel and

ticlopidine that was undergoing clinical testing at the time WO ’500 was published.

(EX1002 ¶¶ 56, 100.) When WO ’500 discloses that the “ADP-receptor blocking

antiplatelet drug” according to the invention includes “clopidogrel, ticlopidine and

the like,” a POSA would have understood, given the state of the art, that prasugrel

was included in the disclosure. (EX1003 at 3:33-35 (emphasis added); EX1002,

Hirsh Decl. ¶ 100.) Thus, a POSA would have understood that WO ’500 discloses

the use of known thienopyridine compounds—including prasugrel—as the ADP-


20

receptor blocking agents useful in following the teachings of WO ’500. (Id.)

WO ’500 also discloses that “aspirin may optionally be included in the

combination of the invention.” (Id. at 9:1-2.) WO ’500 discloses that, “[w]here

present, the aspirin (employed with the ADP receptor blocking antiplatelet drug

and antihypertensive agent) will be employed in daily dosages within the range

from about 1 mg to about 500 mg, preferably from about 20 mg to about 100 mg,

and in a weight ratio to the ADP receptor blocking antiplatelet drug within the

range from about 0.02:1 to about 1000:1, preferably from about 0.04:1 to about

20:1.” (Id. at 10:20-27.) WO ’500 also discloses that “[t]he ADP-receptor

blocking antiplatelet drug and the antihypertensive agent, and optionally drugs for

preventing or treating cerebral infarction may be employed together in the same

oral dosage form or in separate oral dosage forms taken at the same time,” and that

“[a]ccording to another modification, in order to more finely regulate the dosage

schedule, the active substances may be administered separately in individual

dosage units at the same time or carefully coordinated times.” (Id. at 10:28-32;

11:16-19.) Thus, the use of aspirin in combination with thienopyridine derivatives

in treating cardiovascular diseases is expressly disclosed in WO ’500.

Although WO ʼ500 also discloses the use of an antihypertensive drug, it

would have been obvious for a POSA to use a thienopyridine derivative and aspirin

as disclosed in WO ʼ500 independently of an antihypertensive drug. (EX1002,


21

Hirsh Decl. ¶ 101.) Indeed, a POSA would have known that thienopyridine

derivatives and aspirin each inhibit platelet aggregation, whereas an

antihypertensive drug reduces blood pressure and is not directed to inhibiting

platelet aggregation. (Id.) Thus, for treating and preventing diseases related to

platelet aggregation, it would have been obvious for a POSA to use the

combination of prasugrel as the ADP-receptor blocking drug together with aspirin,

as taught by WO ʼ500, without also including an antihypertensive drug. (Id.)

Further, WO ʼ500 discloses the formulation of ADP-receptor blocking drugs

and aspirin using “the necessary carrier material, excipient, lubricant, buffer,

antibacterial, bulking agent (such as mennitol), anti-oxidants (ascorbic acid of

sodium bisulfite) or the like.” (EX1003 at 9:11-13.) Thus, the limitation in

independent claim 1 of the ʼ703 patent for pharmaceutically acceptable excipients

(EX1001, cl. 1) is also expressly disclosed in WO ʼ500.

As seen above, WO ’500 teaches that aspirin can be combined with

thienopyridine derivatives to treat cardiovascular diseases, and a POSA would

have known that prasugrel is encompassed within the genus of ADP-receptor

blocking antiplatelet agents that are disclosed in WO ’500. A POSA, therefore,

would have reasonably expected from the disclosure of WO ’500 that prasugrel

could be successfully used in combination with aspirin to treat cardiovascular

diseases in humans. (EX1002, Hirsh Decl. ¶¶ ¶¶ 94, 99-101, 107.) And there are


22

no teachings in WO ’500 that would have discouraged such a combination.

Therefore, claim 1 would have been obvious to a POSA in view of WO ’500. (Id.)

For essentially the same reasons, the remaining independent claims—all of

which describe minor variations in the known conditions to be treated using the

combination therapy of prasugrel and aspirin—would also have been obvious.

Claim 3 is nearly identical to independent claim 1 except that claim 3

requires a method for the treatment of a patient undergoing stenting, angioplasty,

and/or to prevent restenosis comprising administering a pharmaceutical

composition comprising prasugrel and aspirin as the active ingredients to a warm-

blooded animal. (EX1001, cl. 3.) As discussed above, WO ʼ500 broadly discloses

treating various symptoms associated with cardiovascular or cerebrovascular

disorders using a combination that includes an ADP-receptor inhibitor such as

prasugrel in combination with aspirin. (EX1003 at 4:4-13, 9:1-2.) Specifically,

WO ʼ500 discloses the use of that combination therapy for treating patients

undergoing angioplasty or stent therapy. (EX1003 at 2:9-15.) Thus, for the same

reasons seen above with respect to claim 1, claim 3 also would have been obvious

to a POSA. (See EX1002, Hirsh Decl. ¶¶ 99-101.)

Claim 7 is nearly identical to claim 1 except that claim 7 claims a method for

inhibiting thrombogenesis, platelet aggregation, or thromboembolization, wherein

the prasugrel and aspirin are administered in pharmacologically effective amounts


23

to a human having cardiovascular disease. (EX1001, cl. 7.) As discussed above,

WO ’500 discloses using a combination that includes an ADP-receptor blocking

antiplatelet drug and aspirin to treat “diseases involved with platelet aggregation,

thrombus formation and ischemic events, in that the combination may provide

additional antiplatelet aggregation, anti-ischemic and anti-thrombus effects over

that which may be obtained using each of the components of the combination

alone.” (EX1003 at 4:4-13, 9:1-2.) Moreover, WO ’500 contains examples of

inhibiting platelet aggregation and thrombus formation. (Id. at Example 3,

Example 4.) WO ’500 also teaches that such treatments can be provided to

humans. (Id. at 3:22-28.) Thus, for the same reasons seen above with respect to

claim 7, claim 3 also would have been obvious to a POSA. (EX1002 ¶¶ 99-101.)

Claim 14 is nearly identical to independent claim 1 except that claim 14

requires a method of reducing thrombotic symptoms associated with

cardiovascular or cerebrovascular disorders in humans in need of reducing said

symptoms. (EX1001, cl. 14.) As discussed above, WO ʼ500 broadly discloses

treating various symptoms associated with cardiovascular or cerebrovascular

disorders. (EX1003 at 4:4-13.) Moreover, WO ʼ500 specifically claims methods

“for preventing or inhibiting or treating a cerebral infarction,” including “wherein

the cerebral infarction” is either “a primary or secondary ischemic event.” (Id. at


24

16:31-17:3.) Thus, for the same reasons seen above with respect to claim 1, claim

14 also would have been obvious to a POSA. (See EX1002 ¶¶ 99-101.)

Independent claim 20 is also substantively the same as independent claim 1

except that claim 20 requires a method of reducing thrombotic cardiovascular

events in humans in need of reduction of thrombogenesis or reduction of platelet

aggregation. (EX1001, cl. 20.) WO ’500 specifically teaches that the claimed

combinations may be used for “treating diseases involved with platelet

aggregation, thrombus formation and ischemic events, in that the combination may

provide additional antiplatelet aggregation, antiischemic and anti-thrombus

effects.” (EX1003 at 4:8-12; 10:20-27.) WO ʼ500 further teaches such therapeutic

use specifically with respect to “humans.” (Id. at 3:22-28; 9:7.) WO ʼ500 also

discloses that the ADP-receptor blocking antiplatelet drugs of the invention “may

be employed in secondary prevention of ischemic events such as myocardial

infarction unstable or stable angina, acute reocclusion after percutaneous

transluminal coronary angioplasty (PTCA), restenosis after PTCA, thrombotic

stroke, transient ischemic attack, reversible ischemic neurological deficit, and

intermittent claudication.” (Id. at 2:8-15.) And WO ʼ500 specifically claims

methods “for preventing or inhibiting or treating a cerebral infarction,” including

“wherein the cerebral infarction” is either “a primary or secondary ischemic

event.” (Id. at 16:31-17:3.) Thus, for the same reasons seen above with respect to


25

claim 1, claim 20 also would have been obvious to a POSA. (EX1002 ¶¶ 99-101.)

Independent claim 24 is also substantively the same as independent claim 1

except that claim 24 requires a method of preventing a disease caused by thrombus

or embolus in humans in need of reduction of thrombogenesis or reduction of

platelet aggregation. (EX1001, cl. 24.) The disclosures of WO ’500 discussed

above all teach or disclose preventing a disease caused by thrombus or embolus in

humans in need of reduction of thrombogenesis or reduction of platelet aggregation

by administering an ADP-inhibitor blocking antiplatelet drug and optionally

aspirin. (Supra at 18-19, 21-22; EX1002, Hirsh Decl. ¶ 81.) Thus, for the same

reasons seen above with respect to claim 1, claim 24 also would have been obvious

to a POSA. (See EX1002 ¶¶ 99-101.)

2. Dependent challenged claims

The additional limitations of the dependent challenged claims are all

expressly disclosed by WO ’500, and thus would have been obvious.

a) Dependent claims 8, 12, 18, and 22

Claims 8, 12, 18, and 22 depend from claims 7, 1, 14, and 20, respectively,

and further require administration of pharmacologically effective amounts of

prasugrel and aspirin individually. (EX1001, cls. 8, 18, 22.) WO ’500 teaches

adjusting drug dosages according to various conditions of the patient, and teaches

administration of ADP-receptor blocking antiplatelet drugs from about 10 to about


26

1000 mg. (EX1003 at 9:15-27.) WO ’500 further teaches that aspirin can be

employed in daily dosages of from about 1 mg to about 500 mg, and in a weight

ratio to the ADP receptor blocking antiplatelet drug within the range from about

0.02:1 to about 1000:1. (Id. at 10:20-27.) In addition, WO ’500 specifically

teaches that “the active substances may be administered separately in individual

dosage units at the same time or carefully coordinated times.” (Id. at 11:17-22.)

As Dr. Hirsh confirms, these disclosures in WO ’500 disclose pharmacologically

effective amounts of the ADP-receptor blocking antiplatelet agents and aspirin

individually. (EX1002 ¶ 107.) Thus, claims 8, 18, and 22 would have been

obvious.

b) Dependent claims 2, 4, 9, 15, 21, and 25

Claims 2, 4, 9, 15, 21, and 25 depend from claims 1, 3, 7, 14, 20, and 25,

respectively, and further require that the pharmaceutically acceptable salt is a

hydrochloride salt. (EX1001, cls. 9, 15, 21, 25.) WO ʼ500 states that “[r]eferences

to the base substances are therefore intended to include those common salts known

to be substantially equivalent to the parent compound.” (EX1003 at 12:16-21.)

Further, WO ʼ500 specifically discloses “the hydrochloride salt” as a

“pharmaceutically acceptable salt.” (Id. at 4:34-35.) Thus, claims 2, 4, 9, 15, 21,

and 25 would also have been obvious. (EX1002 ¶ 107.)


27

c) Dependent claim 5

Claim 5 depends from claims 3 or 4 and further requires that the warm-

blooded animal is a human. (EX1001, cl. 5.) As discussed above, WO ’500

teaches that the disclosed cardiovascular treatments can be provided to humans.

(Id. at 3:22-28.) Thus, claim 5 would also have been obvious. (EX1002 ¶ 107.)

d) Dependent claim 6

Claim 6 depends form claim 1, and further requires that the disease caused

by thrombus or embolus is selected from the group consisting of stable angina

pectoris, unstable angina pectoris, thromboembolism, cerebral ischemic insult,

restenosis, and embolism. (EX1001, cl. 6.) As discussed above, WO ’500

discloses treating “diseases involved with platelet aggregation, thrombus formation

and ischemic events, in that the combination may provide additional antiplatelet

aggregation, anti-ischemic and anti-thrombus effects over that which may be

obtained using each of the components of the combination alone.” (EX1003 at

4:4-13.) Thus, as confirmed by Dr. Hirsh, claim 6 would have been obvious.

(EX1002 ¶ 107.)

e) Dependent claims 10, 17, and 27

Claims 10, 17, and 27 depend directly or indirectly from claim 7, 14, and 24,

respectively, and further require that the human patient is undergoing or has

received angioplasty, endarterectomy, or stent therapy. (EX1001, cls. 7, 14, 24.)

Angioplasty, endarterectomy, and stent therapy are all procedures to prevent


28

ischemic events by widening arteries that are narrowed or obstructed. (EX1002,

Hirsh Decl. ¶¶ 49, 107.) WO ʼ500 discloses that the ADP-receptor blocking

antiplatelet drugs of the invention “may be employed in secondary prevention of

ischemic events,” including for example “after percutaneous transluminal coronary

angioplasty.” (EX1003 at 2:9-15.) Thus, claims 10, 17, and 27 would have been

obvious as well. (EX1002, Hirsh Decl. ¶ 107.)

f) Dependent claims 11, 13, and 19

Claims 11, 13, and 19 depend from claims 7, 1, and 14 respectively and

require that prasugrel and aspirin are administered. As seen above, WO ’500

discloses administering aspirin in combination with an ADP-receptor blocking

antiplatelet drug to treat cardiovascular diseases, and that a POSA would

understand that prasugrel is included in the teachings of WO ’500 as an example of

the ADP-receptor blocking antiplatelet drug. (EX1002 ¶ 100.) Thus, claims 11,

13, and 19 would have been obvious.

g) Dependent claims 16 and 26

Claims 16 and 26 depend from claims 14 and 24, respectively, and further

require that the human has a cardiovascular disorder. (EX1001, cls. 16, 26.) WO

’500 discloses that combinations of ADP-receptor inhibitors and aspirin “can be

used in the treatment of various cardiovascular complaints, especially

hypertension.” (EX1003 at 2:24-25.) As discussed above, WO ʼ500 also discloses


29

that the ADP-receptor blocking antiplatelet drugs of the invention may be

employed in treating a variety of cardiovascular and thrombotic events. (Id. at 4:4-

13.) Moreover, WO ʼ500 specifically claims methods “for preventing or inhibiting

or treating a cerebral infarction,” including “wherein the cerebral infarction” is

either “a primary or secondary ischemic event.” (Id. at 16:31-17:3.) Thus, claims

16 and 26 would have been obvious. (EX1002 ¶ 107.)

B. The challenged claims would have been obvious over any of the combinations of (i) Bernat in view of Asai, (ii) Bernat in view of Koike, and (iii) WO ’500 in view of Bernat, Asai, and Koike.

Even assuming that any challenged claim is not obvious over the disclosures

of WO ʼ500 alone, all of the claims would have been obvious to a POSA over (i)

the combined teachings of Bernat (EX1006) in view of Asai (EX1010); (ii) the

combined teachings of Bernat (EX1006) in view of Koike (EX1012); and (iii) the

combined teachings of WO ʼ500 (EX1003) in view of Bernat (EX1006), Asai

(EX1010), and Koike (EX1012).

WO ’500 was published on December 23, 1999 (EX1003); Bernat issued

November 23, 1999 (EX1006); Asai has on its face a date of September 29, 1999

(EX1010); and Koike (EX1012) issued on February 22, 1994. Thus, these

references are all prior art to the ʼ703 patent under 35 U.S.C. § 102(b).

1. Independent claims 1, 3, 7, 14, 20, and 24

As discussed above, each limitation of the independent claims of the ʼ703


30

patent are expressly disclosed or obvious over the disclosures of WO ʼ500. Supra

at 18-25. Additional prior art further confirms that a POSA would have been

motivated, with a reasonable expectation of success, to use the combination

therapy of prasugrel and aspirin as a method of treatment as specifically claimed in

the ʼ703 patent. Indeed, the benefits of combining thienopyridine derivatives and

aspirin were well known in the prior art. Supra at 15-17;(EX1002 Hirsh Decl. ¶¶

64-66, 71-82). Bernat teaches that combining clopidogrel—a thienopyridine

derivative—with aspirin improves the inhibition of thrombogenesis and platelet

aggregation that can be obtained from using either ingredient in monotherapy.

(EX1006, Bernat at 5:18-20, 2:48-54, 5:32-60, 5:57-6:15, Tbl. 1, Tbl. 2.) A POSA

would have known from Bernat and Asai that thienopyridine derivatives, including

prasugrel, are effective in inhibiting thrombosis, platelet aggregation, and

thromboembolism. (EX1006 at 1:35- 2:65, cls. 9-12, cls. 23-25; EX1010 at 10-22;

see also EX1011, Sugidachi at 1444-45.).

Moreover, a POSA would have been motivated to select prasugrel as the

known thienopyridine derivative that should be combined with aspirin to treat

cardiovascular disorders. Indeed, both Asai and Koike, among other prior art,

teach that prasugrel is superior to the structurally similar ticlopidine and

clopidogrel in preventing or inhibiting thrombus and platelet aggregation.

(EX1002, Hirsh Decl. ¶ 87, 92; EX1010 at 10-22; EX1012 at 21:52-55, 39:40-


31

40:60; see also EX1011, Sugidachi at 1444-45.) Among the benefits of prasugrel

over the other thienopyridine derivatives is significantly more potency, faster

onset, and longer duration. (EX1002, Hirsh Decl. ¶ 87; EX1010 at 10-22; EX1012

at 21:52-55, 39:40-40:60; see also EX1011, Sugidachi at 1444-45.)

Thus, a POSA would have been motivated to combine the teachings of the

prior art regarding combinations of thienopyridine derivatives with aspirin (e.g.,

EX1003, WO ʼ500 at 4:4-13, 9:1-2, 10:20-22, 14:9-11; EX1006, Bernat at 1:45-59,

2:48-65, 4:35-5:62) with the teachings of the prior art regarding the development

of prasugrel as a newer, better thienopyridine derivative (e.g., EX1010, Asai at 3-4;

EX1012, Koike at 1:34-44, 21:52-55, 39:40-40:60). In view of these teachings, a

POSA would have been motivated to substitute prasugrel for other known

thienopyridine derivatives in combination with aspirin to treat diseases caused by

thrombus or embolus, and would have reasonably expected that the combination

would successfully treat cardiovascular diseases caused by thrombus or embolus.

(See EX1002, Hirsh Decl. ¶¶ 103-106.)

For similar reasons, even assuming that the combination therapy of prasugrel

and aspirin would not have been obvious over WO ʼ500 alone, it would have been

obvious over WO ʼ500 in view of Bernat, Asai, and Koike. Asai and Koike taught

that prasugrel is a potent thienopyridine derivative (EX1010 at 3-4; EX1012 at

1:34-44), which a POSA would have known was an “ADP-receptor blocking


32

antiplatelet drug” such as “clopidogrel, ticlopidine and the like,” as taught in WO

ʼ500 (EX1003 at 4:4-13, 3:33-35). And while WO ʼ500 disclosed the addition of

an antihypertensive drug to the combination of an ADP-receptor blocking drug and

aspirin, Bernat taught that these two drugs could successfully be combined to treat

or prevent diseases caused by thrombus or embolus independently of an

antihypertensive agent. (EX1006, Bernat at abst., 1:5-9, 3:29-31.)

Further, both WO ’500 and Bernat teach thienopyridine compositions using

pharmaceutically acceptable excipients. (EX1003 at 11:28-12:15; EX1006 at 3:34-

4:13.) Koike also teaches combining prasugrel with conventional excipients.

(EX1012 at 39:40-45, 40:8-12, 40:62-65.) In addition, while determining

pharmacologically effective amounts of prasugrel and aspirin would require no

more than routine experimentation, at least WO ’500, Bernat, Asai, and Koike

teach dosage ranges of thienopyridine derivatives (including prasugrel) and aspirin

that are pharmacologically effective. (EX1003 at 9:15-27, 10:9-32; EX1006 at

4:18-34, 6:26-31; EX1010 at 4:10-14; EX1012 at 41:3-13.)

Thus, for the above reasons, the independent challenged claims would have

been obvious over at least the cited combinations of prior art references. (EX1002,

Hirsh Decl. ¶¶ 93-106.)

2. Dependent claims 8, 12, 18, and 22

Claims 8, 12, 18, and 22 depend from claims 7, 1, 14, and 20, respectively,


33

and further require administration of pharmacologically effective amounts of

prasugrel and aspirin individually. (EX1001 cls. 8, 12, 18, 22.) As discussed

above, WO ʼ500, Bernat, Asai, and Koike all teach pharmaceutically effective

amounts of prasugrel and/or aspirin, showing that the combination of

thienopyridine derivatives and aspirin were individually effective but demonstrated

a greater effectiveness when combined. (EX1003 at 9:151-27, 10:9-32; EX1006 at

4:18-34, 6:26-31; EX1010 at 4:10-14; EX1012 at 41:3-13.) Thus, based on these

teachings a POSA would have been motivated, with a reasonable expectation of

success, to administer pharmacologically effective amounts of prasugrel and

aspirin. Accordingly, claims 8, 12, 18, and 22 would have been obvious over the

cited combinations of prior art references. (See EX1002 ¶ 107.)

3. Dependent claims 2, 4, 9, 15, 21, and 25

Claims 2, 4, 9, 15, 21, and 25 depend from claims 1, 3, 7, 14, 20, and 24,

respectively, and further require that the pharmaceutically acceptable salt is a

hydrochloride salt. (EX1001 cls. 2, 4, 9, 15, 21, 25.) Koike discloses the

hydrochloride salt of prasugrel for use in anti-aggregation therapy. (EX1012 at

13:43-63, 21:52-55, 28:14-21.) Further, several other references disclosed salt

forms of thienopyridine derivatives, including the hydrochloride salt, which was

known as among the most common, if not the most common pharmaceutically

acceptable acid addition salt. (E.g., EX1003, WO ʼ500 at 12:16-21; id. at 4:34-35.)


34

Thus, claims 2, 4, 9, 15, 21, and 25 would have been obvious over the cited

combinations of prior art references. (See EX1002, Hirsh Decl. ¶ 107.)

4. Dependent claim 5

Claim 5 depends from claims 3 or 4 and further requires that the warm-

blooded animal is a human. As discussed above, WO ’500 discloses treating

humans. (EX1003 at 3:22-28.). In addition, Bernat teaches the use of combination

therapy of thienopyridine derivatives with aspirin in humans (EX1006 at 2:48-3:2,

3:21-24, 3:34-39, cl. 6; see also EX1007 at 1643), and Koike and Asai teach the

use of prasugrel specifically for treating cardiovascular diseases of humans

(EX1010 at 3-4, 22, 35-42; EX1012 at 3:62-65; see also EX1011 at 1445). Thus,

for the above reasons, claim 5 would have been obvious over the cited

combinations of prior art references. (See EX1002, Hirsh Decl. ¶ 107.)

5. Dependent claim 6

Claim 6 depends from claim 1, and further requires that the disease caused

by thrombus or embolus is selected from the group consisting of stable angina

pectoris, unstable angina pectoris, thromboembolism, cerebral ischemic insult,

restenosis, and embolism. (EX1001, cl. 6.) As discussed above, WO ’500

discloses treating “diseases involved with platelet aggregation, thrombus formation

and ischemic events, in that the combination may provide additional antiplatelet

aggregation, anti-ischemic and anti-thrombus effects over that which may be


35

obtained using each of the components of the combination alone.” (EX1003 at

4:4-13.) A POSA also would have known from Asai and Koike that

thienopyridine derivatives, including prasugrel, are effective in inhibiting

thrombosis, platelet aggregation, and thromboembolism. (EX1010 at 10-22;

EX1012 at 3:55-61; see also EX1011 at 1444-45; EX1007 at 1645-46.) And a

POSA would have known from Bernat that combining a thienopyridine derivative

with aspirin is even more effective than using a thienopyridine alone. (EX1006 at

1:35- 2:65, cls. 9-12, cls. 23-25.) Thus, claim 6 would have been obvious over the

cited combinations of prior art references. (See EX1002, Hirsh Decl. ¶ 107.)

6. Dependent claims 10, 17, and 27

Claims 10, 17, and 27 depend from claims 7, 14, and 24, respectively and

further require that the human patient is undergoing angioplasty, endarterectomy,

or stent therapy. (EX1001 cls. 10, 17, 27.) Bernat teaches that thienopyridine

derivatives, combined with aspirin, can be beneficial in relation to pathological

states associated with “restenosis following angioplasty” and “fitting of metallic

endovascular prostheses.” (EX1006 at 2:22-33; 1:52-9.)2 Because a POSA would

2 Similarly, references such as Mishkel, Müller, Moussa, Harker, and

Bertrand all discuss the clinical use of thienopyridine derivatives in combination

with aspirin in conjunction with or following stent therapy. (EX1016 at 1884,


36

have been motivated to substitute prasugrel for the thienopyridine derivatives

combined with aspirin as disclosed in Bernat, claims 10, 17, and 27 would have

been obvious over the cited combinations of prior art references. (See EX1002,

Hirsh Decl. ¶ 107.)

7. Dependent claims 11, 13, and 19

Claims 11, 13, and 19 depend from claims 7, 1, and 14, respectively, and

require that prasugrel and aspirin are administered. As seen above, WO ’500

discloses administering aspirin in combination with an ADP-receptor blocking

antiplatelet drug to treat cardiovascular diseases, and a POSA would understand

that prasugrel is included in the teachings of WO ’500 as an example of the ADP-

receptor blocking antiplatelet drug. (EX1003 at 4:4-13, 9:1-2; EX1002, Hirsh

Decl. ¶ 100.) In addition, a POSA would have understood from Bernat, Asai, and

Koike that thienopyridine derivatives, including prasugrel, in combination with

aspirin are effective in inhibiting thrombosis, platelet aggregation, and

thromboembolism. (EX1002, Hirsh Decl. ¶¶ 71-92; EX1006 at 1:35- 2:65, cls. 9-

12, cls. 23-25; EX1010 at 10-22; EX1012 at 21:52-55, 39:40-40:60.) Thus, claims

11, 13, and 19 would have been obvious over the cited combinations of prior art

1890; EX1017 at 590, 592-93; EX1018 at 2364-66; EX1019 at 2461, 2467-68;

EX1020 at 624, 628.)


37

references.

8. Dependent claims 16 and 26

Claims 16 and 26 depend from claims 14 and 24, respectively, and further

require that the human has a cardiovascular disorder. (EX1001 cls. 16, 26.) As

discussed above, both Bernat and WO ’500 are directed to the use of combinations

of thienopyridine derivatives and aspirin for treating humans with cardiovascular

disorders. (EX1003 at ; EX1006 at 1:5-59, 2:48-3:2.) EX1010 at 10-22; EX1011

at 1444-45.) Further, Asai and Koike specifically teach the use of prasugrel for use

in treating cardiovascular diseases. (EX1010 at 3-4, 22, 35-42; EX1012 at 3:55-

68, 21:52-55.) Thus, it would have been obvious to substitute prasugrel for

clopidogrel in the combination therapy disclosed in Bernat or WO ’500 for treating

cardiovascular disorders in humans. Accordingly, claims 16 and 26 would have

been obvious over the cited combinations of prior art references. (EX1002 ¶ 107.)

C. Objective indicia of obviousness and nonobviousness

Although objective indicia of obviousness and nonobviousness must be

taken into account, they do not necessarily control the obviousness conclusion.

Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988). In fact,

a strong case of obviousness, like Petitioners have made here, cannot be overcome

by objective evidence of non-obviousness. See Pfizer, Inc. v. Apotex, Inc., 480

F.3d 1348, 1372 (Fed. Cir. 2008); Hoffmann-La Roche Inc. v. Apotex Inc., 748


38

F.3d 1326, 1334 (Fed. Cir. 2014). Especially “[w]here a claimed invention

represents no more than the predictable use of prior art elements according to

established functions, as here, evidence of secondary indicia are frequently deemed

inadequate to establish non-obviousness.” Ohio Willow Wood Co. v. Alps South,

LLC, 735 F.3d 1333, 1344 (Fed. Cir. 2013).

Nevertheless, Petitioners preliminarily address below both the objective

evidence of obviousness as well as potential objective indicia arguments for non-

obviousness that Daiichi may raise. However, to the extent Daiichi does in fact

assert any objective indicia in this proceeding, detailed consideration of Daiichi’s

evidence should not be undertaken until Petitioners have had an opportunity to

respond to it. Amneal Pharmaceuticals, LLC v. Supernus Pharmaceuticals, Inc.,

No. IPR2013-00368, Paper 8 at 12-13 (P.T.A.B. Dec. 17, 2013).

1. Near-simultaneous invention by different inventors confirms the obviousness of the claimed subject matter.

Fully independent of the applicants for the ʼ703 patent, a different entity also

disclosed the obvious combination of prasugrel and aspirin to treat cardiovascular

diseases, specifically for inhibiting platelet aggregation and thrombus formation,

and filed a patent application just a few months before Daiichi filed its Japanese

application, the earliest application to which the ʼ703 patent claims priority.

(EX1004, Ogletree; EX1001.) This evidence of near-simultaneous invention

corroborates Petitioners’ prima facie obviousness arguments and undermines any


39

evidence of non-obviousness that the Patent Owner may put forth. Ecolochem,

Inc. v. S. Cal. Edison Co., 227 F.3d 1361, 1367 (Fed. Cir. 2000). Indeed, if a

separate party independently and simultaneously arrives at the same purported

invention “within a comparatively short period of time,” that is persuasive

evidence that the claims were the product of ordinary skill. Geo. M. Martin Co. v.

Alliance Mach. Sys. Int’l LLC, 618 F.3d 1294, 1306 (Fed. Cir. 2010).

Here, Ogletree discloses a method wherein a combination of an ADP-

receptor blocking antiplatelet drug and a thromboxane A2 receptor antagonist, and

optionally aspirin, is employed to prevent or inhibit platelet aggregation and

thrombus formation and to prevent or inhibit any of the disease states disclosed

therein, including thrombotic stroke. (EX1004 at 4:18-24.) Ogletree further

discloses that “[t]he ADP-receptor blocking antiplatelet drug suitable for use

herein includes antiplatelet drugs which inhibit ADP-induced platelet aggregation

and include clopidogrel and/or ticlopidine and/or [prasugrel].” (Id. at 4:25-30.)

Ogletree demonstrates that scientists at another drug company, Bristol-

Myers Squibb (id. at cover), also recognized that the combination of prasugrel and

aspirin could be useful for inhibiting thrombogenesis and platelet aggregation.

That recognition was made within a short period of time from when the named

inventors of the ʼ703 patent arrived at their claimed methods. Indeed, during

prosecution of the application that led to the ʼ703 patent, Daiichi filed an inventor


40

declaration to antedate Ogletree in order to avoid an anticipation finding. (EX1023

(May 26, 2011 Office Action, Non-Final Rejection; EX1024 (Declaration Under

37 C.F.R. § 1.131).) Thus, this evidence of near-simultaneous invention is an

objective indication of obviousness and undermines any evidence Daiichi may

bring forward with respect to secondary considerations of non-obviousness.

2. The bases cited by the examiner for allowing the claims do not support a finding that the ʼ703 patent’s claims are valid.

As seen above, it would have been at least prima facie obvious to substitute

prasugrel for ticlopidine or clopidogrel in combination therapy with aspirin to

inhibit, reduce, or prevent the disease states of the challenged claims. A POSA

would have expected that combination therapy using prasugrel and aspirin is more

effective than using either ingredient in monotherapy. Supra at 30-32. Indeed,

during prosecution of the ʼ703 patent, the Patent Office repeatedly found that the

claimed combination therapy of prasugrel and aspirin was prima facie obvious—a

finding that was never retracted. (See EX1022, EX1023.)

Daiichi, however, argued that the claimed invention is not obvious over the

combination of cited prior art references because the claimed methods allegedly

produce unexpected results. (E.g., EX1025, Gurbel Decl.) As the examiner’s

stated reasons for allowing the claims, she accepted Daiichi’s argument with

respect to two alleged unexpected results: (a) an unexpectedly lower bleeding risk

for combination therapy with prasugrel and aspirin than for combination therapy


41

with clopidogrel and aspirin; and (b) an unexpectedly lower number of non-

responders for combination therapy with prasugrel and aspirin than for

combination therapy with clopidogrel and aspirin. (EX1026 at 2.) As shown

below, however, neither of these purportedly unexpected results can overcome the

evidence that the methods claimed in the ʼ703 patent would have been obvious.

a) There is no evidence of an unexpectedly lower bleeding risk for combination therapy with prasugrel and aspirin.

The examiner allowed the claims of the ʼ703 patent on the basis that the

claimed combination therapy of prasugrel and aspirin produces an “unexpectedly

lower bleeding risk” compared to combination therapy with clopidogrel and

aspirin. (EX1026 at 2.) The examiner was apparently led to believe that this result

was “demonstrated by the TRITON-TIMI 38 trial.” (Id.)3 Yet the TRITON trial,

which was reported in Wiviott I (EX1027), does not show a lower bleeding risk for

combination therapy with prasugrel and aspirin.

On the contrary, the TRITON trial shows that the bleeding risk for

combination therapy with prasugrel and aspirin is higher—not lower—than

3 The full name of the TRITON trial is the “Trial to Assess Improvement in

Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-

Thrombolysis In Myocardial Infarction 38” (EX1027).


42

combination therapy with clopidogrel and aspirin. (EX1002 ¶ 115.) Indeed,

Wiviott I reports that the combination of prasugrel and aspirin “was associated …

with an increased risk of major bleeding, including fatal bleeding.” (EX2007 at

2001 (emphasis added).) Moreover, the authors acknowledged that they expected

this increase in bleeding, just as they expected an increase in efficacy: “The

reduction in ischemic events we observed with prasugrel as compared with

standard-dose clopidogrel was, as expected, associated with a significant increase

in the rate of bleeding.” (Id. at 2008 (emphasis added).)

Other evidence further confirms this increased bleeding risk. For instance,

FDA’s Office of Surveillance Epidemiology (“OSE”) determined that “[a]lthough

prasugrel has been shown to be more efficacious than [clopidogrel], it is also

associated with a significant increased risk of bleeding, including fatal bleeding.”

(EX1045 at 2.) Further, OSE “determined that a REMS [i.e., risk evaluation and

mitigation strategy] would be necessary to ensure that the benefits of the drug

outweigh the risks” given “the four-fold increased risk of fatal bleeding events

with prasugrel compared with clopidogrel.” (Id.) In addition, the FDA-approved

labeling for prasugrel expressly warns that “overall rates” of most “bleeding

adverse reactions … were significantly higher on [prasugrel] than on clopidogrel,”

and includes a black-box warning for bleeding risks that does not appear in the

approved labeling for clopidogrel. (EX1046 at 1, 5; EX1047.)


43

Thus, contrary to the examiner’s finding, there is no “unexpectedly lower

bleeding risk” for the claimed combination of prasugrel and aspirin that could

rebut the evidence of prima facie obviousness above. To do so, moreover, the

alleged result would need to be both “unexpected” and “superior” to the closest

prior art. In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). Yet as Wiviott I and Dr.

Hirsh confirm, the bleeding risk for combination therapy with prasugrel and aspirin

is neither unexpected nor superior to combination therapy with clopidogrel and

aspirin. Thus, contrary to what the examiner was led to believe during prosecution

of the ’703 patent, there is no unexpected lower bleeding risk.

b) The fewer number of nonresponders for combination therapy with prasugrel and aspirin would have been expected, and lacks any nexus to the claimed invention.

The examiner also relied on Daiichi’s argument that the combination of

prasugrel and aspirin surprisingly and unexpectedly addresses interpatient

variability by reducing the number of non-responders to therapy with clopidogrel

and aspirin. (EX1026 at 2.) As explained by Dr. Hirsh, however, a POSA would

have expected that combination therapy with prasugrel and aspirin would have

fewer nonresponders, because prasugrel was expected to have fewer nonresponders

than clopidogrel in monotherapy, and there was no reason to believe that adding

aspirin would affect this difference between the two drugs. (EX1002 ¶ 128.) For

that same reason, there is no nexus between the claimed invention and this


44

allegedly unexpected result, which is therefore irrelevant.

As Dr. Hirsh explains, the lower number of non-responders for the

combination therapy of prasugrel and aspirin as compared to the combination

therapy of clopidogrel and aspirin results from differences between the two drugs

with respect to (1) their relative potencies and (2) the way they are metabolized.

(Id.) There is no evidence, however, that either of these differences is affected by

co-administration of the drugs with aspirin, particularly since the two classes of

drugs have separate and independent mechanisms of action. (Id.) A POSA thus

would have expected the same improvement in interpatient variability for prasugrel

in combination therapy as would be expected for monotherapy. (Id.)

As explained above, prasugrel’s anti-aggregation efficacy was known to be

approximately 10 times greater than that of clopidogrel. (See EX1011, Sugidachi

at 1439, 1444-45; EX1010, Asai at 10-22.) A POSA would have fully expected, as

Dr. Hirsh shows, that this difference in potency would reduce the number of non-

responders as compared to clopidogrel. (EX1002 ¶¶ 128, 130.)

Differences in the metabolism of clopidogrel and prasugrel were also

known, and likewise would have led a POSA to expect a reduction in non-

responders. (Id.) A POSA would have understood from Asai that clopidogrel is

converted to its active metabolite via a two-step oxidation process involving the

CYP450 enzymes. (EX1010 at 27; EX1002, Hirsh Decl. ¶ 61.) Patients having a


45

high amount of the CYP enzymes exhibit higher antiplatelet activity—increasing

the chances of bleeding—whereas patients with lower amounts of CYP enzymes

exhibit lower antiplatelet activity, thus subjecting the patient to a greater risk of

thrombosis. (See EX1002, Hirsh Decl. ¶¶ 61, 131-32.)

On the other hand, prasugrel was known to convert to its active metabolite

via a one-step oxidation process involving CYP450, and thus would be expected to

exhibit lower inter-patient variation as compared to the two-step metabolic

pathway of clopidogrel. (EX1002 ¶¶ 61, 127-32; EX1010, Asai at 27.) A POSA

would have understood that clopidogrel’s metabolic pathway could result in inter-

patient variability due to differences in levels of CYP450 enzymes related to

genetic polymorphism—a factor that is not be implicated by prasugrel’s one-step

metabolic pathway. (See EX1002 ¶¶ 61, 127-32.)

Just as importantly, these differences between prasugrel and clopidogrel

confirm that the reduction in non-responders has no nexus to the invention claimed

by the ʼ703 patent, which concerns the combination of prasugrel and aspirin. As

discussed, there is no evidence that the metabolic differences between prasugrel

and clopidogrel that account for the reduction in non-responders are in any way

affected by the co-administration with aspirin. (EX1002 ¶¶ 128, 130, 132, 139.)

Thus, there is no “nexus between” the “merits of the claimed invention” and the

observed reduction in non-responders, which “actually results from” the


46

advantages of prasugrel over clopidogrel—i.e., “something other than what is both

claimed and novel in the claim[s]” of the ʼ703 patent. In re Kao, 639 F.3d 1057,

1068 (Fed. Cir. 2011). For this additional reason, the difference in inter-patient

variability that the examiner relied upon in allowing the claims is irrelevant.

3. The other “unexpected results” asserted by Daiichi also fail to rebut the strong showing that the claimed combination therapy is obvious.

As additional unexpected results, which the examiner did not rely on,

Daiichi also asserted that the claimed combination therapy of prasugrel and aspirin

unexpectedly (a) produces a synergistic effect against thrombosis in vivo; (b)

provides a superior net clinical benefit over combination therapy with clopidogrel

and aspirin; and (c) provides an unexpectedly enhanced benefit to diabetes mellitus

patients. (See EX1025, Gurbel Decl. ¶ 9.) These assertions of unexpected results

likewise fail to rebut the obviousness of the ʼ703 patent’s claims.

a) Any synergistic effects exhibited by the claimed methods are neither unexpected nor surprising.

Dr. Gurbel asserted that combination therapy with prasugrel and aspirin has

“a clear synergistic effect,” based on the results of an experimental thrombosis

model described in the ʼ703 patent’s specification. (EX1025 ¶ 60; EX1001 at

5:57-6:15, Tbl. 1.) According to Dr. Gurbel, these results demonstrate “synergy,”

because they show that the combined administration of prasugrel and aspirin

produced an inhibition rate “which is greater than the sum of the rates of inhibition


47

for each of the components.” (EX1025 ¶ 60.)

Even if that were true, however, any alleged synergistic effect exhibited by

the combination of prasugrel and aspirin would have been expected, because

Bernat discloses that clopidogrel—a thienopyridine ADP-receptor inhibitor like

prasugrel—exhibits a greater-than-additive effect in combination with aspirin. As

Dr. Hirsh explains, Tables 1 and 2 of Bernat show that a greater-than-additive

effect was achieved in a thrombosis model by the combination of clopidogrel and

aspirin. (EX1006, Bernat at 5:32-60, Tbls. 1, 2; EX1002, Hirsh Decl. ¶¶ 141-46.)

In particular, in Table 2, Bernat shows that the effect achieved by administration of

clopidogrel and aspirin together is greater than the sum of effects achieved by

administration of clopidogrel and aspirin alone. (Id.) Bernat further describes a

greater-than-additive effect in a collagen aggregation model, and specifically calls

these results “synergistic.” (EX1006 at 5:18-32.)

In addition, other prior art references teach potentiation of antiaggregation

and antithrombotic activities of clopidogrel by aspirin. (See EX1008, Herbert at

512, 514-517; EX1009, Moshfegh at 699, 701-05 (“Clopidogrel in combination

with aspirin showed synergistic inhibitory effects after stimulation with collagen

and thrombin compared with monotherapies.”).) This was a known improvement

over the combination of the prior-generation thienopyridine, ticlopidine, which

showed additive benefits when combined with aspirin. (See, e.g., EX1007,


48

Uchiyama at 1643-45; EX1008, Herbert at 512.)

With respect to prasugrel, the prior art teaches that prasugrel, the next-

generation thienopyridine after clopidogrel, has the same mechanism of action as

clopidogrel but has greater potency, a faster onset of action, and a longer duration

of action. (E.g., EX1010, Asai at 3). Thus, a POSA would have expected that the

combination of prasugrel and aspirin would produce the same greater-than-additive

effect described in Bernat for the combination of clopidogrel and aspirin. (EX1002

¶¶ 143, 145.) In other words, having found that “earlier … combinations” of

clopidogrel with aspirin “were generally understood to yield synergy,” a POSA in

2000 “would have expected [prasugrel] to be likewise synergistic when combined

with [aspirin].” Caraco, 719 F.3d at 1354-55; (EX1002, Hirsh Decl. ¶ 145).

Moreover, as noted, results cannot show that an invention is not obvious

unless they are both “unexpected” and “superior” to the closest prior art. In re

Soni, 54 F.3d at 750. Here, however, the greater-than-additive effect of

combination therapy with prasugrel and aspirin is not superior to combination

therapy with clopidogrel and aspirin. Rather, as Dr. Hirsh explains, the magnitude

of the greater-than-additive effect obtained from combining prasugrel and aspirin

(as reported in the ʼ703 patent’s specification) is no greater than the magnitude of

the greater-than-additive effect obtained from combining clopidogrel and aspirin

(as reported in Bernat). (EX1002 ¶ 146.) Thus, the observed result with the


49

claimed combination of prasugrel and aspirin is not only expected, but also not

superior to the closest prior art. In any event, even assuming there is other

evidence of superiority for the combination therapy of prasugrel and aspirin, that

superiority would not have been unexpected, given prasugrel’s known superior

efficacy over clopidogrel. (Id.; EX1010, Asai at 11; EX1011, Sugidachi at 1445.)

b) Combination therapy with prasugrel and aspirin does not provide an unexpectedly superior net clinical benefit over combination therapy with clopidogrel and aspirin.

During prosecution of the patents-in-suit, Daiichi’s declarant, Dr. Gurbel,

asserted that the combination of prasugrel and aspirin exhibited an unexpectedly

superior net clinical benefit over the combination of clopidogrel and aspirin.

(EX1025 ¶¶ 9(E), 61-70.) For that assertion, Dr. Gurbel relied on the results of the

TRITON trial reported by Wiviott I, which found “a significant net clinical benefit

with the prasugrel [and aspirin] regimen studied, as compared with the clopidogrel

[and aspirin] regimen.” (EX1027 at 2011.) Dr. Gurbel argued that this result was

“surprising[].” (EX1025 ¶ 68.) Yet for four reasons, that assertion is incorrect and

fails to overcome the evidence of obviousness discussed above.

First, as Dr. Hirsh explains, a POSA would have expected the results of the

TRITON trial, which reported that combination therapy with prasugrel and aspirin

(1) had superior efficacy and (2) caused more bleeding than combination therapy

with clopidogrel and aspirin. (EX1027 at 2008, Tbl. 2, Tbl. 3.) Given prasugrel’s


50

known superior potency and faster onset of action over clopidogrel, both of these

results would have been expected. (EX1002, Hirsh Decl. ¶ 148.) Indeed, the

authors of Wiviott I concluded that “[t]he reduction in ischemic events … observed

with prasugrel as compared with standard-dose clopidogrel was, as expected,

associated with a significant increase in the rate of bleeding.” (EX1027 at 2008

(emphasis added); see supra at 41-43.)

Second, the authors’ “net clinical benefit” calculation was also expected.

Wiviott I reported three efficacy end points—myocardial infarction (“MI”), stroke,

and cardiovascular death—and only one safety end point—major bleeding.

(EX1027 at 2005.) The authors then calculated a composite “net clinical benefit”

by simply combining all four end points, weighting each end point equally and

without attempting to account for any end point’s relative clinical significance to

any other. (Id.) As Dr. Hirsh explains, the decision to use an equal weight for

each end point was purely subjective. (EX1002 ¶ 150.) And taking into account

the authors’ subjective definition, the “net clinical benefit” results reported in

Wiviott I—much like the underlying end points that were used to calculate them—

would have been entirely expected. (Id.)

Indeed, changing the weights of the individual end points according to their

clinical significance alters the net clinical benefit results. (Id. ¶ 151.) For

example, as reported in the Journal of the American College of Cardiology, Drs.


51

Sanjay Kālu and George A. Diamond recalculated the TRITON data by placing the

most weight on cardiovascular death (1.0), an intermediate weight for stroke (0.5),

and the least weight on MI (0.06). (EX1028 at 421.) Under this weighting, which

they justified based on the respective clinical importance of each end point, “[t]he

data show no statistically significant difference between the 2 groups” (i.e.,

prasugrel and aspirin versus clopidogrel and aspirin). (Id.) In fact, they found “a

statistically significant difference in favor of prasugrel” only “at an MI weight of

0.4 or more—in other words, only when MI is considered nearly one-half as

important as death, which is highly unlikely given the case fatality rate of only

6%.” (Id.) Thus, as Dr. Hirsh confirms, the net clinical benefit calculation in

Wiviott I is merely subjective and depends entirely on how the end points are

weighted. (EX1002 ¶¶ 150-53.) It was only by defining the net clinical benefit in

a way that inherently maximizes benefits and minimizes risks that the authors were

able to conclude that prasugrel and aspirin has superior net clinical benefits. Under

that definition, however, the observed superior results were entirely expected.

Third, Daiichi cannot establish that the reported improvement in net clinical

benefit over the combination of clopidogrel and aspirin results from the claimed

combination of prasugrel and aspirin, rather than from substituting prasugrel for

clopidogrel. (Id. ¶ 155.) As Dr. Hirsh explains, there is no evidence that the

change in net clinical benefit is attributable or even related to the claimed


52

combination with aspirin. (Id.) In fact, the difference in result can be explained

entirely by differences between prasugrel and clopidogrel themselves. (Id.) Thus,

Daiichi cannot establish any “nexus between” the observed difference in net

clinical benefit and the “merits of the claimed invention,” as required to show that

the claims are not obvious. In re Kao, 639 F.3d at 1068.

Fourth, Daiichi cannot meet the legal requirement of showing “[u]nexpected

results that are … are different in kind and not merely in degree from the results of

the prior art.” Galderma Labs. v. Tolmar, 737 F.3d 731, 739 (Fed. Cir. 2013)

(quotation omitted). As Dr. Hirsh shows, combining aspirin with either prasugrel

or clopidogrel produces the same type of clinical result, and even the same type of

relationship between efficacy and safety. (EX1002 ¶ 156.) In other words, while

“there are some differences in degree” between the combinations, they each

produce “the same type of biological activity.” In re Merck & Co., Inc., 800 F.2d

1091, 1098-99 (Fed. Cir. 1986). Because such a mere difference in degree is

legally irrelevant, the improvement in net clinical benefit reported in Wiviott I

cannot overcome the prima facie obviousness of the ʼ703 patent’s claims.

c) Any alleged unexpected results obtained for diabetes mellitus patients are not commensurate in scope with the claimed invention.

During prosecution, Daiichi and Dr. Gurbel alleged that the combination of

prasugrel and aspirin provides unexpectedly superior results as compared to the


53

combination of clopidogrel and aspirin in patients with diabetes mellitus. (EX1025

¶ 9(G), ¶¶ 82-84.) But even if that were true, the scope of these alleged

unexpected results is limited only to a patient group having diabetes mellitus and is

not commensurate in scope with the claimed methods, since the claims were

intended to treat a much larger population. That is fatal to Daiichi’s assertion of

unexpected results, because “objective evidence of non-obviousness must be

commensurate in scope with the claims which the evidence is offered to support.”

Asyst Techs. v. Emtrak, Inc., 544 F.3d 1310, 1316 (Fed. Cir. 2008).

Here, the alleged unexpected results do not encompass all patients in need of

reduction of thrombogenesis or reduction of platelet aggregation as required by

claims 1, 20, and 24; all warm-blooded animals undergoing stenting, angioplasty,

and/or in need of prevention of restenosis as required by claim 3; all humans

having a cardiovascular disease as required by claim 7; or all humans in need of

reducing thrombotic symptoms associated with cardiovascular or cerebrovascular

disorders as required by claim 14. In other words, the claims of the ’703 patent are

not restricted or even directed to patients with diabetes mellitus. Accordingly, the

results obtained with respect to diabetes mellitus patients are not commensurate in

scope with the claimed invention. (EX1002 ¶ 157.)

Furthermore, as Dr. Hirsh also explains, the superiority of the combination

of prasugrel and aspirin relative to clopidogrel and aspirin in diabetic patients is


54

due to the decreased ability of those patients to activate clopidogrel. (Id. ¶ 158;

EX1029, Erlinge (showing that both poor responders and diabetic patients show a

full response when administered the active metabolite of clopidogrel, rather than

clopidogrel itself).) Because the improved results are due exclusively to the

prasugrel compound and not to the combination of prasugrel and aspirin, the

results lack any nexus to the claimed invention and are therefore irrelevant to the

obviousness analysis of the claims of the ’703 patent. In re Kao, 639 F.3d at 1068.

4. No evidence of copying can overcome the showing of obviousness.

Any assertion of “copying” is irrelevant in this context of generic

manufacturers seeking FDA approval to market generic versions of prasugrel. To

be probative, alleged copying by the accused infringer must be accompanied by

additional evidence, such as failed development efforts by the accused infringer.

Cable Elec. Products, Inc. v. Genmark, Inc., 770 F.2d 1015, 1028 (Fed. Cir. 1985)

(“[M]ore than the mere fact of copying by an accused infringer is needed to make

that action significant to a determination of the obviousness issue”); B.F. Goodrich

Co. v. Aircraft Braking Sys. Corp., 72 F.3d 1577, 1583 (Fed. Cir. 1996). As the

Federal Circuit has made clear, “evidence of copying in the ANDA context is not

probative of nonobviousness.” Bayer Healthcare Pharms., Inc. v. Watson

Pharms., Inc., 713 F.3d 1369, 1377 (Fed. Cir. 2013); accord Purdue Pharma

Prods. L.P. v. Par Pharm., Inc., 377 F. App’x 978, 983 (Fed. Cir. 2010).


55

5. No evidence of commercial success can overcome the showing of obviousness.

Daiichi did not raise commercial success during prosecution of the ‘703

patent, and in any event there is no nexus between any sales for prasugrel and the

claimed methods, each of which require administering prasugrel together with

aspirin. Prasugrel is an effective antiplatelet inhibitor and would have achieved

significant sales for that reason alone. There is thus no relevant commercial

success that could overcome the obviousness of the ’703 patent claims. See, e.g., In

re Huang, 100 F.3d 135, 140 (Fed. Cir. 1996) (evidence of commercial success

alone is insufficient to demonstrate nonobviousness). In addition, any purported

commercial success would be of minimal probative value due to the blocking

patent, U.S. Patent No. 5,288,726 to Koike (EX1012), which claimed the

compound prasugrel and its pharmaceutically acceptable salts. See Merck & Co. v.

Teva Pharma. USA, Inc., 395 F.3d 1364, 1376-77 (Fed. Cir. 2005).

6. No long-felt need

There can also be no relevant evidence of long-felt need, as well as no

indication of a nexus between the long-felt need and the scope of the claimed

invention, which is required for any secondary consideration to be deemed

relevant. In re Kao, 639 F.3d at 1068. Because the Koike patent covered the

compound prasugrel, everyone other than Daiichi or its licensees were blocked

from practicing the claimed methods of administering prasugrel with aspirin. See


56

Merck, 395 F.3d at 1376-77. Moreover, ticlopidine, clopidogrel, and aspirin have

long been available as treatments for the same conditions that are treated by the

claimed combination therapy of prasugrel and aspirin. Thus, while the methods

claimed in the ʼ703 patent are also “beneficial” for treating those conditions,

“others had previously solved” any “long-felt need” for such treatment. In re

PepperBall Techs., Inc., 469 F. App’x 878, 882-83 (Fed. Cir. 2012).

XII. CONCLUSION

Petitioners have demonstrated at least a reasonable likelihood that claims

1-27 of the ’703 patent are unpatentable as obvious under 35 U.S.C. § 103 over the

prior art patents and printed publications cited herein, and therefore respectfully

request that the Board institute inter partes review.

Respectfully submitted,

Dated: March 12, 2015 /Samuel S. Park/ Samuel S. Park Reg. No. 59,656

Lead Counsel for Petitioners

WINSTON & STRAWN LLP 35 W. Wacker Drive Chicago, IL 60601 Telephone: (312) 558-7931 Fax: (312) 558-5700 Email: [email protected]

CERTIFICATION OF SERVICE ON PATENT OWNER

Pursuant to 37 C.F.R. §§ 42.6(e) and 42.105(a), I certify that, on March 12,

2015, I caused to be served true and correct copies of the foregoing “PETITION

FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,404,703,” and all

Exhibits thereto, by EXPRESS MAIL® on the Patent Owner at the correspondence

address of record for U.S. Patent No. 8,404,703, and additionally at another

address known as likely to effect service, as follows:

KING & SPALDING LLP 1185 Avenue of the Americas New York, NY 10036 Bruce R. Genderson WILLIAMS & CONNOLLY LLP 725 Twelfth Street, N.W. Washington, DC 20005

Dated: March 12, 2015 WINSTON & STRAWN LLP 35 W. Wacker Drive Chicago, IL 60601 Telephone: (312) 558-7931 Fax: (312) 558-5700 Email: [email protected]

Respectfully submitted,

/Samuel S. Park/ Samuel S. Park Reg. No. 59,656

Lead Counsel for Petitioners

Documents

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE …fishpostgrant.com/wp-content/uploads/IPR2015-00864.pdfPharmaceuticals USA, Inc., Zydus Pharmaceuticals USA, Inc., and Cadila Healthcare