IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`Panacea Biotec Ltd.,
`Petitioner
`
`v.
`
`Daiichi Sankyo Company, Limited and Ube Industries, Ltd.,
`Patent Owners
`
`U.S. Patent No. 8,404,703 B2 to Asai et al.
`Issue Date: March 26, 2013
`Title: Medicinal Compositions Containing Aspirin
`_____________________
`
`Inter Partes Review No.: IPR2015-01496
`_____________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,404,703 B2 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 (IPR2015-01496)
`
`
`
`TABLE OF CONTENTS
`
`Petitioner’s 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. 
`
`B. 
`
`Each real party-in-interest (37 C.F.R. § 42.8(b)(1)) ............................. 7 
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 7 
`
`1. 
`
`2. 
`
`Judicial matters involving the ’703 patent ................................. 7 
`
`Administrative matters ............................................................... 8 
`
`C. 
`
`Designation of counsel (37 C.F.R. § 42.8(b)(3)) .................................. 9 
`
`D.  Notice of service information (37 C.F.R. § 42.8(b)(4)) ........................ 9 
`
`VI.  STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFOR (37 C.F.R. § 42.22(a)) .............................. 9 
`
`VII.  THE ’703 PATENT AND CLAIM CONSTRUCTION ............................ 9 
`
`VIII.  PERSON OF SKILL IN THE ART (“POSA”) ....................................... 10 
`
`IX. 
`
`IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) ........... 10 
`
`X. 
`
`BACKGROUND ......................................................................................... 11 
`
`A. 
`
`The antiplatelet aggregation benefits of thienopyridine
`derivatives—including prasugrel—were well known. ........................ 12 
`
`ii
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`

`

`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`
`
`B. 
`
`The benefits of combining aspirin with thienopyridine
`derivatives were well known. .............................................................. 14 
`
`XI.  ANALYSIS OF GROUNDS FOR TRIAL ............................................... 16 
`
`A. 
`
`The challenged claims would have been obvious in view of
`WO ’500 alone. ................................................................................... 16 
`
`1. 
`
`2. 
`
`Independent claims 1, 3, 7, 14, 20, and 24 .............................. 17 
`
`Dependent challenged claims .................................................. 24 
`
`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. ........................................................................................... 28 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`7. 
`
`8. 
`
`Independent claims 1, 3, 7, 14, 20, and 24 .............................. 28 
`
`Dependent claims 8, 12, 18, and 22 ......................................... 31 
`
`Dependent claims 2, 4, 9, 15, 21, and 25 ................................. 32 
`
`Dependent claim 5 ................................................................... 33 
`
`Dependent claim 6 ................................................................... 33 
`
`Dependent claims 10, 17, and 27 ............................................. 34 
`
`Dependent claims 11, 13, and 19 ............................................. 35 
`
`Dependent claims 16 and 26 .................................................... 36 
`
`C. 
`
`Objective indicia of obviousness and nonobviousness ....................... 36 
`
`1. 
`
`2. 
`
`Near-simultaneous invention by different inventors
`confirms the obviousness of the claimed subject
`matter........................................................................................ 37 
`
`The bases cited by the examiner for allowing the
`claims do not support a finding that the ʼ703 patent’s
`claims are valid. ....................................................................... 39 
`
`iii
`
`

`

`
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`The other “unexpected results” asserted by Daiichi
`also fail to rebut the strong showing that the claimed
`combination therapy is obvious. .............................................. 45 
`
`No evidence of copying can overcome the showing of
`obviousness. ............................................................................. 53 
`
`No evidence of commercial success can overcome the
`showing of obviousness. .......................................................... 54 
`
`No long-felt need ..................................................................... 54 
`
`XII.  CONCLUSION ........................................................................................... 55 
`
`
`
`iv
`
`

`

`
`
`Exhibit
`#
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`Petitioner’s Exhibit List
`
`Description
`
`Asai et al., U.S. Patent No. 8,404,703 B2, “Medicinal Compositions
`Containing Aspirin” (“the ʼ703 patent”)
`
`Declaration of Jack Hirsh, MD, in Support of Petition for Inter
`Partes Review (“Hirsh Decl.)
`
`International Patent Application Publication No. WO 99/65500
`(“WO ʼ500”)
`
`U.S. Patent No. 6,509,348 to Ogletree (“Ogletree”)
`
`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”)
`
`U.S. Patent No. 5,989,578 (“Bernat”)
`
`Uchiyama, S. et al., “Combination Therapy With Low-Dose Aspirin
`And Ticlopidine In Cerebral Ischemia,” Stroke, 20:1643-47 (1989)
`(“Uchiyama”)
`
`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”)
`
`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”)
`
`v
`
`

`

`
`
`Exhibit
`#
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`Description
`
`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”)
`
`U.S. Patent No. 5,288,726 to Koike (“Koike”)
`
`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”)
`
`Rupprecht, H.J. et al., “Comparison of Antiplatelet Effects of
`Aspirin, Ticlopidine, or Their Combination After Stent
`Implantation” Circulation , 97:1046 1052 (1998) (“Rupprecht”)
`
`U.S. Patent No. 4,080,447 to Amselem (“Amselem”)
`
`Mishkel, G.J. et al., “Clopidogrel as Adjunctive Antiplatelet
`Therapy During Coronary Stenting,” J. Am. Coll. Cardiol., 34
`(7):1884 1890 (1999) (“Mishkel”)
`
`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”)
`
`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”)
`
`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”)
`
`vi
`
`

`

`
`
`Exhibit
`#
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`Description
`
`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”)
`
`Patrono et al., “Platelet-Active Drugs: The Relationships Among
`Dose, Effectiveness, and Side Effects,” Chest, 114:470S-488S
`(1998) (“Patrono”)
`
`May 1, 2009 Office Action (excerpt from the prosecution history of
`the ’703 patent)
`
`May 26, 2011 Office Action (excerpt from the prosecution history
`of the ’703 patent)
`
`Nov. 25, 2011 Declaration Under 37 C.F.R § 1.131 (excerpt from
`the prosecution history of the ’703 patent)
`
`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.”)
`
`Feb. 5, 2013 Notice of Allowance (excerpt from the prosecution
`history of the ’703 patent)
`
`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”)
`
`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”)
`
`vii
`
`

`

`
`
`Exhibit
`#
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`Description
`
`Chan, N.C., et al., “Role of phenotypic and genetic testing in
`managing clopidogrel therapy,” Blood, 124(5):689-699 (2014)
`(“Chan”)
`
`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”)
`
`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)
`
`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)
`
`July 12, 2012 Amendment and Response (excerpt from the
`prosecution history of the ’703 patent)
`
`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”).
`
`viii
`
`

`

`
`
`Exhibit
`#
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`Description
`
`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”).
`
`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”).
`
`Serebruany VL., et al., “Variability in platelet responsiveness to
`clopidogrel among 544 individuals,” J. Am. Coll. Cardiol., 45(2):
`246-251 (2005) (“Serebruany”).
`
`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”)
`
`Farrell et al., “The Lack Of Augmentation By Aspirin Of Inhibition
`Of Platelet Reactivity By Ticlopidine,” Am. J. Cardiol., 83; 770-774
`(1999) (“Farrell”)
`
`Mar. 30, 2012 Office Action (excerpt from the prosecution history
`of the ’703 patent)
`
`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”)
`
`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”)
`
`ix
`
`

`

`
`
`Exhibit
`#
`
`1045
`
`1046
`
`1047
`
`1048 
`
`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`Description
`
`Office of Surveillance and Epidemiology (OSE), FDA,
`“Background Package for Advisory Committee NDA 22-307” (Jan.
`8, 2009) (“OSE Rept.”)
`
`Labeling for Effient® (prasugrel) (rev. Nov. 2013)
`
`Labeling for Plavix® (clopidogrel) (rev. Dec. 2013)
`
`Colwell, J.A., “Vascular Thrombosis in Type II Diabetes Mellitus,
`Diabetes, ” 42:8-11 (January 1993) (“[I]ndividuals with diabetes
`appear to have an increased tendency toward vascular thrombosis.”)
`
`x
`
`

`

`I.
`
`INTRODUCTION
`Petitioner Panacea Biotec Ltd. petitions for Inter Partes Review, seeking
`
`cancellation of claims 1-26 (“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, and Ube Industries, Ltd. (collectively, “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
`
`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.)
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`
`
`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.
`
`Petitioner 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
`
`(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
`
`2
`
`

`

`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`
`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 Petitioner
`
`will show, the alleged “unexpected results” were entirely expected and wholly
`
`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.
`
`3
`
`

`

`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`
`
`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
`
`“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.
`
`4
`
`

`

`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`
`
`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.)
`
`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
`
`5
`
`

`

`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
`
`
`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
`
`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
`
`
`1 Citations are as follows: X:YY-ZZ (col:lines; patent); X:Y:Z (page:col:para;
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`journal article); X:Y (page:para; journal article).
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`6
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`were each already known to be useful.
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`IV. STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL STATEMENTS
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`Petitioner certifies that (1) the ’703 patent is available for IPR; and (2)
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`Petitioner is not barred or estopped from requesting IPR of any claim of the ’703
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`patent on the grounds identified herein. The required fee is paid through the Patent
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`Review Processing System. The Office is authorized to charge fee deficiencies
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`and credit overpayments to Deposit Acct. No. 50-1814.
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`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))
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`Petitioner certifies that Panacea Biotec Ltd. is the real party-in-interest to
`
`this proceeding.
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`B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`
`1.
`
`Judicial matters involving the ’703 patent
`
`Petitioner was served with a complaint asserting infringement of the ʼ703
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`patent in Eli Lilly & Co., et al. v. Panacea Biotec, Ltd., No. 1:14-cv-01064-SEB-
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`TAB (S.D. Ind.), on June 27, 2014. That matter has been consolidated with Eli
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`Lilly & Co., et al. v. Accord Healthcare, Inc., et al., No. 14-cv-00389-SEB-TAB
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`(S.D. Ind.), which remains pending. The ’703 patent is also asserted in Eli Lilly &
`
`Co., et al. v. Lupin Ltd. and Lupin Pharmaceuticals, Inc., No. 1:15-cv-00673-SEB-
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`TAB (S.D. Ind.), and in Eli Lilly & Co., et al. v. HEC Pharm USA, Inc. and HEC
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`7
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`Pharm Co., Ltd., No. 1:15-cv-00792-SEB-TAB (S.D. Ind.), which remain pending.
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`2.
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`Administrative matters
`
`The ʼ703 patent is also the subject of a pending petition for inter partes
`
`review in Case IPR2015-00864. A related patent, 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, is the subject of pending petitions for inter partes
`
`review in Cases IPR2015-00865 and IPR2015-01492.
`
`Petitioner recognizes that the instant Petition presents the same prior art and
`
`arguments that have been presented to the Office in the petition in Case IPR2015-
`
`00864. However, the patent owners in Case IPR2015-00864 have filed a
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`preliminary response arguing that the petition should be denied based on patent
`
`owners’ allegation that two petitioners in that case (Apotex Inc. and Apotex Corp.),
`
`which are not related to Petitioner, did not disclose one of their real parties-in-
`
`interest. See IPR2015-00864, Paper 17. Petitioner disagrees. Nevertheless, in the
`
`event that the Office agrees with the patent owners and denies the petition in Case
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`IPR2015-00864 on that basis, Petitioner respectfully submits that the prior art and
`
`arguments presented in the instant Petition, which would not have been previously
`
`considered by the Board on the merits in Case IPR2015-00864, should be
`
`considered in this proceeding.
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`
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`C. Designation of counsel (37 C.F.R. § 42.8(b)(3))
`
`Lead Counsel
`Samuel S. Park (Reg. # 59,656)
`WINSTON & STRAWN LLP
`35 W. Wacker Drive
`Chicago, IL 60601
`Telephone: (312) 558-7931
`Fax: (312) 558-5700
`Email: spark@winston.com
`
`Back-Up Counsel
`Andrew R. Sommer (Reg. # 53,932)
`WINSTON & STRAWN LLP
`1700 K. Street NW
`Washington, D.C. 20006
`Telephone: (202) 558-5000
`Fax: (202) 282-5100
`Email: asommer@winston.com
`
`D. Notice of service information (37 C.F.R. § 42.8(b)(4))
`
`Please direct all correspondence to lead counsel and back-up counsel at the
`
`above addresses. Petitioner consents to email service at the above-listed email
`
`addresses of lead and back-up counsel, and Prasugrel-IPR@winston.com.
`
`VI. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`
`Petitioner requests 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, Petitioner submits 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.
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`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
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`hematology and thrombosis research. (Id. ¶¶ 1-22.)
`
`References
`
`Basis
`
`Claims Challenged
`
`WO ’500 (EX1003)
`
`§ 103 All challenged claims
`
`Bernat (EX1006) in view of
`
`§ 103 All challenged claims
`
`Asai (EX1010)
`
`Bernat (EX1006) in view of
`
`§ 103 All challenged claims
`
`Koike (EX1012)
`
`WO ʼ500 (EX1003) in view of
`
`§ 103 All challenged claims
`
`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.
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`A. The
`thienopyridine
`of
`aggregation benefits
`antiplatelet
`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
`
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`Petition for Inter Partes Review of USPN 8,404,703 (IPR2015-01496)
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`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