Filed on behalf of Bristol-Myers Squibb Company
`By: David L. Cavanaugh, Reg. No. 36,476 (Lead Counsel)
`Heather M. Petruzzi, Reg. No. 71,270 (Back-up Counsel)
`Wilmer Cutler Pickering Hale and Dorr LLP
`1875 Pennsylvania Avenue NW
`Washington, DC 20006
`Tel: (202) 663-6025
`Email: David.Cavanaugh@wilmerhale.com
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`COALITION FOR AFFORDABLE DRUGS IX LLC,
`Petitioner,
`
`v.
`
`BRISTOL-MYERS SQUIBB COMPANY,
`Patent Owner.
`
`
`Case IPR2015-01723
`Patent No. 6,967,208
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`

`
`Table of Contents
`
`I. 
`II. 
`
`Introduction ...................................................................................................... 1 
`Background ...................................................................................................... 7 
`A. 
`Thrombosis and Its Treatment Before the Present Invention ............... 7 
`Eliquis® Is the Result of a Decades-Long Research Effort that
`B. 
`Changed the Paradigm for Oral Anticoagulation Therapy ................... 8 
`The ’208 Patent ................................................................................... 11 
`C. 
`III.  The Petition’s Proposed Level of Skill in the Art and Claim
`Constructions Are Not Grounded in the Specification of the
`’208 Patent ..................................................................................................... 14 
`A. 
`Person of Ordinary Skill in the Art ..................................................... 14 
`B. 
`Claim Construction ............................................................................. 15 
`1. 
`“1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-
`piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-
`pyrazolo[3,4-c]pyridine-3-carboxamide” ....................... 16 
`“Pharmaceutically Acceptable Salts” ............................. 17 
`2. 
`IV.  The Petition Fails to Establish a Reasonable Likelihood that Any
`Challenged Claim Is Anticipated by the Fevig References (Grounds
`1 and 2) .......................................................................................................... 18 
`A. 
`Legal Standard ..................................................................................... 20 
`B. 
`The Petition Does Not Attempt to Show that One of Ordinary
`Skill in the Art Would “at Once Envisage” Apixaban ........................ 22 
`Even if the Petition Had Attempted a Proper Anticipation
`Analysis, There Is No Disclosure in the Fevig References
`that Would Allow One of Ordinary Skill in the Art to “at
`Once Envisage” Apixaban or the Claimed Lactam-Containing
`Compounds .......................................................................................... 27 
`1. 
`Claim 13: There Is No Disclosure in the Fevig
`References that Would Lead One of Ordinary Skill
`in the Art to Apixaban .................................................... 28 
`Claims 1-8: There Is No Disclosure in the Fevig
`References that Would Lead One of Ordinary Skill
`in the Art to the Lactam Genera Compounds ................. 34 
`
`C. 
`
`2. 
`
`– ii –
`
`
`
`

`
`3. 
`
`Claims 9-12, 20-27, and 34-61: The Pharmaceutical
`Composition and Method-of-Treatment Claims
`Depend from Claims 1-8 and 13, and Thus Are
`Not Anticipated for the Same Reasons ........................... 36 
`The Petition Fails to Establish a Reasonable Likelihood that Any
`Challenged Claim Is Obvious in View of the Fevig References
`(Grounds 3 and 4) .......................................................................................... 36 
`A. 
`Legal Standard ..................................................................................... 37 
`B. 
`The Petition Has Not Carried Its Burden Because It Misapplies
`the Law for Species-Genus Obviousness Cases ................................. 39 
`The Petition Improperly Dismisses Objective Considerations ........... 44 
`Fevig II Is Not Available as Prior Art to Establish Obviousness
`Under 35 U.S.C. § 103(c) .................................................................... 46 
`VI.  Conclusion ..................................................................................................... 47 
`
`V. 
`
`C. 
`D. 
`
`
`
`– iii –
`
`
`
`
`
`

`
`TABLE OF AUTHORITIES
`
`
`CASES
`Actavis, Inc. v. Research Corp. Techs., Inc.,
`IPR2014-01126, 2015 WL 5468710 (Jan. 9, 2015) ................................ 26, 32
`
`Page(s)
`
`Apotex Inc. v. Merck Sharp & Dohme Corp.,
`IPR2015-00419, 2015 WL 4036000 (June 25, 2015) ................................... 39
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ....................................................... 4, 19, 20, 22
`
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) ................................................................. 4, 22
`
`Daiichi Sankyo Co. v. Matrix Labs, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) ..................................................................... 39
`
`Ecolochem, Inc. v. S. Calif. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000) ..................................................................... 46
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) ................................................................. 5, 24
`
`Eli Lilly & Co. v. Bd. of Regents of Univ. of Wash.,
`334 F.3d 1264 (Fed. Cir. 2003) ....................................................................... 4
`
`Eli Lilly & Co. v. Teva Pharm. USA, Inc.,
`619 F.3d 1329 (Fed. Cir. 2010) ..................................................................... 37
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) ............................................................... 21, 39
`
`Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`No. 99-cv-00038, 2001 WL 1397304 (S.D. Ind. Oct. 29, 2001) .............. 5, 25
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ..................................................................................... 37, 40
`
`Idle Free Sys., Inc. v. Bergstrom, Inc.,
`IPR2012-00027, 2013 WL 5947697 (June 11, 2013) ................................... 18
`– iv –
`
`
`
`

`
`Impax Labs., Inc. v. Aventis Pharm. Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ............................................................... 30, 31
`
`In re Baird,
`16 F.3d 380 (Fed. Cir. 1994) ................................................... 5, 38, 41, 42, 43
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) ..................................................................... 15
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig., 676 F.3d 1063 (Fed. Cir. 2012) ............................................... 37
`
`In re Gleave,
`560 F.3d 1331 (Fed. Cir. 2009) ..................................................................... 21
`
`In re Jones,
`958 F.2d 347 (Fed. Cir. 1992) ............................................................. 5, 41, 43
`
`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962) ................................................................... 4, 31
`
`In re Schaumann,
`572 F.2d 312 (C.C.P.A. 1978) ....................................................................... 31
`
`In re Susi,
`440 F.2d 442 (C.C.P.A. 1971) ................................................................. 25, 42
`
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ....................................................................... 31
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)....................................................................................... 37
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ..................................................................... 45
`
`Merck & Co. v. Biocraft Labs., Inc.,
`874 F.2d 804 (Fed. Cir. 1989) ...............................................25, 36, 40, 41, 42
`
`Moses Lake Indus., Inc. v. Enthone, Inc.,
`IPR2014-00243, 2014 WL 2810484 (June 18, 2014) ............................. 20, 37
`
`– v –
`
`
`
`

`
`Mylan Pharms. Inc. v. Nissan Chem. Indus., Ltd.,
`IPR2015-01069, Paper No. 24 (Oct. 20, 2015) ....................................... 26, 32
`
`NetApp Inc. v. Crossroads Sys., Inc.,
`IPR2014-01233, 2015 WL 996342 (Feb. 10, 2015) ...................................... 37
`
`OSRAM Sylvania, Inc. v. Am. Induction Techs., Inc.,
`701 F.3d 698 (Fed. Cir. 2012) ....................................................................... 21
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ........................................................... 6, 38, 39
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ..................................................................... 31
`
`Prometheus Labs., Inc. v. Roxane Labs., Inc.,
`No. 2014-1634, 2015 WL 6875218 (Fed. Cir. Nov. 10, 2015) ............... 38, 41
`
`Reflectix, Inc. v. Promethean Insulation Tech. LLC,
`IPR2015-00047, 2015 WL 1927414 (Apr. 24, 2015) ................................... 48
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`470 F.3d 1368 (Fed. Cir. 2006) ..................................................... 4, 21, 30, 31
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ......................................................... 21, 22, 25
`
`Takeda Chem. Indus. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ................................................................. 6, 39
`
`Tessera, Inc. v. Int’l Trade Comm’n,
`646 F.3d 1357 (Fed. Cir. 2011) ..................................................................... 20
`
`Torrent Pharm. Ltd. v. Merck Frosst Can. & Co.,
`IPR2014-00559, 2014 WL 4961577 (Oct. 1, 2014) ................................ 26, 33
`
`STATUTES, RULES & REGULATIONS
`
`37 C.F.R. § 1.68 ....................................................................................................... 29
`
`37 C.F.R. § 41.2 ....................................................................................................... 29
`
`37 C.F.R. § 42.12 ..................................................................................................... 44
`– vi –
`
`
`
`

`
`37 C.F.R. § 42.100(b) .............................................................................................. 15
`
`37 C.F.R. § 42.104(b) .............................................................................................. 14
`
`37 C.F.R. § 42.108 ..................................................................................................... 1
`
`28 U.S.C. § 1746 ...................................................................................................... 30
`
`35 U.S.C. § 102(e)(2) ............................................................................................... 46
`
`35 U.S.C. § 103(c) ............................................................................................. 46, 47
`
`35 U.S.C. § 254 ........................................................................................................ 13
`
`35 U.S.C. § 312(a)(2) ............................................................................................... 48
`
`35 U.S.C. § 314 .......................................................................................................... 1
`
`35 U.S.C. § 316(e) ................................................................................................... 40
`
`
`
`– vii –
`
`
`
`
`
`

`
`Patent Owner’s Exhibit List
`
`BMS
`Exhibit No.
`
`Description
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`Donald J.P. Pinto et al., Factor Xa Inhibitors: Next-Generation
`Antithrombotic Agents, 53 J. MEDICINAL CHEMISTRY 6243, 6243
`(2010)
`
`Pancras C. Wong et al., Apixaban, an Oral, Direct and Highly
`Selective Factor Xa Inhibitor: In Vitro, Antithrombotic and
`Antihemostatic Studies, 6 J. THROMBOSIS & HAEMOSTATIS 820
`(2008)
`
`Donald J.P. Pinto et al., Case History: Eliquis (Apixaban), a Potent
`and Selective Inhibitor of Coagulation Factor Xa for the Prevention
`and Treatment of Thrombotic Diseases, 47 ANN. REP. MEDICINAL
`CHEMISTRY 123 (2012)
`
`Yun-Long Li et al., Preparation of 1-(3-aminobenzo[d]isoxazol-5-
`yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as Potent, Selective,
`and Efficacious Inhibitors of Coagulation Factor Xa, 16
`BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 5176 (2006)
`
`Donald J.P. Pinto et al., Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-
`(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-
`pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a
`Highly Potent, Selective, Efficacious, and Orally Bioavailable
`Inhibitor of Blood Coagulation Factor Xa, 50 J. MEDICINAL
`CHEMISTRY 5339 (2007)
`
`Press Release, American Chemical Society, “Heroes of Chemistry”
`Developed Products That Improve Health, Homes and Automobiles
`(June 29, 2015)
`
`2007
`
`Excerpts of File History for U.S. Patent No. 6,967,208
`
`– viii –
`
`
`
`

`
`BMS
`Exhibit No.
`
`Description
`
`2008
`
`2009
`
`2010
`
`
`
`Bengt I. Eriksson et al., Novel Oral Factor Xa and Thrombin
`Inhibitors in the Management of Thromboembolism, 62 ANN. REV.
`MED. 41 (2011)
`
`Bristol-Myers Squibb Co., Annual Report (Form 10-K) (Feb. 13,
`2015)
`
`Bristol-Myers Squibb Co., Quarterly Report (Form 10-Q) (Oct. 27,
`2015)
`
`– ix –
`
`
`
`

`
`I.
`
`Introduction
`
`Hedge fund subsidiary Coalition for Affordable Drugs IX LLC
`
`(“Petitioner”) petitions the Board to institute inter partes review based on grounds
`
`that are factually and legally deficient. The Petition and accompanying
`
`Declaration of Dr. George Burton (Ex. 1008) (“Burton Declaration” or “Burton
`
`Decl.”) rely on an erroneous factual premise concerning the disclosure of the
`
`asserted prior art, and they fail to address—much less satisfy—the legal
`
`requirements for establishing anticipation and/or obviousness for claims covering
`
`pharmaceutical compounds that fall within a broad prior art genus disclosure.
`
`In view of Petitioner’s failure—and inability—to satisfy these requirements, the
`
`Petitioner cannot demonstrate that it is reasonably likely to prevail in establishing
`
`the unpatentability of any challenged claim, and the Board should decline to
`
`institute inter partes review. See 35 U.S.C. § 314; 37 C.F.R. § 42.108.
`
`Petitioner has challenged 49 of the 103 claims of U.S. Patent No. 6,967,208
`
`(the “’208 patent”) (Ex. 1001).1 The challenged claims cover pharmaceutical
`
`compounds including apixaban, the active pharmaceutical ingredient of Eliquis®,
`
`Patent Owner’s successful anticoagulant product. The Petition focuses its
`
`
`1 Petitioner challenges claims 1-13, 20-27, and 34-61 as unpatentable. See
`
`– 1 –
`
`Pet. at 15.
`
`
`
`

`
`challenge primarily on claim 13 of the ’208 patent, which specifically recites the
`
`chemical name for apixaban. The Petition also challenges various other claims,
`
`each of which includes a genus of chemical compounds having an important
`
`functional group called a lactam ring on one end of the molecule (the “lactam
`
`genera claims”). The Petition asserts four grounds of invalidity based on two
`
`references (Fevig I and Fevig II, Ex. 1003 and 1004, respectively) that disclose
`
`very broad genera but do not specifically disclose the lactam ring, let alone
`
`apixaban. The Petition alleges that each Fevig reference anticipates or renders
`
`obvious the challenged claims. Petitioner’s invalidity arguments consist solely of
`
`the unremarkable proposition that apixaban and the lactam genera claims are
`
`encompassed by the genus disclosed in the Fevig references. Each of these
`
`grounds fails.2
`
`
`2 The Petition also contains statements regarding the purported overbreadth
`
`of some or all of the claims and/or insufficient disclosure with respect to the
`
`’208 patent. See Pet. at 4-5, 8, 13, 20-21, 28-29, 55-56; Ex. 1008 (Burton Decl.)
`
`¶¶ 24-25, 63-64, 79, 131. The Patent Owner disagrees with these assertions, but
`
`they need not be addressed because they are not properly raised in a petition for
`
`– 2 –
`
`inter partes review.
`
`
`
`

`
`Petitioner’s anticipation grounds (Grounds 1 and 2) suffer from both factual
`
`and legal errors. As a factual matter, Petitioner incorrectly asserts that apixaban
`
`and the challenged lactam genera claims are specifically disclosed in Fevig I and
`
`Fevig II. Pet. at 17 (“[T]he compound disclosed in claim 13 of the ‘208 Patent is
`
`also explicitly disclosed in Fevig I.”), 43 (“[E]xactly as was the case with Fevig I,
`
`Fevig II anticipates the challenged claims of the ‘208 Patent by disclosing, among
`
`other compounds, apixaban, which is explicitly disclosed by name in claims 13 and
`
`8 and generically in claims 1-7.”). In fact, there can be no dispute that neither
`
`Fevig reference specifically identifies apixaban, the lactam ring, or the compounds
`
`making up the lactam genera. At best, such compounds can be derived from the
`
`Fevig references only by selecting particular substituent groups from among
`
`numerous alternative choices at a number of different locations on the generic
`
`chemical structure identified by Petitioner (i.e., structure 4, or the “Fevig genus”).
`
`To get from the compounds in the Fevig genus to apixaban, one must piece
`
`together the lactam ring, which is not specifically disclosed in the Fevig references.
`
`Indeed, as Petitioner acknowledges, the genera disclosed in the Fevig references
`
`encompass an “enormous number of compounds.” Id. at 16.
`
`As a legal matter, the Petition rests on the faulty premise that the disclosure
`
`of the Fevig genus in Fevig I and Fevig II necessarily anticipates any compound
`
`that is encompassed by that genus. That is not the law. As the Federal Circuit has
`– 3 –
`
`
`
`

`
`repeatedly held, the “disclosure of a genus in the prior art is not necessarily a
`
`disclosure of every species that is a member of that genus.” Atofina v. Great Lakes
`
`Chem. Corp., 441 F.3d 991, 999 (Fed. Cir. 2006); see also Eli Lilly & Co. v. Bd. of
`
`Regents of Univ. of Wash., 334 F.3d 1264, 1270 (Fed. Cir. 2003) (citing Bristol-
`
`Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1380 (Fed. Cir. 2001)
`
`(“[The] earlier disclosure of a genus does not necessarily prevent patenting a
`
`species member of the genus.”)). Rather, a genus only anticipates a specific
`
`compound if the genus disclosure leads a person of ordinary skill in the art to “at
`
`once envisage” In re Petering, 301 F.2d 676, 681 (C.C.P.A. 1962), the specific
`
`claimed compound or class, for example, by following “a pattern of preferences”
`
`disclosed in the art. Sanofi-Synthelabo v. Apotex, Inc., 470 F.3d 1368, 1377
`
`(Fed. Cir. 2006). The Petition does not even attempt to conduct this analysis; it
`
`only identifies a genus and it does not identify how Fevig I or Fevig II would lead
`
`a person of ordinary skill to envisage the claimed compound. Nor could Petitioner
`
`satisfy this requirement given (1) the “enormous” size of the genera disclosed in
`
`the Fevig references, Pet. at 16; Ex. 1008 (Burton Decl.) ¶ 55, including the
`
`“labyrinth of nested components with variations on variations,” Pet. at 60; Ex.
`
`1008 (Burton Decl.) ¶ 133; (2) the preferred embodiments in the Fevig references
`
`do not indicate a preference for a lactam ring and only a subset of the preferred
`
`embodiments even encompass apixaban; and (3) the unpredictability associated
`– 4 –
`
`
`
`

`
`with the chemical arts. See Eisai Co. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353,
`
`1359 (Fed. Cir. 2008); Eli Lilly & Co. v. Zenith Goldline Pharm., Inc.,
`
`No. 99-cv-00038, 2001 WL 1397304, at *5 (S.D. Ind. Oct. 29, 2001).
`
`Petitioner’s obviousness grounds (Grounds 3 and 4) are also factually and
`
`legally flawed. Again, Petitioner erroneously suggests that apixaban and the
`
`lactam genera claims are specifically disclosed in the Fevig references. See Pet. at
`
`57 (“Fevig I and II disclose a vast number of compounds that undeniably includes
`
`apixaban . . . .”). Moreover, Petitioner misapplies the law with respect to
`
`obviousness and fails to perform the necessary legal analysis. Petitioner’s
`
`obviousness argument rests entirely on Petitioner’s suggestion that apixaban and
`
`the lactam genera claims are encompassed by the Fevig genus. See id. But that is
`
`not enough. It is well established that “[t]he fact that a claimed compound may be
`
`encompassed by a disclosed generic formula does not by itself render that
`
`compound obvious.” In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994); see also
`
`In re Jones, 958 F.2d 347, 350 (Fed. Cir. 1992).
`
`The Petition makes no effort to conduct the legally required steps of an
`
`obviousness analysis. It fails to identify any particular compounds specifically
`
`disclosed in the Fevig references and compare them to the compounds covered by
`
`the asserted claims, nor does it explain why a person would be motivated to modify
`
`a prior art compound in a particular manner to make the claimed compounds with a
`– 5 –
`
`
`
`

`
`reasonable expectation of success. See Otsuka Pharm. Co. v. Sandoz, Inc.,
`
`678 F.3d 1280, 1291-92 (Fed. Cir. 2012) (“[W]hether a new chemical compound
`
`would have been prima facie obvious over particular prior art compounds
`
`ordinarily follows a two-part inquiry. First, the court determines whether a
`
`chemist of ordinary skill would have selected the asserted prior art compounds as
`
`lead compounds, or starting points, for further development efforts. . . . The
`
`second inquiry in the analysis is whether the prior art would have supplied one of
`
`ordinary skill in the art with a reason or motivation to modify a lead compound to
`
`make the claimed compound with a reasonable expectation of success.”); Takeda
`
`Chem. Indus. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)
`
`(“[I]n cases involving new chemical compounds, it remains necessary to identify
`
`some reason that would have led a chemist to modify a known compound in a
`
`particular manner to establish prima facie obviousness of a new claimed
`
`compound.”).
`
`Nor could Petitioner establish a reasonable likelihood of prevailing on its
`
`obviousness grounds, given the broad and complex Fevig genus, the absence of the
`
`claimed compounds from the Fevig references’ most preferred embodiments, and
`
`the general unpredictability in the field. Furthermore, the Petition mishandles the
`
`analysis of objective considerations of non-obviousness by inappropriately
`
`assuming they need not be considered if the claimed compounds are encompassed
`– 6 –
`
`
`
`

`
`in a prior art genus. In so doing, the Petitioner improperly merges the anticipation
`
`and obviousness analyses and misapplies the law. Because Petitioner’s
`
`obviousness analysis is flawed at every level, it is far from sufficient to justify
`
`institution of inter partes review on any claim.
`
`II. Background
`
`A. Thrombosis and Its Treatment Before the Present Invention
`
`The invention disclosed in the ’208 patent is the result of a decades-long
`
`effort to develop a better treatment for thrombosis-related diseases. Thrombosis
`
`refers to the formation of blood clots (“thrombi”) inside the blood vessels, which
`
`can cause deep vein thrombosis, pulmonary embolisms, or stroke. See Ex. 2001,
`
`Donald J.P. Pinto et al., Factor Xa Inhibitors: Next-Generation Antithrombotic
`
`Agents, 53 J. MEDICINAL CHEMISTRY 6243, 6243 (2010). Thrombosis is a disorder
`
`that underlies many of the most common and deadly cardiovascular disorders in
`
`modern medicine. Id.
`
`Many patients who suffer from thrombosis disorders take anticoagulants, or
`
`blood thinners. See Ex. 2008, Bengt I. Eriksson et al., Novel Oral Factor Xa and
`
`Thrombin Inhibitors in the Management of Thromboembolism, 62 ANN. REV. MED.
`
`41, 42 (2011). For many years, the oral standard of care was the Vitamin K
`
`antagonist (“VKA”) warfarin. Id. VKAs like warfarin, however, “have a slow
`
`onset of action, a narrow therapeutic window, and an unpredictable anticoagulant
`
`– 7 –
`
`
`
`

`
`effect resulting from multiple food and drug interactions and genetic
`
`polymorphisms that affect drug metabolism . . . and vitamin K turnover . . . .” Id.
`
`“Because VKAs interact with food and drugs, patients must take dietary
`
`precautions, and prescribers must take special care when modifying concomitant
`
`drug therapy. Because of their unpredictable anticoagulant effects, VKAs require
`
`routine coagulation monitoring and dose adjustment . . . .” Id.
`
`In the 1990s, the challenges associated with VKAs prompted several major
`
`pharmaceutical companies to launch research initiatives to develop an improved
`
`oral anticoagulant with fewer side effects. See Ex. 2001 (Pinto, Factor Xa
`
`Inhibitors) at 6244. Groups from Sanofi-Aventis, Daiichi Sankyo, Berlex-Pfizer,
`
`Boehringer Ingelheim, Astellas Pharma, Portola Pharmaceuticals, Kissei
`
`Laboratories, Bayer HealthCare AG, Eli Lilly, Johnson & Johnson, Merck & Co.,
`
`Takeda, AstraZeneca, and DuPont Pharmaceuticals, which was later acquired by
`
`Patent Owner Bristol-Myers Squibb Co. (“BMS”), all attempted to address
`
`warfarin’s limitations. Id. at 6243-64.
`
`B.
`
`Eliquis® Is the Result of a Decades-Long Research Effort that
`Changed the Paradigm for Oral Anticoagulation Therapy
`
`Beginning in the mid-1990s, scientists from DuPont (and later BMS) began
`
`the process of identifying a target for a new oral anticoagulation drug. This
`
`drug-discovery process required the scientists to overcome a number of significant
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`– 8 –
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`challenges over the course of decades of work and is well documented in the
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`scientific literature. After initially researching thrombin inhibitors, the scientists
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`shifted their focus to a protein called “Factor Xa.” See Ex. 2003, Donald J.P. Pinto
`
`et al., Case History: Eliquis (Apixaban), a Potent and Selective Inhibitor of
`
`Coagulation Factor Xa for the Prevention and Treatment of Thrombotic Diseases,
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`47 ANN. REPORTS MEDICINAL CHEMISTRY 123, 124 (2012); Ex. 2002, Pancras C.
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`Wong et al., Apixaban, an Oral, Direct and Highly Selective Factor Xa Inhibitor:
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`In Vitro, Antithrombotic and Antihemostatic Studies, 6 J. THROMBOSIS &
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`HAEMOSTATIS 820, 820 (2008). Because Factor Xa produces thrombin, the
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`inhibition of Factor Xa limits the body’s production of dangerous clots. See Ex.
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`2003 (Pinto, Case History) at 124.
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`The BMS/DuPont research team screened dozens of compound classes and
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`designed thousands of molecules in the process of identifying potent, selective,
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`orally bioavailable Factor Xa inhibitors. See, e.g., id. at 125-36 (describing work
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`on, e.g., dibasic compounds, bis-benzamidines, isoxazolines, pyrazoles,
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`benzamidine mimics, and dihydropyrazolopyridinones); see generally Ex. 2001
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`(Pinto, Factor Xa Inhibitors); Ex. 2002 (Wong); Ex. 2003 (Pinto, Case History);
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`Ex. 2004, Yun-Long Li et al., Preparation of 1-(3-aminobenzo[d]isoxazol-5-yl)-
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`1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones as Potent, Selective, and Efficacious
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`Inhibitors of Coagulation Factor Xa, 16 BIOORGANIC & MEDICINAL CHEMISTRY
`– 9 –
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`

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`LETTERS 5176 (2006); Ex. 2005, Donald J.P. Pinto et al., Discovery of 1-(4-
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`Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-
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`pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly
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`Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood
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`Coagulation Factor Xa, 50 J. MEDICINAL CHEMISTRY 5339 (2007). After years of
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`compound identification work, the inventors identified a compound class—
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`dihydropyrazolopyridinones—for further investigation. See Ex. 2003 (Pinto, Case
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`History) at 133-34. From among this expansive class, the team evaluated hundreds
`
`of compounds and discovered that molecules with a lactam ring3 on the far right
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`side of the molecule—as shown below—had favorable pharmacokinetic properties
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`that made them superior drug candidates. See, e.g., Ex. 2005 (Pinto, Discovery) at
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`5345-46.
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`
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`After several years of research, the inventors identified a superior
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`anticoagulant—apixaban (illustrated above and claimed specifically in claim 13).
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`3 Lactams are cyclic amides that include a nitrogen in a ring structure.
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`– 10 –
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`See id. The lactam that appears in apixaban is identified by the red box in the
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`figure above. Published preclinical studies of apixaban indicate that apixaban has
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`good bioavailability, low clearance, a small volume of distribution in animals and
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`humans, a low potential for drug-drug interactions, and is not significantly affected
`
`by the patient’s diet. See, e.g., Ex. 2003 (Pinto, Case History) at 136-37.
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`Apixaban is a potentially lifesaving anticoagulation treatment. For their
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`groundbreaking contributions in discovering and developing apixaban, members of
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`the BMS/DuPont team, including several inventors on the ’208 patent, received the
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`American Chemical Society’s 2015 Heroes in Chemistry Award. That award
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`honored them “[f]or the discovery of ELIQUIS® (apixaban), a novel oral
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`anticoagulant therapy used most often in patients with atrial fibrillation for whom
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`the risks of stroke, bleeding and death are significantly lower than the decades long
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`standard of care.” Ex. 2006, Press Release, American Chemical Society, ‘Heroes
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`of Chemistry’ Developed Products That Improve Health, Homes and Automobiles
`
`(June 29, 2015).
`
`C. The ’208 Patent
`
`The ’208 patent is titled “Lactam-Containing Compounds and Derivatives
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`Thereof as Factor Xa Inhibitors” and is directed to “lactam-containing compounds
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`. . . that are useful as factor Xa inhibitors” and “pharmaceutically acceptable salts
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`or prodrugs” of those compounds. ’208 patent, col. 5:53-56 (Ex. 1001). Claim 1
`– 11 –
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`

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`of the ’208 patent is directed to lactam genera—that is, compounds (or
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`pharmaceutically acceptable salts thereof) having the following lactam-containing
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`core structure:
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`
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`The portion of the structure identified within the red box above is a lactam. As
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`explained above, a lactam ring structure must be present in any compound that
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`falls within the scope of claim 1.4
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`Claims 2 through 8 are claims to progressively smaller subgenera of claim 1.
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`Each of these claims depends on the previous one, and each further limits the
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`variety of functional groups that can be appended to the core shown above. Claim
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`8 depends from claim 7 and is further limited to include 65 enumerated compounds
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`(and their pharmaceutically acceptable salts). One of the compounds listed in
`
`claim 8 is apixaban. Claim 13 depends from claim 8 and specifically claims
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`apixaban by chemical name, 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-
`
`
`4 A carbon-containing ring with no double bonds is shown in the figure
`
`above, but claim 1 does not expressly limit the other four atoms that may be
`
`contained in the lactam ring and allows for up to two double bonds within the ring.
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`– 12 –
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`
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`

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`piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-
`
`carboxamide.5 The remaining challenged claims of the ’208 patent are directed to
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`pharmaceutical compositions and methods of treatment, and each depends either
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`directly or indirectly on claims 1-8 and 13.
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`The prosecution history of the ’208 patent is straightforward. The Examiner
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`never rejected any claim as anticipated or obvious, despite considering numerous
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`references—including the only two references on which the Petition relies.
`
`See Pet. at 11. Indeed, both references on which the Petition relies were cited to
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`the Examiner and one of them is also addressed and distinguished in the ’208
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`patent specification. See ’208 patent, col. 2:62-63 (Ex. 1001) (“Compounds
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`specifically described in WO00/39131 are not considered to be part of the present
`
`invention.”).
`
`After the ’208 patent issued, BMS requested and was granted a Certificate of
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`Correction. The Patent Office issued the Certificate of Correction under 35 U.S.C.
`
`§ 254 to correct its own printing errors. As explained in the file history, “[a]ll
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`errors in the printed patent for which the correction is requested are a result of
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`Patent and Trademark Office mistakes.” Ex. 2007, Excerpt of ’208 Patent File
`
`
`5 Example 18 of the ’208 patent describes the synthesis and physical
`
`properties of apixaban. See ’208 patent, cols. 174:21-175:51 (Ex. 1001).
`
`– 13 –
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`

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`History Relating to Certificate of Correction, at 1. Indeed, the Patent Office issued
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`the Certificate without requiring a fee. Id. at 244 (Ex. 2007).6
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`III. The Petition’s Propos