UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______________
`
`Sawai USA Inc., and Sawai Pharmaceutical Co., Ltd,
`Petitioners,
`
`v.
`
`Nissan Chemical Industries, Ltd.,
`Patent Owner
`________________
`
`
`
`U.S. Patent No. 5,856,336
`
`Issue Date: January 5, 1999
`
`Title: Quinoline Type Mevalonolactones
`
`________________
`
`Inter Partes Review No. IPR2015-01647
`
`
`
`NISSAN CHEMICAL INDUSTRIES, LTD.’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`______________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`______________
`
`Sawai USA Inc., and Sawai Pharmaceutical Co., Ltd,
`Petitioners,
`
`v.
`
`Nissan Chemical Industries, Ltd.,
`Patent Owner
`________________
`
`
`
`U.S. Patent No. 5,856,336
`
`Issue Date: January 5, 1999
`
`Title: Quinoline Type Mevalonolactones
`
`________________
`
`Inter Partes Review No. IPR2015-01647
`
`
`
`NISSAN CHEMICAL INDUSTRIES, LTD.’S
`PRELIMINARY RESPONSE
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`
`
`
`
`PAGE
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`SAWAI’S OBVIOUSNESS ARGUMENTS FAIL ......................................... 6
`
`A.
`
`RELEVANT ASPECTS OF THE PROSECUTION HISTORY AND
`INTERFERENCE PROCEEDINGS .................................................... 6
`
`B.
`
`SUMMARY OF THE ‘336 PATENT .................................................. 10
`
`C.
`
`PERSON OF ORDINARY SKILL IN THE ART ............................... 11
`
`D.
`
`E.
`
`
`F.
`
`
`
`LEGAL STANDARD FOR INSTITUTION OF INTER PARTES
`REVIEW ............................................................................................. 11
`
`LEGAL PRINCIPLES REGARDING CHEMICAL
`OBVIOUSNESS ................................................................................. 12
`
`SAWAI HAS FAILED TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT CLAIM 1 OF THE ‘336 PATENT WOULD
`HAVE BEEN OBVIOUS OVER PICARD IN VIEW OF
`KESSELER. ........................................................................................ 14
`
`1.
`
`Sawai fails to supply a coherent reason for why the compound
`disclosed as Example 3 in Picard would have been an obvious
`choice of a “lead compound” for an HMG-CoA reductase
`inhibitor ..................................................................................... 14
`
`(a)
`
`Picard itself discloses compounds with better HMG-CoA
`reductase inhibitory activity than Example 3 ................. 16
`
`(b) Other prior art taught away from selecting Picard
`Example 3 as a “lead compound.” .................................. 23
`
`i.
`
`ii.
`
`Sawai’s own selected art (Kesseler) taught away
`from Picard Example 3. ........................................ 23
`
`The prior art identified in a related IPR petition
`taught away from Picard Example 3. ................... 26
`
`i
`
`
`
`
`
`iii. Numerous other pieces of prior art taught away
`from Picard Example 3 . ....................................... 27
`
`2.
`
`Even if Picard Example 3 were a proper selection of a “lead
`compound” for an HMG-CoA reductase inhibitor, it would not
`have been obvious to modify the substituent at the 2-position of
`Picard Example 3 from isopropyl to cyclopropyl. .................... 31
`
`(a)
`
`(b)
`
`
`
`(c)
`
`Picard taught away from replacing the 2-isopropyl
`moiety with a 2-cyclopropyl moiety .................... 32
`
`Sawai provides no reason for a POSA to have
`equated results from the pyridine and pyrimidine
`cores of Kesseler to the quinoline cores
`of Picard. .............................................................. 34
`
`Sawai’s reliance on selected excerpts from the NCI
`Interference proceedings is a red herring. ............ 38
`
`3.
`
`4.
`
`Sawai fails to identify any reason to change the final form of
`the quinoline compound to a calcium salt. ............................... 41
`
`Secondary considerations of record demonstrate non-
`obviousness. .............................................................................. 43
`
`G.
`
`SAWAI HAS FAILED TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT CLAIM 2 OF THE ‘336 PATENT WOULD
`HAVE BEEN OBVIOUS OVER PICARD IN VIEW OF
`KESSELER. ........................................................................................ 46
`
`
`
`III. SAWAI’S PETITION SHOULD BE REJECTED AS DUPLICATIVE
`UNDER 35 U.S.C. §325(d) ........................................................................... 46
`
`IV. SAWAI’S “INTERFERENCE ESTOPPEL” ARGUMENTS ARE NOT
`PROPERLY POSED IN AN IPR PROCEEDING, AND LACK MERIT ... 48
`
`V.
`
`CONCLUSION .............................................................................................. 53
`
`
`
`
`
`ii
`
`
`
`TABLE OF AUTHORITIES
`
`
`
`PAGE
`
`Cases
`
`Altana Pharma AG v. KUDco,
`2010 U.S. Dist. LEXIS 146152 (D.N.J. July 15, 2010) ..................................... 30
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ............................................................................ 35
`
`Bayer AG v. Carlsbad Tech., Inc.,
`No. 01-CV-0867-B, 2002 U.S. Dist. LEXIS 27830
`(S. D. Cal. Aug. 6, 2002) .................................................................................... 36
`
`
`
`Daiichi Sankyo Co. v. Matrix Labs, Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010)
`cert. denied, 131 S. Ct. 1678 (2011) ...........................................13, 21, 25, 27, 29
`
`
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 14
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs. Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .................................................................... 21, 33
`
`Eli Lilly & Co. v. Zenith Goldline Pharm. Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .................................................................... 13, 22
`
`Endo Pharm. Inc. v. Mylan Pharm. Inc.,
`Civ. No. 11-CV-00717, 2014 U.S. Dist. LEXIS 10037
`(D. Del. Jan. 28, 2014) .................................................................................. 19, 30
`
`
`
`Ex Parte Cullis,
`11 U.S.P.Q. 2d 1876 (BPAI 1989) ................................................................. 5, 48
`
`Exxon Corp. v. Phillips Petroleum Co.,
`265 F.3d 1249 (Fed. Cir. 2001) ................................................................ 5, 49, 50
`
`Fujikawa v. Wattanasin,
`93 F.3d 1559 (Fed. Cir. 1996) ........................................................................ 9, 40
`
`iii
`
`
`
`
`
`Grain Processing Corp. v. Am. Maize-Prods. Co.,
`840 F.2d 902 (Fed. Cir. 1988) ............................................................................ 12
`
`In re Deckler,
`977 F.2d 1449 (Fed. Cir. 1992) .......................................................................... 50
`
`In re Hedges,
`783 F.2d 1038 (Fed. Cir. 1986) .......................................................................... 12
`
`In re Kroekel,
`803 F.2d 705 (Fed. Cir. 1986) ............................................................................ 50
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 23
`
`In re Ogiue,
`517 F.2d 1382 (CCPA 1975) .............................................................................. 48
`
`In re Risse,
`378 F.2d 948 (CCPA 1967) ................................................................................ 48
`
`In re Rosuvastatin Calcium Patent Litig.
`703 F.3d 511 (Fed. Cir. 2012) .................................................................. 3, 37, 40
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ................................................................................ 15, 21, 27
`
`Orthopedic Equip. Co. v. United States,
`702 F.2d 1005 (Fed. Cir. 1983) .......................................................................... 12
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012),
`cert. denied, 133 S. Ct. 940 (2013) ..............................................................passim
`
`
`
`Pfizer Inc. v. Mylan Pharm. Inc.,
`71 F. Supp. 3d 458 (D. Del. 2014) ...................................................................... 30
`
`Pfizer Inc. v. Teva Pharm. U.S.A., Inc.,
`555 Fed. App’x 961 (Fed. Cir. 2014) ........................................................... 16, 28
`
`Shire LLC v. Amneal Pharm.,
`2015 U.S. App. LEXIS 16908, (Fed. Cir. Sept. 24, 2015) ................................. 23
`
`iv
`
`
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ........................................................ 13, 16, 28, 31
`
`
`
`
`
`PTAB
`
`Apotex Inc. v. Wyeth LLC,
`IPR2014-00115, Paper No. 94 (PTAB Apr. 20, 2015) ...................................... 35
`
`Apotex Inc. v. Merck Sharpe & Dohme, Corp.,
`IPR2015-00419, Paper No. 14 (PTAB June 25, 2015) ...................................... 13
`
`Athena Automation Ltd. v. Husky Injection Molding Systems Ltd.,
`IPR2013-00290, Paper No. 45 (PTAB Oct. 23, 2014) ....................................... 43
`
`Conopco, Inc. DBA Unilever v. The Procter & Gamble Co.,
`IPR2014-00506, Paper No. 17 (PTAB Jul. 7, 2014) .......................................... 47
`
`LG Electronics, Inc. v. ATI Technologies,
`ULC, IPR2015-00327, Paper No. 15 (PTAB Sep. 2, 2015) ............................... 47
`
`Mylan Pharm. Inc. v. Gilead Sciences, Inc.,
`IPR2014-00885, Paper No. 15 (PTAB Dec. 9, 2014) ........................................ 12
`
`Mylan Pharm. Inc. v. Gilead Sciences, Inc.,
`IPR2014-00887, Paper No. 16 (PTAB Dec. 9, 2014) ........................................ 31
`
`Mylan Pharm. Inc. v. Nissan Chemical Indus., Ltd.,
`IPR2015-01069, Paper No. 24 (PTAB Oct. 20, 2015) ................................passim
`
`Torrent Pharm., Ltd. v. Merck Frosst Canada & Co.,
`IPR2014-00559, Paper No. 8 (PTAB Oct. 1, 2014) ..................................... 12, 31
`
`Unified Patents Inc. v. PersonalWeb Technologies, LLC
`IPR2014-00702 Paper No. 13 (PTAB Jul. 24, 2014) ......................................... 47
`
`WL Gore & Associates, Inc. v. Lifeport Science LLC,
`IPR2014-01319, Paper No. 7 (PTAB Feb. 23, 2015) ..................................... 5, 51
`
`
`
`v
`
`
`
`Rules
`
`37 C.F.R. § 42.65 ..................................................................................................... 43
`
`
`
`
`
`Statutes
`
`35 U.S.C. § 102 ........................................................................................................ 51
`
`35 U.S.C. § 103 ........................................................................................................ 51
`
`35 U.S.C. § 112 .......................................................................................................... 2
`
`35 U.S.C. § 311 ........................................................................................................ 51
`
`35 U.S.C. § 314 ........................................................................................................ 11
`
`35 U.S.C. § 316 .................................................................................................. 47, 52
`
`35 U.S.C. § 325 .................................................................................................. 46, 47
`
`
`
`
`
`vi
`
`
`
`
`
`
`
`Exhibit No.
`
`2002
`
`2003
`
`PATENT OWNER’S EXHIBIT LIST
`
`
`Livalo® Package Insert
`
`Description
`
`Hoffman, W. F., et al., “3-hydroxy-3-methylglutaryl-coenzyme A
`Reductase Inhibitors, 4. Side Chain Ester Derivatives of Mevinolin,”
`Journal of Medicinal Chemistry 29, 5 (1986): 849-852.
`
`vii
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`Sawai USA Inc. and Sawai Pharmaceutical Co., Ltd’s (“Sawai,” or
`
`“Petitioners”) Petition (“Pet.”) seeking inter partes review of U.S. Patent No.
`
`5,856,336 (the “’336 Patent”) should be denied.
`
`The claims of the ‘336 Patent are directed to a novel compound, pitavastatin
`
`calcium, and to a method for reducing hyperlipidemia, hyperlipoproteinemia, or
`
`atherosclerosis by administering that compound. Pitavastatin calcium is sold under
`
`the trademark Livalo® and has enjoyed substantial commercial success. Prior to
`
`the invention claimed in the ‘336 Patent, no one had disclosed a compound with
`
`pitavastatin calcium’s unique structure. The two claims of the ‘336 Patent issued
`
`after a years-long interference proceeding in which both the Board of Patent
`
`Appeals and Interferences and the Federal Circuit expressly found the
`
`incorporation of a cyclopropyl substituent on the quinoline core of the molecule to
`
`be nonobvious. Livalo® remains the only statin product ever approved by the FDA
`
`with a quinoline core, as well as the only statin ever approved by the FDA with a
`
`cyclopropyl substituent:
`
`
`
`1
`
`
`
`
`
`[Ex. 2002 (Livalo® Package Insert, Oct. 2013).]
`
`In its petition, Sawai relies primarily upon two references – Picard [Ex.
`
`1009] and Kesseler [Ex. 1010]. Sawai relies on one of the many compounds
`
`identified in Picard as a supposed “lead” compound, and argues that it would have
`
`been obvious to modify it based on Kesseler.1 Sawai’s attempts to build a case for
`
`invalidity based on Picard and Kesseler are contrary to law, reason, and sound
`
`chemistry.
`
`
`1 In order to make Kesseler and Picard available as prior art to the ‘336
`
`Patent, Sawai relies on extensive expert testimony to try to support an argument
`
`that the ‘336 Patent is not entitled to claim priority from earlier filed Japanese
`
`patent applications. In making this argument, Sawai misapplies the law of priority
`
`under 35 U.S.C. § 112, ignores specific disclosures found in the foreign Japanese
`
`priority applications that support the effective filing date of the ‘336 Patent, treats
`
`those priority applications as broad genus applications, and generally mis-frames
`
`the issue surrounding whether or not the foreign applications adequately support
`
`the ‘336 Patent claims. The Board, however, need not address priority at this time,
`
`because Sawai’s obviousness arguments are so clearly without merit. In the event
`
`the Board were to decide to institute review, Patent Owner reserves its right to
`
`submit evidence and argument in order to establish the entitlement of the ‘336
`
`Patent to the August 20, 1987 priority date.
`
`2
`
`
`
`
`
`First, Sawai’s “lead compound” selection is critically flawed. Sawai
`
`proposes Picard Example 3 as a lead compound for developing an HMG-CoA
`
`reductase inhibitor, yet the disclosures in Picard itself actually teach away from the
`
`selection of Example 3, as do dozens of other references. Sawai fails to present
`
`evidence that Picard Example 3 possesses particularly promising biological
`
`activity. In fact, there is no data indicating that Picard Example 3 possessed any
`
`biological activity at all.
`
`Second, even if, contrary to the evidence, a person of ordinary skill in the art
`
`(POSA) would have selected Picard Example 3 as a lead compound, Sawai fails to
`
`provide a coherent reason for why a POSA would have changed the 2-isopropyl
`
`moiety of Picard Example 3 to a 2-cyclopropyl moiety. This is especially true
`
`given the “unpredictability . . . associated with statin development” in the late
`
`1980s and early 1990s. See In re Rosuvastatin Calcium Patent Litig. v. Aurobindo
`
`Pharma Ltd., 703 F.3d 511, 517 (Fed. Cir. 2012). Sawai has no answer for the
`
`unique and unexpected properties that the cyclopropyl moiety confers on the
`
`pitavastatin molecule. Indeed, in a related proceeding in which the Board declined
`
`to institute review, the Board’s decision was based in part on the non-obviousness
`
`of the cyclopropyl moiety in pitavastatin. See Mylan Pharm. Inc. v. Nissan
`
`Chemical Indus., Ltd., IPR2015-01069, Paper No. 24 at 7 (PTAB Oct. 20, 2015).
`
`3
`
`
`
`
`
`Third, Sawai fails to show why a POSA would have taken the additional
`
`step to create the calcium salt of pitavastatin. For this argument, Sawai tries to rely
`
`on alleged statements made by NCI during the prior interference proceedings, and
`
`yet Sawai’s characterization of those statements is both false and misleading.
`
`There is a certain irony to Sawai’s selection of a lead compound that is
`
`decidedly different from the lead compound it posits in its simultaneously filed
`
`IPR petition, IPR2015-01648. This is evidence of the scattershot approach being
`
`used by Sawai in its attempt to attack the ‘336 claims. It is a reflection of the
`
`novelty of the pitavastatin compound that even Sawai cannot decide on a single
`
`lead compound and must instead come at it from two diverging angles in two
`
`separate IPR petitions. Add to this a third structurally distinct “lead” compound
`
`proposed by a different generic company (which had previously filed its own IPR
`
`petition against the same ‘336 Patent claims), and it is clear that even today, with
`
`the benefit of hindsight, there is no direction in the prior art on where even to
`
`begin. [Compare this Petition, IPR2015-01647 (proposing quinoline lead
`
`compound) with Sawai’s other Petition, IPR2015-01648 (proposing pyridine lead
`
`compound) and with Mylan’s Petition, IPR2015-01069 (proposing indole lead
`
`compound).]
`
`Grasping at straws, Sawai tries to manufacture an interference estoppel
`
`invalidity argument based on the interference proceedings involving the
`
`4
`
`
`
`
`
`grandparent application of the ‘336 Patent. This argument is fundamentally
`
`flawed: the doctrine of interference estoppel simply does not exist as a mechanism
`
`by which a third party can challenge the validity of an issued patent. See Exxon
`
`Corp. v. Phillips Petroleum Co., 265 F.3d 1249, 1254 (Fed. Cir. 2001). Rather,
`
`interference estoppel applies only to patent applicants challenging decisions of the
`
`Patent Office. Even if interference estoppel were available to Sawai as a defense –
`
`and it is not – it would not apply here, because the subject matter that Sawai
`
`alleges was disclaimed was not described in the application of the party that won
`
`the interference proceeding. See Ex Parte Cullis, 11 U.S.P.Q. 2d 1876 (BPAI
`
`1989). Even if interference estoppel were applicable here, Sawai could not raise it
`
`as a proposed basis of invalidity in this IPR proceeding because it is not a
`
`“patented or printed publication” on which inter partes review can be based. See
`
`WL Gore & Associates, Inc. v. Lifeport Science LLC, IPR2014-01319, Paper No. 7
`
`at 15 (PTAB Feb. 23, 2015).
`
`Worse than the legal missteps Sawai makes in trying to manufacture a new
`
`invalidity defense of interference estoppel is Sawai’s attempt to take factual
`
`arguments made in connection with the interference that were rejected by the
`
`Board of Patent Appeals and Interferences and the Federal Circuit and, without
`
`explanation or qualification, hold them forth as “unquestionably correct” or
`
`“undoubtedly correct.” [See Pet. at 4, 40, 43.] While Sawai discusses the
`
`5
`
`
`
`
`
`interference at length, devoting nineteen (19) pages of its Petition to interference-
`
`related arguments, the Petition is devoid of any meaningful discussion of the
`
`Federal Circuit’s decision or the Board’s rulings with respect to the interference.
`
`Sawai’s silence is telling. Clearly, arguments already rejected by the Federal
`
`Circuit do not form a sound foundation for an invalidity challenge.
`
`II.
`
`SAWAI’S OBVIOUSNESS ARGUMENTS FAIL
`
`Sawai’s attempts to build a case for invalidity based on Picard and Kesseler
`
`cannot form a reasonable basis for invalidity of compound claim 1 or method claim
`
`2 of the ‘336 Patent, because those hindsight efforts are so contrary to law, reason,
`
`and sound chemistry.
`
`A. RELEVANT ASPECTS OF THE PROSECUTION HISTORY
`AND INTERFERENCE PROCEEDINGS
`
`Throughout its petition, Sawai repeatedly states that NCI lost the
`
`interference proceedings involving U.S. Patent Application No. 08,233,752
`
`(“Fujikawa ‘752 Application”), the grandparent application of the ‘336 Patent.
`
`The interference proceedings, however, did not involve the claims of the ‘336
`
`Patent. While NCI tried repeatedly to add a count corresponding to the claims of
`
`the ‘336 Patent, the Board rejected NCI’s efforts because the disclosure of the
`
`other party to the interference, Wattanasin, did not support the proposed additional
`
`count.
`
`6
`
`
`
`
`
`The Fujikawa ‘752 Application was filed on August 19, 1988. [Ex. 1004 at
`
`1.] After the Fujikawa ‘752 Application was filed, NCI requested that an
`
`interference be declared between its application and Picard. [Id. at 130-33.] In an
`
`August 27, 1990 interview, the Examiner indicated that an interference “will be
`
`declared in the near future.” [Id. at 419.] On December 19, 1990, long before any
`
`interference was declared, the patentee filed an amendment cancelling claim 10, a
`
`claim that corresponds to, but is slightly broader than current claim 1 of the ‘336
`
`Patent. [Id. at 422-23.] Patentee explained:
`
`Applicants have discovered that the subject matter of Claim 10, and
`
`related subject matter, exhibits unobvious and distinguishing
`
`properties, with respect to the genus circumscribed by the remaining
`
`claims, as well as the claims of the patent with which an Interference
`
`is to be declared. Accordingly, that claim will be pursued in a
`
`separate application.
`
`[Id. at 423.] On the same day, the patentee filed a continuation application in
`
`which it pursued claims corresponding to the cancelled claim 10. [Ex. 1003 at 3-
`
`4.]
`
`On March 11, 1992, interference No. 102,648 was declared between the
`
`Fujikawa ‘752 Application, Picard, and U.S. Patent App. No. 07/498,301
`
`(“Wattanasin”). [Ex. 1004 at 429.] The interference included two counts: the first
`
`directed to a broad genus of compounds encompassing, inter alia, the species of
`
`7
`
`
`
`
`
`claim 1 of the ‘336 Patent, and the second directed to a method of inhibiting
`
`cholesterol biosynthesis by administering a compound from the genus of count 1.2
`
`Shortly thereafter, Picard requested an adverse judgment, effectively conceding
`
`that it could not establish an invention date before Fujikawa’s priority date. [Ex.
`
`1005 at 27.]
`
`As noted above, the interference did not include a count corresponding to the
`
`claims of the ‘336 Patent. In its initial motions, NCI moved to redefine the
`
`interference by adding Counts 3 and 4, directed to compounds of Count 1 where R5
`
`was cyclopropyl, and to a method of inhibiting cholesterol biosynthesis by
`
`administering a compound of proposed Count 3. [Ex. 1005 at 35-45.] In support
`
`of its motion to redefine the interference, the patentee included the declaration of
`
`Masaki Kitahara, Ph.D., who explained that compounds having a cyclopropyl
`
`substituent at R5 showed unexpected and enhanced inhibitory activity even as
`
`compared to otherwise identical compounds where R5 was isopropyl or n-propyl.
`
`[Id. at 46-54.]
`
`The Board declined to add Counts 3 and 4, finding that the subgenus of
`
`Count 3 was not disclosed in Wattanasin. Importantly, in finding that Wattanasin
`
`(not Fujikawa) did not support a count corresponding to the claims of the ‘336
`
`
`2 The interference was ultimately combined with interference No. 102,975. [Ex.
`
`1005 at 1948-49.]
`
`8
`
`
`
`
`
`Patent, the Board had to decide whether a disclosure of cycloalkyl for R5 in
`
`Wattanasin would have led a POSA to the cyclopropyl compounds of proposed
`
`additional count. The Board found unequivocally that it would not. [See Ex. 1005
`
`at 4149 (Final Decision in Interference No. 102,648) at 10 (finding no “motivation
`
`to guide one skilled in the art to select the cyclopropyl compounds of proposed
`
`claims . . . .”)); see also Ex. 1005 at 4192-3 (Decision on Request for
`
`Reconsideration) at 3-4 (maintaining this finding).] On appeal, the Federal Circuit
`
`reached the same conclusion, explaining:
`
`Although, in hindsight, the substitution of cyclopropyl for isopropyl
`
`might seem simple and foreseeable, Wattanasin’s disclosure provides
`
`no indication that position R would be a better candidate for
`
`substitution than any other.
`
`Fujikawa v. Wattanasin, 93 F.3d 1559, 1571 (Fed. Cir. 1996).
`
`While the interference was pending, prosecution of the patent application
`
`that resulted in the ‘336 Patent (U.S. Patent Application No. 883,398, “the ‘398
`
`Application”) was suspended. After the Board found, and the Federal Circuit
`
`affirmed, that Wattanasin had proved an earlier invention date than Fujikawa
`
`(NCI) for the genus claim of Count 1, prosecution of the ‘398 Application
`
`resumed. The Examiner was undoubtedly aware of the interference proceedings,
`
`as is clear from the office communications referencing the interference. In fact,
`
`Examiner Richter, who was the primary Examiner in the ‘398 Application, had
`
`9
`
`
`
`
`
`taken over as Examiner in the Fujikawa ‘752 Application, the application involved
`
`in the interference. [See Ex. 1004 at 1, 425-26.] The Examiner, correctly, did not
`
`view the interference as affecting the patentability of the claims of the ‘398
`
`Application, and allowed those claims. [See Ex. 1002 at 144.]
`
`With the ‘336 Patent in place, NCI and its licensee Kowa Company Ltd.
`
`spent the large amounts of both money and time necessary to conduct clinical trials
`
`of the compound claimed in claim 1 for the uses claimed in claim 2, and obtained
`
`FDA approval to market that compound for those uses on August 3, 2009. [See
`
`Ex. 1002 at 161-176 (describing IND and NDA timeline for Livalo®).]
`
`B.
`
`SUMMARY OF THE ‘336 PATENT
`
`The ‘336 Patent has two claims. Claim 1 provides:
`
`[Ex. 1001 at Col. 32:22-36.] Claim 2 is directed to a “method for reducing
`
`hyperlipidemia, hyperlipoproteinemia or atherosclerosis which comprises
`
`
`
`10
`
`
`
`
`
`administering an effective amount of the compound of the formula A as defined in
`
`claim 1.” [Id. at Col. 32:36-40.]
`
`C.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`Patent Owner disagrees with Sawai’s definition of the person of ordinary
`
`skill in the art (“POSA”) to the extent that Sawai contends such a person would
`
`need to have what appears to be an expert level of familiarity with
`
`mevalonolactones. However, although NCI disagrees with Sawai’s definition of
`
`the POSA, Sawai’s Petition does not warrant institution even under its own
`
`definition. Patent Owner reserves the right to offer evidence and argument on the
`
`proper definition of a POSA for this proceeding in the event the Board were to
`
`institute review.
`
`D. LEGAL STANDARD FOR INSTITUTION OF INTER PARTES
`REVIEW
`
`
`The Board may not institute review unless it determines that there is “a
`
`reasonable likelihood that the petitioner would prevail with respect to at least one
`
`of the claims challenged in the petition.” 35 U.S.C. § 314(a). The Board has, on
`
`multiple occasions, found that this standard was not met in validity challenges
`
`based on chemical obviousness, for reasons which have direct applicability in this
`
`case. See, e.g., Mylan Pharm. Inc., IPR2015-01069, Paper No. 24 at 7 (PTAB
`
`Oct. 20, 2015) (no reasonable likelihood of invalidity for obviousness where the
`
`process of modifying the proposed lead compound “would have required a number
`
`11
`
`
`
`
`
`of chemical alterations, each having a number of possible combinations”); Mylan
`
`Pharm. Inc. v. Gilead Sciences, Inc., IPR2014-00885, Paper No. 15 at 9-11 (PTAB
`
`Dec. 9, 2014) (denying institution of IPR for failure to identify teachings which
`
`would have “prompted an ordinary artisan to modify [a lead compound] so as to
`
`arrive at a compound encompassed by the challenged claims”); see also Torrent
`
`Pharm., Ltd. v. Merck Frosst Canada & Co., IPR2014-00559, Paper No. 8 at 7, 9
`
`(PTAB Oct. 1, 2014).
`
`E.
`
`LEGAL PRINCIPLES REGARDING CHEMICAL
`OBVIOUSNESS
`
`Patent challengers may not prove obviousness through “hindsight
`
`reconstruction by using ‘the patent in suit as a guide through the maze of prior art
`
`references, combining the right references in the right way so as to achieve the
`
`result of the claims in suit.’” Grain Processing Corp. v. Am. Maize-Prods. Co.,
`
`840 F.2d 902, 907 (Fed. Cir. 1988) (citing Orthopedic Equip. Co. v. United States,
`
`702 F.2d 1005, 1012 (Fed. Cir. 1983)); see also Mylan Pharm. Inc., IPR2014-
`
`00885, Paper No. 15 at 9 (“[I]t is impermissible within the framework of section
`
`103 to pick and choose from any one reference only so much of it as will support a
`
`given position, to the exclusion of other parts necessary to the full appreciation of
`
`what such reference fairly suggests to one of ordinary skill in the art.”) (citing In re
`
`Hedges, 783 F.2d 1038, 1041 (Fed. Cir. 1986)).
`
`12
`
`
`
`
`
`“[W]hether a new chemical compound would have been prima facie obvious
`
`over particular prior art compounds ordinarily follows a two-part inquiry.” Otsuka
`
`Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012), cert. denied, 133
`
`S. Ct. 940 (2013). The first part asks whether a POSA at the time of the invention
`
`would have selected the asserted prior art compound as a lead compound. Id.
`
`(noting that a lead compound is “a compound in the prior art that would be most
`
`promising to modify in order to improve upon its . . . activity and obtain a
`
`compound with better activity.”) (citation omitted)); see also Takeda Chem. Indus.,
`
`Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007). The second
`
`part asks whether the prior art would have provided the POSA with a reason or
`
`motivation to modify the lead compound and make the claimed compound with a
`
`reasonable expectation of success. Otsuka Pharm. Co., 678 F.3d at 1292; see also
`
`Daiichi Sankyo Co., Ltd. v. Matrix Labs, Ltd., 619 F.3d 1346, 1352 (Fed. Cir.
`
`2010), cert. denied, 131 S. Ct. 1678 (2011); Apotex Inc. v. Merck Sharp & Dohme
`
`Corp., IPR2015-00419, Paper No. 14 at 7-8 (PTAB June 25, 2015). “[P]roving a
`
`reason to select a compound as a lead compound depends on more than just
`
`structural similarity, but also knowledge in the art of the functional properties and
`
`limitations of the prior art compounds.” Daiichi Sankyo Co., Ltd., 619 F.3d at
`
`1354; see also Eli Lilly & Co. v. Zenith Goldline Pharm. Inc., 471 F.3d 1369, 1377-
`
`79 (Fed. Cir. 2006). Moreover, references teach away from a claimed invention
`
`13
`
`
`
`
`
`where a POSA would be discouraged from following the path set out in the
`
`reference, or would be led in a different direction than the applicant. Depuy Spine,
`
`Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009).
`
`F.
`
`SAWAI HAS FAILED TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT CLAIM 1 OF THE ‘336 PATENT
`WOULD HAVE BEEN OBVIOUS OVER PICARD IN VIEW OF
`KESSELER.
`
`
`
`Sawai’s Petition fails to mention that both Picard and Kesseler were raised
`
`during NCI’s lengthy, prior interference proceedings before the Patent Office. [See
`
`Ex. 1005 at 27, 203.] Indeed, as discussed above, Picard requested adverse
`
`judgment in the interference, effectively conceding that it could not establish
`
`priority to NCI. Nevertheless, Sawai’s obviousness arguments fail for multiple
`
`other reasons, as discussed below.
`
`1.
`
`Sawai fails to supply a coherent reason for why the
`compound disclosed as Example 3 in Picard would have
`been an obvious choice of a “lead compound” for an HMG-
`CoA reductase inhibitor.
`
`
`Sawai’s Petition is fundamentally flawed in that it posits Picard Example 3
`
`as a “lead compound” for an HMG-CoA reductase inhibitor at the time of the ‘336
`
`Patented invention, but never once provides a sound reason for that choice. The
`
`very references on which Sawai relies in fact taught away from selection of
`
`Example 3. That is the epitome of impermissible hindsight reconstruction. See,
`
`e.g., Otsuka Pharm. Co., 678 F.3d at 1292 (“A factfinder should be aware . . . of
`
`14
`
`
`
`
`
`the distortion caused by hindsight bias and must be cautious of arguments reliant
`
`upon ex post reasoning.”) (quoting KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398,
`
`421 (2007)).
`
`Sawai concedes that “[b]y 1988 there were a number of pharmaceutical
`
`companies researching HMG-CoA reductase inhibitors directed to use as
`
`cholesterol-lowering agents.” [Pet. at 15.] Sawai also concedes that some of the
`
`HMG-CoA reductase inhibitors being investigated at that time were “based on
`
`natural products,” some were “synthetic,” and some were “semisynthetic.” [Id. at
`
`17.] Sawai further concedes that among the “synthetic” inhibitors, multiple
`
`different molecular cores were being investigated. [Id. at 18.] Still further,
`
`Sawai’s expert admits that any distinction between these “natural product,”
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`“synthetic,” and “semisynthetic” inhibitors of HMG-CoA reductase is entirely
`
`“arbitrary.” [Ex. 1012 (Brown Decl.) at ¶ 25 n.1.] This is a concession that at the
`
`time of the ‘336 Patented invention there were not only myriad “reasonable
`
`starting points for further development,” but also myriad ways in which each of
`
`those starting point structures might be modified. [See, e.g., Pet. at 18 (admitting
`
`that
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