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`Filed: February 25, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`LUPIN LTD. and LUPIN PHARMACEUTICALS INC., INNOPHARMA
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`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
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`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and .
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`MYLAN INC.
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`Petitioners,
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`SENJU PHARMACEUTICAL CO., LTD.,
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`Patent Owner.
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`Case IPR2015-01097’
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`Patent 8,754,131
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`PATENT OWNER RESPONSE
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`PURSUANT TO 37 C.F.R. § 42.120
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`1 Case IPR2016—00089 has been joined with this proceeding.
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Table of Contents
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`I.
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`II.
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`Preliminary Statement
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`Claim construction
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`III. Level of ordinary skill in the art
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`IV. The ’131 patent
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`V.
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`Background of ophthalmic formulations
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`VI. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the ’131 patent obvious
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`A. No reason to focus on Ogawa and bromfenac preparations
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`B.
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`Design need and market demands would not have led a POSA
`in the direction that the inventors of the ’131 patent took
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`C.
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`A POSA would not have combined Ogawa and Sallmann
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`1.
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`2.
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`3.
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`4.
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`Ogawa and the problem it sought to solve
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`Sallmann’s singular purpose does not align with
`Ogawa’s
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`It would not have been obvious to modify Ogawa
`Example 6 in view of Sallmann Example 2
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`Lupin’s arguments of motivation and expectation
`of success ring hollow
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`D.
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`Sallmann in view of Ogawa: another hindsight-laden
`combination
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`1.
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`2.
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`The proposed combination destroys the essential
`purpose of Sallmann and ignores the blaze marks
`in the art
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`Lupin’s arguments to modify Sallmann in view of
`Ogawa are legally insufficient, internally
`inconsistent, and belied by the very art Lupin cites
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`i
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`1
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`6
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`7
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`7
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`7
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`8
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`8
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`10
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`14
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`14
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`16
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`18
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`24
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`29
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`29
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`32
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`36
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`36
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`36
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`38
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`39
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`45
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`46
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`52
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`52
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`56
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`58
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`60
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`VII. Compelling objective evidence of patentability
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`A.
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`Tyloxapol’s unexpectedly superior chemical stabilizing effect
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`1.
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`2.
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`3.
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`4.
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`Testing against the closest prior art
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`A POSA’s expectation, if anything, of polysorbate
`80
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`Tyloxapol’s unexpectedly superior stabilizing
`effect
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`Tyloxapol’s unexpectedly better maintenance of
`preservative efficacy
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`B.
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`Additional compelling objective evidence of patentability
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`VIII. Separate patentability of individual claims
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`A.
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`B.
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`C.
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`Separate patentability of claims 4, 6, 10-12, 16, 18, 22-23, and
`26
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`Separate patentability of claims 7-12, 19-23, and 27-28
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`Separate patentability of claims 25-29
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`IX. Conclusion
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`ii
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`TABLE OF AUTHORITIES
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` Page(s)
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`Federal Cases
`Allergan v. Sandoz,
`796 F.3d 1293 (Fed. Cir. 2015) ...................................................................passim
`
`In re Antonie,
`559 F.2d 618 (C.C.P.A. 1977) ...................................................................... 53, 55
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`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ............................................................................ 58
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`Atlas Powder Co. v. E.I. du Pont De Nemours & Co.,
`750 F.2d 1569 (Fed. Cir. 1984) .......................................................................... 31
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`Cadence Pharm. Inc. v. Exela PharmSci Inc.,
`780 F.3d 1364 (Fed. Cir. 2015) ...................................................................passim
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`Catalina Lighting, Inc. v. Lamps Plus, Inc.,
`295 F.3d 1277 (Fed. Cir. 2002) .......................................................................... 36
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`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ........................................................ 11, 12, 27, 32
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`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
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`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 20
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`Galderma Labs. v. Tolmar, Inc.,
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`737 F.3d 731 (Fed. Cir. 2013) ........................................................................... 54
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`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ............................................................................ 30
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`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) ........................................................................ 13, 24
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`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 44
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`iii
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Insite Vision Inc., v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ...................................................................... 13, 31
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`Institut Pasteur v. Focarino,
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`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 51
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`Janssen Pharm. NV v. Mylan Pharm., Inc.,
`456 F. Supp. 2d 644 (D.N.J. 2006), aff’d per curiam, 223 Fed.
`Appx. 999 (Fed. Cir. 2007) ................................................................................. 50
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`KSR Int’l Co. v. Teleflex Inc.,
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`550 U.S. 398 (2007) ............................................................................................ 33
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`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) ............................................................................ 7
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`Ortho-McNeil Pharm. Inc. v. Mylan Labs, Inc.,
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`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 36
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`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ............................................................................ 44
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`Par Pharm., Inc. v. TWI Pharms., Inc.,
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`773 F.3d 1186 (Fed. Cir. 2013) ................................................................... 56, 57
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`Pfizer Inc. v. Mylan Pharm. Inc.,
`2014 WL 5388100 (D. Del. 2014) .......................................................... 22, 26, 31
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`In re Shetty,
`566 F.2d 81 (C.C.P.A. 1977) .............................................................................. 57
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`Specialty Composites v. Cabot Corp.,
`845 F.2d 981 (Fed. Cir. 1988) ............................................................................ 50
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`Syntex LLC v. Apotex Inc.,
`2006 U.S. Dist. Lexis 36089 (N.D. Cal. 2006), aff’d 221 Fed.
`Appx. 1002 (Fed. Cir. 2007) ......................................................................... 19, 24
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`Unigene Labs., Inc. v. Apotex, Inc.,
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`655 F.3d 1352 (Fed. Cir. 2011) .............................................................. 20, 21, 52
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ...................................................................... 23, 30
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`Federal Statutes
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`35 U.S.C. § 119 .......................................................................................................... 7
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`35 U.S.C. § 316(e) ................................................................................................. 1, 6
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`Other Authorities
`Apotex Inc., v. Wyeth LLC,
`IPR2014-00115, slip op. (P.T.A.B. Apr. 20, 2015) . .................................... 16, 26
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`Sandoz, Inc. v. EKR Therapeutics, LLC,
`IPR2015-00005, slip op. (P.T.A.B. Apr. 24, 2015) ............................................ 57
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`Ex parte Whalen et al.,
`Appeal 207-4423, slip op. (B.P.A.I. July 23, 2008) ............................... 53, 54, 55
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Patent Owner Senju Pharmaceutical Co., Ltd. et al. (“Senju”) responds to the
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`Petition filed by Lupin Ltd. and Lupin Pharmaceuticals Inc. (“Lupin”) concerning
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`claims 1-30 of U.S. Patent No. 8,754,131 (“the ’131 patent”). The Board instituted
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`trial on Lupin’s Ground No. 1 that claims 1-30 are allegedly obvious over U.S.
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`Patent No. 5,891,913 to Sallmann et al. (“Sallmann”) (EX1021) in view of U.S.
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`Patent No. 4,910,225 to Ogawa et al. (“Ogawa”) (EX1010). As discussed below,
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`Lupin has failed to meet its “burden of proving a proposition of unpatentability by
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`a preponderance of the evidence.” 35 U.S.C. § 316(e).
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`Indeed, as discussed further below, Lupin has failed to prove that a person of
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`ordinary skill in the art would have combined Ogawa and Sallmann with any
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`expectation of arriving at the claimed subject matter. Lupin also has failed to prove
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`the existence of all elements of the ’131 patent claims in the art of record and has
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`failed to carry the high burden of proving the inherency of several claim elements
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`in the obviousness context. In addition, Lupin either ineffectively assails or simply
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`ignores significant objective indicia of patentability, which further support the non-
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`obviousness of the ’131 patent claims. The Board accordingly should uphold the
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`patentability of claims 1-30 of the ’131 patent.
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`I.
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`Preliminary Statement
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`The ’131 patent discloses and claims stable aqueous liquid preparations of
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`the non-steroidal anti-inflammatory drug (“NSAID”) bromfenac, marketed as
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`1
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`Parent Owner Response, IPR2015-01097, US. Patent No. 8, 754, I31
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`Prolensa® prescription eye drops for treatment of inflammation and pain in cataract
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`surgery patients. 1 These formulations are chemically stable,
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`lack microbial
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`contamination, and can be administered safely and effectively for ophthalmic use
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`at a pH that does not cause eye irritation. (EXl002, 2:30-42; EX2082, 1117.)
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`The inventors successfully formulated these preparations using the non—ionic
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`surfactant
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`tyloxapol.
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`(EX2082, 111116-17.) Tyloxapol unexpectedly chemically
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`stabilized bromfenac better than did the surfactant polysorbate 80, even at a low
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`pH known to accelerate bromfenac’s degradation.
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`(Id.,
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`1111 181, 190, 197.)
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`Tyloxapol also unexpectedly maintained preservative eff1cacy—i.e., prevented
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`microbial contamination—as compared to polysorbate 80, even when measured
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`under the stringent European Pharmacopoeia standards. (Id., 11201.)
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`Tyloxapol’s unexpected stabilizing effect translated into significant medical
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`benefits in Prolensa®. Tyloxapol’s stabilization effect permitted fonnulating
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`Prolensa® at pH 7.8, down from pH 8.3 in non-prior art Xibrom® and Bromday®
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`formulations (EX1049, 4; EX1008, 3; EX1009, 7), a substantial reduction on a
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`logarithmic scale and closer to the pH of natural
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`tears, which made it more
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`comfortable to patients. (EX2l16, 1140.)
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`1 Lupin’s expert Dr. Lawrence admits that Prolensa® is an embodiment of
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`certain of the ’131 patent claims. (EX1005, 1111266, 374.)
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`Parent Owner Response, IPR2015-01097, US. Patent No. 8, 754, 131
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`Both the reduction in pH in Prolensa®
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`increased ocular comfort and eliminated the burning and stinging associated with
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`all other approved NSAID eye drops.
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`(Id.) Lowering the pH also improved
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`bromfenac’s intraocular penetration and permitted lowering its concentration to
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`007%, down from 0.09% in Xibrom® and Bromday®, meaning that Prolensa®
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`advantageously puts less drug in contact with surgically compromised ocular tissue
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`without a reduction in efficacy. (Id., 1141; EX2033, 1718.) More than a difference
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`in degree,
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`tyloxapol’s unexpectedly superior stabilizing effect constitutes a
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`material and substantial difference, producing a more comfortable, non-irritating
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`and more efficacious formulation embodied in Prolensa®.
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`As a result, Prolensa® has received significant medical industry acclaim by
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`numerous leaders in the field of cataract surgery extolling “the benefits of the new
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`formulation.” (EX2l 16, 1155.) Since its April 2013 launch, Prolensa® had generated
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`$246.9 million in revenue by August 2015, despite entering a market with at least
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`six branded drugs and three generic drugs FDA-approved to treat similar
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`indications. (EX2130, 111117, 147.) In fact, Prolensa® has achieved one of the
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`highest shares of prescriptions and revenue among branded drugs with similar
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`indications. (Id.)
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Moreover, six generic companies, including Lupin, have submitted ANDAs
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`seeking to market exact copies of Prolensa®. (EX2082, ¶206.) In fact, Lupin has
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`projected Prolensa®’s sales to exceed $100 million annually, which will occur this
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`year. (EX2026, 4; EX2130, ¶73.) Three others, Apotex, Metrics and Paddock,
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`initially challenged the ’131 patent and/or related patents in district court (EX2130,
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`¶¶77-80; EX2022; EX2019; EX2021), but all three licensed the ’131 patent and
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`took consent judgments and injunctions, tying their acknowledgement of the ’131
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`patent’s validity to their generic copies of Prolensa®. (EX2130, ¶¶77-80; EX2027;
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`EX2029; EX2028.)
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`Against these compelling objective indicia of non-obviousness, Lupin
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`contends that tyloxapol in Sallmann’s Example 2 would have been “swapped” for
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`polysorbate 80 in Ogawa’s Example 6, or alternatively, bromfenac in Ogawa’s
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`Example 6 would have been “swapped” for diclofenac in Sallmann’s Example 2.
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`(Pet., 38-39.) The Board instituted trial on this sole ground but emphasized that it
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`did so “on the current record” and “may change upon consideration of the whole
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`record.” (Inst. Op. at 9, 11, 12, 22.) As discussed below, upon consideration of the
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`full record, Lupin offers no reason, other than impermissible hindsight looking
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`backward from the ’131 patent claims, why a person of ordinary skill in the art
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`(“POSA”) would have chosen Ogawa’s Example 6 or Sallmann’s Example 2 and
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`modified either with any reasonable expectation of arriving at any of the claimed
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`formulations. Indeed, the evidence establishes that a POSA would not have been
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`motivated to pursue bromfenac or tyloxapol at all, and would not have found
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`bromfenac and diclofenac, or tyloxapol and polysorbate 80, interchangeable given
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`their vast chemical, physical and functional differences. Tellingly, Lupin has not
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`proffered a scintilla of evidence for the claims that specifically require greater than
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`about 90% [or 92%] bromfenac remaining after four weeks at 60° C., or the claims
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`that identify the preservative efficacy standard of European Pharmacopoeia
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`Criteria B, and thus Lupin has wholly failed to meet its burden of proving these
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`claims obvious.
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`Lupin and its expert Dr. Jayne Lawrence contend that its “swapping” theory
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`allegedly solves the problem of a “complex” that bromfenac purportedly forms
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`with the preservative benzalkonium chloride (“BAC”). Yet Dr. Paul Laskar,
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`Lupin’s expert in related proceeding IPR2015-00903, candidly admits that no prior
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`art shows that bromfenac actually forms a “complex” with BAC. Consistent with
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`the teachings of the art, given that BAC was known to have significant toxicity to
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`the eye, a POSA as of 2003 would have pursued non-BAC preservatives or
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`unpreserved formulations to entirely eliminate a serious health risk. Proceeding
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`contrary to accepted wisdom, the ’131 patent’s formulations utilize BAC, which
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`alone constitutes strong evidence of non-obviousness.
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`5
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Accordingly, and as discussed below, Lupin’s petition fails (i) to prove that
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`a person of ordinary skill in the art would have combined Ogawa and Sallmann
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`with any reasonable expectation of arriving at the claimed subject matter; (ii) to
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`prove the existence of each element of each challenged claim from Ogawa and
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`Sallmann, including the alleged inherency of various claim elements; and (iii) to
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`rebut the compelling objective indicia of non-obviousness of the claimed subject
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`matter. As result, Lupin has not carried its “burden of proving . . . unpatentability
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`by a preponderance of the evidence,” 35 U.S.C. § 316(e), and the Board should
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`enter judgment against Lupin and uphold the patentability of the claims.
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`II. Claim construction
`In parallel district court litigation before Judge Simandle of the U.S. District
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`Court for the District of New Jersey, Judge Simandle held that “stable” as used in
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`the claims of the ’131 patent means having sufficient resistance to degradation
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`(i.e., chemical stability) and having sufficient preservative efficacy to be
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`formulated and maintained for ophthalmic use, and the phrase “amount sufficient
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`to stabilize” as used in the claims of the ’131 patent means an amount sufficient to
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`confer sufficient resistance to degradation (i.e., chemical stability) to be formulated
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`and maintained for ophthalmic use. (EX2082, ¶¶46-50; EX2065, 5-6.) Judge
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`Simandle also construed the term “satisfies the preservative efficacy standard of
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`the US Pharmacopeia . . .” as used in claims 25-29 of the ’131 patent to mean
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`6
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`“satisfies the preservative efficacy standard of EP-criteria B of the European
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`Pharmacopeia . . . .” (EX2065, 6.) Senju submits that the above terms should be
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`construed in this proceeding in the same way the District Court construed them.
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`Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015).
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`III. Level of ordinary skill in the art
`A person of ordinary skill in the art of the ’131 patent would have at least a
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`bachelor’s degree in a field such as chemistry, pharmaceutical chemistry or a
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`related discipline with 3–5 years of work experience. (EX2082, ¶¶44-45.)
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`IV. The ’131 patent
`The application for the ’131 patent was filed on January 28, 2014, and
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`claims priority benefit of the January 21, 2003, filing date of JP 2003-012427
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`under 35 U.S.C. §119. (EX1002.) The ’131 patent has three independent claims
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`(claims 1, 7 and 13) and 27 dependent claims, which are separately patentable. The
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`’131 patent is listed in the FDA’s Orange Book, and the parties agree that it covers
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`Prolensa® ophthalmic bromfenac (0.07%) solution. (EX1005, ¶¶266, 374; EX2082,
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`¶¶177, 238.)
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`V. Background of ophthalmic formulations
`As of the January 21, 2003 priority date of the ’131 patent, drug formulation
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`was a difficult and unpredictable endeavor, and it remains so today. The
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`formulation of ophthalmic drugs is particularly complex. Formulating stable
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`ophthalmic dosage forms such as the stable aqueous liquid preparations of the ’131
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`patent is more challenging and critical than with other dosage forms such as tablets
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`or capsules. In addition, the surface area of the eye is extremely small, and the
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`residence time for an eye drop is quite short, which increases the challenge in
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`designing an aqueous dosage form that can pass through the hydrophobic cornea
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`membrane of the eye to reach the intended site of action. Indeed, Dr. Laskar has
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`acknowledged these formulation challenges in his prior sworn testimony in a
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`patent infringement case involving the ophthalmic product Combigan®. (EX2135,
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`989, 1020, 1022.)
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`VI. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the ’131 patent obvious
`A. No reason to focus on Ogawa and bromfenac preparations
`Lupin’s central theme is one of “swapping”; that is, swapping tyloxapol in
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`Sallmann’s Example 2 for polysorbate 80 in Ogawa’s Example 6, or alternatively,
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`swapping bromfenac in Ogawa’s Example 6 for diclofenac in Sallmann’s Example
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`2, allegedly would have been obvious. (Pet., 38-39.) The full record shows this
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`swapping theory is premised on a POSA having had a reason to focus on
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`bromfenac formulations. There was none, absent hindsight.
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`By January 21, 2003, there were a number of FDA-approved aqueous
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`ophthalmic formulations containing NSAIDs, including diclofenac (Voltaren®),
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`ketorolac (Acular®), flurbiprofen (Ocufen®), and suprofen (Profenal®). (Id., 7;
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`EX2082, ¶¶70-71.) A POSA therefore would have had no reason or need to focus,
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`for further development, on bromfenac to the exclusion of other NSAIDs.
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`(EX2082, ¶¶70-71.) Indeed, Lupin admits there was no such reason, stating “[t]o
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`the extent there was even any need for the claimed bromfenac ophthalmic
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`formulations claimed in the ’131 patent, it would have been met by the disclosures
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`of the ’225 patent and Hara.” (Pet., 58 (emphasis added).) In fact, Ogawa states
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`that its bromfenac formulations displayed remarkably enhanced stability (EX1010,
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`8:46-9:3), and Dr. Laskar acknowledged that Ogawa satisfied bromfenac’s stability
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`problem. (EX2114, 115:2-116-4.)
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`Moreover, contrary to Lupin’s position, neither Hara nor Yanni supports a
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`preference for bromfenac over diclofenac. (EX2082, ¶¶72-75.) Hara teaches that
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`(1) both have “superior” anti-inflammatory action (EX1006, 2, 3), (2) both treat
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`postoperative inflammation of the eye (id.), (3) diclofenac could treat anterior
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`uveitis, while bromfenac was expressly not approved for this indication (id.), and
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`(4) no toxicity issues were noted for commercialized diclofenac, while bromfenac
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`had serious liver disorders and even fatalities (id.), which prompted the FDA to
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`pull bromfenac’s oral form, Duract®, from the market. (EX2032, 1.) Hara thus
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`certainly does not endorse bromfenac over diclofenac. (EX2082, ¶73.)
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`The same applies to Yanni, which actually disparages bromfenac, preferring
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`esters and amides, like nepafenac. (EX1007, 1:54-59, 4:84-52; EX2082, ¶¶74-75.)
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`Focusing on a single in vitro result from Table 1 of Yanni (EX1005, ¶77), Dr.
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Lawrence ignores important ex vivo and in vivo data (EX2082, ¶¶74-75), which do
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`not show superiority of bromfenac over diclofenac and in fact show superiority of
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`other compounds. (Id.; EX1007, Table 1.)
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`B. Design need and market demands would not have led a POSA in
`the direction that the inventors of the ’131 patent took
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`Lupin’s proffered motivation to substitute polysorbate 80 with tyloxapol is
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`to prevent the alleged formation of an insoluble complex between an acidic
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`NSAID and BAC. (Pet., 8-9.) Dr. Laskar admits, however, that he has no evidence
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`that any such complex actually forms between bromfenac and BAC. (EX2114,
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`45:18-46:4.) Even if such a precipitate did form, which Lupin has not established,
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`a POSA would not have used tyloxapol to address this issue.
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`BAC was known to have significant toxicity to the eye. (EX2082, ¶¶78-
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`79.) In fact, in Allergan v. Sandoz, 796 F.3d 1293, 1305 (Fed. Cir. 2015), the
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`defendant’s expert referred to BAC as a “natural born killer” that was “from
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`Satan.” Dr. Laskar also characterized BAC as a “killer,” known to cause adverse
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`reactions in vitro and in vivo. (EX2114, 78:13-25, 79:13-23.) A POSA objectively
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`viewing this alleged precipitation issue would have sought to eliminate BAC,
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`thereby eliminating its harmful effects and avoiding the precipitation issue entirely,
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`rather than only attempting to reduce it to some extent by adding a surfactant.
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`(EX2082, ¶76.) By January 2003, the art taught using preservative-free
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`formulations and well-tolerated preservatives in place of BAC (EX2082, ¶77;
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`EX2116, ¶¶44-46.) Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d
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`1314, 1326 (Fed. Cir. 2009) (strong inference of non-obviousness when the prior
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`art undermines very reason offered for combining references).
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`Indeed by 2003, market demands sought to eliminate the highly toxic BAC
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`from ophthalmic formulations. The art urged that “[i]t is . . . of striking
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`importance to become aware of preservative toxicity in order to develop in the
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`near future many more unpreserved drugs.” (EX2064, 115, emphasis added;
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`EX2082, ¶¶79-80.) The art taught a preservative-free formulation of Fu’s ketorolac
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`“may be a better as a postoperative ocular analgesic” than preserved ketorolac.
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`(EX2090, abstract; EX2116, ¶43.) By November 1997, Acular® PF—a
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`preservative-free ketorolac ophthalmic solution—received FDA approval.
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`(EX2061, 1; EX2116, ¶29.)
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`The art also taught using better-tolerated preservatives in place of BAC. By
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`2001, published clinical studies demonstrated that the preservative “stabilized
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`oxychloro complex” (“SOC”) could replace BAC in brimonidine ophthalmic
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`formulations. By March 2001, brimonidine-SOC was approved as Alphagan® P,
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`with a superior comfort and reduced ocular allergy profile as compared to
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`brimonidine-BAC. (EX2092; EX2116, ¶44.)
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`Other replacement options for BAC included the preservative lauralkonium
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`chloride (“LAC”), which Dr. Laskar admittedly used previously to avoid the
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`interaction of an acidic drug and BAC. IPR2015-00903, EX1003, ¶104; (EX2114,
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`33:4-34:1; EX2082, ¶82; EX1027, 3:28-4:2, 6:11-7:10). Dr. Lawrence admits that
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`Desai also teaches the use of a different polymeric quaternary ammonium
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`preservative compound, POLYQUAD®, as the solution to the interaction problem.
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`(EX1012, 1:27-2:31; EX2316, 243:4-15; EX2082, ¶84.) Even if a POSA still
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`would have wanted to use BAC, the art provided a solution that would have
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`addressed the NSAID/BAC interaction that underlies Lupin’s proffered motivation
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`to use a solubilizer. Yanni teaches bromfenac derivatives without free carboxyl
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`groups, which would not interact with BAC and which have better ocular
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`penetration and stability than bromfenac. (EX1007, 1:60-2:29; EX2082, ¶89);
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`Depuy Spine, 567 F.3d at 1326.
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`Notwithstanding these clear teachings, Dr. Lawrence selectively relies on
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`Ogawa Example 6, which reported a residual amount of bromfenac of 100.9%.
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`(EX1005, ¶¶332-33.) But she ignores Ogawa Example 7, reporting an equally high
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`residual amount of bromfenac (99.2%) and containing methylparaben and
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`ethylparaben instead of BAC, which Dr. Lawrence testified do not interact and
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`precipitate with bromfenac. (EX2316, 296:4-7.) Thus, Ogawa implements a
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`solution to Dr. Lawrence’s interaction/precipitation problem in a chemically stable
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`formulation, yet Dr. Lawrence ignores it, because, as she testified, she focused first
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`on the patents-in-suit in her obviousness analysis. (EX2316, 15:18-22.)
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`Based on a post hoc analysis that started with the claimed subject matter, Dr.
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`Lawrence postulated a motivation position premised on the interaction of an
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`NSAID and BAC. Defining a problem by its solution reveals improper hindsight,
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`particularly in selecting the prior art “relevant” to the question of obviousness.
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`Insite Vision Inc., v. Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir. 2015). Selecting
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`Ogawa, which does not teach that bromfenac had an interaction/precipitation
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`problem (EX2082, ¶¶84-85, 121), and focusing on Example 6 rather than Example
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`7, which admittedly solved his proffered problem, clearly exposes Dr. Lawrence’s
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`improper post hoc analysis. (Id.)
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`Contrary to Dr. Lawrence’s opinion, a POSA as of 2003 would have pursued
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`non-BAC preservatives or unpreserved formulations to entirely eliminate a serious
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`health risk. (EX2082, ¶77.) This also would have addressed any alleged interaction
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`problem. (EX2082, ¶87.) As such, the art led in a direction divergent from the path
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`chosen by the inventors of the ’131 patent, thereby supporting the non-obviousness
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`of the ’131 patent claims. (EX2082, ¶¶81-84); See Allergan, 796 F.3d at 1305,
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`citing In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) (“A reference may be said to
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`teach away when a person of ordinary skill, upon reading the reference, . . . would
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`be led in a direction divergent from the path that was taken by the [patentee].”);
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`C. A POSA would not have combined Ogawa and Sallmann
`1. Ogawa and the problem it sought to solve
`Ogawa successfully formulated ophthalmic bromfenac preparations that are
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`stable for a long period of time without degradation of bromfenac or the formation
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`of red insoluble matters. (EX1010, 2:32-36; EX2082, ¶123.) Ogawa’s solution
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`involved a water soluble polymer, e.g., polyvinyl pyrrolidone, and a sulfite, i.e.,
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`sodium sulfite. (EX1010, 3:7-15; EX2082, ¶123.) Sodium sulfite is a well-known
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`antioxidant. (EX2013, 3:51-55; EX2082, ¶123.) A POSA would have understood
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`that Ogawa used sodium sulfite because bromfenac chemically degrades by
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`oxidation (EX2105, ¶41), and an antioxidant would prevent that degradation
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`process. Dr. Lawrence acknowledges that it is “standard” to add an antioxidant “to
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`decrease the decomposition of the active ingredient” by oxidation, thereby
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`reducing the potential for detrimental effects to the eye. (EX2316, 66:15-67:2;
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`EX1005, ¶66(e).)
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`When bromfenac oxidizes, its forms an oxidation degradant referred to
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`throughout Ogawa as red insoluble matters. (EX1010, 8:3-45; EX2082, ¶124.) Dr.
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`Laskar agrees that red insoluble matters indicate that bromfenac is chemically
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`degrading. (EX2114, 228:16-24.) These red insoluble particles do not constitute,
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`therefore, the result of any physical interaction such as any precipitation between
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`bromfenac and BAC. (EX2082, ¶125.) Dr. Lawrence in fact admits that an alleged
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`complex between an NSAID and BAC is not chemical degradation. (EX2316,
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`142:14-20.) In fact, none of the art of record ever states that bromfenac interacts
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`with BAC to form a precipitate, and nowhere in Ogawa is such interaction ever
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`mentioned. (EX2082, ¶125.) Given the complexities of ophthalmic formulation
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`systems, a POSA could not have reasonably predicted whether such an interaction
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`does occur. (EX2082, ¶125; EX2105, ¶¶75-80.)
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`Polysorbate 80, moreover, plays no role in chemically stabilizing bromfenac
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`from oxidizing. (EX2082, ¶126.) Ogawa is completely silent on the function of
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`polysorbate 80. (Id.) It was not used to solubilize bromfenac, for a POSA knew
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`that bromfenac is freely soluble in water. (EX2248, 29; EX2140, 156:20-157:6;
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`EX2082, ¶126.) Indeed, Dr. Lawrence admits that it is no use trying to increase the
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`solubility of a water-soluble hydrophilic drug. (EX2316 at 195:3-8.) Nor was it
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`used as a stabilizer, for Ogawa’s examples establish that sodium sulfite produces
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`“remarkably enhanced” stability. (EX1010, 8:46-9:3; EX2082, ¶126.)
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`Citing Ogawa, Dr. Lawrence incorrectly states that polysorbate 80
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`contributes to stabilizing bromfenac. (EX1005, ¶84; EX2082, ¶127.) The data from
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`Ogawa Experimental Examples 4-6 actually confirm that polysorbate 80 does not
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`stabilize bromfenac. (EX2095, 107; EX2082, ¶127.) Upon storage at 60 °C for four
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`weeks, the formulations in Experimental Examples 4-6 containing polysorbate 80
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`without sodium sulfite exhibited chemical instability, as evidenced by the
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`formation of red insoluble matter; i.e., degradation of bromfenac. (EX1010, 8:4-
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`9:5; EX2095, 107; EX2082, ¶128.) But adding sodium sulfite prevented the
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`formation of red insoluble matter, prompting Ogawa to comment that bromfenac
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`decomposition was not observed and bromfenac’s stability was remarkably
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`enhanced. (EX1010, 8:45-9:4; EX2095, 107, Table 10; EX2082, ¶128.) Thus,
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`polysorbate 80 has no effect on the stability of bromfenac. (EX2082, ¶128.)
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`Dr. Lawrence’s attempt to imbue polysorbate 80 with an ability to stabilize
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`bromfenac is fundamental to Lupin’s position that a POSA would have simply
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`“swapped” tyloxapol for polysorbate 80 with a reasonable expectation of success.
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`(Pet., 38-39; EX1005, ¶365.) The data in Ogawa Experimental Examples 4-6,
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`however, completely undermine Lupin’s foundational premise for its obviousness
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`arguments. (EX2082, ¶129.) See Apotex Inc., v. Wyeth LLC, IPR2014-00115, slip
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`op. at 22 (Paper 94) (P.T.A.B. Apr. 20, 2015) (it is improper hindsight to “imbue
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`one of ordinary skill in the art with knowledge of the claimed invention, when no
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`prior art reference or references of record conveys or suggests that knowledge.”).
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`Sallmann’s singular purpose does not align with Ogawa’s
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`2.
`Sallmann is uniquely directed to formulations of the potassium salt of
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`di