Paper No. __
`Filed: February 25, 2016
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC., INNOPHARMA
`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and
`MYLAN INC.
`
`Petitioners,
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`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`__________________
`Case IPR2015-011001
`Patent 8,927,606
`__________________
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
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`1 Case IPR2016-00091 has been joined with this proceeding.
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`PAGE 1 OF 69
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`Patent Owner Response, IPRZOI5-01100, US. Patent No. 8,92 7, 606
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`Table of Contents
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`1.
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`II.
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`Preliminary Statement
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`Claim construction
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`III.
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`Level of ordinary skill in the art
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`IV.
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`The ’606 patent
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`V.
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`Background of ophthalmic formulations
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`VI.
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`The combination of Ogawa and Sallmann, in either direction, does not
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`render any claim of the ’606 patent obvious
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`No reason to focus on Ogawa and bromfenac preparations
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`Design need and market demands would not have led a POSA
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`in the direction that the inventors of the ’606 patent took
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`A.
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`B.
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`C.
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`A POSA would not have combined Ogawa and Sallmann
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`Ogawa and the problem it sought to solve
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`Sallmann’s singular purpose does not align with
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`Ogawa’ s
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`It would not have been obvious to modify Ogawa
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`Example 6 in view of Sallmann Example 2
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`Lupin’s arguments of motivation and expectation
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`of success ring hollow
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`1.
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`2.
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`3.
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`4.
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`D.
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`Sallmann in view of Ogawa: another hindsight-laden
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`combination
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`1.
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`2.
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`The proposed combination destroys the essential
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`purpose of Sallmann and ignores the blaze marks
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`in the art
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`Lupin’s arguments to modify Sallmann in view of
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`Ogawa are legally insufficient, internally
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`inconsistent, and belied by the very art Lupin cites
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`PAGE 2 OF 69
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`PAGE 2 OF 69
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`Patent Owner Response, IPRZOI5-01100, US. Patent No. 8,92 7,606
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`VII. Compelling objective evidence of patentability
`A.
`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
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`80
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`Tyloxapol’s unexpectedly superior stabilizing
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`effect
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`Tyloxapol’s unexpectedly better maintenance of
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`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 5-8, 15-16, 23 and 27
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`Separate patentability of claims 11-18, 26 and 29
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`Separate patentability of claims 28-30
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`IX.
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`Conclusion
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`5 8
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`PAGE 3 OF 69
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`ii
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`PAGE 3 OF 69
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`Patent Owner Response, IPR20I 5-01 I 00, US. Patent No. 8,92 7,606
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`TABLE OF AUTHORITIES
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`Page(s)
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`Federal Cases
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`Allergan v. Sandoz,
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`796 F.3d 1293 (Fed. Cir. 2015) ................................................................. ..passim
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`In re Antonie, '
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`559 F.2d 618 (C.C.P.A. 1977) .................................................................... ..52, 55
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`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
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`776 F.2d 281 (Fed. Cir. 1985) .......................................................................... ..57
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`Atlas Powder Co. v. E.I. du Pont De Nemours & Co.,
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`750 F.2d 1569 (Fed. Cir. 1984) ........................................................................ ..32
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`Cadence Pharm. Inc. v. Exela P/1armSci Inc.,
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`780 F.3d 1364 (Fed. Cir. 2015) ................................................................. ..passim
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`Catalina Lighting, Inc. v. Lamps Plus, Inc.,
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`295 F.3d 1277 (Fed. Cir. 2002) ........................................................................ ..36
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`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
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`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, 21
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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,
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`733 F.2d 900 (Fed. Cir. 1984) .......................................................................... ..30
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`In re Gurley,
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`27 F.3d 551 (Fed. Cir. 1994) ...................................................................... ..14, 24
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`In re Huai-Hung Kao,
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`639 F.3d 1057 (Fed. Cir. 2011) ........................................................................ ..44
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`PAGE 4 OF 69
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`iii
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`PAGE 4 OF 69
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`Patent Owner Response, IPR2015-0] 100, US. Patent No. 8,92 7, 606
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`Insite Vision Inc., v. Sandoz, Inc.,
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`783 F.3d 853 (Fed. Cir. 2015) .................................................................... ..13, 31
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`.
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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 P/1arm., Inc.,
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`456 F. Supp. 2d 644 (D.N.J. 2006), afi”dper curiam, 223 Fed.
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`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.,
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`789 F.3d 1292 (Fed. Cir. 2015) .......................................................................... ..7
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`0rtho—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,
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`315 F.2d 381 (C.C.P.A. 1963) .......................................................................... ..44
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`Par Pharm., Inc. v. TW] Pharms., Inc.,
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`773 F.3d 1186 (Fed. Cir. 2013) ....................................................................... ..56
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`Pfizer Inc. v. Mylan Pharm. Inc.,
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`2014 WL 5388100 (D. Del. 2014) ........................................................ ..23, 26, 31
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`In re Shetty,
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`566 F.2d 81 (C.C.P.A. 1977) ............................................................................ ..56
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`Specialty Composites v. Cabot Corp.,
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`845 F.2d 981 (Fed. Cir. 1988) ...........................................
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`............................. ..50
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`Syntex LLC v. Apotex Inc.,
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`2006 U.S. Dist. Lexis 36089 (N.D. Cal. 2006), afi"d 221 Fed.
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`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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`PAGE 5 OF 69
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`PAGE 5 OF 69
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`Patent Owner Response, IPR20I5-01100, US. Patent No. 8,92 7, 606
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`In re Wesslau,
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`353 F.2d 238 (C.C.P.A. 1965) .................................................................... ..24, 31
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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(6) ............................................................................................... ..l, 6
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`Other Authorities
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`Apotex Inc., v. Wyeth LLC,
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`IPR2014-00115, slip op. (P.T.A.B. Apr. 20, 2015) ................................... ..l6, 26
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`Sandoz, Inc. v. EKR Therapeutics, LLC,
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`IPR2015-00005, slip op. (P.T.A.B. Apr. 24, 2015) .......................................... ..57
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`Ex parte Whalen et al.,
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`Appeal 207-4423, slip op. (B.P.A.l. July 23, 2008) ............................. ..52, 53, 55
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`PAGE 6 OF 69
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`Patent Owner Response, IPR20I 5-01 I 00, US. Patent No. 8,92 7, 606
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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. 8,927,606 (“the ’606 patent”). The Board instituted
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`trial on Lupin’s Ground No.
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`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”) (EXl010). 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
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`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 ’606 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 ’606 patent claims. The Board accordingly should uphold the
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`patentability of claims 1-30 of the ’606 patent.
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`1.
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`Preliminary Statement
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`The ’606 patent discloses and claims methods for treating an inflammatory
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`disease of an eye, comprising administering to said eye a stable aqueous liquid
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`Patent Owner Response, IPR2015-01100, US. Patent No. 8, 92 7, 606
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`preparation of the non-steroidal anti-inflammatory drug (“NSAID”) bromfenac,
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`marketed as Prolensa® prescription eye drops for treatment of inflammation and
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`pain in cataract surgery patients] These formulations are chemically stable, lack
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`microbial contamination, and can be administered safely and effectively for
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`ophthalmic use at a pH that does not cause eye irritation. (EX1004, 2:26-38;
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`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,
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`‘l[1l16—l7.) 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., W180, 189, 196.)
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`Tyloxapol also unexpectedly maintained preservative efficacy—z'.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., 1l200.)
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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 formulating
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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 (EXIO49, 4; EXl008, 3; EXIOO9, 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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`' Lupin’s expert Dr. Lawrence admits that Prolensa® is an embodiment of
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`certain ofthe ’606 patent claims. (EX1005, W266, 600.)
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`PAGE 8 OF 69
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`PAGE 8 OF 69
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`Patent Owner Response, IPR2015-01100, US. Patent No. 8,92 7, 606
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`comfortable to patients. (Exam, 1140.)—
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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. (Id.) Lowering the pH also improved
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`bromfenac’s intraocular penetration and permitted lowering its concentration to
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`0.07%, 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.” (EX2116, 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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`PAGE 9 OF 69
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`PAGE 9 OF 69
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`Patent Owner Response, IPR2015-01100, U.S. Patent No. 8,92 7,606
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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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`Moreover, six generic companies, including Lupin, have submitted ANDAS
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`seeking to market exact copies of Prolensa®. (EX2082, 11205.) 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, 1173.) Three others, Apotex, Metrics and Paddock,
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`"initially challenged related patents in district court (EX2130, W77-80; EX2022;
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`EX2019; EX2021) but licensed the ’606 patent and took consent judgments and
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`injunctions,
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`tying their acknowledgement of the ’606 patent’s validity to their
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`generic copies of Prolensa®. (EX2130, ‘W77-80; EX2027; EX2029; EX2028.)
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`Against
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`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., 40-41.) The Board instituted trial on this sole ground but emphasized that it
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`did so “on the current record.” (Inst. Op. at 10-12, 14.) As discussed below, upon
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`consideration of the full record, Lupin offers no reason, other than impermissible
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`hindsight looking backward from the ’606 patent claims, why a person of ordinary
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`skill in the art (“POSA”) would have chosen Ogawa’s Example 6 or Sallmann’s
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`Example 2 and modified either with any reasonable expectation of arriving at any
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`PAGE 10 OF 69
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`PAGE 10 OF 69
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`Patent Owner Response, IPRZOI5-01100, US. Patent No. 8,92 7, 606
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`of the claimed formulations. Indeed, the evidence establishes that a POSA would
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`not have been motivated to pursue bromfenac or tyloxapol at all, and would not
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`have found bromfenac and diclofenac, or
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`tyloxapol and polysorbate 80,
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`interchangeable given their vast chemical, physical and functional differences.
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`Tellingly, Lupin has not proffered a scintilla of evidence for the claims that
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`specifically require greater than about 90% [or 92%] bromfenac remaining after
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`four weeks at 60° C., or the claims that identify the preservative efficacy standard
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`of European Pharmacopoeia Criteria B, and thus Lupin has wholly failed to meet
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`its burden of proving these 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 IPR20l5-00903, 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 ’606 patent’s formulations utilize BAC, which
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`alone constitutes strong" evidence ofnon—obviousness.
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`I
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`Accordingly, and as discussed below, Lupin’s petition fails (i) to prove that
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`PAGE 11 OF 69
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`PAGE 11 OF 69
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`Patent Owner Response, IPR20I 5-01 100, US. Patent No. 8,92 7, 606
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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
`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 .
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`. 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.
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`Claim construction
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`All claims of the ’606 patent contain the term “stable,” and claims 1-10
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`further contain the phrase “amount sufficient
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`to stabilize.” Senju and Lupin
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`disputed the meaning of this term and phrase in parallel district court litigation
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`before Chief Judge Simandle of the U.S. District Court for the District of New
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`Jersey. On behalf of Senju, Dr. Robert Williams, III. Ph.D., who is an expert in the
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`field of pharmaceutical formulation and development and who, based on his
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`education and experience,
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`is qualified to provide his opinions in this matter
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`(EX2082, 11112-l 1), has submitted a declaration in this proceeding and in the claim
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`construction proceedings before Judge Simandle (EX2l25). Adopting Dr.
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`Williams’ construction of the elements “stable” and
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`amount sufficient
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`to
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`stabilize” (EX2082, W49-53; EX2125; EX2065, 5-6), Judge Simandle held that
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`PAGE 12 OF 69
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`PAGE 12 OF 69
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`Patent Owner Response, IPR20I5—01100, US. Patent No. 8,92 7,606
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`.“stable” as used in the claims of the ’606 patent means having sufficient resistance
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`to degradation (z'.e., chemical stability) and having sufficient preservative efficacy
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`to be formulated and maintained for ophthalmic use, and the phrase “amount
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`sufficient to stabilize” as used in the claims of the ’606 patent means an amount
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`sufficient to confer sufficient resistance to degradation (z'.e., chemical stability) to
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`be formulated and maintained for ophthalmic use. (EX2082, 1152; EX2065, 5-6.)
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`Senju submits that the above terms should be construed in this proceeding in the
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`same way the District Court construed them. Microsoft Corp. v. Proxyconn, Inc.,
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`789 F.3d 1292, 1298 (Fed. Cir. 2015).
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`III.
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`Level of ordinary skill in the art
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`A person of ordinary skill in the art of the ’606 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, W47-48.)
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`IV.
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`The ’606 patent
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`The application for the ’606 patent was filed on September 23, 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. (EX1004.) The ’606 patent has three independent claims
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`(claims 1, 11 and 19) and 27 dependent claims, which are separately patentable.
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`The ’606 patent is listed in the FDA’s Orange Book, and the parties agree that it
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`covers Prolensa® ophthalmic bromfenac (0.07%) solution. (EXl005, W266, 600;
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`PAGE 13 OF 69
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`PAGE 13 OF 69
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`Patent Owner Response, IPRZOI 5-01 I 00, US. Patent No. 8, 92 7, 606
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`EX2082, 1111176, 237.)
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`V.
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`0 Background of ophthalmic formulations
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`As of the January 21, 2003 priority date of the ’606 patent, drug formulation
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`was a difficult and unpredictable‘ endeavor, and it
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`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 ’606
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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.
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`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.
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`The combination of Ogawa and Sallmann, in either direction, does not
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`render any claim of the ’606 patent obvious
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`A.
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`No reason to focus on Ogawa and bromfenac preparations
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`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, 40-41.) The full record shows this
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`PAGE 14 OF 69
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`PAGE 14 OF 69
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`Patent Owner Response, IPR20]5—0J I 00, U.S. Patent No. 8,92 7, 606
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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,
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`there were a number of FDA-approved aqueous
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`ophthalmic formulations containing NSAIDS,
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`including diclofenac (Voltaren®),
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`ketorolac (Acular®), flurbiprofen (Ocufen®), and suprofen (Profena1®).
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`(Id., 7;
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`EX2082, W68-69.) A POSA therefore would have had no reason or need to focus,
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`further development, on bromfenac to the exclusion of other NSAIDS.
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`(EX2082, 1Hl68—69.) Indeed, Dr. Lawrence admits there was no such reason, stating
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`“[t]o the extent there was even any need for the claimed bromfenac ophthalmic
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`formulation claimed in the asserted claims of the asserted patents, it is my opinion
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`that that need would have been met by the disclosures of the ’225 patent and
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`Hara.”
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`(EX2253 at
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`1] 727, emphasis added.)
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`In fact, Ogawa states that
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`its
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`bromfenac formulations displayed remarkably enhanced stability (EX1010, 8:46-
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`9:3), and Dr. Laskar acknowledged that Ogawa satisfied bromfenac’s stability
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`problem. (EX21 14, 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 diclofenae. (EX2082, 1l‘fl70—73.) Hara teaches that
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`(1) both have “superior” anti-inflammatory action (EXIOO6, 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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`PAGE 15 OF 69
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`PAGE 15 OF 69
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`Patent Owner Response, IPR20I5—0I100, US. Patent No. 8,92 7, 606
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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, 1l71.)
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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, W72-73.)
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`Focusing on a single in vitro result from Table 1 of Yanni (EXl005, 1177), Dr.
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`Lawrence ignores important ex vivo and in vivo data (EX2082, W72-73), 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.
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`Design need and market demands would not have led a POSA in
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`the direction that the inventors of the ’606 patent took
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`Lupin’s proffered motivation to substitute polysorbate 80 with tyloxapol is
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`to prevent
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`the alleged formation of an insoluble complex between an acidic
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`NSAID and BAC. (Pet., 8.) 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
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`toxicity to the eye.
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`(EX2082,
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`1Hl76—77.) In fact, in Allergan v. Scmdoz, 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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`10
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`PAGE 16 OF 69
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`Patent Owner Response, IPR20I 5-0] I 00, US. Patent No. 8,92 7, 606
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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,
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`1174.) By January 2003,
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`the art
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`taught using preservative-free
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`formulations and well-tolerated preservatives in place of BAC (EX2082, 1175;
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`EX2116, 111144-46.) 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
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`is
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`. 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 anpreserved drugs.” (EX2064, 115, emphasis added;
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`EX2082, 1177-78.) 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,
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`abstract; EX2116,
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`1143.) By November
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`1997, Acular® PF—a
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`preservative-free
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`ketorolac
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`ophthalmic
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`so1ution——received FDA approval.
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`(EX2061, 1; EX2116, 1129.)
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`The art also taught using better-tolerated preservatives in place of BAC. By
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`PAGE 17 OF 69
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`11
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`PAGE 17 OF 69
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`Patent Owner Response, IPR20I 5-01 I 00, US. Patent No. 8,92 7, 606
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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; EX21 16, fl[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, 11104; (EX2114,
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`33:4—34:1; EX2082, 1180; 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,