Paper No. __
`Filed: February 25, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`__________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`__________________
`
`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.
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`SENJU PHARMACEUTICAL CO., LTD.,
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`Patent Owner.
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`__________________
`Case IPR2015-010971
`Patent 8,754,131
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`__________________
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`PATENT OWNER RESPONSE
`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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`PAGE 1 OF 69
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`Patent Owner Response, IPR20]5-01 09 7, US. Patent No. 8, 754,131
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`Table of Contents
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`Preliminary Statement
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`II.
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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 ’l3l patent
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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 ’ l31 patent obvious
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`\l\l\lO\
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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 ’ 131 patent took
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`10
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`C.
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`A POSA would not have combined Ogawa and Sallmann
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`14
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`A.
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`B.
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`Ogawa and the problem it sought to solve
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`14
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`Sallmann’s singular purpose does not align with
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`Ogawa’s
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`16
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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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`18
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`1.
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`2.
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`3.
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`4.
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`Lupin’s arguments of motivation and expectation
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`of success ring hollow
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`24
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`29
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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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`29
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`32
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`PAGE 2 OF 69
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`PAGE 2 OF 69
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`Patent Owner Response, IPR201 5-01 09 7, U.S. Patent No. 8,754,131
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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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`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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`Tyloxap0l’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 4, 6, 10-12, 16, 18, 22-23, and
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`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.
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`Conclusion
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`38
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`45
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`52
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`56
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`PAGE 3 OF 69
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`PAGE 3 OF 69
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`Patent Owner Response, IPR20I5—0I 097, US. Patent No. 8,754,131
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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) .................................................................... ..53, 55
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`Aslzland Oil, Inc. v. Delta Resins & Refractories, Inc.,
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`776 F.2d 281 (Fed. Cir. 1985) .......................................................................... ..58
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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) ........................................................................ ..31
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`Cadence Pharm. Inc. v. Exela PlzarmSci 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
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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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`L 27 F.3d 551 (Fed. Cir. 1994) ...................................................................... ..13, 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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`11i
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`PAGE 4 OF 69
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`PAGE 4 OF 69
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`Patent Owner Response, IPR201 5-0] 09 7, U.S. Patent No. 8, 754, I 3 I
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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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`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.,
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`456 F. Supp. 2d 644 (D.N.J. 2006), afl’a’per 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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`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,
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`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.,
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`2014 WL 5388100 (D. Del. 2014) ........................................................ ..22, 26, 31
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`In re Shettj/,
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`566 F.2d 81 (C.C.P.A. 1977) ............................................................................ ..57
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`Specialty Composites v. Cabot Corp.,
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`845 F.2d 981 (Fed. Cir. 1988) .......................................................................... ..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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`1V
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`PAGE 5 OF 69
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`PAGE 5 OF 69
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`Patent Owner Response, IPR20]5—0]097, US. Patent No. 8,754,131
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`In re Wesslau,
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`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(6) ............................................................................................... ..1, 6
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`Other Authorities
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`Apotex Inc., v. Wyeth LLC,
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`IPR2014-001 15, slip op. (P.T.A.B. Apr. 20, 2015) ................................... ..16, 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.I. July 23, 2008) ............................. ..53, 54, 55
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`V
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`PAGE 6 OF 69
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`Patent Owner Response, IPR2015—0] 09 7, US. Patent No. 8, 754, 13]
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`Patent Owner Senju Pharmaceutical C0,, 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 ’l3l 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”) (EXlOl0). 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 ’l31 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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`PAGE 7 OF 69
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`Patent Owner Response, IPR2015—0] 09 7, US. Patent No. 8, 754,131
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`Prolensa® prescription eye drops for treatment of inflammation and pain in cataract
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`surgery patients. ' 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. (EX1002, 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 efficacy—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 formulating
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`Prolensa® at pH 7.8, down fiom pH 8.3 in non-prior art Xibrom® and Bromday®
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`formulations (EXIO49, 4; EXIOO8, 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. (EX2116, 1140.)
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`'Lupin’s expert Dr. Lawrence admits that Prolensa® is an embodiment of
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`certain of the ’l31 patent claims. (EX1005, 1111266, 374.)
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`PAGE 8 OF 69
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`Patent Owner Response, 1PR20I5-0109 7, US. Patent No. 8, 754,131
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`Both the reduction in pH in Pro1ensa®
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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, 1[55.) 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, 1[1]17, 147.) In fact, Pro1ensa® 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, IPR20I5—01097, US. Patent No. 8, 754,13]
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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, 11206.) 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; EX2l30, 1173.) 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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`111177-80; EX2022; EX20l9; EX202l), but all three licensed the ’l3l patent and
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`took consent judgments and injunctions, tying their acknowledgement of the ’13l
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`patent’s validity to their generic copies of Prolensa®. (EX2130, 111177-80; EX2027;
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`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.
`(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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`backward from the ’l3l 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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`PAGE 10 OF 69
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`PAGE 10 OF 69
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`Patent Owner Response, IPR20I5—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
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`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 IPR20l5—O0903, 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 ’l3l patent’s formulations utilize BAC, which
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`alone constitutes strong evidence of non—obviousness.
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`PAGE 11 OF 69
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`PAGE 11 OF 69
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`Patent Owner Response, IPR20I5—0] 097, US. Patent No. 8, 754, 13]
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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 .
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`. unpatentability
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`by a preponderance of the evidence,” 35 U.S.C. § 3l6(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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`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 ’l3l patent means having sufficient resistance to degradation
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`(z'.e., chemical
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`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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`(EX2082, W46-50; 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 .
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`.” as used in claims 25-29 of the ’13l patent to mean
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`PAGE 12 OF 69
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`PAGE 12 OF 69
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`Patent Owner Response, IPR2015-01 097, US. Patent No. 8, 754,13]
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`“satisfies the preservative efficacy standard of EP-criteria B of the European
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`Pharmacopeia .
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`.” (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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`Microsofi‘ Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015).
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`III. Level of ordinary skill in the art
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`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, 111144-45.)
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`IV.
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`The ’131 patent
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`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. §1l9. (EX1002.) The ’l31 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. (EXl005, 1111266, 374; EX2082,
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`1111177, 238.)
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`V.
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`Background of ophthalmic formulations
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`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
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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 ’l3l
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`PAGE 13 OF 69
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`PAGE 13 OF 69
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`Patent Owner Response, IPR2015-0109 7, 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.
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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®.
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`(EX2l35,
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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 ’131 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., 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,
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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 (Profenal®). (Id., 7;
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`EX2082, 1[1l70—7l.) A POSA therefore would have had no reason or need to focus,
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`PAGE 14 OF 69
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`PAGE 14 OF 69
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`Patent Owner Response, IPR2015-0] 09 7, US. Patent No. 8, 754, 13]
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`for
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`further development, on bromfenac to the exclusion of other NSAIDS.
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`(EX2082, W70-71.) Indeed, Lupin admits there was no such reason, stating “[t]o
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`the extent
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`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 (EXIOIO,
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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, W72-75.) 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, 1173.)
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`The same applies to Yanni, which actually disparages bromfenac, preferring
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`esters and amides, like nepafenac. (EXIOO7, 1:54-59, 4:84-52; EX2082, M74-75.)
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`Focusing on a single in vitro result from Table 1 of Yanni (EX1005, 1177), Dr.
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`PAGE 15 OF 69
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`PAGE 15 OF 69
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`Patent Owner Response, IPR20I5—0I097, US. Patent No. 8, 754,131
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`Lawrence ignores important ex vivo and in vivo data (EX2082, W74-75), 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.
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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 ’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 havesignificant toxicity to the eye. (EX2082, 111178-
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`79.) In fact,
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`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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`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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`1176.) 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, 1177;
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`10
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`PAGE 16 OF 69
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`PAGE 16 OF 69
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`Patent Owner Response, IPR2015-01097, US. Patent No. 8, 754,13]
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`EX21 16, 1144-46.) 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 unpreserved drugs.” (EX2064, 115, emphasis added;
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`EX2082, 1179-80.) 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,
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`abstract; EX2l16,
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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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`solution——received
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`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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`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, 1144.)
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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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`11
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`PAGE 17 OF 69
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`PAGE 17 OF 69
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`Patent Owner Response, IPRZOI 5-01 09 7, U.S. Patent No. 8, 754, [3]
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`interaction of an acidic drug and BAC. IPR20l5-00903, EX1003, 11104; (EX2114,
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`33:4-34:1; EX2082, 1182; 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, 1184.) Even if a POSA still
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`would have wanted to use BAC,
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`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
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`interact with BAC and which have better ocular
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`penetration and stability than bromfenac. (EX1007, 1:60-2:29; EX2082, 1189);
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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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`(EXl005, 1111332-33.) 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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