Paper No. _
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`Filed: December 28, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
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`INNOPHARMA INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS
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`INC., and MYLAN INC.
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`Petitioner,
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`SENJU PHARMACEUTICAL C0,, LTD., BAUSCH & LOMB, INC., and
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`BAUSCH & LOMB PHARMA HOLDINGS CORP.
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`Patent Owner.
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`Case IPR20I5-00902
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`Patent 8,669,290
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`PATENT OWNER RESPONSE
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`PURSUANT TO 37 C.F.R. § 42.120
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`IPR20l 5—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`Table of Contents
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`'--.JO'\C\
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`10
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`15
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`I7
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`19
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`26
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`30
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`Introduction
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`II.
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`Statement of relief requested
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`III.
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`Claim construction
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`IV.
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`Level of ordinary skill in the art
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`The ‘Z90 patent
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`VI.
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`Background of ophthalmic formulations
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`VII.
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`The combination of Ogawa and Sallmann, in either direction, does not
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`render any claim of the ’290 patent obvious
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`A.
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`B.
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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 ’290 patent took
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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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`lnnoPharma’s arguments of motivation and
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`expectation 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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`I.
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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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`IPR20 1 5-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`34
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`2.
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`InnoPharma’s arguments to modify Sallmann in
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`view of Ogawa are legally insufficient, internally
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`inconsistent, and belied by the very art
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`InnoPham1a cites
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`VIII. Compelling objective evidence of patentability
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`A.
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`Tyl0xapol’s unexpectedly superior chemical stabilizing effect
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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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`2.
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`3.
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`4.
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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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`IX.
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`Separate patentability of individual claims
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`Separate patentability of claims 4-5, 11-12, 17-18 and 23-24
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`Separate patentability of claims 8-13, 20-25, 27, 29 and 30
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`Separate patentability of claims 26-30
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`A.
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`B.
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`C.
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`X.
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`Conclusion
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`TABLE OF AUTHORITIES
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`IPR2015-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`Page(s)
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`Federal Cases
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`Allergen v. Sandoz,
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`796 F.3d 1293 (Fed. Cir. 2015) ................................................................. ..passirn
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`In re Antonie,
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`559 F.2d 618 (C.C.P.A. 1977) .................................................................... ..54, 56
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`Ashland Oil, Inc. v. Deita Resins & Refi'acI0rz’es, Inc.,
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`776 F.2d 281 (Fed. Cir. 1985) .......................................................................... ..58
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`Atlas Powder Co. v. E.I. du Pom‘ De Nemours & C0,,
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`750 F.2d 1569 (Fed. Cir. 1984) ........................................................................ ..33
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`Cadence Pharm. Inc. v. Exela PharmSci Inc.,
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`780 F.3d 1364 (Fed. Cir. 2015) ................................................................. ..passim
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`Catczlina Lighting, Inc. v. Lamps Plus, Inc.,
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`295 F.3d 1277 (Fed. Cir. 2002) ........................................................................ ..37
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`Deputy Spine, Inc. 1/. Medtronic Sofamor Danek, Inc.,
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`567 F.3d 1314(Fed. Cir. 2009) ...................................................... ..1l, 13,29, 33
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`Eisai Co. Ltd. 12. Dr. Reddy’s Labs., Ltd,
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`533 F.3d 1353, (Fed. Cir. 2008) ........................................................... ..20, 24, 26
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`Galderma Labs. v. Tolmar, Inc,
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`737 F.3d 731 (Fed. Cir. 2013) ......................................................................... ..S6
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`In re Gordon,
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`733 F.2d 900 (Fed. Cir. 1984) .......................................................................... ..31
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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 H1:m'—H:mg K00,
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`639 F.3d 1057 (Fed. Cir. 2011) ........................................................................ ..-45
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`iii
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`IPR2015-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`Insitc Vision Inc, v. Scmdoz, Inc,
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`783 F.3d 853 (Fed. Cir. 2015) .................................................................... ..14, 32
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`Instimt Pasteur V. Focarino,
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`738 F.3d 1337 (Fed. Cir. 2013) ........................................................................ ..52
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`Janssen Phorm. NV v. Mylan Pharm, Inc.,
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`456 F. Supp. 2d 644 (D.N.J. 2006), afl’dper curiam, 223 Fed.
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`Appx. 999 (Fed. Cir. 2007) ............................................................................... ..52
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`KSR Int’! Co. v. Teleflex Inc.,
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`550 U.S. 398 (2007) .......................................................................................... ..35
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`Microsofl Corp. v. Proxycorm, 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 l358(Fed. Cir. 2008) ......................................................................... ..37
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`In re Papesch,
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`315 F.2d 381 (C.C.P.A. 1963) .......................................................................... ..45
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`Par Pharm, Inc. v. TWI P/1arms., Inc.,
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`773 F.3d 1186 (Fed. Cir. 2013) ....................................................................... ..57
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`Pfizer Inc. v. Mylar: Pharm. Inc,
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`2014 WL 5388100 (D. Del. 2014) ........................................................ ..22, 28, 32
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`In re Sherry,
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`566 F.2d 81 (C.C.P.A. 1977) ............................................................................ ..57
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`In re Siebentritt,
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`372 F.2d 566 (C.C.P.A. 1967) .......................................................................... ..20
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`Specialty Composites v. Cabot Corp,
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`845 F.2d 981 (Fed. Cir. 1988) .......................................................................... ..52
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`Syntax LLC v. Apofex Inc,
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`2006 U.S. Dist. Lexis 36089 (ND. Cal. 2006), aff’d 221 Fed.
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`Appx. 1002 (Fed. Cir. 2007) ....................................................................... ..24, 26
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`iv
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`lPR20 1 13-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`Unigene Labs. v. Apotex, Inc,
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`655 F.3d 1352 (Fed. Cir. 2011) .................................................................. ..20, 53
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`In re Wesslcm,
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`353 F.2d 238 (C.C.P.A. 1965) .................................................................... ..23, 31
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`Federal Statutes
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`35 U.S.C. § 119 ........................................................................................................ ..8
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`35 U.S.C. § 316(6) ................................................................................................... ..1
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`Other Authorities
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`Apotex Inc., v. Wyeth LLC,
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`1PR2014—00115, slip op. (P.T.A.B. Apr. 20, 2015) ................................... ..17, 28
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`Scmdoz, Inc. v. EKR Therapeutics, LLC,
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`1PR201 5-00005, slip op. (P.T.A.B. Apr. 24, 2015) .......................................... ..58
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`Ex parre Whalen et al.,
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`Appeal 207-4423, slip op. (B.P.A.I. July 23, 2008) ............................. ..54, 55, 56
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`IPR2015—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`Patent Owner Senju Pharmaceutical Co., Ltd. et al. (“Senju”) responds to the
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`Petition filed by InnoPhanna Licensing, Inc. et al. (“lnnoPharma”) concerning
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`claims 1-30 of U.S. Patent No. 8,669,290 (“the ’290 patent”). The Board instituted
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`trial on lnnoPharma’s sole ground that claims 1-30 are allegedly obvious over U.S.
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`Patent No. 4,910,225 to Ogawa et al. (“Ogawa”) (EXIOO4) and U.S. Patent No.
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`5,891,913 to Sallmann et al.
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`(“Sallmann”)
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`(EXIOO9). As discussed below,
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`InnoPharma has
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`failed to meet
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`its “burden of proving a proposition of
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`unpatentability by a preponderance of the evidence.” 35 U.S.C. § 316(6).
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`Indeed, as discussed further below, ln11oPhanna has failed to prove that a
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`person of ordinary skill in the art would have combined Ogawa and Sallmann with
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`any expectation of arriving at the claimed subject matter.
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`I11r1oPharma also has
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`failed to prove the existence of all elements of the ’290 patent claims in the art of
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`record and has failed to carry the high burden of proving the inherency of several
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`claim elements in the obviousness context.
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`In addition,
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`InnoPharma either
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`ineffectively assails or simply ignores significant objective indicia of patentability,
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`which further support the non-obviousness of the ’290 patent claims. The Board
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`accordingly should uphold the patentability of claims 1-30 of the ’290 patent.
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`IPR20l 5-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`I.
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`Introduction
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`The ’290 patent discloses and claims stable aqueous liquid preparations of
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`the non—steroidal anti-inflammatory drug (“NSAID”) brornfenac, marketed as
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`Prolensa® prescription eye drops for treatment of inflammation and pain in cataract
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`surgery patients. I 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. (EX1001, 2:35-47; EX2082, fi|l-44.)
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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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`1]142.) 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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`111] 147, 157,
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`I62.)
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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. (1d., 1]l67.)
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`Tyloxapol’s unexpected stabilizing effect translated into significant medical
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`benefits
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`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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`' lnnoPharma’s expert admits that Prolensa® falls within the scope of the
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`’290 patent claims. (EX2082, fl[l49.)
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`lPR20 1 5-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`formulations (EX2013, 4; EX2026, 5; EX2027, 4), a substantial reduction on a
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`logarithmic scale and closer to the pH of natural tears. (EX2l16, 1141.)‘
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`Both the
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`in paT-
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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., fi[42; EX2030, 1718.) More than a difference
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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 Pro1ensa®.
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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, 1156.) Since its April 2013 launch, Prolensa® has generated
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`$246.9 million in revenue, despite entering a market with at least six branded drugs
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`lPR20 1 5—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`and three generic drugs FDA—approVed to treat similar indications. (EX2l30,
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`11133.) In fact, Pro1ensa®has achieved one of the highest shares of prescriptions and
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`revenue among branded drugs with similar indications. (Id)
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`Moreover, six generic companies,
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`including InnoPharma, have submitted
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`ANDAS seeking to market exact copies of Prolensa®. (EX2082, 11172.) One of
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`these six, Lupin, which also has filed an IPR petition challenging the ’290 patent,
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`has projected Prolensa®’s sales to exceed $100 million annually, which will occur
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`this year. (EX2022, 4; EX2l30, 1175.) Three others, Apotex, Metrics and Paddock,
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`initially challenged the ’290 patent in district court (EX2l30, 111178-80; EX2023;
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`EX20l9; EX2017; EX20l8) but licensed the patent and took consent judgments
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`and injunctions, tying their acknowledgement of the ’290 patent°s validity to their
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`generic copies of Prolensa®. (EX2130,111178—80; EX2024; EX2122; EX2123.)
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`Against these compelling objective indicia of non—obviousness, InnoPharma
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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., 6-9.) As discussed below,
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`lnnoPharma offers no reason, other
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`impermissible hindsight looking backward from the ’29O patent claims, why a
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`person of ordinary skill in the art (“POSA”) would have chosen Ogawa’s Example
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`1PR2015-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`6 or Sallmann’s Example 2 and modified either with any reasonable expectation of
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`arriving at any of the claimed formulations. Indeed, the evidence establishes that a
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`POSA would not have been motivated to pursue bromfenac or tyloxapol at all, and
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`would not have found bromfenac and diclofenac, or tyloxapol and polysorbate 80,
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`interchangeable given their vast chemical, physical and functional differences.
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`Tellingly, InnoPharma has not proffered a scintilla of evidence for the claims that
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`specifically require greater than about 90% [or 92%] brornfenac 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 InnoPharma has wholly failed to
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`InnoPharma contends that
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`its “swapping” theory allegedly Solves the
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`problem of a “complex” that bromfenac purportedly forms with the preservative
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`benzalkonium chloride (“BAC”). Yet
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`InnoPharma’s expert Dr. Paul Laskar
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`candidly admits that no prior art shows that bromfenac actually forms a “complex”
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`with BAC, and that he in fact
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`focused on BAC only because the claimed
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`formulations of the ’290 patent contain it, exposing Im1oPharma’s theory as
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`impermissibly based on hindsight. Consistent with the teachings of the art, Dr.
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`Laskar further admits that BAC is a “killer” that should be eliminated from
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`formulations wherever possible. Proceeding contrary to accepted wisdom, the ’290
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`IPR20l5-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`patent’s formulations utilize BAC, which alone constitutes strong evidence of non-
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`The Board accordingly should reject
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`the Petition and uphold the
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`patentability of all challenged claims.
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`I].
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`Statement of relief requested
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`Senju respectfully requests that InnoPharma’s Petition be denied at least
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`because: (i) it fails to prove that a person of ordinary skill in the art would have
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`combined Ogawa and Sallmann with any reasonable expectation of arriving at the
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`claimed subject matter; (ii) it fails to prove the existence of each element of each
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`challenged claim from Ogawa and Sallmann, including the alleged inherency of
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`various claim elements; and (iii) it fails to rebut the compelling objective indicia of
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`non-obviousness of the claimed subject matter.
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`III. Claim construction
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`All claims of the ’290 patent contain the term “stable,” and claims 1-7
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`further contain the phrase “amount sufficient to stabilize.” Senju and lnnoPharma
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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 US. 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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`IPR20l 5—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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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, fi[‘|]2—l 1), has submitted a declaration in this proceeding and _in the claim
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`construction proceedings before Chief Judge Simandle (EX2l25). Adopting Dr.
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`Williams’ construction of the elements “stable” and “amount sufficient
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`to
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`stabilize” (EX2082, 1147-50; EX2l25; EX2065, 5-6), Judge Simandle held that
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`“stable” as used in the claims of the ’290 patent means having sufficient resistance
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`to degradation (i.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 ’290 patent means an amount
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`sufficient to confer sufficient resistance to degradation (t'.e., chemical stability) to
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`be formulated and maintained for ophthalmic use.
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`(EX2082, 1151; EX2065, 5-6.)
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`Senju submits that these terms should be similarly construed in this proceeding.
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`Microsoft Corp. v. Proxycorm, Inc, 789 F.3d 1292, 1298 (Fed. Cir. 2015).
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`IV.
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`Level ofordinary skill in the art
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`A person of ordinary skill in the art of the ’290 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, W45-46.)
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`V.
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`The ’290 patent
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`The application for the ’290 patent was "filed on January 16, 2004, and
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`lPR201 5—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`claims priority benefit of the January 21, 2003, filing date of JP 2003-01242?
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`under 35 U.S.C. -$119. (EXl001; EX2002.) The ’290 patent has three independent
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`claims (claims 1, 8 and 14) and 27 dependent claims, which are separately
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`patentable. The ’290 patent is listed in the FDA’s Orange Book, and the parties
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`agree that it covers Prolensa® ophthalmic brornfenac (0.07%) solution. (EX1003,
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`fl44;EX2082,fl143J
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`V1. Background of ophthalmic formulations
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`As of the January 21, 2003 priority date of the ’290 patent, drug formulation
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`was a difficult and unpredictable endeavor, and it
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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 ’290
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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. Dr. Laskar himself has
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`acknowledged these formulation challenges in sworn testimony in a patent
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`infringement case involving the ophthalmic product Combiganm.
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`1020,1022)
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`IPR20 l 5-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`VII. The combination of Ogawa and Sallmann, in either direction, does not
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`render any claim of the ’290 patent obvious
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`A.
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`No reason to focus on Ogawa and bromfenac preparations
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`InnoPharma’s central theme of unpatentability is one of “swapping,” that is,
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`Swapping tyloxapol
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`in Sallmann’s Example 2 for polysorbate 80 in Ogawa’s
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`Example 6, or alternatively, swapping bromfenac in Ogawa’s Example 6 for
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`diclofenac in Sallmann’s Example 2, allegedly would have been obvious. (Pet, 6-
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`9.) But this swapping theory is premised on a POSA having had a reason to focus
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`on 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., 26-27.)
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`A POSA therefore would have had no reason or need to focus,
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`development, on bromfenac to the exclusion of other NSAIDS. (EX2082, ‘[|1]65—66.)
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`Indeed, InnoPharma admits there was no such reason, stating “[t]o the extent there
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`was even any need for the claimed bromfenac ophthalmic formulation, it was met
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`by the disclosures of Ogawa and Hara.” (Pet., 51 (emphasis added).) In fact,
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`Ogawa states that
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`its bromfenac formulations displayed remarkably enhanced
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`stability (EXIOO4, 8:46~9:3), and Dr. Laskar acknowledged that Ogawa satisfied
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`bromfenac’s stability problem. (EX2l 14, 115:2-116-4.)
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`IPR2015-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`Moreover, neither Hara nor Yanni supports a preference for bromfenac over
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`diclofenac, contrary to lnnoPharma’s position. (EX2082, 111167-70.) Hara teaches
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`that (1) both have “superior” anti-inflammatory action (EX1002, 2, 3), (2) both
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`treat 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. (EX2029, 1.) Hara thus
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`certainly does not endorse bromfenac over diclofenac. (EX2082, 1168.)
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`The same applies to Yanni, which actually disparages bromfenac, preferring
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`esters and amides, like nepafenac. (EX1028, 1:54-59, 4:84-52; EX2082, 111169-'70.)
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`Focusing on a single in vitro result from Table 1 of Yanni (EXIOO3, 1130), Dr.
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`Laskar ignores important ex vivo and in vivo data (EX2082, 111169-70), which do not
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`Show superiority of bromfenac over diclofenac and in fact show superiority of
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`other compounds. (1d.; EXl028, Table l.)
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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 ’290 patent took
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`InnoPharma’s proffered motivation to substitute polysorbate 80 with
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`tyloxapol is to prevent the alleged formation of a precipitate between an acidic
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`NSAID and BAC. (EXl003, 11104.) Dr. Laskar admits, however, that he has no
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`IPR20 1 5—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`evidence that any such precipitate actually forms between bromfenac and BAC.
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`(EX2l14, 45:18-46:4.) But even if such a precipitate did form, which Dr. Laskar
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`has not established,
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`there would have been no motivation to use tyloxapol to
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`address this issue.
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`BAC was known to have significant toxicity to the eye. (EX2082, f[74.) In
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`fact, in Allergcm v. Scmdoz, 796 F.3d 1293, 1305 (Fed. Cir. 2015), the defendant’s
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`expert referred to BAC as a “natural born killer” that was “from Satan.” Dr. Laskar
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`also characterized BAC as a “killer,” known to cause adverse reactions in vitro and
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`in viva. (EX2l14, 78:13-25, 79:13-23.)
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`A POSA objectively viewing this alleged precipitation issue would have
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`sought to eliminate BAC, thereby eliminating its harmful effects and avoiding the
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`precipitation issue entirely, rather than only attempting to reduce it to some extent
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`by adding a surfactant. (EX2082, 1[7l.) By January 2003,
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`the art taught using
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`preservative-free formulations and well-tolerated preservatives in place of BAC
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`(EX2082, W2; EX2l 16, 1N-45-47.) Depuy Spine, Inc. v. Medtr0nt'c Sofamor Dcmek,
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`Inc., 567 F.3d 1314, 1326 (Fed. Cir. 2009) (strong inference of non-obviousness
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`when the prior art undermines very reason offered for combining references). Dr.
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`Laskar did not consider these solutions. He admitted to focusing on BAC because
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`the ’290 patent claims recite it. (EX2114, 69:21-70:10.)
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`IP R201 5-00902
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`Patent Owner Response
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`Patent No. 8,669,290
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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, 111174-75.) The art taught a preservative-free formulation of F u’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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`1144.) 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 FDA approval.
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`(EX206l, 1; EX2l 16, 1l29.)
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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; EX2l ] 6, '[[45.)
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`Other replacement options for BAC included the preservative lauralkonium
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`chloride (“LAC”), which Dr. Laskar himself admittedly used previously to avoid
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`the interaction of an acidic drug and BAC.
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`lPR20l5-00903, EXIOO3, 1ll04;
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`(EX2l14, 33:4-34:]; EX2082, 1[60; EXl020, 3:28-4:2, 6:'ll-7:10). Desai also
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`IPR2015—00902
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`Patent Owner Response
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`Patent No. 8,669,290
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`teaches the use of a different polymeric quaternary ammonium preservative
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`compound, POLYQUAD®, which Dr. Laskar admits would avoid the interaction
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`problem. (EX1005, 1:27-2:31; EX21l4, 93:3-16; EX2082, 1177.) Even if a POSA
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`still would have wanted to use BAC, the art provided a solution that would have
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`addressed the NSAID/BAC interaction that underlies Dr. Laskar’s proffered
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`motivation to use a solubilizer. Yanni teaches brornfenac derivatives without free
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`carbo