`Filed: February 25, 2016
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC., INNOPHARMA
`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and
`MYLAN INC.
`
`Petitioners,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`__________________
`Case IPR2015-011001
`Patent 8,927,606
`__________________
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`
`
`
`1 Case IPR2016-00091 has been joined with this proceeding.
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR201 5-01 I 00, US. Patent No. 8,92 7, 606
`
`
`
`
`
`Table of Contents
`
`
`
`
`1.
`
`II.
`
`
`
`
`Preliminary Statement
`
`
`
`
`Claim construction
`
`
`
`III.
`
`
`
`
`
`
`
`
`
`Level of ordinary skill in the art
`
`
`
`IV.
`
`
`
`
`
`The ’606 patent
`
`
`
`V.
`
`
`
`
`
`
`Background of ophthalmic formulations
`
`
`
`VI.
`
`
`
`
`
`
`
`
`
`
`
`
`
`The combination of Ogawa and Sallmann, in either direction, does not
`
`
`
`
`
`
`
`
`render any claim of the ’606 patent obvious
`
`
`
`
`
`1
`
`6
`
`
`
`
`
`7
`
`
`
`7
`
`8
`
`
`
`
`
`8
`
`
`
`8
`
`
`
`10
`
`14
`
`14
`
`17
`
`
`
`18
`
`
`
`25
`
`
`
`29
`
`
`
`30
`
`
`
`33
`
`
`
`
`
`
`
`
`
`
`
`No reason to focus on Ogawa and bromfenac preparations
`
`
`
`
`
`
`
`
`
`
`
`
`Design need and market demands would not have led a POSA
`
`
`
`
`
`
`
`
`
`
`
`in the direction that the inventors of the ’606 patent took
`
`
`
`
`
`
`
`
`
`
`
`A POSA would not have combined Ogawa and Sallmann
`
`
`
`
`
`
`
`
`
`
`Ogawa and the problem it sought to solve
`
`
`
`
`
`
`
`
`
`Sal1mann’s singular purpose does not align with
`
`Ogawa’ s
`
`
`
`
`
`
`
`
`
`
`
`It would not have been obvious to modify Ogawa
`
`
`
`
`
`
`
`
`Example 6 in view of Sallmann Example 2
`
`
`
`
`
`
`
`
`Lupin’s arguments of motivation and expectation
`
`
`
`
`of success ring hollow
`
`
`
`
`
`1.
`
`2.
`
`3.
`
`
`
`4.
`
`
`
`
`
`A.
`
`B.
`
`C.
`
`
`D.
`
`
`
`
`
`
`
`Sallmann in view of Ogawa: another hindsight—laden
`
`combination
`
`
`
`
`
`
`
`
`
`The proposed combination destroys the essential
`
`
`
`
`
`
`
`
`purpose of Sallmann and ignores the blaze marks
`
`
`
`in the art
`
`
`
`
`
`
`
`
`Lupin’s arguments to modify Sallmann in View of
`
`
`
`
`
`Ogawa are legally insufficient, internally
`
`
`
`
`
`
`
`
`inconsistent, and belied by the very art Lupin cites
`
`
`
`
`
`
`
`l.
`
`
`2.
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR201 5-01 100, US. Patent No. 8, 92 7, 606
`
`
`
`
`
`36
`
`
`
`
`
`
`
`
`
`
`VII. Compelling objective evidence of patentability
`
`
`
`
`A.
`
`
`
`
`
`
`Tyloxapol’s unexpectedly superior chemical stabilizing effect
`
`
`
`1.
`
`
`
`
`2.
`
`
`
`
`
`
`
`
`
`
`Testing against the closest prior art
`
`
`
`
`
`
`
`
`
`A POSA’s expectation, if anything, of polysorbate
`
`80
`
`
`
`
`
`
`Tyloxapol’s unexpectedly superior stabilizing
`
`effect
`
`
`
`
`
`
`
`Tyloxapol’s unexpectedly better maintenance of
`
`
`preservative efficacy
`
`
`
`B.
`
`
`
`A Additional compelling objective evidence of patentability
`
`
`
`
`
`
`
`
`
`
`
`
`
`VIII. Separate patentability of individual claims
`
`
`
`
`A.
`
`B.
`
`
`
`
`C.
`
`
`
`
`
`
`
`
`
`Separate patentability of claims 5-8, 15-16, 23 and 27
`
`
`
`
`
`
`
`
`
`
`Separate patentability of claims 11-18, 26 and 29
`
`
`
`
`
`
`
`Separate patentability of claims 28-30
`
`
`
`IX.
`
`
`
`Conclusion
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPRZOI 5-01 I 00, US. Patent No. 8,92 7,606
`
`
`
`
`
`TABLE OF AUTHORITIES
`
`
`
`Page(s)
`
`
`
`
`Federal Cases
`
`
`
`
`
`
`Allergan v. Sandoz,
`
`
`
`
`
`
`
`796 F.3d 1293 (Fed. Cir. 2015) ................................................................. ..passim
`
`
`
`
`
`
`In re Antonie,
`
`
`
`
`
`
`
`
`559 F.2d 618 (C.C.P.A. 1977) .................................................................... ..52, 55
`
`
`
`
`
`
`
`
`
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`
`
`
`
`
`
`
`776 F.2d 281 (Fed. Cir. 1985) .......................................................................... ..57
`
`
`
`
`
`
`
`
`
`
`
`
`
`Atlas Powder Co. v. E.I. du Pont De Nemours & Co.,
`
`
`
`
`
`
`
`750 F.2d 1569 (Fed. Cir. 1984) ........................................................................ ..32
`
`
`
`
`
`
`
`
`
`
`Cadence Pharm. Inc. v. Exela PharmSci Inc.,
`
`
`
`
`
`
`
`780 F.3d 1364 (Fed. Cir. 2015) ................................................................. ..passim
`
`
`
`
`
`
`
`
`
`
`Catalina Lighting, Inc. v. Lamps Plus, Inc.,
`
`
`
`
`
`
`
`295 F.3d 1277 (Fed. Cir. 2002) ........................................................................ ..36
`
`
`
`
`
`
`
`
`
`
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`
`
`
`
`
`
`
`
`
`
`567 F.3d 1314 (Fed. Cir. 2009) ...................................................... ..11, 12, 27, 32
`
`
`
`
`
`
`
`
`
`
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs, Ltd.,
`
`
`
`
`
`
`
`
`
`533 F.3d 1353 (Fed. Cir. 2008) .................................................................. ..20, 21
`
`
`
`
`
`
`Galderma Labs. v. Tolmar, Inc.,
`
`
`
`
`
`
`
`
`737 F.3d 731 (Fed. Cir. 2013) ......................................................................... ..54
`
`
`
`
`In re Gordon,
`
`
`
`
`
`
`
`
`733 F.2d 900 (Fed. Cir. 1984) .......................................................................... ..30
`
`
`
`
`In re Gurley,
`
`
`
`
`
`
`
`
`
`27 F.3d 551 (Fed. Cir. 1994) ...................................................................... ..14, 24
`
`
`
`
`
`In re Huai-Hung Kao,
`
`
`
`
`
`
`
`639 F.3d 1057 (Fed. Cir. 2011) ........................................................................ ..44
`
`
`
`iii
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20I5-OI I00, US. Patent No. 8,92 7, 606
`
`
`
`
`
`
`
`
`
`Insite Vision Inc., v. Sandoz, Inc.,
`
`
`
`
`
`
`
`
`
`783 F.3d 853 (Fed. Cir. 2015) .................................................................... ..13, 31
`
`
`
`
`
`Institut Pasteur v. Focarino,
`
`
`
`
`
`
`
`
`738 F.3d 1337 (Fed. Cir. 2013) ........................................................................ ..51
`
`
`
`
`
`
`
`Janssen Pbarm. NV v. Mylan Pharm., Inc.,
`
`
`
`
`
`
`
`
`
`
`
`
`456 F. Supp. 2d 644 (D.N.J. 2006), aff’a’per curiam, 223 Fed.
`
`
`
`
`
`
`
`Appx. 999 (Fed. Cir. 2007) ............................................................................... ..50
`
`
`
`
`
`
`
`KSR Int’! Co. v. Teleflex Inc.,
`
`
`
`
`550 U.S. 398 (2007) ........................................................................
`
`
`
`................ ..33
`
`
`
`
`
`
`Microsoft Corp. v. Proxyconn, Inc.,
`
`
`
`
`
`
`
`. 789 F.3d 1292 (Fed. Cir. 2015) .......................................................................... ..7
`
`
`
`
`
`
`
`Ortho-McNeil Pharm. Inc. v. Mylan Labs, Inc.,
`
`
`
`
`
`
`
`520 F.3d 1358 (Fed. Cir. 2008) ........................................................................ ..36
`
`
`
`
`
`
`In re Papesch,
`
`
`
`
`
`
`315 F.2d 381 (C.C.P.A. 1963) .......................................................................... ..44
`
`
`
`
`
`
`
`
`
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`
`
`
`
`
`
`773 F.3d 1186 (Fed. Cir. 2013) .............................
`
`
`
`
`........................................ ..56
`
`
`
`
`
`
`
`
`Pfizer Inc. v. Mylan Pharm. Inc.,
`
`
`
`
`
`
`
`
`2014 WL 5388100 (D. Del. 2014) ........................................................ ..23, 26, 31
`
`
`
`
`
`
`In re Shetty,
`
`
`
`
`
`
`
`566 F.2d 81 (C.C.P.A. 1977) ............................................................................ ..56
`
`
`
`
`
`
`Specialty Composites v. Cabot Corp.,
`
`
`
`
`
`
`
`
`845 F.2d 981 (Fed. Cir. 1988) .......................................................................... ..50
`
`
`
`
`
`Syntex LLC V. Apotex Inc,
`
`
`
`
`
`
`
`
`
`
`
`2006 U.S. Dist. Lexis 36089 (N.D. Cal. 2006), afi”a’ 221 Fed.
`
`
`
`
`
`
`
`
`Appx. 1002 (Fed. Cir. 2007) ....................................................................... ..19, 24
`
`
`
`
`
`
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`
`
`
`
`
`
`
`
`
`
`655 F.3d 1352 (Fed. Cir. 2011) ............................................................ ..20, 21, 52
`
`iv
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20I 5-01 I 00, US. Patent No. 8,92 7, 606
`
`
`
`
`
`
`In re Wesslau,
`
`
`
`
`
`
`
`
`353 F.2d 238 (C.C.P.A. 1965) .................................................................... ..24, 31
`
`
`Federal Statutes
`
`
`
`35 U.S.C. § 119 ................................. .§ ......................................................... ..; ......... ..7
`
`
`
`
`
`
`
`
`
`
`
`35 U.S.C. §316(e) ...........................................................
`
`
`
`.................................. ..1, 6
`
`
`
`
`Other Authorities
`
`
`
`
`
`
`
`
`/
`Apotex Inc., v. Wyeth LLC,
`
`
`
`
`
`
`
`
`
`IPR2014-00115, slip op. (P.T.A.B. Apr. 20, 2015) ................................... ..16, 26
`
`
`
`
`
`
`
`
`
`Sandoz, Inc. v. EKR Therapeutics, LLC,
`
`
`
`
`
`
`
`
`IPR2015-00005, slip op. (P.T.A.B. Apr. 24, 2015) .......................................... ..57
`
`
`
`
`
`
`
`
`Ex parte Whalen et al.,
`
`
`
`
`
`
`
`
`
`
`
`Appeal 207-4423, slip op. (B.P.A.I. July 23, 2008) ............................. ..52, 53, 55
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR2015-01100, US. Patent No. 8,92 7, 606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Senju Pharmaceutical Co., Ltd. et al. (“Senju”) responds to the
`
`
`
`
`
`
`
`
`
`
`
`Petition filed by Lupin Ltd. and Lupin Pharmaceuticals Inc. (“Lupin”) concerning
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`claims 1-30 of U.S. Patent No. 8,927,606 (“the ’606 patent”). The Board instituted
`
`
`
`
`
`
`
`
`trial on Lupin’s Ground No.
`
`
`
`
`
`
`
`
`
`
`1 that claims 1-30 are allegedly obvious over U.S.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent No. 5,891,913 to Sallmann et al. (“Sallmann”) (EX1021) in View of U.S.
`
`
`
`
`
`
`
`
`
`
`
`
`Patent No. 4,910,225 to Ogawa et al. (“Ogawa”) (EX1010). As discussed below,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lupin has failed to meet its “burden of proving a proposition of unpatentability by
`
`
`
`
`
`
`
`
`
`a preponderance of the evidence.” 35 U.S.C. § 3l6(e).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Indeed, as discussed further below, Lupin has failed to prove that a person of
`
`
`
`
`ordinary skill
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`in the art would have combined Ogawa and Sallmann with any
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`expectation of arriving at the claimed subject matter. Lupin also has failed to prove
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the existence of all elements of the ’606 patent claims in the art of record and has
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`failed to carry the high burden of proving the inherency of several claim elements
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`in the obviousness context. In addition, Lupin either ineffectively assails or simply
`
`
`
`
`
`
`
`
`
`
`
`
`
`ignores significant objective indicia of patentability, which further support the non-
`
`
`
`
`
`
`
`
`
`
`
`
`obviousness of the ’606 patent claims. The Board accordingly should uphold the
`
`
`
`
`
`
`
`
`
`patentability of claims 1-30 of the ’606 patent.
`
`
`
`
`
`I.
`
`
`Preliminary Statement
`
`
`
`
`
`
`
`
`
`
`
`
`
`The ’606 patent discloses and claims methods for treatingyan inflammatory
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`disease of an eye, comprising administering to said eye a stable aqueous liquid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPRZOI 5-01 I 00, US. Patent No. 8, 92 7, 606
`
`
`
`
`
`
`
`
`
`
`preparation of the non-steroidal anti-inflammatory drug (“NSAID”) bromfenac,
`
`
`
`
`
`
`
`
`
`
`
`
`
`marketed as Prolensa® prescription eye drops for treatment of inflammation and
`
`
`
`
`
`
`
`
`
`
`
`
`
`pain in cataract surgery patients.‘ These formulations are chemically stable, lack
`
`
`
`
`
`
`
`
`
`
`
`
`
`microbial contamination, and can be administered safely and effectively for
`
`
`
`
`
`
`
`
`
`
`
`
`
`ophthalmic use at a pH that does not cause eye irritation. (EX1004, 2:26-38;
`
`
`
`
`EX2082, 1117.)
`
`
`
`
`
`
`
`
`
`
`
`The inventors successfully formulated these preparations using the non-ionic
`
`
`
`surfactant
`
`
`
`
`tyloxapol.
`
`
`
`
`
`
`
`
`(EX2082, 111116-17.) Tyloxapol unexpectedly chemically
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`stabilized bromfenac better than did the surfactant polysorbate 80, even at a low
`
`
`
`
`
`
`
`
`pH known to accelerate bromfenac’s degradation.
`
`
`
`
`(Id.,
`
`
`1111180, 189,
`
`
`
`196.)
`
`
`
`Tyloxapol also unexpectedly maintained preservative eff1cacy—z'.e., prevented
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`microbial contamination—as compared to polysorbate 80, even when measured
`
`
`
`
`
`
`
`
`
`
`under the stringent European Pharmacopoeia standards. (Id., 11200.)
`
`
`
`
`
`
`
`
`
`
`Tyloxapol’s unexpected stabilizing effect translated into significant medical
`
`
`
`1
`
`benefits
`
`
`
`®
`
`
`
`
`
`
`
`in Prolensa . Tyloxapol’s stabilization effect permitted formulating
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Prolensa® at pH 7.8, down from pH 8.3 in non-prior art Xibrom® and Bromday®
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulations (EX1049, 4; EXl008, 3; EX1009, 7), a substantial reduction on a
`
`
`
`
`
`
`
`
`
`
`
`logarithmic scale and closer to the pH of natural
`
`
`
`
`
`
`
`tears, which made it more
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`I Lupin’s expert Dr. Lawrence admits that Prolensa® is an embodiment of
`
`
`
`
`
`
`
`
`
`
`
`
`certain ofthe ’606 patent claims. (EXl005, 1111266, 600.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, JPR201 5~01 I 00, US. Pa1femN0. 8, 92 7, 606
`
`
`
`comfortable to patients. (EX2ll6, 1l40.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Both the reduction in pH in Prolensalm
`
`
`
`
`
`
`
`
`
`
`
`increased ocular comfort and eliminated the burning and stinging associated with
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`all other approved NSAZD eye drops. (Id) Lowering the pH also improved
`
`
`
`
`
`
`
`
`
`
`
`bromfenac’s iritraoeular penetration and permitted lowering its concentration to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0.07%, down from 0.09% in Xibrom® and Bromclay®, meaning that Prolensag’
`
`
`
`
`
`
`
`
`
`
`
`advantageously puts less drug in contact with surgically compromised ocular tissue
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`without a reduction in efficacy: (161,, ‘K41; EX2033, 1718.) More than a difference
`
`
`
`
`in degree,
`
`
`
`
`
`
`
`
`
`
`tyloXepol’s unexpectedly superior stabilizing effect constitutes a
`
`
`
`
`
`
`
`
`
`material and substantial difference, producing a. more comfortable, non-irritating
`
`
`
`
`
`
`
`
`
`
`and more efficacious forlrmlation embodied in Prolensagl.
`
`
`
`
`
`
`
`
`
`
`
`As a result, Prolensa® has received significant medical industry acclaim by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`numerous leaders in the field of cataract surgery extolling “the benefits of the new
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulation.” (EX2l 16, 1155.) Since its April 2013 launch, Pro1ensa® had generated
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`$246.9 million in revenue by August 2615, despite entering a market with at least
`
`
`
`
`
`
`
`
`
`
`
`
`
`six branded drugs and three generic drugs FDA-approved to treat similar
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`indications. (EX2130, M17, 147.) In fact, Prolensafig‘ has achieved one of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR2 0] 5-01 I 00, U.S. Patent No. 8,92 7,606
`
`
`
`
`
`
`
`
`
`
`
`
`
`highest shares of prescriptions and revenue among branded drugs with similar
`
`
`
`
`
`indications. (Id)
`
`
`
`
`
`
`
`
`
`Moreover, six generic companies, including Lupin, have submitted ANDAS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`seeking to market exact copies of Pro1ensa®. (EX2082, 11205.) In fact, Lupin has
`
`
`
`
`
`
`
`
`
`
`
`
`projected Prolensa®’s sales to exceed $100 million annually, which will occur this
`
`
`
`
`
`
`
`
`
`
`
`
`
`year. (EX2026, 4; EX2130, 1173.) Three others, Apotex, Metrics and Paddock,
`
`
`
`
`
`
`
`
`
`
`
`
`initially challenged related patents in district court (EX2130, 1H[77—80; EX2022;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EX2019; EX2021) but licensed the ’606 patent and took consent judgments and
`
`
`
`
`
`
`
`
`
`
`
`
`
`injunctions, tying their acknowledgement of the ’606 patent’s validity to their
`
`
`
`
`
`
`
`
`
`
`generic copies of Prolensa®. (EX2130, 111177-80; EX2027; EX2029; EX2028.)
`
`
`
`Against
`
`
`
`
`
`
`
`
`
`these compelling objective indicia of non-obviousness, Lupin
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`contends that tyloxapol in Sallmann’s Example 2 would have been “swapped” for
`
`
`
`
`
`
`
`
`
`
`
`polysorbate 80 in Ogawa’s Example 6, or alternatively, bromfenac in Ogawa’s
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Example 6 would have been “swapped” for diclofenac in Sallmann’s Example 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(Pet., 40-41.) The Board instituted trial on this sole ground but emphasized that it
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`did so “on the current record.” (Inst. Op. at 10-12, 14.) As discussed below, upon
`
`
`
`consideration of the full record, Lupin offers no reason, ‘other than impermissible
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`hindsight looking backward from the ’606 patent claims, why a person of ordinary
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`skill in the art (“POSA”) would have chosen Ogawa’s Example 6 or Sallmann’s
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Example 2 and modified either with any reasonable expectation of arriving at any
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20]5—0I100, US. Patent No. 8,92 7,606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the claimed formulations. Indeed, the evidence establishes that a POSA would
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`not have been motivated to pursue bromfenac or tyloxapol at all, and would not
`
`
`
`
`
`
`
`
`have found bromfenac and diclofenac, or
`
`
`
`tyloxapol
`
`
`
`
`
`
`and polysorbate 80,
`
`
`
`
`
`
`
`
`
`interchangeable given their vast chemical, physical and functional differences.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Tellingly, Lupin has not proffered a scintilla of evidence for the claims that
`
`
`
`
`
`
`
`
`
`
`
`
`
`specifically require greater than about 90% [or 92%] bromfenac remaining after
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`four weeks at 60° C., or the claims that identify the preservative efficacy standard
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of European Pharmacopoeia Criteria B, and thus Lupin has wholly failed to meet
`
`
`
`
`
`
`
`
`
`its burden of proving these claims obvious.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lupin and its expert Dr. Jayne Lawrence contend that its “swapping” theory
`
`
`
`
`
`
`
`
`
`
`
`
`
`allegedly solves the problem of a “complex” that bromfenac purportedly forms
`
`
`
`
`
`
`
`
`
`
`with the preservative benzalkonium chloride (“BAC”). Yet Dr. Paul Laskar,
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lupin’s expert in related proceeding IPR20l5-00903, candidly admits that no prior
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`art shows that bromfenac actually forms a “complex” with BAC. Consistent with
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the teachings of the art, given that BAC was known to have significant toxicity to
`
`
`
`
`
`
`
`
`
`
`
`
`
`the eye, a POSA as of 2003 would have pursued non—BAC preservatives or
`
`
`
`
`
`
`
`
`
`
`
`
`unpreserved formulations to entirely eliminate a serious health risk. Proceeding
`
`
`
`
`
`
`
`
`
`
`
`
`
`contrary to accepted wisdom, the ’606 patent’s formulations utilize BAC, which
`
`
`
`
`
`
`
`
`alone constitutes strong evidence of non-obviousness.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Accordingly, and as discussed below, Lupin’s petition fails (i) to prove that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20./5—01I00, US. Patent No. 8,92 7,606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`a person of ordinary skill in the art would have combined Ogawa and Sallmann
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`with any reasonable expectation of arriving at the claimed subject matter; (ii) to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`prove the existence of each element of each challenged claim from Ogawa and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sallmann, including the alleged inherency of various claim elements; and (iii) to
`
`
`
`
`
`
`
`
`
`
`
`
`
`rebut the compelling objective indicia of non—obviousness of the claimed subject
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`matter. As result, Lupin has not carried its “burden of proving .
`
`
`. unpatentability
`
`
`
`.
`
`by a preponderance of the evidence,” 35 U.S.C. § 316(6), and the Board should
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`enter judgment against Lupin and uphold the patentability of the claims.
`
`
`
`II.
`
`
`
`
`Claim construction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`All claims of the ’606 patent contain the term “stable,” and claims 1-10
`
`
`
`
`
`
`
`
`further contain the phrase “amount sufficient
`
`
`
`
`
`
`
`to stabilize.” Senju and Lupin
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`disputed the meaning of this term and phrase in parallel district court litigation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`before Chief Judge Simandle of the U.S. District Court for the District of New
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Jersey. On behalf of Senju, Dr. Robert Williams, III. Ph.D., who is an expert in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`field of pharmaceutical formulation and development and who, based on his
`
`
`
`
`
`education and experience,
`
`
`
`
`
`
`
`
`
`
`
`is qualified to provide his opinions in this matter
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(EX2082, W2-1 1), has submitted a declaration in this proceeding and in the claim
`
`
`
`
`
`
`
`construction proceedings before Judge Simandle
`
`
`
`
`
`(EX2l25). Adopting Dr.
`
`
`
`
`
`
`
`
`
`Williams’ construction of the elements “stable” and
`
`
`
`
`amount sufficient
`
`
`
`to
`
`
`
`(.C
`
`
`
`
`
`
`
`
`
`
`stabilize” (EX2082, 111149-53; EX2l25; EX2065, 5-6), Judge Simandle held that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPRZOI5-01100, US. Patent No. 8,92 7, 606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“stable” as used in the claims of the ’606 patent means having sufficient resistance
`
`
`
`
`
`
`
`
`
`
`
`
`to degradation (z'.e., chemical stability) and having sufficient preservative efficacy
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to be formulated and maintained for ophthalmic use, and the phrase “amount
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`sufficient to stabilize” as used in the claims of the ’606 patent means an amount
`
`
`
`
`
`
`
`
`
`
`
`
`
`sufficient to confer sufficient resistance to degradation (i.e., chemical stability) to
`
`
`
`
`
`
`
`
`
`
`
`
`
`be formulated and maintained for ophthalmic use. (EX2082, 1152; EX2065, 5-6.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Senju submits that the above terms should be construed in this proceeding in the
`
`
`
`same way the District Court construed them. Microsoft Corp. v. Proxyconn, Inc.,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`789 F.3d 1292, 1298 (Fed. Cir. 2015).
`
`
`
`III.
`
`
`
`
`
`
`
`
`
`Level of ordinary skill in the art
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`A person of ordinary skill in the art of the ’606 patent would have at least a
`
`
`
`
`
`
`
`
`
`
`
`
`
`bachelor’s degree in a field such as chemistry, pharmaceutical chemistry or a
`
`
`
`
`
`
`
`
`
`related discipline with 3-5 years of work experience. (EX2082, ‘H1147-48.)
`
`
`
`IV.
`
`
`
`
`
`The ’606 patent
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The application for the ’606 patent was filed on September 23, 2014, and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`claims priority benefit of the January 21, 2003, filing date of JP 2003-012427
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`under 35 U.S.C. § 119. (EX1004.) The ’606 patent has three independent claims
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(claims 1, 11 and 19) and 27 dependent claims, which are separately patentable.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The ’606 patent is listed in the FDA’s Orange Book, and the parties agree that it
`
`
`
`
`
`
`
`
`
`covers Prolensa® ophthalmic bromfenac (0.07%) solution. (EX1005, W266, 600;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR2015~01I00, US. Patent No. 8,92 7, 606
`
`
`
`
`
`EX2082, W176, 237.)
`
`
`
`
`V.
`
`
`
`
`Background of ophthalmic formulations
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`As of the January 21, 2003 priority date of the ’606 patent, drug formulation
`
`
`
`
`
`
`
`
`
`was a difficult and unpredictable endeavor, and it
`
`
`
`
`remains so today. The
`
`
`
`
`
`
`
`
`
`
`
`formulation of ophthalmic drugs is particularly complex. Formulating stable
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`ophthalmic dosage forms such as the stable aqueous liquid preparations of the ’606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`patent is more challenging and critical than with other dosage forms such as tablets
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`or capsules. In addition, the surface area of the eye is extremely small, and the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`residence time for an eye drop is quite short, which increases the challenge in
`
`
`
`
`
`
`
`
`
`
`
`
`designing an aqueous dosage form that can pass through the hydrophobic cornea
`
`
`
`
`
`
`
`
`
`
`
`
`
`membrane of the eye to reach the intended site of action.
`
`
`
`
`
`
`Indeed, Dr. Laskar has
`
`
`
`
`
`
`
`
`
`
`
`
`
`acknowledged these formulation challenges in his prior sworn testimony in a
`
`
`
`
`
`
`
`
`
`
`
`patent infringement case involving the ophthalmic product Combigan®. (EX2l35,
`
`
`
`
`
`989, 1020, 1022.)
`
`
`
`VI.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The combination of Ogawa and Sallmann, in either direction, does not
`
`
`
`
`
`
`
`
`render any claim of the ’606 patent obvious
`
`
`
`
`
`
`
`
`
`
`
`
`A.
`No reason to focus on Ogawa and bromfenac preparations
`Lupin’s centralltheme is one of “swapping”; that is, swapping tyloxapol in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sallmann’s Example 2 for polysorbate 80 in Ogawa’s Example 6, or alternatively,
`
`
`
`
`
`
`
`
`
`
`
`
`
`swapping bromfenac in Ogawa’s Example 6 for diclofenac in Sallmann’s Example
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2, allegedly would have been obvious. (Pet, 40-41.) The full record shows this
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20I5-01100, US. Patent No. 8,92 7,606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`swapping theory is premised on a POSA having had a reason to focus on
`
`
`
`
`
`
`
`
`
`bromfenac formulations. There was none, absent hindsight.
`
`
`
`
`
`
`By January 21, 2003,
`
`
`
`
`
`
`
`
`
`there were a number of FDA-approved aqueous
`
`
`
`
`
`
`ophthalmic formulations containing NSAIDS,
`
`
`
`
`
`
`
`including diclofenac (Vo1taren®),
`
`
`
`
`
`
`
`ketorolac (Acular®), flurbiprofen (Ocufen®), and suprofen (Profenal®).
`
`
`
`
`
`(Id., 7;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EX2082, W68-69.) A POSA therefore would have had no reason or need to focus,
`
`
`for
`
`
`
`
`
`
`
`
`
`
`further development, on bromfenac to the exclusion of other NSAIDS.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(EX2082, W68-69.) Indeed, Dr. Lawrence admits there was no such reason, stating
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“[t]0 the extent there was even any need for the claimed bromfenac ophthalmic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulation claimed in the asserted claims of the asserted patents, it is my opinion.
`
`that that need would have been met by the disclosures of the ’225 patent and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Hara.”
`
`
`
`
`
`
`
`(EX2253 at 11727, emphasis added.)
`
`
`
`
`
`
`
`In fact, Ogawa states that
`
`
`
`its
`
`
`
`
`
`
`
`
`
`
`bromfenac formulations displayed remarkably enhanced stability (EX10l0, 8:46-
`
`
`
`
`
`
`
`
`
`
`9:3), and Dr. Laskar acknowledged that Ogawa satisfied bromfenac’s stability
`
`
`
`
`
`problem. (EX21 14, 115:2-116-4.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Moreover, contrary to Lupin’s position, neither Hara nor Yanni supports a
`
`
`
`
`
`
`
`
`
`
`
`
`preference for bromfenac over diclofenac. (EX2082, W70-73.) Hara teaches that
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(1) both have “superior” anti-inflammatory action (EXl006, 2, 3), (2) both treat
`
`
`
`
`
`
`
`
`
`
`
`
`
`postoperative inflammation of the eye (id.), (3) diclofenac could treat anterior
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`uveitis, while bromfenac was expressly not approved for this indication (id.), and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20I5-01100, US. Patent No. 8,92 7,606
`
`
`
`
`
`
`
`
`
`
`
`
`
`(4) no toxicity issues were noted for commercialized diclofenac, while bromfenac
`
`
`
`had serious liver disorders and even fatalities (id.), which prompted the FDA to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`pull bromfenac’s oral form, Duract®, from the market. (EX2032, 1.) Hara thus
`
`
`
`
`
`
`
`
`
`
`
`
`certainly does not endorse bromfenac over diclofenac. (EX2082, 1171.)
`
`
`
`
`
`
`
`
`
`
`The same applies to Yanni, which actually disparages bromfenac, preferring
`
`
`
`
`
`
`
`
`
`
`
`
`
`esters and amides, like nepafenac. (EXl007, 1:54-59, 4:84-52; EX2082, 111172-73.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Focusing on a single in vitro result from Table l of Yanni (EXl005, 1177), Dr.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lawrence ignores important ex vivo and in vivo data (EX2082, 1172-73), which do
`
`
`
`
`
`
`
`
`
`
`
`
`
`not show superiority of bromfenac over diclofenac and in fact show superiority of
`
`
`
`
`
`
`
`
`other compounds. (Id.; EXl007, Table 1.)
`
`
`
`B.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Design need and market demands would not have led a POSA in
`
`
`
`
`
`
`
`
`
`
`the direction that the inventors of the ’606 patent took
`
`
`
`
`
`
`
`
`
`
`
`
`
`Lupin’s proffered motivation to substitute polysorbate 80 with tyloxapol is
`
`
`to prevent
`
`
`
`
`
`
`
`
`
`
`
`
`the alleged formation of an insoluble complex between an acidic
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NSAID and BAC. (Pet., 8.) Dr. Laskar admits, however, that he has no evidence
`
`
`
`
`
`
`
`
`
`
`
`
`
`that any such complex actually forms between bromfenac and BAC. (EX2ll4,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`45:18-46:4.) Even if such a precipitate did form, which Lupin has not established,
`
`
`
`
`
`
`
`
`
`
`
`
`
`a POSA would not have used tyloxapol to address this issue.
`
`
`
`
`
`
`
`
`BAC was known to have significant
`
`
`
`
`
`
`toxicity to the eye.
`
`
`
`(EX2082,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1176-77.) In fact, in Allergan v. Scmdoz, 796 F.3d 1293, 1305 (Fed. Cir. 2015), the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`defendant’s expert referred to BAC as a “natural born killer” that was “from
`
`
`
`
`
`10
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20I 5-01 I 00, US. Patent No. 8,92 7, 606
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Satan.” Dr. Laskar also characterized BAC as a “killer,” known to cause adverse
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`reactions in vitro and in vivo. (EX2114, 78:13-25, 79:13-23.) A POSA objectively
`
`
`
`
`
`
`
`
`
`
`
`
`
`viewing this alleged precipitation issue would have sought to eliminate BAC,
`
`
`
`
`
`
`
`
`
`
`
`
`
`thereby eliminating its harmful effects and avoiding the precipitation issue entirely,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`rather than only attempting to reduce it to some extent by adding a surfactant.
`
`
`
`(EX2082,
`
`
`
`
`
`
`1174.) By January 2003,
`
`
`
`the
`
`
`
`
`art
`
`
`
`taught using preservative—free
`
`
`
`formulations and well-tolerated preservatives in place of BAC (EX2082, 1175;
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`EX2116, 111144-46.) Depuy Spine, Inc. V. Medtronic Sofamor Danek, Inc., 567 F.3d
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1314, 1326 (Fed. Cir. 2009) (strong inference of non-obviousness when the prior
`
`
`
`
`
`
`
`
`
`
`art undermines very reason offered for combining references).
`
`
`
`Indeed by 2003, market demands sought to eliminate the highly toxic BAC
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`from ophthalmic formulations. The art urged that “[i]t
`
`
`
`
`is
`
`
`
`.
`
`
`
`.
`
`
`
`. of striking
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`importance to become aware of preservative toxicity in order to develop in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`near future many more unpreserved drugs.” (EX2064, 115, emphasis added;
`
`
`
`
`
`
`
`
`
`EX2082, 1177-78.) The art taught a preservative—free formulation of Fu’s ketorolac
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“may be a better as a postoperative ocular analgesic” than preserved ketorolac.
`
`
`
`(EX2090,
`
`
`
`
`abstract; EX21 16,
`
`
`
`
`
`1143.) By November
`
`
`
`
`
`1997, Acular® PF——a
`
`
`
`preservative—free
`
`
`
`ketorolac
`
`
`
`ophthalmic
`
`
`
`
`
`solution——received FDA approval.
`
`
`
`
`
`
`
`(EX2061, 1; EX21 16, 1129.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`The art also taught using better-tolerated preservatives in place of BAC. By
`
`11
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patent Owner Response, IPR20I5-01100, US. Patent No. 8,92 7, 606
`
`
`
`
`
`
`
`
`
`
`
`2001, published clinical studies demonstrated that the preservative “stabilized
`
`
`
`
`
`
`
`
`
`
`
`oxychloro complex” (“SOC”) could replace BAC in brimonidine ophthalmic
`
`
`
`
`
`
`
`
`
`
`
`
`
`formulations. By March 2001, brimonidine—SOC was approved as Alphagan® P,
`
`
`
`
`
`
`
`
`
`
`
`
`
`with a superior comfort and reduced ocular allergy profile as compared to
`
`
`
`
`
`brimonidine-BAC. (EX2092; EX21 16, 1144.)
`
`Other replacement options for BAC included the preservative lauralkonium
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`chloride (“LAC”), which Dr. Laskar admittedly used previously to avoid the
`
`
`
`
`
`
`
`
`
`
`
`
`
`interaction of an acidic drug and BAC. lPR2015-00903, EX1003, 11104; (EX21 14,
`
`
`
`
`
`
`
`
`
`
`
`
`33:4-34:1; EX2082, 1180; EX1027, 3:28-4:2, 6:11-7:10). Dr. Lawrence admits that
`
`
`
`
`
`
`
`
`
`
`
`
`
`Desai also teaches the use of a different polymeric quaternary ammonium
`
`
`
`
`
`
`
`
`
`
`
`
`
`preservative compound, POLYQUAD®, as the solution to the interaction problem.
`
`
`
`
`
`
`
`
`
`
`
`
`
`(EX1012, 1:27-2:31;'EX2316, 243:4-15; EX2082, 1182.)