`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 IPR2015-010971
`Patent 8,754,131
`
`__________________
`
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`
`
`
`1 Case IPR2016-00089 has been joined with this proceeding.
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8, 754,131
`
`Table of Contents
`
`I.
`
`II.
`
`Preliminary Statement
`
`Claim construction
`
`III. Level of ordinary skill in the art
`
`IV. The '131 patent
`
`V.
`
`Background of ophthalmic formulations
`
`VI. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the ' 131 patent obvious
`
`A.
`
`B.
`
`C.
`
`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 ' 131 patent took
`
`A POSA would not have combined Ogawa and Sallmann
`
`1.
`
`2.
`
`3.
`
`4.
`
`Ogawa and the problem it sought to solve
`
`Sallmann' 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
`
`D.
`
`Sallmann in view of Ogawa: another hindsight-laden
`combination
`
`1.
`
`2.
`
`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
`
`1
`
`6
`
`7
`
`7
`
`7
`
`8
`
`8
`
`10
`
`14
`
`14
`
`16
`
`18
`
`24
`
`29
`
`29
`
`32
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No.8, 754,131
`
`VII. Compelling objective evidence of patentability
`
`A.
`
`Tyloxapol's unexpectedly superior chemical stabilizing effect
`
`1.
`
`2.
`
`3.
`
`4.
`
`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.
`
`Additional compelling objective evidence of patentability
`
`VIII. Separate patentability of individual claims
`
`A.
`
`B.
`
`C.
`
`Separate patentability of claims 4, 6, 10-12, 16, 18, 22-23, and
`26
`
`Separate patentability of claims 7-12, 19-23, and 27-28
`
`Separate patentability of claims 25-29
`
`IX. Conclusion
`
`36
`
`36
`
`36
`
`38
`
`39
`
`45
`
`46
`
`52
`
`52
`
`56
`
`58
`
`60
`
`11
`
`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
`
`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) ...................................................................... 53, 55
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ............................................................................ 58
`
`Atlas Powder Co. v. E.!. du Pont De Nemours & Co.,
`750 F.2d 1569 (Fed. Cir. 1984) .......................................................................... 31
`
`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
`
`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) ........................................................................ 13, 24
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ......................................................................... .44
`
`111
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8, 754,131
`
`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 Pharm. NV v. Mylan Pharm., Inc.,
`456 F. Supp. 2d 644 (D.N.J. 2006), aff'd per curiam, 223 Fed.
`Appx. 999 (Fed. Cir. 2007) ................................................................................. 50
`
`KSR Int'l 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. My/an 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, 57
`
`Pfizer Inc. v. My/an Pharm. Inc.,
`2014 WL 5388100 (D. Del. 2014) .......................................................... 22, 26,31
`
`In re Shetty,
`566 F.2d 81 (C.C.P.A. 1977) .............................................................................. 57
`
`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), aff'd 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, IPR2015-01097, U.S. Patent No. 8,754,131
`
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ...................................................................... 23, 30
`
`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 a/.,
`Appeal207-4423, slip op. (B.P.A.I. July 23, 2008) ............................... 53, 54, 55
`
`v
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
`
`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 ofU.S. Patent No. 8,754,131 ("the '131 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. § 316(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 '131 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(cid:173)
`
`obviousness of the '131 patent claims. The Board accordingly should uphold the
`
`patentability of claims 1-30 ofthe '131 patent.
`
`I.
`
`Preliminary Statement
`
`The '131 patent discloses and claims stable aqueous liquid preparations of
`
`the non-steroidal anti-inflammatory drug ("NSAID") bromfenac, marketed as
`
`1
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Prolensa® prescription eye drops for treatment of inflammation and pain in cataract
`
`surgery patients. 1 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. (EX1002, 2:30-42; EX2082, ~17.)
`
`The inventors successfully formulated these preparations using the non-ionic
`
`surfactant tyloxapol. (EX2082, ~~16-17.) Tyloxapol unexpectedly chemically
`
`stabilized bromfenac better than did the surfactant polysorbate 80, even at a low
`
`pH known to accelerate bromfenac's degradation. (Id., ~~ 181, 190, 197.)
`
`Tyloxapol also unexpectedly maintained preservative efficacy-i.e., prevented
`
`microbial contamination-as compared to polysorbate 80, even when measured
`
`under the stringent European Pharmacopoeia standards. (I d., ~20 1.)
`
`Tyloxapol's unexpected stabilizing effect translated into significant medical
`
`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; EX1008, 3; EX1009, 7), a substantial reduction on a
`
`logarithmic scale and closer to the pH of natural tears, which made it more
`
`comfortable to patients. (EX2116, ~40.)
`
`1 Lupin's expert Dr. Lawrence admits that Prolensa® is an embodiment of
`
`certain of the' 131 patent claims. (EX1 005, ~~266, 374.)
`
`2
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No.8, 754,131
`
`Both the reduction in pH
`
`in Prolensa®
`
`increased ocular comfort and eliminated the burning and stinging associated with
`
`all other approved NSAID eye drops. (!d.) Lowering the pH also improved
`
`bromfenac's intraocular penetration and permitted lowering its concentration to
`
`0.07%, down from 0.09% in Xibrom® and Bromday®, meaning that Prolensa®
`
`advantageously puts less drug in contact with surgically compromised ocular tissue
`
`without a reduction in efficacy. (!d., ,-[41; EX203 3, 1718.) More than a difference
`
`in degree, ty loxapol' s unexpectedly superior stabilizing effect constitutes a
`
`material and substantial difference, producing a more comfortable, non-irritating
`
`and more efficacious formulation embodied in Prolensa®.
`
`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." (EX2116, ,-[55.) Since its April2013 launch, Prolensa® had generated
`
`$246.9 million in revenue by August 2015, despite entering a market with at least
`
`six branded drugs and three generic drugs FDA-approved to treat similar
`
`indications. (EX2130, ,-[,-[17, 147.) In fact, Prolensa® has achieved one of the
`
`highest shares of prescriptions and revenue among branded drugs with similar
`
`indications. (!d.)
`
`3
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
`
`Moreover, six generic companies, including Lupin, have submitted ANDAs
`
`seeking to market exact copies of Prolensa®. (EX2082, ~206.) In fact, Lupin has
`
`projected Prolensa®'s sales to exceed $100 million annually, which will occur this
`
`year. (EX2026, 4; EX2130, ~73.) Three others, Apotex, Metrics and Paddock,
`
`initially challenged the '131 patent and/or related patents in district court (EX2130,
`
`~~77-80; EX2022; EX2019; EX2021), but all three licensed the '131 patent and
`
`took consent judgments and injunctions, tying their acknowledgement of the '131
`
`patent's validity to their generic copies ofProlensa®. (EX2130, ~~77-80; 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., 38-39.) The Board instituted trial on this sole ground but emphasized that it
`
`did so "on the current record" and "may change upon consideration of the whole
`
`record." (Inst. Op. at 9, 11, 12, 22.) As discussed below, upon consideration of the
`
`full record, Lupin offers no reason, other than impermissible hindsight looking
`
`backward from the ' 131 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 of the claimed
`
`4
`
`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
`
`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").
`
`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 '131 patent's formulations utilize BAC, which
`
`alone constitutes strong evidence of non-obviousness.
`
`5
`
`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Accordingly, and as discussed below, Lupin's petition fails (i) to prove that
`
`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(e), and the Board should
`
`enter judgment against Lupin and uphold the patentability of the claims.
`
`II. Claim construction
`
`In parallel district court litigation before Judge Simandle of the U.S. District
`
`Court for the District of New Jersey, Judge Simandle held that "stable" as used in
`
`the claims of the '131 patent means having sufficient resistance to degradation
`
`(i.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 '131 patent means an amount sufficient to
`
`confer sufficient resistance to degradation (i.e., chemical stability) to be formulated
`
`and maintained for ophthalmic use. (EX2082, ~~46-50; EX2065, 5-6.) Judge
`
`Simandle also construed the term "satisfies the preservative efficacy standard of
`
`the US Pharmacopeia ... " as used in claims 25-29 of the '131 patent to mean
`
`6
`
`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`"satisfies the preservative efficacy standard of EP-criteria B of the European
`
`Pharmacopeia .... " (EX2065, 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 '131 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, ~~44-45.)
`
`IV. The '131 patent
`
`The application for the '131 patent was filed on January 28, 2014, and
`
`claims priority benefit of the January 21, 2003, filing date of JP 2003-012427
`
`under 35 U.S.C. §119. (EX1002.) The '131 patent has three independent claims
`
`(claims 1, 7 and 13) and 27 dependent claims, which are separately patentable. The
`
`'131 patent is listed in the FDA's Orange Book, and the parties agree that it covers
`
`Prolensa® ophthalmic bromfenac (0.07%) solution. (EX1005, ~~266, 374; EX2082,
`
`~~177, 238.)
`
`V.
`
`Background of ophthalmic formulations
`
`As of the January 21, 2003 priority date of the '131 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 '131
`
`7
`
`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`patent is more challenging and critical than with other dosage forms such as tablets
`
`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®.
`
`(EX2135,
`
`989, 1020, 1022.)
`
`VI. The combination of Ogawa and Salim ann, in either direction, does not
`render any claim of the '131 patent obvious
`
`A.
`
`No reason to focus on Ogawa and bromfenac preparations
`
`Lupin's central theme is one of "swapping"; that is, swapping tyloxapol in
`
`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., 38-39.) The full record shows this
`
`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 (Voltaren ®),
`
`ketorolac (Acular®), flurbiprofen (Ocufen®), and suprofen (Profenal®). (!d., 7;
`
`EX2082, ~~70-71.) A POSA therefore would have had no reason or need to focus,
`
`8
`
`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8, 754,131
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`for further development, on bromfenac to the exclusion of other NSAIDs.
`
`(EX2082, ~~70-71.) Indeed, Lupin admits there was no such reason, stating "[t]o
`
`the extent there was even any need for the claimed bromfenac ophthalmic
`
`formulations claimed in the '131 patent, it would have been met by the disclosures
`
`of the '225 patent and Hara." (Pet., 58 (emphasis added).) In fact, Ogawa states
`
`that its bromfenac formulations displayed remarkably enhanced stability (EX 1010,
`
`8:46-9:3),
`
`Moreover, contrary to Lupin's position, neither Hara nor Yanni supports a
`
`preference for bromfenac over diclofenac. (EX2082, ~~72-75.) Hara teaches that
`
`(1) both have "superior" anti-inflammatory action (EX1006, 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
`
`(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, ~73.)
`
`The same applies to Yanni, which actually disparages bromfenac, preferring
`
`esters and ami des, like nepafenac. (EX1 007, 1:54-59, 4:84-52; EX2082, ~~74-75.)
`
`Focusing on a single in vitro result from Table 1 of Yanni (EX1005, ~77), Dr.
`
`9
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`
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Lawrence ignores important ex vivo and in vivo data (EX2082, ~~74-75), which do
`
`not show superiority of bromfenac over diclofenac and in fact show superiority of
`
`other compounds. (!d.; EX1007, Table 1.)
`
`B.
`
`Design need and market demands would not have led a POSA in
`the direction that the inventors of the '131 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., 8-9.)
`
`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, ~~78-
`
`79.) In fact, in Allergan v. Sandoz, 796 F.3d 1293, 1305 (Fed. Cir. 2015), the
`
`defendant's expert referred to BAC as a "natural born killer" that was "from
`
`Satan."
`
`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, ~76.) By January 2003,
`
`the art
`
`taught using preservative-free
`
`formulations and well-tolerated preservatives in place of BAC (EX2082, ~77;
`
`10
`
`
`
`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
`
`EX2116, ~~44-46.) 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
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`. . . 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;
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`EX2082, ~~79-80.) The art taught a preservative-free formulation ofFu's ketorolac
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`"may be a better as a postoperative ocular analgesic" than preserved ketorolac.
`
`(EX2090, abstract; EX2116, ~43.) By November 1997, Acular® PF-a
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`preservative-free ketorolac ophthalmic
`
`solution-received FDA approval.
`
`(EX2061, 1; EX2116, ~29.)
`
`The art also taught using better-tolerated preservatives in place of BAC. By
`
`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; EX2116, ~44.)
`
`Other replacement options for BAC included the preservative lauralkonium
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`chloride ("LAC"),
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`Patent Owner Response, IPR2015-01097, U.S. Patent No.8, 754,131
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`IPR2015-00903, EX1003, ~104;
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`- ; EX2082, ~82; EX1027, 3:28-4:2, 6:11-7:10).
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`Desai also teaches the use of a different polymeric quaternary ammomum
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`preservative compound, POL YQUAD®, as the solution to the interaction problem.
`
`(EX1012, 1:27-2:31;
`
`; EX2082, ~84.) Even if a POSA still
`
`would have wanted to use BAC, the art provided a solution that would have
`
`addressed the NSAID/BAC interaction that underlies Lupin's proffered motivation
`
`to use a solubilizer. Yanni teaches bromfenac derivatives without free carboxyl
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`groups, which would not interact with BAC and which have better ocular
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`penetration and stability than bromfenac. (EX1007, 1 :60-2:29; EX2082, ~89);
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`Depuy Spine, 567 F.3d at 1326.
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`Notwithstanding these clear teachings, Dr. Lawrence selectively relies on
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`Ogawa Example 6, which reported a residual amount of bromfenac of 100.9%.
`
`(EX1005, ~~332-33.) But she ignores Ogawa Example 7, reporting an equally high
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`residual amount of bromfenac (99.2%) and containing methylparaben and
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`ethylparaben instead of BAC,
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`solution to Dr. Lawrence's interaction/precipitation problem in a chemically stable
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`formulation, yet Dr. Lawrence ignores it,
`
`Thus, Ogawa implements a
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Based on a post hoc analysis that started with the claimed subject matter, Dr.
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`Lawrence postulated a motivation position premised on the interaction of an
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`NSAID and BAC. Defining a problem by its solution reveals improper hindsight,
`
`particularly in selecting the prior art "relevant" to the question of obviousness.
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`Insite Vision Inc., v. Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir. 2015). Selecting
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`Ogawa, which does not teach that bromfenac had an interaction/precipitation
`
`problem (EX2082, ~~84-85, 121), and focusing on Example 6 rather than Example
`
`7, which admittedly solved his proffered problem, clearly exposes Dr. Lawrence's
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`improper post hoc analysis. (Jd.)
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`Contrary to Dr. Lawrence's opinion, a POSA as of2003 would have pursued
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`non-BAC preservatives or unpreserved formulations to entirely eliminate a serious
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`health risk. (EX2082, ~77.) This also would have addressed any alleged interaction
`
`problem. (EX2082, ~87.) As such, the art led in a direction divergent from the path
`
`chosen by the inventors of the '131 patent, thereby supporting the non-obviousness
`
`of the '131 patent claims. (EX2082, ~~81-84 ); See Allergan, 796 F .3d at 1305,
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`citing In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994) ("A reference may be said to
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`teach away when a person of ordinary skill, upon reading the reference, ... would
`
`be led in a direction divergent from the path that was taken by the [patentee].");
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`13
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`C.
`
`A POSA would not have combined Ogawa and Sallmann
`
`1.
`
`Ogawa and the problem it sought to solve
`
`Ogawa successfully formulated ophthalmic bromfenac preparations that are
`
`stable for a long period of time without degradation of bromfenac or the formation
`
`of red insoluble matters. (EX1010, 2:32-36; EX2082, ~123.) Ogawa's solution
`
`involved a water soluble polymer, e.g., polyvinyl pyrrolidone, and a sulfite, i.e.,
`
`sodium sulfite. (EX1010, 3:7-15; EX2082, ~123.) Sodium sulfite is a well-known
`
`antioxidant. (EX2013, 3:51-55; EX2082, ~123.) A POSA would have understood
`
`that Ogawa used sodium sulfite because bromfenac chemically degrades by
`
`oxidation (EX21 05, ~41 ), and an antioxidant would prevent that degradation
`
`process.
`
`EX1005, ~66(e).)
`
`When bromfenac oxidizes, its forms an oxidation degradant referred to
`throughout Ogawa as red insoluble matters. (EX1010, 8:3-45; EX2082, ~124.) II
`
`therefore, the result of any physical interaction such as any precipitation between
`
`These red insoluble particles do not c;onstitute,
`
`bromfenac and BAC. (EX2082, ~125.)
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`Patent Owner Response, IPR2015-01097, U.S. Patent No.8, 754,131
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`In fact, none of the art of record ever states that bromfenac interacts
`
`with BAC to form a precipitate, and nowhere in Ogawa is such interaction ever
`
`mentioned. (EX2082, ~125.) Given the complexities of ophthalmic formulation
`
`systems, a POSA could not have reasonably predicted whether such an interaction
`
`does occur. (EX2082, ~125; EX2105, ~~75-80.)
`
`Polysorbate 80, moreover, plays no role in chemically stabilizing bromfenac
`
`from oxidizing. (EX2082, ~126.) Ogawa is completely silent on the function of
`
`polysorbate 80. (Jd.) It was not used to solubilize bromfenac, for a POSA knew
`
`that bromfenac is freely soluble in water. (EX2248, 29; EX2140, 156:20-157:6;
`
`EX2082, ~126.)
`
`Nor was it
`
`used as a stabilizer, for Ogawa's examples establish that sodium sulfite produces
`
`"remarkably enhanced" stability. (EX1010, 8:46-9:3; EX2082, ~126.)
`
`Citing Ogawa, Dr. Lawrence
`
`incorrectly states
`
`that polysorbate 80
`
`contributes to stabilizing bromfenac. (EX1 005, ~84; EX2082, ~127.) The data from
`
`Ogawa Experimental Examples 4-6 actually confirm that polysorbate 80 does not
`
`stabilize bromfenac. (EX2095, 1 07; EX2082, ~127.) Upon storage at 60 oc for four
`
`weeks, the formulations in Experimental Examples 4-6 containing polysorbate 80
`
`without sodium sulfite exhibited chemical instability, as evidenced by the
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`15
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`formation of red insoluble matter; i.e., degradation of bromfenac. (EX1010, 8:4-
`
`9:5; EX2095, 107; EX2082, ~128.) But adding sodium sulfite prevented the
`
`formation of red insoluble matter, prompting Ogawa to comment that bromfenac
`
`decomposition was not observed and bromfenac's stability was remarkably
`
`enhanced. (EX1010, 8:45-9:4; EX2095, 107, Table 10; EX2082, ~128.) Thus,
`
`polysorbate 80 has no effect on the stability ofbromfenac. (EX2082, ~128.)
`
`Dr. Lawrence's attempt to imbue polysorbate 80 with an ability to stabilize
`
`bromfenac is fundamental to Lupin's position that a POSA would have simply
`
`"swapped" ty loxapol for polysorbate 80 with a reasonable expectation of success.
`
`(Pet., 38-39; EX1005, ~365.) The data in Ogawa Experimental Examples 4-6,
`
`however, completely undermine Lupin's foundational premise for its obviousness
`
`arguments. (EX2082, ~129.) See Apotex Inc., v. Wyeth LLC, IPR2014-00115, slip
`
`op. at 22 (Paper 94) (P.T.A.B. Apr. 20, 2015) (it is improper hindsight to "imbue
`
`one of ordinary skill in the art with knowledge of the claimed invention, when no
`
`prior art reference or references of record conveys or suggests that knowledge.").
`
`2.
`
`Sallmann's singular purpose does not align with Ogawa's
`
`Sallmann is uniquely directed to formulations of the potassium salt of
`
`diclofenac. (EX2082, ~~131, 166.) The essence of the Sallmann patent, indeed its
`
`entire purpose for existing, is the use of diclofenac potassium in treating ocular
`
`inflammation. (EX2082, ~131.) The patent was presumably awarded because
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`Patent Owner Response, IPR2015-0l 097, U.S. Patent No. 8, 754,131
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`diclofenac potassium had surprisingly better ocular penetration than diclofenac
`
`sodium,
`
`. (EX1021, 1:1-65; EX2082, ~131;-
`
`Sallmann formulates diclofenac potassium with a number of additional
`
`inactive components, including separate categories of solubilizers, chelating
`
`agents, and stabilizers. Tyloxapol is listed as one of a number of solubilizers, but
`
`Sallmann identifies the Cremophor® solubilizers as "especially preferred," for they
`
`are "tolerated extremely well by the eye." (EX1021, 4:52-64; EX2082, ~132.)
`
`A POSA would not have selectively picked Sallmann's tyloxapol for use in
`
`Ogawa. Ogawa teaches instead using antioxidants, like sodium sulfite, to stabilize
`
`bromfenac,
`
`. (EX2082, ~130;
`
`Sallmann lists tyloxapol as one of many solubilizers, but
`
`bromfenac, known to be freely water soluble, does not need a solubilizer and
`
`tyloxapol would not be expected to address bromfenac's oxidative degradation.
`
`(EX2082, ~~130, 132; EX2248, 29; EX2140, 156:20-157:6.) There would have
`
`been no reason to look to Sallmann unless one knew from the '131 patent that
`
`tyloxapol works to stabilize bromfenac. (EX2082, ~130.)
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`17
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`Patent Owner Response, IPR2015-01097, U.S. Patent No. 8,754,131
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`Also, Sallmann separately teaches using stabilizers, such as cyclode