Paper No. __
`Filed: December 28, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS
`INC., and MYLAN INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`__________________
`
`Case IPR2015-00903
`Patent 8,129,431
`
`__________________
`
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`PAGE 1 OF 69
`
`
`Filed: December 28, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________
`
`INNOPHARMA LICENSING, INC., INNOPHARMA LICENSING LLC,
`INNOPHARMA INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS
`INC., and MYLAN INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.
`Patent Owner.
`
`__________________
`
`Case IPR2015-00903
`Patent 8,129,431
`
`__________________
`
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`PAGE 1 OF 69
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`
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
`
`
`Table of Contents
`
`
`2
`
`6
`
`6
`
`6
`
`7
`
`7
`
`8
`
`8
`
`9
`
`14
`
`14
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`16
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`18
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`25
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`28
`
`28
`
`Introduction
`
`I.
`
`II.
`
`Statement of relief requested
`
`III. Claim construction
`
`IV. Level of ordinary skill in the art
`
`V.
`
`The ’431 patent
`
`VI. Background of ophthalmic formulations
`
`VII. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the ’431 patent obvious
`
`A. No reason to focus on Ogawa and bromfenac preparations
`
`B.
`
`Design need and market demands would not have led a POSA
`in the direction that the inventors of the ’431 patent took
`
`C.
`
`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
`
`InnoPharma’s arguments of motivation and
`expectation of success ring hollow
`
`D.
`
`Sallmann in view of Ogawa: another hindsight-laden
`combination
`
`1.
`
`The proposed combination destroys the essential
`purpose of Sallmann and ignores the blaze marks
`in the art
`
`i
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`PAGE 2 OF 69
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`
`2.
`
`InnoPharma’s arguments to modify Sallmann in
`view of Ogawa are legally insufficient, internally
`inconsistent, and belied by the very art
`InnoPharma cites
`
`31
`
`35
`
`35
`
`36
`
`40
`
`45
`
`46
`
`46
`
`47
`
`48
`
`54
`
`55
`
`60
`
`E.
`
`Fu does not remedy the deficiencies of Ogawa and Sallmann
`
`1.
`
`2.
`
`3.
`
`A POSA would not have looked to Fu
`
`InnoPharma’s attempted connection between Fu
`and tyloxapol is untenable
`
`InnoPharma has failed to prove unpatentability of
`claims 6, 15-17 and 20-22, requiring about 0.02
`w/v % tyloxapol
`
`VIII. 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
`
`IX. Conclusion
`
`
`
`ii
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`PAGE 3 OF 69
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`
`Table of Authorities
`
` Page(s)
`
`Cases
`Allergan v. Sandoz,
`796 F.3d 1293 (Fed. Cir. 2015) ...................................................................passim
`
`In re Antonie,
`559 F.2d 618 (C.C.P.A. 1977) ................................................................ 41, 42, 45
`
`Atlas Powder Co. v. E.I. 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) .......................................................................... 45
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ........................................................ 10, 12, 27, 31
`
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) ............................................................. 19, 23, 24
`
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ............................................................................ 28
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) ........................................................................ 13, 23
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 53
`
`Insite Vision Inc., v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ................................................................ 13, 30, 37
`
`Institut Pasteur v. Focarino,
`
`738 F.3d 1337 (Fed. Cir. 2013) ......................................................................... 60
`
`iii
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`PAGE 4 OF 69
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`
`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) ................................................................................. 59
`
`KSR Int’l Co. v. Teleflex Inc.,
`
`550 U.S. 398 (2007) ..................................................................................... …...32
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F. 3d 1292 (Fed. Cir. 2015) ........................................................................... 6
`
`Ortho-McNeil Pharm. Inc. v. Mylan Labs, Inc.,
`
`520 F.3d 1358(Fed. Cir. 2008) ........................................................................... 45
`
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ...................................................................... 42, 53
`
`Pfizer Inc. v. Mylan Pharm. Inc.,
`2014 WL 5388100 (D. Del. 2014) .................................................... 21, 30, 36, 37
`
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) ...................................................................... 18, 19
`
`Specialty Composites v. Cabot Corp.,
`845 F.2d 981 (Fed. Cir. 1988) ............................................................................ 59
`
`Syntex LLC v. Apotex Inc.,
`2006 U.S. Dist. Lexis 36089 (N.D. Cal. 2006), aff’d 221 Fed.
`Appx. 1002 (Fed. Cir. 2007) ................................................................... 23, 25, 39
`
`Unigene Labs. v. Apotex, Inc.,
`
`655 F.3d 1352 (Fed. Cir. 2011) ......................................................................... 19
`
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ...................................................................... 22, 29
`
`Statutes
`
`35 U.S.C. §119 ........................................................................................................... 7
`
`35 U.S.C. § 316(e) ..................................................................................................... 1
`
`iv
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`PAGE 5 OF 69
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`
`Other Authorities
`Apotex Inc., v. Wyeth LLC,
`IPR2014-00115, slip op. (P.T.A.B. Apr. 20, 2015). ..................................... 16, 35
`
`Ex parte Whalen et al.,
`Appeal 207-4423 (B.P.A.I. July 23, 2008) ............................................. 41, 44, 45
`
`v
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`PAGE 6 OF 69
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`Patent Owner Senju Pharmaceutical Co., Ltd. et al. (“Senju”) responds to the
`
`Petition filed by InnoPharma Licensing, Inc. et al. (“InnoPharma”) concerning
`
`claims 1-22 of U.S. Patent No. 8,129,431 (“the ’431 patent”). The Board instituted
`
`trial on InnoPharma’s grounds that (a) claims 1-5, 7-14 and 18-19 are allegedly
`
`obvious over U.S. Patent No. 4,910,225 to Ogawa et al. (“Ogawa”) (EX1004) and
`
`U.S. Patent No. 5,891,913 to Sallmann et al. (“Sallmann”) (EX1009), and (b)
`
`claims 6, 15-17 and 20-22 are allegedly obvious over Ogawa, Sallmann and AU-B-
`
`22042/88 to Fu et al. (“Fu”) (EX1011). As discussed below, InnoPharma 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, InnoPharma has failed to prove that a
`
`POSA would have combined any of Ogawa, Sallmann and Fu with any expectation
`
`of arriving at the claimed subject matter. InnoPharma, moreover, has wholly failed
`
`to prove the existence of any prior art formulation containing 0.02 w/v% tyloxapol,
`
`which is an element of claims 6, 15-17 and 20-22. In addition, InnoPharma either
`
`ineffectively assails or simply ignores significant objective indicia of patentability,
`
`which further support the non-obviousness of the ’431 patent claims. The Board
`
`accordingly should uphold the patentability of claims 1-22 of the ’431 patent.
`
`1
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`PAGE 7 OF 69
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`
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`I.
`
`Introduction
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
`
`
`The ’431 patent discloses and claims aqueous liquid preparations of the non-
`
`steroidal anti-inflammatory drug (“NSAID”) bromfenac, which are marketed as
`
`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. (EX1001, 2:34-47; EX2082, ¶153.)
`
`The inventors successfully formulated these preparations using the non-ionic
`
`surfactant
`
`tyloxapol. (EX2082, ¶151.) Tyloxapol unexpectedly chemically
`
`stabilized bromfenac better than did the surfactant polysorbate 80, even at a low
`
`pH known to accelerate bromfenac’s degradation. (Id., ¶¶ 156, 166, 171.)
`
`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. (Id., ¶177.)
`
`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®
`
`1 InnoPharma’s expert admits that Prolensa® falls within the scope of the
`
`’431 patent claims. (EX2082, ¶149.)
`
`2
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`PAGE 8 OF 69
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`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`formulations (EX2013, 4; EX2026, 5; EX2027, 4), a substantial reduction on a
`
`logarithmic scale and closer to the pH of natural tears. (EX2116, 1141.)‘
`
`Both the reduction in pH in Prolensa®
`
`increased ocular comfort and eliminated the burning and stinging associated with
`
`all other approved NSAID eye drops. (Id.) 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. (Id., 1] 42; EX2030, 1718.) More than a difference
`
`in degree,
`
`tyloxapol’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, 1156.) Since its April 2013 launch, Prolensa® has generated
`
`$246.9 million in revenue, despite entering a market with at least six branded drugs
`
`PAGE 9 OF 69
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`PAGE 9 OF 69
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`IPR2015-00903
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`Patent No. 8,129,431
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`and three generic drugs approved by the FDA to treat similar indications.
`
`(EX2130, ¶133.) In fact, Prolensa® has achieved one of the highest shares of
`
`prescriptions and revenue among branded drugs with similar indications. (Id.)
`
`Moreover, six generic companies, including InnoPharma, have submitted
`
`ANDAs seeking to market exact copies of Prolensa®. (EX2082, ¶182.) One of
`
`these six, Lupin, which also has filed an IPR petition challenging the ’431 patent,
`
`has projected Prolensa®’s sales to exceed $100 million annually, which will occur
`
`this year. (EX2022, 4; EX2130, ¶75.) Three others, Apotex, Metrics and Paddock,
`
`initially challenged the ’431 patent in district court (EX2130, ¶¶78-80; EX2023;
`
`EX2019; EX2017; EX2018) but licensed the patent and took consent judgments
`
`and injunctions, tying their acknowledgement of the ’431 patent’s validity to their
`
`generic copies of Prolensa®. (EX2130, ¶¶78-80; EX2024; EX2122; EX2123.)
`
`Against these compelling objective indicia of non-obviousness, InnoPharma
`
`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., 6-7.) As discussed below, InnoPharma offers no reason, other than
`
`impermissible hindsight looking backward from the ’431 patent claims, why a
`
`person of ordinary skill in the art (“POSA”) would have chosen Ogawa’s Example
`
`4
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`PAGE 10 OF 69
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`Patent No. 8,129,431
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`6 or Sallmann’s Example 2 and modified either with any reasonable expectation of
`
`arriving at any 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, InnoPharma has failed to identify any prior art formulation containing
`
`0.02 w/v% tyloxapol, which is an element of claims 6, 15-17, and 20-22, and thus
`
`InnoPharma has wholly failed to meet its burden of proving these claims obvious.
`
`InnoPharma contends that its “swapping” theory allegedly solves the
`
`problem of a “complex” that bromfenac purportedly forms with the preservative
`
`benzalkonium chloride (“BAC”). Yet InnoPharma’s expert Dr. Paul Laskar
`
`candidly admits that no prior art shows that bromfenac actually forms a “complex”
`
`with BAC, and that he in fact focused on BAC only because the claimed
`
`formulations of the ’431 patent contain it, exposing InnoPharma’s theory as
`
`impermissibly based on hindsight. Consistent with the teachings of the art, Dr.
`
`Laskar further admits that BAC is a “killer” that should be eliminated from
`
`formulations wherever possible. Proceeding contrary to accepted wisdom, the ’431
`
`patent’s formulations utilize BAC, which alone constitutes strong evidence of non-
`
`obviousness.
`
`5
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`PAGE 11 OF 69
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`
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`The Board accordingly should reject
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`the
`
`the Petition and uphold
`
`patentability of all challenged claims.
`
`II.
`
`Statement of relief requested
`
`Senju respectfully requests that InnoPharma’s Petition be denied at least
`
`because: (i) it fails to prove that a person of ordinary skill in the art would have
`
`combined Ogawa and Sallmann, or Ogawa, Sallmann and Fu, with any reasonable
`
`expectation of arriving at the claimed subject matter; (ii) it fails to prove the
`
`existence of any prior art formulation containing 0.02 w/v% tyloxapol, which is an
`
`element of claims 6, 15-17, and 20-22; and (iii) it fails to rebut the compelling
`
`objective indicia of non-obviousness of the claimed subject matter.
`
`III. Claim construction
`Senju believes that no claim term needs express construction and that the
`
`plain and ordinary meaning consistent with the specification and the prosecution
`
`history should apply. Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298
`
`(Fed. Cir. 2015).
`
`IV. Level of ordinary skill in the art
`A person of ordinary skill in the art of the ’431 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, ¶¶41-42.)
`
`6
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`PAGE 12 OF 69
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`IPR2015-00903
`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`V. The ’431 patent
`The application for the ’431 patent was filed on January 16, 2004, and
`
`claims priority benefit of the January 21, 2003 filing date of JP 2003-012427 under
`
`35 U.S.C. §119. (EX1001; EX2002.) The ’431 patent has two independent claims
`
`(claims 1 and 18) and 20 dependent claims, which are separately patentable. The
`
`’431 patent is listed in the FDA’s Orange Book, and the parties agree that it covers
`
`Prolensa® ophthalmic bromfenac (0.07%) solution. (EX1003, ¶42; EX2082, ¶152.)
`
`VI. Background of ophthalmic formulations
`As of the 2003 priority date of the ’431 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 aqueous liquid preparations of the ’431 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. Dr. Laskar himself has acknowledged these
`
`formulation challenges in sworn testimony in a patent infringement case involving
`
`the ophthalmic product Combigan®. (EX2135, 989, 1020, 1022.)
`
`7
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`PAGE 13 OF 69
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`Patent No. 8,129,431
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`VII. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the ’431 patent obvious
`A. No reason to focus on Ogawa and bromfenac preparations
`InnoPharma’s central theme of unpatentability 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., 6-
`
`7.) But 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®). (Id., 27-28.)
`
`A POSA therefore would have had no reason or need to focus, for further
`
`development, on bromfenac to the exclusion of the other NSAIDs. (EX2082, ¶¶60-
`
`61.) Indeed, InnoPharma admits there was no such reason, stating “[t]o the extent
`
`there was even any need for the claimed bromfenac ophthalmic formulation, it was
`
`met by the disclosures of Ogawa and Hara.” (Pet., 53 (emphasis added).) In fact,
`
`Ogawa states that its bromfenac formulations displayed remarkably enhanced
`
`stability (EX1004, 8:46-9:3), and Dr. Laskar acknowledged that Ogawa satisfied
`
`bromfenac’s stability problem. (EX2114, 115:2-116-4.)
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`8
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`Patent No. 8,129,431
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`Moreover, neither Hara nor Yanni supports a preference for bromfenac over
`
`diclofenac, contrary to InnoPharma’s position. (EX2082, ¶¶59-62.) Hara teaches
`
`that (1) both have “superior” anti-inflammatory action (EX1002, 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. (EX2029, 1.) Hara thus
`
`certainly does not endorse bromfenac over diclofenac. (EX2082, ¶60.)
`
`The same applies to Yanni, which actually disparages bromfenac, preferring
`
`esters and amides, like nepafenac. (EX1033, 1:54-59, 4:84-52; EX2082, ¶62.)
`
`Focusing on a single in vitro result from Table 1 of Yanni (EX1003, ¶ 28), Dr.
`
`Laskar ignores important ex vivo and in vivo data (EX2082, ¶¶61-62), which do not
`
`show superiority of bromfenac over diclofenac and in fact show superiority of
`
`other compounds. (Id., EX1033, Table 1.)
`
`B. Design need and market demands would not have led a POSA in
`the direction that the inventors of the ’431 patent took
`
`InnoPharma’s proffered motivation to substitute polysorbate 80 with
`
`tyloxapol is to prevent the alleged formation of a precipitate between an acidic
`
`NSAID and BAC. (EX1003, ¶96.) Dr. Laskar admits, however, that he has no
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`9
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`evidence that any such precipitate actually forms between bromfenac and BAC.
`
`(EX2114, 45:18-46:4.] But even if such a precipitate did form, which Dr. Laskar
`
`has not established, there would have been no motivation to use tyloxapol to
`
`address this issue.
`
`BAC was known to have significant toxicity to the eye. (EX2082, ¶65.) 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.” 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, ¶63.) By January 2003, the art taught using
`
`preservative-free formulations and well-tolerated preservatives in place of BAC
`
`(EX2082, ¶64; EX2116 ¶¶45-47.) Depuy Spine, Inc. v. Medtronic Sofamor Danek,
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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 ’431 patent claims recite it. (EX2114, 69:21-70:10.)
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`Patent No. 8,129,431
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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 is … of striking importance
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`to become aware of preservative toxicity in order to develop in the near future
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`many more unpreserved drugs.” (EX2064, 115, emphasis added; EX2082, ¶¶67-
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`68.) The art taught that a preservative-free formulation of Fu’s ketorolac “may be
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`better as a postoperative ocular analgesic” than preserved ketorolac. (EX2090,
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`abstract; EX2116, ¶44.) By November 1997, Acular® PF—a preservative-free
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`ketorolac ophthalmic solution—received FDA approval. (EX2061, 1; EX2116,
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`¶29.)
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`The art also taught using better-tolerated preservatives in place of BAC. By
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`2001, published clinical studies demonstrated that the preservative “stabilized
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`oxychloro complex” (“SOC”) could replace BAC in brimonidine ophthalmic
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`formulations. By March 2001, brimonidine-SOC was approved as Alphagan® P,
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`with a superior comfort and reduced ocular allergy profile as compared to
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`brimonidine-BAC. (EX2092; EX2116, ¶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. (EX1003, ¶104; EX2114, 33:4-34:1;
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`EX2082, ¶52; EX1020, 3:28-4:2, 6:11-7:10.) Desai also teaches the use of a
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`Patent No. 8,129,431
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`different polymeric quaternary ammonium preservative compound, POLYQUAD®,
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`which Dr. Laskar admits would avoid the interaction problem. (EX1005, 1:27-
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`2:31; EX2114, 93:3-16; EX2082, ¶69.) Even if a POSA still would have wanted to
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`use BAC, the art provided a solution that would have addressed the NSAID/BAC
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`interaction that underlies Dr. Laskar’s proffered motivation to use a solubilizer.
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`Yanni teaches bromfenac derivatives without free carboxyl groups, which would
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`not interact with BAC and which have better ocular penetration and stability than
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`bromfenac. (EX1033, 1:60-2:29; EX2082, ¶73); Depuy Spine, 567 F.3d at 1326.
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`Notwithstanding these clear teachings, Dr. Laskar selectively relies on
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`Ogawa Example 6, which reported a residual amount of bromfenac of 100.9%.
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`(EX1003, ¶¶48.) But he 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, which Dr. Laskar testified do not interact and
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`precipitate with bromfenac. (EX2114, 229:6-21.) Thus, Ogawa implements a
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`solution to Dr. Laskar’s interaction/precipitation problem in a chemically stable
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`formulation, yet Dr. Laskar ignores it because, as he testified, he focused on the
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`fact that the claims of the ’431 patent recite BAC. (EX2114, 69:21-70:10.)
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`Based on a post hoc analysis that started with the claims, Dr. Laskar
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`postulated a motivation position premised on the interaction of an NSAID and
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`Patent No. 8,129,431
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`BAC. Defining a problem by its solution reveals improper hindsight, particularly in
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`selecting the prior art “relevant” to the question of obviousness. Insite Vision Inc.,
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`v. Sandoz, Inc., 783 F.3d 853, 859 (Fed. Cir. 2015). Selecting Ogawa, which does
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`not teach that bromfenac had an interaction/precipitation problem (EX2082, ¶100),
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`and focusing on Example 6 rather than Example 7, which admittedly solved his
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`proffered problem, clearly exposes Dr. Laskar’s improper post hoc analysis. (Id.)
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`Contrary to Dr. Laskar’s opinion, a POSA as of 2003 would have pursued
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`non-BAC preservatives or unpreserved formulations to entirely eliminate a serious
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`health risk. (EX2116, ¶47.) This also would have addressed any alleged interaction
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`problem. (EX2082, ¶71.) As such, the art led in a direction divergent from the path
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`chosen by the inventors of the ’431 patent, as Dr. Laskar admitted, thereby
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`supporting the non-obviousness of the ’431 patent claims. (EX2114, 32:22-34:1;
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`EX2082, ¶¶69-73); See Allergan, 796 F.3d at 1305, citing In re Gurley, 27 F.3d
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`551, 553 (Fed. Cir. 1994) (“A reference may be said to teach away when a person
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`of ordinary skill, upon reading the reference, . . . would be led in a direction
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`divergent from the path that was taken by the [patentee].”)
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`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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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
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`stable for a long period of time without degradation of bromfenac or the formation
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`of red insoluble matters. (EX1004, 2:32-36; EX2082, ¶97.) Ogawa’s solution
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`involved a water soluble polymer, e.g., polyvinyl pyrrolidone, and a sulfite, i.e.,
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`sodium sulfite. (EX1004, 3:7-15; EX2082, ¶97.) Sodium sulfite is a well-known
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`antioxidant. (EX2014, 3:51-55; EX2082, ¶97.) A POSA would have understood
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`that Ogawa used sodium sulfite because bromfenac chemically degrades by
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`oxidation (EX2105, ¶37), and an antioxidant would prevent that degradation
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`process. InnoPharma acknowledges that sodium sulfite is added “to prevent
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`oxidation reactions.” (Pet., 49.)
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`When bromfenac oxidizes, its forms an oxidation degradant referred to
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`throughout Ogawa as red insoluble matters. (EX1004, 8:3-45; EX2082, ¶98.) Dr.
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`Laskar agrees that red insoluble matters indicate that bromfenac is chemically
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`degrading. (EX2114, 228:16-24.) These red insoluble particles do not constitute,
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`therefore, the result of any physical interaction such as any precipitation between
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`bromfenac and BAC. (EX2082, ¶99.) In fact, none of the art of record ever states
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`that bromfenac interacts with BAC to form precipitate, and nowhere in Ogawa is
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`Patent Owner’s Preliminary Response
`Patent No. 8,129,431
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`such interaction ever mentioned. (Id.) Dr. Laskar admitted that he cited no prior art
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`and conducted no test to establish bromfenac interacts with BAC. (EX2114, 45:18-
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`46:4.) Given the complexities of ophthalmic formulation systems, one cannot
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`predict whether such an interaction does occur. (EX2082, ¶99; EX2105, ¶77.)
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`Polysorbate 80, moreover, plays no role in chemically stabilizing bromfenac
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`from oxidizing. (EX2082, ¶97.) Ogawa is completely silent on the function of
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`polysorbate 80. (Id.) It was not used to solubilize bromfenac, for a POSA knew
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`that bromfenac is freely soluble in water. (EX2039, 6; EX2140, 156:20-157:6;
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`EX2082, ¶100.) Nor was it used as a stabilizer, for Ogawa’s examples establish
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`that sodium sulfite produces “remarkably enhanced” stability. (EX1004, 8:46-9:3;
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`EX2082, ¶100.) Citing to column 3, lines 49-53 of Ogawa, Dr. Laskar incorrectly
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`states that polysorbate 80 contributes to stabilizing bromfenac. (EX1003, ¶50;
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`EX2082, ¶101.) This passage, however, nowhere refers to polysorbate 80,
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`explicitly or implicitly. (EX2082, ¶101.)
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`The data from Ogawa Experimental Examples 4-6 actually confirm that
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`polysorbate 80 does not stabilize bromfenac. (EX2095, 107; EX2082, ¶101.) Upon
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`storage at 60 °C for four weeks, the formulations in Experimental Examples 4-6
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`containing polysorbate 80 without sodium sulfite exhibited chemical instability, as
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`evidenced by the formation of red insoluble matter; i.e., degradation of bromfenac.
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`(EX1004, 8:4-9:5; EX2095, 107; EX2082, ¶102.) But adding sodium sulfite
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`prevented the formation of red insoluble matter, prompting Ogawa to comment
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`that bromfenac decomposition was not observed and bromfenac’s stability was
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`remarkably enhanced. (EX1004, 8:45-9:4; EX2095, 107, Table 10; EX2082, ¶101.)
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`Thus, polysorbate 80 has no effect on the stability of bromfenac. (EX2082, ¶101.)
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`Dr. Laskar’s attempt to imbue polysorbate 80 with an ability to stabilize
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`bromfenac is fundamental to InnoPharma’s position that a POSA would have
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`simply “swapped” tyloxapol for polysorbate 80 with a reasonable expectation of
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`success. (Pet., 51-52; EX1003, ¶¶98-99.) The data in Ogawa Experimental
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`Examples 4-6, however, completely undermine InnoPharma’s foundational
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`premise for its obviousness arguments. (EX2082, ¶103.) See Apotex Inc., v. Wyeth
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`LLC, IPR2014-00115, slip op. at 22 (Paper 94) (P.T.A.B. Apr. 20, 2015) (it is
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`improper hindsight to “imbue one of ordinary skill in the art with knowledge of the
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`claimed invention, when no prior art reference or references of record conveys or
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`suggests that knowledge.”).
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`Sallmann’s singular purpose does not align with Ogawa’s
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`2.
`Sallmann is uniquely directed to formulations of the potassium salt of
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`diclofenac. (EX2082, ¶126.) The essence of the Sallmann patent, indeed its entire
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`purpose for existing, is the use of diclofenac potassium in treating ocular
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`Patent No. 8,129,431
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`inflammation. (Id.) The patent was presumably awarded because diclofenac
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`potassium had surprisingly better ocular penetration than diclofenac sodium.
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`(EX1009, 1:1-65; EX2082, ¶105.)
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`Sallmann formulates diclofenac potassium with a number of additional
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`inactive components, including separate categories of solubilizers, chelating
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`agents, and stabilizers. Tyloxapol is listed as one of a number of solubilizers, but
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`Sallmann identifies the Cremophor® solubilizers as “especially preferred,” for they
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`are “tolerated extremely well by the eye.” (EX1009, 4:52-62; EX2082, ¶106.)
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`A POSA would not have selectively picked Sallmann’s tyloxapol for use in
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`Ogawa. Ogawa teaches instead using antioxidants, like sodium sulfite, to stabilize
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`bromfenac. (EX2082, ¶104.) Sallmann lists tyloxapol as one of many solubilizers,
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`but bromfenac, known to be freely water soluble, does not need a solubilizer and
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`tyloxapol would not be expected to address bromfenac’s oxidative degradation.
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`(EX2082, ¶104; EX2039, 6; EX2140, 156:20-157:6.) Indeed, there would have
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`been no reason to look to Sallmann unless one knew from the ’431 patent that
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`tyloxapol works to stabilize bromfenac. (EX2082, ¶104.) Dr. Las
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