PaperNo._
`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 IPR2015-00902
`Patent 8,669,290
`
`PATENT OWNER RESPONSE
`PURSUANT TO 37 C.F.R. § 42.120
`
`

`
`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`Table of Contents
`
`I.
`
`II.
`
`Introduction
`
`Statement of relief requested
`
`III. Claim construction
`
`IV. Level of ordinary skill in the art
`
`V.
`
`The '290 patent
`
`VI. Background of ophthalmic formulations
`
`VII. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the '290 patent obvious
`
`A.
`
`B.
`
`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 '290 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
`
`InnoPhanna'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
`
`2
`
`6
`
`6
`
`7
`
`7
`
`8
`
`9
`
`9
`
`10
`
`15
`
`15
`
`17
`
`19
`
`26
`
`30
`
`30
`
`

`
`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`2.
`
`InnoPhanna's arguments to modify Sallmann in
`view of Ogawa are legally insufficient, internally
`inconsistent, and belied by the very art
`lnnoPhanna cites
`
`VIII. Compelling objective evidence of patentability
`
`A.
`
`Tyloxapol's unexpectedly superior chemical stabilizing effect
`
`I.
`
`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.
`
`Separate patentability of individual claims
`
`A.
`
`B.
`
`C.
`
`Separate patentability of claims 4-5, 11-12, 17-18 and 23-24
`
`Separate patentability of claims 8-13, 20-25, 27, 29 and 30
`
`Separate patentability of claims 26-30
`
`X.
`
`Conclusion
`
`34
`
`37
`
`38
`
`38
`
`39
`
`40
`
`46
`
`48
`
`53
`
`53
`
`57
`
`58
`
`60
`
`11
`
`

`
`TABLE OF AUTHORITIES
`
`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`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) ....................... .. ... ....... .. .......... ... ........... ......... 54, 56
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ..... ...... ................................................................. 53
`
`Atlas Powder Co. v. E.!. duPont De Nemours & Co.,
`750 F.2d 1569 (Fed. Cir. 1984) ........... .. ............................................................. 33
`
`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) .......................................................................... 37
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ....... ................................................ .11, 13, 29, 33
`
`Eisai Co. Ltd. v. Dr. Reddy's Labs., Ltd.,
`533 F.3d 1353, (Fed. Cir. 2008) ......................... .. ....... ................ ........... 20, 24, 26
`
`Gal derma Labs. v. To/mar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) .................... ... ... ... .. .. .... ......... ... .......................... 56
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ................................... ..... ............ .. ... ................. .. 31
`
`In re Gurley,
`27F.3d551 (Fed. Cir.1994) ............... .. .. ........... .. .............. ................... ....... 14,24
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .. .................... .. .. ...... ............ .................. ........ .. . .45
`
`111
`
`

`
`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`Insite Vision Inc., v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ............... .............. .... .. ................................... 14, 32
`
`Institut Pasteur v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......... ..... ... .......... .............................................. 52
`
`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) ................................................................................. 52
`
`KSR Int'l Co. v. Telejlex Inc.,
`550 U.S. 398 (2007) ...................... ...................................................................... 35
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) ............................................................... ........ ..... 7
`
`Ortho-McNeil Pharm. Inc. v. My ian Labs, Inc.,
`520 F.3d 1358(Fed. Cir. 2008) ................ .................................................. ......... 37
`
`In re Papesch,
`315 F.2d 381 (C.C.P.A. 1963) ...... ................................... ........ ............. ............. .45
`
`Par Pharm, Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2013) ................ ............................... ... .. .............. ....... 57
`
`Pfizer Inc. v. My ian Pharm. Inc.,
`2014 WL 5388100 (D. Del. 2014) .......................................................... 22, 28,32
`
`In re Shetty,
`566 F.2d 81 (C.C.P.A. 1977) ................... ......................... .......... ............ ... .... ..... 57
`
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) .... .. ............ ........................ ...... .. .......... ......... ....... 20
`
`Specialty Composites v. Cabot Corp.,
`845 F.2d 981 (Fed. Cir. 1988) ................... ....... ......... ............. ...... .. ... ................. 52
`
`Syntex LLC v. Apotex Inc.,
`2006 U.S. Dist. Lexis 36089 (N.D. Cal. 2006), aff'd 221 Fed.
`Appx. 1002 (Fed. Cir. 2007) ....................... ..... ............................................. 24, 26
`
`IV
`
`

`
`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`Unigene Labs. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ........................ .. ............ ......... .. ................... 20, 53
`
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) .................................................................. .. .. 23, 31
`
`Federal Statutes
`
`35 U.S.C. § 119 ........................... ........................... ... ... ............................................... 8
`
`35 U.S.C. § 316(e) ..................................................................................................... 1
`
`Other Authorities
`
`Apotex Inc., v. Wyeth LLC,
`IPR2014-00115, slip op. (P.T.A.B. Apr. 20, 2015) ..................................... 17, 28
`
`Sandoz, Inc. v. EKR Therapeutics, LLC,
`IPR2015-00005, slip op. (P.T.A.B. Apr. 24, 2015) ............................................ 58
`
`Ex parte Whalen et a!.,
`Appeal207-4423, slip op. (B.P.A.I. July 23, 2008) ............................... 54, 55, 56
`
`v
`
`

`
`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`Patent Owner Senju Phannaceutical Co., Ltd. et al. ("Senju") responds to the
`
`Petition filed by InnoPhanna Licensing, Inc. et al. ("InnoPharma") concerning
`
`claims 1-30 of U.S. Patent No. 8,669,290 ("the '290 patent"). The Board instituted
`
`trial on InnoPhanna's sole ground that claims 1-30 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). 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
`
`person of ordinary skill in the art would have combined Ogawa and Sallmann with
`
`any expectation of arriving at the claimed subject matter. InnoPhanna also has
`
`failed to prove the existence of all elements of the '290 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, InnoPharma either
`
`ineffectively assails or simply ignores significant objective indicia of patentability,
`
`which further support the non-obviousness of the '290 patent claims. The Board
`
`accordingly should uphold the patentability of claims 1-30 of the '290 patent.
`
`

`
`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`I.
`
`Introduction
`
`The '290 patent discloses and claims stable aqueous liquid preparations 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. 1 These fonnulations 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, 2:35-47; EX2082, ~144 .)
`
`The inventors successfully fonnulated these preparations using the non-ionic
`
`surfactant
`
`tyloxapol.
`
`(EX2082, ~142.) Tyloxapol unexpectedly chemically
`
`stabilized bromfenac better than did the surfactant polysorbate 80, even at a low
`
`pH known to accelerate bromfenac's degradation. (!d., ~~ 147, 157, 162.)
`
`Tyloxapol also unexpectedly maintained preservative efficacy-i.e., prevented
`
`microbial contamination-as compared to polysorbate 80, even when measured
`
`under the stringent European Phannacopoeia standards. (!d., ~167.)
`
`Tyloxapol ' s unexpected stabilizing effect translated into significant medical
`
`benefits in Prolensa®. Tyloxapol's stabilization effect pennitted 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
`
`' 290 patent claims. (EX2082, ~149.)
`
`2
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`

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`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
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`fonnulations (EX2013, 4; EX2026, 5; EX2027, 4), a substantial reduction on a
`
`logarithmic scale and closer to the pH of natural tears. (EX2116, ~41.)
`
`Both the reduction in pH
`
`increased ocular comfort and eliminated the burning and stinging associated with
`
`all other approved NSAID eye drops. (I d.) Lowering the pH also improved
`
`bromfenac' s intraocular penetration and pennitted 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. (ld., ~ 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 fonnulation 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, ~56.) Since its April2013 launch, Prolensa® has generated
`
`$246.9 million in revenue, despite entering a market with at least six branded drugs
`
`3
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`

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`IPR20 15-00902
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`Patent No. 8,669,290
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`and three generic drugs FDA-approved 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. (Jd.)
`
`Moreover, six generic companies, including InnoPharma, have submitted
`
`ANDAs seeking to market exact copies of Prolensa®. (EX2082, ~172.) One of
`
`these six, Lupin, which also has filed an IPR petition challenging the '290 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 '290 patent in district court (EX2130, ~~78-80; EX2023;
`
`EX20 19; EX20 17; EX20 18) but licensed the patent and took consent judgments
`
`and injunctions, tying their acknowledgement of the '290 patent's validity to their
`
`generic copies ofProlensa®. (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., 6-9.) As discussed below, InnoPhanna offers no reason, other than
`
`impermissible hindsight looking backward from the '290 patent claims, why a
`
`person of ordinary skill in the art ("POSA") would have chosen Ogawa's Example
`
`4
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`

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`IPR2 0 15-00902
`Patent Owner Response
`Patent No. 8,669,290
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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 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 InnoPhanna has wholly failed to
`
`meet its burden of proving these claims obvious.
`
`InnoPhanna 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 fonns a "complex"
`
`with BAC, and that he in fact focused on BAC only because the claimed
`
`formulations of the '290 patent contain it, exposing InnoPharma's theory as
`
`impennissibly 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 '290
`
`5
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`

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`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
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`patent's fonnulations utilize BAC, which alone constitutes strong evidence of non-
`
`obviousness.
`
`The Board accordingly should reject
`
`the Petition and uphold
`
`the
`
`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 with any reasonable expectation of arriving at the
`
`claimed subject matter; (ii) it fails 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) it fails to rebut the compelling objective indicia of
`
`non-obviousness of the claimed subject matter.
`
`III. Claim construction
`
`All claims of the '290 patent contain the tenn "stable," and claims 1-7
`
`further contain the phrase "amount sufficient to stabilize." Senju and InnoPhanna
`
`disputed the meaning of this tenn and phrase in parallel district com1 litigation
`
`before Chief Judge Simandle of the U.S. District Court for the District of New
`
`Jersey. On behalf of Senju, Dr. Robe11 Williams, III. Ph.D., who is an expert in the
`
`field of phannaceutical formulation and development and who, based on his
`
`6
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`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
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`education and expenence, is qualified to provide his opinions in this matter
`
`(EX2082, ~~2-11 ), has submitted a declaration in this proceeding and in the claim
`
`construction proceedings before Chief Judge Simandle (EX2125). Adopting Dr.
`
`Williams' construction of the elements "stable" and "amount sufficient to
`
`stabilize" (EX2082, ~47-50; EX2125; EX2065, 5-6), Judge Simandle held that
`
`"stable" as used in the claims of the '290 patent means having sufficient resistance
`
`to degradation (i.e., chemical stability) and having sufficient preservative efficacy
`
`to be fonnulated and maintained for ophthalmic use, and the phrase "amount
`
`sufficient to stabilize" as used in the claims of the '290 patent means an amount
`
`sufficient to confer sufficient resistance to degradation (i.e., chemical stability) to
`
`be formulated and maintained for ophthalmic use. (EX2082, ~51; EX2065, 5-6.)
`
`Senju submits that these terms should be similarly construed in this proceeding.
`
`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 '290 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, ~~45-46.)
`
`V.
`
`The '290 patent
`
`The application for the '290 patent was filed on January 16, 2004, and
`
`7
`
`

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`IPR2 0 15-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`claims priority benefit of the January 21, 2003, filing date of JP 2003-012427
`
`under 35 U.S.C. §119. (EX1001; EX2002.) The '290 patent has three independent
`
`claims (claims 1, 8 and 14) and 27 dependent claims, which are separately
`
`patentable. The '290 patent is listed in the FDA's Orange Book, and the parties
`
`agree that it covers Prolensa® ophthalmic bromfenac (0.07%) solution. (EX1003,
`
`~44; EX2082, ~143.)
`
`VI. Background of ophthalmic formulations
`
`As of the January 21, 2003 priority date of the '290 patent, drug fonnulation
`
`was a difficult and unpredictable endeavor, and it remains so today. The
`
`formulation of ophthalmic drugs is particularly complex. Formulating stable
`
`ophthalmic dosage fonns such as the stable aqueous liquid preparations of the '290
`
`patent is more challenging and critical than with other dosage fonns 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 fonn 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, 1 022.)
`
`8
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`IPR20 15-00902
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`Patent No. 8,669,290
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`VII. The combination of Ogawa and Sallmann, in either direction, does not
`render any claim of the '290 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-
`
`9.) 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 conta,ining NSAIDs, including diclofenac (Voltaren ®),
`
`kctorolac (Acular®), flurbiprofen (Ocufen®), and suprofen (Profenal®). (!d., 26-27.)
`
`A POSA therefore would have had no reason or need to focus, for further
`
`development, on bromfenac to the exclusion of other NSAIDs. (EX2082, ~~65-66.)
`
`Indeed, InnoPhanna 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., 51 (emphasis added).) In fact,
`
`Ogawa states that its bromfenac fonnulations displayed remarkably enhanced
`
`stability (EXl 004, 8:46-9:3),
`
`9
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`

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`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`Moreover, neither Hara nor Yanni supports a preference for bromfenac over
`
`diclofenac, contrary to InnoPhanna's position. (EX2082, ~~67-70.) Hara teaches
`
`that (1) both have "superior" anti-inflammatory action (EX1 002, 2, 3), (2) both
`
`treat postoperative inflammation of the eye (id.), (3) diclofemic 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, ~68.)
`
`The same applies to Yanni, which actually disparages bromfenac, preferring
`
`esters and amides, like nepafenac. (EX1028, 1:54-59, 4:84-52; EX2082, ~~69-70.)
`
`Focusing on a single in vitro result from Table 1 of Yanni (EX1003, ~30), Dr.
`
`Laskar ignores important ex vivo and in vivo data (EX2082, ~~69-70), which do not
`
`show superiority of bromfenac over diclofenac and in fact show superiority of
`
`other compounds. (Id.; EX1028, Table 1.)
`
`B.
`
`Design need and market demands would not have led a POSA in
`the direction that the inventors of the '290 patent took
`
`InnoPhanna's proffered motivation to substitute polysorbate 80 with
`
`tyloxapol is to prevent the alleged fonnation of a precipitate between an acidic
`
`NSAID and BAC. (EX1003, ~104.)
`
`10
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`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
`
`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, ~74.) In
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`fact, in Allergan v. Sandoz, 796 F.3d 1293, 1305 (Fed. Cir. 2015), the defendant's
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`expert referred to BAC as a "natural born killer" that was "from Satan."-
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`A POSA objectively viewing this alleged precipitation issue would have
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`sought to eliminate BAC, thereby eliminating its hannful effects and avoiding the
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`precipitation issue entirely, rather than only attempting to reduce it to some extent
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`by adding a surfactant. (EX2082, ~71.) By January 2003, the art taught using
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`preservative-free fonnulations and well-tolerated preservatives in place of BAC
`
`(EX2082, ~72; 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
`when the prior art undennines very reason offered for combining references). II
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`Patent Owner Response
`Patent No. 8,669,290
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`Indeed by 2003, market demands sought to eliminate the highly toxic BAC
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`from ophthalmic formulations. The art urged that "[i]t is
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`. . . of striking
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`importance to become aware of preservative toxicity in order to develop in the
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`near future many more unpreserved drugs." (EX2064, 115, emphasis added;
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`EX2082, ~~74-75.) 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.
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`(EX2090, abstract; EX2116, ~44.) By November 1997, Acular® PF-a
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`preservative-free ketorolac ophthalmic
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`solution-received FDA approval.
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`(EX2061, 1; EX2116, ~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. IPR2015-00903, EXl 003, ~1 04;
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`; EX2082, ~60; EX1020, 3:28-4:2, 6:11-7:10). Desai also
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`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
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`teaches the use of a different polymeric quaternary ammonium preservative
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`compound, POLYQUAD®,
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`-
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`(EX1005, 1:27-2:31;
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`; EX2082, ~77 .) Even if a POSA
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`still would have wanted to use BAC, the art provided a solution that would have
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`addressed the NSAID/BAC interaction that underlies Dr. Laskar's proffered
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`motivation to use a solubilizer. Yanni teaches bromfenac derivatives without free
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`carboxyl groups, which would not interact with BAC and which have better ocular
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`penetration and stability than bromfenac. (EX1028, 1:60-2:29; EX2082, ~81);
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`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, ~50.) 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,
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`solution to Dr. Laskar' s interaction/precipitation problem in a chemically stable
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`Thus, Ogawa implements a
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`fonnulation,
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`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
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`Based on a post hoc analysis that started with the claims, Dr. Laskar
`
`postulated a motivation position premised on the interaction of an NSAID and
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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, ,-r11 0),
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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. (!d.)
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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, ,-r47.) This also would have addressed any alleged interaction
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`problem. (EX2082, ,-r80.) As such, the art led in a direction divergent from the path
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`chosen by the inventors of the '290 patent,
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`, thereby
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`supporting the non-obviousness of the '290 patent claims.
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`EX2082, ,-r,-r77-81); 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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`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
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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, ,-r107.) 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, ,-r107.) Sodium sulfite is a well-known
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`antioxidant. (EX2014, 3:51-55; EX2082, ,-r107.) 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, ,-r4I), and an antioxidant would prevent that degradation
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`process. InnoPhanna acknowledges that sodium sulfite is added "to prevent
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`oxidation reactions." (Pet., 41.)
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`When bromfenac oxidizes, its forms an oxidation degradant referred to
`throughout Ogawa as red insoluble matters. (EX1004, 8:3-45; EX2082, ,-ri08.) II
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`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, ,-r109.) In fact, none of the m1 of record ever states
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`that bromfenac interacts with BAC to fonn precipitate, and nowhere in Ogawa is
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`such interaction ever mentioned. (!d.)
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`IPR20 15-00902
`Patent Owner Response
`Patent No. 8,669,290
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`-
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`Given the complexities of ophthalmic formulation systems, one cannot
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`predict whether such an interaction does occur. (EX2082, ~109; EX2105, ~75-80.)
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`Polysorbate 80, moreover, plays no role in chemically stabilizing bromfenac
`
`from oxidizing. (EX2082, ~110.) Ogawa is completely silent on the function of
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`polysorbate 80. (!d.) 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, ~110.) 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, ~11 0.) 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, ~54;
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`EX2082, ~Ill.) This passage, however, nowhere refers to polysorbate 80,
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`explicitly or implicitly. (EX2082, ~111.)
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`The data from Ogawa Experimental Examples 4-6 actually confinn that
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`polysorbate 80 does not stabilize bromfenac. (EX2095, 1 07; EX2082, ~111.) Upon
`storage at 60 oc for four weeks, the fonnulations 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 fonnation of red insoluble matter; i.e., degradation of bromfenac.
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`Patent No. 8,669,290
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`(EX1004, 8:4-9:5; EX2095, 107; EX2082, ,-rii2.) But adding sodium sulfite
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`prevented the formation of red insoluble matter, prompting Ogawa to comment
`
`that bromfenac decomposition was not observed and bromfenac's stability was
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`remarkably enhanced. (EXI 004, 8:45-9:4; EX2095, I 07, Table 1 0; EX2082, ,-rill.)
`
`Thus, polysorbate 80 has no effect on the stability ofbromfenac. (EX2082, ,-rill.)
`
`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., 7; EXI 003, ,-r54.) The data in Ogawa Experimental Examples 4-6,
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`however, completely undennine InnoPharma's foundational premise for its
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`obviousness arguments. (EX2082, ,-ri13.) See Apotex Inc., v. Wyeth LLC, IPR2014-
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`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,
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`when no prior art reference or references of record conveys or suggests that
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`knowledge.").
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`2.
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`Sallmann's singular purpose does not align with Ogawa's
`
`Sallmann is uniquely directed to fonnulations of the potassium salt of
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`diclofenac. (EX2082, ,-ri36.) 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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`IPR2015-00902
`Patent Owner Response
`Patent No. 8,669,290
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`inflammation. (ld.) 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, ,-r115.)
`
`Sallmann fonnulates 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, ,-r116.)
`
`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, ,-r114.) Sallmann lists tyloxapol as one of many solubilizers,
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`but bromfenac, known to be free