Paper No. __
`Filed: May 26, 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.
`Petitioners,
`
`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’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`Filed: May 26, 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.
`Petitioners,
`
`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’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`
`I.
`
`Introduction
`
`TABLE OF CONTENTS
`
`
`A.
`
`B.
`
`C.
`
`Background of related litigations
`
`InnoPharma’s failed prima facie case of obviousness
`
`Senju’s compelling objective evidence of patentability
`
`II.
`
`Statement of relief requested
`
`III. Claim construction
`
`IV. Level of skill in the art
`
`V.
`
`The petition should be denied for failing to establish a reasonable
`likelihood that any of the challenged claims is unpatentable
`
`A.
`
`B.
`
`C.
`
`The inventive stable ophthalmic preparations of the ’290 patent
`
`The combination of Ogawa and Sallmann, in either direction,
`does not render any claim of the ’290 patent obvious
`
`InnoPharma has established no reason, other than hindsight, to
`focus on Ogawa and bromfenac preparations
`
`D. Ogawa in view of Sallmann: a combination that a person of
`ordinary skill in the art would not have made
`
`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’s
`Example 6 in view of Sallmann’s Example 2
`
`InnoPharma’s arguments of motivation and expectation
`of success ring hollow in view of the demonstratively
`strong evidence counseling against the proposed
`combination of Ogawa in view of Sallmann
`
`i
`
`2
`
`2
`
`4
`
`9
`
`13
`
`14
`
`14
`
`15
`
`15
`
`17
`
`18
`
`20
`
`20
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`22
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`23
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`27
`
`
`
`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`
`E.
`
`Sallmann in view of Ogawa: a hindsight-laden combination that
`would not have been made prior to invention
`
`1.
`
`2.
`
`The proposed combination destroys the essential purpose
`of Sallmann, ignores the blaze marks in the art, and runs
`afoul of the ’290 patent’s claim language
`
`InnoPharma’s arguments to modify Sallmann’s Example
`2 in view of Ogawa’s Example 6 are legally insufficient,
`internally inconsistent, and belied by the very art it relies
`on
`
`VI. Senju’s compelling objective evidence of patentability enhances an
`already strong case of no prima facie obviousness, which InnoPharma
`fails to adequately rebut
`
`A.
`
`InnoPharma fails to offer evidence refuting unexpected results
`
`1.
`
`2.
`
`3.
`
`The ’290 patent compares against the closest prior art for
`purposes of showing unexpected results
`
`Polysorbate 80’s expected ability to stabilize
`
`Tyloxapol’s unexpectedly superior stabilizing effect
`
`B.
`
`Additional compelling objective evidence of patentability
`
`VII. Separate patentability of individual claims
`
`A.
`
`B.
`
`C.
`
`D.
`
`InnoPharma has failed to demonstrate unpatentability of claims
`1 and 4
`
`InnoPharma has failed to demonstrate unpatentability of claims
`8 and 11 and claims 20 and 23
`
`InnoPharma has failed to demonstrate unpatentability of claims
`27 and 29
`
`InnoPharma has failed to demonstrate unpatentability of claims
`13 and 25 and claims 7 and 19
`
`VIII. Conclusion
`
`ii
`
`32
`
`32
`
`36
`
`42
`
`42
`
`42
`
`44
`
`45
`
`48
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`51
`
`51
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`52
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`54
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`55
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`59
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ................................................................ 35, 54, 57
`
`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) .................................................................... 42, 50
`
`Depuy Spine, Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) .......................................................................... 36
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) .................................................................. 8, 33, 57
`
`In re Gurley,
`27 F.3d 551 (Fed. Cir. 1994) .............................................................................. 26
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (2011) .......................................................................................... 48
`
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ...................................................................... 18, 34
`
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .................................................................... 13, 50
`
`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
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ............................................................................ 42
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) .......................................................................... 14, 17, 19, 38
`
`iii
`
`
`
`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .................................................................... 19, 28
`
`Leo Pharm. Prod., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................... 31, 32
`
`Novartis Pharm. Corp. v. Watson Labs., Inc.,
`No. 2014-1799, 2015 WL 2403308 (Fed. Cir. May 21. 2015)
`(unpublished) ............................................................................................ 7, 18, 25
`
`Ortho-McNeil Pharm. Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .................................................................... 28, 42
`
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ...................................................................... 9, 53
`
`Pfizer Inc. v. Mylan Pharm. Inc.,
`No. 10-528-GMS, 2014 WL 5388100 (D. Del. Oct. 22, 2014) ........ 18, 25, 30, 34
`
`RCA Corp. v. Applied Digital Data Sys., Inc.,
`730 F.2d 1440 (Fed. Cir. 1984) .................................................................... 13, 50
`
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 54
`
`In re Shetty,
`566 F.2d 81 (C.C.P.A. 1977) .............................................................................. 53
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) ................................................................................ 4
`
`Specialty Composites v. Cabot Corp.,
`845 F.2d 981 (Fed. Cir. 1988) ............................................................................ 49
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ........................................................ 14, 17, 18, 51
`
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ................................................................ 32, 33, 58
`
`iv
`
`
`
`Federal Statutes
`
`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`
`35 U.S.C. § 103 ............................................................................................ 15, 32, 58
`
`35 U.S.C. § 119 ........................................................................................................ 15
`
`35 U.S.C. § 314(a) ............................................................................................... 1, 13
`
`35 U.S.C. § 315(b) ..................................................................................................... 3
`
`Other Authorities
`Accord Healthcare, Inc. v. Eli Lilly & Co.,
`IPR2013-00356 (PTAB Oct. 1, 2013) (Paper 13) ................................................ 3
`
`Apotex Inc. v. Wyeth LLC,
`IPR2014-00115 (PTAB Apr. 20, 2015) (Paper 94) .............................. 7, 9, 22, 25
`
`Ariosa Diagnostics v. Verinata Health, Inc.,
`IPR2013-00276 (PTAB Oct. 23, 2014) (Paper 43) ............................................ 17
`
`BSP Software v. Motio Inc.,
`IPR2013-00307, 2013 WL 8563944 (PTAB 2013)............................................ 17
`
`Intellectual Ventures Mgmt. LLC v. Xilinx Inc.,
`IPR2012-00020 (PTAB Feb 11, 2014) (Paper 34) ................................. 35, 54, 57
`
`Kinetic Techs., Inc. v. Skyworks Solutions, Inc.,
`IPR2014-00530 (PTAB Sep. 29, 2014) (Paper 8) .................................. 35, 54, 57
`
`Sandoz, Inc. v. EKR Therapeutics, LLC,
`IPR2015-00005 (PTAB Apr. 24, 2015) (Paper 20) ............................................ 53
`
`Texas Instruments v. VantagePointTech., Inc.,
`IPR2014-01105 (PTAB Jan. 5, 2015) (Paper 8) ..................................... 35, 54, 57
`
`
`
`v
`
`
`
`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`The petition filed by Petitioners (collectively “InnoPharma”) attacking the
`
`patentability of USP 8,669,290 (“the ’290 patent”) is fundamentally flawed.
`
`Tainted by improper hindsight, it proffers legally inadequate motivation to
`
`combine the cited references of USP 4,910,225 to Ogawa et al. (EX1004) and USP
`
`5,891,913 to Sallmann et al. (EX1009). In fact, in either direction, it would not
`
`have been obvious to a person of ordinary skill in the art (“a POSA”) at the time of
`
`invention to manipulate this art as InnoPharma proposes today. Modifying Ogawa,
`
`which InnoPharma admits to be the closest prior art, in view of Sallmann would
`
`not have solved the problem presented in Ogawa. And modifying Sallmann in view
`
`of Ogawa would have defied common sense—an innate attribute of a POSA—for
`
`doing so would have destroyed the entire essence of Sallmann and would have
`
`been expected to only exacerbate the problem presented in Ogawa.
`
`InnoPharma also has failed to prove the existence of all elements of the ’290
`
`patent claims in the cited art and has failed to carry the high burden of proving
`
`inherent obviousness of several claim elements. In addition, the present record
`
`demonstrates significant objective indicia of patentability, which InnoPharma
`
`ineffectively assails or simply ignores, and which further enhance an already
`
`strong case of nonobviousness. The Board accordingly should deny this petition
`
`under 35 U.S.C. § 314(a).
`
`1
`
`
`
`I.
`
`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
`
`
`Introduction
`A. Background of related litigations
`The ’290 patent covers and is listed in the FDA’s Orange Book for
`
`Prolensa®, an ophthalmic bromfenac (0.07%) solution1 whose commercial and
`
`medicinal success is the impetus for InnoPharma’s filing of an Abbreviated New
`
`Drug Application (“ANDA”) seeking FDA approval to sell generic copies of
`
`Prolensa® before the Orange Book-listed patents covering it expire. (EX2006;
`
`EX2007; EX2008.) On September 19, 2014, InnoPharma notified Senju that it
`
`filed an ANDA with Paragraph IV certifications challenging the ’431 and ’290
`
`patents.2 (EX2006.) Senju subsequently sued InnoPharma on November 3, 2014,
`
`
`1 Other patents listed in the Orange Book as covering Prolensa® include U.S. Patent
`
`No. 8,129,431 (“the ’431 patent”) (EX2002), U.S. Patent No. 8,754,131 (“the ’131
`
`patent”) (EX2003), U.S. Patent No. 8,871,813 (“the ’813 patent”) (EX2004), and
`
`U.S. Patent No. 8,927,606 (“the ’606 patent”) (EX2005). Senju Pharmaceutical
`
`Co., Ltd. owns the ’290 patent, the ’431 patent, the ’131 patent, the ’813 patent,
`
`and the ’606 patent, which it licenses to Bausch & Lomb Pharma Holdings Corp, a
`
`subsidiary of Bausch & Lomb, Inc.
`
`2 InnoPharma later notified Senju that InnoPharma had amended its Paragraph IV
`
`certification to include the ’131 patent and the ’606 patent. (EX2007; EX2008)
`
`2
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`
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`for infringing the ’431 patent, the ’290 patent, the ’131 patent, and the ’813 patent,
`
`which cover Prolensa®. (EX2009.) It later sued InnoPharma for infringing the ’606
`
`patent, which also covers Prolensa®. (EX2010.) InnoPharma’s Paragraph IV letter
`
`did not advance any non-infringement positions, thus confirming InnoPharma’s
`
`intention to copy Prolensa®. (EX2006; EX2007; EX2008.)
`
`The parties have proceeded for over six months in the U.S. District Court of
`
`the District of New Jersey toward a final resolution of this case. In addition,
`
`litigation is ongoing against three other generic companies, also seeking to sell
`
`generic copies of Prolensa® and capitalize on its commercial success. The Court
`
`consolidated all actions for discovery purposes (EX2011) and set a trial date for all
`
`cases for March 7, 2016. (EX2012.) Thus, a Final Written Decision from the
`
`Board would not be expected until after the anticipated district court decision.
`
`The timing of InnoPharma’s petition confirms its intent to use the IPR as a
`
`“tool for harassment,” not as an inexpensive alternative to litigation. As the Board
`
`has previously recognized, the legislative history of 35 U.S.C. § 315(b)
`
`admonishes that Congress did not intend IPR proceedings to be used as “tools for
`
`harassment” by “repeated
`
`litigation and administrative attacks.” Accord
`
`Healthcare, Inc. v. Eli Lilly & Co., IPR2013-00356, slip op. at 3 (PTAB Oct. 1,
`
`2013) (Paper 13) (citing H.R. Rep. No. 112-98 at 48 (2011)). InnoPharma,
`
`3
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`
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`moreover, chose to challenge only two of the five Prolensa® patents asserted
`
`against it in the district court, effectively either 1) confirming InnoPharma’s
`
`intention to hedge the outcome of the district court case and subsequently partake
`
`in protracted, piecemeal litigation before the Board—clearly not a cost effective
`
`alternative, or 2) suggesting that InnoPharma does not believe in the strength of its
`
`obviousness arguments.
`
`InnoPharma’s failed prima facie case of obviousness
`
`B.
`On the latter point, InnoPharma has proposed a single ground of
`
`unpatentability based on the combination of Ogawa and Sallmann: first, Ogawa in
`
`view of Sallmann, and then Sallmann in view of Ogawa. InnoPharma’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. (Petition at 6-7.)
`
`InnoPharma, however, ignores that this is chemistry, well-recognized as an
`
`unpredictable art “where minor changes in a product or process may yield
`
`substantially different results.” In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). It is
`
`not at all simple as InnoPharma portrays, and certainly not so with ophthalmic
`
`formulation chemistry, at issue in this case.
`
`4
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`Indeed, components in ophthalmic formulations, whether active or inactive,
`
`can interact and affect one another in unpredictable ways, impacting the
`
`formulation’s efficacy, risk profile (e.g., irritation, redness of the eyes, etc.) and
`
`stability, including chemical and physical stability as well as preservative efficacy.
`
`These formulations represent dynamic systems with many “moving parts.”
`
`Addressing a problem arising with one aspect of the formulation can give rise to
`
`multiple other problems, often leading to “start overs,” failures, frustration, and
`
`further experimentation, none of which yields obvious solutions.
`
`Because
`
`the ’290 patent’s formulations,
`
`including
`
`the commercial
`
`embodiment Prolensa®, treat ocular inflammation post-surgery, they require FDA
`
`approval. One does not just simply “swap” one component for another and receive
`
`FDA approval to market the “swapped” product. If that were true, there would be a
`
`new FDA approved ophthalmic formulation almost every day. The reality, of
`
`course, is that it takes years of trial and error, testing and experimentation, and
`
`thousands of person hours before a new ophthalmic product is ready for use and
`
`commercialization. InnoPharma has innovated nothing, however, and instead has
`
`simply copied the FDA-approved Prolensa® formulation. InnoPharma now seeks to
`
`evade liability for its willfully infringing actions by creating ex-post facto
`
`5
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`
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`“swapping” theories of unpatentability in an attempt to invalidate the patents
`
`covering these valuable assets.
`
`InnoPharma’s overly simplistic view of the technology at issue in the ’290
`
`patent, a view shared by its expert Dr. Paul A. Laskar, dooms its objectivity in
`
`considering the art as it would have been considered by a POSA before January 21,
`
`2003, the patent’s earliest effective filing date. Such a view ultimately betrays
`
`InnoPharma’s analysis as no more than a hindsight reconstruction, driven by
`
`litigation-induced distortion of the underlying facts.
`
`Ogawa taught the use of sodium sulfite, a well-known antioxidant (EX2014
`
`at 3:51-55), to chemically stabilize bromfenac from degradation. (EX1004 at
`
`Experimental Example 6.) A POSA would have readily understood, therefore, that
`
`oxidation caused bromfenac’s degradation. (EX1033 at 5.) Sallmann is directed to
`
`formulations of the potassium salt of diclofenac, an NSAID known to be poorly
`
`soluble in water. (EX1050 at 12 (diclofenac is “poorly soluble in water.”).) The
`
`essence of the Sallmann patent, indeed its entire purpose for existing, is the use of
`
`diclofenac potassium in ocular formulations. The patent was presumably awarded
`
`by showing that diclofenac potassium had surprisingly better ocular penetration
`
`than previous diclofenac sodium formulations. (EX1009 at 1:48-59.) Sallmann
`
`formulates diclofenac potassium with a number of additional inactive components,
`
`6
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`including solubilizers to solubilize the poorly-water soluble diclofenac. Tyloxapol
`
`is listed as one of a number of solubilizers. (EX1009 at 4:52-67.)
`
`Just from this initial assessment, InnoPharma’s position quickly unravels to
`
`reveal the improper ex-post facto analysis at its core. A POSA would not have
`
`sought to address the oxidation of bromfenac with a solubilizer, for it would not
`
`have been expected to have any effect on the oxidation process. A proposed
`
`solution that does not address a problem disclosed in the art is not an obvious
`
`solution. See Cadence Pharm. Inc. v. Exela PharmSci Inc., 780 F.3d 1364, 1375
`
`(Fed. Cir. 2015); Novartis Pharm. Corp. v. Watson Labs., Inc., No. 2014-1799,
`
`2015 WL 2403308, at *7 (Fed. Cir. May 21. 2015) (unpublished); Apotex Inc. v.
`
`Wyeth LLC, IPR2014-00115, slip op. at 18 (PTAB Apr. 20, 2015) (Paper 94). To a
`
`POSA, solubilizers typically solubilize poorly-soluble drugs, like diclofenac.
`
`(EX1050 at 12.) Because bromfenac was known to readily dissolve in water
`
`(EX1007 at 6), there simply would not have been any reason, other than hindsight,
`
`to use a solubilizer such as tyloxapol with bromfenac, nor any expectation that it
`
`would prevent bromfenac’s oxidative degradation.
`
`Similarly, a POSA would not have been motivated to swap Sallmann’s
`
`diclofenac potassium for Ogawa’s bromfenac. Doing so would eviscerate the entire
`
`purpose of the Sallmann patent and its reason for being, i.e., the use of diclofenac
`
`7
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`potassium. See In re Gordon, 733 F.2d 900, 902 (Fed. Cir. 1984) (holding that
`
`modification of a reference is not obvious if it would render the reference
`
`inoperable for its intended purpose). Moreover, bromfenac’s oxidative degradation
`
`would have been expected to persist after dropping bromfenac into Sallmann’s
`
`formulations, for Sallmann’s Example 2 does not include any components, not
`
`already in Ogawa, that would have prevented bromfenac’s oxidation. Only a
`
`person devoid of common sense, or a person using hindsight to work backwards
`
`from the solution in the ’290 patent, would have attempted such a combination.
`
`In addition, InnoPharma’s proposed combination is riddled with failures of
`
`proof regarding various elements of the ’290 patent claims. All claims of the ’290
`
`patent require that bromfenac be the sole active pharmaceutical ingredient. Some
`
`claims also recite the transition term “consisting essentially of,” excluding
`
`unrecited elements that would materially affect the basic and novel properties of
`
`the claimed stable aqueous preparations, including other active ingredients besides
`
`bromfenac. To be true to the essence of Sallmann, if combined with Ogawa, a
`
`POSA would have had a formulation with two active ingredients. Not only would
`
`that violate the “sole active pharmaceutical ingredient” requirement of the ’290
`
`patent claims, it could also lead to drug–drug interactions affecting the properties
`
`8
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`IPR2015-00902
`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`of the claimed formulations. InnoPharma, whose burden it is to prove otherwise,
`
`has not done so.
`
`InnoPharma has also failed to carry its heavy and high burden of proving
`
`inherent obviousness with regard to the claim elements dealing with chemical
`
`stability, e.g., greater than about [90 or 92]% bromfenac remaining after four
`
`weeks at 60° C., and preservative efficacy (EP-Criteria B). Par Pharm., Inc. v. TWi
`
`Pharms., Inc., 773 F.3d 1186, 1195-96 (Fed. Cir. 2014) (“A party must, therefore,
`
`meet a high standard in order to rely on inherency to establish the existence of a
`
`claim limitation in the prior art in an obviousness analysis ….”); see also Apotex,
`
`IPR2014-00115, slip op. at 14 (Paper 94). Indeed, InnoPharma has not proffered a
`
`scintilla of evidence in this regard.
`
`Senju’s compelling objective evidence of patentability
`C.
`Notwithstanding InnoPharma’s contrived and weak prima facie arguments,
`
`Senju proffers compelling objective indicia of patentability, which InnoPharma has
`
`failed to counter. The art of record provides no guidance regarding how
`
`polysorbate 80 will perform relative to tyloxapol with respect to chemical stability.
`
`To the extent that solubilizing ability would have been an indicator of chemical
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`stability for bromfenac, which it would not have been because bromfenac dissolves
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`Patent No. 8,669,290
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`readily in water (EX1007 at 6), the art of record establishes that polysorbate 80
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`should outperform tyloxapol. (EX1012 at Table 1; EX1050 at 7.)
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`Using the same stress test disclosed in Ogawa (four weeks at 60° C.), Senju
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`has demonstrated in the ’290 patent vastly superior and completely unexpected
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`stability results for tyloxapol over polysorbate 80 at the harsh pH of 7.0. (EX1001
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`at Table 1.) This low pH challenges the formulations because it enhances
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`bromfenac’s degradation (EX1004 at Experimental Example 4, Table 8) and quite
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`effectively delineates the relative stabilization capability of the tested compounds.
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`The comparative test reported in Table 1 of the ’290 patent, moreover, constitutes a
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`scientifically proper head-to-head comparison varying only one component—
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`polysorbate 80 versus tyloxapol—to further enhance the clarity of the relative
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`ability of the surfactants to stabilize bromfenac from chemical degradation under
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`the highly stressed conditions of 60° C. for four weeks.
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`The results in Table 1 show that, when compared with polysorbate 80 at
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`0.15 g, which is the amount of polysorbate 80 used in Ogawa, tyloxapol was 44%3
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`3 The percent increase in stability is calculated throughout as the difference in
`
`remaining rate of bromfenac for the tyloxapol and polysorbate 80-containing
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`formulations, over the remaining rate of bromfenac for the polysorbate 80-
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`containing formulation, multiplied by 100.
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`Patent No. 8,669,290
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`better at stabilizing bromfenac from degradation. (EX1004 at Table 1, Comparison
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`Example 1 and A-02.) And in a completely unexpected and counterintuitive
`
`manner, when the amount of tyloxapol was lowered to 0.02%, about 1/8 the
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`amount of polysorbate 80 taught in Ogawa, tyloxapol was 75% better at stabilizing
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`bromfenac degradation. (Id. at Table 1, A-03.) This is a truly remarkable and
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`surprising result considering the harsh pH conditions and the significantly reduced
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`amount of tyloxapol versus polysorbate 80. By any metric, no one would have
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`expected this huge disparity in chemical stability results for tyloxapol.
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`At a higher pH > 8, one far less conducive to degrading bromfenac (see
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`EX1004 at Experimental Example 4, Table 8), formulations of tyloxapol achieved
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`stabilization results comparable to those of polysorbate 80 in Ogawa’s Example 6,4
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`but notably did so using amounts of tyloxapol of about 1/3, 1/5, and 1/8 the amount
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`of polysorbate 80. (EX1001 at Table 2; EX1004 at Example 6.) Additionally, these
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`results were achieved without using the antioxidant sodium sulfite, touted by
`
`Ogawa as instrumental in achieving “remarkably enhanced” stability results.
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`4 Ogawa’s Example 6 reports 100.9% remaining bromfenac. Because matter cannot
`
`be created, the reported value likely reflects measurement error or the presence of
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`water not removed before the measurement was made.
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`Patent No. 8,669,290
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`(EX1004 at Experimental Example 6, 8:46-9:4.) To achieve this level of stability
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`without sodium sulfite is entirely unexpected in view of Ogawa.
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`Tyloxapol’s unexpected stabilization benefits translated into real world
`
`benefits in producing Prolensa® with a comfortable pH of 7.8, close to that of
`
`natural tears, that led to improved ocular penetration, a lowering of the amount of
`
`bromfenac to 0.07% from 0.09%, and ultimately less drug contacting surgically
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`compromised ocular tissue without a reduction in efficacy. (EX2030; EX2026;
`
`EX2027.) With these new benefits, Prolensa® garnered significant acclaim in the
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`medical community (EX2015), drawing in doctors and patients alike, despite the
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`availability of
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`lower-priced generic, non-prior art commercial bromfenac
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`formulations. (EX2028.)
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`Seeking to capitalize on Prolensa’s®
`
` commercial success, generic companies
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`began submitting ANDAs to market generic copies of Prolensa®, driven by sales of
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`Prolensa® they projected would exceed $100 million annually. (EX2022 at 4.)
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`Even they, however, have recognized the strength and inventiveness of the
`
`Prolensa® patents. Apotex, a giant in the generic drug industry that actively sells
`
`ophthalmic products, initially challenged the ’290 patent in district court.
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`(EX2023; EX2019.) Apotex recently, however, licensed the patent and took a
`
`consent judgment and injunction specifically acknowledging the ’290 patent’s
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`Patent No. 8,669,290
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`validity. (EX2024.) See Institut Pasteur & Universite Pierre Et Marie Curie v.
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`Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013) (“Pasteur's licensing activities
`
`provide ‘probative and cogent evidence’ of non-obviousness of the claims at
`
`issue.”); RCA Corp. v. Applied Digital Data Sys., Inc., 730 F.2d 1440, 1448 (Fed.
`
`Cir. 1984) (holding the commercial acquiescence of competitors, evidenced by
`
`RCA's licensing of the invention, is relevant to non-obviousness).
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`Given InnoPharma’s failure to establish a prima facie case of obviousness,
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`as well as its failure to rebut significant secondary evidence of patentability,
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`InnoPharma’s mere “swapping” obviousness allegation fails to meet the minimum
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`institution threshold of a reasonable likelihood of prevailing on at least one
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`challenged claim. 35 U.S.C. § 314(a). The Board should therefore deny
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`InnoPharma’s petition in its entirety.
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`II.
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`Statement of relief requested
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`Senju respectfully requests that InnoPharma’s petition be denied for at least
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`the following reasons: (i) it fails to provide legally proper motivation to combine
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`Ogawa and Sallmann, in either direction; (ii) it fails to prove the existence of each
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`element of each challenged claim from Ogawa and Sallmann, including failing to
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`prove inherent obviousness of various claim elements; and (iii) it fails to rebut the
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`compelling objective indicia of nonobviousness of the claimed subject matter.
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`Patent No. 8,669,290
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`III. Claim construction
`InnoPharma does not propose any particular claim constructions, relying on
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`the Board’s determination in IPR2014-01043 that “[n]o claim term [in the
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`challenged claims] requires express construction” for the purposes of rendering a
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`decision to institute review in that proceeding. Petition at 16; Metrics, Inc. v. Senju
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`Pharm. Co., Ltd., IPR2014-01043 (Paper No. 19 at 10). Senju agrees that the terms
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`do not need express construction at this stage in light of the claim language,
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`specification, and prosecution history of the ’290 patent.
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`IV. Level of skill in the art
`InnoPharma states that a POSA “thinks along conventional wisdom in the
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`art, and is a person of ordinary creativity,” relying on the Supreme Court’s decision
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`in KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007). (Petition at 17.) But the law
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`also makes clear that a POSA “interprets the prior art using common sense and
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`appropriate perspective.” Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d 1352, 1361
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`(Fed. Cir. 2011) (citing KSR, 550 U.S. at 402).
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`InnoPharma and its expert Dr. Laskar further state that the education and
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`experience level of the skilled person can vary, from someone with a bachelor’s
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`degree with 5–10 years of work experience to someone with a Ph.D. with fewer
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`years of experience. (Petition at 17; EX1003 at ¶ 20.) Senju disagrees with this
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`Patent No. 8,669,290
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`definition as overly inflated for “ordinary skill,” as required by the statute. 35
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`U.S.C. § 103. A person with just “ordinary skill” would more likely have a
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`bachelor’s degree with 3–5 years of work experience.
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`V. The petition should be denied for failing to establish a reasonable
`likelihood that any of the challenged claims is unpatentable
`A. The inventive stable ophthalmic preparations of the ’290 patent
`Prolensa® is approved for the treatment of postoperative inflammation and
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`reduction of ocular pain in patients who have undergone cataract surgery.
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`(EX2013.) Prolensa® received FDA approval in April 2013, and immediately
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`garnered acclaim in the medical community based on highly favorable clinical
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`study data demonstrating “the benefits of the new formulation.” (EX2015.) The
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`patents that cover Prolensa® claim formulations of bromfenac for ophthalmic
`
`administration and methods of treatment using these formulations. The ’290 patent
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`was filed on November 28, 2012, and claims priority benefit of the January 21,
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`2003, filing date of JP 2003-012427 under 35 U.S.C. §119. (EX1001; EX2002.)
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`The ’290 patent claims are directed, generally speaking, to stable aqueous
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`ophthalmic preparations of bromfenac and
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`tyloxapol.
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`(EX1001.) These
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`preparations are “useful for the treatment of . . . postoperative inflammation.”
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`(EX1001 at abstract.) The ’290 patent has three independent claims (claims 1, 8,
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`and 14) and 27 dependent claims.
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`Patent Owner’s Preliminary Response
`Patent No. 8,669,290
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`Claim 1 recites, generally speaking, a stable aqueous liquid preparation
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`comprising bromfenac and tyloxapol, formulated for ophthalmic administration,
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`where bromfenac is the sole pharmaceutical active ingredient in the preparation
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`and tyloxapol is present in an amount “sufficient to stabilize” bromfenac.
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`Claim 8 recites, gen
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