Paper No. __
`Filed: August 3, 2015
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`Petitioner
`
`
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`__________________
`
`Case IPR2015-01100
`Patent 8,927,606 B2
`
`__________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`Filed: August 3, 2015
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________
`
`LUPIN, LTD. and LUPIN PHARMACEUTICALS INC.,
`Petitioner
`
`
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner
`
`__________________
`
`Case IPR2015-01100
`Patent 8,927,606 B2
`
`__________________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`IPR2015-01100
`Patent Owner’s Preliminary Response
`Patent No. 8,927,606
`
`
`TABLE OF CONTENTS
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`2
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`2
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`4
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`10
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`13
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`14
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`14
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`14
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`14
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`15
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`16
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`18
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`18
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`20
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`24
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`
`
`I.
`
`Introduction
`
`A.
`
`B.
`
`C.
`
`Background of related litigations
`
`Lupin’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 claims of the ’606 patent
`
`The combinations of Ogawa in view of Fu and Ogawa in view
`of Sallmann do not render any claim of the ’606 patent obvious
`
`Lupin has established no reason, other than hindsight, to focus
`on Ogawa and bromfenac preparations
`
`D. Ogawa in view of Fu: 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
`
`It would not have been obvious to modify Ogawa’s
`Example 6 in view of Fu’s Example 5
`
`Because neither Ogawa nor Fu disclose tyloxapol, their
`combination fails to satisfy all elements of the claims
`
`Lupin’s arguments of motivation and expectation of
`success ring hollow in view of the demonstratively strong
`
`i
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`IPR2015-01100
`Patent Owner’s Preliminary Response
`Patent No. 8,927,606
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`evidence counseling against the proposed combination of
`Ogawa in view of Fu
`
`E.
`
`Sallmann in view of Ogawa: a hindsight-laden combination that
`would not have been made prior to invention
`
`1.
`
`2.
`
`3.
`
`The proposed combination destroys the essential purpose
`of Sallmann, ignores the blaze marks in the art, and runs
`afoul of the ’606 patent’s claim language
`
`Lupin’s alternative modification of Ogawa Example 6 in
`view of Sallmann similarly fails
`
`Lupin’s arguments to modify Sallmann in view of
`Ogawa, in any direction, are legally insufficient,
`internally inconsistent, and belied by the very art Lupin
`relies on
`
`VI. Senju’s compelling objective evidence of patentability enhances an
`already strong case of no prima facie obviousness, which Lupin fails
`to adequately rebut
`
`A.
`
`Lupin fails to offer evidence refuting unexpected results
`
`1.
`
`2.
`
`3.
`
`The ’606 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.
`
`Lupin has failed to demonstrate unpatentability of claims 1 and
`5
`
`Lupin has failed to demonstrate unpatentability of claims 11
`and 15
`
`C.
`
`Lupin has failed to demonstrate unpatentability of claim 29
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`ii
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`28
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`34
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`35
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`38
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`40
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`43
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`44
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`44
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`45
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`47
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`51
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`53
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`53
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`54
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`56
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`57
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`60
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`D.
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`Lupin has failed to demonstrate unpatentability of claim 18 and
`claim 25
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`VIII. Conclusion
`
`
`
`iii
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`Patent No. 8,927,606
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Application of Merchant, 575 F.2d 865 (C.C.P.A 1978) ......................................... 49
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) .......................................................... 38, 47, 56, 58
`
`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) .................................................................... 43, 53
`
`CFMT, Inc. v. Yieldup Intern. Corp.,
`349 F.3d 1333 (Fed. Cir. 2003) .......................................................................... 24
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) .................................................................. 9, 36, 58
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (2011) .......................................................................................... 50
`
`Insite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ................................................................ 16, 25, 37
`
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .................................................................... 13, 53
`
`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. Teleflex Inc.,
`550 U.S. 398 (2007) ...................................................................................... 15, 18
`
`Leo Pharm. Prod., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .................................................................... 31, 34
`
`iv
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`Patent No. 8,927,606
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`
`In re Ochiai,
`71 F.3d 1565 (Fed. Cir. 1995) ............................................................................ 50
`
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) .......................................................................... 17
`
`Ortho-McNeil Pharm. Inc. v. Mylan Labs., Inc.,
`
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 43
`
`Par Pharm., Inc. v. TWi Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 55
`
`Pfizer Inc. v. Mylan Pharm. Inc.,
`No. 10-528-GMS, 2014 WL 5388100
`(D. Del. Oct. 22, 2014) ..................................................................... 16, 25, 30, 37
`
`In re Shetty,
`566 F.2d 81 (C.C.P.A. 1977) .............................................................................. 55
`
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995) ................................................................................ 4
`
`Specialty Composites v. Cabot Corp.,
`845 F.2d 981 (Fed. Cir. 1988) ............................................................................ 52
`
`Unigene Labs., Inc. v. Apotex Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ........................................................ 16, 54, 55, 57
`
`In re Wesslau,
`353 F.2d 238 (C.C.P.A. 1965) ................................................................ 34, 37, 59
`
`Federal Statutes
`
`35 U.S.C. § 103 ........................................................................................................ 14
`
`35 U.S.C. § 119 ........................................................................................................ 14
`
`35 U.S.C. § 314(a) ............................................................................................... 1, 13
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`35 U.S.C. § 315(b) ..................................................................................................... 3
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`v
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`Patent No. 8,927,606
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`
`Other Authorities
`Accord Healthcare, Inc. v. Eli Lilly & Co.,
`IPR2013-00356, slip op. (PTAB Oct. 1, 2013) .................................................... 3
`
`Apotex Inc. v. Wyeth LLC,
`IPR2014-00115, slip op. (PTAB Apr. 20, 2015) ...................................... 7, 20, 23
`
`Ariosa Diagnostics v. Verinata Health, Inc.,
`IPR2013-00276, slip op. (PTAB Oct. 23, 2014) ................................................ 15
`
`BSP Software v. Motio Inc.,
`IPR2013-00307, 2013 WL 8563944 (PTAB 2013)............................................ 15
`
`Sandoz, Inc. v. EKR Therapeutics, LLC,
`IPR2015-00005, slip op. (PTAB Apr. 24, 2015) .......................................... 56, 57
`
`
`
`vi
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`IPR2015-01100
`Patent Owner’s Preliminary Response
`Patent No. 8,927,606
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`The petition filed by Petitioners (collectively “Lupin”) attacking the
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`patentability of USP 8,927,606 (“the ’606 patent”) should be denied under 35
`
`U.S.C. § 314(a), as it is fundamentally flawed. Tainted by improper hindsight, it
`
`proffers legally inadequate motivation to combine USP 4,910,225 to Ogawa et al.
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`(EX1010), EP 0306 984 to Fu et al. (EX1014), and USP 5,891,913 to Sallmann et
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`al. (EX1021). In fact, in any combination, it would not have been obvious to a
`
`person of ordinary skill in the art (“POSA”) at the time of invention to manipulate
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`this art as Lupin proposes today.
`
`Ogawa, which Lupin admits to be the closest prior art, would not have been
`
`combined with Fu. They are incompatible as such, solving different problems
`
`using different approaches. Lupin also has failed to prove the existence of all
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`elements of the ’606 patent claims in Ogawa and Fu. The proposed combination of
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`Ogawa and Sallmann similarly fails. A POSA would not have modified Ogawa by
`
`Sallmann because it 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.
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`1
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`Patent Owner’s Preliminary Response
`Patent No. 8,927,606
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`In addition, the present record demonstrates significant objective indicia of
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`patentability, which Lupin ineffectively assails or simply ignores, and which
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`further enhance an already strong case of nonobviousness. Denial of the Petition is
`
`warranted.
`
`I.
`
`Introduction
`A. Background of related litigations
`The ’606 patent covers and is listed in the FDA’s Orange Book for
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`Prolensa®, an ophthalmic bromfenac (0.07%) solution whose commercial and
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`medicinal success is the impetus for Lupin’s filing of an Abbreviated New Drug
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`Application (“ANDA”) seeking FDA approval to sell generic copies of Prolensa®
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`before the patents covering it expire. (EX2002; EX2003; EX2004; EX2005;
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`EX2006.) On February 19, 2015, Lupin notified Senju that it filed an ANDA with
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`a Paragraph IV certification challenging the ’606 patent. (EX2006.) Senju sued
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`Lupin on January 16, 2015, for infringing the ’606 patent, which covers
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`Prolensa®.1 (EX2010.) Lupin’s Paragraph IV letter did not advance any non-
`
`
`1 Other patents listed in the Orange Book as covering Prolensa® include U.S. Patent
`
`No. 8,129,431 (“the ’431 patent”) (EX2001), U.S. Patent No. 8,669,290 (“the ’290
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`patent”) (EX1001), U.S. Patent No. 8,754,131(“the ’131 patent”) (EX1002), and
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`U.S. Patent No. 8,871,813 (“the ’813 patent”) (EX1003). Lupin also certified under
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`2
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`IPR2015-01100
`Patent Owner’s Preliminary Response
`Patent No. 8,927,606
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`infringement positions as to many of the claims of the ’606 patent, thus confirming
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`Lupin’s intention to copy Prolensa®. (EX2006.)
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`The parties have proceeded for over a year and a half in the U.S. District
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`Court for the District of New Jersey toward a final resolution of the matter. In
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`addition, litigation has expanded to five other generic companies, also seeking to
`
`sell generic copies of Prolensa® and capitalize on its commercial success, and is
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`currently ongoing against three generics, including Lupin. The Court consolidated
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`the actions for discovery purposes (EX2011) and set a trial date for all cases for
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`March 7, 2016. (EX2012.) Thus, a Final Written Decision from the Board would
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`not be expected until after the anticipated district court decision.
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`The timing of Lupin’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
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`previously recognized, the legislative history of 35 U.S.C. § 315(b) admonishes
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`that Congress did not intend IPR proceedings to be used as “tools for harassment”
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`by “repeated litigation and administrative attacks.” Accord Healthcare, Inc. v. Eli
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`Lilly & Co., IPR2013-00356, slip op. at 3 (PTAB Oct. 1, 2013) (Paper 13) (citing
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`Paragraph IV against the ’431, ’290, ’131, and ’813 patents (EX2002; EX2003;
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`EX2004; EX2005), and Senju later sued Lupin on these patents. (EX2007;
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`EX2008; EX2009; EX2010.)
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`H.R. Rep. No. 112-98 at 48 (2011)). Lupin, moreover, chose to challenge only four
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`of the five Prolensa® patents asserted against it in the district court, effectively
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`either 1) confirming Lupin’s intention to hedge the outcome of the district court
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`case and subsequently partake in protracted, piecemeal litigation before the
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`Board—clearly not a cost effective alternative, or 2) suggesting that Lupin does not
`
`believe in the strength of its obviousness arguments.
`
`Lupin’s failed prima facie case of obviousness
`
`B.
`On the latter point, Lupin has proposed two grounds of unpatentability based
`
`on Ogawa, Fu, and Sallmann: First, Ogawa in view of Fu, and then Sallmann in
`
`view of Ogawa. Lupin’s central theme is one of substituting ethoxylated
`
`octylphenols in Fu, which does not even disclose tyloxapol, for polysorbate 80 in
`
`Ogawa’s Example 6, or alternatively, substituting bromfenac in Ogawa’s Example
`
`6 for diclofenac in Sallmann’s Example 2. (Petition at 11-12.) Lupin, 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 Lupin portrays,
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`and certainly not so with ophthalmic formulation chemistry, at issue in this case.
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`Indeed, components in ophthalmic formulations, whether active or inactive,
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`can interact and affect one another in unpredictable ways, impacting the
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`4
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`Patent No. 8,927,606
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`formulation’s efficacy, risk profile, and stability, including chemical and physical
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`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 unexpectedly give rise to multiple other problems, often
`
`leading to “start overs,” failures, frustration, and further experimentation, none of
`
`which yields obvious solutions. In fact, Lupin’s own expert, Dr. Jayne Lawrence,
`
`recognizes the unpredictability of such systems and that simply changing one
`
`parameter (e.g., temperature) does not yield predictable results: “[W]ithout further
`
`testing, it is not possible to predict whether the data related to the elevated
`
`temperature will have any relevance to the lower temperature.” (EX1005 at ¶ 530.)
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`Because the ’606 patent covers methods of administering formulations,
`
`including Prolensa®, to treat ocular inflammation post-surgery, these formulations
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`require FDA approval. One does not just simply substitute one component for
`
`another and receive FDA approval to market the substituted product. If that were
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`true, there would be a new FDA approved ophthalmic formulation almost every
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`day. The reality, of course, is that these ophthalmic systems are unpredictable, as
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`Dr. Lawrence acknowledges (id.), and it takes years of trial and error, testing and
`
`experimentation, and thousands of person hours to develop new products suitable
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`for ophthalmic use. Lupin has innovated nothing, however, and instead has simply
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`Patent No. 8,927,606
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`copied the FDA-approved Prolensa® formulation. Lupin now seeks to evade
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`liability for its willfully infringing actions by creating post hoc, simplistic
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`substitution theories of unpatentability in an attempt to invalidate the patents
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`covering these valuable assets.
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`Lupin’s overly simplistic view of the technology at issue in the ’606 patent
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`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
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`view ultimately betrays Lupin’s analysis as no more
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`than a hindsight
`
`reconstruction, driven by litigation-induced distortion of the underlying facts.
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`Ogawa taught the use of sodium sulfite, a well-known antioxidant (EX2013
`
`at 3:51-55), to chemically stabilize bromfenac from degradation evidenced by red
`
`insoluble particles. (EX1010 at Exp. Ex. 6.) A POSA would have readily
`
`understood, therefore, that oxidation caused bromfenac’s degradation. (EX2036 at
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`5.) Fu, by contrast, taught the use of a solubilizer (an ethoxylated octylphenol,
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`particularly Octoxynol 40 (see, e.g., EX1014 at 3:10-12; 5:25-27; Ex. 5)) to
`
`physically stabilize a solution of ketorolac (a structurally dissimilar NSAID from
`
`bromfenac) and benzalkonium chloride (BAC) against complexation. (Id. at 1:10-
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`20; 3:10-12; Ex. 5.) The physical instability is manifested by the turbidity or
`
`cloudiness of the formulation. Fu indicates that it is Octoxynol 40’s ability to
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`Patent No. 8,927,606
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`solubilize the complex that clarifies the formulation and physically stabilizes it.
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`(Id. at 9:34-36.)
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`Ogawa and Fu would not have been combined as Lupin proposes. Lupin
`
`confuses chemical stability with physical stability, blending them together as if
`
`they were one and the same. But they constitute different problems eliciting
`
`different solutions. Lupin has postulated an obviousness position premised on
`
`Ogawa, which it admits is the closest prior art and which addresses the oxidative
`
`chemical degradation of bromfenac using an antioxidant. Arguing that Fu broadly
`
`teaches stabilizing aqueous NSAID formulations that contain BAC (Petition at 17-
`
`18), Lupin inappropriately seeks to address bromfenac’s chemical stability with
`
`Fu, which instead addresses the physical stability of an entirely different NSAID
`
`using a solubilizer. A POSA would not have sought to address the oxidation of
`
`bromfenac with a nonionic surfactant effectively taught as a solubilizer, for it
`
`would not have been expected to impede the oxidation process. And solubilizing
`
`the oxidized degradants would have done no good, for they are no longer
`
`bromfenac and would be inactive. A proposed solution that does not address the
`
`problem disclosed in the art is not an obvious solution. See Cadence Pharm. Inc. v.
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`Exela PharmSci Inc., 780 F.3d 1364, 1375 (Fed. Cir. 2015); Apotex Inc. v. Wyeth
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`LLC, IPR2014-00115, slip op. at 18 (PTAB Apr. 20, 2015) (Paper 94).
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`Moreover, even if combined, Ogawa and Fu to do not teach all of the
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`elements of the claims and cannot legally establish obviousness. Neither Ogawa
`
`nor Fu discloses or ever alludes to tyloxapol. The ethoxylated octylphenols broadly
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`referred to by Fu constitute an enormous class of compounds, from which
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`tyloxapol would not be envisaged or suggested. Lupin traces a path to tyloxapol
`
`through Octoxynol 9, sparingly mentioned in Fu, contending that tyloxapol is an
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`oligomer of Octoxynol 9. That is wrong. In fact, their repeating units are different,
`
`and when the compounds are viewed in their entirety, their extreme structural
`
`dissimilarity becomes readily apparent.
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`Lupin’s proposed combination of Ogawa in view of Sallmann similarly fails.
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`Sallmann is directed to formulations of the potassium salt of diclofenac, an NSAID
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`known to be poorly soluble in water. (EX2035 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. (EX1011 at 1:48-
`
`59.) Sallmann formulates diclofenac potassium with a number of additional
`
`excipients, including solubilizers to solubilize the poorly-water soluble diclofenac.
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`Tyloxapol is listed as one of a number of solubilizers. (EX1011 at 4:52-67.)
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`Patent No. 8,927,606
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`As with Fu, a POSA would not have addressed the oxidation of bromfenac
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`with a solubilizer like tyloxapol. See Cadence, 780 F.3d at 1375. It would not have
`
`been expected to inhibit oxidation. Nor would solubilizing the oxidized degradants
`
`help, for they are not bromfenac. To a POSA, solubilizers typically solubilize
`
`poorly-soluble drugs, like diclofenac. (EX2035 at 12.) Because bromfenac was
`
`known to readily dissolve in water (EX1053 at 6), there simply would not have
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`been any reason, other than hindsight, to use tyloxapol with bromfenac.
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`Similarly, a POSA would not have been motivated to substitute Sallmann’s
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`diclofenac potassium for Ogawa’s bromfenac. Doing so would eviscerate the entire
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`purpose of the Sallmann patent and its reason for being, i.e., the use of diclofenac
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`potassium. See In re Gordon, 733 F.2d 900, 902 (Fed. Cir. 1984) (holding that
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`modification of a reference is not obvious if it would render the reference
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`inoperable for its intended purpose). Moreover, bromfenac’s oxidative degradation
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`would have been expected to persist after dropping bromfenac into Sallmann’s
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`formulations, for Sallmann’s Example 2 does not include any components, not
`
`already in Ogawa, that would have prevented bromfenac’s oxidation.
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`Lastly, all claims of the ’606 patent require that bromfenac be the sole
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`pharmaceutical active ingredient. Some claims also recite the transition term
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`“consists essentially of.” To be true to the essence of Sallmann, if combined with
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`Patent No. 8,927,606
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`Ogawa, a POSA would have had a formulation with two active ingredients. Not
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`only would that violate the “sole pharmaceutical active ingredient” requirement of
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`the ’606 patent claims, it could also lead to drug–drug interactions affecting the
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`properties of the claimed formulations. Lupin, whose burden it is to prove
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`otherwise, has not done so.
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`Senju’s compelling objective evidence of patentability
`
`C.
`Senju proffers compelling objective indicia of patentability, which Lupin has
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`failed to counter. The art of record provides no guidance regarding how
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`polysorbate 80 will perform relative to tyloxapol with respect to chemical stability.
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`To the extent that solubilizing ability would have been an indicator of chemical
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`stability for bromfenac, which Lupin has not substantiated, the art of record
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`establishes that polysorbate 80 should outperform tyloxapol. (EX1022 at Table 1;
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`EX2035 at 7:34-37.)
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`Bromfenac becomes vulnerable to degradation at a pH of about 8 and
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`precipitously degrades as the pH approaches 7.0, passing through the pH of natural
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`tears at 7.4. (EX1010 at Exp. Ex. 4, Table 8.) Using the same stress test disclosed
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`in Ogawa (four weeks at 60° C.), Senju has demonstrated in the ’606 patent vastly
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`superior and completely unexpected chemical stability results for tyloxapol over
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`polysorbate 80 at the harsh pH of 7.0. (EX1004 at Table 1.) Because of
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`Patent No. 8,927,606
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`bromfenac’s enhanced degradation at pH 7.0, this test severely challenges the
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`formulations and effectively delineates the relative stabilization capability of the
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`tested compounds. The comparative test reported in Table 1 of the ’606 patent,
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`moreover, constitutes a scientifically proper head-to-head comparison varying only
`
`one component—polysorbate 80 versus tyloxapol—to further enhance the clarity
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`of the relative ability of the surfactants to stabilize bromfenac from chemical
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`degradation under 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%
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`better at stabilizing bromfenac from degradation. (EX1010 at Table 1, Comparison
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`Ex. 1 and A-02.) And in a completely unexpected and counterintuitive manner,
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`when the amount of tyloxapol was lowered to 0.02%, about 1/8 the amount of
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`polysorbate 80 taught in Ogawa, tyloxapol was 75% better at stabilizing bromfenac
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`degradation. (Id. at Table 1, A-03.) This is a truly remarkable and surprising result
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`considering the harsh pH conditions and the significantly reduced amount of
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`tyloxapol versus polysorbate 80. By any metric, no one would have expected this
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`huge disparity in chemical stability results for tyloxapol.
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`At a higher pH > 8, one less conducive to degrading bromfenac (see EX1010
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`at Exp. Ex. 4, Table 8), formulations of tyloxapol achieved stabilization results
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`comparable to those of polysorbate 80 in Ogawa’s Example 6, but notably did so
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`using amounts of tyloxapol of about 1/3, 1/5, and 1/8 the amount of polysorbate
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`80. (EX1004 at Table 2; EX1010 at Ex. 6.) Additionally, these results were
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`achieved without using the antioxidant sodium sulfite, touted by Ogawa as
`
`instrumental in achieving “remarkably enhanced” stability results. (EX1010 at
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`Exp. Ex. 6, 8:46-9:4.) To achieve this level of stability without sodium sulfite is
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`entirely unexpected in view of Ogawa.
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`Tyloxapol’s unexpected stabilization benefits translated into real world
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`benefits in producing Prolensa® with a comfortable pH of 7.8, close to that of
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`natural tears, that led to improved ocular penetration, a lowering of the amount of
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`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. (EX2033; EX1008;
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`EX1009.) With these new benefits, Prolensa® garnered significant acclaim in the
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`medical community (EX2014), 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. (EX2031.)
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`Seeking to capitalize on Prolensa’s®
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` 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. (See Lupin’s
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`projections in EX2026 at 4.) Even they, however, have recognized the strength and
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`inventiveness of the Prolensa® patents. Apotex, Paddock, and Metrics, all generic
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`drug manufacturers selling or seeking to sell ophthalmic products, initially
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`challenged the ’606 patent in district court. Yet they all licensed the patent and
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`took consent judgments and injunctions specifically acknowledging the ’606
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`patent’s validity. (EX2027; EX2028; EX2029.) See Institut Pasteur & Universite
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`Pierre Et Marie Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013)
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`(“Pasteur’s licensing activities provide ‘probative and cogent evidence’ of non-
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`obviousness of the claims at issue.”).
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`Given Lupin’s failure to establish a prima facie case of obviousness, as well
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`as its failure to rebut significant objective evidence of patentability, Lupin has
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`failed to show a reasonable likelihood of prevailing on at least one challenged
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`claim. The Board should deny Lupin’s petition. 35 U.S.C. § 314(a).
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`II.
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`Statement of relief requested
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`Senju respectfully requests that Lupin’s petition be denied at least because:
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`(i) it fails to provide legally proper motivation to combine Ogawa with Fu or
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`Sallmann with Ogawa; (ii) it fails to prove the existence of each element of each
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`challenged claim from Ogawa, Fu, and Sallmann; 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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`III. Claim construction
`Lupin does not propose any particular claim constructions. (Petition at 4-5.)
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`Senju agrees that the claims do not need express construction at this stage in light
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`of the claim language, specification, and prosecution history of the ’606 patent.
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`IV. Level of skill in the art
`Lupin states that a POSA would generally be “a pharmaceutical scientist
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`involved in the research and development of pharmaceuticals, and would have a
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`Ph.D. and several years of experience in the field. The amount of post-graduate
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`level experience would depend upon the level of formal education and particular
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`experience in the field.” (Petition at 6; EX1005 at ¶ 21.) Senju disagrees with this
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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. (See, e.g., EX2037, a
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`declaration of a petitioner’s expert from related IPR2014-01043, offered in a
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`litigation on a patent similarly involving ophthalmic formulations.)
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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 claims of the ’606 patent
`The ’606 patent was filed on September 23, 2014, and claims priority benefit
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`of the January 21, 2003, filing date of JP 2003-012427 under 35 U.S.C. §119.
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`(EX1004.) The ’606 patent has three independent claims (claims 1, 11, and 19) and
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`27 dependent claims.
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`The dependent claims do not stand or fall with the independent claims but
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`rather constitute separate claims assessed for patentability on their own merits.
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`Senju will first address the impropriety of Lupin’s obviousness arguments,
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`applicable to all claims, followed by a discussion in Section VII infra on the
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`separate patentability of various individual claims.
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`B.
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`The combinations of Ogawa in view of Fu and Ogawa in view of
`Sallmann do not render any claim of the ’606 patent obvious
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`Lupin’s positions on obviousness are legally deficient. “[A] patent
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`composed of several elements is not proved obvious merely by demonstrating that
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`each of its elements was, independently, known in the prior art.” KSR Int’l Co. v.
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`Teleflex Inc., 550 U.S. 398, 418 (2007); see also Ariosa Diagnostics v. Verinata
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`Health, Inc., IPR2013-00276, slip op. at 7 (PTAB Oct. 23, 2014) (Paper 43). More
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`is needed. A sufficient rationale to substantiate a motivation to combine the art in
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`the manner proposed is required. See BSP Software v. Motio Inc., IPR2013-00307,
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`2013 WL 8563944, at *9 (PTAB 2013) (the “reason to combine the teachings . . .
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`appears to be that both references are concerned with version control . . . which,
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`without more, is an insufficient rationale to combine . . . .”). Lupin has not met this
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`requirement.
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`Indeed, a POSA interprets the prior art using common sense and an
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`appropriate perspective. Unigene Labs., Inc. v. Apotex Inc., 655 F.3d 1352, 1361
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`(Fed. Cir. 2011). The proper perspective considers both the problem the prior art
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`sought to solve and other blaze marks, such as data, to direct and guide how a
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`POSA would have viewed the teachings. See Cadence, 780 F.3d at 1375 (relying
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`on the problem in the art to be solved in discerning how a POSA would have
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`viewed the proposed combination of prior art teachings); Insite Vision Inc. v.
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`Sandoz, Inc., 783 F.3d 853, 862 (Fed. Cir. 2015) (indicating how data in the art, or
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`the lack thereof, impacts a POSA’s trek through the art and selection of teachings);
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`Pfizer Inc. v. Mylan Pharm. Inc., No. 10-528-GMS, 2014 WL 5388100, at *9 (D.
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`Del. Oct. 22, 2014) (POSA would not have found optimization argument obvious
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`without some data to support it). “To render an invention obvious, prior art cannot
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`be ‘vague’ and must collectively, although not explicitly, guide an artisa
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