`571-272-7822
`
` Paper: 82
` Entered: July 28, 2016
`
`
`
`
`
`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., MYLAN INC.,
`LUPIN LTD., and LUPIN PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.,
`Patent Owner.
`_______________
`
`Case IPR2015-009031
`Patent 8,129,431 B2
`_______________
`
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`OBERMANN, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 and 37 C.F.R. § 42.73
`
`
`1 IPR2015-01871 has been joined with this proceeding. Specifically, in an
`Institution Decision dated January 25, 2016, we joined Lupin Ltd. and Lupin
`Pharmaceuticals, Inc., as parties to this proceeding. Paper 37.
`
`
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`
`I. INTRODUCTION
`This is a Final Written Decision in an inter partes review challenging
`the patentability of claims 1–22 (“the challenged claims”) of U.S. Patent
`No. 8,129,431 B2 (Ex. 1001, “the ’431 patent”). We have jurisdiction under
`35 U.S.C. § 6(c). For reasons that follow, we determine that Petitioner fails
`to show by a preponderance of evidence that claims 1–22 are unpatentable.
`We also address the parties’ Motions to Exclude.
`
`A. Procedural History
`The Petition (Paper 2, “Pet.”) for inter partes review was filed
`pursuant to 35 U.S.C. § 311. We instituted trial on two grounds of
`unpatentability stated in the Petition:
`(1) Whether the subject matter of claims 1–5, 7–14, and 18–19 would
`have been obvious under 35 U.S.C. § 103 based on the combined disclosures
`of Ogawa2 and Sallmann3; and
`(2) Whether the subject matter of claims 6, 15–17, and 20–22 would
`have been obvious over Ogawa, Sallmann, and Fu4. Paper 15 (“Dec.”).
`Patent Owner filed a Response (Paper 32, “Resp.”) and Petitioner
`filed a Reply (Paper 49, “Reply”). 5 The parties’ fully briefed Motions to
`
`
`2 U.S. Patent No. 4,910,225, issued Mar. 20, 1990 (Ex. 1004, “Ogawa”).
`
` 3
`
` U.S. Patent No. 6,107,343, issued Aug. 22, 2000 (Ex. 1009, “Sallmann”).
`
` 4
`
` Austrl. Patent Application No. AU-B-22042/88, issued Mar. 16, 1989
`(Ex. 1011, “Fu”).
`
` 5
`
` To the extent that we rely on information in papers and exhibits for which
`confidentiality is claimed, we determine that the general nature of the
`discussions of such information herein does not require that this Decision be
`
`
`
`2
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`Exclude also are pending. Papers 56, 59 (Motions to Exclude); Papers 64,
`66 (Oppositions to Motions to Exclude); Papers 69, 70 (Replies to Motions
`to Exclude). The record includes a transcript of a consolidated final oral
`hearing conducted on April 19, 2016, in this proceeding and related
`proceeding IPR2015-00902 (“IPR 902”). Paper 75 (“Tr.”).
`
`B. Related Proceedings
`Petitioner identifies eight district court actions involving the ’431
`patent, including two that involve Petitioner as a defendant. Pet. 11–12; see
`Senju Pharmaceutical Co. v. Lupin, Ltd., No. 1:14-CV-00667-MAS-LHG
`(D.N.J. filed Jan. 31, 2014); Senju Pharmaceutical Co. v. InnoPharma
`Licensing, Inc., C.A. No. 1:14-CV-06893-JBS-KMW (D.N.J. filed Nov. 3,
`2014). Concurrently herewith, we issue a final written decision in IPR 902,
`which involves the same parties and is directed to U.S. Patent No. 8,669,290
`(“the ’290 patent”). The ’290 patent claims priority to the ’431 patent.
`
`C. The ’431 Patent (Ex. 1001)
`The ’431 patent is titled “Aqueous Liquid Preparation Containing 2-
`Amino-3-(4-Bromobenzoyl) Phenylacetic Acid.” Ex. 1001, Title. The
`claimed invention relates to an aqueous liquid preparation consisting
`essentially of two components: (1) bromfenac (or its salts and hydrates);
`
`
`treated as confidential. The parties are reminded that confidential
`information that is subject to a protective order ordinarily becomes public 45
`days after final judgment in a trial. Office Patent Trial Practice Guide, 77
`Fed. Reg. 48,756, 48,761 (Aug. 14, 2012). Further, there is an expectation
`that information will be made public where the existence of the information
`is identified in a final written decision. Id. We provided the parties advance
`notice “that information subject to a protective order will become public if
`identified in a final written decision in this proceeding.” Paper 77, 4.
`
`
`
`3
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`and (2) tyloxapol. Id. at 11:66–12:10 (independent claim 1). Bromfenac is a
`non-steroidal anti-inflammatory drug (“NSAID”). Id. at 1:24–40.
`Tyloxapol is added to the claimed formulation “to stabilize an aqueous
`liquid preparation of” the bromfenac component “and inhibit decrease in
`preservative effect of” quaternary ammonium compounds in the formulation.
`Id. at 2:4–11. The preparation is useful for ophthalmic administration, for
`example, in an eye drop to treat blepharitis, conjunctivitis, scleritis, or
`postoperative inflammation. Id., Abstract, 12:5–6. Claim 1 specifies that a
`quaternary ammonium compound, specifically, benzalkonium chloride
`(“BAC”), may be included in the liquid preparation. Id. at 12:8–9.
`An object of the invention is to provide an aqueous liquid preparation
`of bromfenac that “is stable within a pH range giving no irritation to eyes”
`when preserved with a quaternary ammonium compound, such as
`benzalkonium chloride (“BAC”). Id. at 2:15–22. The inventors claim to
`have discovered that the addition of an alkyl aryl polyether alcohol type
`polymer, such as tyloxapol, provides the sought-after stability, giving no
`irritation to the eyes. Id. at 2:35–49. Specifically, tyloxapol both inhibits
`the change or degradation of bromfenac “over time” and also inhibits
`“deterioration in the preservative effect” when a preservative is included in
`the formulation. Id. The inventors describe tyloxapol as “a non-ionic
`surfactant.” Id. at 4:37–39.
`
`D. Illustrative Claim
`Claim 1, reproduced below, is illustrative of the subject matter.
`1. An aqueous liquid preparation consisting essentially of the
`following two components, wherein the first component is 2-
`amino-3-(4-bromobenzoyl)phenylaceticacid or a
`
`
`
`4
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`
`pharmacologically acceptable salt thereof or a hydrate thereof,
`wherein the hydrate is at least one selected from a 1/2 hydrate,
`1 hydrate, and 3/2 hydrate and the second component is
`tyloxapol, wherein said liquid preparation is formulated for
`ophthalmic administration, and wherein when a quaternary
`ammonium compound is included in said liquid reparation, the
`quaternary ammonium compound is benzalkonium chloride.
`
`Ex. 1001, 11:66–12:10.
`
`
`
`E. Declaration Testimony
`The Petition is supported by the Declaration of Dr. Paul A.
`Laskar. Ex. 1003.
`The Response is supported by the Declaration of Dr. Robert O.
`Williams, III (Ex. 2082), the Declaration of Mr. Shirou Sawa
`(Ex. 2098); the Declaration of Dr. Stephen G. Davies (Ex. 2105), the
`Declaration of Dr. William B. Trattler (Ex. 2116), and the Declaration
`of Mr. John C. Jarosz (Ex. 2130).
`The Reply is supported by the Reply Declaration of Dr. Paul A.
`Laskar (Ex. 1104) and the Declaration of Mr. Ivan T. Hofmann
`(Ex. 1150).
`
`II. ANALYSIS
`
`A. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. See Cuozzo Speed Techs.,
`LLC v. Lee, 136 S. Ct. 2131, 2144-46 (2016) (upholding the use of the
`broadest reasonable interpretation standard); 37 C.F.R. § 42.100(b). Claim
`terms generally are given their ordinary and customary meaning, as
`
`
`
`5
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`understood by one of ordinary skill in the art in the context of the entire
`disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir.
`2007). If an inventor acts as his or her own lexicographer, the definition
`must be set forth in the specification with reasonable clarity, deliberateness,
`and precision. Renishaw PLC v. Marposs Societa’ per Azioni, 158 F.3d
`1243, 1249 (Fed. Cir. 1998). The construction that stays true to the claim
`language, and most naturally aligns with the inventor’s description, is likely
`the correct interpretation. Id. at 1250.
`Petitioner addresses the transitional phrase “consisting essentially of”
`as applied in claims 1–22. Pet. 15–16. Patent Owner proposes no specific
`claim construction for any claim term. Resp. 6. No claim term requires
`express construction for the purposes of this decision. See Vivid Techs., Inc.
`v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (only those
`terms that are in controversy need to be construed, and only to the extent
`necessary to resolve the controversy).
`
`B. Principles of Law
`Petitioner bears the burden of persuasion in proving unpatentability of
`the challenged claims, and that burden of persuasion never shifts to Patent
`Owner. Dynamic Drinkware, LLC v. Nat’l Graphics, Inc., 800 F.3d 1375,
`1378 (Fed. Cir. 2015). To prevail, Petitioner must establish facts supporting
`its challenge by a preponderance of the evidence. 35 U.S.C. § 316(e); 37
`C.F.R. § 42.1(d).
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the subject matter sought to be patented and the prior art
`are such that the subject matter as a whole would have been obvious at the
`
`
`
`6
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`time the invention was made to a person of ordinary skill in the art. KSR
`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007). Obviousness is resolved
`based on underlying factual determinations, including: (1) the scope and
`content of the prior art; (2) any differences between the claimed subject
`matter and the prior art; (3) the level of skill in the art; and (4) objective
`evidence of nonobviousness, i.e., secondary considerations. See Graham v.
`John Deere Co., 383 U.S. 1, 17–18 (1966). As explained below, taking
`account of those factors, including Patent Owner’s evidence of secondary
`considerations, we determine that Petitioner fails to establish the
`unpatentability of claims 1–22 by a preponderance of the evidence.
`
`C. The Applied Prior Art
`We instituted trial on two grounds of unpatentability stated in the
`Petition; whether the subject matter of claims 1–5, 7–14, 18, and 19 would
`have been obvious over the combined disclosures of Ogawa and Sallmann,
`and whether the subject matter of claims 6, 15–17, and 20–22 would have
`been obvious over the combined disclosures of Ogawa, Sallmann, and Fu.
`In this case, the prior art itself is representative of the level of ordinary skill
`in the art. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001)
`(“[T]he absence of specific findings on the level of skill in the art does not
`give rise to reversible error ‘where the prior art itself reflects an appropriate
`level and a need for testimony is not shown.’” (quoting Litton Indus. Prods.,
`Inc. v. Solid State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985))).
`
`1. Ogawa (Ex. 1004)
`Ogawa is directed to an aqueous, stable, ophthalmic preparation for
`topical administration in the treatment of inflammatory conditions of the
`
`
`
`7
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`eye, such as uveitis. Ex. 1004, Abstract, 1:60–2:3. Ogawa’s Example 6
`discloses a stable aqueous liquid preparation, formulated for ophthalmic
`administration, which comprises bromfenac, as the sole pharmaceutical
`active ingredient, and polysorbate 80. Id. at 10:5–18, 49–57 (for stable
`aqueous liquid preparation), 10:5–9 (for bromfenac, as sole pharmaceutical
`active ingredient, and polysorbate 80), 14:45–50 (Table 11, reporting 100%
`stability for the Example 6 preparation). The ophthalmic preparation of
`Ogawa’s Example 6 also includes BAC, a component that may be included
`in the formulation of claim 1. Ex. 1004, 10:13; Ex. 1001, 12:6–9. Ogawa
`does not disclose or suggest a function for the polysorbate 80 in the
`bromfenac formulation of Example 6. We find that Ogawa’s Example 6
`meets every limitation of claim 1, but for the recited use of tyloxapol in the
`formulation. Ex. 1001, 12:4–5; see Pet. 21–22 (claim chart for claim 1).
`
`2. Sallmann (Ex. 1009)
`Sallmann discloses tyloxapol as a solubilizer in an ophthalmic
`preparation of a specific NSAID—diclofenac potassium salt. Ex. 1009,
`4:52–56. Sallmann’s Example 2 discloses an aqueous ophthalmic
`preparation that includes diclofenac potassium salt and tyloxapol. Id. at 8:1–
`15. The remaining ingredients of Sallmann’s Example 2 would not have
`been expected to adversely affect the stability or preservative efficacy of the
`preparation. Ex. 1003 ¶ 54. Like Ogawa’s Example 6, Sallmann’s
`Example 2 formulation includes BAC. Ex. 1009, 8:1–10. The entire thrust
`of Sallmann’s disclosure, however, is uniquely directed to formulations of
`diclofenac potassium salt. Ex. 1009, 1:35–3:26 (focusing exclusively on
`diclofenac potassium salt, which Sallmann describes as “[s]urprisingly” and
`
`
`
`8
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`“especially suitable” for treating inflammatory ocular processes (id. at 1:48–
`51)); Ex. 2082 ¶ 126. Sallmann does not discuss a formulation of any
`NSAID other than diclofenac potassium salt. See generally Ex. 1009.
`The ’431 patent discloses that tyloxapol effectively stabilizes an
`aqueous formulation of bromfenac when included in a range from about 0.01
`and 0.5 w/v %. Ex. 1001, 5:36–47. Sallmann’s Example 2 formulation of
`diclofenac potassium salt includes tyloxapol in a concentration of 0.1 w/v %,
`which falls within the range described in the ’431 patent as useful for
`stabilizing a bromfenac formulation. Pet. 42 (citing Ex. 1009, 8:10, 4:65–
`67; Ex. 1003 ¶ 71). Sallmann describes tyloxapol as a “solubilizer[]” for
`diclofenac potassium salt, but does not suggest using tyloxapol to solubilize
`any other NSAID or assign a stabilizing function to tyloxapol. Ex. 1009,
`4:52–53. Sallmann identifies a different component as the stabilizer in the
`formulation of diclofenac potassium salt. Id. at 5:59–6:17, 8:1–15.
`
`3. Fu (Ex. 1011)
`Fu discloses an ophthalmic preparation comprising a NSAID, BAC,
`and an ethoxylated octylphenol, such as Octoxynol 9 or Octoxynol 40.
`Ex. 1011, 18:5–28, Examples 2, Example 5. Petitioner asserts that tyloxapol
`is an ethoxylated octylphenol non-ionic surfactant. Ex. 1003 ¶ 33 (citing
`Ex. 1024, 1:1:1–2:1:2). Petitioner also asserts that Fu “expressly discloses a
`non-ionic surfactant concentration of 0.02 w/v %.” Pet. 44–45 (citing
`Ex. 1011, 18:5–28, Example 2, Example 5; Ex. 1003 ¶¶ 75, 93). Petitioner
`applies Fu in a ground of unpatentability raised against certain dependent
`claims, which limit the concentration of tyloxapol in the formulation. Pet. 1
`(asserting Fu in the ground raised as to claims 6, 15–17, and 20–22).
`
`
`
`9
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`
`With respect to those dependent claims, Petitioner asserts that Fu
`would have led a person of ordinary skill in the art to modify Ogawa’s
`Example 6 formulation of bromfenac to include tyloxapol in a concentration
`that meets the claimed concentrations. Pet. 45. Specifically, Petitioner
`directs us to Fu’s disclosure of a class of compounds that allegedly would
`have been understood to stabilize formulations containing both an NSAID
`and BAC—and to stabilize such formulations better than polysorbate 80. Id.
`Claims 1 and 18, the only independent challenged claims, both require
`an aqueous ophthalmic formulation of bromfenac and tyloxapol. Ex. 1001,
`11:64–12:9, 13:16–14:9. The Petition asserts only the combined disclosures
`of Ogawa and Sallmann to show the obviousness of a formulation of
`bromfenac and tyloxapol—Fu is not applied in the ground of unpatentability
`asserted against claim 1 or 18. Pet. 1, 20–26. Petitioner raises Fu, however,
`as a background reference bearing on the understanding of an ordinary
`artisan at the time of the invention of those claims. See id. at 23–24
`(bridging paragraph) (including Fu in a list of background references that
`allegedly show that the prior art describes “ophthalmic formulations of
`acidic NSAIDs containing a non-ionic surfactant like tyloxapol”) (citing
`Ex. 1011, 12:1–11). Specifically, Petitioner asserts that Fu, among other
`background references, would have caused an ordinary artisan to form “a
`reasonable expectation of success in substituting tyloxapol for
`polysorbate 80, because the prior art included multiple examples of stable
`aqueous preparations containing NSAIDs (similar to bromfenac) formulated
`with BAC and tyloxapol (and other closely related non-ionic surfactants).”
`Id. at 25 (citing, among other background references, Ex. 1011, 18:5–28). In
`
`
`
`10
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`our analysis below, we consider Fu as a background reference bearing on
`claims 1 and 18, to the extent that it is raised and discussed in the Petition
`regarding the ordinary artisan’s understanding of the combined disclosures
`of the two applied references, namely, Ogawa and Sallmann. Pet. 23–25.
`
`4. Background References Cited in the Petition
`Petitioner directs us to background references to show the knowledge
`
`and understanding of an ordinary artisan at the time of the invention. For
`example, we are directed to Desai6 for a disclosure of “a formulation that
`included bromfenac and tyloxapol, and BAC, in addition to other
`ingredients.” Pet. 17. Desai does not teach a specific formulation
`containing both bromfenac and tyloxapol, but rather, includes lists of
`ingredients generally suitable for use in ophthalmic formulations. Ex. 1005,
`3:12–45. Desai discloses bromfenac and diclofenac in a list of suitable
`ophthalmic agents and tyloxapol and polysorbates in a list of suitable
`surfactants. Id. Petitioner also directs us to Yasueda,7 which relates to the
`degradation pathway of a non-NSAID active ingredient (pranlukast).
`Ex. 1012, 1:16–24; Pet. 33.
`
`
`
`6 U.S. Patent No. 5,603,929, issued Feb. 18, 1997 (Ex. 1005, “Desai”).
`
` 7
`
` U.S. Patent No. 6,274,609 B1, issued Aug. 14, 2001 (Ex. 1012,
`“Yasueda”).
`
`
`
`
`11
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`
`D. Asserted Grounds of Unpatentability
`1. Claim 1: Replacing Polysorbate 80 in Ogawa’s Example 6
`a. Prior Art Evidence of Obviousness
`Claim 1 requires an aqueous liquid preparation consisting essentially
`of bromfenac (or a pharmacologically acceptable salt or hydrate thereof) and
`tyloxapol. In addition, BAC may be included in the formulation of claim 1.
`Ex. 1001, 11:64, 12:9. Ogawa’s Example 6 meets every limitation of
`claim 1, but for the addition of tyloxapol. Ex. 1001, 12:4–5; see Pet. 21–22
`(claim chart for claim 1). Petitioner directs us to Sallmann for a teaching
`“that tyloxapol (another non-ionic surfactant) was the preferred surfactant
`for use in aqueous ophthalmic preparations of diclofenac (another acidic
`NSAID).” Pet. 24 (citing Ex. 1009, 4:62). Petitioner asserts that a person of
`ordinary skill in the art “would have known that substituting polysorbate 80
`with tyloxapol would successfully, and predictably, result in a stable
`ophthalmic formulation of bromfenac because tyloxapol and polysorbate 80
`had previously been used interchangeably as surfactants in ophthalmic
`formulations.” Id. (citing Ex. 1021, 13:8–10; Ex. 1022, 4:24–31; Ex. 1003
`¶ 38). Petitioner further directs us to a disclosure in Desai that includes
`“poloxamers such as Pluronics; polysorbates such as Tweens; tyloxapol;
`sarcosinates such as Hamposyl; and polyethoxylated castor oils such as
`Cremophor.” Ex. 1005, 3:38–41; Pet. 17.
`In our Institution Decision, we determined that the Petition provides
`information sufficient to show that an ordinary artisan would have
`recognized that “tyloxapol and polysorbate 80 had previously been used
`interchangeably as surfactants in ophthalmic formulations.” Dec. 12
`
`
`
`12
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`(quoting Pet. 24); Ex. 1003 ¶¶ 38, 50 (Dr. Laskar’s testimony that, at the
`time of the invention, “tyloxapol was a widely-used surfactant in aqueous
`liquid preparations comprising anti-inflammatory agents, and was used
`interchangeably with polysorbate 80”). We also determined that such
`known interchangeability, absent persuasive objective evidence to the
`contrary, was enough to support the proposed substitution, even in the
`absence of an express suggestion to do so. Dec. 12 (citing In re Mayne, 104
`F.3d 1339, 1340 (Fed. Cir. 1997); In re Fout, 675 F.2d 297, 301 (CCPA
`1982); In re Siebentritt, 372 F.2d 566, 568 (CCPA 1967)).
`We put Patent Owner on notice that, “absent evidence to the contrary,
`it would have been well within the level of ordinary skill in the art to replace
`one non-ionic surfactant (polysorbate 80) with another non-ionic surfactant
`(tyloxapol) in Ogawa’s Example 6, because both were known to be useful as
`surfactants in ophthalmic preparations.” Dec. 12 (citing KSR Int’l, 550 U.S.
`at 417 (“If a person of ordinary skill in the art can implement a predictable
`variation, and would see the benefit of doing so, § 103 likely bars its
`patentability.”)). In that regard, we take account of objective considerations
`of non-obviousness raised by Patent Owner in the Response, before reaching
`an ultimate conclusion on whether the subject matter of the challenged
`claims would have been obvious at the time of the invention.
`b. Evidence of Secondary Considerations
`Our reviewing court recently rejected the proposition “that objective
`considerations of non-obviousness can never overcome a strong prima facie
`case of obviousness.” WBIP, LLC, v. Kohler Co., Nos. 2015-1038, 2015-
`1044, 2016 WL 3902668, at *5 (Fed. Cir. July 19, 2016). Factual inquiries
`
`
`
`13
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`for an obviousness determination include secondary considerations based on
`objective evidence of nonobviousness. See Graham, 383 U.S. at 17–18.
`The totality of the evidence submitted may show that the challenged claims
`would not have been obvious to one of ordinary skill in the art. In re
`Piasecki, 745 F.2d 1468, 1471–72 (Fed. Cir. 1984). Secondary
`considerations may include long-felt but unsolved need, failure of others,
`unexpected results, commercial success, copying, licensing, and industry
`praise. Graham, 383 U.S. at 17; Transocean Offshore Deepwater Drilling,
`Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349, 1355 (Fed. Cir.
`2012). “[E]vidence rising out of the so-called ‘secondary considerations’
`must always when present be considered en route to a determination of
`obviousness.” Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1538 (Fed.
`Cir. 1983).
`
`(1) Unexpected Results
`Patent Owner directs us to evidence that the inventors of the ’431
`patent discovered that tyloxapol provides a surprising stabilizing effect that
`inhibits bromfenac degradation in aqueous solution. Resp. 45–60.
`Specifically, Patent Owner argues that a unique aspect of the claimed
`invention “is at least the use of tyloxapol with bromfenac.” Pet. 46 (citing
`Ex. 2082 ¶ 151). According to Patent Owner, a second “unique aspect” of
`the invention “is the use of 0.01 to 0.05 w/v% tyloxapol with bromfenac.”
`Id. (citing Ex. 1001, claims 6, 15–17, 20–22; Ex. 2082 ¶ 151). Patent Owner
`identifies evidence asserted to compare the claimed invention to the closest
`prior art “admitted by Dr. Laskar [Petitioner’s witness] to be Ogawa because
`it discloses ‘examples of ophthalmic formulations containing bromfenac,
`
`
`
`14
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`BAC, and the non-ionic surfactant polysorbate 80.’” Id. (citing Pet. 51;
`Ex. 1003 ¶ 95; Ex. 2082 ¶ 154).
`Petitioner counter argues that Patent Owner’s evidence of unexpected
`results “should be afforded no weight” because it focuses on Ogawa’s
`Example 4 formulation instead of Ogawa’s Example 6 formulation.
`Reply 20. That argument is unpersuasive for several reasons. First,
`Petitioner’s own witness explicitly refers to Ogawa’s Example 4 formulation
`in a discussion of “the closest prior art.” Ex. 1003 ¶ 94 (citing Ex. 1004,
`8:3–14 (Ogawa’s Example 4)). Second, as explained below, Patent Owner
`shows persuasively that the claimed formulation achieved surprising results
`compared to both Ogawa’s Example 4 and Example 6 formulations.
`Resp. 48–46.
`Ogawa’s Example 4 formulation contains bromfenac, BAC, and
`polysorbate 80. Ex. 1004, 8:3–14. Patent Owner directs us to evidence that
`bromfenac’s chemical stability—that is, the ability to resist degradation—is
`“44% better” when tyloxapol is used in place of polysorbate 80 in Ogawa’s
`Example 4. Ex. 2082 ¶ 164; see id. at ¶ 163 (chart tabulating experimental
`results); Resp. 49. Patent Owner, moreover, establishes a further unexpected
`result—that by replacing polysorbate 80 with tyloxapol, and decreasing the
`amount of the non-ionic surfactant from about 0.15 g to about 0.02 g, the
`inventors increased significantly the stability of the bromfenac formulation.
`Ex. 2082 ¶ 163–171 (Dr. Williams, explaining the test results showing that
`when tyloxapol is added to an aqueous formulation of bromfenac and BAC
`in an amount of 0.02 g, the tyloxapol stabilizes bromfenac better than when
`tyloxapol is added in the greater amounts of 0.05 g, 0.1 g, or 0.15 g—and
`
`
`
`15
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`that all of the tyloxapol formulations stabilize bromfenac better than a
`comparable formulation containing polysorbate 80 at 0.17 g), ¶ 165
`(explaining that those results would have been unexpected by a person of
`ordinary skill in the art). Specifically, when the amount of tyloxapol added
`to the formulation is lowered to 0.02 g, or about one-eighth the amount of
`polysorbate 80 (0.17 g), tyloxapol is about 75% better at stabilizing
`bromfenac against degradation. Resp. 41; Ex. 2082 ¶ 164. We are
`persuaded by Dr. Williams’ testimony that those results would have been
`“entirely unexpected” to one of ordinary skill in the art at the time of the
`invention. Ex. 2082 ¶¶ 160, 164–165.
`Ogawa’s Example 6 formulation, by contrast, includes not only
`polysorbate 80 but also two additional components—polyvinyl pyrrolidone
`and sodium sulfite—which, according to Ogawa, “remarkably enhance[]”
`bromfenac stability. Ex. 1004, 3:50–51; see id. at 8:47–51; 10:12–18
`(further discussing the remarkable enhancement of bromfenac stability
`accomplished by those two additional components). Patent Owner shows
`persuasively that tyloxapol stabilizes bromfenac as effectively as Ogawa’s
`Example 6 formulation even when the tyloxapol formulation lacks polyvinyl
`pyrrolidone and sodium sulfite. Ex. 2082 ¶¶ 167–171; Ex. 2098, Sections
`III.B and C. We find credible Dr. Williams’ testimony that those “results
`are highly unexpected” and “materially contribute to the art as a whole in
`potentially eliminating sodium sulfite from being administered to a patient’s
`surgically compromised eye.” Ex. 2082 ¶¶ 165, 170.
`Petitioner disagrees and contends that Patent Owner’s evidence of
`unexpected results is not commensurate in scope with the claimed invention.
`
`
`
`16
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`Reply 20. On that point, however, we find that Patent Owner’s evidence is
`sufficient to establish a trend demonstrating a surprising stabilizing effect of
`tyloxapol that is not suggested by the prior art. Ex. 2082 ¶ 163 (comparative
`chart, showing unexpected result that tyloxapol at amount of 0.02 g
`stabilizes bromfenac better than tyloxapol at 0.05 g, 0.1 g, and 0.15 g—and
`that all of the tyloxapol formulations unexpectedly stabilize bromfenac
`better than a comparable formulation containing polysorbate 80 at 0.17 g).
`Further, we are persuaded by Dr. Williams’ testimony that the comparative
`data shows a superior stabilizing effect of tyloxapol across “disparate pH
`ranges, which are representative of the useable pH range” and “effectively
`demonstrate tyloxapol’s unexpectedly superior stabilizing effect
`commensurate with the scope of the claims.” Id. at ¶ 172.
`
`(2) Commercial Success
`Patent Owner comes forward with additional evidence that “[t]he
`unexpected stabilization benefits of tyloxapol translated into unexpected
`medical benefits in the commercial product Prolensa.” Resp. 53. On that
`point, Patent Owner directs us to specific information pertaining to the
`composition of Prolensa, indicating that the commercial product falls within
`the scope of claims 1–4, 6–10, and 18–20. Id. at 55–56 (citing Ex. 2082
`¶¶ 152, 178). Petitioner admits that “[t]he subject matter of many of the
`challenged claims of the ’431 patent is commercially embodied by
`Prolensa.” Pet. 9. At the final oral hearing, Petitioner confirmed that
`Prolensa falls within the scope of the ’431 patent claims. Tr. 27:15–19. In
`the absence of persuasive evidence to the contrary, we presume that the
`commercial success of Prolensa is attributable to the claimed invention of
`
`
`
`17
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`the ’431 patent. See PPC Broadband, Inc. v. Corning Optical Commc’ns
`RF, LLC, 815 F.3d 734, 746–47 (Fed. Cir. 2016) (evidence showing that a
`commercial product embodies the claimed invention gives rise to a
`presumption that the commercial success of that product is due to the
`claimed invention, absent persuasive evidence to the contrary).
`Patent Owner identifies evidence that tyloxapol’s stabilizing effect
`permitted the formulation of Prolensa at a pH lower than other commercially
`available bromfenac formulations, representing “a substantial reduction on a
`logarithmic scale” that was “beneficially closer to the pH of natural tears.”
`Resp. 56 (citing Ex. 2030, 1; Ex. 2026, 5; Ex. 2027, 4; Ex. 2082 ¶ 178).
`According to Patent Owner, the stabilizing effect of tyloxapol further
`permitted the use of substantially less surfactant in Prolensa than in other
`commercial products. Id.; Ex. 2082 ¶ 178. Patent Owner directs us to
`evidence that “[b]oth the reduction in pH and lower amount of surfactant
`eliminated the burning and stinging upon administration present with all
`approved NSAID ophthalmic eye drops besides Prolensa.” Resp. 56 (citing
`Ex. 2082 ¶ 179; Ex. 2116 ¶ 41). Patent Owner further identifies evidence
`that other commercially available eye drops “are limited by their burning
`and stinging side effects.” Id. (citing Ex. 2116 ¶ 36; Ex. 2057, 6; Ex. 2060,
`7–8; Ex. 2111, 1, col. 2; Ex. 2026, 5–6; Ex. 2027, 6).
`Petitioner disagrees, directing us to evidence that the prescribing
`information for Prolensa states that adverse reactions “are limited to the
`‘most commonly reported adverse reactions,’” which, according to
`Petitioner, indicates “that less common adverse reactions were not
`included.” Reply 21–22 (emphasis omitted) (citing Ex. 2013, 3). To the
`
`
`
`18
`
`
`
`IPR2015-00903
`Patent 8,129,431 B2
`
`
`extent that Petitioner suggests that Prolensa may cause burning and stinging,
`but that it remains unreported as a “less common adverse reaction[]” (id.),
`we find that suggestion to be speculative and unsupported by the evidence to
`which we are directed. Ex. 2013, 3.
`Petitioner also argues that certain other asserted benefits of Prolensa
`are not shown to be commensurate in scope with the challenged claims
`because Patent Owner fails to come forward with evidence showing that
`“other embodiments” would “exhibit similar benefits.” Reply 22–23.
`Petitioner, however, admits that Prolensa embodies “many of the challenged
`claims.” Pet. 9. Under the circumstances, Petitioner must overcome a
`presumption that the benefits of Prolensa flow from the claimed invention.
`PPC Broadband, Inc., 815 F.3d at 746–47. Petitioner has not established
`persuasively that a lack of evidence regarding the benefits of “other claimed
`embodiments” detracts from the force of the evidence showing the benefits
`of Prolensa. Reply 22.
`Patent Owner comes forward with persuasive evidence that Prolensa
`is the only approved NSAID-containing eye d