Trials@uspto.gov
`571-272-7822
`
` Paper: 90
` 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., and MYLAN INC.,
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.,
`Patent Owner.
`_______________
`
`Case IPR2015-00902
`Patent 8,669,290 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
`
`
`
`
`571-272-7822
`
` Paper: 90
` 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., and MYLAN INC.,
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD., BAUSCH & LOMB, INC., and
`BAUSCH & LOMB PHARMA HOLDINGS CORP.,
`Patent Owner.
`_______________
`
`Case IPR2015-00902
`Patent 8,669,290 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
`
`
`
`
`
`IPR2015-00902
`Patent 8,669,290 B2
`
`
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`I. INTRODUCTION
`This is a Final Written Decision in an inter partes review challenging
`the patentability of claims 1–30 (“the challenged claims”) of U.S. Patent
`No. 8,669,290 B2 (Ex. 1001, “the ’290 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 1–30 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 a single ground of
`unpatentability stated in the Petition: Whether the subject matter of
`claims 1–30 would have been obvious under 35 U.S.C. § 103 based on the
`combined disclosures of Ogawa1 and Sallmann2. Paper 17 (“Dec.”).
`Patent Owner filed a Response (Paper 32, “Resp.”) and Petitioner
`filed a Reply (Paper 54, “Reply”).3 The parties’ fully briefed Motions to
`
`1 U.S. Patent No. 4,910,225, issued Mar. 20, 1990 (Ex. 1004, “Ogawa”).
`
` 2
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` U.S. Patent No. 6,107,343, issued Aug. 22, 2000 (Ex. 1009, “Sallmann”).
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` 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
`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 85, 4.
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`Exclude also are pending. Papers 62, 65 (Motions to Exclude); Papers 70,
`74 (Oppositions to Motions to Exclude); Papers 77, 78 (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 IPR2015-00903 (“IPR 903”). Paper 83 (“Tr.”).
`
`B. Related Proceedings
`Petitioner identifies eight district court actions involving the ’290
`patent, including one that involves Petitioner as a defendant. Pet. 11–13; see
`Senju Pharmaceutical Co. v. InnoPharma Licensing, Inc., No. 1:14-CV-
`06893-JBS-KMW (D.N.J. filed Nov. 3, 2014). Concurrently herewith, we
`issue a final written decision in IPR 903, which involves the same parties
`and is directed to U.S. Patent No. 8,129,431 B2 (“the ’431 patent”).
`The ’290 patent claims priority to the ’431 patent.
`
`C. The ’290 Patent (Ex. 1001)
`The ’290 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 comprising two
`components: (1) bromfenac (or its salts and hydrates); and (2) tyloxapol. Id.
`at 12:2–13 (independent claim 1). Bromfenac is a non-steroidal anti-
`inflammatory drug (“NSAID”). Id. at 1:26–49. Tyloxapol is present in the
`preparation “in an amount sufficient to stabilize” the bromfenac component.
`Id. at 12:10–11. The preparation is useful for ophthalmic administration, for
`example, in an eye drop to treat blepharitis, conjunctivitis, scleritis, or
`postoperative inflammation. Id., Abstract, 12:12.
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`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 2:16–23. 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. A stable aqueous liquid preparation comprising: (a) a
`first component; and (b) a second component; wherein the first
`component is 2-amino-3-(4-bromobenzoyl)phenylacetic acid or
`a 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; the first component is the sole
`pharmaceutical active ingredient contained in the preparation;
`the second component is tyloxapol and is present in said liquid
`preparation in an amount sufficient to stabilize said first
`component; and wherein said stable liquid preparation is
`formulated for ophthalmic administration.
`
`Ex. 1001, 12:2–13.
`
`E. Declaration Testimony
`The Petition is supported by the Declaration of Dr. Paul A.
`Laskar. Ex. 1003.
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`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
`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.
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`Petitioner proposes no specific claim construction for any claim term.
`Pet. 16. Patent Owner, by contrast, proposes constructions for the terms
`“stable” and “amount sufficient to stabilize” in claim 1. Resp. 6–7. Patent
`Owner argues that we should assign, as the broadest reasonable
`interpretations of those terms, the same constructions adopted in related
`litigation filed in the U.S. District Court for the District of New Jersey. Id.
`(citing Ex. 2065 (Markman Opinion)).
`Based on our review of the record, including the language of the
`claims and the disclosure of the ’290 patent specification, we conclude that
`the broadest reasonable interpretations of the terms “stable” and “amount
`sufficient to stabilize” are the same as the constructions resolved by the
`district court. Specifically, we hold that the term “stable” in claim 1 means
`“having sufficient resistance to degradation and having sufficient
`preservative efficacy to be formulated and maintained for ophthalmic use.”
`Ex. 2065, 6. In that regard, preservative efficacy, as discussed in the ’290
`patent disclosure, relates to the ability of a stabilizing component to inhibit
`the formation of complexes that form between the NSAID and a preservative
`such as BAC. Ex. 1001, 1:64–2:12. Resistance to degradation relates to the
`tendency of bromfenac to change over time by degradation, which is
`distinguished from deterioration of the preservative effect. Id. at 2:35–49.
`Like the district court, we hold that the term “amount sufficient to stabilize”
`the bromfenac in claim 1 means “an amount sufficient to confer sufficient
`resistance to degradation to be formulated and maintained for ophthalmic
`use.” Ex. 2065, 5–6. We add only the clarification, based on the disclosure
`of the ’290 patent specification, that the claim term is broad enough to
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`embrace also stability related to preservative efficacy when a preservative is
`included in the formulation—that is, the ability of tyloxapol (the stabilizing
`component) to inhibit the formation of complexes between the bromfenac
`and any added preservative. Ex. 1001, 1:64–2:12, 2:35–49.
`No other 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 the 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
`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
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`account of those factors, including Patent Owner’s evidence of secondary
`considerations, we determine that Petitioner fails to establish the
`unpatentability of claims 1–30 by a preponderance of the evidence.
`
`C. The Applied Prior Art
`We instituted trial on a single ground of unpatentability stated in the
`Petition; whether the subject matter of claims 1–30 would have been obvious
`over the combined disclosures of Ogawa and Sallmann. 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) (“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
`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, which, as a pharmaceutically
`inactive ingredient, is not excluded by the terms of claim 1. Ex. 1004,
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`10:13. 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 an amount sufficient to stabilize” the bromfenac. Ex. 1001,
`12:10–11; 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 ¶ 58. Like Ogawa’s Example 6, Sallmann’s
`Example 2 formulation includes BAC. Ex. 1009, 8:1–10. The entire thrust
`of Sallmann’s disclosure 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 “especially
`suitable” for treating inflammatory ocular processes (id. at 1:48–51));
`Ex. 2082 ¶ 136. Sallmann does not discuss a formulation of any NSAID
`other than diclofenac potassium salt. See generally Ex. 1009.
`The ’290 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, 5:34–45. 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 ’290 patent as sufficient to
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`provide the bromfenac stability required by claim 1. Pet. 39 (citing
`Ex. 1009, 8:10, 4:65–67; Ex. 1003 ¶ 80). 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. 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 a list of “surfactants” in Desai4 that includes
`“poloxamers such as Pluronics; polysorbates such as Tweens; tyloxapol;
`sarcosinates such as Hamposyl; and polyethoxylated castor oils such as
`Cremophor.” Pet. 5 (citing Ex. 1005, 3:38–41). Desai also discloses
`bromfenac and diclofenac in a list of ophthalmic agents suitable for use in
`aqueous ophthalmic formulations. Ex. 1005, 3:12–27. 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; cf. Pet. 17–18 (arguing that Desai
`“disclosed a formulation that included bromfenac and tyloxapol, and BAC,
`in addition to other ingredients”).
`Petitioner identifies additional background references that allegedly
`support the proposition that the prior art discloses “a storage-stable
`ophthalmic formulation containing bromfenac, and optionally any one of a
`
`4 U.S. Patent No. 5,603,929, issued Feb. 18, 1997 (Ex. 1005, “Desai”).
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`number of conventional surfactants, including tyloxapol.” Pet. 5 (citing
`Ex. 1002, Ex. 1006, Ex. 1007, and Ex. 1008). Petitioner also directs us to
`Yasueda,5 which relates to the degradation pathway of a non-NSAID active
`ingredient (pranlukast). Ex. 1012, 1:16–24. Petitioner further asserts that
`Fu6 demonstrates that “the prior art taught that tyloxapol was effective in
`stabilizing NSAIDs, like bromfenac.” Pet. 6 (citing Ex. 1011).
`
`D. Asserted Ground of Unpatentability
`1. Claim 1: Replacing Polysorbate 80 in Ogawa’s Example 6
`a. Prior Art Evidence of Obviousness
`Claim 1 requires a “stable” bromfenac formulation that includes
`tyloxapol “in an amount sufficient to stabilize” the bromfenac. Ex. 1001,
`12:2, 12:10–11. Ogawa’s Example 6 meets every limitation of claim 1, but
`for the recited use of tyloxapol, in place of polysorbate 80, “in an amount
`sufficient to stabilize” the bromfenac. Ex. 1001, 12:10–11; 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. 23 (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
`
`
`5 U.S. Patent No. 6,274,609 B1, issued Aug. 14, 2001 (Ex. 1012,
`“Yasueda”).
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` Austrl. Patent Application No. AU-B-22042/88, issued Mar. 16, 1989
`(Ex. 1011, “Fu”).
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`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
`¶ 40). Petitioner further directs us to a list of “surfactants” in Desai that
`includes “poloxamers such as Pluronics; polysorbates such as Tweens;
`tyloxapol; sarcosinates such as Hamposyl; and polyethoxylated castor oils
`such as Cremophor.” Id. at 5 (citing Ex. 1005, 3:38–41).
`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. 11
`(quoting Pet. 23); Ex. 1003 ¶ 40 (Dr. Laskar’s testimony that, at the time of
`the invention, “tyloxapol was a widely-used non-ionic 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. 11 (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. 11–12 (citing KSR Int’l, 550
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`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
`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).
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`(1) Unexpected Results
`Patent Owner directs us to evidence that the inventors of the ’290
`patent discovered that tyloxapol provides a surprising stabilizing effect that
`inhibits bromfenac degradation in aqueous solution. Resp. 38–42.
`Specifically, Patent Owner argues that a unique aspect of the claimed
`invention “is at least the use of tyloxapol with bromfenac.” Pet. 38 (citing
`Ex. 2082 ¶ 142). 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 4, 11, 17–18, 23–24; Ex. 2082 ¶ 142). 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, BAC, and the non-ionic surfactant polysorbate 80.’” Id. (citing
`Pet. 48; Ex. 1003 ¶ 103; Ex. 2082 ¶ 145).
`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 18–19. 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 ¶ 103 (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. 40–46.
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`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 ¶ 155; see id. at ¶ 154 (chart tabulating experimental
`results); Resp. 41. 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 ¶ 154–159 (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
`that all of the tyloxapol formulations stabilize bromfenac better than a
`comparable formulation containing polysorbate 80 at 0.17 g), ¶ 156
`(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 ¶ 155. 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 ¶¶ 151, 156.
`Ogawa’s Example 6 formulation, by contrast, includes not only
`polysorbate 80 but also two additional components—polyvinyl pyrrolidone
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`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 ¶¶ 158–163; 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 ¶ 161.
`Petitioner disagrees and contends that Patent Owner’s evidence of
`unexpected results is not commensurate in scope with the claimed invention.
`Reply 19–20. 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 ¶ 154
`(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 ¶ 163.
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`(2) Commercial Success
`Patent Owner comes forward with additional evidence that “[t]he
`unexpected stabilization benefits of tyloxapol translated into unexpected
`medical benefits, manifested in the commercial product Prolensa.”
`Resp. 48. 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 and 6–30. Id. (citing Ex. 2082
`¶¶ 143, 168). Petitioner admits that “[t]he subject matter of many of the
`challenged claims of the ’290 patent is commercially embodied by
`Prolensa.” Pet. 9. At the final oral hearing, Petitioner confirmed that
`Prolensa falls within the scope of the ’290 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
`the ’290 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. 48 (citing Ex. 2082 ¶ 168). 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
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`¶ 168. 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. 48 (citing Ex. 2082 ¶ 168; Ex. 2116 ¶ 41). Patent
`Owner further identifies evidence that other commercially available eye
`drops “are limited by their side effects of burning and stinging.” Id. at 49
`(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 20 (emphasis omitted) (citing Ex. 2013, 3). To the 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 20–21.
`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
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`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 21.
`Patent Owner comes forward with persuasive evidence that Prolensa
`is the only approved NSAID-containing eye drop that is not limited by
`“significant, painful side effects that adversely impact patient compliance.”
`Resp. 49; Ex. 2116 ¶ 36. Patent Owner’s witness, Dr. Trattler, provides
`credible testimony that non-compliant post-operative patients are at risk of
`developing a serious complication involving retinal swelling and reduced
`vision. Ex. 2116 ¶ 36. We find that the stabilizing benefits of tyloxapol in
`an aqueous formulation of bromfenac permitted the formulation of a
`commercial product, represented by Prolensa, at a lower pH than other
`commercially available bromfenac formulations—specifically, at a pH
`beneficially closer to that of natural tears. Resp. 48; Ex. 2030, 1; Ex. 2026,
`5; Ex. 2027, 4; Ex. 2082 ¶ 168.
`By using a lower amount of surfactant and bringing the pH of the
`formulation closer to that of natural tears, the claimed invention resulted in a
`commercial product that effectively eliminated the burning and stinging
`associated with other approved NSAID ophthalmic eye drops. Ex. 2082
`¶ 168; Ex. 2116 ¶ 41; see Resp. 48–49 (bridging paragraph, identifying other
`commercial ey
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