Trials@uspto.gov Paper No. 14
`
`571-272-7822
`Date Entered: September 12, 2016
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`LUPIN LTD., LUPIN PHARMACEUTICALS INC., INNOPHARMA
`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and
`MYLAN INC.,
`Petitioners,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`________________
`
`Case IPR2015-010971
`Patent 8,754,131 B2
`________________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`1 Case IPR2016-00089 has been joined with this proceeding.
`
`
`
`571-272-7822
`Date Entered: September 12, 2016
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`LUPIN LTD., LUPIN PHARMACEUTICALS INC., INNOPHARMA
`LICENSING, INC., INNOPHARMA LICENSING LLC, INNOPHARMA
`INC., INNOPHARMA LLC, MYLAN PHARMACEUTICALS INC., and
`MYLAN INC.,
`Petitioners,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`________________
`
`Case IPR2015-010971
`Patent 8,754,131 B2
`________________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
`
`1 Case IPR2016-00089 has been joined with this proceeding.
`
`
`
`IPR2015-01097
`Patent 8,754,131 B2
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`
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`
`I. INTRODUCTION
`A. Statement of the Case
`Lupin Ltd. and Lupin Pharmaceuticals, Inc. (collectively, “Lupin”)
`filed a Petition (Paper 1, “Pet.”) requesting an inter partes review of claims
`1–30 of U.S. Patent No. 8,754,131 B2 (Ex. 1002, “the ’131 patent”). Senju
`Pharmaceutical Co., Ltd. (“Patent Owner”) filed a Preliminary Response.
`Paper 8 (“Prelim. Resp.”).
`Upon review of those papers and cited information, we instituted trial
`as to claims 1–30 of the ’131 patent in relation to a single ground of
`unpatentability: obviousness over Sallmann2 and Ogawa3 under 35 U.S.C.
`§ 103(a). Paper 9, 21–22 (“Decision to Institute,” or “Dec.”).
`After the Decision to Institute, InnoPharma Licensing, Inc.,
`InnoPharma Licensing LLC, InnoPharma Inc., InnoPharma LLC, Mylan
`Pharmaceuticals Inc., and Mylan Inc. (“InnoPharma and Mylan”), timely
`filed a separate petition to institute an inter partes review of claims 1–30 of
`the ’131 patent, the petition including an obviousness ground relying on the
`same combination of prior art for which trial was instituted in this
`proceeding. InnoPharma Licensing, Inc. v. Senju Pharmaceutical Co., Ltd.,
`Case IPR2016-00089, Paper 1. At the same time, InnoPharma and Mylan
`filed a Motion for Joinder with the instituted case. Id., Paper 3. Patent
`Owner filed a Preliminary Response and an Opposition to the Motion for
`Joinder. Id., Papers 10, 11.
`
`
`2 Sallmann et al., U.S. Patent No. 5,891,913 (issued Apr. 6, 1999)
`(“Sallmann,” Ex. 1021).
`3 Ogawa et al., U.S. Patent No. 4,910,225 (issued Mar. 20, 1990) (“Ogawa,”
`Ex. 1010).
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`
`We instituted inter partes review of claims 1–30 of the ’131 patent in
`IPR2016-00089, granted the Motion for Joinder, and terminated IPR2016-
`00089. Id., Paper 17. Therefore, in the instant inter partes review, Lupin,
`InnoPharma, and Mylan are, collectively, the “Petitioner.”
`Thereafter, Patent Owner filed a Response (Paper 25; “PO Resp.”),
`and Petitioner filed a Reply (Paper 35, “Reply”).4
`Both parties filed Motions to Exclude Evidence. Paper 45 (“Pet. Mot.
`to Exclude”) and Paper 46 (“PO Mot. to Exclude”).
`Each party filed an Opposition to the other party’s Motion to Exclude
`Evidence. Paper 51 (“Pet. Opp.”); Paper 49 (“PO Opp.”). Each party filed
`also a Reply to the other party’s Opposition to the Motion to Exclude
`Evidence. Paper 55 (“Pet. Reply Opp.”); Paper 56 (“PO Reply Opp.”).
`Patent Owner filed a Motion for Observation Regarding Cross
`Examination of Reply Witnesses (Paper 47; “PO Mot. Observ.”) and
`Petitioner filed a Response to that motion (Paper 52; “Resp. Observ.”).
`An oral hearing was held on June 9, 2016, and the hearing transcript
`has been entered in the record. Paper 63 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6(b). This Final Written
`Decision is entered pursuant to 35 U.S.C. § 318(a).
`
`
`4 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.
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`“In an inter partes review instituted under this chapter, the petitioner
`shall have the burden of proving a proposition of unpatentability by a
`preponderance of the evidence.” 35 U.S.C. § 316(e).
`We conclude that Petitioner has not proved by a preponderance of the
`evidence that claims 1–30 of the ’131 patent are unpatentable for
`obviousness over Sallmann and Ogawa under 35 U.S.C. § 103(a).
`Petitioner’s Motion to Exclude Evidence is dismissed as moot. Patent
`Owner’s Motion to Exclude Evidence is denied-in-part and dismissed-in-
`part as moot.
`B. Related Proceedings
`Petitioner identifies eight district court proceedings involving the ’131
`patent. Pet. 2–3; see Senju Pharmaceutical Co. v. Lupin Ltd. et al., C.A. No.
`1:14-CV-05144-JBS-KMW (D.N.J.); Senju Pharmaceutical Co v.
`InnoPharma Licensing, Inc. et al., C.A. No. 1:14-cv-06893-JBS-KMW
`(D.N.J.).
`Petitioner also identifies inter partes proceedings involving two
`patents to which the ’131 patent claims priority. Pet. 3. Specifically, the
`claims of U.S. Patent No. 8,669,290 B2 (“the ’290 patent”) were challenged
`in Metrics, Inc. v. Senju Pharmaceutical Co., Ltd., IPR2014-01043, and
`InnoPharma Licensing Inc. v. Senju Pharmaceutical Co., Ltd., IPR2015-
`00902. Metrics v. Senju, IPR2014-01043, was terminated after settlement.
`IPR2014-01043, Paper 39. In InnoPharma v. Senju, Case IPR2015-00902,
`claims 1–30 of the ’290 patent were held not to have been shown to be
`unpatentable. IPR2015-00902, Paper 90.
`The claims of U.S. Patent No. 8,129,431 B2 (“the ’431 patent”), to
`which the ’131 patent also claims priority, were challenged in Metrics, Inc.
`
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`v. Senju Pharmaceutical Co., Ltd., IPR2014-01041, and InnoPharma
`Licensing Inc. v. Senju Pharmaceutical Co., Ltd., IPR2015-00903. Metrics
`v. Senju, IPR2014-01041, was terminated after settlement. IPR2014-01041,
`Paper 39. In InnoPharma v. Senju, Case IPR2015-00903, claims 1–22 of the
`’431 patent were held not to have been shown to be unpatentable. IPR2015-
`00903, Paper 83.
`Petitioner filed, concurrently with the Petition under consideration
`herein, petitions challenging the claims of the ’290 patent mentioned above
`(IPR2015-01099), the claims of U.S. Patent No. 8,871,813 B2 (“the ’813
`patent;” IPR2015-01105), and the claims of U.S. Patent No. 8,927,606 B1
`(“the ’606 patent;” IPR2015-01100). Pet. 3–4. The ’813 and ’606 patents
`claim priority to the ’131 patent. Id.
`Decisions in IPR2015-01099, IPR2015-01100, and IPR2015-01105
`are issued concurrently herewith.
`C. The ’131 Patent (Ex. 1002)
`The ’131 patent relates to an aqueous liquid preparation that includes
`two components: (1) 2-amino-3-(4-bromobenzoyl)phenylacetic acid (or its
`salts and hydrates), generically named “bromfenac”; and (2) tyloxapol.
`Ex. 1002, 2:45–59; id. at 1:20–22.
`The ’131 patent discloses that bromfenac was known in the prior art
`as a non-steroidal anti-inflammatory drug (“NSAID”) used in eye drops to
`treat inflammatory disorders of the eye, including blepharitis, conjunctivitis,
`scleritis, as well as postoperative inflammation. Id. at 1:35–44.
`
`The ’131 patent discloses that alkyl aryl polyether polymers, which
`are non-ionic surfactants, and which include tyloxapol, may be used to
`stabilize bromfenac-containing ophthalmic solutions. Id. at 4:36–5:15. In
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`particular, the ’131 patent discloses that when tyloxapol is added to a
`bromfenac-containing aqueous ophthalmic solution, the solution “becomes
`stable within a pH range giving no irritation to eyes, and change of the
`[bromfenac] over time can be inhibited, and furthermore, when the aqueous
`solution contains a preservative, deterioration in the preservative effect of
`said preservative can be inhibited for a long period of time.” Id. at 2:37–42.
`
`Experimental Example 1 of the ’131 patent compares the stability of
`pH 7.0 bromfenac-containing ophthalmic solutions that included 0.15 w/v%
`and 0.02 w/v% tyloxapol, to solutions containing 0.15 w/v% of the
`surfactants polysorbate 80 and polyoxyl 40 stearate. See id. at 7:1–67. The
`results of the comparison are shown in Table 1, reproduced below:
`
`
`Id. at 7:35–53. As seen in Table 1, after 4 weeks at 60° C, the bromfenac
`activity remaining in the polysorbate 80-containing solution was 51.3%, and
`the remaining bromfenac activity in the polyoxyl 40 stearate solution was
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`63.7%, whereas the remaining activity in the tyloxapol solutions was 73.8%
`(0.15 w/v% tyloxapol) and 89.6% (0.02 w/v% tyloxapol). Id.
`
`Claim 1 of the ’131 patent illustrates the challenged subject matter
`and reads as follows (paragraphing added):
`
`
`
`
`1. A stable aqueous liquid preparation comprising:
`(a) a first component; and
`(b) a second component;
`2-amino-3-(4-
`is
`wherein
`the
`first
`component
`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 and is present in the
`preparation at a concentration from about 0.05 w/v % to about
`0.2 w/v %;
`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.
`
`
`Id. at 12:2–15; 12:26–36.
`II. ANALYSIS
`A. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are given
`
`their broadest reasonable construction in light of the specification of the
`patent in which they appear. See In re Cuozzo Speed Techs., LLC, 793 F.3d
`1268, 1278–79 (Fed. Cir. 2015), aff’d sub nom. Cuozzo Speed Techs., LLC v.
`Lee, 136 S. Ct. 2131, 2144 (2016) (upholding the use of the broadest
`reasonable interpretation standard); 37 C.F.R. § 42.100(b). Under that
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`standard, claim terms are generally 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).
`Petitioner proposes no specific claim construction for any claim term.
`See Pet. 5–6; Reply 25. Patent Owner, in contrast, proposes constructions
`for the terms “stable” and “amount sufficient to stabilize” as used in the
`claims of the ’131 patent. PO 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); also citing Microsoft Corp. v. Proxyconn, Inc., 789 F.3d 1292,
`1298 (Fed. Cir. 2015)). Petitioner replies that Patent Owner provides no
`justification for adopting the district court’s claim construction of those
`terms. Reply 25.
`We conclude that Petitioner has the better position on this issue. We
`acknowledge that, under Microsoft v. Proxyconn, claim construction in inter
`partes reviews must not be unreasonably broad or inconsistent with the
`specification of the patent under consideration. 789 F.3d at 1298. In
`general, however, only those claim terms that are in controversy need to be
`construed, and only to the extent necessary to resolve the controversy. Vivid
`Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999).
`In the instant case, Patent Owner does not identify any controversy as
`to the scope of the claim terms for which it seeks construction. Nor does
`Patent Owner explain specifically why adoption of the district court’s
`construction of the identified terms is necessary to resolve any of the issues
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`critical to this proceeding. Accordingly, we decline to adopt the district
`court’s claim construction. Rather, because the parties identify no
`controversy as to the scope of any claim terms, we conclude that, for the
`purposes of this decision, no claim term requires express construction.
`B. Obviousness—Independent claims 1, 7, and 13
`1. Prior Art Evidence of Obviousness
`As the Supreme Court has stated, when evaluating claims for
`obviousness, “the scope and content of the prior art are to be determined;
`differences between the prior art and the claims at issue are to be
`ascertained; and the level of ordinary skill in the pertinent art resolved.”
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v.
`John Deere Co., 383 U.S. 1, 17–18 (1966)). Secondary considerations, if
`present, also must be considered. Id.
`As to the level of ordinary skill in this art, the parties’ expert
`witnesses advance somewhat different opinions. See Pet. 6–7 (citing Ex.
`1005 ¶ 40 (Lawrence Decl.));5 see also PO Resp. 7 (citing Ex. 2082 ¶¶ 44–
`45 (Williams Decl.)).6 Nonetheless, neither party asserts specifically that
`the ultimate conclusion of obviousness turns on adoption of a particular level
`of ordinary skill.
`In any event, both experts generally agree that an ordinarily skilled
`artisan at the critical time would have had at least a bachelor’s degree in a
`field such as chemistry, pharmaceutical chemistry, or a related discipline,
`with 3–5 years of work experience, and potentially a Ph.D., depending on
`
`
`5 Declaration of M. Jayne Lawrence, Ph.D., dated April 21, 2015 (Ex. 1005).
`6 Declaration of Robert O. Williams III, Ph.D., dated February 22, 2016 (Ex
`2082).
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`the extent of formal education and practical experience. See id. When
`evaluating the parties’ contentions regarding the scope and content of the
`prior art, and the differences between the prior art and the challenged claims,
`we take into consideration both parties’ assertions regarding the level of
`ordinary skill. We also consider that the cited references provide evidence
`as to the level of ordinary skill in the art. See Okajima v. Bourdeau, 261
`F.3d 1350, 1355 (Fed. Cir. 2001).
`As to the scope and content of the prior art, and the differences
`between the art and claims 1, 7, and 13, the independent claims of the ’131
`patent, Petitioner cites Sallmann as disclosing aqueous ophthalmic solutions
`which include the acidic NSAID diclofenac, in combination with tyloxapol.
`Pet. 35–36. Petitioner contends that the “only difference between the
`formulation described by [Sallmann] and the formulation in the claims of the
`‘131 patent is the choice of NSAID (diclofenac vs. bromfenac).” Id. at 37.
`Petitioner cites Example 6 of Ogawa as disclosing an aqueous
`ophthalmic solution containing bromfenac, as well as the non-ionic
`surfactant polysorbate 80. Id. Petitioner contends that “Example 6 of
`[Ogawa] includes each of the elements of independent claims 1, 7, and 13
`except for the inclusion of tyloxapol.” Id.
`Petitioner contends, in an initial obviousness rationale we did not
`discuss in our Decision to Institute, that an ordinary artisan would have
`considered it obvious to substitute Ogawa’s bromfenac for the diclofenac
`used in Sallmann’s Example 2, thereby arriving at a formulation having all
`of the ingredients required by the claims of the ’131 patent. Id. at 37–38
`(citing Ex. 1005 ¶ 333 (Lawrence Decl.)).
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`As Patent Owner points out, however (PO Resp. 29–36), Sallmann
`uniquely focuses on diclofenac potassium formulations. See Ex. 1021, 1:60–
`65 (“[T]he present invention relates to an ophthalmic composition for
`treating inflammatory ocular conditions, for treating glaucoma or for treating
`ear inflammatory and/or painful conditions (otitis), which composition
`comprises a therapeutically effective amount of diclofenac potassium and a
`carrier.”) (emphasis added); see also id. at 1:48–54 (background section
`explaining the significantly superior ocular penetration of diclofenac
`potassium as compared to diclofenac sodium). Indeed, other than
`comparative examples advanced to show the superiority of diclofenac
`potassium over diclofenac sodium, Sallmann exemplifies no active
`ingredient other than diclofenac potassium. See id. at 7:56–14:23 (Examples
`1–19).
`Given Sallmann’s unique focus on preparing diclofenac potassium
`formulations, Petitioner does not persuade us that an ordinary artisan, having
`read Sallmann, would have considered it obvious to substitute bromfenac for
`the diclofenac potassium in Sallmann’s formulations. Accordingly,
`Petitioner does not persuade us that, based on this rationale, it has shown by
`a preponderance of the evidence that an ordinary artisan would have
`considered claims 1, 7, and 13 of the ’131 patent, or their dependent claims,
`obvious.
`Petitioner contends, alternatively, that an ordinary artisan would have
`been motivated to substitute the tyloxapol used in Sallmann’s formulations
`for the polysorbate 80 used in Ogawa’s Example 6, thereby arriving at an
`aqueous preparation encompassed by claims 1, 7, and 13 of the ’131 patent.
`Id. at 38. In particular, Petitioner contends that the state of the art was such
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`that an ordinary artisan would have recognized that substitution of tyloxapol
`for polysorbate 80 was known to improve the stability of acidic drugs in
`ophthalmic solutions. Id. (citing Ex. 1005 ¶ 335 (Lawrence Decl.); Ex.
`1022, 6:56–7:44 (“Yasueda”);7 Ex. 1014, 5:23–28; 9:1–48 (Fu)).8
`Petitioner contends also that it was known in the art that tyloxapol and
`polysorbate 80 could be used interchangeably in drug-containing ophthalmic
`solutions, with tyloxapol being preferred over polysorbate 80. Id. (citing
`Ex. 1005 ¶ 336; Ex. 1012, 3:13–45 (“Desai”)).9
`Having reviewed the parties’ contentions and supporting evidence
`regarding the scope and content of the prior art, as compared to the subject
`matter recited in claims 1, 7, and 13 of the ’131 patent, Petitioner persuades
`us that, based on the teachings in the prior art, an ordinary artisan would
`have been prompted to substitute Sallmann’s tyloxapol for the polysorbate
`80 used in Ogawa’s formulations.
`Each of claims 1, 7, and 13 of the ’131 patent recites a stable aqueous
`liquid formulated for ophthalmic administration, the liquid containing two
`ingredients: (1) bromfenac, its salts, or hydrates, as the sole
`pharmaceutically active ingredient at a concentration of 0.05 to 0.2 w/v%,
`and (2) tyloxapol. Ex. 1002, 12:2–14 (claim 1), 12:37–47 (claim 7), 13:13–
`22 (claim 13).
`Example 6 of Ogawa discloses an ophthalmic solution that includes,
`as the sole pharmaceutically active ingredient, 0.1 g per 100 ml, that is, 0.1
`
`
`7 Yasueda et al., U.S. Patent No. 6,274,609 B1 (issued Aug. 14, 2001)
`(“Yasueda,” Ex. 1022).
`8 Fu et al., EP 0 306 984 A1 (published Mar. 15, 1989) (“Fu,” Ex. 1014).
`9 Desai et al., U.S. Patent No. 5,603,929 (issued Feb. 18, 1997) (“Desai,” Ex.
`1012).
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`w/v%, of the sodium salt of bromfenac monohydrate, which falls within the
`bromfenac concentration range recited in claims 1, 7, and 13. Ex. 1010,
`10:5–17. Ogawa discloses that the solution described in Example 6 also
`contains 0.15 w/v% polysorbate 80 (0.15 g/100ml). Id.
`Ogawa discloses that, after four weeks at 60° C, the solution described
`in Example 6 maintained 100.9 % of its original bromfenac activity. Id. at
`10:49–51, 14:45–48 (Table 11). Accordingly, the solution of Ogawa’s
`Example 6 meets the stability requirements of independent claims 1 and 13,
`as well as claim 7’s additional stability requirement of greater than 90%
`bromfenac activity present after four weeks at 60° C. Ex. 1002, 12:48–51.
`Thus, as Petitioner contends, Example 6 of Ogawa differs from claims
`1, 7, and 13 only in that Ogawa’s solution contains polysorbate 80 instead of
`tyloxapol. As Petitioner discusses, however, Example 2 of Sallmann
`describes the use of 0.1 mg/ml tyloxapol, that is, 0.1 w/v%, in an aqueous
`eye drop formulation that also contains the acidic group-containing NSAID
`diclofenac potassium. Ex. 1021, 8:1–13.
`Petitioner directs us to Dr. Lawrence’s testimony to support its
`contention that an ordinary artisan would have considered Sallmann’s
`tyloxapol and Ogawa’s polysorbate 80 to be interchangeably useful in
`aqueous ophthalmic solutions. Pet. 38 (citing Ex. 1005 ¶¶ 334–336). Given
`her qualifications, experience, and explanation, we credit her testimony on
`this issue. See Ex. 1005 ¶¶ 3–15. Dr. Lawrence’s testimony in this regard,
`moreover, is supported by the Yasueda and Desai references cited in Dr.
`Lawrence’s Declaration.
`In particular, Yasueda describes the use of both tyloxapol and
`polysorbate 80 as solubilizing surfactants in ophthalmic solutions containing
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`the anti-allergic drug pranlukast. Ex. 1022, 4:61–65, see also id. at 1:16–24
`(pranlukast used to treat allergic diseases in ophthalmology). In the
`experiment cited by Petitioner and Dr. Lawrence, Yasueda discloses that
`aqueous tyloxapol-containing formulations showed more than 98% residual
`drug activity after 2 weeks at 60° C, and that solutions containing
`polysorbate 80 had more than 95% remaining drug activity, with no
`deposition of insoluble material in solutions using either surfactant. Id. at
`7:34–44.
`Desai describes stabilizing aqueous acidic NSAID-containing
`ophthalmic solutions with the combination of a polymeric quaternary
`ammonium compound and boric acid. Ex. 1012, 2:18–30. As Petitioner and
`Dr. Lawrence note, Desai discloses that the NSAID in its compositions may
`be diclofenac or bromfenac, and that polysorbates and/or tyloxapol may be
`used as surfactants in the ophthalmic solutions. Id. at 3:12–38.
`Given these prior art teachings, Petitioner persuades us that an
`ordinary artisan would have recognized that tyloxapol and polysorbate 80
`were interchangeably useful as non-ionic surfactants in acidic NSAID-
`containing ophthalmic aqueous solutions, and, absent persuasive objective
`evidence to the contrary, that is enough to support the proposed substitution,
`even in the absence of an express suggestion to do so. 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)).
`As to the stability requirements in claims 1, 7, and 13, the ’131 patent
`discloses that the tyloxapol range effective to stabilize a bromfenac-
`containing solution is between about 0.01 and 0.5 w/v %. Ex. 1001, 5:37–
`38. Both the tyloxapol concentration described in Sallmann (0.1 w/v %) and
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`the polysorbate 80 concentration described in Ogawa (0.15 w/v %),
`discussed above, fall within the stabilizing range set out in the ’131 patent.
`Therefore, in addition to having a reason to substitute the tyloxapol
`recited in claims 1, 7, and 13 of the ’131 patent for the polysorbate 80 in
`Ogawa’s Example 6, an ordinary artisan also had a reason to include the
`tyloxapol at a concentration encompassed by claims 1, 7, and 13.
`Patent Owner’s arguments do not convince us to the contrary.
`Patent Owner contends that a number of NSAID ophthalmic
`compositions other than Ogawa’s bromfenac compositions would have been
`viewed as suitable for modification, and would have been preferred over the
`bromfenac compositions. PO Resp. 8–10 (citing Ex. 2082 ¶¶ 70–75, 77
`(Williams Decl.)). Patent Owner contends, moreover, that because of the
`benzalkonium chloride (“BAC”) in Ogawa’s formulations, an ordinary
`artisan would have been led away from Ogawa’s compositions to non-BAC-
`containing compositions. PO Resp. 10–13 (citing Allergan v. Sandoz, 796
`F.3d 1293, 1305 (Fed. Cir. 2015); Ex. 2082 ¶¶ 76–89, 121 (Williams Decl.)).
`As our reviewing court has explained, however, when evaluating
`claims for obviousness, “a finding that the prior art as a whole suggests the
`desirability of a particular combination need not be supported by a finding
`that the prior art suggests that the combination claimed by the patent
`applicant is the preferred, or most desirable, combination.” In re Fulton,
`391 F.3d 1195, 1200 (Fed. Cir. 2004). Given Ogawa’s undisputed
`disclosure that its compositions are useful for ophthalmic administration,
`that an ordinary artisan might not have viewed Ogawa as describing the
`most art-preferred NSAID-containing ophthalmic formulations does not
`convince us that an ordinary artisan would have considered Ogawa’s
`
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`compositions unsuitable for the disclosed use or unsuitable for further
`modification, such as the substitution of known interchangeably useful
`ophthalmically acceptable non-ionic surfactants.
`We acknowledge that Ogawa does not disclose expressly why it
`included polysorbate 80 in its compositions. PO Resp. 15 (citing Ex. 2082 ¶
`126). Ogawa, nonetheless, includes polysorbate 80, a well known non-ionic
`surfactant, in every one of the exemplified bromfenac-containing
`compositions that is described as an ophthalmic solution, including Example
`6. See Ex. 1010, 9:5–10:68 (Examples 1, 2, 4, and 5–9).
`Accordingly, although Ogawa does not expressly state its reason for
`including polysorbate 80 in its compositions, we agree with Petitioner that
`an ordinary artisan would have recognized from Ogawa that its compositions
`included a non-ionic surfactant in bromfenac-containing ophthalmic
`solutions, and that such non-ionic surfactant had well known ophthalmically
`acceptable equivalents. That Ogawa’s reason for including a non-ionic
`surfactant in its bromfenac-containing solutions may have differed from the
`stabilization effect discovered by the inventors of the ’131 patent, discussed
`above, does not demonstrate a deficiency in Petitioner’s contention that,
`based on the cited prior art, an ordinary artisan would have recognized
`Sallmann’s tyloxapol as an ophthalmically acceptable non-ionic surfactant
`that would be an interchangeably useful equivalent to the polysorbate 80 in
`Ogawa’s compositions.10
`
`
`10 In our following analysis of secondary considerations of nonobviousness,
`we consider whether the preponderance of the evidence demonstrates that
`tyloxapol performs as a true equivalent yielding the same result as
`polysorbate 80 in Ogawa’s formulation, or instead yields an unexpected
`result.
`
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`Patent Owner contends that, given the complex and sensitive nature of
`preparing ophthalmic solutions, and given the significant differences in
`structure between tyloxapol and polysorbate 80, which are among numerous
`other non-ionic surfactants that were available for use, an ordinary artisan
`would not have viewed tyloxapol and polysorbate 80 as interchangeably
`substitutable equivalents and, therefore, would not have been motivated to
`substitute one for the other. PO Resp. 18–21.
`Even acknowledging the complexities of ophthalmic solution
`formulation, however, because Sallmann and Ogawa, as discussed above,
`describe the use of tyloxapol and polysorbate 80 in similar acidic NSAID-
`containing ophthalmic solutions, Petitioner persuades us that an ordinary
`artisan would have recognized that both were non-ionic surfactants that
`would be useful in acidic NSAID-containing ophthalmic formulations. As
`also discussed above, Yasueda describes the use of both tyloxapol and
`polysorbate 80 as solubilizing surfactants in separate ophthalmic solutions
`containing an anti-allergy drug, thereby suggesting that both surfactants
`would be interchangeably useful in the same ophthalmic formulation and
`that no significant adverse effects would be expected when substituting one
`for the other. Thus, that many non-ionic surfactants may have existed in the
`prior art does not convince us that an ordinary artisan would have failed to
`recognize, based on the cited prior art, that tyloxapol specifically would have
`been useful in the particular type of formulation described in Ogawa’s
`Example 6.
`In sum, for the reasons discussed, having considered the prior art,
`evidence, and arguments advanced by Petitioner in light of Patent Owner’s
`arguments and evidence regarding the cited references’ teachings, we find
`
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`that an ordinary artisan had a reason to substitute Sallmann’s tyloxapol,
`recited in claims 1, 7, and 13 of the ’131 patent, for the polysorbate 80 in
`Ogawa’s Example 6, and to include the tyloxapol at a concentration
`encompassed by claims 1, 7, and 13.
`2. Secondary Considerations/Objective Indicia
`When assessing obviousness, the objective indicia of nonobviousness
`must be considered, alongside the teachings in the prior art, “as part of all
`the evidence, not just when the decisionmaker remains in doubt after
`reviewing the art.” Eurand, Inc. v. Mylan Pharm. Inc. (In re
`Cyclobenzaprine Hydrochloride Extended–Release Capsule Patent Litig.),
`676 F.3d 1063, 1076 (Fed. Cir. 2012) (quoting Stratoflex, Inc. v. Aeroquip
`Corp., 713 F.2d 1530, 1538–39 (Fed. Cir. 1983)).
`“Indeed, evidence of secondary considerations may often be the most
`probative and cogent evidence in the record. It may often establish that an
`invention appearing to have been obvious in light of the prior art was not.”
`Id. at 1075–76 (quoting Stratoflex, 713 F.2d at 1538). In Eurand v. Mylan,
`the court explained further that, “not only is Stratoflex the law, it is sound in
`requiring that a fact finder consider the objective evidence before reaching
`an obviousness determination. The objective considerations, when
`considered with the balance of the obviousness evidence in the record, guard
`as a check against hindsight bias.” Id. at 1079.
`Secondary considerations may include long-felt but unsolved need,
`failure of others, unexpected results, commercial success, copying, licensing,
`and industry praise. Graham v. Deere, 383 U.S. at 17; Transocean Offshore
`Deepwater Drilling, Inc. v. Maersk Drilling USA, Inc., 699 F.3d 1340, 1349,
`1355 (Fed. Cir. 2012).
`
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`a. Unexpected Results
`Patent Owner contends that comparisons between the closest prior art
`and compositions encompassed by claims 1, 7, and 13 of the ’131 patent
`show that including tyloxapol in bromfenac-containing aqueous solutions
`unexpectedly inhibits bromfenac degradation. PO Resp. 36–44. Having
`reviewed Patent Owner’s evidence and arguments regarding unexpected
`results, in light of Petitioner’s responsive evidence and arguments on that
`issue, we agree with Patent Owner that the evidence of record supports a
`finding that the claimed compositions exhibit properties that an ordinary
`artisan would not have expected.
`To show unexpectedness, Patent Owner directs us to several sets of
`comparative data. Patent Owner presents data from a first comparison,
`which includes data from Table 1 of the ’131 patent shown above, in the
`following table:
`
`PO Resp. 40; see also Ex. 2098 ¶¶ 7–9 (Declaration of co-inventor Shirou
`Sawa describing conditions of comparative tests, complete ingredient lists,
`
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`and results underlying data presented in Table 1 of ’131 patent).11 The table
`shows a comparison of bromfenac formulations containing either tyloxapol,
`or the polysorbate 80 used in Ogawa, stored for four weeks at 60º C at pH 7.
`PO Resp. 39–40; Ex. 2098 ¶¶ 7–9. As is evident from the table, and as
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