Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`
` Paper 14
` 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 IPR2015-011051
`Patent 8,871,813 B2
`________________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`1 IPR2016-00090 has been joined with this proceeding.
`
`
`571-272-7822
`
`
`
`
`
`
` Paper 14
` 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 IPR2015-011051
`Patent 8,871,813 B2
`________________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`1 IPR2016-00090 has been joined with this proceeding.
`
`
`
`IPR2015-01105
`Patent 8,871,813 B2
`
`
`INTRODUCTION
`
`Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively, “Lupin”)
`filed a Petition requesting an inter partes review of claims 1–27 of U.S.
`Patent No. 8,871,813 B2 (Ex. 1003, “the ’813 patent”). Paper 1 (“Petition”
`or “Pet.”). Senju Pharmaceutical Co., Ltd. (“Patent Owner”) filed a
`Preliminary Response to the Petition. Paper 8 (“Prelim. Resp.”).
`On October 27, 2015, we instituted an inter partes review of claims
`1–27 of the ’813 patent. Paper 9 (“Dec. Inst.”). Patent Owner filed a Patent
`Owner Response to the Petition. Paper 23 (Board Only), Paper 24 (Parties
`and Board Only), Paper 25 (Public), (collectively, “PO Resp.”).
`On February 25, 2016, we instituted an inter partes review in
`IPR2016-00090 and granted the motion for joinder with IPR2015-01105,
`adding InnoPharma Licensing, Inc., InnoPharma Licensing LLC,
`InnoPharma Inc., InnoPharma LLC, Mylan Pharmaceuticals, and Mylan Inc.
`to the Lupin petitioner (collectively “Petitioners”). Paper 22. Petitioners
`filed a Reply to the Patent Owner Response. Paper 35 (Public), Paper 37
`(Parties and Board Only), (collectively, “Reply”).
`Both parties filed a Motion to Exclude Evidence. Paper 44 (“Pet.
`Mot.”) and Paper 46 (“PO Mot.”). Each party filed an Opposition to the
`other party’s Motion to Exclude Evidence. Paper 49 (“PO Opp.”); Paper 51
`(“Pet. 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, and Petitioners filed a Response
`to that motion, Paper 52.
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`
`On June 9, 2016, the parties presented arguments at an oral hearing.
`The hearing transcript has been entered in the record. Paper 63 (“Tr.”).
`The Board has jurisdiction under 35 U.S.C. § 6(b). In this Final
`Written Decision, issued pursuant to 35 U.S. C. § 318(a) and 37 C.F.R.
`§ 42.73, Petitioners have not proved by a preponderance of the evidence that
`claims 1–27 of the ’813 patent are unpatentable.
`Petitioners’ 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.
`Related Proceedings
`A.
`Petitioners and Patent Owner identify a number of related district
`court proceedings involving the ’813 patent, including one that involves both
`parties in this proceeding: Senju Pharmaceutical Co., Ltd., et al. v. Lupin,
`Ltd.et al., C.A. No. 1:15-cv-00335-JBS-KMW (D.N.J). Pet. 2; Paper 5, 3.
`The parties identify also two related inter partes proceedings. Pet. 3;
`Paper 5, 3. An inter partes review of claims of U.S. Patent No. 8,669,290
`B2 (“the ’290 patent”)was instituted in Metrics, Inc. v. Senju
`Pharmaceutical Co., Ltd., IPR2014-01043 (trial terminated after settlement,
`IPR2014-01043, Paper 39) and in InnoPharma Licensing Inc. v. Senju
`Pharmaceutical Co., Ltd., IPR2015-00902 (claims 1–30 of the ’290 patent
`were held not to have been shown to be unpatentable in a Final Written
`Decision, IPR2015-00902, Paper 90). The ’813 patent claims priority to the
`’290 patent. An inter partes review of claims of U.S. Patent No. 8,129,431
`was instituted in Metrics, Inc. v. Senju Pharmaceutical Co., Ltd.,
`IPR2014-01041 (trial terminated after settlement, IPR2014-01041, Paper 39)
`and in InnoPharma Licensing Inc. v. Senju Pharmaceutical Co., Ltd.,
`
`
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`IPR2015-00903 (claims 1–22 of the ’431 patent were held not to have been
`shown to be unpatentable in a Final Written Decision, IPR2015-00903,
`Paper 83).
`Additionally, an inter partes review was instituted for claims of U.S.
`Patent 8,754,131 (IPR2015-01097), U.S. Patent 8,669,290
`(IPR2015-01099), and Final Written Decisions have been entered
`determining that the challenged claims of those patents have not been shown
`to be unpatentable. Also, an inter partes review was instituted for claims 1–
`30 of U.S. Patent 8,927,606 (IPR2015-01100) and a Final Written Decision
`in that case is entered concurrently herewith determining that the challenged
`claims have not been shown to be unpatentable.
`The ’813 Patent (Ex. 1003)
`B.
`The ’813 patent relates to a stable aqueous liquid ophthalmic
`preparation comprising: (a) 2-amino-3-(4-bromobenzoyl)phenylacetic acid,
`or a pharmacologically acceptable salt or a hydrate thereof, also known by
`its generic name, “bromfenac”; and (b) tyloxapol. Ex. 1003, 1:7–31, 2:26–
`28.
`
`The Specification explains that, prior to the invention, bromfenac was
`known as a non-steroidal anti-inflammatory agent (“NSAID”) effective
`against inflammatory diseases of the anterior and posterior segments of the
`eye, such as blepharitis, conjunctivitis, scleritis, and postoperative
`inflammation. Id. at 1:33–38. According to the Specification, the inventors
`of the ’813 patent found that by adding an alkyl aryl polyether alcohol type
`polymer, such as tyloxapol, which is an non-ionic surfactant, to an aqueous
`liquid preparation of bromfenac, the preparation “becomes stable within a
`pH range giving no irritation to eyes, and change of the [bromfenac] . . . over
`
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`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 2:24–37, 4:13–15.
`
`Experimental Example 1 of the ’813 patent compares the stability of
`bromfenac-containing ophthalmic solutions comprising 0.15 w/v%
`tyloxapol, 0.02 w/v% tyloxapol, 0.15 w/v% polysorbate 80, or 0.15 w/v%
`polyoxyl 40 stearate. See id. at 6:44–7:5. The stability of each preparation
`was tested under conditions of pH 7.0 at 60° C for 4 weeks. Id. at 6:62–64.
`The results of the comparison are shown in Table 1, reproduced below:
`
`
`Id. at 6:43–60, Table 1. As seen in Table 1, the bromfenac activity
`remaining in each of the tyloxapol-containing preparations (73.8% for the
`0.15 w/v% tyloxapol-containing preparation and 89.6% for the 0.02 w/v%
`tyloxapol-containing preparation) was greater than the remaining activity in
`either the polysorbate 80-containing preparation (51.3%) or the polyoxyl 40
`stearate-containing preparation (63.7%). Id.
`
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`
`Illustrative Claims
`C.
`Claims 1 and 7 of the ’813 patent are illustrative and reproduced
`below:
`1. A stable aqueous liquid preparation consisting essentially
`of: (a) a first component; (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; (c) boric acid; (d) sodium tetraborate; and (e) water;
`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.
`
`7. A stable aqueous liquid preparation consisting essentially
`of: (a) a first component; (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; (c) boric acid; (d) sodium tetraborate; and (e) water;
`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; wherein said stable liquid preparation is formulated
`for ophthalmic administration; and wherein the stable aqueous
`liquid preparation is characterized in that greater than about 90%
`of the original amount of the first component remains in the
`preparation after storage at about 60° C. for 4 weeks.
`
`Ex. 1003, 11:30–43, 11:64–12:15.
`
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`
`The Cited References
`D.
`Petitioners rely upon the following prior art references:
`
`Ogawa
`
`Fu
`
`Sallmann
`
`
`
`Ex. 1010
`
`
`Ex. 1014
`
`
`Ex. 1021
`
`Ogawa et al., U.S. Patent No. 4,910,225,
`issued Mar. 20, 1990.
`
`Fu et al., EP 0 306 984 A1, published Mar.
`15, 1989.
`
`Sallmann et al., U.S. Patent No. 5,891,913,
`issued Apr. 6, 1999.
`
`
`Petitioners rely also upon the declarations of M. Jayne Lawrence,
`Ph.D. (Exs. 1005, 1094), and Ivan T. Hofmann, CPA/CFF, CLP (Exs. 1097,
`1122).
`Patent Owner relies upon the declarations of Robert O. Williams, III,
`Ph.D. (Ex. 2082), Shirou Sawa (Ex. 2098), Stephen G. Davies, D. Phil. (Ex.
`2105), William B. Trattler, M.D. (Ex. 2116), Adam C. Myers, Ph.D. (Ex.
`2126), Daryl S. Paulson, Ph.D., M.B.A. (Ex. 2128), and John C. Jarosz (Ex.
`2130).
`
`The Instituted Ground of Unpatentability
`E.
`We instituted an inter partes review as to claims 1–27 of the ’813
`patent on the following ground:
`
`Claims 1–27 under 35 U.S.C. § 103(a) as obvious over Sallmann and
`Ogawa.
`
`
`
`PATENTABILITY ANALYSIS
`Claim Construction
`A.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`
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`of the specification of the patent in which they appear. 37 C.F.R.
`§ 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142 (2016)
`(affirming applicability of broadest reasonable construction standard to inter
`partes review proceedings). Under that standard, and absent any special
`definitions, we generally give claim terms their ordinary and customary
`meaning, as would be understood by one of ordinary skill in the art at the
`time of the invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
`with reasonable clarity, deliberateness, and precision. In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994).
`Petitioners do not propose any specific claim construction for any
`claim term. See Pet. 5; Reply 25. Patent Owner proposes constructions for
`the terms “stable” and “amount sufficient to stabilize” as used in the claims
`of the ’813 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)). Petitioners reply that Patent Owner provides no justification for
`adopting the district court’s claim construction of those terms. Reply 25.
`We agree with Petitioners. 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). Patent Owner has not identified any controversy as to
`the scope of the claim terms for which it seeks construction. Nor does
`Patent Owner explain specifically why adopting the district court’s
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`construction of the identified terms is necessary to resolve an issue in 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. Level of Ordinary Skill in the Art
`The level of skill in the art is a factual determination that provides a
`primary guarantee of objectivity in an obviousness analysis. Al-Site Corp. v.
`VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing Graham v. John
`Deere Co., 383 U.S. 1, 17–18 (1966) and Ryko Mfg. Co. v. Nu-Star, Inc.,
`950 F.2d 714, 718 (Fed. Cir. 1991)).
`Petitioners assert that a person of ordinary skill in the art “would
`generally be a pharmaceutical scientist involved in the research and
`development of pharmaceuticals, and would have a Ph.D. and several years
`of experience in the field.” Pet. 6. Patent Owner asserts, more broadly, that
`a person of ordinary skill in the art would have 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. PO Resp. 7 (citing Ex. 2082 ¶¶ 47–48
`(Williams Decl.)).
`Based on the record as a whole, we find that Patent Owner’s
`description more appropriately encompasses the broad education that the
`person of ordinary skill in the relevant art may possess. Thus, we adopt that
`description. We note, however, that neither party asserts specifically that the
`ultimate conclusion of obviousness turns on adoption of a particular level of
`ordinary skill.
`
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`
`Analysis of Independent Claims 1, 7, and 13
`C.
`Petitioners assert that independent claims 1, 7, and 13 of the ’813
`patent would have been obvious over the combination of Sallmann and
`Ogawa. Pet. 34–42, 53–60; Reply 1–25. Patent Owner disagrees. PO Resp.
`8–59.
`
`When evaluating claims for obviousness, we consider and determine
`the scope and content of the prior art, the differences between the prior art
`and the claims at issue, the level of ordinary skill in the pertinent art, and
`secondary considerations of nonobviousness. See KSR Int’l Co. v. Teleflex
`Inc., 550 U.S. 398, 406 (2007) (citing Graham, 383 U.S. at 17–18).
`1.
`Sallmann
`Sallmann is directed to ophthalmic compositions to treat inflammatory
`
`conditions of the eye. Ex. 1021, 1:7–10. Sallmann’s composition comprises
`diclofenac potassium, an NSAID, as the only active ingredient. Id. at 1:7–8,
`29–31. The composition comprises also a solubilizer, wherein tyloxapol is
`disclosed as one of the preferred solubilizers. Id. at 4:64. Sallmann teaches
`that the concentration of the solubilizer may be from 0.1 to 5000 times the
`concentration of the active ingredient. Id. at 5: 1–2.
`2. Ogawa
`Ogawa is directed to stable aqueous ophthalmic compositions for
`
`treating inflammatory eye disease topically. Ex. 1010, 1:15–17. In Example
`6, Ogawa discloses a formulation comprising sodium salt of bromfenac
`monohydrate, an NSAID, as the only active ingredient, in an amount of 0.1
`g/ 100 ml, i.e., 0.1 w/v%, and polysorbate 80 in an amount of 0.15 g/100 ml,
`i.e., 0.15 w/v%. Id. at 10:5–18. The composition comprises also a water-
`soluble polymer, i.e., polyvinyl pyrrolidone, and a sulfite, both of which
`
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`Ogawa credits for the “remarkably enhanced” stability of its compositions.
`Id. at 3:48–52, 10:5–18.
`3. Combined Teachings of the Cited References
`Petitioners present two different arguments to support their assertion
`that independent claims 1, 7, and 13 would have been obvious over the
`combined teachings of Sallmann and Ogawa. Petitioners contend, in an
`initial obviousness rationale, that Sallmann discloses stable aqueous
`ophthalmic solutions which include the acidic NSAID diclofenac, in
`combination with tyloxapol. Pet. 35–37. According to Petitioners, the “only
`difference between the formulations described by [Sallmann] and the
`formulation in the claims of the ‘813 patent is the choice of NSAID
`(diclofenac vs. bromfenac).” Id. at 36.
`Petitioners rely also upon Example 6 of Ogawa as disclosing an
`aqueous ophthalmic solution containing bromfenac, boric acid, borax, BAC,
`water, and the non-ionic surfactant polysorbate 80. Id. Petitioners contend
`that “Example 6 of [Ogawa] includes each of the elements of independent
`claims 1, 7, and 13 except for the inclusion of tyloxapol.” Id. at 37.
`According to Petitioners, 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 ’813 patent. Id. (citing Ex. 1005
`¶ 443 (Lawrence Decl.)).
`Based on the record as a whole, we disagree with Petitioners. As
`Patent Owner correctly asserts, (PO Resp. 30–32), Sallmann specifically
`focuses on diclofenac potassium formulations. See Ex. 1021, 1:60–65. For
`example, Sallmann states: “[T]he present invention relates to an ophthalmic
`
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`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.” Id. (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 does not
`exemplify or discuss using another active ingredient for its composition. See
`id. at 7:56–14:23 (Examples 1–19).
`Given Sallmann’s specific focus on preparing diclofenac potassium
`formulations, Petitioners do 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,
`Petitioners do not persuade us that, based on this rationale, a preponderance
`of the evidence supports a conclusion that claims 1, 7, and 13 of the ’813
`patent, or their dependent claims, would have been obvious to a person of
`ordinary skill in the art.
`
`Alternatively, Petitioners assert that it would have been obvious to a
`person of ordinary skill in the art to modify Ogawa’s formulation by
`substituting the tyloxapol used in Sallmann’s formulations for the
`polysorbate 80 used in Ogawa’s Example 6, thereby arriving at a stable
`aqueous preparation encompassed by claims 1, 7, and 13 of the ’813 patent.
`Pet. 37. Petitioners assert that, at the time of the invention, it was known in
`the art that polysorbate 80 could be substituted for tyloxapol in ophthalmic
`formulations. Id. In support of this assertion, Petitioners rely upon the
`
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`Declaration of Dr. Lawrence. Id. (citing Ex. 1005 ¶ 444). According to Dr.
`Lawrence, at the time of the invention, it was known that “polysorbate 80
`and tyloxapol could be used interchangeably” and that “substituting
`tyloxapol for polysorbate 80 in ophthalmic formulations had been shown to
`improve the stability of acidic group-containing drugs.” Ex. 1005 ¶ 444
`(citing Ex. 1022, 6:57–7:45) (“Yasueda”).2
`
`Moreover, Petitioners assert that a person of ordinary skill in the art
`would have understood from Sallmann that tyloxapol was a suitable additive
`in a formulation comprising a carboxyl group-containing NSAID, i.e.,
`diclofenac or bromfenac. Pet. 40. As exemplary support, Dr. Lawrence
`describes a known bromfenac ophthalmic formulation that includes
`tyloxapol as a suitable surfactant. Ex. 1005 ¶ 444 (citing Ex. 1012, 3:13–45)
`(“Desai”).3 According to Dr. Lawrence, a skilled artisan would have
`understood that diclofenac and bromfenac have similar properties and are
`subject to similar formulation issues, such that the two compounds “could be
`successfully formulated in the same way.” Id.
`Having considered the arguments and evidence advanced by
`Petitioners and Patent Owner, we are persuaded that a person of ordinary
`skill in the art at the time of the invention would have had a reason to
`substitute Sallmann’s tyloxapol for the polysorbate 80 used in Ogawa’s
`formulations. Each of claims 1, 7, and 13 recites a stable aqueous liquid
`preparation that consists essentially of bromfenac, its salts, or hydrates, as
`the sole pharmaceutically active ingredient, and tyloxapol. Ex. 1003.
`
`
`2 Yasueda et al., U.S. Patent No. 6,274,609 B1, issued Aug. 14, 2001
`(“Yasueda”).
`3 Desai et al., U.S. Patent No. 5,603,929, issued Feb. 18, 1997 (“Desai”).
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`
`We find that Ogawa discloses ophthalmic solutions containing the
`sodium salt of bromfenac monohydrate as the sole pharmaceutically active
`ingredient, meeting the “first component” of the preparation recited by
`claims 1, 7, and 13. Ex. 1010, 1:60–2:3, Example 6.
`We find also that Ogawa discloses that the solution described in
`Example 6 contains 0.15 w/v% polysorbate 80 (0.15 g/100ml). Id.
`According to Ogawa, 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.
`Thus, as Petitioners contend, Example 6 of Ogawa differs from
`claims 1, 7, and 13 only in that Ogawa’s solution contains polysorbate 80
`instead of tyloxapol. As Petitioners assert, however, Example 2 of Sallmann
`describes using 0.1 mg/ml tyloxapol, i.e., 0.1 w/v%, in an aqueous eye drop
`formulation that also contains an acidic group-containing NSAID diclofenac
`potassium. Ex. 1021, 8:1–13.
`Petitioners rely upon the declaration testimony of Dr. Lawrence to
`support their 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 ¶ 444).
`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
`
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`cited in Dr. Lawrence’s Declaration. Ex. 1005 ¶ 444 (citing Exs. 1012 and
`1022).
`In particular, Yasueda describes the use of both tyloxapol and
`polysorbate 80 as solubilizing surfactants in ophthalmic solutions containing
`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 Petitioners 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 Petitioners
`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, Petitioners persuade 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, therefore, 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)).
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`As to the stability requirements in claims 1, 7, and 13, the ’813 patent
`discloses that the tyloxapol range effective to stabilize a bromfenac-
`containing solution is between about 0.01 and 0.5 w/v %. Ex. 1003, 5:19–
`25. Both the tyloxapol concentration described in Sallmann (0.1 w/v %) and
`the polysorbate 80 concentration described in Ogawa (0.15 w/v %), fall
`within the stabilizing range set out in the ’813 patent.
`Therefore, in addition to having a reason to substitute the tyloxapol
`recited in claims 1, 7, and 13 of the ’813 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 each of those claims.
`Patent Owner’s arguments do not convince us otherwise.
`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 ¶¶ 68–77
`(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 ¶¶ 74–78, 80, 82, 87 (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,
`
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`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
`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. ¶ 125).
`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 Petitioners 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 ’813 patent, discussed
`above, does not demonstrate a deficiency in Petitioners’ contention that,
`based on the cited prior art, an ordinary artisan would have recognized
`Sallmann’s tyloxapol as an ophthalmically acceptable non-ionic surfactant
`
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`that would be an interchangeably useful equivalent to the polysorbate 80 in
`Ogawa’s compositions.4
`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. 18–36.
`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, Petitioners persuade 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
`
`4 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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`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 Petitioners in light of Patent Owner’s
`arguments and evidence regarding the cited references’ teachings, we find
`that an ordinary artisan had a reason to substitute Sallmann’s tyloxapol,
`recited in claims 1, 7, and 13 of the ’813 patent, for the polysorbate 80 in
`Ogawa’s Example 6, and to include the tyloxapol at a concentration
`encompassed by each of those claims.
`We next analyze and weigh the secondary considerations of
`nonobviousness asserted by Patent Owner to determine if, on balance, that
`evidence renders nonobvious the challenged claims.
`
`4. Secondary Considerations
`We have also considered Patent Owner’s contention that objective
`
`evidence exists establishing that an ordinary artisan would not have
`considered the claimed aqueous formulations obvious. Id. at 36–52. Factual
`inquiries for an obviousness determination include secondary considerations
`based on evaluation and crediting of objective evidence of nonobviousness.
`Graham, 383 U.S. at 17. Notwithstanding what the teachings of the prior art
`would have suggested to one with ordinary skill in the art at the time of the
`invention, the totality of the evidence submitted, including objective
`evidence of nonobviousness, may lead to a conclusion that the claimed
`invention 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).
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`“Indeed, evidence of secondary considerations may often be the most
`probative and cogent evidence in the record. It may o
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