Trials@uspto.gov
`571-272-7822
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` Paper 9
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`Entered: October 27, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`________________
`
`Case IPR2015-01097
`Patent 8,754,131 B2
`________________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`DECISION
`Instituting Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`I. INTRODUCTION
`A. Statement of the Case
`Lupin Ltd. and Lupin Pharmaceuticals, Inc. (collectively,
`“Petitioner”) 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
`
`
`571-272-7822
`
` Paper 9
`
`Entered: October 27, 2015
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.,
`Patent Owner.
`________________
`
`Case IPR2015-01097
`Patent 8,754,131 B2
`________________
`
`
`Before FRANCISCO C. PRATS, ERICA A. FRANKLIN, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`PRATS, Administrative Patent Judge.
`
`
`
`DECISION
`Instituting Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`I. INTRODUCTION
`A. Statement of the Case
`Lupin Ltd. and Lupin Pharmaceuticals, Inc. (collectively,
`“Petitioner”) 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
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`patent”). Senju Pharmaceutical Co., Ltd. (“Patent Owner”) filed a
`Preliminary Response. Paper 8 (“Prelim. Resp.”).
`We have jurisdiction under 35 U.S.C. § 314(a), which provides that an
`inter partes review may be instituted only if “the information presented in
`the [Petition and Preliminary Response] . . . shows that there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.”
`Having considered the Petition and Preliminary Response, we
`determine, for the reasons discussed, that Petitioner has established a
`reasonable likelihood that it would prevail in its challenge to claims 1–30 of
`the ’131 patent. Accordingly, we institute an inter partes review of those
`claims.
`
`B. Related Proceedings
`Petitioner identifies eight district court proceedings involving the ’131
`patent, including one that involves Petitioner as a defendant. Pet. 2–3; see
`Senju Pharmaceutical Co. v. Lupin Ltd. et al., C.A. No. 1:14-CV-05144-
`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. Trial was instituted in InnoPharma v. Senju,
`IPR2015-00902, and the proceeding remains pending. IPR2015-00902,
`Paper 17.
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`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.
`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. Trial was instituted in InnoPharma v. Senju, IPR2015-00903, and
`the proceeding remains pending. IPR2015-00903, Paper 15.
`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.
`Concurrently herewith, we issue decisions to institute trial in each of
`IPR2015-01099, IPR2015-01100, and IPR2015-01105.
`C. Proposed Grounds of Unpatentability
`Petitioner advances the following two grounds of unpatentability
`(Pet. 12):
`
` Reference[s]
`
`Statutory Basis
`
`Ogawa1 and Fu2
`
`35 U.S.C. § 103(a)
`
`Challenged
`Claims
`1–30
`
`
`1 Ogawa et al., U.S. Patent No. 4,910,225 (issued Mar. 20, 1990) (“Ogawa,”
`Ex. 1010).
`2 Fu et al., EP 0 306 984 A1 (published March 15, 1989) (“Fu,” Ex. 1014).
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` Reference[s]
`
`Statutory Basis
`
`Sallmann3 and Ogawa
`
`35 U.S.C. § 103(a)
`
`Challenged
`Claims
`1–30
`
`Petitioner supports its challenge with a Declaration by M. Jayne
`Lawrence, Ph.D. (“Lawrence Decl.”) (Ex. 1005).
`D. 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
`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.
`
`
`3 Sallmann et al., U.S. Patent No. 5,891,913 (issued Apr. 6, 1999)
`(“Sallmann,” Ex. 1021).
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`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
`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.
`
`Claims 1 and 6 of the ’131 patent illustrate the challenged subject
`matter and read as follows (paragraphing added):
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`6
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`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.
`
`6. The stable aqueous liquid preparation of claim 1;
`
`wherein
`the stable aqueous
`liquid preparation consists
`essentially of:
`(a)
`2-amino-3-(4-bromobenzoyl)phenylacetic
`sodium salt,
`(b) tyloxapol,
`(c) boric acid,
`(d) sodium tetraborate,
`(e) EDTA sodium salt,
`(f) benzalkonium chloride,
`(g) polyvinylpyrrolidone, and
`(h) sodium sulfite,
`wherein said
`liquid preparation
`ophthalmic administration,
`the 2-amino-3-(4-
`wherein
`the concentration of
`bromobenzoyl)phenylacetic acid sodium salt is from about 0.02
`w/v % to about 0.1 w/v %, and wherein the concentration of
`tyloxapol is from about 0.01 w/v % to about 0.05 w/v %.
`
`Id. at 12:2–15; 12:26–36.
`
`acid
`
`is formulated for
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`II. ANALYSIS
`A. Claim Construction
`The Board interprets claims in an unexpired patent using the “broadest
`
`reasonable construction in light of the specification of the patent in which
`[they] appear[].” 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268, 1275 (Fed. Cir. 2015). Under that standard, claim terms are
`given their ordinary and customary meaning, as would be 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.
`Neither Petitioner nor Patent Owner proposes a specific claim
`construction for any claim term. Pet. 5–6; Prelim. Resp. 14. For the
`purposes of this decision, we determine that no claim term requires express
`construction.
`B. Obviousness—Sallmann and Ogawa
`Petitioner contends that Sallmann and Ogawa would have rendered
`the aqueous preparations recited in claims 1–30 of the ’131 patent obvious to
`an ordinary artisan. Pet. 35–53. Specifically, Petitioner cites Sallmann as
`disclosing aqueous ophthalmic solutions which include the acidic NSAID
`diclofenac, in combination with tyloxapol. Id. at 35–36. Petitioner contends
`that the “only difference between the formulation described by [Sallmann]
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`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
`[of the ’131 patent] except for the inclusion of tyloxapol.” Id.
`Petitioner contends 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 the challenged claims. Id. at 38. In particular,
`Petitioner contends that the state of the art was such 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”);4
`Ex. 1014, 5:23–28; 9:1–48 (Fu)). 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”)).5
`Patent Owner argues, for a number of reasons, that an ordinary artisan
`would not have been prompted to substitute Sallman’s tyloxapol for the
`polysorbate 80 used in Ogawa’s Example 6. Prelim. Resp. 38–39. Patent
`Owner contends also that objective evidence shows that an ordinary artisan
`
`4 Yasueda et al., U.S. Patent No. 6,274,609 B1 (issued Aug. 14, 2001)
`(“Yasueda,” Ex. 1022).
`5 Desai et al., U.S. Patent No. 5,603,929 (issued Feb. 18, 1997) (“Desai,” Ex.
`1012).
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`would not have considered the claimed aqueous formulations obvious. Id.
`at 43–53.
`Having considered Petitioner’s contentions and accompanying
`evidence in light of Patent Owner’s arguments and evidence, Petitioner
`persuades us, on the current record, that it has established a reasonable
`likelihood of prevailing in showing that an ordinary artisan would have
`considered obvious the aqueous preparations recited in claims 1–30.
`Each of claims 1, 7, and 13, the independent claims 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
`w/v%, of the sodium salt of bromfenac monohydrate, which falls within the
`bromfenac concentration range recited in claims 1, 7, and 13 of the ’131
`patent. 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.
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`Thus, as Petitioner contends, based on the current record, 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). Based
`on the record developed at this stage of the proceeding, we credit her
`testimony on this issue. See Ex. 1005 ¶¶ 3–15. Dr. Lawrence’s testimony in
`this regard 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
`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
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`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.
`Thus, on the current record, we determine that Petitioner has advanced
`information sufficient to show that an ordinary artisan would have
`considered Sallmann’s tyloxapol and Ogawa’s polysorbate 80 to be
`interchangeably useful surfactants in aqueous acidic NSAID-containing
`ophthalmic solutions. Accordingly, Petitioner persuades us, on the current
`record, that an ordinary artisan would have been prompted to substitute
`Sallmann’s tyloxapol for Ogawa’s polysorbate 80 in the aqueous ophthalmic
`solution described in Ogawa’s Example 6, thereby producing a composition
`having all of the ingredients required by claims 1, 7, and 13 of the ’131
`patent. See KSR Int’l v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“[W]hen a
`patent claims a structure already known in the prior art that is altered by the
`mere substitution of one element for another known in the field, the
`combination must do more than yield a predictable result.”); see also In re
`Mayne, 104 F.3d 1339, 1340 (Fed. Cir. 1997) (“Because the applicants
`merely substituted one element known in the art for a known equivalent, this
`court affirms [the conclusion of obviousness].”).
`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
`the polysorbate 80 concentration described in Ogawa (0.1 w/v %), discussed
`above, fall within the stabilizing range set out in the ’131 patent.
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`In sum, for the reasons discussed, Petitioner persuades us, on the
`current record, that an ordinary artisan would have been prompted to prepare
`aqueous liquid preparations having all of the ingredients required by claims
`1, 7, and 13, in the amounts required by the claims. As to dependent
`claims 2–6, 8–12, and 14–30, having reviewed Petitioner’s contentions
`regarding the relevant disclosures in the cited prior art, Petitioner persuades
`us, on the current record, that the posited combination of Sallmann and
`Ogawa also suggests compositions having all of the ingredients and
`properties required by those claims. See Pet. 42–53.
`On the current record, Patent Owner’s arguments do not persuade us
`that Petitioner has failed to establish a reasonable likelihood that an ordinary
`artisan would have had a reason to substitute Sallmann’s tyloxapol for the
`polysorbate 80 in the composition of Ogawa’s Example 6.
`Specifically, Patent Owner contends that an ordinary artisan would
`not have used a solubilizer like tyloxapol to address the alleged oxidative
`degradation of bromfenac, or the products resulting from that oxidation.
`Prelim. Resp. 38. Moreover, Patent Owner contends, Ogawa does not
`ascribe any particular role to its polysorbate 80, “which makes sense because
`bromfenac was known to readily dissolve in water. (EX1053 at 6.) There
`simply would not have been any reason, other than hindsight, to use
`tyloxapol with bromfenac.” Id. at 39.
`We are not persuaded. We acknowledge that Ogawa does not appear
`to disclose expressly why it included polysorbate 80 in its compositions. As
`discussed above, however, Petitioner has advanced evidence supporting a
`finding that, on the current record, polysorbate 80, like tyloxapol, was
`known in the prior art to be a non-ionic surfactant, and was known to be
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`useful in aqueous ophthalmic solutions, also like tyloxapol. Indeed, Patent
`Owner effectively concedes that polysorbate 80 and tyloxapol were known
`prior art non-ionic surfactants. See id. at 32–33 (presenting chemical
`structures of polysorbate 80 and tyloxapol to show an ordinary artisan’s
`prior art understanding of the compounds’ properties).
`Moreover, despite the alleged water solubility of bromfenac, Ogawa
`nonetheless includes polysorbate 80, a 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 might not
`expressly state its reason for including polysorbate 80 in its compositions,
`Petitioner nonetheless persuades us, on the current record, that an ordinary
`artisan would have been prompted to include a non-ionic surfactant such as
`polysorbate 80, or a known ophthalmically acceptable equivalent non-ionic
`surfactant such as tyloxapol, in bromfenac-containing ophthalmic solutions,
`such as the one described in Example 6 of Ogawa.
`Patent Owner argues also that Petitioner inaccurately characterizes the
`Yasueda reference as teaching that tyloxapol was known in the art to be a
`better solubilizer than polysorbate 80. Prelim. Resp. 39. Moreover, Patent
`Owner argues, the experiment in Yasueda cited by Petitioner does not
`include benzalkonium chloride (BAC) in the polysorbate 80 formulations,
`and therefore is not an adequate side-by-side comparison. Id.
`Even assuming for argument’s sake, however, that polysorbate 80 was
`known to be more water soluble than tyloxapol, and that Yasueda’s
`experiments would not have been viewed as indicative of the relative
`stabilities imparted by tyloxapol and polysorbate 80, both Yasueda and
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`Desai, as discussed above, support Dr. Lawrence’s testimony and
`Petitioner’s assertion that Sallmann’s tyloxapol and Ogawa’s polysorbate 80
`were non-ionic surfactants known in the art to be interchangeably useful in
`acidic NSAID-containing ophthalmic solutions. Accordingly, on the current
`record, Patent Owner’s arguments do not persuade us that Petitioner failed to
`establish a reasonable likelihood that an ordinary artisan would have had a
`reason, based on the art-recognized interchangeability of tyloxapol and
`polysorbate 80 in aqueous ophthalmic compositions, to substitute
`Sallmann’s tyloxapol for the polysorbate 80 in the composition of Ogawa’s
`Example 6.
`Patent Owner contends further that Petitioner has not established that
`Sallmann and Ogawa teach or suggest claim 1’s requirement for the
`tyloxapol to be present in the composition in a concentration sufficient to
`stabilize the bromfenac, or claim 4’s requirement for the tyloxapol to be
`present at a concentration from about 0.01 w/v % to about 0.05 w/v %.
`Prelim. Resp. 52–53.
`We are not persuaded. While it might be true that Ogawa’s
`Experimental Example 5 was not reported as stable, Example 6 of Ogawa,
`discussed above, contained the same concentration of polysorbate 80, and
`was reported to retain 100.9% bromfenac activity after four weeks at 60° C.
`Ex. 1010, 14:45–48 (Table 11). As also discussed above, 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. 1002, 5:37–
`38. Both the tyloxapol concentration described in Sallmann (0.1 w/v %) and
`the polysorbate 80 concentration described in Ogawa (0.1 w/v %), discussed
`above, fall within the stabilizing range set out in the ’131 patent.
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`As to claim 4, to the extent that the recited tyloxapol concentration
`range is critical, the evidence presented on the current record supports a
`reasonable inference that an ordinary artisan would have arrived at the
`specified range using only routine experimentation. Pet. 49; see In re Aller,
`220 F.2d 454, 456–58 (CCPA 1955) (“where the general conditions of a
`claim are disclosed in the prior art, it is not inventive to discover the
`optimum or workable ranges by routine experimentation”); In re Peterson,
`315 F.3d 1325, 1330 (Fed. Cir. 2003) (“The normal desire of scientists or
`artisans to improve upon what is already generally known provides the
`motivation to determine where in a disclosed set of percentage ranges is the
`optimum combination of percentages.”).
`As to claim 7’s additional stability requirement of greater than 90%
`bromfenac activity present after four weeks at 60° C (Ex. 1002, 12:48–51),
`as Petitioner points out (Pet. 41), Ogawa discloses that, after four weeks at
`60° C, the solution described in Example 6 maintained 100.9 % of its
`original bromfenac activity. Ex. 1010, 10:49–51, 14:45–48 (Table 11).
`Accordingly, Patent Owner does not persuade us that Petitioner failed to
`address that claim requirement, or that the cited references fail to teach or
`suggest it. See Prelim. Resp. 55.
`As to the tyloxapol concentrations recited in claims 10, 12, and 22, as
`noted above, the evidence presented on the current record supports a
`reasonable inference that an ordinary artisan would have arrived at the
`required concentrations using only routine experimentation. As to the
`alleged unexpectedness of the tyloxapol concentration recited in claim 12
`(Prelim. Resp. 54, 57), for the reasons discussed below, we are not
`persuaded that, on this record, Patent Owner has advanced evidence
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`sufficient to show that the results achieved using that concentration of
`tyloxapol actually were unexpected.
`As to claims 27 and 28, Petitioner contends that Ogawa’s Example 6
`formulation with tyloxapol substituted for polysorbate 80 would have
`satisfied the preservative efficacy standard of US Pharmacopoeia, because of
`the preservative agent (BAC) present in that formulation, and because of the
`formulation’s similarity to Composition A-04 of the ’131 patent, which
`satisfies the more demanding EP-criteria A of the European Pharmacopoeia.
`Pet. 51–52. Accordingly, on the current record, Patent Owner does not
`persuade us (Prelim. Resp. 56–57), that Petitioner failed to advance an
`adequate evidentiary basis to establish a reasonable likelihood that the cited
`references taught or suggested an aqueous liquid preparation meeting the
`requirements of claims 27 and 28.
`Lastly, as to the requirement in claims 12 and 18 that the recited
`compositions “consist[] essentially of” the recited ingredients (Prelim. Resp.
`57–58), Patent Owner does not explain adequately how Petitioner’s posited
`substitution of Sallman’s tyloxapol for the polysorbate 80 in Example 6 of
`Ogawa would result in a composition that contained any ingredients beyond
`those recited in claims 12 and 18.
`In sum, for the reasons discussed, Patent Owner does not persuade us
`that Petitioner has failed to establish a reasonable likelihood of prevailing in
`showing that Sallmann and Ogawa would have taught or suggested an
`aqueous liquid preparation having all of the elements and properties required
`by claims 1–30 of the ’131 patent.
`On the current record, moreover, Patent Owner’s contentions and
`evidence regarding the secondary indicia of nonobviousness do not persuade
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`us that Petitioner has failed to establish a reasonable likelihood of prevailing
`as to the ultimate conclusion of obviousness.
`Patent Owner directs us to Table 1 of the ’131 patent, discussed
`above, to show that a side-by-side comparison between tyloxapol and the
`polysorbate 80 of Ogawa, allegedly the closest prior art to the claims,
`demonstrates that tyloxapol “was 44% better at stabilizing bromfenac from
`degradation. And in a completely unexpected and counterintuitive manner,
`when the amount of tyloxapol was lowered to 0.02 g, about 1/8 the amount
`of polysorbate 80 (0.15 g), tyloxapol was 75% better at stabilizing
`bromfenac degradation.” Prelim Resp. 47 (citing Ex. 1002, Table 1). Patent
`Owner contends that this is “a truly remarkable and surprising result
`considering the harsh pH conditions and the significantly reduced amount of
`tyloxapol versus polysorbate 80.” Id. at 47–48.
`Patent Owner also directs us to Table 2 of the ’131 patent, in which
`Formulations A-04, A-05, and A-06, which contained 0.02 g, 0.05 g, and
`0.03 g of tyloxapol per 100 ml of solution, resulted in 92.6%, 90.9%, and
`92.0%, remaining bromfenac activity after four weeks at 60° C and a pH of
`8.15 (A-04, A-06) or 8.16 (A-05). Prelim. Resp. 47–48; see also Ex. 1002,
`8:13–34 (Table 2 of the ’131 patent). Patent Owner contends that “despite
`using an amount of tyloxapol that was about 1/3, 1/5, and 1/8 the amount of
`polysorbate 80 used by Ogawa, these formulations achieved comparable
`stabilization results to Ogawa’s Example 6,” which was “entirely
`unexpected in view of Ogawa,” particularly given the ’131 patent’s omission
`of sodium sulfite. Prelim. Resp. 48–49
`Based on the current record, we are not persuaded by Patent Owner’s
`argument, as Patent Owner has not directed us to any clear or specific
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`description in the Specification of the ’131 patent, or elsewhere,
`characterizing or establishing the results shown in the ’131 patent as being
`unexpected. When characterizing the results presented in Table 1, the ’131
`patent itself simply notes that bromfenac-containing solutions were more
`stable when they included tyloxapol, as compared to polysorbate 80. Ex.
`1002, 7:56–61 (“[Bromfenac] in each eye drop was stable in the order of
`tyloxapol-containing preparation >polyoxyl 40 stearate-containing
`preparation >polysorbate 80-containing preparation.”). As to the results in
`Table 2, the ’131 patent simply states that, given the results of the
`experiments, the tyloxapol-containing solutions “have sufficient stability for
`eye drops.” Id. at 8:47–48.
`Moreover, while Patent Owner contends that the claims are
`commensurate in scope with the purported showing of unexpected results
`(Prelim. Resp. 50), independent claims 1, 7, and 13, as discussed above,
`require only two ingredients, tyloxapol and bromfenac, whereas the
`formulations allegedly demonstrating unexpected results include a number
`of additional ingredients. Ex. 1002, 7:35–53, 8:13–34 (Tables 1 and 2 of
`’131 patent). As seen above, claim 6 of the ’131 patent expressly includes
`sodium sulfite, as do claims 12, 18, and 24. Id. at 12:31, 13:9, 13:45, and
`14:11. Accordingly, on the current record, given the breadth of the claimed
`subject matter, Patent Owner has not established that the claims of the ’131
`patent are commensurate in scope with the asserted showing of unexpected
`results advanced by Patent Owner. See In re Grasselli, 713 F.2d 731, 743
`(Fed. Cir. 1983).
`As to Patent Owner’s contentions regarding the advantages of
`Prolensa®, the asserted commercial embodiment of the ’131 patent claims,
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`as compared to competing commercial formulations (Prelim. Resp. 50–51),
`Patent Owner does not direct us to clear or specific evidence explaining
`whether the asserted advantageous properties of Prolensa® would have been
`unexpected. As our reviewing court has explained, “any superior property
`must be unexpected to be considered as evidence of non-obviousness.”
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). Patent
`Owner, moreover, does not direct us to evidence in the record explaining
`with specificity what ingredients are in Prolensa®, and the concentrations of
`those ingredients, such that we may determine whether the challenged
`claims are commensurate in scope with the commercial embodiment Patent
`Owner advances.
`To show industry acclaim, Patent Owner advances what appears to be
`a Prolensa® product brochure (Ex. 2014), and a webpage listing other
`bromfenac-containing commercial products (Ex. 2031). Prelim. Resp. 51.
`Patent Owner does not explain adequately, however, how a company’s own
`product brochure touting the benefits of its product, or a listing of alternative
`drugs, demonstrates industry acclaim.
`In that regard, Patent Owner directs us also to what appears to be a
`financial report, which is alleged to show a sales projection of $100 million
`annually for Prolensa®. Id. (citing Ex. 2026, 4). Patent Owner does not
`discuss or explain, however, the specific disclosures in the report upon
`which it bases its assertion regarding projected sales, nor does Patent Owner
`advance objective evidence of revenues based on actual sales. Further,
`Patent Owner has not established how the projected sales would amount to a
`significant share of the relevant market.
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`As to Patent Owner’s contentions regarding copying (Prelim. Resp.
`51–52), Patent Owner does not direct us to the specific portions of the cited
`Paragraph IV letters that demonstrate the competing generic companies’
`intentions to market “exact copies of Prolensa®.” Id. at 51. Moreover, as
`our reviewing court has explained, “evidence of copying in the ANDA
`context is not probative of nonobvi
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