`571.272.7822
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` Paper No. 8
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` Entered: December 8, 2016
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-01132
`Patent 9,248,191 B2
`____________
`
`
`
`
`Before SHERIDAN K. SNEDDEN, TINA E. HULSE, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
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`IPR2016-01132
`Patent 9,248,191 B2
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`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) filed a Petition requesting
`an inter partes review of claims 1–27 of U.S. Patent No. 9,248,191 B2
`(Ex. 1001, “the ’191 patent”). Paper 3 (“Pet.”). Allergan, Inc. (“Patent
`Owner”) filed a Preliminary Response to the Petition. Paper 7 (“Prelim.
`Resp.”).
`We have jurisdiction under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). Upon considering
`the Petition and Preliminary Response, we determine that Petitioner has
`established a reasonable likelihood that it would prevail in showing the
`unpatentability of claims 1–27. Accordingly, we institute an inter partes
`review of those claims.
`
`Related Proceedings
`A.
`The parties identify several petitions for inter partes review
`previously filed by Apotex Corp. and Apotex Inc. and challenging claims of
`related patents. Pet. 11; Paper 6, 2 (referring to IPR2015-01278, IPR2015-
`01282, IPR2015-01283, IPR2015-01284, and IPR2015-01286). All of the
`petitions were terminated before institution decisions were entered. Pet. 11;
`Paper 6, 2. The parties also identify several district court cases that may
`affect or be affected by a decision in this proceeding: Allergan, Inc. v. Teva
`Pharms. USA, Inc., et al., No. 2:15-cv-01455 (E.D. Tex.); Allergan, Inc., v.
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`Innopharma, Inc., No. 2:15-cv-1504 (E.D. Tex.); and Allergan, Inc. v. Famy
`Care, Ltd., No. 2:16-cv-0401 (E.D. Tex.). Pet. 11; Paper 6. 2.
`Petitioner has also sought inter partes review for related patents in the
`following proceedings: Case IPR2016-01127 (U.S. Patent No. 8,685,930
`B2), Cases IPR2016-01128 and IPR2016-01232 (U.S. Patent No. 8,629,111
`B2), Case IPR2016-01129 (U.S. Patent No. 8,642,556 B2), Case IPR2016-
`01130 (U.S. Patent No. 8,633,162 B2), and Case IPR2016-01131 (U.S.
`Patent No. 8,648,048 B2).
`
`The ’191 Patent
`B.
`The ’191 patent generally relates to methods of providing therapeutic
`effects using cyclosporin components, and more specifically to a
`formulation containing cyclosporin-A (“CsA”) and castor oil emulsions for
`treating dry eye syndrome (i.e., keratoconjunctivitis sicca or “KCS”). Ex.
`1001, 1:20–22, 1:60–67, 2:66–67. According to the specification, the prior
`art recognized the use of emulsions containing CsA and CsA-derivatives to
`treat ophthalmic conditions. Id. at 1:28–67. The specification notes,
`however, “[o]ver time, it has become apparent that cyclosporin A emulsions
`for ophthalmic use preferably have less than 0.2% by weight of cylcosporin
`A.” Id. at 1:66–2:1. Moreover, if reduced amounts of cyclosporin are used,
`reduced amounts of castor oil are needed because one of the functions of
`castor oil is to solubilize CsA. Id. at 2:1–8.
`Accordingly, the specification states that “[i]t has been found that the
`relatively increased amounts of hydrophobic component together with
`relatively reduced, yet therapeutically effective, amounts of cyclosporin
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`component provide substantial and advantageous benefits.” Id. at 2:38–41.
`The relatively high concentration of hydrophobic component provides for a
`more rapid breaking down of the emulsion in the eye, which reduces vision
`distortion and/or facilitates the therapeutic efficacy of the composition. Id.
`at 2:45–51. Furthermore, using reduced amounts of cyclosporin component
`mitigates against undesirable side effects or potential drug interactions. Id.
`at 2:51–54.
`The patent identifies two particular compositions that were selected
`for further testing, as shown below:
`
`
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`Id. at 14:26–38. Based on the results of a Phase 3 clinical study, the
`specification concludes that “Composition II . . . provides overall efficacy in
`treating dry eye disease substantially equal to that of Composition I.” Id. at
`14:42–46. The patent indicates “[t]his is surprising for a number of
`reasons.” Id. at 14:47. According to the specification, a reduced
`concentration of CsA in Composition II would have been expected to result
`in reduced overall efficacy in treating dry eye disease. Id. at 14:47–50.
`Moreover, although the large amount of castor oil relative to the amount of
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`CsA in Composition II might have been expected to cause increased eye
`irritation, it was found to be substantially non-irritating in use. Id. at 14:50–
`55. Accordingly, the specification states that physicians can prescribe
`Composition II “to more patients and/or with fewer restrictions and/or with
`reduced risk of the occurrence of adverse events, e.g., side effects, drug
`interactions and the like, relative to providing Composition I.” Id. at 15:10–
`14.
`
`Illustrative Claim
`C.
`Petitioner challenges claims 1–27 of the ’191 patent, of which
`claims 1, 13, 17, and 21 are independent claims. Claim 1 is
`illustrative, and is reproduced below:
`1. A method of treating dry eye disease, the method
`comprising topically administering to a human eye in need
`thereof a first topical ophthalmic emulsion at a frequency
`of twice a day, wherein the first ophthalmic emulsion
`comprises cyclosporin A in an amount of about 0[.]05%
`by weight, polysorbate 80, acrylate/C10-30 alkyl acrylate
`cross-polymer, water, and castor oil in an amount of about
`1.25% by weight;
`wherein the method is therapeutically effective in
`treating dry eye disease;
`wherein
`the method provides overall efficacy
`substantially equal to administration of a second
`topical ophthalmic emulsion to a human eye in need
`thereof at a frequency of twice a day, the second
`emulsion comprising cyclosporin A in an amount of
`about 0.1% by weight and castor oil in an amount
`of about 1.25% by weight; and
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`Patent 9,248,191 B2
`in substantially no
`wherein
`the method results
`detectable concentration of cyclosporin A in the
`blood of the human.
`Independent claim 13 recites that the concentration of
`cyclosporin A in the blood of the human is less than about 0.1
`ng/ml.
`Independent claim 17 also recites that the first topical
`emulsion breaks down more quickly in the human eye
`compared to a second emulsion that contains only about 50% as
`much castor oil as the first emulsion.
`Independent claim 21 recites a method of restoring
`tearing comprising administering a topical ophthalmic emulsion
`similar to claim 1.
`The Asserted Grounds of Unpatentability
`D.
`Petitioner challenges the patentability of claims 1–27 of the ’191
`patent on the following grounds:
`References
`Ding ’9791 and Sall2
`
`Basis
`§ 103(a)
`
`Claim(s) challenged
`1–16 and 21–27
`
`
`1 Ding et al., US 5,474,979, issued Dec. 12, 1995 (Ex. 1006).
`2 Sall et al., Two Multicenter, Randomized Studies of the Efficacy and Safety
`of Cyclosporine Ophthalmic Emulsion in Moderate to Severe Dry Eye
`Disease, 107 OPHTHALMOLOGY 631–39 (2000) (Ex. 1007).
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`References
`Ding ’979, Sall, and
`Acheampong3
`Ding ’979, Sall, and Glonek4
`
`Ding ’979, Sall, Acheampong,
`and Glonek
`
`Basis
`§ 103(a)
`
`§ 103(a)
`
`§ 103(a)
`
`Claim(s) challenged
`1–16 and 21–27
`
`17–20
`
`20
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`Petitioner also relies on the Declaration of Mansoor Amiji, Ph.D.
`Ex. 1002.
`
`ANALYSIS
`
`Person of Ordinary Skill in the Art
`A.
`Petitioner asserts that as of September 15, 2003, a person of ordinary
`skill in the art would likely have had “some combination of: (a) experience
`formulating pharmaceutical products; (b) experience designing and
`preparing drug emulsions intended for topical ocular administration; and (c)
`the ability to understand results and findings presented or published by
`others in the field. Pet. 9 (citing Ex. 1002 ¶ 36). Petitioner further contends
`that this person typically would have an advanced degree, such as a medical
`degree, or a Ph.D. in organic chemistry, pharmaceutical chemistry,
`medicinal chemistry, pharmaceutics, physical pharmacy, or a related field, or
`
`
`3 Acheampong et al., Cyclosporine Distribution into the Conjunctiva,
`Cornea, Lacrimal Gland, and Systemic Blood Following Topical Dosing of
`Cyclosporine to Rabbit, Dog, and Human Eyes, LACRIMAL GLAND, TEAR
`FILM, AND DRY EYE SYNDROMES 2: BASIC SCIENCE AND CLINICAL
`RELEVANCE 1001–04 (David A. Sullivan et al. eds., 1998) (Ex. 1008).
`4 Glonek et al., US 5,578,586, issued Nov. 26, 1996 (Ex. 1009).
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`less education but considerable professional experience in these fields. Id.
`(citing Ex. 1002 ¶ 35). Patent Owner does not explicitly address the level of
`ordinary skill in the art in its Preliminary Response.
`On this record, we adopt Petitioner’s definition of the level of
`ordinary skill in the art. We further note that the prior art itself demonstrates
`the level of skill in the art at the time of the invention. See Okajima v.
`Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001) (explaining that specific
`findings regarding ordinary skill level are not required “where the prior art
`itself reflects an appropriate level and a need for testimony is not shown”)
`(quoting Litton Indus. Prods., Inc. v. Solid State Sys. Corp., 755 F.2d 158,
`163 (Fed. Cir. 1985)).
`
`Claim Construction
`B.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`of the specification of the patent in which they appear. 37 C.F.R. § 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. See 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. See In re Paulsen, 30
`F.3d 1475, 1480 (Fed. Cir. 1994).
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`“therapeutically effective in treating dry eye disease”
`1.
`and “therapeutic efficacy
`
`Claims 1–16 recite treatment methods utilizing a topical ophthalmic
`emulsion that is “therapeutically effective in treating dry eye disease” and
`claims 21–27 recite a method comprising administering a first emulsion that
`achieves at least as much “therapeutic efficacy” as a second emulsion.
`Petitioner asserts that the ’191 patent teaches that cyclosporin A “acts to
`enhance or restore lacrimal gland tearing in providing the desired therapeutic
`effect.” Pet. 15 (quoting Ex. 1001, 9:15–16). Petitioner then argues that in
`light of the specification, “an emulsion effective in increasing tear
`production is an example of an emulsion therapeutically effective in
`enhancing and restoring lacrimal gland tearing and in treating dry eye
`disease.” Id. Petitioner asserts that because the plain meaning of the word
`“therapeutic” includes palliative as well as curative treatments, the broadest
`reasonable interpretation of the terms includes palliative and curative
`treatments. Id. (citing Ex. 1002 ¶¶ 42–43; Ex. 1022, 7, 4, 5).
`Patent Owner argues that Petitioner’s proposed construction is too
`broad, and that the claims should be construed to require that “the emulsion
`treat the underlying disease,” and not just its symptoms. Prelim. Resp. 21–
`22. Patent Owner argues that its construction is supported by a dictionary
`definition of “therapeutic,” defined as “[r]elating to therapeutics or to the
`treatment, remediating, or curing of a disease or disorder.” Id. at 22 (citing
`Exs. 2005, 2006). Patent Owner contrasts this definition of “therapeutic”
`with the definition of “palliative,” defined as “[r]educing the severity of;
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`denoting the alleviation of symptoms without curing the underlying
`disease,” thereby suggesting that the phrase “therapeutically effective”
`would not include palliative effects. Id. at 22 n.2 (citing Ex. 2007). We
`disagree. The definition of “therapeutic” provided by the Patent Owner is
`not limited to a cure of a disease or disorder, but also includes either
`treatment or remediating of a disease or disorder. We thus conclude, on the
`current record, that the ordinary meaning of the phrase “therapeutically
`effective” is not so limited as to exclude palliative effects.
`Patent Owner further argues that the specification supports its
`construction because “throughout the specification, the ‘191 patent uses the
`word ‘therapeutic’ in connection with the action of cyclosporin. . . . In
`contrast, the ‘191 patent specification does not use the word ‘therapeutic’ to
`refer to the activity of the other components of the emulsion, including
`castor oil.” Id. at 22. We disagree. Contrary to Patent Owner’s assertion,
`the specification does refer to the “therapeutic effects” of castor oil: “it is
`believed that castor oil includes a relatively high concentration of ricinoleic
`acid which itself may be useful in benefitting ocular tissue and/or in
`providing one or more therapeutic effects when administered to an eye.” Ex.
`1001, 9:58–62 (emphasis added). Thus, notwithstanding Patent Owner’s
`extrinsic evidence it offers in support of its more-limited construction
`(Prelim. Resp. 23), we decline to construe the claims in a manner
`inconsistent with the specification.
`Accordingly, at this stage of the proceeding, we find that
`“therapeutically effective in treating dry eye disease,” “therapeutically
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`effective,” and similar terms encompass both palliative and curative
`treatments of dry eye disease.
`Remaining Claim Terms
`2.
`Petitioner proposes constructions for a number of additional claim
`terms. At this stage of the proceeding, we determine it is unnecessary to
`expressly construe any other claim terms for purposes of this Decision. See
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`(“[C]laim terms need only be construed ‘to the extent necessary to resolve
`the controversy.’”) (quoting Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795, 803 (Fed. Cir. 1999)).
`C. Obviousness over Ding ’979 and Sall
`Petitioner argues that claims 1–16 and 21–27 are unpatentable as
`obvious over the combination of Ding ’979 and Sall. Pet. 22–42. Petitioner
`relies on the testimony of Dr. Amiji in support. Ex. 1002 ¶¶ 91–115. Patent
`Owner opposes. Prelim. Resp. 24–33. Based on the current record, we
`determine that Petitioner has established a reasonable likelihood that it
`would prevail in showing claims 1–16 and 21–27 are unpatentable over the
`cited prior art.
`
`Ding ’979 (Ex. 1006)
`1.
`Ding ’979, assigned to Patent Owner, relates to ophthalmic emulsions
`including cyclosporin, castor oil, and polysorbate 80 that have a high
`comfort level and low irritation potential. Ex. 1006, cover, 1:4–9. Ding
`’979 explains that cyclosporins have “known immunosuppressant activity”
`and have been found “effective in treating immune medicated
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`keratoconjunctivitis sicca (KCS or dry eye disease) in a patient suffering
`therefrom.” Id. at 1:10–16. Although the solubility of cyclosporins in water
`is extremely low, cyclosporins have some solubility in oily preparations
`containing higher fatty acid glycerides such as castor oil. Id. at 1:40–41,
`2:39–42. Ding ’979 notes, however, that formulations with a high
`concentration of oils have several drawbacks, including exacerbation of the
`symptoms of dry eyes and low thermodynamic activity of cyclosporin,
`which leads to poorer drug bioavailability. Id. at 2:42–57. Accordingly,
`Ding ’979 “is directed to an emulsion system which utilizes higher fatty acid
`glycerides but in combination with polysorbate 80 which results in an
`emulsion with a high comfort level and low irritation potential suitable for
`delivery of medications to sensitive areas such as ocular tissues.” Id. at
`2:65–3:3.
`Ding ’979 discloses that the preferable weight ratio of cyclosporin to
`castor oil is below 0.16, and more preferably between 0.12 and 0.02. Id. at
`3:15–20. Specifically, Ding ’979 discloses several compositions as Example
`1, shown below:
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`Id. at 4:32–43. Example 1 identifies compositions A through E, which
`contain varying amounts of cyclosporin A, castor oil, polysorbate 80,
`Pemulen® (an acrylate/C10-30 alkyl acrylate cross-polymer), glycerine,
`sodium hydroxide, and purified water at a pH range of 7.2–7.6. Id.
`According to Ding ’979, the formulations of Example 1 was “made for
`treatment of keratoconjunctivitis sicca (dry eye) syndrome.” Id. at 5:10–12.
`Sall (Ex. 1007)
`2.
`Sall describes the results of two identical clinical trials—supported by
`a grant from Patent Owner—in which patients were treated twice daily with
`either cyclosporin A 0.05% or 0.1% ophthalmic emulsions or vehicle for six
`months. Ex. 1007, Abstract. The study sought to compare the efficacy and
`safety of cyclosporin A 0.05% and 0.1% to vehicle in patients with moderate
`to severe dry eye disease. Id. Sall found that topical treatment with either
`cyclosporin A 0.05% or 0.1% resulted in significantly greater improvements
`than vehicle treatment in two objective signs of dry eye disease. Id. at 637.
`Sall also found that treatment with cyclosporin A 0.05% resulted in
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`significantly greater improvements in several subjective parameters. Id.
`Sall also found that trough blood concentrations of cyclosporin A were
`undetectable (i.e., below 0.1 ng/ml) in all samples of cyclosporin A 0.05%,
`whereas cyclosporin A was quantifiable in only six samples for six different
`patients in the cyclosporin 0.1% group. Id.
`Sall notes that the only treatments available for dry eye disease are
`palliative in nature. Id. at 638. In light of the results of the study, Sall states
`that it “represents the first therapeutic treatment specifically for dry eye
`disease and a significant breakthrough in the management of this common
`and frustrating condition.” Id.
`
`Analysis
`3.
`Petitioner argues that the combination of Ding ’979 and Sall teaches
`each limitation of claims 1–16 and 21–27 of the ’191 patent. For example,
`Petitioner asserts that Ding ’979 teaches emulsions for treatment of dry eye
`syndrome that are “suitable for topical application to ocular tissue.” Pet. 25
`(citing Ex. 1006, 5:9–11, 6:3–7). Petitioner also notes that Ding ’979
`teaches that cyclosporin A is “‘an immunosuppressant’ that works ‘in the
`enhancement or restoring of lacrimal gland tearing” and has been found
`effective in treating KCS. Id. at 25–26 (citing Ex. 1006, 1:10–16, 37–39).
`Thus, Petitioner asserts that Ding ’979 teaches the emulsion is
`“therapeutically effective in treating dry eye disease,” as recited by claims 1
`and 13, and “effective in restoring lacrimal gland tearing,” as recited in
`claims 16 and 26.
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`Example 1D of Ding ’979 teaches every ingredient of the emulsion in
`claims 1–27, except 0.05% cyclosporin A. Ex. 1006, 4:32–43. That is,
`Example 1D teaches an emulsion with 1.25% castor oil, 1.0% polysorbate
`80, 0.05% Pemulen (i.e., acrylate/C10-30 alkyl acrylate cross-polymer),
`2.2% glycerine, sodium hydroxide, and water. Id. Example 1E of Ding
`’979 teaches an emulsion with 0.05% cyclosporin A. Id. According to Dr.
`Amiji, a person of ordinary skill in the art would recognize Ding ’979’s
`emulsions to include an emulsion containing the cyclosporin A/castor oil
`amounts in the claimed combination, i.e., 0.05% cyclosporin A and 1.25%
`castor oil, because such an emulsion would fall within the preferred ratio of
`cyclosporin A to castor oil. Ex. 1002 ¶ 98 (citing Ex. 1006, 4:32–43).
`Petitioner also asserts that Sall teaches treating patients twice daily
`with an emulsion containing 0.05% cyclosporin A. Pet. 29; Ex. 1007, 631.
`Sall concluded that both the 0.05% and the 0.10% cyclosporin A emulsions
`“were safe and effective in the treatment of moderate to severe dry eye
`disease . . . yielding improvements in both objective and subjective
`measures.” Pet. 30 (quoting Ex. 1007, 631). As such, Petitioner asserts that
`one of ordinary skill in the art would have expected the castor oil emulsion
`vehicle containing 0.05% by weight cyclosporin A to be at least as safe and
`effective at enhancing and restoring lacrimal tear production and treating dry
`eye disease/KCS as the castor oil emulsion containing 0.10% cyclosporin A.
`Id. at 31. Moreover, Petitioner asserts that Sall provides a strong rationale to
`deliver 0.05% cyclosporin A using the 1.25% castor oil vehicle taught by
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`Ding ’979 (i.e., Example 2C) in light of the preferred ratio of cyclosporin A
`to castor oil taught in Ding ’979. Pet. 32–33; Ex. 1002 ¶ 110.
`In its Preliminary Response, Patent Owner does not argue that the
`combination of references fails to teach any particular limitation of the
`claims. Accordingly, we are persuaded that Petitioner has shown
`sufficiently that the combination of Ding ’979 and Sall teaches each
`limitation of claims 1–16 and 21–27. That is, Ding ’979 specifically
`identifies examples that include 0.05% CsA and 1.25% castor oil, albeit not
`as part of the same composition. Ex. 1006, 4:32–43. Thus, the only issue
`before us is whether it would have been obvious to use the particular
`concentrations of 0.05% CsA and 1.25% castor oil in the emulsion together,
`as recited in the challenged claims.
`Patent Owner argues that this case is closely analogous to Allergan,
`Inc. v. Sandoz Inc., 796 F.3d 1293, 1302 (Fed. Cir. 2015), in which the court
`addressed the obviousness of claims requiring specific amounts of about
`0.01% bimatoprost and about 200 ppm benzalkonium chloride (BAK) over
`prior art that generally taught a formulation comprising 0.001%–1%
`bimatoprost and 0–1000 ppm BAK. Prelim. Resp. 24–27. We agree that the
`issues are similar. In Allergan, the court reiterated the framework for
`evaluating obviousness in the context of a claimed invention falling within a
`broader range disclosed in the prior art:
`[W]here there is a range disclosed in the prior art, and the claimed
`invention falls within that range, a relevant inquiry is whether
`there would have been a motivation to select the claimed
`composition from the prior art ranges. . . . In those circumstances,
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`“the burden of production falls upon the patentee to come
`forward with evidence that (1) the prior art taught away from the
`claimed invention; (2) there were new and unexpected results
`relative to the prior art; or (3) there are other pertinent secondary
`considerations.”
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`796 F.3d at 1304–05 (quoting Galderma Labs., L.P. v. Tolmar, Inc., 737
`F.3d 731, 738 (Fed. Cir. 2013)).
`As discussed above, Petitioner’s evidence of obviousness, in
`accordance with Allergan, shifts the burden of production to Patent Owner
`to come forward with evidence of teaching away, unexpected results, or
`other secondary considerations. Patent Owner argues that increasing the
`amount of castor oil to 1.25% and cutting the amount of cyclosporin in half
`without loss of efficacy was not only unexpected, but counterintuitive to a
`person of ordinary skill in the art. Prelim. Resp. 26–27, 31–32. As support,
`Patent Owner points to results from pharmacokinetic (“PK”) experiments
`presented during prosecution as part of the Declarations of Dr. Rhett
`Schiffman and Dr. Mayssa Attar. Prelim Resp. 3 (citing Ex. 1023, 184–
`242); see also id. at 31–32. Patent Owner asserts that these results predicted
`that the claimed emulsion would have been less effective than the two
`emulsions disclosed in Ding ’979. According to Patent Owner, it was
`surprising that the claimed emulsion was “more effective than the
`0.05%/0.625%/1.00% emulsion and at least as effective as the
`0.1%/1.25%/1.00% emulsion.” Id. at 3.
`We have considered the declarations submitted during prosecution,
`but note that neither Dr. Schiffman nor Dr. Attar has been subject to cross-
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`examination in this proceeding. Moreover, Petitioner offers the declaration
`of Dr. Amiji, calling into question the alleged unexpected results based on
`the Schiffman and Attar Declarations. Ex. 1002 ¶¶ 131–155. At this
`preliminary stage, we determine that Petitioner has offered sufficient
`evidence to institute trial. That being said, we will be able to evaluate both
`parties’ arguments regarding secondary considerations more thoroughly
`once the record is developed further during trial.
`Patent Owner also argues that Sall would not have motivated a person
`of ordinary skill in the art to combine 0.05% cyclosporin with 1.25% castor
`oil. Prelim. Resp. 27–29. Contrary to Petitioner’s argument, Patent Owner
`asserts that a person of ordinary skill in the art would not have assumed that
`both the 0.05% and 0.10% cyclosporin emulsions in Sall would have
`contained the same amount of castor oil (i.e., 1.25%). Id. at 28. Rather,
`Patent Owner contends that a skilled artisan would have expected the
`emulsions to have the same ratio of cyclosporin to castor oil (i.e., 0.05%
`cyclosporin with 0.625% castor oil, and 0.10% cyclosporin with 1.25%
`castor oil). Id. On the current record, however, we determine that Petitioner
`has shown sufficiently that a skilled artisan reading Ding ’979 and Sall
`would have had a reason to formulate an emulsion with 0.05% cyclosporin
`A and 1.25% castor oil in light of the preferred cyclosporin to castor oil ratio
`taught by Ding ’979. Ex. 1006, 3:17–20.
`Patent Owner further argues that there was no reasonable expectation
`that increasing castor oil concentration would increase therapeutic efficacy.
`Prelim. Resp. 29–31. In particular, Patent Owner contends that Sall
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`distinguishes between therapeutic and palliative treatments, and that the
`vehicle is not responsible for the “clinically significant” effects observed.
`Id. at 29–30. Accordingly, Patent Owner asserts that a person of ordinary
`skill reading Sall would not have expected to achieve this level of efficacy
`by increasing the amount of castor oil relative to the amounts disclosed in
`Ding ’979. Id. at 30. Patent Owner’s argument, however, relies on its
`construction of “therapeutically effective” as excluding palliative treatments.
`As explained above, we decline to so limit the term. Accordingly, we are
`not persuaded by Patent Owner’s argument.
`Upon considering the arguments set forth in the Petition and
`Preliminary Responses, we determine that Petitioner has shown a reasonable
`likelihood that it would prevail in showing claim 1 is unpatentable as
`obvious over the combination of Ding ’979 and Sall. We have considered
`the parties’ arguments and evidence with respect to claims 2–16 and 21–27,
`and we determine that Petitioner has made a sufficient showing as to those
`claims, as well.
`D. Obviousness over Ding ’979, Sall, and Acheampong
`Petitioner also asserts that claims 1–16 and 21–27 are unpatentable as
`obvious over Ding ’979, Sall, and Acheampong. Pet. 43–44. Patent Owner
`opposes for the same reasons stated above. Prelim. Resp. 34. We
`incorporate here our findings and discussion above regarding the disclosure
`of Ding ’979 and Sall.
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`Acheampong (Ex. 1008)
`1.
`Acheampong describes a study by Patent Owner as part of its
`evaluation of the clinical efficacy of 0.05%–0.4% cyclosporin emulsion for
`the treatment of immuno-inflammatory eye diseases such as dry eye
`syndrome. Ex. 1008, 3–4. Acheampong describes the results of its research
`to determine the ocular tissue distribution of cyclosporin in rabbits and dogs,
`and to compare tissue concentrations in rabbits, dogs, and humans after
`topical administration. Id.
`In the study of humans, the subjects with dry eye disease received an
`eyedrop of vehicle or 0.05%, 0.1%, 0.2%, or 0.4% cyclosporin emulsions
`twice daily for 12 weeks. Id. at 4. Blood samples were collected from all
`subjects at morning troughs after 1, 4, and 12 weeks of dosing, and from
`certain subjects at 1, 2, and 4 hours after the last dose at week 12. Id.
`Acheampong found that the human blood cyclosporin A concentrations were
`less than 0.2 ng/ml for each emulsion, which is lower than the 20–100 ng/ml
`blood trough concentration used for monitoring the safety of patients
`receiving systemic cyclosporin therapy. Id. at 6.
`Analysis
`2.
`Independent claims 1 and 13 and dependent claims 12, 22, and 27
`recite that the method results in a CsA blood concentration that is
`substantially undetectable or below 0.1 ng/ml. Petitioner asserts that
`Acheampong teaches that CsA blood levels were substantially undetectable
`and below 0.1 ng/ml at both peak and trough levels after administration of
`an emulsion with 0.05% CsA. Pet. 43 (citing Ex. 1008, 1002; Ex. 1002 ¶
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`119). Petitioner further asserts that a person of ordinary skill in the art
`reading Acheampong and Sall would have had a reasonable expectation of
`success that when the 0.05% cyclosporin A emulsion is administered to the
`eye, there is “substantially no detectable concentration of cyclosporin A” in
`the blood. Id. at 44 (citing Ex. 1002 ¶ 120).
`In response, Patent Owner relies on the same reasoning given with
`respect to claims 1, 13, and 21. Prelim. Resp. 34. For the same reasons
`stated above, we are persuaded on the current record that Petitioner has
`demonstrated a reasonable likelihood that it would prevail in its assertion
`that claims 1–16 and 21–27 are unpatentable as obvious over the
`combination of Ding ’979, Sall, and Acheampong.
`E. Obviousness over Ding ’979, Sall, and Glonek
`Petitioner asserts that claims 17–20 are unpatentable as obvious over
`Ding ’979, Sall, and Glonek. Pet. 44–47. Patent Owner opposes for the
`same reasons stated with respect to claim 1 above. Prelim. Resp. 34. We
`incorporate here our findings and discussion above regarding the disclosure
`of Ding ’979 and Sall.
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`Glonek (Ex. 1009)
`1.
`Glonek relates to a composition for augmenting and maintaining a
`stable tear film over the ocular surface and delivering a medicine to the eye
`without causing substantial blurring of vision. Ex. 1009, 1:21–29. Glonek
`explains that an emulsion over the surface of the eye is expected to cause
`blurring, which is likely to occur until the emulsion differentiates. Id. at
`6:37–42. If the emulsion is too stable, excess emulsion will be discharged
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`from the eye. Id. at 6:42–44. Thus, Glonek states that it is preferred that an
`emulsion be stable for long term storage, but rapidly differentiate in the eye.
`Id. at 6:48–50.
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`Analysis
`2.
`Independent claim 17 recites the same emulsion as claims 1, 13, and
`21, but further recites that “the emulsion breaks down more quickly in the
`eye of a human, . . . thereby reducing vision distortion in the human eye as
`compared to a second topical ophthalmic emulsion that contains only 50% as
`much castor oil as the first topical ophthalmic emulsio