Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`
`Paper 8
`Entered: December 8, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`_______________
`
`Case IPR2016-01131
`Patent 8,648,048 B2
`_______________
`
`
`Before SHERIDAN K. SNEDDEN, TINA E. HULSE, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`Tel: 571-272-7822
`
`
`
`
`
`Paper 8
`Entered: December 8, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`ALLERGAN, INC.,
`Patent Owner.
`_______________
`
`Case IPR2016-01131
`Patent 8,648,048 B2
`_______________
`
`
`Before SHERIDAN K. SNEDDEN, TINA E. HULSE, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`SNEDDEN, Administrative Patent Judge.
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`IPR2016-01131
`Patent 8,648,048 B2
`
`I. INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) filed a Petition to institute
`an inter partes review of claims 1−23 (Paper 3; “Pet.”) of US 8,648,048 B2
`(Ex. 1001; “the ’048 patent”). Allergan, Inc. (“Patent Owner”) filed a Patent
`Owner Preliminary response. 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 consideration
`of the above-mentioned Petition and Preliminary Responses, we conclude
`that Petitioner has established that there is a reasonable likelihood that it will
`prevail with respect to at least one of the challenged claims. We institute an
`inter partes review as to claims 1−23 of the ’048 patent.
`Related Proceedings
`A.
`The parties indicate that the following judicial matter may affect or be
`affected by a decision in this proceeding: Allergan, Inc. v. Teva
`Pharmaceuticals USA, Inc., et al., No. 2:15-cv-01455 (E.D. Texas),
`Allergan, Inc., v. Innopharma, Inc. and Pfizer, Inc., No. 2:15cv1504 (E.D.
`Texas), and Allergan, Inc. v. Famy Care, Ltd., No. 2:16-cv-0401 (D. Texas).
`Pet. 12; Paper 6, 2.
`Moreover, Petitioner has sought inter partes review for related patents
`in the following proceedings: Case IPR2016-01127 (U.S. Patent No.
`8,685,930 B2), Case IPR2016-01128 (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 IPR2016-01132 (U.S. Patent No.
`9,248,191 B2).
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`B. The ’048 patent (Ex. 1001)
`The ’048 patent generally relates to methods of providing therapeutic
`effects using cyclosporin components, and more specifically to a
`formulation containing, inter alia, cyclosporin-A (“CsA”) and castor oil
`emulsions for treating dry eye syndrome (i.e., keratoconjunctivitis sicca).
`Ex. 1001, 2:55–3:11. According to the specification, the prior art recognized
`the use of emulsions containing CsA and CsA derivatives to treat ophthalmic
`conditions. Id. at 1:26–65. The specification notes, however, that “[o]ver
`time, it has been apparent that cyclosporin A emulsions for ophthalmic use
`preferably have less than 0.2% by weight of cyclosporin A.” Id. at 1:66–2:1.
`Moreover, if reduced amounts of CsA are used, reduced amounts of castor
`oil are needed because one of the functions of castor oil is to solubilize
`cyclosporin A. Id. at 2:1–2:6.
`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
`component provide substantial and advantageous benefits.” Id. at 2:35–38.
`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 effectiveness of the composition.
`Id. at 2:42–48. Furthermore, using reduced amounts of cyclosporin
`component mitigates against undesirable side effects or potential drug
`interactions. Id. at 2:48–51.
`The patent identifies two particular compositions that were selected
`for further testing, as shown below:
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`Id. at 14:15–30. Based on the results of a Phase III 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
`14:35–40. The patent indicates that “[t]his is surprising for a number of
`reasons.” Id. at 14:41. 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 14:41–44.
`Moreover, although the large amount of castor oil relative to the amount of
`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
`14:44–49. 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 15:4–8.
`
`C. Illustrative Claims
`
`Petitioner challenges claims 1–23 of the ’048 patent. Independent
`claims 1, 18, and 22 are illustrative of the challenged claims, and are
`reproduced below:
`1. A method of increasing tear production in the eye of a human,
`the method comprising topically administering to the eye of the
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`human in need thereof an emulsion at a frequency of twice a day,
`wherein the 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; and
`wherein the topical ophthalmic emulsion is effective in
`increasing tear production.
`
`18. A method of treating keratoconjunctivitis sicca, the method
`comprising the step of topically administering to an eye of a
`human in need thereof an emulsion at a frequency of twice a day,
`the emulsion comprising:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10−30 alkyl acrylate cross-polymer in an
`amount of about 0.05% by weight;
`a tonicity component or a demulcent component in an
`amount of about 2.2% by weight;
`a buffer; and
`water;
`treating
`in
`effective
`is
`emulsion
`the
`wherein
`keratoconjunctivitis sicca and wherein the topical ophthalmic
`emulsion has a pH in the range of about 7.2 to about 7.6.
`
`22. A method comprising:
`administering an emulsion topically to the eye of a human
`having keratoconjunctivitis sicca at a frequency of twice a day,
`wherein the emulsion comprises:
`cyclosporin A in an amount of about 0.05% by weight;
`castor oil in an amount of about 1.25% by weight;
`polysorbate 80 in an amount of about 1.0% by weight;
`acrylate/C10−30 alkyl acrylate cross-polymer in an
`amount of about 0.05% by weight;
`glycerine in an amount of about 2.2% by weight;
`sodium hydroxide; and
`water; and
`wherein the emulsion is effective in increasing tear
`production in the human having keratoconjunctivitis sicca.
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`Claims 2–17 depend from claim 1, either directly or indirectly.
`Claims 19–21 depend from claim 18, either directly or indirectly. Claim 23
`depend from claim 22, either directly or indirectly.
`
`D. The Asserted Grounds
`
`Petitioner challenges claims 1−23 of the ’048 patent on the following
`grounds. Pet. 17–18.
`Ground
`
`Reference[s]
`
`Basis
`
`Claims challenged
`1−10, 12−14, 16−20,
`22, and 23
`11 and 21
`
`1
`
`2
`
`3
`
`Ding ’979, 1 and Sall2
`Ding ’979, Sall, and
`Acheampong3
`Ding ’979, Sall, and
`Acheampong, and Glonek4
`Petitioner further relies on the Declarations of Dr. Mansoor Amiji,
`Ph.D. (Ex. 1002).
`
`§ 103
`
`§ 103
`
`§ 103
`
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`
`1 Ding et al., U.S. Patent No. 5,474,979, issued December 12, 1995 (Ex.
`1006, “Ding ’979”).
`2 Kenneth 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 631−639 (2000) (Ex. 1007, “Sall”).
`3 Andrew 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, in
`LACRIMAL GLAND, TEAR FILM, AND DRY EYE SYNDROMES 2, BASIC SCIENCE
`AND CLINICAL RELEVANCE, 1001−1004 (1998) (Ex. 1008, “Acheampong”).
`4 Glonek et al., U.S. Patent No. 5,578,586, issued Nov. 26, 1996. Ex. 1009
`(“Glonek”).
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`II. ANALYSIS
`A. Claim Interpretation
`
`We interpret claims using the “broadest reasonable construction in
`light 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, 2144–46
`(2016). Under the broadest reasonable construction standard, claim terms
`are generally given 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) (quoting
`Phillips v. AWH Corp, 415 F.3d 1303, 1312 (Fed. Cir. 2006)). “Absent
`claim language carrying a narrow meaning, the PTO should only limit the
`claim based on the specification . . . when [it] expressly disclaim[s] the
`broader definition.” In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004)
`(citation omitted). “Although an inventor is indeed free to define the
`specific terms used to describe his or her invention, this must be done with
`reasonable clarity, deliberateness, and precision.” In re Paulsen, 30 F.3d
`1475, 1480 (Fed. Cir. 1994).
`1. “effective in treating”
`Claims 1–17 and 22–23 recite that the emulsion is “effective in
`increasing tear production,” whereas claims 18–21 recite an emulsion that is
`“effective in treating keratoconjunctivitis sicca.” The dependent claims
`recite other variations such as an emulsion that is “substantially
`therapeutically effective as a second emulsion” or achieves “at least as much
`therapeutic effectiveness as a second emulsion.”
`Petitioner asserts that because the plain meaning of the word
`“therapeutic” includes palliative as well as curative treatments, the broadest
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`reasonable interpretation of the terms includes “an emulsion that is effective
`in increasing tear production is an example of an emulsion therapeutically
`effective in treating dry eye disease/KCS” palliative and curative treatments.
`Pet. 14–15 (citing Ex. 1002 ¶¶ 41–44; Ex. 1022, 3, 7)
`Patent Owner argues that an emulsion that is “effective in treating
`keratoconjunctivitis sicca” must treat the disease itself, and not just its
`symptoms. Prelim. Resp. 21–23. Patent Owner also argues that the inability
`to produce tears is a hallmark of dry eye disease and that an emulsion that is
`“effective in increasing tear production” must address the inability to
`produce natural tears, as opposed to supplementing with artificial tears. Id.
`at 21–22. According to Patent Owner, 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 Ex. 2005). Patent Owner contrasts this definition of “therapeutic”
`with the definition of “palliative,” defined as “[r]educing the severity of;
`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.3 (citing Ex. 2007).
`We disagree. The definition of “therapeutic” provided by the Patent
`Owner does not require a cure of a disease or disorder, but also includes
`either treatment or remediating of a disease or disorder; a cure is not
`necessarily required. We thus conclude, on the current record, that the
`ordinary meaning of the phrase “therapeutically effective” is not so specific
`so as to exclude palliative effects.
`Patent Owner further argues that the specification supports its
`construction because the ’048 patent uses the word “therapeutic” in
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`connection with the action of cyclosporin. Id. at 22. Patent Owner further
`argues that “the ’048 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, 9:50–55 (emphasis added). Thus, notwithstanding Patent Owner’s
`extrinsic evidence it offers in support of its more-limited construction
`(Prelim. Resp. 21–23), we decline to construe the claims in a manner
`inconsistent with the specification.
`That being said, at this stage of the proceeding, we find that “effective
`in increasing tear production” does not require further construction as its
`meaning is clear on its face. We also find that “effective in treating
`keratoconjunctivitis sicca” encompasses both the treatment of the symptoms
`of dry eye disease as well as the disease itself.
`2. Remaining Claim Terms
`We determine that no explicit construction of any claim term is
`necessary to determine whether to institute a trial in this case. See, e.g.,
`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)).
`At this stage of the proceeding, we have not made a final
`determination as to the construction of any claim term.
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`B. Principles of Law
`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.” 35 U.S.C. § 314(a). To
`prevail in its challenges to the patentability of the claims, a petitioner must
`establish facts supporting its challenges by a preponderance of the evidence.
`35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`We analyze the proposed grounds of unpatentability in accordance
`with the following stated principles.
`A patent may not be obtained if the differences between the subject
`matter sought to be patented and the prior art are such that the subject matter
`as a whole would have been obvious at the time the invention was made to a
`person having ordinary skill in the art to which the subject matter pertains.
`35 U.S.C. § 103(a). The legal question of obviousness is resolved on the
`basis of underlying factual determinations, including: (1) the scope and
`content of the prior art; (2) any differences between the claimed subject
`matter and the prior art; (3) the level of skill in the art; and (4) objective
`evidence of nonobviousness, i.e., secondary considerations. See Graham v.
`John Deere Co., 383 U.S. 1, 17–18 (1966).
`In KSR International Co. v. Teleflex Inc., the Supreme Court stated
`that an invention may be found obvious if trying a course of conduct would
`have been obvious to a person having ordinary skill:
`
`When there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this leads
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`to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
`550 U.S. 398, 421 (2007). “KSR affirmed the logical inverse of this
`statement by stating that § 103 bars patentability unless ‘the improvement is
`more than the predictable use of prior art elements according to their
`established functions.’” In re Kubin, 561 F.3d 1351, 1359−60 (Fed. Cir.
`2009) (citing KSR, 550 U.S. at 417).
`The factual inquiries for an obviousness determination also include
`secondary considerations based on evaluation and crediting of objective
`evidence of nonobviousness. Graham, 383 U.S. at 17−18. 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 with ordinary skill in the art. In re Piasecki, 745 F.2d 1468, 1471–72
`(Fed. Cir. 1984).
`Such a conclusion, however, requires the finding of a nexus to
`establish that the evidence relied upon traces its basis to something novel in
`the claim and not to something in the prior art. Institut Pasteur & Universite
`Pierre et Marie Curie v. Focarino, 738 F.3d 1337, 1347 (Fed. Cir. 2013).
`Generally, objective evidence of nonobviousness must be shown to have a
`nexus. In re GPAC Inc., 57 F.3d 1573, 1580 (Fed. Cir. 1995) (nexus
`generally); In re Kao, 639 F.3d 1057, 1069 (Fed. Cir. 2011) (unexpected
`results); In re Huang, 100 F.3d 135, 140 (Fed. Cir. 1996) (commercial
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`success); Rambus Inc. v. Rea, 731 F.3d 1248, 1256 (Fed. Cir. 2013) (long-
`felt need).
`Objective evidence of nonobviousness also must be reasonably
`commensurate in scope with the claim. Kao, 639 F.3d at 1068. This does
`not mean that the proffered evidence must reach every embodiment within
`the scope of the claim, so long as there is an “adequate basis to support the
`conclusion that other embodiments falling within the claim will behave in
`the same manner.” Id.
`
`C. Content of the Prior Art
`Petitioner relies upon the following prior art in its challenges.
`1. Ding ’979 (Ex. 1006)
`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
`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
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`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 CsA 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:
`
`
`
`Id. at 4:32–43. Example 1 identifies compositions A through E, which
`contain varying amounts of CsA, castor oil, polysorbate 80, Pemulen®(an
`acrylate/C10-30 alkyl acrylate cross-polymer) (id. at 4:1–5), glycerine,
`sodium hydroxide, and purified water at a pH range of 7.2–7.6. Id. at 4:32–
`43. According to Ding ’979, the formulations of Example 1 was “made for
`treatment of keratoconjunctivitis sicca (dry eye) syndrome.” Id. at 5:10–12.
`2. Sall (Ex. 1007)
`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 CsA 0.05% or 0.1% ophthalmic emulsions or vehicle for six months.
`Ex. 1007, Abstract, 631. The study sought to compare the efficacy and
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`safety of CsA 0.05% and 0.1% to vehicle in patients with moderate to severe
`dry eye disease. Id. Sall found that “topical treatment with either CsA
`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 CsA 0.05% resulted in significantly greater
`improvements in several subjective parameters. Id. Sall also found that
`trough blood concentrations of CsA were undetectable in all samples of CsA
`0.05%, whereas CsA was quantifiable in only six samples for six different
`patients in the CsA 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.
`3. Acheampong (Ex. 1008)
`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, 1001. 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 1002. Blood samples were collected from
`all subjects at morning troughs after 1, 4, and 12 weeks of dosing, and from
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`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.
`4. Glonek (Ex. 1009)
`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
`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.
`
`D. Asserted Grounds of Unpatentability
`
`1. Obviousness of Claims 1−10, 12−14, 16−20, 22, and 23
`Based on Ding ’979 and Sall
`Petitioner contends that claims 1−10, 12−14, 16−20, 22, and 23 are
`rendered obvious by the combined teachings of Ding ’979 and Sall. Pet. 22–
`40. Petitioner sets forth the foregoing teachings of Ding ’979 and Sall and
`provides a detailed discussion and claim charts explaining how each claim
`limitation of the challenged claims is disclosed in Ding ’979 and/or Sall. Id.
`The issue before us is whether it would have been obvious to use the
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`particular concentrations of 0.05% CsA and 1.25% castor oil recited in the
`challenged claims. Id.
`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. Petitioner contends, however, Sall “provides a strong rationale to
`deliver 0.05% CsA using the 1.25% castor oil vehicle taught by Ding ’979
`(Example 2C).” Pet. 31. Petitioner contends that Sall teaches that either the
`0.05% or 0.10% CsA emulsion is therapeutically effective in increasing tear
`production and treating dry eye disease/KCS. Id. (citing Ex. 1007, 632, 638;
`EX1002 ¶¶ 83, 106). Petitioner contends that Sall discloses that the vehicle
`used in the study reported in Sall (castor oil) “contributed to the overall
`improvements observed in all treatment groups in this study.” Id. Petitioner
`further contends that:
`
`The 1.25% castor oil vehicle is the only vehicle from Ding
`ʼ979 Example 2 for which both 0.05% and 0.10% CsA have a
`ratio of CsA-to-castor oil inside Ding ’979’s more preferred
`range of between 0.12 and 0.02 (id. at 3:17-20) and also within
`the ratio range found with each of the Example 1 emulsions
`(0.04-0.08).
`Id. at 31 (citing Ex. 1006, 3:17–20). Finally, Petitioner provides the
`following rationale for combining Ding ’979 and Sall:
`
`In light of Ding ’979 and Sall, a person of ordinary skill in
`the art would have had a reasonable expectation that this
`emulsion would be effective in treating KCS and in increasing
`tear production (including in a human with KCS). EX1002,
`¶109. As explained by Dr. Amiji, it would have been a routine
`matter for a skilled artisan to make and then confirm the efficacy
`of the emulsion comprising 1.25% castor oil and 0.05% CsA.
`
`16
`
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`IPR2016-01131
`Patent 8,648,048 B2
`
`
`EX1002, ¶109; EX1001, 14:14–16 (“These compositions are
`produced in accordance with well known techniques[.]”).
`Id. at 32.
`
`Patent Owner argues in its Preliminary Response that this case is
`closely analogous to Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293 (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. 24–37. 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, “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.”
`796 F.3d at 1304–5 (citation omitted) (quoting Galderma Labs., L.P. v.
`Tolmar, Inc., 737 F.3d 731, 737–38 (Fed. Cir. 2013)).
`
`Upon consideration of the arguments set forth in the Petition and
`Preliminary Responses, we conclude that Petitioner has shown a reasonable
`likelihood that a skilled artisan would have found it obvious to optimize the
`castor oil concentration in the emulsion to reach the claimed amount of
`1.25% by balancing the need to minimize any undesirable effects associated
`with castor oil used at an excessive concentration with the desire to take
`
`17
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`IPR2016-01131
`Patent 8,648,048 B2
`
`advantage of the “substantial palliative benefits” of castor oil for the
`treatment of dry eye. Prelim. Resp. 29 (citing Ex. 1007, 8). See 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.”); In re Boesch, 617 F.2d
`272, 276 (CCPA 1980) (“[D]iscovery of an optimum value of a result
`effective variable in a known process is ordinarily within the skill of the
`art.”).
`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. As evidence of unexpected results, Patent Owner points to
`data presented as part of the Declarations of Dr. Rhett Schiffman and Dr.
`Mayssa Attar, which were submitted during prosecution. Prelim Resp.
`15−17, 20−21. Patent Owner asserts that these data “show[ed] that the
`claimed emulsions . . . performed better than the Ding ‘979 emulsions
`containing 0.05% cyclosporin/0.625% castor oil, and at least as well as the
`Ding ‘979 emulsions containing 0.10% cyclosporin/1.25% castor oil, despite
`PK data that predicted the opposite should have been true.” Id. at 31–32.
`We have considered the declarations submitted during prosecution, but note
`that neither Dr. Schiffman nor Dr. Attar has yet been subject to cross-
`examination in this proceeding.5 At this preliminary stage, we determine
`
`
`5 Routine discovery in an inter partes review includes “the deposition of
`witnesses submitting affidavits or declarations.” See 35 U.S.C.
`§ 316(a)(5)(A).
`
`18
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`IPR2016-01131
`Patent 8,648,048 B2
`
`that it is more appropriate to allow further evidence regarding any alleged
`unexpected results or other secondary considerations to be developed during
`trial.
`Patent Owner further argues that there was no reasonable expectation
`that increasing castor oil concentration would increase therapeutic efficacy.
`Id. at 29–31. In particular, Patent Owner contends that Sall distinguishes
`between therapeutic and palliative treatments, and that the vehicle is not
`responsible for the “clinically significant” effects observed. Id. at 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.
`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.
`Thus, based on the arguments presented and evidence of record, we
`determine that Petitioner has demonstrated a reasonable likelihood that
`claims 1−10, 12−14, 16−20, 22, and 23 are obvious over the teachings of
`Ding ’979 and Sall.
`2. Obviousness of Claims 11 and 21 Based on Ding ’979, Sall,
`and Acheampong
`Petitioner asserts that claims 11 and 21 are unpatentable as obvious
`over Ding ’979, Sall, and Acheampong. Pet. 45–47. Patent Owner opposes
`for the same reasons stated with respect to claims 1 and 18 above. Prelim.
`
`19
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`IPR2016-01131
`Patent 8,648,048 B2
`
`Resp. 34. We incorporate here our findings and discussion above regarding
`the teachings of Ding ’979 and Sall.
`Claims 11 and 21 depend directly from claims 1 and 18 and further
`recite as follows: “wherein, when the emulsion is administered to the eye of
`a human in an effective amount in treating keratoconjunctivitis sicca, the
`blood of the human has substantially no detectable concentration of the
`cyclosporin A.” Petitioner asserts that Acheampong teaches that an
`emulsion with 0.05% CsA resulted in no detectable CsA in the blood, even
`at the maximum time point. Pet. 41−42 (citing Ex. 1008, 6 (Table 1); Ex.
`1002 ¶ 120). Petitioner further asserts that “Acheampong and Sall together
`provide one of ordinary skill in the art with a reasonable expectation of
`success that when the 0.05% CsA emulsion is administered to the eye there
`is ‘substantially no detectable concentration of cyclosporin A’ in the blood.”
`Id. at 41 (citing Ex. 1002 ¶ 121).
`Based on the arguments pres
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