UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner
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`v.
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`ALLERGAN, INC.
`Patent Owner
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`Case IPR2016-01131
`Patent 8,648,048
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`PATENT OWNER ALLERGAN, INC.’S
`PRELIMINARY RESPONSE
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`

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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`TABLE OF CONTENTS
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`
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`I. INTRODUCTION ....................................................................................... 1
`II. BACKGROUND OF THE ‘048 PATENT ................................................ 7
`A. Dry Eye Disease is a Serious Disease .................................................... 7
`B. Palliative Treatments Only Alleviate the Symptoms of Dry Eye
`Disease ......................................................................................................... 8
`C. Allergan’s Development of RESTASIS® .............................................. 9
`III. THE ‘048 PATENT ................................................................................ 10
`A. It was counterintuitive to combine 0.05% cyclosporin with a vehicle
`containing 1.25% castor oil ....................................................................... 11
`1. Castor oil is cytotoxic and an irritant ................................................. 11
`2. Increasing the amount of castor oil in the emulsion would be
`expected to reduce the thermodynamic activity of the emulsion .......... 12
`3. PK data predicted 0.05% cyclosporin/1.25% castor oil would be
`less effective than 0.05% cyclosporin/0.625% castor oil and 0.10%
`cyclosporin/1.25% castor oil .................................................................. 13
`B. During prosecution the Examiner agreed that the performance of the
`claimed emulsion relative to the Ding ‘979 patent emulsions was
`unexpected ................................................................................................. 17
`IV. ARGUMENT .......................................................................................... 19
`A. An emulsion that is “therapeutically effective” must treat the
`underlying disease ..................................................................................... 21
`B. Claims 1-10, 12-14, 16-20, and 22-23 would not have been obvious
`over Ding ‘979 plus Sall ............................................................................ 24
`1. The inventors proceeded contrary to the teachings of the prior art
`and developed an emulsion that has surprising therapeutic efficacy
`against dry eye disease ........................................................................... 24
`2. Sall would not have motivated a person of ordinary skill to prepare
`an emulsion containing 0.05% cyclosporin and 1.25% castor oil ......... 27
`3. There was no reasonable expectation that increasing castor oil
`concentration would increase therapeutic efficacy ................................ 29
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`4. The differences between the claimed emulsion and the Ding ‘979
`emulsions are differences in kind, not degree ....................................... 31
`5. Allergan did not admit that the claims were unpatentable ................ 32
`C. Claims 11 and 21 would not have been obvious over Ding ‘979 plus
`Sall plus Acheampong ............................................................................... 34
`D. Claim 15 would not have been obvious over Ding ‘979 plus Sall plus
`Glonek. ...................................................................................................... 34
`V. CONCLUSION ........................................................................................ 34
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
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`LIST OF EXHIBITS
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`EX. 2002
`EX. 2003
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`Exhibit No. Description
`EX. 2001
`NDA 21-023 Cyclosporine Ophthalmic Emulsion 0.05%, Original
`NDA Filing, Vol. 1 (Feb. 24, 1999)
`U.S. Pat. No. 4,839,342
`Said et al., Investigative Ophthalmology & Visual Science, vol. 48,
`No. 11 (Nov. 2007):5000-5006
`Alba et al., Folia Ophthalmol. Jpn. 40:902-908 (1989)
`Stedman’s Medical Dictionary, definition of therapeutic
`Dorland’s Illustrated Medical Dictionary, definition of therapeutic
`Stedman’s Medical Dictionary, definition of palliative
`RESTASIS® label
`Murphy, R., “The Once and Future Treatment of Dry Eye,” Review
`of Optometry, pp. 73-75 (Feb. 15, 2000)
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`EX. 2004
`EX. 2005
`EX. 2006
`EX. 2007
`EX. 2008
`EX. 2009
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
`Allergan, Inc. v. Sandoz Inc.,
`No. 2014-1275, slip op. (Fed. Cir. Aug. 4, 2015) ............................ passim
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`Arkie Lures, Inc. v. Gene Larew Tackle, Inc.,
`119 F.3d 953 (Fed. Cir. 1997) ................................................................. 38
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ................................................................. 24
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ............................................................................. 22
`
`In re Cyclobenzaprine Hydrochloride Extended-Release
`Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ............................................................... 35
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`Galderma Laboratories L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013), explained .......................................... 31, 39
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`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ............................................................... 24
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`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ............................................................... 22
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`Verdegaal Bros. v. Union Oil Co. of California,
`814, F.2d 628, 631 (Fed. Cir. 1987) ........................................................ 24
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`Other Authorities
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`37 C.F.R. ....................................................................................................... 22
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`37 CFR §§ 42.6(e)(4) and 42.205(b) ............................................................ 43
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`Case IPR2016-01131
`Attorney Docket No: 13351-0008IP5
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`I.
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`INTRODUCTION
`U.S. Patent No. 8,648,048 (“the ‘048 patent”) covers Allergan’s
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`RESTASIS® medication for treating a serious eye condition known as dry eye
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`disease. Keratoconjunctivitis sicca (“KCS”) is a type of dry eye disease. Allergan
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`has five other Orange Book-listed patents that cover RESTASIS® and its use, each
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`of which is the subject of an IPR petition that Mylan filed.1
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`RESTASIS® is the only prescription medication indicated for treating the
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`underlying disease itself, as opposed to relieving symptoms of the disease. See
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`EX. 2008 (RESTASIS® label), p. 1; EX. 1007 (Sall), p. 8 (“[T]here is currently no
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`therapeutic treatment for dry eye disease. The only treatments available are
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`palliative in nature and provide insufficient relief for many patients”).
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`RESTASIS® is a therapeutic emulsion that contains 0.05% by weight cyclosporin
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`A in a liquid vehicle that includes 1.25% by weight castor oil, polysorbate 80, and
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`other excipients. EX. 2008, pp. 3-4; EX. 2001, p. 256. Cyclosporin is an
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`immunosuppressant that, when delivered to the eye, suppresses the inflammatory
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`processes underlying dry eye disease. EX. 1007 (Sall), pp. 1-2. The distinction
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`between treating the disease itself—i.e., therapeutic treatment—versus merely
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`relieving symptoms—i.e., palliative treatment—is important for purposes of this
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`1 The other 5 patents are U.S. Patent Nos. 8,633,162; 8,642,556; 8,629,111;
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`8,685,930; and 9,248,191.
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`Case IPR2016-01131
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`IPR proceeding.
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`Although Mylan refers to the “therapeutic effect” of castor oil in the petition,
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`see, e.g., Petition at pp. 20-21, castor oil has no therapeutic effect because it does
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`not treat the disease itself. Cyclosporin is the only therapeutic agent present in
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`RESTASIS®. However, because cyclosporin has limited solubility in water, it is
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`necessary to combine it with a lipophilic material, such as castor oil, in a vehicle to
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`deliver it to the eye. See EX. 1006 (Ding ‘979), 1:40-53.
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`Castor oil was known to irritate the sensitive tissues of the eye and the
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`conventional teaching was to limit its use in ophthalmic formulations. See, e.g.,
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`id., 3:43-48. Allergan’s prior art Ding ‘979 patent, however, disclosed that
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`combining castor oil with an emulsifier and dispersing agent such as polysorbate
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`80, along with other excipients, could reduce the irritation potential of an emulsion
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`vehicle using castor oil. Id., 3:49-53. When cyclosporin was added to a vehicle
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`formulated in this way, the resulting composition exhibited reasonably high
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`thermodynamic activity, yet avoided the cyclosporin crystallizing and precipitating
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`out of the vehicle. Id., 3:21-28; 3:58-63. But even in these emulsions, the castor
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`oil remains a component in the vehicle used to deliver the therapeutic agent—the
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`cyclosporin—to tissues of the eye.
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` The claims of the ‘048 patent recite the specific combination of 0.05%
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`cyclosporin/1.25% castor oil/polysorbate 80 found in RESTASIS®. This
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`particular combination is unique and has unexpected therapeutic effect against dry
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`eye disease relative to emulsions containing 0.05% cyclosporin/0.625% castor
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`oil/polysorbate 80 and 0.10% cyclosporin/1.25% castor oil/polysorbate 80. The
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`latter two emulsions are disclosed in Allergan’s Ding ‘979 patent (EX. 1006, 4:30-
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`45, Example 1, compositions D and E), over which the Examiner rejected the
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`claims during the original prosecution of the ‘048 patent.
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`The Ding ‘979 patent is the closest prior art to the ‘048 patent. During
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`prosecution of the ‘048 patent, Allergan presented the results of pharmacokinetic
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`(“PK”) experiments comparing the claimed emulsion to the two emulsions
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`disclosed in the Ding ‘979 patent. EX. 1004, pp. 240-258 (Response to Office
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`Action dated 10/11/13; Declaration of Dr. Rhett Schiffman, pp. 261-64, ¶¶ 9-20;
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`Declaration of Dr. Mayssa Attar, pp. 286-89, ¶¶ 6-14). The PK experiments
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`predicted that on the basis of bioavailability, the claimed emulsion would have
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`been less effective than the two emulsions disclosed in the Ding ‘979 patent. Id.
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`Surprisingly, however, the claimed emulsion was more effective than the
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`0.05%/0.625%/1.00% emulsion and at least as effective as the 0.1%/1.25%/1.00%
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`emulsion. Id.
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`The claimed emulsion cut the amount of cyclosporin in half without loss of
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`efficacy. This feature is particularly advantageous because cyclosporin has been
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`known to cause serious liver and kidney damage. See EX. 2002, 3:59-66.
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`Moreover, it was achieved by doubling the amount of castor oil relative to the
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`composition in the Ding ‘979 patent that contained 0.05% cyclosporin, a choice
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`that was counterintuitive given that castor oil was cytotoxic and known to irritate
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`patients’ eyes. See, e.g., EX. 2003 (Said et al.), p. 1 (“Castor oil is the commonly
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`used lipophilic vector but has been shown to be cytotoxic”); EX. 2004 (Alba et al.),
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`p. 7 (describing “significant corneal edema” associated with castor oil when used
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`as a vehicle for cyclosporin).
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`The natural inclination of a person of skill in the art would have been to use
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`the minimum amount of castor oil necessary to dissolve the cyclosporin. In the
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`case of 0.05% cyclosporin, that amount would have been no greater than the
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`0.625% amount of castor oil that the Ding ‘979 patent used and described as
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`reducing the irritation associated with the cyclosporin while maintaining
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`reasonably high thermodynamic activity. Using more castor oil would be expected
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`to possibly increase irritation and reduce thermodynamic activity.
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` The Examiner allowed the claims over the Ding ‘979 patent on the basis of
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`these surprising results. EX. 1004, pp. 468, 473. Mylan now asks the Board to re-
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`visit the patentability of the ‘048 patent claims over the very same Ding ‘979
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`patent. But Mylan offers no credible evidence to rebut the surprising results on
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`which the Examiner relied when she allowed the claims. Neither Mylan nor its
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`expert, Dr. Amiji, compares the observed results with what the PK experiments
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`would have predicted based upon bioavailability. These PK experiments provide
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`the baseline for judging unexpected results.
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`Mylan wrongly argues that any improvement would have been expected due
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`to the “therapeutic benefits” of castor oil. See EX. 1002 (Amiji Decl’n), ¶¶ 143-
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`44; Petition, pp. 20-21. But castor oil has no therapeutic effect on dry eye disease.
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`Cyclosporin is responsible for the therapeutic effect and must be delivered from
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`the lipophilic vehicle into the ophthalmic tissue.
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`Mylan further alleges that the Sall paper (EX. 1007) would have motivated a
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`person of ordinary skill to combine 0.05% cyclosporin with 1.25% castor oil. See
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`EX. 1002 (Amiji Decl’n), ¶¶ 105-07; Petition, pp. 29-32. Sall concludes that
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`emulsions containing both 0.05% and 0.1% cyclosporin were “safe and effective.”
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`EX. 1007 (Sall), p. 1. However, Sall does not disclose the amount of castor oil,
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`polysorbate 80, and other excipients in each “proprietary” vehicle with which the
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`cyclosporin was combined.
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`Mylan admits that Sall does not disclose the amount of castor oil,
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`polysorbate 80, and other excipients in each “proprietary vehicle.” See EX. 1002
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`(Amiji Decl’n), ¶ 105; Petition, pp. 8, 28. However, Mylan argues that because
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`Sall discloses both 0.05% cyclosporin and 0.10% cyclosporin in a common
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`vehicle, each vehicle necessarily contained the same amount of castor oil. EX.
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`1002 (Amiji Decl’n), ¶ 106; Petition, p. 31. Mylan then argues both the 0.05%
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`cyclosporin emulsion and the 0.10% cyclosporin emulsion would have contained
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`1.25% castor oil because “[t]he 1.25% castor oil vehicle is the only vehicle from
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`Ding ‘979 Example 2 for which both 0.05% and 0.10% CsA have a ratio of CsA-
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`to-castor oil inside Ding ‘979’s more preferred range of between 0.12 and 0.02 …
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`and also within the ratio range found with each of the Example 1 emulsions (0.04-
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`0.08).” Petition, pp. 31-32; EX. 1002 (Amiji Decl’n), ¶ 107.
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` Mylan’s argument fails. The art, including Ding ‘979 itself, would have
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`taught persons of ordinary skill that the emulsions in Sall would have had the same
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`ratio of cyclosporin to castor oil, rather than the same amount of castor oil. A
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`person of ordinary skill would have recognized that using the same ratio would
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`achieve the goal of selecting the minimum amount of cytotoxic castor oil needed to
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`dissolve the cyclosporin. This means that the 0.05% cyclosporin emulsion would
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`have contained 0.625% castor oil and the 0.10% cyclosporin emulsion would have
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`contained 1.25% castor oil because in both cases the cyclosporin to castor oil ratio
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`is 0.08. Example 1 of the Ding ‘979 patent describes these very two emulsions.
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`Nowhere does the Ding ‘979 patent describe an emulsion having 0.05%
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`cyclosporin and 1.25% castor oil.
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`The PK data that the Examiner considered during prosecution predicted that
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`emulsions with 0.05% cyclosporin/0.625% castor oil would be more effective than
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`emulsions with 0.05% cyclosporin/1.25% castor oil. Moreover, as noted above,
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`castor oil was known to be cytotoxic and irritating. Both points are consistent with
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`the Ding ‘979 patent, where the only example of an emulsion with 0.05%
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`cyclosporin included 0.625% castor oil. Therefore, a person of ordinary skill
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`reading Sall logically would have used 0.05% cyclosporin with 0.625% castor
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`oil—not 1.25%. The inventors’ decision to use 1.25% castor oil was
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`counterintuitive and produced an emulsion that was surprisingly effective.
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` Mylan’s petition merely recycles references and grounds raised during the
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`original prosecution, but offers no credible new evidence that would compel a
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`different conclusion. Mylan’s petition, therefore, fails to establish a reasonable
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`likelihood that at least one claim of the ’048 patent is unpatentable. Accordingly,
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`Allergan requests that the Board deny the petition.
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`II. BACKGROUND OF THE ‘048 PATENT
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`A. Dry Eye Disease is a Serious Disease
`Dry eye disease is a serious ocular disease that afflicts millions of patients.
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`Indeed, it is one of the most common patient complaints treated by
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`ophthalmologists. It is estimated that it affects millions of people worldwide. EX.
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`1007 (Sall), pp. 1-2; EX. 1015 (Stevenson), pp. 1-2. Dry eye disease is not simply
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`occasionally feeling eye dryness; it is a serious condition that can substantially
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`impact the quality of life in patients who have it. Patients who suffer from dry eye
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`disease generally experience symptoms such as ocular discomfort, which can
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`include a dry, gritty feeling in the eye and foreign body sensation; burning;
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`irritation; photophobia; and blurred vision. Id. Severe dry eye disease can also
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`lead to an inability to produce tears and an increased risk of ocular surface damage
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`and ocular infection. Id.
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`Palliative Treatments Only Alleviate the Symptoms of Dry Eye
`Disease
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`B.
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` Dry eye disease is the result of an underlying inflammatory process.
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`Conventional medications for dry eye disease, though, do not affect these
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`underlying processes, and thus do not treat dry eye. Rather, they merely provide
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`palliative relief in the form of tear replacement or eye lubrication. EX. 1007 (Sall),
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`pp. 1-2; EX. 1015 (Stevenson), pp. 2-3.
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`Prior to the filing date of the ‘048 patent, a number of palliative treatments
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`for dry eye were known. Examples included artificial tear formulations, punctal
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`plugs, and topical steroids. EX. 2009, pp. 2-3. Emulsions comprising admixtures
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`of polysorbate 80 and oils such as castor oil, corn oil, sunflower oil, and light
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`mineral oil were also known to provide palliative relief. EX. 1010 (Ding ‘607),
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`3:41-48. For example, the Ding ‘607 patent describes the ability of these
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`emulsions, when applied to the surface of the eye, to form a film that remained in
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`place and “retard[ed] water evaporation from the eye which alleviates dry eye
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`symptoms.” Id., 3:66 to 4:3. As the Ding ‘607 patent notes, these treatments were
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`palliative—they alleviated dry eye symptoms, but did not treat the disease itself.
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`C. Allergan’s Development of RESTASIS®
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`RESTASIS® is formulated as an emulsion of 0.05% by weight cyclosporin
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`A, 1.25% by weight castor oil, and 1% by weight polysorbate 80, along with other
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`excipients. EX. 2008, pp. 3-4; EX. 2001, p. 256. RESTASIS® is different from
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`any other drug prescribed for dry eye disease. Its active ingredient, cyclosporin A,
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`is a drug with immunomodulatory and anti-inflammatory properties. EX. 1007
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`(Sall), pp. 1-2. Unlike other dry eye medications—which relieve the symptoms of
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`dry eye disease, but do not treat it—RESTASIS® actually affects the underlying
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`processes that are thought to lead to dry eye disease. In other words, it treats the
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`disease rather than just relieving the symptoms. See EX. 2008, p. 1.
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`In late 2002, FDA approved RESTASIS®, the first prescription ophthalmic
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`emulsion ever approved, “to increase tear production in patients whose tear
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`production is presumed to be suppressed due to ocular inflammation associated
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`with keratoconjunctivitis sicca.” EX. 2008, p. 1. RESTASIS® remains the only
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`product approved by FDA that increases the eye’s production of natural tears, even
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`12 years after its original approval and despite a substantial commercial incentive
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`for developing dry eye treatments. See id.
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`III. THE ‘048 PATENT
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`The ‘048 patent is one of several patents covering Allergan’s RESTASIS®
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`medication and its use to treat conditions such as dry eye disease. It contains 23
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`claims, each directed towards a method of increasing tear production or treating
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`keratoconjunctivitis sicca by administering to a patient’s eye an ophthalmic
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`emulsion that includes 0.05% by weight cyclosporin A, 1.25% by weight castor
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`oil, and polysorbate 80. Claim 1 is representative. It recites:
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`1. A method of increasing tear production in the eye of a
`human, the method comprising topically administering to the eye of
`the 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.
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`This is the formulation of RESTASIS® and its FDA-approved use for
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`increasing tear production. Independent claim 18 is similar to claim 1 but recites
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`treating keratoconjunctivitis sicca and requires that the emulsion be effective in
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`treating this condition. Independent claim 22 recites administering the emulsion to
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`the eye of a human having keratoconjunctivitis sicca and requires that the emulsion
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`be effective in increasing tear production in this human.
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`It was counterintuitive to combine 0.05% cyclosporin with a
`vehicle containing 1.25% castor oil
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`The claims reflect the inventors’ discovery that emulsions containing 0.05%
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`cyclosporin A in a vehicle containing 1.25% castor oil, polysorbate 80, and
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`acrylate/C10-30 alkyl acrylate cross-polymer were surprisingly effective, measured
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`by standard ophthalmic criteria, for treating dry eye disease relative to emulsions
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`containing twice as much cyclosporin or half as much castor oil described in the
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`prior art Ding ‘979 patent. These results were surprising for a number of reasons.
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`1.
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`Castor oil is cytotoxic and an irritant
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`Prior to the filing date of the ‘048 patent, castor oil was known to be
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`cytotoxic and an irritant. For example, one group of researchers wrote (EX. 2003
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`(Said et al.), p. 1):
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`Castor oil, which mainly contains ricinoleic acid (90% of total
`fatty acid content), is one of the lipophilic vehicles used in
`cyclosporine eye drops. However, it presents both a low-stability and
`an epithelial and conjunctival toxicity as well as systemic adverse
`effects such as purgative effects, hypersensitivity, nephrotoxicity, and
`neurotoxicity. Since castor oil is presumed to be responsible for
`cytotoxic effects in the eye, its replacement by another lipophilic
`vector could result in better tolerance of the drops.
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`These researchers then investigated four other vegetable oils as replacements for
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`castor oil. Id. Similarly, a different group noted that there was “significant corneal
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`edema” associated with castor oil when used as a vehicle for cyclosporin, causing
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`the group to discard it in favor of other lipophilic carriers. EX. 2004 (Alba et al.),
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`p. 7. And Ding ‘979 states that “conventional teaching in the art is away from a
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`formulation which utilizes a higher fatty acid glyceride, such as castor oil, and
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`cyclosporine.” EX. 1006 (Ding ‘979), 3:46-48.
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`Because of the cytotoxic and other undesirable properties of castor oil, a
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`person of ordinary skill looking for a lipophilic vehicle in which to dissolve the
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`highly lipophilic cyclosporin either would have chosen a carrier other than castor
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`oil or, if he chose castor oil, would have used the minimum amount necessary to
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`dissolve cyclosporin. Given that the Ding ‘979 patent described emulsions
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`containing 0.05% cyclosporin in a vehicle with 0.625% castor oil and polysorbate
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`80, a person of ordinary skill would have recognized that a concentration of
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`0.625% was sufficient to dissolve cyclosporin and would not have selected a
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`higher amount—certainly not 1.25% castor oil, which was twice as high.
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`2.
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`Increasing the amount of castor oil in the emulsion would be
`expected to reduce the thermodynamic activity of the emulsion
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`A person of ordinary skill would know the basic thermodynamic principles
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`
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`governing diffusion, and that increasing the amount of castor oil in the emulsion
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`would reduce the diffusion of the lipophilic cyclosporin out of the lipophilic castor
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`oil and into the hydrophilic tissues of the eye. The Ding ‘979 patent discussed
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`using enough oil to maintain a stable composition that did not cause the
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`cyclosporin to precipitate, but not too much to reduce the necessary
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`thermodynamic activity necessary for the cyclosporin to diffuse out of the
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`emulsion and into the eye. EX. 1006 (Ding ‘979), 2:46-57; 3:7-38; 5:18-25. The
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`Ding ‘979 patent discloses emulsions containing 0.05% cyclosporin/0.625% castor
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`oil and 0.10% cyclosporin/1.25% castor oil. Id., Ex. 1 at 4:32-43. The Ding ‘979
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`patent explains that when formulated in the way instructed, “the drug has
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`reasonably high thermodynamic activity.” Id., 3:25-27.
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`
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`Neither Mylan nor Dr. Amiji explains why the Ding ‘979 patent would not
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`cause a person of skill to prepare an emulsion by combining 0.05% cyclosporin
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`with 0.625% castor oil. A person of ordinary skill would expect an emulsion
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`containing 0.05% cyclosporin and 0.625% castor oil to have better thermodynamic
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`properties than an emulsion containing the same amount of cyclosporin but twice
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`as much of the lipophilic castor oil vehicle. The inventors’ decision to combine
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`0.05% cyclosporin with a vehicle containing 1.25% castor oil and polysorbate 80
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`was counterintuitive and not obvious.
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`
`
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`3.
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`PK data predicted 0.05% cyclosporin/1.25% castor oil would be
`less effective than 0.05% cyclosporin/0.625% castor oil and 0.10%
`cyclosporin/1.25% castor oil
`
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`Allergan performed PK studies on animal eyes that compared the PK
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`properties of 3 different ophthalmic emulsions:
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`(1) 0.05% cyclosporin/1.25% castor oil/1.00% polysorbate 80,
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`Attorney Docket No: 13351-0008IP5
`(2) 0.05% cyclosporin/0.625% castor oil/1.00% polysorbate 80,and
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`(3) 0.10% cyclosporin/1.25% castor oil/1.00% polysorbate 80.
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`The latter two emulsions are described in the Ding ‘979 patent. Dr. Mayssa
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`Attar, in her declaration submitted during prosecution of the ‘048 patent, described
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`these experiments. EX. 1004, pp. 286-87 (Decl’n of Dr. Mayssa Attar, ¶¶ 6-8).
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`Mylan fails to consider the PK studies and what they would have predicted with
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`respect to emulsion performance.
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`Dr. Attar explained in her declaration that in order to obtain cyclosporin’s
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`anti-inflammatory and anti-apoptotic therapeutic effects, cyclosporin must be
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`delivered to ocular tissues such as the cornea, conjunctiva, and lacrimal gland. Id.
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`(¶ 6)). The more cyclosporin that reaches these tissues, the more therapeutically
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`effective the drug will be in treating dry eye. Id.
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`PK studies involving animal eyes are used to evaluate the amount of drug
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`absorbed in ocular tissues. Allergan performed PK studies comparing the extent to
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`which the cyclosporin in the 3 above-described emulsions was absorbed in two
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`ocular tissues: the cornea and the conjunctiva. Id. (¶ 7). As shown in the graph,
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`reproduced below, and explained by Dr. Attar, the results show that in both the
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`cornea and conjunctiva, the amount of cyclosporin delivered to the ocular tissue
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`was greater in emulsions containing 0.05% cyclosporin/0.625% castor oil and
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`Case IPR2016-01131
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`0.1% cyclosporin/1.25% castor oil than in the claimed emulsion containing 0.05%
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`cyclosporin/1.25% castor oil. Id.
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`
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`Based upon these results, according to Dr. Attar, a person of ordinary skill would
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`have expected that both a 0.05% cyclosporin/0.625% castor oil emulsion and a
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`0.1% cyclosporin/1.25% castor oil emulsion would have been more therapeutically
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`effective for treating dry eye disease than the claimed emulsion having 0.05%
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`cyclosporin/1.25% castor oil. Id., p. 273 (¶ 8). In other words, one would expect
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`that increasing the amount of castor oil relative to the amount of cyclosporin would
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`decrease bioavailability and thus therapeutic effectiveness.
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`But the actual results, based upon standard ophthalmic measures of efficacy,
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`tell a different story. During prosecution, Allergan presented the results of
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`Case IPR2016-01131
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`experiments comparing the claimed emulsion to the two emulsions disclosed in the
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`Ding ‘979 patent, measured according to two key objective testing parameters for
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`dry eye: Schirmer Tear Testing and decrease in Corneal Staining. Exhibit E,
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`attached to the Declaration of Dr. Rhett Schiffman, shows the results of two studies
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`comparing the performance of a 0.05% cyclosporin/0.625% castor oil emulsion to
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`that of a 0.05% cyclosporin/1.25% castor oil emulsion. EX. 1004, pp. 263-64 and
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`281-82 (Decl’n of Dr. Rhett Schiffman, ¶¶ 17-19 and Exhibit E). In both studies,
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`the 0.05% cyclosporin/1.25% castor oil emulsion performed significantly better
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`than the 0.05% cyclosporin/0.625% castor oil emulsion—contrary to what the PK
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`experiments predicted. See id.
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`Allergan also presented results comparing the performance of a 0.10%
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`cyclosporin/1.25% castor oil emulsion with the claimed 0.05% cyclosporin/1.25%
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`castor oil emulsion with respect to 4 parameters: Corneal Staining, Schirmer Tear
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`Testing, blurred vision, and decrease in the number of artificial tears (palliative
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`treatment) used by patients. The results are shown in Exhibit D attached to the
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`Declaration of Dr. Rhett Schiffman. EX. 1004, pp. 261, 263, and 278-80 (Decl’n
`
`of Dr. Rhett Schiffman, ¶¶ 8 and 14-16 and Exhibit D). The claimed 0.05%
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`cyclosporin/1.25% castor oil emulsion performed better than the 0.10%
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`cyclosporin/1.25% castor oil emulsion with respect to Schirmer Tear Testing,
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`blurred vision, and use of artificial tears, and was comparable with respect to
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`Corneal Staining. Id. Again, these results were contrary to what the PK
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`experiments predicted. See id.
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` The test results depicted in Exhibit D correspond to Phase 3 clinical
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`testing Allergan conducted, which is also described in the Sall paper (EX. 1007).
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`The important distinction between the two is that Sall does not describe the
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`composition of the vehicles, instead noting that their formulations were
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`proprietary. Sall merely recites emulsions containing either 0.05% cyclosporin or
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`0.10% cyclosporin. Thus, a person of ordinary skill reading the Sall paper would
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`not have known the materials in the vehicles and certainly not the castor oil content
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`of the vehicles tested. Based upon the Ding ‘979 patent, which described
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`emulsions containing 0.05% cyclosporin/0.625% castor oil/1.00% polysorbate 80
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`and 0.10% cyclosporin/1.25% castor oil/1.00% polysorbate 80, it would have been
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`entirely logical for a person of ordinary skill to conclude that Sall was testing those
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`two emulsions, rather than the claimed emulsion.
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`
`
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`B. During prosecution the Examiner agreed that the performance of
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`the claimed emulsion relative to the Ding ‘979 patent emulsions
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`was unexpected
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`The Examiner rejected the ‘048 patent claims as obvious over the Ding ‘979
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`patent during prosecution. The Examiner agreed to withdraw the rejection and
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`allow the claims on the basis of Allergan’s evidence of unexpected results. In her
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`reasons for allowance, the Examiner stated (EX. 1004, p. 473) (emphasis added):
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`Taking the results of the studies and data presented in the
`EXHIBITS 1 and 2 together, it is clear that the specific combination
`of 0.05% by weight cyclosporin A with 1.25% castor oil is
`surprisingly critical for the therapeutic effectiveness in the treatment
`of dry