Case 2:15-cv-01455-WCB Document 523 Filed 10/16/17 Page 1 of 135 PageID #: 26028
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DIVISION
`
`
`
`
`ALLERGAN, INC., and THE SAINT
`REGIS MOHAWK TRIBE,
`
`Plaintiffs,
`
`v.
`
`TEVA PHARMACEUTICALS USA, INC.,
`et al.,
`
`Defendants.
`
`
`
`Case No. 2:15-cv-1455-WCB
`
`§§§§§§§§§§
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`FINDINGS OF FACT AND CONCLUSIONS OF LAW
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`BACKGROUND
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`The dispute in this Hatch-Waxman Act case relates to a condition known as “dry eye”
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`and a pharmaceutical product known as “Restasis” that is intended to address that condition.
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`Restasis is an emulsion consisting of various components, including the active ingredient
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`cyclosporin A, an immunosuppressant, which is dissolved in castor oil, a fatty acid glyceride.
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`Restasis, which is manufactured by plaintiff Allergan, Inc., is protected by six related patents,
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`which will be referred to as “the Restasis patents.” 1
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`The defendants, Teva Pharmaceuticals USA, Inc.; Akorn, Inc.; Mylan, Inc.; and Mylan
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`Pharmaceuticals, Inc., are generic drug manufacturers that wish to manufacture and sell
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`
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`1 Following the trial in this case, Allergan assigned all six of the Restasis patents to the
`Saint Regis Mohawk Tribe and received an exclusive license to the patents from the Tribe.
`Allergan subsequently moved to join the Tribe as a co-plaintiff. In a separate order entered
`today, the Court has granted that motion and added the Tribe as a plaintiff.
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`MYLAN - EXHIBIT 1164
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, -01132
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`Case 2:15-cv-01455-WCB Document 523 Filed 10/16/17 Page 2 of 135 PageID #: 26029
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`bioequivalent drugs having the same components as Restasis. Their principal contention is that
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`the claims asserted by Allergan are invalid.
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`I. “Dry Eye” and KCS
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`Dry eye is a progressive condition that afflicts a substantial number of ophthalmic
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`patients.
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`It can cause great discomfort and sometimes leads to serious complications that can
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`threaten the patient’s eyesight. Dkt. No. 469, Trial Tr. 21; Dkt. No. 471, Trial Tr. 87-90.
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`In normal individuals, tears are produced naturally by the lacrimal glands above the eyes
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`and accessory lacrimal glands in the eyelids. Dkt. No. 469, Trial Tr. 24-27. The tears form a
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`film that covers the surface of the eye, providing protection to the eye and a smooth optical
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`surface. The tear film in a normal individual consists of three distinct layers. The innermost
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`layer is a mucus layer that rests directly on the cornea (the clear outer surface of the eye covering
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`the iris and the pupil) and the conjunctiva (the tissue covering the white of the eye and lining the
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`inside of the eyelids). The mucus layer assists the tear film in adhering to the surface of the eye.
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`The second layer is an aqueous layer containing the tears. The topmost layer is a lipid layer
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`produced by meibomian glands in the eyelid. The lipid layer impedes evaporation of the water
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`from the tear film. In a normal individual, tears are produced continuously by the lacrimal and
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`accessory lacrimal glands. The tears replenish the aqueous layer of the tear film, and then drain
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`though tear ducts that discharge into the interior of the nose. Dkt. No. 469, Trial Tr. 24; Dkt. No.
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`473, Trial Tr. 32, 44.
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`Natural tearing serves important purposes, including providing nutrients and anti-
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`bacterial agents to the surface of the eye and cleaning the ocular surface. The tear film also
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`serves the important purpose of protecting the corneal and conjunctival epithelium, a thin layer
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`of cells on the surface of the cornea and the conjunctiva. When natural tearing is inadequate (a
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`condition known as “aqueous-deficient dry eye”), or when the tear layer evaporates too quickly
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`(a condition known as “evaporative dry eye”), the protective tear layer on top of the epithelium
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`cells can be compromised, resulting in the exposure of those cells and causing damage that can
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`be painful and can lead to adverse effects on vision. Dkt. No. 469, Trial Tr. 24-25; Dkt. No. 473,
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`Trial Tr. 34-35. Individuals may suffer from aqueous-deficient dry eye, evaporative dry eye, or a
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`mixture of both. Dkt. No. 473, Trial Tr. 40. The symptoms of dry eye can include a sandy or
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`gritty feeling in the eyes, blurred vision, and infection. See U.S. Patent No. 5,981,607, col. 1, ll.
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`25-48.
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`Dry eye can be triggered by a variety of conditions. Sometimes, dry eye is caused by
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`inflammation of the lacrimal glands or inflammation on the surface of the eye that interferes with
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`nerve signals that would normally cause the lacrimal glands to produce tears. Dkt. No. 469, Trial
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`Tr. 21-22, 26; see also Dkt. No. 473, Trial Tr. 34-35, 40. The condition in which dry eye is
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`associated with inflammation and involves a deficiency in aqueous tear production is generally
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`referred to as keratoconjunctivitis sicca (“KCS”).2 Dkt. No. 471, Trial Tr. 86-88. Evaporative
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`dry eye can be caused by inadequate production of oil from the glands that normally replenish
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`the lipid layer of the tear film. In a normal individual, oil in the lipid layer impedes the
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`evaporation of tears from the surface of the eye. Dkt. No. 473, Trial Tr. 34-35, 44.
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`Ophthalmologists have used a variety of techniques to treat dry eye and KCS, but none
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`has proved ideal. Frequently, ophthalmologists recommend that patients with mild to moderate
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`
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`2 Terminology used in this field is inconsistent in various respects. In particular,
`different authorities define KCS differently. The Court will use the definition used in the
`common specification and adopted by the Court at claim construction, which is consistent with
`what seems to be the prevailing view among ophthalmologists today. See U.S. Patent No.
`8,629,111 (“the ’111 patent”), col. 2, line 63, through col. 3, line 5; Dkt. No. 214, at 3-13.
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`dry eye use artificial tears several times a day. Dkt. No. 469, Trial Tr. 29-30. While artificial
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`tears provide some temporary palliative relief, they do not address the underlying conditions that
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`cause dry eye. Other pharmaceutical treatments include corticosteroids, which address the
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`inflammation that is often associated with dry eye, but have serious potential side effects that
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`make long-term use problematical. Id. at 30-31; Dkt. No. 475, Trial Tr. 60-61. Non-
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`pharmaceutical treatments have been employed, such as the use of “punctal plugs,” which block
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`the tear ducts and prevent tears from draining from the eye, thereby retaining naturally produced
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`tears in the eye for a longer period of time; those devices, however, also come with undesirable
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`side effects. Dkt. No. 469, Trial Tr. 30.
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`The evidence at trial described several common methods for diagnosing dry eye and KCS
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`as well as methods for testing whether particular treatment regimens are effective. One
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`commonly used diagnostic device is the Schirmer tear test. That test entails placing the end of a
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`strip of filter paper under the patient’s eyelid and measuring how many millimeters of the paper
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`are wetted by the patient’s tears within five minutes. Wetting of less than a certain amount, such
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`as 10 millimeters on the strip, is indicative of an abnormally low amount of tear production. The
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`Schirmer tear test can be conducted either with or without an ocular anesthetic. Conducting the
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`test with anesthesia is considered a better test of baseline tearing, i.e., the tearing that occurs
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`continuously and naturally in the absence of any unusual stimulation. Conducting the test
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`without anesthesia provides a measure of baseline tearing plus “reflexive tearing,” i.e., tearing
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`that results in response to a stimulus such as an irritant in the eye, because the irritation of the
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`paper under the eyelid tends to provoke more tearing. Dkt. No. 469, Trial Tr. 28-30. There is
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`significant variability in Schirmer test scores depending on the circumstances in which the test is
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`conducted, which makes assessment of those scores challenging. Dkt. No. 475, Trial Tr. 131-32.
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`Another commonly used diagnostic device is corneal and conjunctival staining, in which
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`a stain is placed in the eye. Particular stains can be used that highlight dry areas on the surface
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`of the eye or rough areas of the cornea, thus allowing the ophthalmologist to measure the degree
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`of the patient’s dry eye problem and identify areas of the cornea that have been damaged by dry
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`eye conditions. Dkt. No. 469, Trial Tr. 26. “Rose bengal” conjunctival staining is a method to
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`test for drying and damage to the surface of the eye and shows devitalized areas of the
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`conjunctiva. Dkt. No. 470, Trial Tr. 72; Dkt. No. 472, Trial Tr. 25; Dkt. No. 473, Trial Tr. 37.
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`“Fluorescein” corneal staining shows areas of superficial punctate keratitis, also known as
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`punctate epithelial keratopathy, i.e., epithelial defects in which the outer layer of the cornea has
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`been damaged or lost. Fluorescein staining can also be used to detect “tear break-up time,” i.e.,
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`the time it takes for dry spots to appear in the tear film. Dkt. No. 469, Trial Tr. 25; Dkt. No. 473,
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`Trial Tr. 37; Dkt. No. 474, Trial Tr. 15. Other measures of the existence of and severity of dry
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`eye include subjective measures, such as overall discomfort levels reported by patients and
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`specific types of discomfort, such as a sandy or gritty feeling, ocular dryness, photophobia, or a
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`burning or stinging sensation.
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`II. The Development of Restasis
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`Allergan specializes in the development and sale of ophthalmic drugs, among other
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`products. One of Allergan’s long-term projects has been to develop products effective to treat
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`dry eye and its symptoms. For some time, Allergan has manufactured and sold artificial tears,
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`and in 2002, it began selling a product, Refresh Endura, that used a formulation consisting of
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`artificial tears with 2.5% by weight castor oil added to the formulation. That product was
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`designed to have enhanced benefits for persons suffering from dry eye or KCS, but it was not a
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`commercial success. Dkt. No. 473, Trial Tr. 43, 88; Dkt. No. 475, Trial Tr. 174; Dkt. No. 476,
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`Trial Tr. 12.
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`In the 1990s, Allergan began conducting research using combinations of castor oil and an
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`immunosuppressant known as cyclosporin A.3 Allergan’s cyclosporin research program began
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`in earnest in 1993 when Allergan licensed from Sandoz, Inc., the technology of treating aqueous-
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`deficient dry eye with cyclosporin. That technology was the subject of U.S. Patent No.
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`4,839,342 to Kaswan (“the ’342 patent” or “the Kaswan patent”). The Kaswan patent, which is
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`prior art to the Restasis patents, claimed methods for enhancing or restoring lacrimal gland
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`tearing comprising topically administering cyclosporin to the eye in a pharmaceutically
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`acceptable vehicle. ’342 patent, col. 9, ll. 19-22. Topical administration, the Kaswan patent
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`disclosed, provides a way to direct the cyclosporin to the target tissues “without the
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`accompanying high risk of adverse responses and high cost associated with systemic treatments.”
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`Id., col. 5, ll. 15-25.
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`Kaswan disclosed the use of cyclosporin “in any efficacious concentrations, e.g., 0.01 to
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`saturation (e.g., greater than 20 weight percent).” ’342 patent, col. 5, ll. 56-59. The preferred
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`concentration of cyclosporin, according to Kaswan, was from 0.1% to 20% by weight. Id., col.
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`5, ll. 59-61; id., col. 6, ll. 21-26. The Kaswan patent also recited the use of castor oil, among
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`other compounds, as a pharmaceutically acceptable vehicle for delivering cyclosporin to the eye.
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`Id., col. 9, ll. 34-38; id., col. 10, ll. 18-22, 36-40.
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`3 Cyclosporin A is sometimes spelled “cyclosporine” to distinguish it from other
`cyclosporins, such as cyclosporins B, C, and D. See U.S. Pat. No. 4,839,342, col. 3, ll. 7-11. The
`parties in this case, however, have referred to cyclosporin A as simply “cyclosporin” or “CsA.”
`The Court will follow that convention.
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`One of the major problems with using cyclosporin to treat dry eye is that cyclosporin is
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`highly insoluble in water and is therefore very difficult to deliver in an aqueous solution. For
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`that reason, formulating an appropriate vehicle for delivering cyclosporin to the eye posed a
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`difficult challenge. Allergan was able to solve that problem by formulating an oil-in-water
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`emulsion that contained a small amount of castor oil (a hydrophobic vehicle that would dissolve
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`the cyclosporin), together with an emulsifier and an emulsion stabilizer in water. That approach
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`allowed small droplets of the cyclosporin/castor oil solution to be suspended in an emulsion from
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`which the cyclosporin would be available to the target tissue. In addition, the emulsion stabilizer
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`was able to keep the emulsion stable for long periods of time. Allergan’s work on
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`cyclosporin/castor oil emulsions is disclosed and claimed in two Allergan patents, both of which
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`are prior art to the Restasis patents.
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`The first of those two patents is U.S. Patent No. 5,474,979 (“the ’979 patent” or “the
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`Ding I patent”), which issued in 1995 and expired in 2014. That patent is entitled “Nonirritating
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`Emulsions for Sensitive Tissue.” The ’979 patent disclosed and claimed a pharmaceutical
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`emulsion consisting of between about 0.05% and about 0.4% by weight cyclosporin; between
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`about 0.625% and about 0.4% by weight castor oil; about 1% by weight polysorbate 80 (an
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`emulsifier); about 0.05% by weight Pemulen (an emulsion stabilizer); and about 2.2% by weight
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`glycerin. The rest of the emulsion consisted of water and an amount of sodium hydroxide
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`sufficient to adjust the pH to between about 7.2 and 7.6. Ding I patent, col. 6, ll. 21-42. The
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`resulting emulsion was found to be suitable for topical application to ocular tissue.
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`The Ding I patent described the disclosed cyclosporin/castor oil emulsion as having a
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`“high comfort level and low irritation potential,” Ding I patent, col. 1, ll. 8-9, as well as long-
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`term stability, id., col. 3, ll. 58-63. The emulsion was tested in rabbits and was determined to
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`have both therapeutic efficacy and low toxicity.
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`Id., col. 5, ll. 10-28. The Ding I patent
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`contained four examples, the first two of which contained multiple formulations drawn from the
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`disclosed and claimed ranges of components. The individual embodiments in Example 1
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`included amounts of cyclosporin varying between 0.05% and 0.4%, and amounts of castor oil
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`varying between 0.625% and 5%. Example 1D in the Ding I patent contained 0.1% cyclosporin
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`and 1.25% castor oil, while Example 1E contained 0.05% cyclosporin and 0.625% castor oil.
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`Id., col. 4, ll. 31-43. Thus, Example 1D contained the same amount of castor oil as found in
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`Restasis (but twice as much cyclosporin), while Example 1E contained the same amount of
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`cyclosporin as found in Restasis (but half as much castor oil).
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`All of the embodiments in Example 1 of the Ding I patent had a cyclosporin-to-castor oil
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`ratio of 0.08, except for Example 1B, which had a cyclosporin-to-castor oil ratio of 0.04 (the
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`same ratio as in Restasis). The Ding I patent stated that the preferred weight ratio of cyclosporin
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`to castor oil was below 0.16 (which is the maximum solubility level of cyclosporin in castor oil),
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`and that the more preferred weight ratio of cyclosporin to castor oil was between 0.02 and 0.12.
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`Ding I patent, col. 3, ll. 15-20.
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`The Ding I patent stated that the formulations in Examples 1A through 1D were tested for
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`ocular bioavailability in rabbits, and that “a therapeutic level of cyclosporin was found in the
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`tissues of interest after dosage.” Ding I patent, col. 5, ll. 18-25. No difference in toxicity was
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`found between the tested cyclosporin formulations (Examples 1A through 1D) and formulations
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`without cyclosporin. Id., col. 5, ll. 26-28. All five example cyclosporin formulations (Examples
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`1A through 1E) showed long-term stability. Id., col. 5, ll. 29-30. For Examples 1A through 1D,
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`no crystallization of the cyclosporin was detected after nine months at room temperature. Id.,
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`col. 5, ll. 30-32.
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`The second of the two Allergan patents relating to ocular emulsions is the prior art U.S.
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`Patent No. 5,981,607 (“the ’607 patent” or “the Ding II patent”), which is entitled “Emulsion
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`Eye Drop for Alleviation of Dry Eye Related Symptoms in Dry Eye Patients and/or Contact Lens
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`Wearers.” The Ding II patent disclosed and claimed a method for alleviating dry eye related
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`symptoms by topically applying to ocular tissue an emulsion of a higher fatty acid glyceride,
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`polysorbate 80, and an emulsion-stabilizing amount of Pemulen in water, all without
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`cyclosporin. Ding II patent, col. 9, ll. 2-7. One of the dependent claims of that patent recited the
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`claimed emulsion in which the higher fatty acid glyceride was castor oil, in an amount between
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`about 0.625% by weight and about 5% by weight; polysorbate 80 was present in an amount of
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`about 1% by weight; the ratio of the castor oil to the polysorbate 80 was between about 0.3 to
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`about 30; Pemulen was present in an amount of about 0.05% by weight; and glycerine was
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`present in an amount of about 2.2% by weight. Id., col. 10, ll. 4-10.
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`The Ding II patent noted that, unlike palliative agents such as artificial tears, “therapeutic
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`treatments directed at the underlying inflammatory process may prove beneficial in correcting
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`the underlying disorder.” Ding II patent, col. 1, ll. 56-61. The Ding II patent also noted that the
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`lipid layer of the tear film is believed to be responsible for retarding evaporation of water from
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`the tear film. If the lipid layer of the tear film is disturbed, “excessive evaporation of water from
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`the eye may occur, leaving the surface of the eye ‘dry.’” Id., col. 2, ll. 9-17. The Ding II patent
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`stated that the disclosed and claimed emulsion, which contains a higher fatty acid glyceride—and
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`castor oil in particular—“provides for long retention of the fatty acid glyceride when the
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`emulsion is instilled into an eye. This in turn can retard water evaporation from the eye which
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`alleviates dry eye symptoms.” Id., col. 3, line 66, through col. 4, line 3.
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`III. Clinical Studies and the FDA Application
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`In the late 1990s, with the hope of obtaining approval of a cyclosporin/castor oil
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`pharmaceutical from the U.S. Food and Drug Administration (“FDA”), Allergan conducted two
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`phases of clinical trials of cyclosporin/castor oil emulsions of the sort disclosed in the two Ding
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`patents. In the first clinical trial, referred to as the “Phase 2” study, Allergan tested several
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`combinations of the castor oil and cyclosporin components—0.05% cyclosporin with 0.625%
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`castor oil; 0.1% cyclosporin with 1.25% castor oil; 0.2% cyclosporin with 2.5% castor oil; and
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`0.4% cyclosporin with 5% castor oil. Those formulations were the same as the formulations set
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`forth in Examples 1A, 1C, 1D, and 1E in the Ding I patent. Also tested in the Phase 2 study was
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`a vehicle—a solution containing 2.5% castor oil with no cyclosporin.
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`As is commonly the case, the Phase 2 testing was a smaller “dose-ranging” trial designed
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`to determine the effectiveness and safety of particular doses of the drug, so as to enable the
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`researchers to settle on an appropriate dosage level for subsequent large-scale Phase 3 clinical
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`studies. Those Phase 3 studies would be used to support an application to the FDA for
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`permission to market a cyclosporin/castor oil emulsion as a new drug for treating dry eye and
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`KCS. Dkt. No. 469, Trial Tr. 32-34.
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`Allergan’s Phase 2 study was reported in a journal article, Dara Stevenson et al., Efficacy
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`and Safety of Cyclosporin A Ophthalmic Emulsion in the Treatment of Moderate-to-severe Dry
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`Eye Disease, A Dose-Ranging, Randomized Trial, 107 Ophthalmology 967 (May 2000), DTX-
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`1018. The Stevenson paper reported that 88 patients with moderate-to-severe dry eye disease
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`completed the study—16 in the castor-oil-only vehicle, or control, group; 17 in the 0.05% group;
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`18 in the 0.1% group; 20 in the 0.2% group; and 17 in the 0.4% group.
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`Id. at 970. Stevenson
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`revealed the concentration of cyclosporin in each tested formulation. Stevenson did not disclose
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`the percentage of castor oil in each formulation, but it disclosed that the amount of castor oil
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`increased relative to the increase in cyclosporin in each formulation so that all of the cyclosporin
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`would be dissolved. Id. at 968.
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`The conclusion reached by Stevenson was that the treatment with topical cyclosporin at
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`all tested concentrations significantly improved the ocular signs and symptoms of moderate-to-
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`severe dry eye disease, and that those improvements resulted in a significant decrease in the
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`effect of the disease on vision-related functioning. DTX-1018, at 972. That result, according to
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`Stevenson, was consistent with earlier studies regarding the use of topical cyclosporin to treat
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`dry eye disease and Sjögren’s syndrome, a systemic autoimmune disease that is characterized by
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`severe dry eye. Id. at 972-73; see also Dkt. No. 469, Trial Tr. 54.
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`All of the combinations containing cyclosporin proved safe and effective in increasing
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`tearing in certain patient test groups, and all outperformed the castor-oil-only vehicle. Stevenson
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`added, however, that it was “important to note that the vehicle emulsion used in [the Phase 2]
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`study performed well on its own, producing significant improvement from baseline [(i.e., the
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`patients’ pre-treatment condition)] in several parameters.” DTX-1018, at 973. One of the
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`factors contributing to the beneficial effects of the castor-oil-only vehicle, according to
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`Stevenson, “may be its sustained residence time on the ocular surface,” which was three to four
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`hours. Id. The lengthy residence time, Stevenson suggested, “may help reduce evaporation of
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`the limited volume of natural tears present in patients with dry eyes.” Id.
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`With respect to safety, Stevenson reported that few adverse effects—and no serious
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`adverse effects—were reported among the trial participants. DTX-1018, at 973. Stevenson
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`noted that blood analysis showed that even the formulation with the highest concentration of
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`cyclosporin resulted in minimal systemic absorption of cyclosporin. Id. Stevenson also reported
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`that the formulations were all well tolerated by patients, and that there were no complaints of
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`ocular discomfort, burning, or itching. Id.
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`As for comparative results, Stevenson concluded that there was no clear dose-response
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`relationship between the 0.05% cyclosporin formulation and the formulations containing greater
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`amounts of cyclosporin (i.e., efficacy did not increase with increases in dosage amounts).
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`Nonetheless, differences were detected in the performance of the different formulations as to
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`particular efficacy measures. Stevenson concluded that
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`the 0.1% cyclosporin formulation
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`“produced the most consistent improvement in objective and subjective endpoints (such as
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`superficial punctate keratitis and rose bengal staining),” while the 0.05% cyclosporin formulation
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`“produced the most consistent improvements in patient symptoms (such as sandy/gritty feeling
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`and ocular dryness).” DTX-1018, at 974. The fact that the higher concentrations of cyclosporin
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`did not show any additional therapeutic benefit with increased concentration, Stevenson noted,
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`“suggests that subsequent clinical studies should focus on the cyclosporin 0.05% and 0.1%
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`formulations.” Id.
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`Following the Phase 2 study, Allergan proceeded to what is known as the Phase 3 studies.
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`Initially, Allergan proposed in Phase 3 to test only the formulation containing 0.1% cyclosporin
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`and 1.25% castor oil against its vehicle (i.e., 1.25% castor oil with no cyclosporin). Allergan
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`elected that course of action based on its assessment that the 0.1% cyclosporin formulation had
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`done best in the Phase 2 study. However, after considering the same Phase 2 data, the FDA
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`wanted Allergan to test the lower dose of cyclosporin—the 0.05% dosage. So Allergan agreed to
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`add the 0.05% dosage level to the Phase 3 trials, but with a castor oil concentration of 1.25%, the
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`same as that used in the 0.1% cyclosporin formulation and the castor-oil-only vehicle. Dkt. No.
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`470, Trial Tr. 76-84.
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`Two separate Phase 3 trials were conducted simultaneously. A total of 671 patients
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`completed the two Phase 3 trials—235 in the 0.05% cyclosporin group, 218 in the cyclosporin
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`0.1% group, and 218 in the castor-oil-only vehicle group. Each tested formulation contained
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`1.25% castor oil, and each formulation also contained 1% polysorbate 80, 0.05% Pemulen, and
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`2.2% glycerin.
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`Like the Phase 2 study, the Phase 3 studies were the subjects of a published journal
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`article, which is also prior art in this case.
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`See Kenneth Sall et al., Two Multicenter,
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`Randomized Studies of the Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in
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`Moderate to Severe Dry Eye Disease, 107 Ophthalmology 631 (April 2000), DTX-1017A. The
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`Sall paper revealed the percentages of cyclosporin used in each formulation. Like Stevenson,
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`Sall did not expressly reveal the percentage of castor oil used in the formulations.4
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`Sall explained that the purpose of the two Phase 3 trials was to compare the efficacy and
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`safety of the cyclosporin 0.05% and 0.1% formulations to the vehicle in patients with moderate
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`
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`4 Stevenson did not specify that the oil used in the formulations in the Phase 2 study was
`castor oil, but Sall revealed that the study reported in Stevenson used castor oil. See DTX-
`1017A, at 632 (“The doses of [cyclosporin A] used were based on the results of an earlier dose-
`ranging study [citing Stevenson]. Both the [cyclosporin A] emulsions and vehicle were sterile,
`nonpreserved castor oil in water emulsions . . . .”).
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`Case 2:15-cv-01455-WCB Document 523 Filed 10/16/17 Page 14 of 135 PageID #: 26041
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`to severe dry eye disease. DTX-1017A, at 631. According to Sall, the Phase 3 studies showed
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`that both cyclosporin formulations produced significantly better results than the vehicle alone,
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`and that the 0.05% treatment gave significantly greater improvements, as compared to vehicle, in
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`three subjective measures of dry eye disease (blurred vision, the need for artificial tears, and the
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`physician’s evaluation of the patient’s global response to treatment) for at least some time points.
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`Id. at 631, 637. Sall also reported no dose-response effect between the 0.05% cyclosporin/1.25%
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`castor oil formulation and the 0.1% cyclosporin/1.25% castor oil formulation, and that both of
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`the cyclosporin treatments exhibited excellent safety profiles. Id.
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`Sall stated that there was a statistically significant improvement in the corneal staining
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`scores for all three test groups compared to the patients’ baseline scores. In addition, Sall
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`reported statistically significant improvement in the 0.05% cyclosporin group compared to the
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`castor-oil-only vehicle for corneal staining at months 4 and 6. DTX-1017A, at 635.
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`The study reviewed data from the patients’ follow-up physician visits at various points in
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`the course of the trials. At three months into the trials, there was a statistically significant
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`difference between the 0.05% cyclosporin group and the patients’ baseline scores on the
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`categorized Schirmer tear test with anesthesia; and at six months, both the 0.05% cyclosporin
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`group and the 0.1% cyclosporin group showed statistically significant improvements compared
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`to the patients’ baseline scores on that test.5 Sall also reported that at month 3 there was a
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`statistically significant difference between the 0.05% cyclosporin group and the vehicle group,
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`but not a statistically significant difference between the 0.05% cyclosporin group and the 0.1%
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`
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`5 The “categorized” Schirmer tear test places the Schirmer scores derived from the test
`into five categories, ranging from category 1 (0-3 millimeters of wetness on the filter paper) to
`category 5 (more than 14 millimeters of wetness). DTX-1018, at 635.
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`Case 2:15-cv-01455-WCB Document 523 Filed 10/16/17 Page 15 of 135 PageID #: 26042
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`cyclosporin group. As for the categorized Schirmer tear tests without anesthesia, the two
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`cyclosporin formulation groups showed statistically significant improvements over the baseline,
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`but there was no statistically significant difference between the two cyclosporin groups. DTX-
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`1017A, at 635-36.
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`With respect to the subjective ocular symptoms, Sall reported that the decrease in blurred
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`vision from the patients’ baseline scores was statistically significant for both cyclosporin groups
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`at all follow-up visits. For the castor-oil-only vehicle, however, the decrease was statistically
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`significant only at the six-month visit. The improvement in blurred vision was also significantly
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`greater for the 0.05% group as compared to the vehicle group at all follow-up visits. DTX-
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`1017A, at 636.
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`Similarly, statistically significant changes from baseline were observed within all
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`treatment groups at all points with regard to dryness, sandy/gritty feeling, itching, burning and
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`stinging, and pain. However, there were no statistically significant among-group differences
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`with regard to any of those variables.6 DTX-1017A, at 636. There were also statistically
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`significant decreases in the use of artificial tears in the treatment groups compared to baseline,
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`but no statistically significant differences among the treatment groups as to that variable. Id.
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`With respect to the physicians’ subjective assessment of the global response to treatment,
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`Sall reported that the 0.05% and 0.1% cyclosporin groups showed an improvement over the
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`patients’ baseline and somewhat better results than the castor-oil-only vehicle group. The
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`
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`6 An among-group analysis determines whether any one of the groups—vehicle or
`treatment—has results that are significantly different from the rest of the groups. If there are no
`statistically significant among-group differences, there will be no statistical significance in any
`pair-wise comparisons between any two of those groups. See Dkt. No. 469, Trial Tr. 59.
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`Case 2:15-cv-01455-WCB Document 523 Filed 10/16/17 Page 16 of 135 PageID #: 26043
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`improvements seen in the two cyclosporin groups, however, were very similar. See DTX-
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`1017A, at 636.
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`Sall concluded that the most important overall finding of the two Phase 3 trials
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`was 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 (corneal staining and categorized Schirmer values), whereas treatment
`with CsA, 0.05%, resulted in significantly greater improvements than vehicle (P (cid:148)
`0.05) in three subjective parameters (blurred vision, use of lubricating eye drops,
`and the physician’s evaluation of global response to treatment).
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`DTX-1017A, at 637. Significantly, Sall also noted that the castor oil vehicle for t