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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_____________________________
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`MYLAN PHARMACEUTICALS INC., TEVA PHARMACEUTICALS USA,
`INC. and AKORN INC.,1
`Petitioners,
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`v.
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`ALLERGAN, INC.
`Patent Owner.
`
`_____________________________
`
`Case IPR2016-01127 (US 8,685,930 B2)
`Case IPR2016-01128 (US 8,629,111 B2)
`Case IPR2016-01129 (US 8,642,556 B2)
`Case IPR2016-01130 (US 8,633,162 B2)
`Case IPR2016-01131 (US 8,648,048 B2)
`Case IPR2016-01132 (US 9,248,191 B2)
`_____________________________
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`DECLARATION OF ANDREW F. CALMAN, M.D., PH.D.
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`1 Cases IPR2017-00576 and IPR2017-00594, IPR2017-00578 and IPR2017-
`00596, IPR2017-00579 and IPR2017-00598, IPR2017-00583 and IPR2017-00599,
`IPR2017-00585 and IPR2017-00600, and IPR2017-00586 and IPR2017-00601,
`have respectively been joined with the captioned proceedings. The word-for-word
`identical paper is filed in each proceeding identified in the caption pursuant to the
`Board’s Scheduling Order (Paper 10).
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`MYLAN - EXHIBIT 1039
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`PROTECTIVE ORDER MATERIAL
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`TABLE OF CONTENTS
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`I.
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`QUALIFICATIONS ..................................................................................... 1
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`II.
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`SCOPE OF WORK ....................................................................................... 4
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`III. BRIEF OVERVIEW OF THE LEVEL OF SKILL ....................................... 5
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`IV. CLAIM CONSTRUCTION .......................................................................... 6
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`V. UNDERSTANDING AND DIAGNOSING DRY EYE DISEASE ............... 7
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`VI. TREATING DRY EYE DISEASE ............................................................. 12
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`VII. SCHIRMER TEAR TESTS AND LACRIMAL GLAND TEARING ......... 21
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`VIII. THE PATENTED FEATURES OF RESTASIS® WERE
`DISCLOSED IN THE PRIOR ART ........................................................... 29
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`IX. THE CLAIMED FORMULATION IS NOT CRITICALLY OR
`UNEXPECTEDLY DIFFERENT THAN THE FORMULATIONS
`DISCLOSED IN THE PRIOR ART ........................................................... 32
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`X.
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`THE CLAIMED FORMULATION’S PERFORMANCE RELATIVE
`TO THE 0.1% CSA/1.25% CASTOR OIL EMULSION WAS NOT
`UNEXPECTED .......................................................................................... 49
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`XI. CONCLUDING STATEMENTS ................................................................ 55
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`XII. APPENDIX - LIST OF EXHIBITS ............................................................ 56
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`I.
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`I, Andrew F. Calman, M.D., Ph.D., declare as follows:
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`QUALIFICATIONS
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`1.
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`I received my Bachelor of Science in Molecular Biophysics and
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`Biochemistry, summa cum laude, from Yale University in 1982, with Distinction
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`in the Major. I also received my Master of Science in Molecular Biophysics and
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`Biochemistry from Yale University in 1982. I then attended medical school and
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`graduate school at the University of California, San Francisco (UCSF) with a full
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`scholarship from the Medical Scientist Training Program of the National Institutes
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`of Health from 1982 to 1989. In 1989, I received my Doctor of Medicine (M.D.)
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`and Doctor of Philosophy (Ph.D.) in Microbiology and Immunology from UCSF,
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`earning the Dean’s Prize for Student Research, Chancellor’s Fellowship,
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`membership in Alpha Omega Alpha, and the E. E. Osgood Award for best student
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`biomedical research in the Western United States. My graduate research involved
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`identification of the T-cell antigen receptor beta-chain gene, rearrangement and
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`expression of T-cell antigen receptor genes in B-cells, activation of HIV gene
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`expression in T-cells, and an in vitro model of Bare Lymphocyte Syndrome, a form
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`of congenital immune deficiency involving deficient expression of class II major
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`histocompatibility genes.
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`2.
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`From 1989-1990, I completed a one-year internship in Internal
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`Medicine at Kaiser Foundation Hospital in San Francisco, followed by a three-year
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`residency in Ophthalmology at UCSF. During this time, I set up a molecular
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`biology laboratory in the Department of Ophthalmology at UCSF, resulting in the
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`cloning of a human cataract gene by genetic complementation of galactokinase-
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`deficient yeast cells. During my clinical training, I was introduced to the use of
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`compounded cyclosporin for ocular conditions. I have been on the clinical faculty
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`of UCSF since 1993, with a current appointment as Associate Clinical Professor of
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`Ophthalmology. For many years I also held a joint appointment in the Department
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`of Family and Community Medicine at UCSF. I also hold a faculty appointment at
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`California Pacific Medical Center. My teaching activities at these academic
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`institutions include training residents and medical students in diagnosis and
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`treatment of eye disease, and teaching cataract and other ophthalmic surgery. In
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`addition, international medical students from the Netherlands, Thailand, Saudi
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`Arabia, and Colombia have trained in my office, in preparation for residency
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`training in ophthalmology.
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`3.
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`I was board certified in ophthalmology in 1994, and recertified in
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`2004 and 2014. Since 1997, I have served as an Associate Examiner for the
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`American Board of Ophthalmology, administering the Oral Board Examination for
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`candidates for board certification. In this capacity I have examined candidates in
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`multiple subspecialty areas within ophthalmology, most recently in Cornea,
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`External Disease, and Pediatric Ophthalmology from June 3-5, 2016.
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`4.
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`From 1996 to 2004, I served on the Medicare Carrier Advisory
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`Committee for California and several other states, helping to formulate and review
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`Medicare policies on various ophthalmic conditions and procedures, including
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`those involving the cornea and conjunctiva. I held a similar position at the national
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`level from 2004 to 2008, serving on the Health Policy Committee of the American
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`Academy of Ophthalmology. In 2010, I served as President of the California
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`Academy of Eye Physicians and Surgeons, which is the state professional society
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`for California ophthalmologists. In addition to these and other leadership positions
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`in professional societies at the local, state and national level, I am Past Chair of
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`Prevent Blindness California, a non-profit dedicated to finding and treating cases
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`of preventable vision loss in children.
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`5.
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`Since 1993, I have had a busy comprehensive ophthalmology practice
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`in the Mission District of San Francisco, treating a diverse, high-pathology
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`population for a variety of ophthalmic conditions, including corneal and external
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`disease, cataract, glaucoma, retinal disease, and ophthalmic manifestations of
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`neurologic and systemic disease. Many of these patients over the years have had
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`symptoms or clinical findings consistent with the group of clinical entities
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`sometimes colloquially and/or collectively referred to as “dry eye,” and have been
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`diagnosed with various conditions and treated accordingly. Among various
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`treatments, I have prescribed Restasis® to appropriate patients since it was
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`approved by the FDA.
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`6.
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` My education, training, work experience, publications, and honors
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`are set forth in my curriculum vitae, a copy of which is submitted separately as
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`EX1042.
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`II.
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`SCOPE OF WORK
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`7.
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`I understand that the United States Patent Trial and Appeal Board
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`(“PTAB”) has instituted inter partes review of the related U.S. Patent Nos.
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`8,685,930; 8,629,111; 8,642,556; 8,633,162; 8,648,048; and 9,248,191
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`(collectively the “patents-at-issue”), each in one of six related proceedings. See
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`IPR2016-01127, IPR2016-01128, IPR2016-01129, IPR2016 -01130, IPR2016-
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`01131, and IPR2016-01132 (collectively “these proceedings”). I have been
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`retained by the Petitioners as a technical expert to provide my independent analysis
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`in these proceedings.
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`8.
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`I am being compensated for my time at a rate of $770 per hour. For
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`any part of this matter (e.g., depositions) which requires work away from my home
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`and office, I am being compensated $9,360 per weekday (or fraction thereof) that I
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`am out of my office, and $4,360 per weekend day or holiday that I am away from
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`my home. I have no financial interest in the outcome of this matter.
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`III. BRIEF OVERVIEW OF THE LEVEL OF SKILL
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`9.
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`I understand that the PTAB may evaluate the obviousness of a
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`claimed invention from the perspective of a person of ordinary skill in the art, and
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`that the PTAB has adopted Petitioner’s definition of the level of ordinary skill in
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`the art. See, Mylan Pharmaceuticals Inc. v. Allergan, Inc., IPR2016-01132, Paper 8
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`(P.T.A.B. Dec. 8, 2016) at 7-8. I understand that Petitioner asserted that a person
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`of ordinary skill in the art would typically have “an advanced degree, such as a
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`medical degree, or a Ph.D. in organic chemistry, pharmaceutical chemistry,
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`medicinal chemistry, pharmaceutics, physical pharmacy, or a related field, or less
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`education but considerable professional experience in these fields,” and would also
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`likely have had “some combination of: (a) experience formulating pharmaceutical
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`products; (b) experience designing and preparing drug emulsions intended for
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`topical ocular administration; and (c) the ability to understand results and findings
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`presented or published by others in the field.” Id. (citing the declaration of Dr.
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`Mansoor Amiji, EX1002 (“Amiji Declaration”) ¶¶35-36). As of 2002-2003, I had
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`at least these qualifications for a person of skill in the art as defined in the present
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`proceeding. I have applied this definition of a person of ordinary skill in the art
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`while conducting my analysis.
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`IV. CLAIM CONSTRUCTION
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`10.
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`I have been advised that the PTAB has construed any claims from the
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`patents-at-issue that discuss therapeutic efficacy in treating dry eye,
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`keratoconjunctivitis sicca (“KCS”), or in increasing tear production in the eye of a
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`human having KCS, as encompassing both palliative and curative treatments of
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`these diseases. Mylan Pharmaceuticals Inc. v. Allergan, Inc., IPR2016-01127,
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`Paper 8 (P.T.A.B. Dec. 8, 2016) at 7-8. I understand that the PTAB explicitly
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`disagreed with Patent Owner’s attempt to argue that such claims excluded
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`treatments with palliative effects. Id. at 8-9.
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`11.
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`I agree with the PTAB’s interpretation of the term, and add that
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`patients do not come to their doctors complaining of inflammation, or the
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`underlying cause of their symptoms, nor do patients come to their doctors
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`complaining of low Schirmer Tear scores. Prior to 2003, and still today, patients
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`are looking for relief from their symptoms. A patient’s particular dry eye
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`symptoms may require a surgical intervention, an environmental adjustment, the
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`application of artificial tears, or a prescription drug. Any remedy that provides
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`relief to the patient’s dry eye/KCS symptoms would be considered by the patient,
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`as well as by the prescribing physician, to demonstrate therapeutic efficacy.
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`12.
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`I have been advised that the PTAB has determined it unnecessary to
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`expressly construe any other claim terms at this time. Id. at 9. As such, I
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`understand that the Board will interpret other claim terms according to their
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`ordinary and accustomed meaning as they would be understood by one of ordinary
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`skill in the art.
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`V. UNDERSTANDING AND DIAGNOSING DRY EYE DISEASE
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`13. As of September 15, 2003, individuals suffering from dry eye were
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`understood to share a common set of symptoms such as sensations of dryness,
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`“sandy or gritty feeling”, “foreign body sensation” in the eye, as well as irritation,
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`tearing, itching, and/or redness. See, e.g., EX1015 (“Stevenson”) at 967-68.
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`14.
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` Diagnosing a patient presenting with dry eye symptoms involved, as
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`it still involves today, multiple diagnostic parameters. Id.; Lemp, M.A., Report of
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`the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, 21
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`CLAO J. 221-32 (1995) (EX2022, “Lemp”) at 222-23; American Academy of
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`Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern: Dry
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`Eye Syndrome – Limited Revision. San Francisco, CA: AM. ACAD. OPHTHAMOL.
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`2011 (EX1048, “Garralt 2011”) at 6-9. In routine clinical practice, diagnosis of a
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`dry eye condition starts with taking a thorough patient history and performing an
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`eye examination. As dry eye disease is a disease of the ocular surface, special
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`attention is paid to slit lamp examination of the anterior (front) structures of the
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`eye. EX1007 (“Sall”) at 633; EX1048 (“Garralt 2011”) at 8-9. These findings can
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`then be supplemented with other diagnostic procedures and tests.
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`15. Those in the art did not reductively rely on one “primary” test or
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`clinical measure, as asserted by Dr. Sheppard. EX2024 (“Sheppard Declaration”),
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`¶¶20-21. Indeed, as later confirmed by Dr. Sheppard, there is no “primary test,”
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`and Schirmer Tear Testing (“STT”) is but one of many tools used by those of skill
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`in the art. EX1037 (“Sheppard Deposition”), 95:17-101:11 (“[corneal staining is]
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`one of the many best practices utilized in creating the sufficient information set to
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`make a prescription…” emphasis added). Indeed, Dr. Sheppard did not list STT in
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`his initial list of tests that he performs for his dry eye patients, and admitted that he
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`only performs STT in “well over half” of such patients, whereas 90% undergo
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`corneal staining. EX1037 (“Sheppard Deposition”), 99:19-104:18. In my clinical
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`experience, most clinicians outside the academic setting infrequently perform the
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`STT because it is time-consuming, uncomfortable for the patient, and variable in
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`its results.
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`16. As of 2003, an important diagnostic tool included ocular surface
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`staining. In this diagnostic, a dye such as fluorescein, Rose Bengal, or Lissamine
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`Green is administered to the eye to highlight diseased or damaged corneal and
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`conjunctival tissues. See, e.g., EX1007 (“Sall”) at 633; EX2022 (“Lemp”) at 228;
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`EX1048 (“Garralt 2011”) at 9; EX1013 (“Ophthalmology PDR”) at 16. Another
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`important diagnostic tool included tear break-up time (“TBUT”) determination,
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`which measures tear film stability. See, e.g., EX1007 (“Sall”) at 633; EX2022
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`(“Lemp”) at 228; EX1048 (“Garralt 2011”) at 9. Other tests included measurement
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`of tear osmolarity, conjunctival inflammation testing (e.g., MMP-9 assay), and
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`impression cytology. EX1037 (“Sheppard Deposition”), 95:17 – 99:11; EX2022
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`(“Lemp”) at 229-30; EX1014 (“Turner”) at 492. I have personally performed all
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`these procedures for my patients.
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`17. Following examination and appropriate testing, a patient may be
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`found to have a single type of dry eye or may be found to be suffering from
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`multiple disorders affecting one or more components of the tear film. The human
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`tear film can be characterized as comprising (1) an outer oily lipid layer, secreted
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`by the Meibomian oil glands of the eyelid, which are responsible for preventing
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`tear evaporation; (2) a middle aqueous layer, secreted by the lacrimal glands,
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`including the accessory lacrimal glands of the conjunctiva, which provide most of
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`the liquid volume of the tears; and (3) an inner mucin layer, which helps tears
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`adhere to the ocular surface. EX1016 (“Remington’s”) at 821-23.
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`18. Most patients with dry eye have a problem with at least one part of the
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`tear film. EX2022 (“Lemp”) at 222-27; Foulks, G.N., et al., 2007 Report of the
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`International Dry Eye Workshop (DEWS) 5 OCULAR SURF. (2007) 65-202
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`(EX1059, “DEWS 2007”) at 76-88. Prior to 2003, aqueous-deficient dry eye was
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`known to be one type of dry eye and was characterized by a deficient aqueous
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`layer. EX2022 (“Lemp”) at 224-26. A different type of dry eye, evaporative dry
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`eye, was characterized by a deficient lipid layer, resulting in excessive evaporation
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`of tears from the ocular surface. EX1017 (“Goto”) at 2030; EX2022 (“Lemp”) at
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`226-227.
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`19. The term keratoconjunctivitis sicca (KCS) was sometimes used as a
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`synonym for aqueous-deficient dry eye, especially if inflammation was present.
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`However, different authors have used widely varying definitions for KCS,
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`contributing to confusion in the field.
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`20. Aqueous-deficient dry eye may be symptomatic of one or more
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`underlying diseases, including Sjögren’s syndrome. Sjögren’s syndrome is an
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`autoimmune disease affecting the moisture-producing glands of the body that was
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`known to cause dry eye/KCS and inflame the ocular tissues, including the lacrimal
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`glands. EX1012 (“Kunert”) at 1489. Sarcoidosis, graft-versus-host disease, and
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`trachoma are other examples of diseases that were known to result in aqueous-
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`deficient dry eye/KCS with ocular tissue inflammation. EX2022 (“Lemp”) at 225.
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`Other problems, such as age-related lacrimal deficiency (thought to be related to
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`declining androgen levels), autonomic insufficiency, traumatic injury, systemic
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`drug side effects, and thermal or chemical burns, were also understood to cause
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`aqueous-deficient dry eye. Id. at 225-27; EX1013 (“Ophthalmology PDR”) at 13.
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`21. Specific mechanisms resulting in evaporative dry eye were known to
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`include Meibomian gland dysfunction and/or blepharitis, excessive use of air
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`conditioning, dry climates or overly dry environments like offices or airplanes,
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`infrequent blinking or staring (as commonly occurs with prolonged use of
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`computers or personal electronics), mucin deficiency due to a lack of vitamin A,
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`contact lens use, and eyelid problems or disorders (including eyelid malposition or
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`infection). EX2022 (“Lemp”) at 226-27; EX1017 (“Goto”) at 2030.
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`22. A patient’s dry eye may also be symptomatic of problems in multiple
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`layers of the tear film. For example, an elderly patient with age-related lacrimal
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`deficiency and an eyelid disorder resulting in excessive tear evaporation may be
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`diagnosed with both aqueous-deficient and evaporative dry eye. Contrary to Dr.
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`Sheppard’s overly simplistic and imprecise assertion (“evidence suggests that dry
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`eye results from…a common immune-based inflammation of the lacrimal glands
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`and ocular surface,” EX2024, ¶23), those in the art understood by September 2003
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`that dry eye is not always caused by, and does not always present with, ocular
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`inflammation. In some cases, especially in patients in the initial stages of
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`environmental or drug-induced evaporative dry eye, minimal or no detectable
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`inflammation would be present on the ocular surface. EX1010 (“Ding ’607”), 1:18-
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`42, 2:24-40; see also: Facts About Dry Eye, NATIONAL EYE INSTITUTE OFFICE OF
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`SCIENCE COMMUNICATIONS, PUBLIC LIAISON, AND EDUCATION (2013) (EX1045)
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`(“Dry eye occurs when the eye does not produce tears properly, or when the tears
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`are not of the correct consistency and evaporate too quickly. In addition,
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`inflammation of the surface of the eye may occur along with dry eye…. Dry eye
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`can be associated with inflammation of the surface of the eye, the lacrimal gland,
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`or the conjunctiva[.]” (emphasis added)). Thus, I disagree with Dr. Sheppard’s
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`conclusion that “environmental factors such as wind, low humidity, elevated
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`osmolarity, or increased abrasive forces from blinking over an ocular surface with
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`inadequate tear film” necessarily result in “immune activation,” particularly in the
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`early phases. EX2024, (“Sheppard Declaration”), ¶25.
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`23. Even when present in patients with dry eye (as in KCS), observed
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`inflammation may be caused by dry eye (for example by excessive evaporation of
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`tears), not the other way around. EX1010 (“Ding ’607”), 2:24-40. Indeed, dryness
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`itself has been shown to induce inflammation in an animal model of dry eye.
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`Niederkorn et al., Desiccating Stress Induces T Cell-Mediated Sjögren’s
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`Syndrome-Like Lacrimal Keratoconjunctivitis, J. IMMUNOL. 176:3950-57 (2006)
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`(EX1046, “Niederkorn”) at 3950. I also disagree with his odd statement that “to be
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`blunt, aging is inflammation.” EX1037 (“Sheppard Deposition”), 73:3-18.
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`VI. TREATING DRY EYE DISEASE
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`24.
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`In 2003 and still today, I have found in my practice that individualized
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`treatment of dry eye is essential, and the best course of treatment for each patient
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`can vary. Some patients require prescription treatment such as corticosteroids or
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`Restasis, while for others, a simple environmental adjustment may suffice. Dr.
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`Sheppard appears to have acknowledged as much during his deposition. See, e.g.,
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`EX1037, (“Sheppard Deposition”), 113:6-116:17 (“it really depends on the
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`population you’re looking at but a wide variety of treatments exist”), 116:23-
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`117:25 (confirming many of these therapies were all available prior to 2003),
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`121:3-8 (admitting that he pre-treats at least some of his Restasis patients with
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`corticosteroids), 133:16-25 (“Palliative treatment could be turning off the air
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`conditioning.”).
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`25. For those patients whose dry eye is coincident with inflammation,
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`anti-inflammatory agents such as topical corticosteroids can be used to decrease
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`ocular surface inflammation. In 2002-2003 and still today, physicians prescribed
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`topical corticosteroids such as fluorometholone, prednisolone acetate,
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`dexamethasone, and loteprednol to treat dry eye/KCS by reducing inflammation.
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`Indeed, corticosteroid medications (initially systemically, later in eyedrop form)
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`have been known since the 1950’s to be effective for treating KCS patients. See,
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`e.g., Marsh and Pflugfelder, Topical Nonpreserved Methylprednisolone Therapy
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`for Keratoconjunctivitis Sicca in Sjögren Syndrome, 106 OPHTHALMOL. 811 (1999)
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`(EX1052, “Marsh”) at 812; PubMed Abstract for Sainz de la Maza Serra et al.,
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`Nonpreserved Topical Steroids and Punctal Occlusion for Severe
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`Keratoconjunctivitis Sicca, ARCH. SOC. ESP. OFTALMOL. 10:751-756 (2000)
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`(EX1053, “Sainz”); Avunduk et al., The Comparison of Efficacies of Topical
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`Corticosteroids and Nonsteroidal Anti-inflammatory Drops on Dry Eye Patients: A
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`Clinical and Immunocytochemical Study, AM. J. OPHTHAL.136:593-602 (2003)
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`(“Avunduk,” EX1060) at 593; Eadie et al., Kerato-Conjunctivitis Sicca Treated
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`With Cortisone and ACTH, BRIT. J. OPHTHAL. (1955), 39:90 (EX1054, “Eadie”) at
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`95; Gaulhofer, The Effect of Cortisone on Sjögren’s Syndrome, ACTA MEDICA
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`SCANDINAVICA, Vol. CXLIX, fase. VI, 1954 (EX1055, “Gaulhofer”).
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`26. Notably, Dr. Sheppard agreed that corticosteroids were used before
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`the alleged invention of the patents-at-issue and still today to treat dry eye by
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`reducing inflammation, a symptom that he identifies as the underlying cause of dry
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`eye that is addressed by Restasis®. EX1037 (“Sheppard Deposition”), 113:6-114:4,
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`139:19-140:9; see also EX1060 (“Avunduk”) at 593, 596-601 (showing
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`corticosteroids decreased inflammatory markers). Although side effects may occur
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`in some patients treated with topical corticosteroids, these side effects can be
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`minimized with appropriate patient selection, dosing, monitoring, and treatment
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`duration. EX1052 (“Marsh”) at 811, 813-815. Based on my practice experience
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`and my interactions with other practitioners, I agree with Dr. Sheppard that
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`physicians continue to use corticosteroids for dry eye disease today and that they
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`work well.
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`27. Non-steroidal anti-inflammatory drugs were also used successfully for
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`the treatment of dry eye disease by reducing inflammation. Rolando et al., Topical
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`Non-Preserved 0.1% Diclofenac Therapy for Kerato-conjunctivitis Sicca, ADV.
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`EXP. MED. BIOL. (LACRIMAL GLAND, TEAR FILM & DRY EYE SYNDROMES
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`3) 506:1237-40 (2002) (EX1056) at 1237-39.
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`28. For patients whose dry eye was caused by ocular rosacea
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`(inflammation of the ocular tissue caused by the chronic facial skin condition
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`rosacea), oral tetracyclines such as doxycycline and minocycline—which have a
`
`variety of anti-inflammatory properties—could be prescribed. Akpek et al.,
`
`Ocular Rosacea: Patient Characteristics and Follow-up, OPHTHALMOL. 104:1863-
`
`67 (1997) (EX1062, “Akpek”) at 1865. Based on my practice experience and my
`
`interactions with other practitioners, I know that physicians continue to use these
`
`treatments today. I note that Dr. Sheppard agrees. EX1037 (“Sheppard
`
`Deposition”) at 115:22-116:3 (“[w]e use oral antibiotics in the Tetracycline class
`
`because they’re antiinflammatory”).
`
`29. As explained in detail by Dr. Amiji, and confirmed by my own
`
`clinical training and practice, cyclosporin was also known as an anti-inflammatory
`
`useful for the treatment of KCS caused by inflammatory/aqueous deficient
`
`conditions, as well as for other ocular inflammatory diseases. See, e.g., IPR2016-
`
`01127, “Amiji Declaration” at ¶47. Indeed, as noted below, Allergan itself
`
`identified U.S. Patent No. 4,839,342 to Kaswan under Restasis® in the FDA’s
`
`Orange Book. Orange Book 29th Ed. 3-107, 2009 (EX1032 , “Orange Book, 29th
`
`-15-
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`PROTECTIVE ORDER MATERIAL
`
`
`
`
`
`Edition”) at 36. The Kaswan ’342 patent issued in 1989 and teaches the topical
`
`ophthalmic administration of cyclosporin A to treat aqueous-deficient dry eye and
`
`to restore or enhance lacrimal gland tearing. EX2002 (“Kaswan ’342”) at
`
`Abstract, claim 13.
`
`30. More specialized treatments for specific causes of dry eye were also
`
`known to those of skill in the art. For example, Vitamin A supplementation,
`
`applied early in the course of Vitamin A-deficient dry eye, was known to cure the
`
`disease. EX2022 (“Lemp”) at 225. Similarly, surgical treatment for eyelid
`
`malposition, such as ectropion (an outward drooping of the lower eyelid) or trauma
`
`was known to cure some forms of evaporative dry eye. Additionally, bandage
`
`contact lenses could be prescribed to help people who suffer from dry eye. EX1016
`
`(“Remington’s”) at 834. These large-diameter contact lenses vault over the entire
`
`cornea, thus replacing an irregular cornea with a smooth optical surface, while
`
`protecting the surface of the eye and trapping moisture. Id.
`
`31.
`
` Additional products that have been or are currently used for the
`
`treatment of dry eye include: Lacrisert®, Xiidra®, Advanced Eye Relief®,
`
`Aquasite® artificial tears, Bion Tears® products, GenTeal® products, HypoTears®,
`
`HypoTears PF®, Moisture Eyes®, Murocel®, OcuCoat PF®, Optive® products,
`
`Refresh® products (including Refresh Tears®, Refresh P.M.®, Refresh Celluvisc®,
`
`Refresh Endura®, Refresh Contacts®, and Refresh Plus®), Soothe® products,
`
`-16-
`
`PROTECTIVE ORDER MATERIAL
`
`
`
`
`
`Systane® products, Tears Naturale Free®, TheraTears® products, Visine® products,
`
`Alrex® and Lotemax® (loteprednol), FML® (fluorometholone suspension), Vexol®
`
`(rimexolone suspension), Methylprednisolone, Antibiotics, (Oral) Tetracyclines
`
`(such as tetracycline, doxycycline, minocycline), (Oral) Nutritional Supplements
`
`(omega-3 fatty acids), and Lipiflow®, though this is not an exhaustive list. EX1013
`
`(“Ophthalmology PDR”) at 13-14; EX1016 (“Remington’s”) at 832.
`
`32. Some of the OTC products I have personally recommended for my
`
`patients include: Refresh®, Refresh Optive®, Refresh Endura®, Tears Naturale
`
`Free®, Systane®, Systane Ultra®, Systane Balance®, Systane Gel Drops®, Systane
`
`Preservative Free®, Bion Tears®, GenTeal®, GenTeal Gel®, Celluvisc®, and
`
`TheraTears®. I have also personally treated patients with a number of prescription
`
`products for the treatment of dry eye/KCS, including corticosteroids, NSAID’s,
`
`Restasis®, and Xiidra®.
`
`33. As evidenced by his deposition testimony, Dr. Sheppard’s assertion
`
`(EX2024, (“Sheppard Declaration”), ¶29) that “there was no medication or
`
`treatment on the market,” prior to Restasis®, “that increased tear production or
`
`directly impacted the underlying immunological cause of dry eye disease” is
`
`incorrect. For example, corticosteroids were known immunosuppressant agents,
`
`and had been shown to suppress ocular inflammation associated with dry eye in as
`
`little as two weeks. EX1020 (“Murphy”) at 0003 (citing a 1999 study which
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`-17-
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`PROTECTIVE ORDER MATERIAL
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`
`
`
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`“found that a 2-week course of topical methylprednisolone relieved the irritation of
`
`dry eye, and in many patients that relief lasted weeks or months after they stopped
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`therapy.”); see also EX1060 (“Avanduk”) at 593-601, EX1037 (“Sheppard
`
`Deposition”), 118:8-119:21 (confirming corticosteroids are immunosuppressants”),
`
`120:4-25 (“Steroids are anti-inflammatories, yes. And steroids treat dry eye
`
`inflammation pathways.”), 133:11-15 (“Corticosteroids treat a lot of things that are
`
`inflammatory and they include dry eye”), 136:2-19 (“Again, corticosteroids treat
`
`inflammation. It’s an important component of the dry eye disease in a wide variety
`
`of patients and by treating that inflammation, you’re addressing the underlying
`
`cause or one of the underlying causes and steroids provide that anti-inflammatory
`
`therapy for patients and they are effective for a wide variety of conditions on the
`
`eye including …dry eye”); 118:21-120:20 (“[corticosteroids” are
`
`antiinflammatory, and they have a number of intervention points in the
`
`inflammatory cascade” and “Steroids are antiinflammatories, yes, and steroids treat
`
`dry eye inflammation pathways”); 138:3-10 (“Again, we have to remember that
`
`curative means, in this context, addressing the underlying cause rather than just the
`
`symptoms, and steroids address the underlying cause, not just the symptoms.”);
`
`139:11-17 (“I use steroids all the time to treat dry eye disease, and they work.”).
`
`34. Similarly, Dr. Sheppard’s assertion that Restasis® was “unlike any
`
`prior dry eye product,” in that it “had the ability to increase a patient’s own tear
`
`-18-
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`PROTECTIVE ORDER MATERIAL
`
`
`
`
`
`production” is incorrect. EX2024 (“Sheppard declaration”), ¶30. Indeed,
`
`administration of a castor oil emulsion described in Ding ’607 was shown using
`
`STT to yield a statistically significant increase in tear production from patients’
`
`baseline. EX1010 (“Ding ’607”), 6:49-63 and Figure 2. I understand the 2.5%
`
`castor oil emulsion described in Ding ’607 is the formulation of Allergan’s Refresh
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`Endura®, which was approved by the FDA as an over-the-counter artificial tear in
`
`2002, approximately one year before Restasis® was available on the dry eye
`
`market. Glenn, C. New Thinking Spurs New Products, REV. OPHTHALMOL. 1(2),
`
`FEB. 2003 (EX1057) at 3 (“Another new product introduced last year extended the
`
`Refresh (Allergan) line of tear supplements. Refresh Endura.”). Dr. Sheppard
`
`defends his analysis based on the distinction between basal and total tearing, but I
`
`disagree with Dr. Sheppard’s insinuation that an increase in the ability to tear (as
`
`demonstrated by total tear capacity) is irrelevant to an evaluation of therapeutic
`
`efficacy. As discussed below in Section VII, while basal tear production (as
`
`measured by STT with anesthesia) is highly relevant to patient symptoms, total
`
`aqueous tear production capacity (as measured by STT without anesthesia) also
`
`provides important information regarding the severity of a patient’s dry eye
`
`condition.
`
`35. Despite the availability of multiple prescription and OTC drugs which
`
`could actively target an immune or inflammatory response that caused dry eye,
`
`-19-
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`PROTECTIVE ORDER MATERIAL
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`
`
`
`
`these treatments, like Restasis®, were not considered to be curative in 2003, nor are
`
`they today. EX1037 (“Sheppard Deposition”), 77:3-20 (“The use of an artificial
`
`tear is intermittent…the effect is temporary and not curative.”), 131:8-132:13
`
`(“What we’re looking at is therapeutically, effectively treating dry eye disease. So
`
`we have a specific disease and we’re looking at therapies. And therapies can be
`
`intended to temporarily treat symptoms and, therefore, palliate the patient to make
`
`them temporarily happy, or to target the underlying cause of the disease. And in
`
`this particular statement, ‘curative’ refers to addres
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