UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner
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`v.
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`ALLERGAN, INC.,
`Patent Owner
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`Case IPR2016-01128
`Patent 8,629,111
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`DECLARATION OF JOHN D. SHEPPARD, M.D., M.M.Sc.
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`ALL 2024
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner
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`v.
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`ALLERGAN, INC.,
`Patent Owner
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`1
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`Case IPR2016-01128
`Patent 8,629,111
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`DECLARATION OF JOHN D. SHEPPARD, M.D., M.M.Sc.
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`ALL 2024
`MYLAN PHARMACEUTICALS V. ALLERGAN
`IPR2016-01128
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`Case IPR2016-01128
`Attorney Docket No: 13351-0008IP2
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`I, John D. Sheppard, M.D., M.M.Sc., declare as follows:
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`I.
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`Experience and Qualifications
`1.
`I graduated in 1974 with a S.B. in Biology from Brown University. I
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`then earned the M.M.Sc. in Medicine from Brown University in 1976. I obtained
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`my medical degree from Brown University in 1978. Following medical school, I
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`completed a one-year internship in pediatric medicine at the University of Virginia
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`(1978-1979). I was then on active duty in the Navy from 1979-1983. Following
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`active duty, I completed my residency at the University of Pittsburgh in
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`Ophthalmology (1983-1986) and a fellowship at the Proctor Foundation at the
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`University of California, San Francisco where I conducted research involving the
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`cornea and uveitis (1986-1988). I have been a board certified ophthalmologist
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`since 1988, passing the oral examination with honors at the first sitting.
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`2.
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`Following my studies, I joined Virginia Eye Consultants in Norfolk
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`Virginia in 1989, where I am currently employed and serve as the President, Senior
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`Partner and Managing Partner. In this role, I have a busy and comprehensive
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`ophthalmology practice where I treat a diverse population for a variety of
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`ophthalmic conditions, including corneal and external disease, glaucoma, retinal
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`disease, dry eye disease, cataract and ophthalmic manifestations of systemic,
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`neurological and immune diseases.
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`Attorney Docket No: 13351-0008IP2
`In addition to my medical and surgical practice, I have been involved
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`3.
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`in over 120 clinical studies, approximately 50 of which involved dry eye disease.
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`For example, I was a clinical investigator involved in the Phase 3 clinical trials for
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`RESTASIS® for the treatment of dry eye.
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`4.
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`Over the course of my career, I have diagnosed and treated thousands
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`of patients with dry eye disease. Among various treatments, I have used
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`RESTASIS® in treating patients with dry eye disease since the FDA approved it in
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`2003. Through my training and in my practice over the years, including my
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`interactions with scientists and representatives in the pharmaceutical industry I am
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`familiar with the formulation of ophthalmic pharmaceutical preparations, including
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`RESTASIS®.
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`5.
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`Between 1989-2008, I served as the Ophthalmology Program Director
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`at Eastern Virginia Medical School, overseeing the education of ophthalmology
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`residents. In addition, I have served as a visiting professor at several universities
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`including Duke University, Yale University, University of Texas, University of
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`Florida, and the University of California San Diego where I taught courses to
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`practicing physicians, residents and medical students covering ocular diseases,
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`including ocular inflammation and dry eye disease, as well as treatments for ocular
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`diseases with various ophthalmic formulations.
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`Attorney Docket No: 13351-0008IP2
`I have served or currently serve on a number of professional societies
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`6.
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`including the American Academy of Ophthalmology, the American Board of
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`Ophthalmology, American Society for Cataract and Refractive Surgery, the
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`American Uveitis Society, the Association of University Professors of
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`Ophthalmology and the Association for Research in Vision and Ophthalmology.
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`7.
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`I have authored numerous publications in the field of ophthalmology
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`including articles, textbook chapters, and case reports. A significant portion of
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`these publications focus on treatments for dry eye. In addition to actively
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`publishing, I also serve on the editorial and advisory boards for several journals
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`including Clinical Ophthalmology and Eye and Contact Lens, and also serve as
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`Chief Medical Editor for Web MD Medscape Ophthalmology.
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`8.
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`I also serve or have served on numerous medical and scientific
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`advisory boards. For example, I currently serve or have previously served on
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`boards for the following companies: Alcon, Novartis, Aldeyra, Allergan, Bausch
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`& Lomb, Valeant, Ciba Vision Opthalmics, EyeRx Research, Parion, Topivert,
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`EyeGate, Shire, Santen Pharmaceuticals, Sun Pharma and Isis Pharmaceuticals.
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`9.
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`I have received numerous honors and awards over the course of my
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`professional career, including for example, Armed Forces Health Professions
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`Scholarship, National Society to Prevent Blindness Burroughs-Wellcome
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`Scholarship, National Research Service Award from the National Eye Institute,
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`Senior Honor Award from the American Academy of Ophthalmology, and Best
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`Doctors in America Award.
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`10. A more thorough summary of my education, experience, publications,
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`awards, honors, and presentations is provided in my CV, which is attached to this
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`declaration as Exhibit A.
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`II.
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`Scope of Work
`11.
`I understand that the United States Patent Trial and Appeal Board
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`(“PTAB”) has instituted inter partes review of U.S. Patent Nos. 8,629,111,
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`8,633,162, 8,642,556, 8,648,048, 8,685,930 and 9,248,191 (collectively “the
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`patents-in-suit”). (IPR2016-01128, -01130, -01129, -01131, -01127 and -01132,
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`respectively). I have been engaged in the present matter to provide my
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`independent analysis of the issues raised in the petitions for inter partes review of
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`the patents-in-suit.
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`12.
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`I am compensated for my work at the rate of $1000 per hour during
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`normal business hours, and $450 per hour for work conducted after 6:00 PM and
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`over the weekend. For any part of the case that requires work away from my home
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`and office, I am being compensated at $9,000 per day. My compensation does not
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`in any way depend on the outcome the litigation or the inter partes reviews.
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`In writing this Declaration, I have reviewed the patents-in-suit
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`13.
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`assigned to Allergan, Inc.1 I have also considered the following: my own
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`knowledge and experience in the field of ophthalmology, including my work
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`experience in treating patients with dry eye, my experience in working with others
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`involved in the field of ophthalmology, and the state of the art as of the priority
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`date of the patents-in-suit. I have also reviewed and considered other documents in
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`arriving at my opinions, a complete list of which are included as Exhibit B to my
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`declaration.
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`III. Level of Ordinary Skill at the Relevant Time
`14.
`I understand that Petitioner asserts that a person of ordinary skill in
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`the art would likely have had “some combination of: (a) experience formulating
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`pharmaceutical products; (b) experience designing and preparing drug emulsions
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`intended for topical ocular administration; and (c) the ability to understand results
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`and findings presented or published by others in the field.” Paper 8 (citing Ex.
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`1002 ¶ 36). “Petitioner further contends that this person typically would have an
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`advanced degree, such as a medical degree, or a Ph.D. in organic chemistry,
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`pharmaceutical chemistry, medicinal chemistry, pharmaceutics, physical
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`pharmacy, or a related field, or less education but considerable professional
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`experience in these fields.” Id. (citing Ex. 1002 ¶ 35).
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`1 I note the specifications of the patents-in-suit are seemingly identical.
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`I understand the PTAB has adopted Petitioner’s definition of the level
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`15.
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`of ordinary skill in the art in IPR2016-01132 and IPR2016-01130. (IPR2016-
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`01132 Paper 8, at 7; IPR2016-00130 Paper 8, at 7-8). As of 2002-2003, I had at
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`least these qualifications of a person of skill in the art. I have applied this
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`definition of a person of ordinary skill in the art while conducting my analysis.
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`IV. Claim Construction
`16.
`I understand that in the context of the inter partes review of U.S.
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`Patent Nos. 8,629,111, the PTAB has construed the term “therapeutically
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`effective” to encompass both palliative and curative treatments of dry eye disease.
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`(IPR2016-01128 Paper 8, at 6-8). I have applied this definition in my analysis.
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`17.
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`I also understand that the PTAB has determined it was unnecessary to
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`expressly construe any other claim terms at this time. (Id. at 8-9). So, I have
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`interpreted other claim terms according to their ordinary and accustomed meaning
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`as one of ordinary skill in the art would understand them.
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`V.
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`Background
`18. A normal, healthy eye is protected by a layer of natural tear film. The
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`tear film is important to the health of the eye—tears protect the surface of the eye
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`from bacteria, moisten the eyes to prevent abrasion, and wash away foreign bodies
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`and irritants. Tears also deliver oxygen to the cornea, the transparent front part of
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`the eye that, along with the lens, refracts light and accounts for approximately two-
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`thirds of the eye’s optical power.
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`19. Dry eye is a disease affecting the ocular surface, the tear film and
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`related ocular tissues and organs. Stevenson et al., at 967 (EX. 1015). Dry eye is a
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`condition characterized by sensations of discomfort, ocular grittiness, burning,
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`irritation, photophobia and blurred vision, which can be frustrating for patients,
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`substantially altering their productivity and quality of life. Small et al., at 411-12
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`(EX. 1021). Some patients are unable to cry irritative or emotional tears. Kunert
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`et al., at 1489 (EX. 1012); Sall et al., at 631 (EX. 1007). Dry eye disease is not a
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`trivial matter. Rather, dry eye disease can be severe, debilitating and sight-
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`threatening. Depending on the duration and severity of the disease, damage to the
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`ocular surface may occur, and those with chronic, uncontrolled disease have an
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`increased risk of ocular infections. Stevenson et al., at 967 (EX. 1015).
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`20. Dry eye disease is commonly diagnosed using the Schirmer’s tear test
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`with anesthesia. In 2002-2003, the Schirmer’s tear test with anesthesia was the
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`primary test used to evaluate whether the lacrimal glands produce enough tears to
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`keep it moist. Even today, Schirmer’s tear test with anesthesia is a readily
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`available standard test used by ophthalmologists to diagnose dry eye disease, and
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`to determine whether a given treatment, like RESTASIS®, is working to increase a
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`patient’s tear production.
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`21. A Schirmer’s tear test is performed by placing a small strip of test
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`paper inside the lower eyelid. The eyes are closed for 5 minutes and then the paper
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`is removed and the amount of moisture absorbed on the paper is measured. The
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`Schirmer’s tear test is administered in conjunction with a topical anesthetic to
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`ensure that only basal tears, the tears produced by the lacrimal gland, are
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`measured, rather than reflexive tears which are produced in response to an irritant
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`(such as the test paper). Generally speaking, healthy persons normally moisten
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`about 15 mm or more of each paper strip after 5 minutes. Patients with mild dry
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`eye will moisten approximately 14-9 mm of the paper after 5 minutes, whereas
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`severe dry eye patients will moisten less than 4 mm in the same timeframe. A
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`person of skill in the art would understand that Schirmer’s tear test with anesthesia
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`was the primary test used to measure a patient’s basal tear production as of 2002-
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`2003.
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`22. Researchers have made significant advances in understanding the
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`pathology of dry eye disease. In normal individuals, neural reflexes control tear
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`secretion. Stimulation of the ocular surface induces neural stimulation of the
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`lacrimal glands which results in tear production. Under normal conditions in the
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`eye, trafficking immune cells, such as T-cells, migrate through the lacrimal glands
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`and ocular surface tissues in an inactivated state as part of the body’s
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`immunovigilance system. These T-cells undergo normal cell death as they exit the
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`lacrimal glands and travel toward the lymph nodes. Under normal conditions, the
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`ocular machinery is in a state of immunoquiescence and homeostasis is sustained.
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`Sall et al., at 637 (EX. 1007).
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`23. While the exact mechanism underlying dry eye disease has yet to be
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`fully elucidated, evidence suggests that dry eye results from multifactorial
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`etiologies that result in a common immune-based inflammation of the lacrimal
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`glands and ocular surface. Sall et al., at 631-32 (EX. 1007); Kunert et al., at 1497
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`(EX. 1012).
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`24. Two distinct mechanisms can trigger dry eye disease. First, a
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`localized autoimmune event occurs in the ocular tissues, which results in a loss of
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`normal hormonal and neurogenic support to the lacrimal tissues. This creates a
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`local environment that facilitates initiation of the inflammatory process, in which
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`activated T-cells are recruited to the ocular surface and lacrimal glands of dry eye
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`patients. Small et al., at 411-12 (EX. 1021). These T-cells play an important role
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`in the inflammatory response through cytokine synthesis, which in the case of dry
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`eye disease, further feeds the cycle of repeated inflammation and further T-cell
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`activation that can ultimately destroy the lacrimal glands. Small et al., at 411-12
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`(EX. 1021).
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`25. Second, chronic physical irritation to the ocular surfaces may occur,
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`as a result, for example, from environmental factors such as wind, low humidity,
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`elevated osmolarity, or increased abrasive forces from blinking over an ocular
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`surface with inadequate tear film. The result of this irritative pro-inflammatory
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`response is once again immune activation.
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`26. Either etiology alone or the combination of these etiologies results in
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`ocular surface inflammation with immune involvement and produces symptoms
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`that are indistinguishable in the patient.
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`27. Prior to the development of RESTASIS®, the most commonly used
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`treatment for dry eyes consisted of topical application of artificial tears and
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`lubricants. Kunert et al., at 1490 (EX. 1012). Artificial tears may provide
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`temporary comfort to the eye, but they do not mediate the immune-based
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`inflammatory process responsible for dry eye disease. Kunert et al., at 1490 (EX.
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`1012).
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`28. Steroids were also used to treat dry eye, but they were generally
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`recommended only for short-term use because prolonged application can result in
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`adverse events including ocular infection, delayed wound healing, glaucoma, and
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`cataracts. Agarwal & Rupenthal, at 1 (EX. 2011).
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`29. Additional measures used to treat dry eye disease include punctal
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`plugs and punctal surgery to restore tear volume. Murphy, at 2-3 (EX. 1020); Sall
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`et al., at 631 (EX. 1007). Punctal plugs, which can be either temporary or
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`permanent, partially alleviate the symptoms of dry eye disease by prohibiting tears
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`from draining from the eyes. Sall et al., at 631 (EX. 1007). In some extreme
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`cases, patients opt for punctal surgery, in which the tissue at the opening of the
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`punctum is cauterized, sealing the eye’s fluid drainage system permanently.
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`However, until RESTASIS® entered the market in 2003, there was no medication
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`or treatment on the market that increased tear production or directly impacted the
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`underlying immunological cause of dry eye disease.
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`VI. RESTASIS®, an emulsion of 0.05% cyclosporin A in a 1.25% castor oil
`vehicle
`30.
` RESTASIS® is a cyclosporin A oil-in-water emulsion developed by
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`Allergan. RESTASIS®, unlike any prior dry eye product, had the ability to
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`increase a patient’s own tear production. The proven increased tear production in
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`patients treated with RESTASIS® was critical to the FDA’s approval of the drug.
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`As a result, when RESTASIS® was approved, it received a label that stated it was
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`“indicated to increase tear production in patients whose tear production is
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`presumed to be suppressed due to ocular inflammation associated with
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`keratoconjunctivitis sicca.” RESTASIS® Label (EX. 2008). To this date,
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`RESTASIS® is the only product ever approved by the FDA to increase tear
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`production.
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`31. RESTASIS® is an emulsion that delivers cyclosporin A (CsA) to a
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`patient’s eye using a drug-delivery vehicle comprised of castor oil, water and other
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`excipients. (Id.)2 I understand that Allergan has represented to the FDA that
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`RESTASIS® is a commercial embodiment of the patents-in-suit. Approved Drug
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`Products with Therapeutic Equivalence Evaluations (37th. ed. 2017), Patent and
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`Exclusivity for N050790, Products 001 & 002,
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`http://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=001&
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`Appl_No=050790&Appl_type=N;
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`http://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?Product_No=002&
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`Appl_No=050790&Appl_type=N (EX. 2021).
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`32. Unlike prior dry eye treatments, the active ingredient in RESTASIS®,
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`cyclosporin A, directly treats the underlying immune-mediated inflammatory
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`disease. The RESTASIS® approval was groundbreaking, as it became the first
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`product to treat the underlying immune-modulated inflammatory condition that
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`causes dry eye. I prescribe RESTASIS® to my patients with dry eye disease
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`because it increases tear production as described in the RESTASIS® label and as is
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`claimed in the patents-in-suit.
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`33. CsA is a cyclic polypeptide that functions as an immunosuppressant.
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`Acheampong et al., U.S. 8,629,111 (EX. 1001), 9:7-8. CsA has previously been
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`2 An emulsion is a mixture of insoluble liquids. Unlike RESTASIS®, most
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`ophthalmic drugs are formulated as solutions or suspensions.
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`used to treat various autoimmune disorders, for example, uveitis, psoriasis,
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`rheumatoid arthritis, myasthenia gravis and diabetes mellitus type 1. Kanpolat et
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`al., at 119 (EX. 1018). CsA also possesses anti-inflammatory properties,
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`selectively inhibiting T lymphocyte activation. Kaswan, at 654 (EX. 1011).
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`34. CsA, when delivered to the eye, suppresses the immune-mediated
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`inflammatory process responsible for dry eye disease. While the exact mechanism
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`has yet to be elucidated, it is believed that CsA generally affects T-helper cells by
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`modulating their activation and ability to recruit additional T-cells to the ocular
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`surface tissues. Kaswan, at 650 (EX. 1011). By modulating activation of T-cells
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`on the ocular surface and lacrimal glands, CsA prevents the production of
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`inflammatory cytokines, which are necessary for the regulation and amplification
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`of inflammatory responses. Small et al., at 412 (EX. 1021); Turner et al., at 496
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`(EX. 1014). The disruption in inflammation, via inhibition of T-cell activation and
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`down-regulation of inflammatory cytokines in the conjunctiva and lacrimal gland,
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`is believed to result in enhanced tear production. Kaswan, at 650 (EX. 1011).
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`VII. 0.05% CsA in a 1.25% Castor Oil Vehicle Increases Tear Production
`and Treats Dry Eye
`35. This specific formulation of RESTASIS®—0.05% CsA in a 1.25%
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`castor oil vehicle3—is critical for increased tear production in dry eye patients.
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`36. To obtain FDA approval for RESTASIS®, Allergan conducted two
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`multicenter, randomized, double-masked Phase 3 clinical trials of the efficacy and
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`safety of cyclosporin ophthalmic emulsions in patients with moderate to severe dry
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`eye disease. Results of these trials were reported by Sall et al. Sall et al., at 631-
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`34 (EX. 1007).
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`37. The Phase 3 trial reported in Sall et al. involves the parallel
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`assessment of the efficacy and safety of emulsions containing 0.05% CsA in a
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`castor oil vehicle and 0.10% CsA in a castor oil vehicle for the treatment of dry
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`eye. Sall et al., at 632 (EX. 1007). The safety and efficacy of these formulations
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`were compared to a control castor oil vehicle. Sall et al., at 631-34 (EX. 1007).
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`In this study, the CsA/castor oil vehicle formulations were administered to patients
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`3 The 1.25% castor oil vehicle includes 1.25% castor oil, 1.00% polysorbate 80,
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`0.05% acrylate/C10-30 alkyl acrylate cross-polymer (e.g. Pemulen® TR-2,
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`Carbomer 1342), 2.20% glycerin, 0.397% sodium hydroxide, and 95% purified
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`water. NDA 21-023 (EX. 2001), tbl.3.3.2.1-1.
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`in separate groups twice a day and various measurements were tracked and
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`recorded. Sall et al., at 632-33 (EX. 1007).
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`38. Notably, Sall et al. did not disclose the specific compositions of the
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`formulations used in the Phase 3 clinical trials, other than noting the amount of
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`CsA in each formulation. Sall et al., at 631-34 (EX. 1007). Instead, the Sall
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`publication states “the CsA emulsions and vehicle were sterile, nonpreserved
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`castor oil in water emulsions whose precise formulation is proprietary.” Sall et al.,
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`at 632 (EX. 1007.) Thus, skilled artisans reading Sall et al. would not have known
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`the amount of castor oil in each formulation, including the control formulation, or
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`whether each of the formulations had the same amount of castor oil and other
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`excipients or not.
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`39. The shared specification of the patents-in-suit, which published in
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`2013, disclose the amount of castor oil vehicle in the formulations. Acheampong
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`et al., U.S. 8,629,111 (EX. 1001), 14:25-41. Specifically, the specification states
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`Composition I and Composition II were used in the “Phase 3, double-masked,
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`randomized, parallel group study for the treatment of dry eye disease.”
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`Acheampong et al., U.S. 8,629,111 (EX. 1001), 14:25-41. Composition I contains
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`0.1% CsA in a 1.25% castor oil vehicle and Composition II contains 0.05% CsA in
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`a 1.25% castor oil vehicle. Id. This portion of the specification is reproduced
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`below:
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`Id. It was only after the publication of the patents-in-suit that a skilled artisan
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`would have known the formulation of the compositions studied in the Phase 3
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`clinical trials.
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`40. Data from Allergan’s Phase 3 study confirm the RESTASIS®
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`formulation, which contains 0.05% CsA/1.25% castor oil vehicle, acts differently
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`than a formulation of 0.1% CsA/1.25% castor oil vehicle, and is critical for
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`increased tear production in dry eye patients. As discussed above, the primary
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`measure available for determining whether basal tear production was increased at
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`the time of the Phase 3 clinical studies was the Schirmer’s tear test with anesthesia.
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`The Schirmer’s tear test with anesthesia in Allergan’s Phase 3 clinical trials is
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`reported in Figure 2 of Sall et al., which reports the change from baseline in
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`categorized Schirmer values measured with anesthesia for patients who received
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`(a) 0.05% CsA, (b) 0.1% CsA, or (c) control vehicle after 3 and 6 months of
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`treatment. While it is now known that all three formulations in this study
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`contained 1.25% castor oil vehicle, as discussed above, skilled artisans did not
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`know the composition of the formulations, including the amount of castor oil in
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`each formulation, at the time of the Phase 3 study and after reading Sall et al.
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`Acheampong et al., U.S. 8,629,111 (EX. 1001), 14:14-25.
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`41. As discussed throughout this declaration, the Schirmer tear test with
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`anesthesia was the primary test for increased basal tear production as of 2002-
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`2003. Thus, a person of skill in the art reviewing Sall et al. would have
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`understood the data presented in Figure 2 reports on the ability of each formulation
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`to increase tear production. The data demonstrate that, at month 3, the Schirmer
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`tear test (with anesthesia) values for the group of patients treated with 0.05% CsA
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`was significantly greater than the control 1.25% castor oil vehicle group. In fact,
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`there was a significant worsening with the control 1.25% castor oil vehicle group
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`demonstrating the CsA—not the 1.25% castor oil vehicle—was responsible for the
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`therapeutic effect. This was also the case after 6 months of treatment. I note that
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`RESTASIS® was approved by the FDA specifically because of the statistically
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`significant increase in Schirmer tear test with anesthesia as shown in Sall et al.,
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`Fig. 2.
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`Id.
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`42. These data also demonstrate that the 0.05% CsA formulation resulted
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`
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`in a statistically significant change in tear production at month 3 as compared to
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`the control 1.25% castor oil vehicle whereas the 0.1% CsA formulation did not. At
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`month 6, the 0.05% CsA formulation increased tear production to a greater extent
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`than the 0.10% CsA formulation.
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`43.
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`I note U.S. Patent No. 5,981,607 patent (“Ding ’607”) (EX. 1010)
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`discloses Schirmer tear test results from the administration of a formulation
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`containing 2.5% castor oil (and no CsA). Ding ’607 (EX. 1010), 6:49-63. Ding
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`‘607 does not state whether the Schirmer tear tests were conducted with or without
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`anesthesia. As discussed above, the use of anesthetic in the Schirmer tear test
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`ensures that only basal tears produced by the lacrimal gland are measured, rather
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`than reflexive tears, which are produced in response to an irritant such as the test
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`strip itself. Thus, skilled artisans reviewing Ding ’607 would not know how the
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`data was generated (i.e., utilizing a Schirmer tear test with or without anesthesia)
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`and would not know whether the data reports on basal tearing or reflexive tearing.
`
`44.
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`In contrast to Ding ’607, the Schirmer tear test with anesthesia data
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`presented in Sall et al., Fig. 2 informs skilled artisans that the 1.25% castor oil
`
`vehicle formulation does not increase basal tear production. Based on the data
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`presented in Ding ’607 (which does not disclose whether the Schirmer tear test was
`
`conducted with or without anesthesia) and Sall Fig. 2 (in which the Schirmer tear
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`test was conducted with anesthesia and the 1.25% castor oil vehicle formulation
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`reduced tear production), a skilled artisan would not conclude the castor oil vehicle
`
`increased tear production.
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`45.
`
`I have also reviewed the declaration of Dr. Loftsson, and in particular,
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`I have reviewed his summary of the thermodynamic principles governing ocular
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`drug release from oil-in-water emulsions. Loftsson Decl’n (EX. 2025), ¶¶ 37-47.
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`I understand and agree with the principles disclosed in Dr. Loftsson’s declaration,
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`and for that reason, it is my opinion that skilled artisans would have expected less
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`CsA to be released from a formulation of 0.05% CsA in a 1.25% castor oil vehicle
`
`to the lacrimal glands as compared to a formulation of 0.1% CsA in a 1.25% castor
`
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`oil vehicle. It is further my opinion that it would have been unexpected that a
`
`formulation of 0.05% CsA in a 1.25% castor oil vehicle would be more effective at
`
`increasing tear production as compared to a formulation of 0.1% CsA in a 1.25%
`
`castor oil vehicle after three months of treatment, as demonstrated by Sall et al.
`
`Figure 2. Sall et al., fig.2 (EX. 1007). Similarly, it would have been unexpected
`
`that at month six, the 0.05% CsA/1.25% castor oil vehicle formulation increased
`
`tear production to a greater extent than the 0.10% CsA/1.25% castor oil vehicle
`
`formulation.
`
`46. Collectively, these data demonstrate that 0.05% CsA (and not the
`
`1.25% castor oil vehicle) is responsible for the therapeutic effects of RESTASIS®
`
`in restoring tear production and treating dry eye. As discussed above, the ability of
`
`RESTASIS® to increase tear production is unique and unexpected, and was critical
`
`to the FDA’s approval of RESTASIS®.
`
`47. Based on this data, it is my opinion that the specific formulation of
`
`RESTASIS®, 0.05% CsA in a 1.25% castor oil vehicle, acts differently than a
`
`0.1% CsA/1.25% castor oil vehicle formulation, and the formulation of
`
`RESTASIS® is critical to increasing tear production and treating dry eye disease.
`
`48.
`
`In addition, I have also reviewed the declarations submitted by Dr.
`
`Schiffman and Dr. Attar to the Patent Office. I note that they also concluded that
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`the specific combination of the 0.05% by weight cyclosporin in the 1.25% castor
`
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`oil vehicle is unexpectedly and surprisingly critical for optimal therapeutic
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`effectiveness.
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`VIII. Conclusion
`49.
`I currently hold the opinions set expressed in this declaration. But my
`
`analysis may continue, and I may acquire additional information and/or attain
`
`supplemental insights that may result in added observations.
`
`50.
`
`I declare that all statements made in this declaration are of my own
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`knowledge and are true and that all statements made on information and belief are
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`believed to be true; that these statements were made with the knowledge that
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`willful false statements and the like so made are punishable by fine or
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`imprisonment, or both under Section 1001 of Title 18 of the United States Code.
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`John D. Sheppard, M.D., M.M.Sc.
`
`
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`Respectfully submitted,
`
`Date: March 17, 2017
`
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`EXHIBIT A
`
`EXHIBIT A
`
`23
`
`23
`
`
`
`
`
`CURRICULUM VITAE
`
`John D. Sheppard, M.D.
`NAME
` OFFICE ADDRESS
`Virginia Eye Consultants
`241 Corporate Boulevard, Suite 210
`Norfolk, VA 23502*
`Fax: 757-622-4866
`Phone: 757-622-2200
`
` SATELLITE OFFICES
`*preferred mailing address
`2463 Pruden Blvd.
`2101 Executive Drive, Suite 160
`Suffolk, VA 23434
`Hampton, VA 23666
`
`757-925-1136
`
`Phone: 757-826-4702
`
`757-925-0353
`Fax: 757-826-3591
`
` HOME ADDRESS
`3274 Butlers Bluff Drive
`Cape Charles, VA 23310
`
`Fax: 757-331-3333
`Phone: 757-331-3131
`
` EMAIL ADDRESS
`jsheppard@vec2020.com, docshep@hotmail.com
` CITIZENSHIP
`United States of America
` MILITARY
`Navy, Medical Corps, retired
` ETHNIC/RACIAL SELF IDENTIFICATION
`
`non-Hispanic, white
` EDUCATION
` High School: Mt. Lebanon HS
`1968-71
`Magna Cum Laude
`1971-74
`Premedical: Brown University
`S.B. Biology
`1973-76
`Graduate: Brown University
`M.M.Sc. Medicine
`1974-78
`Medical: Brown University
`M.D. Signa Xi Honorary
`1987-89
`Doctoral: UCSF PhD Candidate
`Immunology
`1978-79
`Internship: University of Virginia
`Pediatrics
`1983-86
`Residency: University of Pittsburgh
`Ophthalmology
`Fellowship: Proctor Foundation UCSF
`Research, Cornea, Uveitis 1986-88
`Postdoctoral Training: Ph.D.
`Immunology (initial year) 1987-88
` MEDICAL LICENSURE
` State of Pennsylvania
`# MD-030015-E
`1983
`
`State of California
`# G 058805 (inactive)
`1986
`State of Virginia
`# 0101 043383
`
`1989
`Drug Enforcement Administration
`# AS 2337827
`
`1978
`American Board of Ophthalmology
`No expiration
`
`1988
`
`
`
`
`
`
`1
`
`24
`
`
`
`
`
`2
`
`HOSPITAL STAFF MEMBERSHIPS
` Sentara Norfolk General
`1989-Present
`1989-2014
`Children’s Hospital of the King’s Daughters
`1989-1999
`Hampton Veterans Administrative Hospital
`1989-1999
`Portsmouth Navy Regional Medical Center
`1986-1989
`University of California San Francisco
`1983-1986
`University of Pittsburgh Hospital
`1978-1979
`University of Virginia Hospital
` PROFESSIONAL AND HOSPITAL POSITIONS
` Virginia Eye Consultants, Norfolk, Virginia, Physician
`1989 - Present
`
`
`1989 - Present
`
`NRMC Portsmouth, Virginia, Cornea and Uveitis Consults
`1987-1988
`
`Kaiser Foundation, San Francisco, Corneal Consult
`
`1981-1983
`
`US Navy, NSA Detachment Gaeta, Chief of Family Medicine
`1980-1981
`
`US Navy, USS PUGET Sound AD-38, Operations Me
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