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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`Case IPR 2017-01053
`Patent 8,268,299
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
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`v.
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`ALCON RESEARCH, LTD.,
`Patent Owner
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`Case IPR2017-01053
`Patent 8,268,299
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`DECLARATION OF RICHARD K. PARRISH, II, M.D.
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`ALCON 2027
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
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`I.
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`I, Richard K. Parrish, II, M.D., hereby declare as follows:
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`Case IPR 2017-01053
`Patent 8,268,299
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`INTRODUCTION
`1.
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`I am over the age of eighteen and otherwise competent to make this
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`declaration.
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`2.
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`I have been retained as an expert witness for Alcon Research, Ltd.
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`(“Alcon”) to provide my professional opinion on certain issues relating to the care
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`and treatment of patients with glaucoma and elevated intraocular pressure. I have
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`also been asked to respond to certain points made in the declaration of Dr. Yvonne
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`M. Buys. See Ex. 1021.
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`II. BACKGROUND AND QUALIFICATIONS
`3.
`I am the Director of the Glaucoma Service at the Bascom Palmer Eye
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`Institute and the Edward W.D. Norton Chair of Ophthalmology and Professor in
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`the Department of Ophthalmology at the University of Miami Miller School of
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`Medicine. In those roles, I oversee the coordination of all glaucoma care and
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`treatment at Bascom Palmer. I directly supervise ten faculty members and four
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`glaucoma fellows, all of whom focus their medical practices on teaching and
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`patient care related to glaucoma. Collectively over the past thirteen months, we
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`have provided glaucoma care in more than 8,000 outpatient visits and 600 surgical
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`procedures.
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`I maintain an active clinical practice involving all aspects of the
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`4.
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`treatment of glaucoma, as I have done for more than 35 years. In fact, my clinical
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`practice today is limited almost exclusively to the treatment and management of
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`care of patients with glaucoma. Because of the nature of my practice, I often see
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`patients who present with some of the most complicated and advanced cases of
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`glaucoma. In the past thirteen months alone, I have seen more than 3,000 patients
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`and performed more than 200 surgical procedures as part of my glaucoma practice.
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`5.
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`I have been board certified in ophthalmology by the American Board
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`of Ophthalmology for more than 30 years. I have served as an Associate Examiner
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`for the American Board of Ophthalmology in three different years, and have been
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`invited to serve as an examiner on numerous other occasions.
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`6.
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`As the Director of the Glaucoma Service at Bascom Palmer, I am also
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`responsible for all of that institution’s research and educational activities with
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`respect to glaucoma. As part of these responsibilities, I oversee the training and
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`mentorship of our glaucoma fellows. These fellows are physicians who have been
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`selected for a one-year fellowship to immerse themselves in both the clinical
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`aspects of glaucoma treatment as well as clinical and laboratory research activities
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`related to glaucoma. Our fellows have gone on to become leaders in the field of
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`glaucoma research and care, including the Chairs of the Department of
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`Ophthalmology at the Medical College of Wisconsin, the University of North
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`Patent 8,268,299
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`Carolina School of Medicine, Case Western Reserve University, New York Eye
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`and Ear Infirmary of Mount Sinai, and Yale University School of Medicine. I have
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`also mentored multiple doctors who have gone on to assume senior glaucoma
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`leadership positions within the U.S. military, including the former heads of
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`glaucoma at some of the military’s largest patient care institutions. Dozens of
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`fellows whom I have mentored over the years are now faculty members and
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`clinicians with a practice specialty in glaucoma at leading academic institutions.
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`7.
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`Aside from, and in addition to, my teaching responsibilities at the
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`University of Miami Miller School of Medicine, I have been teaching courses and
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`continuing medical education related to glaucoma to practicing ophthalmologists
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`for more than three decades. As one example, in the past thirteen years, I have
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`organized and directed the annual Miami Mid-Winter Symposium on Glaucoma.
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`These symposia have been attended by more than 1,000 leading ophthalmologists
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`from all over the United States. I have presented frequently at these conferences
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`over the years on multiple glaucoma-related topics. I have also served as a visiting
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`professor at more than 30 different institutions around the world.
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`8.
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`I am an active attendee and participant in professional conferences
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`around the world that center on glaucoma and its treatment. For example, I
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`lectured as an invited presenter at the Seventh International Congress of Glaucoma
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`Surgery in Singapore. I have delivered more than 65 named or invited lectures
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`around the world, almost all of which dealt with some aspect of the treatment of
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`glaucoma, including the John Lynn Lecture at the University of Texas
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`Southwestern in Dallas, the Irvine Lecture at the Jules Stein Eye Institute at
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`UCLA, and similar lectures at McGill University in Montreal and at the University
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`of Louisville. I typically deliver about five named or invited lectures each year.
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`9.
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`I presently hold, or have recently held, senior leadership positions in a
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`number of professional organizations that relate to the research and treatment of
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`glaucoma. For example, I am a member of the American Glaucoma Society and
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`have served as the Society’s counselor and representative to the American
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`Academy of Ophthalmology. I am also a member of the American
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`Ophthalmologic Society and have served as the organization’s President. In past
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`years, I have also served on the Board of Directors of the Glaucoma Research
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`Society, an international organization dedicated to glaucoma research and
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`comprising physicians and researchers accepted for membership by the Society
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`based on a written thesis. I am also a member of the American Academy of
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`Ophthalmology, the American Medical Association, and numerous other
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`professional organizations.
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`10.
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`I am an editor or reviewer for more than twenty different medical
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`publications, including the highly-respected Archives of Ophthalmology,
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`Investigative Ophthalmology and Visual Science, and the American Journal of
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`Ophthalmology, for which I am now the Editor-in-Chief. I have served in a variety
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`of leadership and editorial positions related to these publications, including current
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`service as an executive editor for glaucoma for the American Journal of
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`Ophthalmology. I also serve on the editorial board of Ophthalmology Times.
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`11.
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`I have published more than 25 book chapters and 100 peer-reviewed
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`articles, along with more than 90 abstracts and other professional publications.
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`The vast majority of my publications deal with some aspect of glaucoma or its
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`treatment. A complete listing of my publications is contained in my curriculum
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`vitae. Ex. 2037.
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`12.
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`I am an active member of the medical community in Miami, devoting
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`time and resources to delivering medical care to underserved populations. As one
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`example, I serve on the Board of Directors of the Center for Haitian Studies. This
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`not-for-profit organization centered in Miami focuses in part on providing medical
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`treatment for the Haitian community in South Florida, a population with an
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`extraordinarily high rate of open-angle glaucoma. The organization has provided
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`free medical services to hundreds of patients within this at-risk community.
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`13.
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`I received my M.D. from the Indiana University School of Medicine
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`in 1976. I completed my internship at the University of Alabama, Birmingham in
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`1977, and my residency at the Wills Eye Hospital in Philadelphia in 1980. After
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`my residency, I completed two, one-year fellowships in glaucoma—one focused
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`on the clinical treatment of glaucoma, and one focused on glaucoma research—at
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`the Bascom Palmer Eye Institute. I have held academic and clinical positions since
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`I completed my fellowships.
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`14.
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`I am being compensated at the rate of $800 per hour. My
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`compensation is in no way dependent upon the outcome of this proceeding.
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`15. My complete background is described in my curriculum vitae. Ex.
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`2037.
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`III. MATERIALS CONSIDERED IN FORMULATING MY OPINION
`16.
`In formulating my opinion, I have relied upon my background
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`experience, education and knowledge of the field. I am also relying upon the
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`following documents:
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`1024
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`1025
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`Exhibit Description
`1021 Declaration of Dr. Yvonne M. Buys, M.D.
`1022 Declaration of Richard K. Parrish, II, M.D.
`1023 Dr. Yvonne M. Buys Curriculum Vitae
`Kass, M. et al., The Ocular Hypertension Treatment Study: A
`Randomized Trial Determines That Topical Ocular Hypotensive
`Medication Delays or Prevents the onset of Primary Open-Angle
`Glaucoma, Arch. Opthalmol. 2002;120:701-713.
`Mizoue, S. et al., Travoprost with sofZia® Preservative System Lowered
`Intraocular Pressure of Japanese Normal Tension Glaucoma With
`Minimal Side Effects, Clin. Opthalmol. 2014;8:347-354.
`1026 Bagnis, A., et al., Antiglaucoma Drugs: The Role of Preservative-Free
`Formulations, Saudi J. Opthalmol. 2011;25:389-394.
`Center for Drug Evaluation and Research, Medical Review, NDA No.
`21-994. Available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/
`021994s000TOC.cfm
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`2004
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`7
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`2128
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`2129
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`2130
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`2131
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`2132
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`2133
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`2134
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`Patent 8,268,299
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`2127 Transcript of Deposition of Yvonne M. Buys, M.D. (November 20,
`2017)
`FDA Approved Package insert for TRAVATAN Z® (Revised September
`2017. Available at:
`https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/
`files/travatan_z.pdf
`American Academy of Ophthalmology Glaucoma Panel. Preferred
`Practice Pattern® Guidelines: Primary Open-Angle Glaucoma. San
`Francisco, CA: American Academy of Ophthalmology, 2015. Available
`at: www.aao.org/ppp
`Sponsel, W. et al., Comparative effects of Latanoprost (Xalatan) and
`Unoprostone (Rescula) in patients with open-angle glaucoma and
`suspected glaucoma, Am. J. Ophthalmol. 2002:134, 552–59.
`Baudouin, C. et al., Conjunctival epithelial cell expression of
`interleukins and inflammatory markers in glaucoma patients treated over
`the long term, Ophthalmology 2004:111(12), 2186-2192.
`Katz, G. et al., Ocular surface disease in patients with glaucoma or
`ocular hypertension treated with either BAK-preserved latanoprost or
`BAK-free travoprost, Clin. Ophth. 2010:4, 1253-61.
`Henry, J. et al., Efficacy, safety, and improved tolerability of travoprost
`BAK-free ophthalmic solution compared with prior prostaglandin
`therapy, Clin. Ophth. 2008:2(3), 613-21.
`Baudouin, C. et al., In vitro studies of antiglaucomatous prostaglandin
`analogues: Travoprost with and without benzalkonium chloride and
`preserved latanoprost, Inv. Ophth. & Visual Sci. 2007:48(9), 4123-28.
`2135 Leung, E. et al., Prevalence of Ocular Surface Disease in Glaucoma
`Patients, J. Glaucoma 2008:17(5), 350-55.
`Kahook, M. et al., In vitro toxicity of topical ocular prostaglandin
`analogs and preservatives on corneal epithelial cells, J. of Ocular
`Pharmacol. & Thera. 2010:26(3), 259-63.
`Lewis, R. et al., Travoprost 0.004% with and without benzalkonium
`chloride: A comparison of safety and efficacy, J. Glaucoma 2007:16(1),
`98-103.
`Parrish, R. et al., A comparison of latanoprost, bimatoprost, and
`travoprost in patients with elevated intraocular pressure: A 12-week,
`randomized, masked-evaluator multicenter study, Am. J. of Ophth.
`2003:135(5), 688-703.
`2139 Hong, J. et al., Allergy to Ophthalmic Preservatives, Curr. Op. Allergy
`Clin. Immun. 2009:9;447–453.
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`2136
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`2137
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`2138
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`IV. TRAVATAN Z® SATISFIED A LONG-FELT NEED FOR A HIGHLY
`EFFECTIVE ANTIGLAUCOMA MEDICATION FREE OF
`BENZALKONIUM CHLORIDE
`17. Primary open-angle glaucoma is a disease characterized by chronic,
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`progressive damage to the optic nerve, usually associated with elevated intra-
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`ocular pressure (“IOP”).1 Elevated IOP results from a decrease in the amount of
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`aqueous humor flowing out from the eye. The disease is a significant problem;
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`primary open-angle glaucoma is the second-leading cause of blindness world-wide,
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`and is estimated to afflict 45 million people globally.2 In the United States alone,
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`more than 2.2 million people are known to suffer from glaucoma.3
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`18. The standard of care for the treatment of glaucoma today is to reduce
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`IOP, most often through a medication that lowers IOP.4 This preferred approach is
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`the same today as it was in 2006.5
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`1 Ex. 2129 at P50, P52.
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`2 Ex. 2129 at P50.
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`3 Ex. 2129 at P50.
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`4 Ex. 2129 at P64 (“Medical therapy is presently the most common initial
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`intervention to lower IOP.”).
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`5 If anything, in my experience, the use of medications as the first-line treatment
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`was slightly more prevalent in 2006 than today because some other alternatives—
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`laser therapies, in particular—were less advanced than they are today.
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`19. The most commonly used medications used to treat glaucoma patients
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`with elevated IOP are a class of drugs known as prostaglandin analogues
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`(“PGAs”).6 PGAs are advantageous given that they are generally well-tolerated
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`and need to be dosed only once per day. The PGAs available in 2006 in the United
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`States included TRAVATAN® (travoprost), XALATAN® (latanoprost), and
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`LUMIGAN® 0.03% (bimatoprost). Today, XALATAN® and LUMIGAN® (now, at
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`0.01%) are available in the United States, along with TRAVATAN Z®—a
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`successor product to TRAVATAN® with the same active ingredient (travoprost)
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`but a different preservative system—and ZIOPTAN® (tafluprost). Generic
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`versions of latanoprost, travoprost, and bimatoprost 0.03% are also now available.7
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`6 Ex. 2129 at P64 (“Prostaglandin analogs are the most frequently prescribed initial
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`eye drops for lowering IOP in patients with glaucoma because they are most
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`efficacious, well-tolerated, and instilled once daily. They are also relatively safe.
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`They are, therefore, often considered as initial medical therapy unless other
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`considerations, such as contraindications, cost, side effects, intolerance, or patient
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`refusal preclude this.”).
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`7 I do not consider RESCULA (unoprostone isopropyl) to be a PGA. It is a
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`prostanoid, meaning that it has some similarities to a PGA but is not a PGA. Even
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`if it were considered a PGA as a technical matter, from an ophthalmologic
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`perspective, I do not consider it a competitor to the other PGAs. It is not as
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`20. Aside from the PGAs there were a number of other classes of
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`medications available in 2006 to lower IOP, including beta blockers, alpha-2
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`agonists, topical carbonic anhydrase inhibitors and combination drugs. While
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`these various types of medications were available in 2006, they were generally not
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`as efficacious as PGAs in lowering IOP, and I prescribed them with far less
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`frequency than PGAs, if I prescribed them at all. I describe some of these
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`medications below. Based on my experience with other physicians in the field,
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`including among other things my attendance at professional lectures and
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`conferences, my review of the literature, and my daily interactions and
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`conversations with physicians treating glaucoma, I believe my prescribing
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`practices in that regard are consistent with others in the field.
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`21. Most PGAs available in the United States are preserved with
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`benzalkonium chloride (“BAK”). BAK is an FDA-approved antimicrobial agent
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`that is widely used in the formulation of ophthalmic products. It is used in
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`virtually every category of ophthalmic solutions, including anti-allergics, anti-
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`inflammatories, and anti-infectives.
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`22. As to the PGAs specifically, BAK is used in XALATAN®,
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`LUMIGAN®, and generic latanoprost, bimatoprost, and travoprost. When
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`efficacious as the other PGAs, as studies have shown. See Ex. 2130. It also
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`requires more frequent dosing, and is preserved with benzalkonium chloride.
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`TRAVATAN®, the precursor to TRAVATAN Z®, was launched in the United
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`States, it also contained BAK as a preservative.
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`23.
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`I have not observed any systemic side effects associated with BAK.
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`As to ocular side effects, in my experience, the side effects of acute use of BAK
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`usually are minor and infrequent, such as ocular irritation and scratchiness, foreign
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`body sensation, or blurring vision. It is particularly true that the ocular side effects
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`of BAK are generally minor and infrequent when BAK is used as a preservative in
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`ophthalmic formulations, such as ophthalmic antibiotics, that are used to treat acute
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`conditions, such as conjunctivitis or pink eye, for a short period of time—a period
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`of a few days.
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`24. BAK is cytotoxic, however, meaning that it can kill cells. As a
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`consequence of this cytotoxicity, long-term use of ophthalmic products containing
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`BAK can lead to serious ocular conditions in the eye relating to ocular surface
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`changes and corneal injury.8 One specific adverse effect associated with the long-
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`term use of BAK is that it exacerbates the symptoms associated with various forms
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`8 See Ex. 2131. The serious adverse consequences associated with BAK are
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`accepted by at least one of the references cited by Dr. Buys. See, e.g., Ex. 1026 at
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`391 (“Long-term use of topical drugs, especially those patients receiving a multiple
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`drop regimen, may be detrimental as a dose- and time-dependent consequence to
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`banzalkonium chloride exposure.”).
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`of ocular surface disease (“OSD”).9 OSD is characterized by decreased tear
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`secretion (as measured with a Schirmer test), increased rate of evaporation of the
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`tear-film layer (as measured by tear break-up time and/or increased tear
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`osmolarity), posterior margin blepharitis (chronic inflammation of the oil glands of
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`the eyelid), punctate epithelial erosion (damage to the corneal and/or conjunctival
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`epithelium, as determined by fluoroscein or lissamine green staining), conjunctival
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`chalasis (laxity of the conjunctiva, as determined biomicroscopic examination),
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`filamentary keratitis (a condition arising from the presence of desquamated corneal
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`epithelial cells and mucus on the cornea), among other physical findings.
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`25. OSD is a significant concern among clinicians like myself. As one of
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`the leading causes of patient visits to ophthalmologists, it is estimated that 15% of
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`individuals age 65 and over suffer from the symptoms of the disease.10 It is of
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`particular concern among clinicians when treating glaucoma patients. There is a
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`significant overlap in the population of individuals suffering from OSD and those
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`suffering from glaucoma because the prevalence of glaucoma and the prevalence
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`of OSD are both directly related to age. As a result, as individuals age, they
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`become more likely to develop both glaucoma and OSD.11 Moreover,
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`9 Ex. 2132; Ex. 2133; Ex. 2134.
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`10 Ex. 2135.
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`11 Ex. 2135.
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`antiglaucoma medications are used over a long-period of time, often extending to
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`decades for many patients. This long-term use translates into long-term exposure
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`to antimicrobial agents like BAK, which in turn, significantly increases the risk
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`that these patients, regardless of their age, will see a worsening of their OSD
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`symptoms as a result of the long-term BAK exposure.
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`26. Because the chronic use of BAK-containing ophthalmic formulations
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`over the long-term among patients with OSD will likely exacerbate their OSD
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`symptoms, and therefore decrease the likelihood of their continued compliance
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`with the prescribed regimen, the use of ophthalmic formulations without BAK is
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`preferred. For years prior to 2006, it had been recognized that, with chronic use,
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`BAK was associated with a risk of exacerbation of OSD symptoms. Nevertheless,
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`while PGAs were frequently used chronically to treat glaucoma and elevated IOP,
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`BAK-free formulations of PGAs were not available as of 2006. Thus, as of 2006,
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`there was a long-felt need among those treating glaucoma for a highly-effective,
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`BAK-free antiglauoma drug that would not lead to an increased risk of the
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`exacerbation of OSD symptoms with chronic use.
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`27. Because of its unique preservative system, TRAVATAN Z® satisfied
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`the long-felt, unmet need for a highly-effective, BAK-free antiglaucoma drug, and
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`has been particularly beneficial in patients that had worsening of the OSD
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`symptoms as a result of chronic exposure to BAK. TRAVATAN Z® does not
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`contain BAK. As a direct consequence of its lack of BAK, TRAVATAN Z® has a
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`less toxic effect on the ocular surface. This, in turn, leads to a decreased incidence
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`of the symptoms of OSD among patients with OSD who use TRAVATAN Z®.12
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`28. Dr. Buys faults me for not citing support for the “assertion that
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`TRAVATAN Z® does not result in an increased risk of the exacerbation of OSD
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`symptoms with chronic use.”13 I am not aware of any literature supporting the
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`view that TRAVATAN Z® leads to an increased risk of exacerbation of OSD
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`symptoms with chronic use, and have never heard that view expressed by other
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`physicians in the field, whether at professional lectures and conferences or in my
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`daily interactions and conversations with physicians treating glaucoma.
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`29.
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`In my experience, TRAVATAN Z® is as efficacious as
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`TRAVATAN®—its predecessor, which contains the same active ingredient,
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`travoprost, at the same concentration—and other most-widely prescribed PGAs,
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`including XALATAN®, LUMIGAN®, and generic latanoprost, bimatoprost, and
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`travoprost. My clinical experience on this point aligns with what other clinicians
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`and researchers also have observed regarding the efficacy of TRAVATAN Z® as
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`compared to these other PGAs.14
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`12 Ex. 2136; Ex. 2132; Ex. 2133.
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`13 Ex. 1021 ¶ 14.
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`14 Ex. 2137; Ex. 2138.
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`30. Dr. Buys seems to suggest that TRAVATAN Z® is not as efficacious
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`as other PGAs, opining that at least 10% of glaucoma patients (and in her
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`experience, an even larger percentage) either do not respond or do not adequately
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`respond to TRAVATAN Z®.15 The study on which Dr. Buys relies for her 10%
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`figure, however, says nothing about the ability of TRAVATAN Z® to lower
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`intraocular pressure in those patients with elevated intraocular pressure, which is
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`what TRAVATAN Z® is (and always has been) indicated to treat.16 The study
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`cited by Dr. Buys involves patients with normal range glaucoma, which is a
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`different condition altogether.17 Although PGAs are sometimes prescribed off-
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`label to treat patients with normal tension glaucoma, the effectiveness of
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`TRAVATAN Z® in this patient population says nothing about the effectiveness of
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`TRAVATAN Z® in patients with elevated intraocular pressure.
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`31. Dr. Buys states that her experience regarding the efficacy of
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`TRAVATAN Z® is consistent with a study by Kass et al.18 That study, however,
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`was conducted in its entirety and published more than three years before
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`15 Ex. 1021 ¶ 13.
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`16 Ex. 2004 at 47; Ex. 2128 at 2.
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`17 Ex. 1025 at 347.
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`18 Ex. 1021 ¶ 13.
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`TRAVATAN Z® was approved by the FDA.19 I therefore do not think the Kass
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`study speaks to the efficacy of TRAVATAN Z®. Additionally, there is no
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`information in that article about the percentage of patients who do not adequately
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`respond to any PGAs generally or to any specific PGA.
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`32. Even though TRAVATAN Z®, XALATAN®, LUMIGAN®, and
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`generic latanoprost, bimatoprost, and travoprost are similar in efficacy,
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`TRAVATAN Z® differs in that it does not contain or utilize BAK as its
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`preservative system. XALATAN®, LUMIGAN®, and generic latanoprost,
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`bimatoprost, and travoprost, each uses BAK to provide the preservative efficacy
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`needed in a multi-dose ophthalmic formulation.
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`33. While TRAVATAN Z® is not the only BAK-free glaucoma
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`medication on the market, those other BAK-free medications are not usually good
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`alternatives. ZIOPTAN®, introduced to the market in 2012, does not contain BAK;
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`it does not use any preservative at all. I do not consider ZIOPTAN® to be
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`comparable to the other PGAs. Unlike the other PGAs, ZIOPTAN® is formulated
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`as a single-use product, where the individual package contains a single dose and is
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`discarded after a single use. It is considerably more expensive than products like
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`XALATAN® and the other PGAs that are packaged for multiple uses. This type of
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`packaging also can, at times, be less convenient and harder for a patient to deliver.
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`19 Ex. 1024 at 701-03.
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`In my experience, based on my interactions with other clinicians treating
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`glaucoma, ZIOPTAN® is not considered to be a product comparable to the other
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`PGAs. ZIOPTAN®, of course, was not available in 2006 when TRAVATAN Z®
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`was first approved, and the patent application that led to the ’299 patent was filed.
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`34. There are some non-PGAs available for the long-term treatment of
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`glaucoma that do not contain BAK, but in my experience, these products are not
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`comparable to the PGAs. These products include the beta-blockers TIMOPTIC® in
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`OCUDOSE® (timolol maleate) and COSOPT™ PF (dorzolomide and timolol
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`maleate), and the alpha-2 agonist ALPHAGAN P® (brimonidine tartrate), both at
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`0.1% and 0.15%. I rarely, if ever, prescribe these products instead of a PGA in
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`patients for whom single medication therapy is indicated. They lack the efficacy of
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`the PGAs, they require application multiple times per day, and they carry other
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`undesirable side effects. They are generally used, rather, in combination with other
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`medications (particularly PGAs) in patients for whom a single medication does not
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`provide adequate IOP reduction; the seriousness of glaucoma leads physicians and
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`patients to accept the disadvantages of these non-PGA medications when therapy
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`with a PGA is insufficient and additional medication is needed.
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`35. Furthermore, products like TIMOPTIC® in OCUDOSE® are
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`formulated without any preservative because they are single-use products, making
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`them considerably more expensive and less convenient (particularly for older
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`patients) than products like TRAVATAN Z® and the other PGAs that are packaged
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`for multiple uses.
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`36.
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`In my clinical practice, I generally prescribe generic latanoprost as the
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`first-line treatment for those glaucoma patients who do not present with the signs
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`and symptoms of OSD. I do this because I find generic latanoprost to be equally
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`efficacious as compared either to LUMIGAN® or to TRAVATAN Z®, but more
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`affordable for the patient, particularly since a generic version of XALATAN®
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`entered the market. If the patient’s IOP responds adequately to latanoprost, but the
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`patient develops issues with tolerability or irritation, my practice is to switch the
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`patient to TRAVATAN Z®.
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`37. For those patients who present with OSD, however, I prescribe
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`TRAVATAN Z® as the first-line treatment. TRAVATAN Z® is more expensive
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`than some other medical treatment options that may be similarly efficacious,
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`particularly generic latanoprost. None of the other medical treatment alternatives,
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`however, provide the efficacy, tolerability, and reduced potential for the
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`exacerbation of OSD symptoms that is comparable to TRAVATAN Z®, which are
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`benefits attributable to TRAVATAN Z®’s BAK-free formulation. I prescribe it
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`rather than other PGAs because of this distinct advantage.
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`38. Based on my experience with other physicians in the field, including
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`among other things my attendance at professional lectures and conferences, my
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`19
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`Patent 8,268,299
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`review of the literature, and my daily interactions and conversations with
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`physicians treating glaucoma, I believe my prescribing practices in this regard are
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`consistent with the prescribing habits of most clinicians in the field who treat
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`glaucoma.
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`39. Dr. Buys claims that, in her opinion, the population of patients in need
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`of a BAK-free antiglaucoma medication is smaller than the 15% of individuals
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`over the age of 65 who suffer from OSD.20 Dr. Buys bases her opinion on her
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`practice of prescribing TRAVATAN Z® only to those patients whom she knows
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`are allergic to BAK, and, according to Dr. Buys, only 8% of patients are allergic to
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`BAK. I disagree with Dr. Buys. The 8% figure she suggests is unreliable and,
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`frankly, irrelevant. Although Dr. Buys cites an article by Bagnis et al.21 as the
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`source of her 8% figure, the Bagnis article itself relies on an article by Hong et al.22
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`Reviewing the Hong article reveals that the 8% figure does not represent the
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`percentage of people with a BAK allergy; instead, it is the percentage of search
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`results in the PubMED and OVID databases for the terms “BAC and preservatives
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`and ophthalmology” that also contain the term “irritant.”23 This is not a rigorous or
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`20 See Ex. 1021 ¶ 12.
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`21 Ex. 1026.
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`22 Ex. 1026 at 391 (quoting Ex. 2139 at “Recent Findings”).
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`23 Ex. 2139 at Table 2.
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`accepted methodto determine the percentage of individuals with a BAK allergy.
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`Evenif it were, however, Hong reported the percentage of search results for the
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`terms “BACand preservatives and ophthalmology”that also contain the term
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`“allergic” as 19% in the OVID database and 7% in the PubMEDdatabase.”*
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`Accepting the methodological flaws here for the sake of argument, Hong’s
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`additional search results mean that the 8% figure likely underestimates the
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`percentage of people allergic to BAK.
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`40.
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`I prescribe TRAVATANZ® becauseofits clinical efficacy and
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`because it reduces the risk of worsening the symptomsassociated with OSD.
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`Based on my experience with other physicians in the field, including among other
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`things my attendanceat professional lectures and conferences, my review of the
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`literature, and my daily interactions and conversations with physicianstreating
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`glaucoma, such prescribing practices are consistent with the prescribing habits of
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`most clinicians in the field who treat glaucoma.
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`Respectfully submitted,
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`Dated la}: AIAG! id
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`D1 A Posehn
`. Alien
`kK \ ouehopW)
`
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`Richard K.Parrish, If, M.D.
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`24 See Ex. 2139 at Table 2.
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`21
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`