`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Case IPR 2017-01053
`Patent 8,268,299
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner
`
`
`Case IPR2017-01053
`Patent 8,268,299
`
`
`DECLARATION OF RICHARD K. PARRISH, II, M.D.
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`ALCON 2027
`Argentum Pharm. LLC v. Alcon Research, Ltd.
`Case IPR2017-01053
`
`

`

`
`
`
`
`
`I.
`
`
`
`
`I, Richard K. Parrish, II, M.D., hereby declare as follows:
`
`Case IPR 2017-01053
`Patent 8,268,299
`
`INTRODUCTION
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an expert witness for Alcon Research, Ltd.
`
`(“Alcon”) to provide my professional opinion on certain issues relating to the care
`
`and treatment of patients with glaucoma and elevated intraocular pressure. I have
`
`also been asked to respond to certain points made in the declaration of Dr. Yvonne
`
`M. Buys. See Ex. 1021.
`
`II. BACKGROUND AND QUALIFICATIONS
`3.
`I am the Director of the Glaucoma Service at the Bascom Palmer Eye
`
`Institute and the Edward W.D. Norton Chair of Ophthalmology and Professor in
`
`the Department of Ophthalmology at the University of Miami Miller School of
`
`Medicine. In those roles, I oversee the coordination of all glaucoma care and
`
`treatment at Bascom Palmer. I directly supervise ten faculty members and four
`
`glaucoma fellows, all of whom focus their medical practices on teaching and
`
`patient care related to glaucoma. Collectively over the past thirteen months, we
`
`have provided glaucoma care in more than 8,000 outpatient visits and 600 surgical
`
`procedures.
`
`2
`
`
`

`

`
`
`
`Case IPR 2017-01053
`
`Patent 8,268,299
`
`I maintain an active clinical practice involving all aspects of the
`
`4.
`
`treatment of glaucoma, as I have done for more than 35 years. In fact, my clinical
`
`practice today is limited almost exclusively to the treatment and management of
`
`care of patients with glaucoma. Because of the nature of my practice, I often see
`
`patients who present with some of the most complicated and advanced cases of
`
`glaucoma. In the past thirteen months alone, I have seen more than 3,000 patients
`
`and performed more than 200 surgical procedures as part of my glaucoma practice.
`
`5.
`
`I have been board certified in ophthalmology by the American Board
`
`of Ophthalmology for more than 30 years. I have served as an Associate Examiner
`
`for the American Board of Ophthalmology in three different years, and have been
`
`invited to serve as an examiner on numerous other occasions.
`
`6.
`
`As the Director of the Glaucoma Service at Bascom Palmer, I am also
`
`responsible for all of that institution’s research and educational activities with
`
`respect to glaucoma. As part of these responsibilities, I oversee the training and
`
`mentorship of our glaucoma fellows. These fellows are physicians who have been
`
`selected for a one-year fellowship to immerse themselves in both the clinical
`
`aspects of glaucoma treatment as well as clinical and laboratory research activities
`
`related to glaucoma. Our fellows have gone on to become leaders in the field of
`
`glaucoma research and care, including the Chairs of the Department of
`
`Ophthalmology at the Medical College of Wisconsin, the University of North
`
`
`
`3
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`Carolina School of Medicine, Case Western Reserve University, New York Eye
`
`and Ear Infirmary of Mount Sinai, and Yale University School of Medicine. I have
`
`also mentored multiple doctors who have gone on to assume senior glaucoma
`
`leadership positions within the U.S. military, including the former heads of
`
`glaucoma at some of the military’s largest patient care institutions. Dozens of
`
`fellows whom I have mentored over the years are now faculty members and
`
`clinicians with a practice specialty in glaucoma at leading academic institutions.
`
`7.
`
`Aside from, and in addition to, my teaching responsibilities at the
`
`University of Miami Miller School of Medicine, I have been teaching courses and
`
`continuing medical education related to glaucoma to practicing ophthalmologists
`
`for more than three decades. As one example, in the past thirteen years, I have
`
`organized and directed the annual Miami Mid-Winter Symposium on Glaucoma.
`
`These symposia have been attended by more than 1,000 leading ophthalmologists
`
`from all over the United States. I have presented frequently at these conferences
`
`over the years on multiple glaucoma-related topics. I have also served as a visiting
`
`professor at more than 30 different institutions around the world.
`
`8.
`
`I am an active attendee and participant in professional conferences
`
`around the world that center on glaucoma and its treatment. For example, I
`
`lectured as an invited presenter at the Seventh International Congress of Glaucoma
`
`Surgery in Singapore. I have delivered more than 65 named or invited lectures
`
`
`
`4
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`around the world, almost all of which dealt with some aspect of the treatment of
`
`glaucoma, including the John Lynn Lecture at the University of Texas
`
`Southwestern in Dallas, the Irvine Lecture at the Jules Stein Eye Institute at
`
`UCLA, and similar lectures at McGill University in Montreal and at the University
`
`of Louisville. I typically deliver about five named or invited lectures each year.
`
`9.
`
`I presently hold, or have recently held, senior leadership positions in a
`
`number of professional organizations that relate to the research and treatment of
`
`glaucoma. For example, I am a member of the American Glaucoma Society and
`
`have served as the Society’s counselor and representative to the American
`
`Academy of Ophthalmology. I am also a member of the American
`
`Ophthalmologic Society and have served as the organization’s President. In past
`
`years, I have also served on the Board of Directors of the Glaucoma Research
`
`Society, an international organization dedicated to glaucoma research and
`
`comprising physicians and researchers accepted for membership by the Society
`
`based on a written thesis. I am also a member of the American Academy of
`
`Ophthalmology, the American Medical Association, and numerous other
`
`professional organizations.
`
`10.
`
`I am an editor or reviewer for more than twenty different medical
`
`publications, including the highly-respected Archives of Ophthalmology,
`
`Investigative Ophthalmology and Visual Science, and the American Journal of
`
`
`
`5
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`Ophthalmology, for which I am now the Editor-in-Chief. I have served in a variety
`
`of leadership and editorial positions related to these publications, including current
`
`service as an executive editor for glaucoma for the American Journal of
`
`Ophthalmology. I also serve on the editorial board of Ophthalmology Times.
`
`11.
`
`I have published more than 25 book chapters and 100 peer-reviewed
`
`articles, along with more than 90 abstracts and other professional publications.
`
`The vast majority of my publications deal with some aspect of glaucoma or its
`
`treatment. A complete listing of my publications is contained in my curriculum
`
`vitae. Ex. 2037.
`
`12.
`
`I am an active member of the medical community in Miami, devoting
`
`time and resources to delivering medical care to underserved populations. As one
`
`example, I serve on the Board of Directors of the Center for Haitian Studies. This
`
`not-for-profit organization centered in Miami focuses in part on providing medical
`
`treatment for the Haitian community in South Florida, a population with an
`
`extraordinarily high rate of open-angle glaucoma. The organization has provided
`
`free medical services to hundreds of patients within this at-risk community.
`
`13.
`
`I received my M.D. from the Indiana University School of Medicine
`
`in 1976. I completed my internship at the University of Alabama, Birmingham in
`
`1977, and my residency at the Wills Eye Hospital in Philadelphia in 1980. After
`
`my residency, I completed two, one-year fellowships in glaucoma—one focused
`
`
`
`6
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`on the clinical treatment of glaucoma, and one focused on glaucoma research—at
`
`the Bascom Palmer Eye Institute. I have held academic and clinical positions since
`
`I completed my fellowships.
`
`14.
`
`I am being compensated at the rate of $800 per hour. My
`
`compensation is in no way dependent upon the outcome of this proceeding.
`
`15. My complete background is described in my curriculum vitae. Ex.
`
`2037.
`
`III. MATERIALS CONSIDERED IN FORMULATING MY OPINION
`16.
`In formulating my opinion, I have relied upon my background
`
`experience, education and knowledge of the field. I am also relying upon the
`
`following documents:
`
`1024
`
`1025
`
`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
`
`2004
`
`
`
`7
`
`

`

`2128
`
`2129
`
`2130
`
`2131
`
`2132
`
`2133
`
`2134
`
`Case IPR 2017-01053
`
`Patent 8,268,299
`
`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.
`
`2136
`
`2137
`
`2138
`
`8
`
`
`
`
`
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`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,
`
`progressive damage to the optic nerve, usually associated with elevated intra-
`
`ocular pressure (“IOP”).1 Elevated IOP results from a decrease in the amount of
`
`aqueous humor flowing out from the eye. The disease is a significant problem;
`
`primary open-angle glaucoma is the second-leading cause of blindness world-wide,
`
`and is estimated to afflict 45 million people globally.2 In the United States alone,
`
`more than 2.2 million people are known to suffer from glaucoma.3
`
`18. The standard of care for the treatment of glaucoma today is to reduce
`
`IOP, most often through a medication that lowers IOP.4 This preferred approach is
`
`the same today as it was in 2006.5
`
`
`1 Ex. 2129 at P50, P52.
`
`2 Ex. 2129 at P50.
`
`3 Ex. 2129 at P50.
`
`4 Ex. 2129 at P64 (“Medical therapy is presently the most common initial
`
`intervention to lower IOP.”).
`
`5 If anything, in my experience, the use of medications as the first-line treatment
`
`was slightly more prevalent in 2006 than today because some other alternatives—
`
`laser therapies, in particular—were less advanced than they are today.
`
`
`
`9
`
`

`

`
`
`
`Case IPR 2017-01053
`
`Patent 8,268,299
`
`19. The most commonly used medications used to treat glaucoma patients
`
`with elevated IOP are a class of drugs known as prostaglandin analogues
`
`(“PGAs”).6 PGAs are advantageous given that they are generally well-tolerated
`
`and need to be dosed only once per day. The PGAs available in 2006 in the United
`
`States included TRAVATAN® (travoprost), XALATAN® (latanoprost), and
`
`LUMIGAN® 0.03% (bimatoprost). Today, XALATAN® and LUMIGAN® (now, at
`
`0.01%) are available in the United States, along with TRAVATAN Z®—a
`
`successor product to TRAVATAN® with the same active ingredient (travoprost)
`
`but a different preservative system—and ZIOPTAN® (tafluprost). Generic
`
`versions of latanoprost, travoprost, and bimatoprost 0.03% are also now available.7
`
`6 Ex. 2129 at P64 (“Prostaglandin analogs are the most frequently prescribed initial
`
`eye drops for lowering IOP in patients with glaucoma because they are most
`
`efficacious, well-tolerated, and instilled once daily. They are also relatively safe.
`
`They are, therefore, often considered as initial medical therapy unless other
`
`considerations, such as contraindications, cost, side effects, intolerance, or patient
`
`refusal preclude this.”).
`
`7 I do not consider RESCULA (unoprostone isopropyl) to be a PGA. It is a
`
`prostanoid, meaning that it has some similarities to a PGA but is not a PGA. Even
`
`if it were considered a PGA as a technical matter, from an ophthalmologic
`
`perspective, I do not consider it a competitor to the other PGAs. It is not as
`
`
`
`10
`
`

`

`
`
`
`Case IPR 2017-01053
`
`Patent 8,268,299
`
`20. Aside from the PGAs there were a number of other classes of
`
`medications available in 2006 to lower IOP, including beta blockers, alpha-2
`
`agonists, topical carbonic anhydrase inhibitors and combination drugs. While
`
`these various types of medications were available in 2006, they were generally not
`
`as efficacious as PGAs in lowering IOP, and I prescribed them with far less
`
`frequency than PGAs, if I prescribed them at all. I describe some of these
`
`medications below. Based on my experience with other physicians in the field,
`
`including among other things my attendance at professional lectures and
`
`conferences, my review of the literature, and my daily interactions and
`
`conversations with physicians treating glaucoma, I believe my prescribing
`
`practices in that regard are consistent with others in the field.
`
`21. Most PGAs available in the United States are preserved with
`
`benzalkonium chloride (“BAK”). BAK is an FDA-approved antimicrobial agent
`
`that is widely used in the formulation of ophthalmic products. It is used in
`
`virtually every category of ophthalmic solutions, including anti-allergics, anti-
`
`inflammatories, and anti-infectives.
`
`22. As to the PGAs specifically, BAK is used in XALATAN®,
`
`LUMIGAN®, and generic latanoprost, bimatoprost, and travoprost. When
`
`efficacious as the other PGAs, as studies have shown. See Ex. 2130. It also
`
`requires more frequent dosing, and is preserved with benzalkonium chloride.
`
`
`
`11
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`TRAVATAN®, the precursor to TRAVATAN Z®, was launched in the United
`
`States, it also contained BAK as a preservative.
`
`23.
`
`I have not observed any systemic side effects associated with BAK.
`
`As to ocular side effects, in my experience, the side effects of acute use of BAK
`
`usually are minor and infrequent, such as ocular irritation and scratchiness, foreign
`
`body sensation, or blurring vision. It is particularly true that the ocular side effects
`
`of BAK are generally minor and infrequent when BAK is used as a preservative in
`
`ophthalmic formulations, such as ophthalmic antibiotics, that are used to treat acute
`
`conditions, such as conjunctivitis or pink eye, for a short period of time—a period
`
`of a few days.
`
`24. BAK is cytotoxic, however, meaning that it can kill cells. As a
`
`consequence of this cytotoxicity, long-term use of ophthalmic products containing
`
`BAK can lead to serious ocular conditions in the eye relating to ocular surface
`
`changes and corneal injury.8 One specific adverse effect associated with the long-
`
`term use of BAK is that it exacerbates the symptoms associated with various forms
`
`8 See Ex. 2131. The serious adverse consequences associated with BAK are
`
`accepted by at least one of the references cited by Dr. Buys. See, e.g., Ex. 1026 at
`
`391 (“Long-term use of topical drugs, especially those patients receiving a multiple
`
`drop regimen, may be detrimental as a dose- and time-dependent consequence to
`
`banzalkonium chloride exposure.”).
`
`
`
`12
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`of ocular surface disease (“OSD”).9 OSD is characterized by decreased tear
`
`secretion (as measured with a Schirmer test), increased rate of evaporation of the
`
`tear-film layer (as measured by tear break-up time and/or increased tear
`
`osmolarity), posterior margin blepharitis (chronic inflammation of the oil glands of
`
`the eyelid), punctate epithelial erosion (damage to the corneal and/or conjunctival
`
`epithelium, as determined by fluoroscein or lissamine green staining), conjunctival
`
`chalasis (laxity of the conjunctiva, as determined biomicroscopic examination),
`
`filamentary keratitis (a condition arising from the presence of desquamated corneal
`
`epithelial cells and mucus on the cornea), among other physical findings.
`
`25. OSD is a significant concern among clinicians like myself. As one of
`
`the leading causes of patient visits to ophthalmologists, it is estimated that 15% of
`
`individuals age 65 and over suffer from the symptoms of the disease.10 It is of
`
`particular concern among clinicians when treating glaucoma patients. There is a
`
`significant overlap in the population of individuals suffering from OSD and those
`
`suffering from glaucoma because the prevalence of glaucoma and the prevalence
`
`of OSD are both directly related to age. As a result, as individuals age, they
`
`become more likely to develop both glaucoma and OSD.11 Moreover,
`
`9 Ex. 2132; Ex. 2133; Ex. 2134.
`
`10 Ex. 2135.
`
`11 Ex. 2135.
`
`
`
`13
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`antiglaucoma medications are used over a long-period of time, often extending to
`
`decades for many patients. This long-term use translates into long-term exposure
`
`to antimicrobial agents like BAK, which in turn, significantly increases the risk
`
`that these patients, regardless of their age, will see a worsening of their OSD
`
`symptoms as a result of the long-term BAK exposure.
`
`26. Because the chronic use of BAK-containing ophthalmic formulations
`
`over the long-term among patients with OSD will likely exacerbate their OSD
`
`symptoms, and therefore decrease the likelihood of their continued compliance
`
`with the prescribed regimen, the use of ophthalmic formulations without BAK is
`
`preferred. For years prior to 2006, it had been recognized that, with chronic use,
`
`BAK was associated with a risk of exacerbation of OSD symptoms. Nevertheless,
`
`while PGAs were frequently used chronically to treat glaucoma and elevated IOP,
`
`BAK-free formulations of PGAs were not available as of 2006. Thus, as of 2006,
`
`there was a long-felt need among those treating glaucoma for a highly-effective,
`
`BAK-free antiglauoma drug that would not lead to an increased risk of the
`
`exacerbation of OSD symptoms with chronic use.
`
`27. Because of its unique preservative system, TRAVATAN Z® satisfied
`
`the long-felt, unmet need for a highly-effective, BAK-free antiglaucoma drug, and
`
`has been particularly beneficial in patients that had worsening of the OSD
`
`symptoms as a result of chronic exposure to BAK. TRAVATAN Z® does not
`
`
`
`14
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`contain BAK. As a direct consequence of its lack of BAK, TRAVATAN Z® has a
`
`less toxic effect on the ocular surface. This, in turn, leads to a decreased incidence
`
`of the symptoms of OSD among patients with OSD who use TRAVATAN Z®.12
`
`28. Dr. Buys faults me for not citing support for the “assertion that
`
`TRAVATAN Z® does not result in an increased risk of the exacerbation of OSD
`
`symptoms with chronic use.”13 I am not aware of any literature supporting the
`
`view that TRAVATAN Z® leads to an increased risk of exacerbation of OSD
`
`symptoms with chronic use, and have never heard that view expressed by other
`
`physicians in the field, whether at professional lectures and conferences or in my
`
`daily interactions and conversations with physicians treating glaucoma.
`
`29.
`
`In my experience, TRAVATAN Z® is as efficacious as
`
`TRAVATAN®—its predecessor, which contains the same active ingredient,
`
`travoprost, at the same concentration—and other most-widely prescribed PGAs,
`
`including XALATAN®, LUMIGAN®, and generic latanoprost, bimatoprost, and
`
`travoprost. My clinical experience on this point aligns with what other clinicians
`
`and researchers also have observed regarding the efficacy of TRAVATAN Z® as
`
`compared to these other PGAs.14
`
`
`12 Ex. 2136; Ex. 2132; Ex. 2133.
`
`13 Ex. 1021 ¶ 14.
`
`14 Ex. 2137; Ex. 2138.
`
`
`
`15
`
`

`

`
`
`
`Case IPR 2017-01053
`
`Patent 8,268,299
`
`30. Dr. Buys seems to suggest that TRAVATAN Z® is not as efficacious
`
`as other PGAs, opining that at least 10% of glaucoma patients (and in her
`
`experience, an even larger percentage) either do not respond or do not adequately
`
`respond to TRAVATAN Z®.15 The study on which Dr. Buys relies for her 10%
`
`figure, however, says nothing about the ability of TRAVATAN Z® to lower
`
`intraocular pressure in those patients with elevated intraocular pressure, which is
`
`what TRAVATAN Z® is (and always has been) indicated to treat.16 The study
`
`cited by Dr. Buys involves patients with normal range glaucoma, which is a
`
`different condition altogether.17 Although PGAs are sometimes prescribed off-
`
`label to treat patients with normal tension glaucoma, the effectiveness of
`
`TRAVATAN Z® in this patient population says nothing about the effectiveness of
`
`TRAVATAN Z® in patients with elevated intraocular pressure.
`
`31. Dr. Buys states that her experience regarding the efficacy of
`
`TRAVATAN Z® is consistent with a study by Kass et al.18 That study, however,
`
`was conducted in its entirety and published more than three years before
`
`
`15 Ex. 1021 ¶ 13.
`
`16 Ex. 2004 at 47; Ex. 2128 at 2.
`
`17 Ex. 1025 at 347.
`
`18 Ex. 1021 ¶ 13.
`
`
`
`16
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`TRAVATAN Z® was approved by the FDA.19 I therefore do not think the Kass
`
`study speaks to the efficacy of TRAVATAN Z®. Additionally, there is no
`
`information in that article about the percentage of patients who do not adequately
`
`respond to any PGAs generally or to any specific PGA.
`
`32. Even though TRAVATAN Z®, XALATAN®, LUMIGAN®, and
`
`generic latanoprost, bimatoprost, and travoprost are similar in efficacy,
`
`TRAVATAN Z® differs in that it does not contain or utilize BAK as its
`
`preservative system. XALATAN®, LUMIGAN®, and generic latanoprost,
`
`bimatoprost, and travoprost, each uses BAK to provide the preservative efficacy
`
`needed in a multi-dose ophthalmic formulation.
`
`33. While TRAVATAN Z® is not the only BAK-free glaucoma
`
`medication on the market, those other BAK-free medications are not usually good
`
`alternatives. ZIOPTAN®, introduced to the market in 2012, does not contain BAK;
`
`it does not use any preservative at all. I do not consider ZIOPTAN® to be
`
`comparable to the other PGAs. Unlike the other PGAs, ZIOPTAN® is formulated
`
`as a single-use product, where the individual package contains a single dose and is
`
`discarded after a single use. It is considerably more expensive than products like
`
`XALATAN® and the other PGAs that are packaged for multiple uses. This type of
`
`packaging also can, at times, be less convenient and harder for a patient to deliver.
`
`
`19 Ex. 1024 at 701-03.
`
`
`
`17
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`In my experience, based on my interactions with other clinicians treating
`
`glaucoma, ZIOPTAN® is not considered to be a product comparable to the other
`
`PGAs. ZIOPTAN®, of course, was not available in 2006 when TRAVATAN Z®
`
`was first approved, and the patent application that led to the ’299 patent was filed.
`
`34. There are some non-PGAs available for the long-term treatment of
`
`glaucoma that do not contain BAK, but in my experience, these products are not
`
`comparable to the PGAs. These products include the beta-blockers TIMOPTIC® in
`
`OCUDOSE® (timolol maleate) and COSOPT™ PF (dorzolomide and timolol
`
`maleate), and the alpha-2 agonist ALPHAGAN P® (brimonidine tartrate), both at
`
`0.1% and 0.15%. I rarely, if ever, prescribe these products instead of a PGA in
`
`patients for whom single medication therapy is indicated. They lack the efficacy of
`
`the PGAs, they require application multiple times per day, and they carry other
`
`undesirable side effects. They are generally used, rather, in combination with other
`
`medications (particularly PGAs) in patients for whom a single medication does not
`
`provide adequate IOP reduction; the seriousness of glaucoma leads physicians and
`
`patients to accept the disadvantages of these non-PGA medications when therapy
`
`with a PGA is insufficient and additional medication is needed.
`
`35. Furthermore, products like TIMOPTIC® in OCUDOSE® are
`
`formulated without any preservative because they are single-use products, making
`
`them considerably more expensive and less convenient (particularly for older
`
`
`
`18
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`patients) than products like TRAVATAN Z® and the other PGAs that are packaged
`
`for multiple uses.
`
`36.
`
`In my clinical practice, I generally prescribe generic latanoprost as the
`
`first-line treatment for those glaucoma patients who do not present with the signs
`
`and symptoms of OSD. I do this because I find generic latanoprost to be equally
`
`efficacious as compared either to LUMIGAN® or to TRAVATAN Z®, but more
`
`affordable for the patient, particularly since a generic version of XALATAN®
`
`entered the market. If the patient’s IOP responds adequately to latanoprost, but the
`
`patient develops issues with tolerability or irritation, my practice is to switch the
`
`patient to TRAVATAN Z®.
`
`37. For those patients who present with OSD, however, I prescribe
`
`TRAVATAN Z® as the first-line treatment. TRAVATAN Z® is more expensive
`
`than some other medical treatment options that may be similarly efficacious,
`
`particularly generic latanoprost. None of the other medical treatment alternatives,
`
`however, provide the efficacy, tolerability, and reduced potential for the
`
`exacerbation of OSD symptoms that is comparable to TRAVATAN Z®, which are
`
`benefits attributable to TRAVATAN Z®’s BAK-free formulation. I prescribe it
`
`rather than other PGAs because of this distinct advantage.
`
`38. Based on my experience with other physicians in the field, including
`
`among other things my attendance at professional lectures and conferences, my
`
`
`
`19
`
`

`

`Case IPR 2017-01053
`
`
`Patent 8,268,299
`
`
`review of the literature, and my daily interactions and conversations with
`
`physicians treating glaucoma, I believe my prescribing practices in this regard are
`
`consistent with the prescribing habits of most clinicians in the field who treat
`
`glaucoma.
`
`39. Dr. Buys claims that, in her opinion, the population of patients in need
`
`of a BAK-free antiglaucoma medication is smaller than the 15% of individuals
`
`over the age of 65 who suffer from OSD.20 Dr. Buys bases her opinion on her
`
`practice of prescribing TRAVATAN Z® only to those patients whom she knows
`
`are allergic to BAK, and, according to Dr. Buys, only 8% of patients are allergic to
`
`BAK. I disagree with Dr. Buys. The 8% figure she suggests is unreliable and,
`
`frankly, irrelevant. Although Dr. Buys cites an article by Bagnis et al.21 as the
`
`source of her 8% figure, the Bagnis article itself relies on an article by Hong et al.22
`
`Reviewing the Hong article reveals that the 8% figure does not represent the
`
`percentage of people with a BAK allergy; instead, it is the percentage of search
`
`results in the PubMED and OVID databases for the terms “BAC and preservatives
`
`and ophthalmology” that also contain the term “irritant.”23 This is not a rigorous or
`
`
`20 See Ex. 1021 ¶ 12.
`
`21 Ex. 1026.
`
`22 Ex. 1026 at 391 (quoting Ex. 2139 at “Recent Findings”).
`
`23 Ex. 2139 at Table 2.
`
`
`
`20
`
`

`

`Case [PR 201 7-01053
`
`Patent 8,268,299
`
`accepted method to determine the percentage of individuals with a BAK allergy.
`
`Even if it were, however, Hong reported the percentage of search results for the
`
`terms “BAC and preservatives and ophthalmology” that also contain the term
`
`“allergic” as 19% in the OVID database and 7% in the PubMED database.24
`
`Accepting the methodological flaws here for the sake of argument, Hong’s
`
`additional search results mean that the 8% figure likely underestimates the
`
`percentage of people allergic to BAK.
`
`40.
`
`I prescribe TRAVATAN Z® because of its clinical efficacy and
`
`because it reduces the risk of worsening the symptoms associated with OSD.
`
`Based on my experience with other physicians in the field, including among other
`
`things my attendance at professional lectures and conferences, my review of the
`
`literature, and my daily interactions and conversations with physicians treating
`
`glaucoma, such prescribing practices are consistent with the prescribing habits of
`
`most clinicians in the field who treat glaucoma.
`
`Respectfully submitted,
`
`Dated 13L ' Ll
`
`:'
`
`[:31 ‘7
`
`-/
`'
`
`_.
`y
`,
`01 K7
`‘
`“tr/LAM K \ WL-LLA‘LKLDMO
`
`
`
`Richard K. Parrish, 11, MD.
`
`24 See EX. 2139 at Table 2.
`
`21
`
`