`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`APOTEX CORP.,
`Petitioner
`
`v.
`
`ALCON RESEARCH, LTD.,
`Patent Owner.
`
`
`Case IPR2013-00428
`U.S. Patent No. 8,268,299 B2
`
`
`
`
`DECLARATION OF RICHARD K. PARRISH, II, M.D.
`
`
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`
`
`1
`
`ALCON 2009
`Apotex Corp. v. Alcon Research, Ltd.
`Case IPR2013-00428
`
`
`
`
`
`
`
`I.
`
`
`I, Richard K. Parrish, II, M.D., hereby declare as follows:
`
`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.
`
`II. BACKGROUND AND QUALIFICATIONS
`3.
`I am the Director of the Glaucoma Service at the Bascom Palmer Eye
`
`Institute and a Professor in the Department of Ophthalmology at the University of
`
`Miami Miller School of Medicine. In that role, I oversee the coordination of all
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`glaucoma care and treatment at Bascom Palmer. I directly supervise seven faculty
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`members and four glaucoma fellows, all of whom focus their medical practices on
`
`teaching and patient care related to glaucoma. Collectively, in the past thirteen
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`months, we have provided glaucoma care in more than 26,000 outpatient visits and
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`1,400 surgical procedures.
`
`4.
`
`I maintain an active clinical practice involving all aspects of the
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`treatment of glaucoma, as I have done for more than 30 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
`
`2
`
`
`
`
`
`
`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 4,000 patients
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`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
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`for the American Board of Ophthalmology in three different years, and been
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`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
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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
`
`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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`Carolina School of Medicine, Case Western Reserve University, and Yale
`
`University School of Medicine. I have also mentored multiple doctors who have
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`gone on to assume senior glaucoma leadership positions within the U.S. military,
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`including the former heads of glaucoma at some of the military’s largest patient
`
`
`
`3
`
`
`
`
`
`care institutions. Dozens of fellows whom I have mentored over the years are now
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`faculty members and clinicians with a practice specialty in glaucoma at leading
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`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
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`continuing medical education related to glaucoma to practicing ophthalmologists
`
`for more than three decades. As one example, for the past ten years, I have
`
`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
`
`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
`
`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. I recently attended the
`
`Seventh International Congress of Glaucoma Surgery in Singapore, for example,
`
`where I lectured as an invited presenter. I have delivered more than 65 named or
`
`invited lectures around the world, almost all of which dealt with some aspect of the
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`treatment of glaucoma, including the John Lynn Lecture at the University of Texas
`
`Southwestern in Dallas, and similar lectures at McGill University in Montreal and
`
`
`
`4
`
`
`
`
`
`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
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`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 last year, 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
`
`comprised of 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
`
`Ophthalmology. I have served in a variety of leadership and editorial positions
`
`related to these publications, including current service as an executive editor for
`
`
`
`5
`
`
`
`
`
`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. AL 2010.
`
`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
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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.
`
`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
`
`on the clinical treatment of glaucoma, and one focused on glaucoma research—at
`
`
`
`6
`
`
`
`
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`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 $650 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. AL
`
`2010.
`
`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:
`
`2011
`
`2012
`
`2013
`
`2014
`
`Exhibit Description
`American Academy of Ophthalmology Glaucoma Panel. Preferred
`Practice Pattern® Guidelines: Primary Open-Angle Glaucoma. San
`Francisco, CA: American Academy of Ophthalmology, 2010. 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.
`7
`
`2015
`
`2016
`
`
`
`
`
`
`
`2017
`
`2018
`
`2019
`
`2020
`
`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.
`
`
`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,
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`more than 2.2 million people are known to suffer from glaucoma.3
`
`
`1 AL 2011, at 4, 6.
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`2 AL 2011, at 4.
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`3 AL 2011, at 4.
`
`
`
`8
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`
`
`
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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
`
`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
`
`4 AL 2011, at 17 (“Unless contraindicated, medical therapy is presently the most
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`common initial intervention to lower IOP.”).
`
`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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`6 AL 2011, at 17 (“Prostaglandin analogs are the most effective drugs at lowering
`
`IOP and can be considered as initial medical therapy unless other considerations
`
`such as cost, side effects, intolerance, or patient refusal preclude this.”).
`
`
`
`9
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`
`
`
`
`versions of XALATAN® (latanoprost) and TRAVATAN® (travoprost) are also
`
`now available.7
`
`20. Most PGAs available in the United States are preserved with
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`benzalkonium chloride (“BAK”). BAK is an FDA-approved antimicrobial agent
`
`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-
`
`inflammatories, and anti-infectives.
`
`21. As to the PGAs specifically, BAK is used in XALATAN® and
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`LUMIGAN®, and the generic equivalents to XALATAN® and TRAVATAN®.
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`When TRAVATAN®, the precursor to TRAVATAN Z®, was launched in the
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`United States, it also contained BAK as a preservative.
`
`22.
`
`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
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`usually are minor and infrequent, such as ocular irritation and scratchiness, foreign
`
`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
`
`efficacious as the other PGAs, as studies have shown. See AL 2012. It also
`
`requires more frequent dosing, and is preserved with benzalkonium chloride.
`
`
`
`10
`
`
`
`
`
`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.
`
`23. 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 In particular, the long-term use of BAK exacerbates
`
`the symptoms associated with various forms of ocular surface disease (“OSD”),9
`
`which 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 blephartis
`
`(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 lissanamine green staining), conjunctival chalasis (laxity of the
`
`conjunctiva, as determined biomicroscopic examination), filamentary keratitis (a
`
`
`8 See AL 2013.
`
`9 AL 2014; AL 2015; AL 2016.
`
`
`
`11
`
`
`
`
`
`condition arising from the presence of desquamated corneal epithelial cells and
`
`mucus on the cornea), among other physical findings.
`
`24. 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,
`
`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.
`
`25. 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
`
`10 AL 2017.
`
`11 AL 2017.
`
`
`
`12
`
`
`
`
`
`with the prescribed regimen, the use of ophthalmic formulations without BAK is
`
`preferred. Thus, for years prior to 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.
`
`26. 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
`
`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
`
`27.
`
`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. My clinical
`
`experience on this point aligns with what other clinicians and researchers also have
`
`
`12 AL 2018; AL 2014; AL 2015.
`
`
`
`13
`
`
`
`
`
`observed regarding the efficacy of TRAVATAN Z® as compared to these other
`
`PGAs.13
`
`28. Even though TRAVATAN Z®, TRAVATAN®, XALATAN® and
`
`LUMIGAN® are similar in efficacy, TRAVATAN Z® differs in that it does not
`
`contain or utilize BAK as its preservative systems. XALATAN®, LUMIGAN®,
`
`TRAVATAN®, and generic latanoprost each use BAK as their antimicrobial agent.
`
`29. ZIOPTAN™, which was 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. 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.
`
`30. 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 like XALATAN®, LUMIGAN®, TRAVATAN®, and
`
`13 AL 2019; AL 2020.
`
`
`
`14
`
`
`
`
`
`TRAVATAN Z®. 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. Furthermore, products like TIMOPTIC® in OCUDOSE®
`
`are formulated without any preservative because they are single-use products,
`
`making it considerably more expensive and less convenient (particularly for older
`
`patients) than products like TRAVATAN Z® and the other PGAs that are packaged
`
`for multiple uses.
`
`31.
`
`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 a patient responds to latanoprost but develops issues with
`
`tolerability or irritation, my practice is to switch the patient to TRAVATAN Z®.
`
`32. For those patients who present with OSD, however, I prescribe
`
`TRAVATAN Z® as the first-line treatment. TRAVATAN Z® is more expensive
`
`
`
`15
`
`
`
`
`
`than some other medical treatment options that may be similarly efficacious. None
`
`of the other medical treatment alternatives, however, provide a level of efficacy,
`
`tolerability, and reduced potential for the exacerbation of OSD symptoms that is
`
`comparable to TRAVATAN Z®.
`
`33. 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 this regard are
`
`consistent with the prescribing habits of most clinicians in the field who treat
`
`glaucoma.
`
`34.
`
`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.
`
`
`
`16
`
`
`
`
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