`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`APOTEX CORP.
`APOTEX, INC.
`Petitioner
`
`v.
`
`ALLERGAN, INC.
`Patent Owner
`
`U.S. Patent No. 8,629,111
`_____________________
`
`Case To be assigned
`_____________________
`
`DECLARATION OF CHRISTOPHER N. TA, M.D.
`
`APOTEX 1007
`
`

`

`
`
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`TABLE OF CONTENTS
`Overview .......................................................................................................... 1 
`I. 
`II.  My background and qualifications .................................................................. 2 
`III.  Summary of opinions ....................................................................................... 5 
`IV.  List of documents I considered in formulating my opinions ........................... 7 
`V. 
`Person of ordinary skill in the art .................................................................... 9 
`VI.  Basis of my analysis with respect to obviousness and objective indicia of
`non-obviousness ............................................................................................ 10 
`VIII.  Dry eye background ....................................................................................... 12 
`i.  Symptoms and diagnosis of dry eye ...................................................... 12 
`ii.  Causes of dry eye ................................................................................... 13 
`iii.  Dry eye treatments were known before 2003 ........................................ 14 
`IX.  The '111 patent ............................................................................................... 19 
`X. 
`The '979 patent is the closest prior art ........................................................... 20 
`XI.  The inventions as claimed in the '111 patent do not show unexpectedly
`superior results over the closest prior art ....................................................... 21 
`i.  Exhibit B of the Schiffman Declaration ................................................ 22 
`ii.  Exhibit C of the Schiffman Declaration ................................................ 28 
`iii.  Exhibit D of the Schiffman Declaration ................................................ 31 
`iv.  Exhibits E and F of the Schiffman Declaration ..................................... 44 
`XII.  The inventions as claimed in the '111 patent do not satisfy a long-felt unmet
`need for a therapeutic treatment for dry eye .................................................. 48 
`i.  There was no long-felt, unmet, need for a dry eye treatment ................ 48 
`ii.  Any purported need for a therapeutic treatment for dry eye would have
`been satisfied by the prior art ................................................................. 49 
`XIII.  The industry praise referenced by Dr. Schiffman is generally directed to
`topical cyclosporine A treatments, not Restasis ............................................ 50 
`XIV.  The second Schiffman Declaration does not show a "failure of others" ....... 52 
`XV.  Conclusion ..................................................................................................... 54 
`
`
`
`
`- i -
`
`APOTEX 1007
`
`

`

`
`
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`I, Christopher N .Ta, hereby declare as follows.
`
`I.
`
`Overview
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of APOTEX CORP.
`
`and APOTEX, INC. ("APOTEX") for the above-captioned inter partes review (IPR). I
`
`am being compensated for my time in connection with this IPR at my standard
`
`consulting rate, which is $500 per hour for time less than one hour, then $375 per
`
`hour thereafter. I understand that the petition for inter partes review involves U.S.
`
`Patent No. 8,629,111 ("the '111 patent"), Exhibit 1001, which resulted from U.S.
`
`Application No. 13/967,163 ("the '163 application"), filed on August 14, 2013,
`
`naming Andrew Acheampong, Diane D. Tang-Liu, James N. Chang, and David F.
`
`Power as inventors. The '111 patent issued on January 14, 2014, from the '163
`
`application. I further understand that, according to the USPTO records, the '111
`
`patent is currently assigned to Allergan, Inc. ("the patentee"). I understand that the
`
`earliest possible priority date for the '111 patent is September 15, 2003.
`
`3.
`
`I understand that independent claims 1, 13, and 18 of the '111 patent
`
`are directed to topical ophthalmic emulsions comprising cyclosporine A,
`
`polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer, water, and castor oil.
`
`I understand that these claims specifically recite a topical ophthalmic emulsion
`
`
`
`- 1 -
`
`APOTEX 1007
`
`

`

`
`
`
`comprising 0.05% by weight cyclosporine A and 1.25% by weight castor oil. I
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`understand that claims 11 and 16 of the '111 patent recite that the topical
`
`emulsions, when administered to the eye of a human, show substantially no
`
`detectable blood levels of cyclosporine A. I understand that claims 17 and 20-27 of
`
`the '111 patent recite topical ophthalmic emulsions that are therapeutically
`
`effective for treating dry eye, keratoconjunctivitis sicca, and increasing tear
`
`production.
`
`II.
`
`My background and qualifications
`
`4.
`
`I am an expert in the field of ophthalmology and the treatment of
`
`patients suffering from ophthalmological disorders. I have been an expert in this
`
`field since before 2003.
`
`5.
`
`I am presently Professor of Ophthalmology at Stanford University
`
`School of Medicine. I am Board Certified in Ophthalmology by the American
`
`Board of Ophthalmology. In my practice, I routinely see and treat patients with dry
`
`eye. My curriculum vitae is provided as Exhibit 1008.
`
`6.
`
`I earned a Bachelor of Arts degree in Physiology from the University
`
`of Minnesota in 1990. I earned an M.D. from University of Minnesota Medical
`
`School in 1994. I completed an internship in internal medicine at Kaiser
`
`Permanente Hospital in Oakland, CA, in 1995. I completed my residency in
`
`ophthalmology at Stanford University Medical Center in 1998. I completed a
`
`
`
`- 2 -
`
`APOTEX 1007
`
`

`

`
`
`
`fellowship in cornea, external diseases, and refractive surgery at the University of
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`Texas Southwestern (Dallas, TX) in 1999. I worked as Acting Assistant Professor
`
`at the Stanford University School of Medicine from 1999-2000, and as Assistant
`
`Professor at Stanford University School of Medicine from 2000-2006. I served as
`
`Associate Professor at Stanford University School of Medicine from 2007-2012. I
`
`became Professor at Stanford University School of Medicine in 2012 and continue
`
`to serve as Professor there today. Throughout my career, I have had extensive
`
`experience consulting, diagnosing, and treating patients with ophthalmologic
`
`conditions, including dry eye. I also have extensive experience evaluating patient
`
`responses to different ophthalmological formulations.
`
`7.
`
`I have
`
`received several honors
`
`in my career
`
`related
`
`to
`
`ophthalmological conditions and treatment, such as the Biodesign Certificate of
`
`Appreciation, Stanford Biodesign (2011); Best Paper Award, American Academy
`
`of Ophthalmology (2008); American Academy of Ophthalmology Achievement
`
`Award, American Academy of Ophthalmology
`
`(2008); America’s Top
`
`Ophthalmologist, Consumers’ Research Council of America (2007-2009); Best
`
`Poster Award, European Society of Cataract and Refractive Surgery Conference
`
`(2005); Stanford Leadership Development Program (2005-2006); Office of
`
`Technology and Licensing Research Incentive Fund Award (2005); Alpha Omega
`
`Alpha (1993); and Phi Beta Kappa Honor Society (1990).
`
`
`
`- 3 -
`
`APOTEX 1007
`
`

`

`
`
`
`
`8.
`
`In addition to my clinical practice and my duties as a professor, I am
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`also actively involved in scientific research programs. My research interests
`
`include ocular infections, dry eye, cornea transplantation, artificial cornea, and
`
`ocular graft-versus-host disease. I have been awarded research funding from many
`
`different sources, including the Stanford University BioX Award (2002); American
`
`Society of Cataract and Refractive Surgery Research Grant (2008); Singapore Eye
`
`Research Institute (2007-2010); and the National Institutes of Health (2007-2012).
`
`9.
`
`I am the author or co-author of numerous medical publications
`
`involving ophthalmological conditions and treatment. I have also authored or co-
`
`authored book chapters in the field and given numerous presentations at medical
`
`and scientific conferences. I regularly attend scientific and medical conferences
`
`where I interact with others in the field of ophthalmology. A complete list of my
`
`publications and presentations is found in my curriculum vitae (Exhibit 1008). I
`
`have served as a peer reviewer for over 20 different journals and serve as an
`
`Editorial Board Member for Advances in Therapy; Graefes Archives of Clinical
`
`and Experimental Ophthalmology; and Journal of Clinical and Experimental
`
`Ophthalmology.
`
`10.
`
`I am a member of or affiliated with a number of organizations related
`
`to ophthalmology, including the American Academy of Ophthalmology, Peninsula
`
`Eye Society, The Cornea Society, and Max Fine Society.
`
`
`
`- 4 -
`
`APOTEX 1007
`
`

`

`
`
`
`
`11.
`
`I have served and currently serve on many committees related to
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`ophthalmology and medicine. For example, I have served as Residency SF Match
`
`Auditor; Residency Selection Committee; Interviewer of applicants for Stanford
`
`School of Medicine, and Ophthalmic News & Educations (ONE) by the American
`
`Academy of Ophthalmology. I have also served on the Data Safety and Monitoring
`
`Committee for clinical trials, including serving as Chairman of the Committee for
`
`"Episcleral implant for the prevention of allograft rejection after cornea
`
`transplantation."
`
`12.
`
`In view of my education, experience, and expertise described above, I
`
`am an expert in the field of ophthalmology and the treatment of ophthalmological
`
`conditions.
`
`III. Summary of opinions
`
`13.
`
`In this declaration, I consider the ophthalmic emulsions of the '111
`
`patent in relation to the state of the art as of September 15, 2003. I also consider
`
`the Declarations of Drs. Rhett M. Schiffman and Mayassa Attar, and the data and
`
`references cited therein. See Exhibit 1019, pp. 246-289 and 301-414. I understand
`
`that Allergan submitted the Schiffman and Attar Declarations to the United States
`
`Patent and Trademark Office to support the purported patentability of the '111
`
`patent claims. A summary of my opinions follows.
`
`
`
`- 5 -
`
`APOTEX 1007
`
`

`

`
`
`
`
`14. First, I disagree with the conclusions drawn by Drs. Schiffman and
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`Attar in their respective declarations regarding the purported "unexpected" results
`
`achieved by the formulations of the '111 patent. The data presented in the
`
`Schiffman and Attar Declarations do not support the declarants' conclusions that
`
`the ophthalmic emulsions claimed in the '111 patent provided unexpectedly
`
`superior results over the closest prior art. Instead, a closer look at Allergan's data in
`
`the Schiffman and Attar declarations shows that, at best, the formulations as
`
`claimed in the '111 patent exhibited properties that were comparable to – not
`
`superior to – the closest prior art, and were not unexpected. Furthermore, the data
`
`presented in the Schiffman and Attar declarations are missing key information. The
`
`omissions and uncertainties surrounding these data render them unreliable.
`
`15. Second, I disagree with Dr. Schiffman's assertion that there was a
`
`long-felt, unmet need for the ophthalmic emulsions claimed in the '111 patent
`
`before September 15, 2003. I am not aware of any evidence showing that a long-
`
`felt, unmet need existed before 2003. I note that Dr. Schiffman does not provide
`
`any evidence of a long-felt, unmet need that was recognized in the art as of this
`
`date. Moreover, even if a long-felt, unmet need did exist, the need would have
`
`been satisfied by disclosures in the prior art before September 15, 2003.
`
`16. Third, I have reviewed the documents cited in Dr. Schiffman’s second
`
`declaration, and I disagree that the documents show industry praise for the
`
`
`
`- 6 -
`
`APOTEX 1007
`
`

`

`
`
`
`formulations of the '111 patent. Instead, the documents provide quotations from
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`physicians who describe their general approval of treating patients with topical
`
`cyclosporine A—a treatment known in the art before 2003. See, e.g., Exhibit 1004.
`
`Dr. Schiffman's documents further show that the same physicians' preferred
`
`treatment for dry eye patients is a combination of topical cyclosporine A and other
`
`dry eye treatments, such as topical steroids or other anti-inflammatory therapies.
`
`17. Finally, I disagree with Dr. Schiffman's opinions that other companies
`
`have tried and "failed" to produce a therapeutic treatment for dry eye. I am not
`
`aware of any evidence that other companies tried to develop a therapeutic
`
`treatment for dry eye but "failed" due to technical reasons and not due to
`
`commercial or business reasons. I note that Dr. Schiffman does not provide any
`
`evidence to show that any alleged failure to develop the formulation as claimed
`
`was due to technical reasons.
`
`IV. List of documents I considered in formulating my opinions
`
`18.
`
`In formulating my opinions, I considered all of the references cited
`
`herein, including the documents listed below.
`
`Exhibit No.
`
`1001
`
`1002
`1003
`
`Description
`U.S. Patent No. 8,629,111 to Acheampong et al. (issued January
`14, 2014)
`U.S. Patent No. 5,981,607 to Ding et al. (filed January 20, 1998;
`issued November 9, 1999)
`U.S. Patent No. 5,474,979 to Ding et al. (filed May 17, 1994;
`
`
`
`- 7 -
`
`APOTEX 1007
`
`

`

`Exhibit No.
`
`1004
`
`1014
`
`1017
`
`1019
`
`1020
`
`1022
`
`1023
`
`1028
`
`1029
`
`1030
`
`1033
`
`1035
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`Description
`issued December 12, 1995)
`Sall, K. et al., "Two Multicenter, Randomized Studies of the
`Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in
`Moderate to Severe Dry Eye Disease," Ophthalmology, 107(4):631-
`639 (2000)
`Freeman, J.M., "The punctum plug: evaluation of a new treatment
`for the dry eye" Trans. Sect. Ophthalmol. Am. Acad. Ophthalmol.
`Otaryngol., 79(6):874-879 (1975)
`Acheampong, A. et al., "Cyclosporine Distribution into the
`Conjunctiva, Cornea, Lacrimal Gland, and Systemic Blood
`Following Topical Dosing of Cyclosporine to Rabbit, Dog, and
`Human Eyes," in Lacrimal Gland, Tear Film, and Dry Eye
`Syndromes 2 – Basic Science and Clinical Relevance, Plenum
`Press, New York (1998), Ch. 144, pp. 1001-1004
`File History of U.S. Patent No. 8,629,111
`Murphy, R., "The Once and Future Treatment of Dry Eye," Review
`of Optometry (January, 2000), available from
`http://legacy.revoptom.com/archive/FEATURES/ro0200f6.htm, last
`accessed January 5, 2015
`Solomon, A. et al., "Doxycycline Inhibition of Interleukin-1
`in the Corneal Epithelium," Invest. Ophthalmology & Visual Sci.
`41(9):2544-2557 (2000)
`Stevenson, D. et al., "Efficacy and Safety of Cyclosporine A
`Ophthalmic Emulsion in the Treatment of Moderate-to-severe Dry
`Eye Disease," Ophthalmology, 107(5):967-974 (2000)
`Pflugfelder, S.C. et al., "The Diagnosis and Management of Dry
`Eye - A Twenty-five–Year Review," Cornea 19(5):644–649 (2000)
`Albietz, J.M., "Dry eye: an update on clinical diagnosis,
`management and promising new treatments," Clin. & Exp.
`Optometry 84:4-18 (2001)
`Liu, K. et al., "Synthetic Approaches to the 2010 New Drugs,"
`Bioorganic & Medicinal Chemistry 20: 1155-1174 (2012)
`Goto, E. et al., "Low-concentration Homogenized Castor Oil Eye
`Drops for Noninflamed Obstructive Meibomian Gland
`Dysfunction," Ophthalmology 109(11):2030-2035 (2002)
`Yeh, S. et al., "Apoptosis of Ocular Surface Cells in
`
`- 8 -
`
`APOTEX 1007
`
`

`

`
`
`
`
`Exhibit No.
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`Description
`Experimentally Induced Dry Eye," Invest. Ophthalmology & Visual
`Sci. 44(1):124-129 (2003)
`Lemp, M.A., "Report of the National Eye Institute/Industry
`Workshop on Clinical Trials in Dry Eyes," CLAO 21(4):221-232
`(1995)
`Gilbard, J.P., "Dry Eye, Blepharitis, and Chronic Eye Irritation:
`Divide and Conquer," J. Ophthalmic Nurs. Technol. 18(3):109-115
`(1999)
`Napper, G. et al., "Ocular therapeutics," Clin. & Exp. Optometry
`86:414-415 (2003)
`Allergan's 2002 Annual Report, downloaded from
`http://agn.client.shareholder.com/financials.cfm, last accessed
`January 16, 2015
`Taban, M. et al., "Update on Punctal Plugs," Comp. Ophthalmology
`Update 7(5):205-2012 (2006)
`Chanana, G.D. et al., "Particle Size Reduction of Emulsions by
`Formulation Design-II: Effect of Oil and Surfactant Concentration,"
`PDA J. Pharm. Sci. & Tech., 49(2):71-76 (1995)
`Chung, H. et al., "Oil components modulate physical characteristics
`and function of the natural oil emulsions as drug or gene delivery
`system," J. Controlled Release 71:339- 350 (2001)
`V. Person of ordinary skill in the art
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`19.
`
`I understand that a person of ordinary skill in the art ("POSA") is a
`
`hypothetical person who is presumed to be aware of all pertinent art, thinks along
`
`conventional wisdom in the art, and is a person of ordinary creativity. With
`
`respect to the subject matter of the '111 patent, a POSA would typically have had
`
`(i) an M.D. or a Ph.D. in chemistry, biochemistry, pharmaceutics, or in a related
`
`field in biological or chemical sciences, and have about two years of experience in
`
`the formulation of topical ophthalmics; or (ii) a Master's degree in chemistry,
`
`
`
`- 9 -
`
`APOTEX 1007
`
`

`

`
`
`
`biochemistry, pharmaceutics, or in a related field in biological or chemical
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`sciences, and have at least five years of experience in the formulation of topical
`
`ophthalmics.
`
`20. A POSA typically would work as part of a multidisciplinary team and
`
`draw upon not only his or her own skills, but also take advantage of certain
`
`specialized skills of others in the team to solve a given problem. For example, a
`
`clinician having experience in treating dry eye may be part of the team. A POSA
`
`would have been aware of other important information and references relating to
`
`dry eye, its causes, and useful treatments.
`
`VI. Basis of my analysis with respect to obviousness and objective indicia of
`non-obviousness
`21.
`
`I understand that an obviousness analysis involves comparing a patent
`
`claim to the prior art to determine whether the claimed invention would have been
`
`obvious to a person of ordinary skill in the art in view of the prior art, and in light
`
`of the general knowledge in the art. I also understand when a person of ordinary
`
`skill in the art would have reached the claimed invention through routine
`
`experimentation, the invention may be deemed obvious. I also understand that
`
`obviousness can be established by combining or modifying the teachings of the
`
`prior art to achieve the claimed invention.
`
`
`
`- 10 -
`
`APOTEX 1007
`
`

`

`
`
`
`
`22.
`
`I understand that, in considering the obviousness of an invention, one
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`must also consider whether there are any objective indicia0F
`
`1 that support the non-
`
`obviousness of the invention. I understand that some objective indicia of non-
`
`obviousness include unexpectedly superior results, long-felt but unmet need,
`
`failure of others, and perception in the industry.
`
`23.
`
`I understand that "unexpectedly superior results" can be evidence of
`
`non-obviousness if the patent owner shows that the results achieved with the
`
`invention as claimed are different from the results of the prior art, and that the
`
`results have a significant and practical advantage. I also understand that
`
`unexpectedly superior results must be achieved with an embodiment of the claimed
`
`invention.
`
`24.
`
`I understand that a long-felt but unmet need may be evidence of non-
`
`obviousness when objective evidence shows (i) the need was a persistent need in
`
`the prior art that was recognized by those of ordinary skill in the art; (ii) the need
`
`was not satisfied by another product, technology, or disclosure in the art before the
`
`invention claimed in the patent; and (iii) the invention claimed in the patent
`
`satisfies the long-felt need. I also understand that actual evidence of a long-felt
`
`
`1 I understand that objective indicia of non-obviousness are sometimes
`
`called secondary considerations of non-obviousness.
`
`
`
`- 11 -
`
`APOTEX 1007
`
`

`

`
`
`
`need (e.g., evidence of the need recognized in the prior art) must be provided to
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`prove the existence of the need, as opposed to mere argument.
`
`25.
`
`I understand that "failure of others" can be evidence of non-
`
`obviousness where competitors have sought over a span of several years to develop
`
`the drug in question. I understand that for such efforts to be considered evidence of
`
`non-obviousness, the "failure" must be due to technical difficulties, as opposed to
`
`business or commercial reasons.
`
`26.
`
`I understand that praise in the industry can be evidence of non-
`
`obviousness; and that commercial acquiescence to the patent rights – such as by
`
`extensive licensing – can be evidence of non-obviousness.
`
`27.
`
`I understand that any objective indicia of non-obviousness must have
`
`a nexus, or "close connection" to novel aspects of the claimed invention. I further
`
`understand that objective evidence resulting from something that is not both
`
`claimed and novel in the claim lacks a nexus to the merits of the invention.
`
`VIII. Dry eye background
`i. Symptoms and diagnosis of dry eye
`28. Before September 15, 2003, dry
`
`eye
`
`(also known
`
`as
`
`keratoconjunctivitis sicca or KCS—see, e.g., Exhibit 1001, col. 2, lines 65-67;
`
`Exhibit 1002, col. 6, lines 25-27; and Exhibit 1003, col. 5, lines 10-12) was defined
`
`as "a disorder of the tear film due to tear deficiency or excessive evaporation that
`
`
`
`- 12 -
`
`APOTEX 1007
`
`

`

`
`
`
`causes damage to the interpalpebral ocular surface and is associated with
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`symptoms of discomfort." Exhibit 1036, p. 2; Exhibit 1028, p. 2. Dry eye was (and
`
`still is) assigned to two major classes: (1) "tear deficient dry eye" – characterized
`
`by a deficiency in aqueous tear production; and (2) "evaporative dry eye" –
`
`characterized by an increase in tear evaporation. Exhibit 1036, p. 4. Symptoms of
`
`dry eye may include grittiness, foreign body sensation, burning, soreness, stinging,
`
`scratchiness, dryness, blurred vision, a "film over the eyes," paradoxical reflex
`
`tearing, and photophobia. Exhibit 1029, p. 6; Exhibit 1004, p. 1.
`
`29. Due to its multifactorial nature, multiple diagnostic tests were used to
`
`clinically diagnose dry eye, such as fluorescein tear breakup time, Schirmer Tear
`
`Test, and ocular surface staining. Exhibit 1028, p. 2. The National Dry Eye
`
`Institute published global guidelines for dry eye diagnosis in 1995. Exhibit 1036, p.
`
`2.
`
`ii. Causes of dry eye
`30. Before September 15, 2003, the cause of dry eye was understood to be
`
`multifactorial. See Exhibit 1002, at 1:49 ("The etiologies of dry eye are varied.") A
`
`2001 publication by Albietz explains that Sjögren's syndrome, aging, menopause,
`
`medicamentosa, neutrophic keratitis, meibomian gland disease, lid surface/blinking
`
`anomalies, contact lens irritation, chronic allergy or toxicity, and cicatricial ocular
`
`
`
`- 13 -
`
`APOTEX 1007
`
`

`

`
`
`
`surface disorder were all considered possible causes of dry eye (including tear-
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`deficient and evaporative types of dry eye). Exhibit 1029, Table 1.
`
`31. Before September 15, 2003, inflammation was known to be a
`
`causative factor in dry eye. For example, U.S. Patent No. 5,981,607, which issued
`
`in 1999, states, "[a] growing body of research suggests that dry eye is the result of
`
`an underlying cytokine and receptor-mediated inflammatory process." Exhibit
`
`1002, 1:53-55. Sall et al. reported in 2000, "there is now sufficient evidence to
`
`suggest that dry eye disease is the result of an underlying cytokine and receptor-
`
`mediated inflammatory process affecting both the lacrimal gland and the ocular
`
`surface." Exhibit 1004, p. 1. Similarly, a 2000 publication by Stevenson et al.
`
`stated, "[a] growing body of evidence suggests that chronic dry eye disease is the
`
`result of an underlying cytokine and receptor-mediated inflammatory process that
`
`affects the lacrimal gland acini and ducts, leading to abnormalities in the tear film
`
`and ultimately disrupting the homeostasis of the ocular surface." Exhibit 1023, p.
`
`1.
`
`iii. Dry eye treatments were known before 2003
`32. Before September 15, 2003, dry eye was routinely treated with simple
`
`therapies such as a warm compress, lid massage, and artificial tears. Exhibit 1037,
`
`p. 6; Exhibit 1029, p. 8. Depending on the individual’s dry eye condition,
`
`
`
`- 14 -
`
`APOTEX 1007
`
`

`

`
`
`
`alternative or additional treatments such as topical steroids or oral tetracyclines
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`could be administered. Exhibit 1037, pp. 6-7; Exhibit 1028, p. 5.
`
`33. Many different artificial
`
`tear preparations were commercially
`
`available before 2003, such as GenTeal® (CIBA Vision), Hypotears® PF (CIBA
`
`Vision), Moisture Eyes® (Bausch & Lomb Pharmaceuticals), Refresh® Plus
`
`(Allergan), Refresh® Tears (Allergan), Tears Naturale Free® (Alcon) and
`
`TheraTears® (Advanced Vision Research). Exhibit 1020, p. 2; Exhibit 1028, p. 5.
`
`Commercial artificial tear formulations ranged in electrolyte content, viscosity,
`
`presence or absence of preservatives like benzalkonium chloride, and other
`
`features, which provided several different treatment options for individual patient
`
`needs. Exhibit 1020, p. 2. Artificial tears were referred to as a palliative therapy for
`
`dry eye because they lubricate the eye and provide relief but do not necessarily
`
`address the underlying cause of dry eye. Exhibit 1020, p. 2. Nonetheless,
`
`depending on the specific dry eye symptoms, artificial tears were known to provide
`
`complete or at least partial relief. See Exhibit 1002, 1:56-58. For example, a 1999
`
`publication noted that "TheraTears has been shown to cure symptoms and restore
`
`conjunctival goblet cells in dry eye patients following LASIK." Exhibit 1037, p. 6.
`
`Artificial tears were (and still are) considered a first line of treatment for dry eye.
`
`Exhibit 1037, p. 6; Exhibit 1020, p. 2.
`
`
`
`- 15 -
`
`APOTEX 1007
`
`

`

`
`
`
`
`34. Another common treatment of dry eye before 2003 was punctual
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`occlusion. Exhibit 1019, p. 302, ¶ 4. Tears drain from our eyes through the
`
`nasolacrimal duct (the "tear duct") into the nasal cavity. A technique used for
`
`decades, punctal occlusion comprises inserting a "plug" into the lacrimal puncta of
`
`the eyelid to slow or prevent tear drainage into the nasolacrimal duct – i.e., retain
`
`moisture on the eye. See, e.g., Exhibit 1040, p. 1 ("[p]unctal plugs have offered a
`
`safe and often reversible treatment option for aqueous-deficient dry eye for over
`
`three decades." (citing Freeman, JM, Trans. Sect. Ophthalmol. Am. Acad.
`
`Ophthalmol. Otaryngol. 79(6):874-879 (1975) (Exhibit 1014)). As Murphy stated
`
`in 2000, "[p]unctal plugs can be effective for moderate to severe dry eye when
`
`artificial tears alone don't bring relief." Exhibit 1020, pp. 2-3.
`
`35. Before September 15, 2003, therapies for dry eye that targeted
`
`underlying causes of the disease were also known. For example, anti-inflammatory
`
`therapies such as topical steroids, oral tetracyclines (e.g., doxycycline), and topical
`
`cyclosporine A (CsA) were known treatments for dry eye. Exhibit 1028, p. 5;
`
`Exhibit 1022, pp. 2 and 13; Exhibit 1004; Exhibit 1023. In 2000, Stevenson et al.
`
`reported the results of a Phase II clinical trial investigating topical ophthalmic
`
`emulsions comprising CsA. Exhibit 1023. Stevenson et al. described the Phase II
`
`trial as a dose-response study testing twice-daily administration of ophthalmic
`
`emulsions comprising 0.05%, 0.1%, 0.2%, or 0.4% CsA for the treatment of
`
`
`
`- 16 -
`
`APOTEX 1007
`
`

`

`
`
`
`moderate-to-severe dry eye. Exhibit 1023, p. 2. Stevenson et al. also described a
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`vehicle control group using the vehicle of the 0.2% CsA formulation. Exhibit 1023,
`
`p. 2. The authors concluded that all four concentrations of CsA were safe, but there
`
`was a lack of any additional therapeutic benefit in the two higher concentrations of
`
`CsA compared to the two lower concentrations. Exhibit 1023, p. 8. Stevenson et al.
`
`recommended that subsequent studies focus on formulations comprising CsA
`
`concentrations of 0.05% and 0.1%. Exhibit 1023, p. 8.
`
`36.
`
`In 2000, Sall et al. reported the results of a Phase III clinical trial
`
`investigating ophthalmic emulsions comprising CsA. Exhibit 1004. Consistent
`
`with the recommendation of Stevenson et al., the Phase III study of Sall et al.
`
`compared twice-daily administration of two concentrations of CsA (0.05% CsA
`
`and 0.1% CsA) to its vehicle (castor oil). Exhibit 1004, p. 2. The authors found that
`
`both concentrations of CsA were effective in reducing corneal staining, increasing
`
`tear production as measured by the Schirmer Tear Test, reducing blurred vision,
`
`and reducing the use of artificial tears. Exhibit 1004, at Figures 1-4. The authors
`
`also stated that there was no dose-response effect for the two different
`
`concentrations of CsA tested. Exhibit 1004, Abstract.
`
`37. Both the Phase II Stevenson study and the Phase III Sall study
`
`acknowledged that the vehicle used in the CsA-containing emulsions provided
`
`"substantial palliative benefits." Exhibit 1004, p. 8; Exhibit 1023, p. 7. Though
`
`
`
`- 17 -
`
`APOTEX 1007
`
`

`

`
`
`
`Stevenson et al. did not explicitly describe the vehicle used in the emulsions, Sall
`
`Inter Partes Review of USPN 8,629,111
`Declaration of Christopher N. Ta, M.D.
`
`et al. stated that the vehicle used in the Phase III study was castor oil. Exhibit
`
`1004, p. 2. Thus, it was understood in the art before September 15, 2003, that
`
`castor oil emulsions had beneficial properties for treating dry eye. For example,
`
`U.S. Patent No. 5,981,607 ("the '607 patent"), which issued in 1999, describes
`
`ophthalmic emulsions comprising castor oil for the treatment of dry eye. See
`
`Exhibit 1002, at 3:42-49; 4:57-62; and 6:1-27. Further, a 2002 publication by Goto
`
`et al. shows that castor oil eye drops were effective in treating meibomian gland
`
`dysfunction (MGD), a major cause of lipid-deficiency dry eye. Exhibit 1033,
`
`Abstract. Even Allergan itself commercially produced a castor-oil-based treatment
`
`for dry eye as early as 2002. I understand from Allergan's 2002 Annual Report that
`
`Refresh Endura®, an over-the-counter dry eye remedy sold by Allergan, was
`
`2, p. 24. Refresh Endura is derived from the same
`launched in 2002. Exhibit 10391F
`
`castor oil/water emulsion that serves as the vehicle for Restasis. See, e.g., Exhibit
`
`1038, p. 1 ("Refresh Endura (Allergan) is derived from the ophthalmic emulsion
`
`vehicle for Restasis.") Thus, even Allergan understood that castor oil could serve
`
`
`2 Exhibit 1039 is a true and correct copy of a document entitled "Allergan's
`
`2002 Annual Report," which I do