`_____________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
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`APOTEX CORP.
`APOTEX, INC.
`Petitioner
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`v.
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`ALLERGAN, INC.
`Patent Owner
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`U.S. Patent No. 8,633,162
`_____________________
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`Case To be assigned
`_____________________
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`DECLARATION OF CHRISTOPHER N. TA, M.D.
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`Inter Partes Review of USPN 8,633,162
`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 '162 patent ............................................................................................... 19
`X.
`The '979 patent is the closest prior art ........................................................... 20
`XI. The inventions as claimed in the '162 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 '162 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
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`Inter Partes Review of USPN 8,633,162
`Declaration of Christopher N. Ta, M.D.
`I, Christopher N .Ta, hereby declare as follows.
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`I.
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`Overview
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`1.
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`I am over the age of eighteen (18) and otherwise competent to make
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`this declaration.
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`2.
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`I have been retained as an expert witness on behalf of APOTEX CORP.
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`and APOTEX, INC. ("APOTEX") for the above-captioned inter partes review (IPR). I
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`am being compensated for my time in connection with this IPR at my standard
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`consulting rate, which is $500 per hour for time less than one hour, then $375 per
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`hour thereafter. I understand that the petition for inter partes review involves U.S.
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`Patent No. 8,633,162 ("the '162 patent"), Exhibit 1001, which resulted from U.S.
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`Application No. 13/967,179 ("the '179 application"), filed on August 14, 2013,
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`naming Andrew Acheampong, Diane D. Tang-Liu, James N. Chang, and David F.
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`Power as inventors. The '162 patent issued on January 21, 2014, from the '179
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`application. I further understand that, according to the USPTO records, the '162
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`patent is currently assigned to Allergan, Inc. ("the patentee"). I understand that the
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`earliest possible priority date for the '162 patent is September 15, 2003.
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`3.
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`I understand that independent claims 1, 18, and 23 of the '162 patent
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`recite a method of treating dry eye disease and a method of reducing side effects in
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`a human treated for dry eye, the methods comprising twice-daily topical
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`administration of ophthalmic emulsions comprising 0.05% by weight cyclosporine
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`A, polysorbate 80, acrylate/C10-30 alkyl acrylate cross-polymer, water, and 1.25%
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`Declaration of Christopher N. Ta, M.D.
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`by weight castor oil. I understand that claims 11 and 21 of the '0162 patent recite
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`that treatment with the claimed method results in no detectable blood levels of
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`cyclosporine A.
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`II.
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`My background and qualifications
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`4.
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`I am an expert in the field of ophthalmology and the treatment of
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`patients suffering from ophthalmological disorders. I have been an expert in this
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`field since before 2003.
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`5.
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`I am presently Professor of Ophthalmology at Stanford University
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`School of Medicine. I am Board Certified in Ophthalmology by the American
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`Board of Ophthalmology. In my practice, I routinely see and treat patients with dry
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`eye. My curriculum vitae is provided as Exhibit 1008.
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`6.
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`I earned a Bachelor of Arts degree in Physiology from the University
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`of Minnesota in 1990. I earned an M.D. from University of Minnesota Medical
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`School in 1994. I completed an internship in internal medicine at Kaiser
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`Permanente Hospital in Oakland, CA, in 1995. I completed my residency in
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`ophthalmology at Stanford University Medical Center in 1998. I completed a
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`fellowship in cornea, external diseases, and refractive surgery at the University of
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`Texas Southwestern (Dallas, TX) in 1999. I worked as Acting Assistant Professor
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`at the Stanford University School of Medicine from 1999-2000, and as Assistant
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`Professor at Stanford University School of Medicine from 2000-2006. I served as
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`Inter Partes Review of USPN 8,633,162
`Declaration of Christopher N. Ta, M.D.
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`Associate Professor at Stanford University School of Medicine from 2007-2012. I
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`became Professor at Stanford University School of Medicine in 2012 and continue
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`to serve as Professor there today. Throughout my career, I have had extensive
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`experience consulting, diagnosing, and treating patients with ophthalmologic
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`conditions, including dry eye. I also have extensive experience evaluating patient
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`responses to different ophthalmological formulations.
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`7.
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`I have
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`received several honors
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`in my career
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`related
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`to
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`ophthalmological conditions and treatment, such as the Biodesign Certificate of
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`Appreciation, Stanford Biodesign (2011); Best Paper Award, American Academy
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`of Ophthalmology (2008); American Academy of Ophthalmology Achievement
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`Award, American Academy of Ophthalmology
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`(2008); America’s Top
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`Ophthalmologist, Consumers’ Research Council of America (2007-2009); Best
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`Poster Award, European Society of Cataract and Refractive Surgery Conference
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`(2005); Stanford Leadership Development Program (2005-2006); Office of
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`Technology and Licensing Research Incentive Fund Award (2005); Alpha Omega
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`Alpha (1993); and Phi Beta Kappa Honor Society (1990).
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`8.
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`In addition to my clinical practice and my duties as a professor, I am
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`also actively involved in scientific research programs. My research interests
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`include ocular infections, dry eye, cornea transplantation, artificial cornea, and
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`ocular graft-versus-host disease. I have been awarded research funding from many
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`Inter Partes Review of USPN 8,633,162
`Declaration of Christopher N. Ta, M.D.
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`different sources, including the Stanford University BioX Award (2002); American
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`Society of Cataract and Refractive Surgery Research Grant (2008); Singapore Eye
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`Research Institute (2007-2010); and the National Institutes of Health (2007-2012).
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`9.
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`I am the author or co-author of numerous medical publications
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`involving ophthalmological conditions and treatment. I have also authored or co-
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`authored book chapters in the field and given numerous presentations at medical
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`and scientific conferences. I regularly attend scientific and medical conferences
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`where I interact with others in the field of ophthalmology. A complete list of my
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`publications and presentations is found in my curriculum vitae (Exhibit 1008). I
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`have served as a peer reviewer for over 20 different journals and serve as an
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`Editorial Board Member for Advances in Therapy; Graefes Archives of Clinical
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`and Experimental Ophthalmology; and Journal of Clinical and Experimental
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`Ophthalmology.
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`10.
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`I am a member of or affiliated with a number of organizations related
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`to ophthalmology, including the American Academy of Ophthalmology, Peninsula
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`Eye Society, The Cornea Society, and Max Fine Society.
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`11.
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`I have served and currently serve on many committees related to
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`ophthalmology and medicine. For example, I have served as Residency SF Match
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`Auditor; Residency Selection Committee; Interviewer of applicants for Stanford
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`School of Medicine, and Ophthalmic News & Educations (ONE) by the American
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`Declaration of Christopher N. Ta, M.D.
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`Academy of Ophthalmology. I have also served on the Data Safety and Monitoring
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`Committee for clinical trials, including serving as Chairman of the Committee for
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`"Episcleral implant for the prevention of allograft rejection after cornea
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`transplantation."
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`12.
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`In view of my education, experience, and expertise described above, I
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`am an expert in the field of ophthalmology and the treatment of ophthalmological
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`conditions.
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`III. Summary of opinions
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`13.
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`In this declaration, I consider the ophthalmic emulsions and methods
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`of the '162 patent in relation to the state of the art as of September 15, 2003. I also
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`consider the Declarations of Drs. Rhett M. Schiffman and Mayassa Attar, and the
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`data and references cited therein. See Exhibit 1019, pp. 2130-2173 and 2185-2298.
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`I understand that Allergan submitted the Schiffman and Attar Declarations to the
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`United States Patent and Trademark Office to support the purported patentability
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`of the '162 patent claims. A summary of my opinions follows.
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`14. First, I disagree with the conclusions drawn by Drs. Schiffman and
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`Attar in their respective declarations regarding the purported "unexpected" results
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`achieved by the formulations and methods of the '162 patent. The data presented in
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`the Schiffman and Attar Declarations do not support the declarants' conclusions
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`that the ophthalmic emulsions and methods of the
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`Inter Partes Review of USPN 8,633,162
`Declaration of Christopher N. Ta, M.D.
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`'162 patent provided
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`unexpectedly superior results over the closest prior art. Instead, a closer look at
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`Allergan's data in the Schiffman and Attar declarations shows that, at best, the
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`formulations and methods of the '162 patent exhibited properties that were
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`comparable to – not superior to – the closest prior art, and were not unexpected.
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`Furthermore, the data presented in the Schiffman and Attar declarations are
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`missing key information. The omissions and uncertainties surrounding these data
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`render them unreliable.
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`15. Second, I disagree with Dr. Schiffman's assertion that there was a
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`long-felt, unmet need for the ophthalmic emulsions and methods of the '162 patent
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`before September 15, 2003. I am not aware of any evidence showing that a long-
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`felt, unmet need existed before 2003. I note that Dr. Schiffman does not provide
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`any evidence of a long-felt, unmet need that was recognized in the art as of this
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`date. Moreover, even if a long-felt, unmet need did exist, the need would have
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`been satisfied by disclosures in the prior art before September 15, 2003.
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`16. Third, I have reviewed the documents cited in Dr. Schiffman’s second
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`declaration, and I disagree that the documents show industry praise for the methods
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`of the '162 patent. Instead, the documents provide quotations from physicians who
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`describe their general approval of treating patients with topical cyclosporine A—a
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`treatment known in the art before 2003. See, e.g., Exhibit 1004. Dr. Schiffman's
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`documents further show that the same physicians' preferred treatment for dry eye
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`Declaration of Christopher N. Ta, M.D.
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`patients is a combination of topical cyclosporine A and other dry eye treatments,
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`such as topical steroids or other anti-inflammatory therapies.
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`17. Finally, I disagree with Dr. Schiffman's opinions that other companies
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`have tried and "failed" to produce a therapeutic treatment for dry eye. I am not
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`aware of any evidence that other companies tried to develop a therapeutic
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`treatment for dry eye but "failed" due to technical reasons and not due to
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`commercial or business reasons. I note that Dr. Schiffman does not provide any
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`evidence to show that any alleged failure to develop the formulation and method as
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`claimed was due to technical reasons.
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`IV. List of documents I considered in formulating my opinions
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`18.
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`In formulating my opinions, I considered all of the references cited
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`herein, including the documents listed below.
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`Exhibit No.
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`1001
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`1002
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`1003
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`1004
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`1014
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`Description
`U.S. Patent No. 8,633,162 to Acheampong et al. (issued February
`11, 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;
`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
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`Declaration of Christopher N. Ta, M.D.
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`Exhibit No.
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`1017
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`Description
`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
`
`1019
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`File History of U.S. Patent No. 8,633,162
`
`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
`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:
`
`1020
`
`1022
`
`1023
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`1028
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`1029
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`1030
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`1033
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`1035
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`1036
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`1037
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`Exhibit No.
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`1038
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`1039
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`1040
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`1041
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`1042
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`Declaration of Christopher N. Ta, M.D.
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`Description
`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)
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`V. Person of ordinary skill in the art
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`19.
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`I understand that a person of ordinary skill in the art ("POSA") is a
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`hypothetical person who is presumed to be aware of all pertinent art, thinks along
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`conventional wisdom in the art, and is a person of ordinary creativity. With
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`respect to the subject matter of the '162 patent, a POSA would typically have had
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`(i) an M.D. or a Ph.D. in chemistry, biochemistry, pharmaceutics, or in a related
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`field in biological or chemical sciences, and have about two years of experience in
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`the formulation of topical ophthalmics; or (ii) a Master's degree in chemistry,
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`biochemistry, pharmaceutics, or in a related field in biological or chemical
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`sciences, and have at least five years of experience in the formulation of topical
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`Inter Partes Review of USPN 8,633,162
`Declaration of Christopher N. Ta, M.D.
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`20. A POSA typically would work as part of a multidisciplinary team and
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`draw upon not only his or her own skills, but also take advantage of certain
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`specialized skills of others in the team to solve a given problem. For example, a
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`clinician having experience in treating dry eye may be part of the team. A POSA
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`would have been aware of other important information and references relating to
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`dry eye, its causes, and useful treatments.
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`VI. Basis of my analysis with respect to obviousness and objective indicia of
`non-obviousness
`21.
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`I understand that an obviousness analysis involves comparing a patent
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`claim to the prior art to determine whether the claimed invention would have been
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`obvious to a person of ordinary skill in the art in view of the prior art, and in light
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`of the general knowledge in the art. I also understand when a person of ordinary
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`skill in the art would have reached the claimed invention through routine
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`experimentation, the invention may be deemed obvious. I also understand that
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`obviousness can be established by combining or modifying the teachings of the
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`prior art to achieve the claimed invention.
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`22.
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`I understand that, in considering the obviousness of an invention, one
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`Declaration of Christopher N. Ta, M.D.
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`must also consider whether there are any objective indicia1 that support the non-
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`obviousness of the invention. I understand that some objective indicia of non-
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`obviousness include unexpectedly superior results, long-felt but unmet need,
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`failure of others, and perception in the industry.
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`23.
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`I understand that "unexpectedly superior results" can be evidence of
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`non-obviousness if the patent owner shows that the results achieved with the
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`invention as claimed are different from the results of the prior art, and that the
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`results have a significant and practical advantage. I also understand that
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`unexpectedly superior results must be achieved with an embodiment of the claimed
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`invention.
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`24.
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`I understand that a long-felt but unmet need may be evidence of non-
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`obviousness when objective evidence shows (i) the need was a persistent need in
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`the prior art that was recognized by those of ordinary skill in the art; (ii) the need
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`was not satisfied by another product, technology, or disclosure in the art before the
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`invention claimed in the patent; and (iii) the invention claimed in the patent
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`satisfies the long-felt need. I also understand that actual evidence of a long-felt
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`1 I understand that objective indicia of non-obviousness are sometimes
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`called secondary considerations of non-obviousness.
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`need (e.g., evidence of the need recognized in the prior art) must be provided to
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`prove the existence of the need, as opposed to mere argument.
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`25.
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`I understand that "failure of others" can be evidence of non-
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`obviousness where competitors have sought over a span of several years to develop
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`the drug in question. I understand that for such efforts to be considered evidence of
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`non-obviousness, the "failure" must be due to technical difficulties, as opposed to
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`business or commercial reasons.
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`26.
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`I understand that praise in the industry can be evidence of non-
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`obviousness; and that commercial acquiescence to the patent rights – such as by
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`extensive licensing – can be evidence of non-obviousness.
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`27.
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`I understand that any objective indicia of non-obviousness must have
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`a nexus, or "close connection" to novel aspects of the claimed invention. I further
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`understand that objective evidence resulting from something that is not both
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`claimed and novel in the claim lacks a nexus to the merits of the invention.
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`VIII. Dry eye background
`i. Symptoms and diagnosis of dry eye
`28. Before September 15, 2003, dry
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`eye
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`(also known
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`as
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`keratoconjunctivitis sicca or KCS—see, e.g., Exhibit 1002, col. 6, lines 25-27; and
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`Exhibit 1003, col. 5, lines 10-12) was defined as "a disorder of the tear film due to
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`tear deficiency or excessive evaporation that causes damage to the interpalpebral
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`ocular surface and is associated with symptoms of discomfort." Exhibit 1036, p. 2;
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`Declaration of Christopher N. Ta, M.D.
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`Exhibit 1028, p. 2. Dry eye was (and still is) assigned to two major classes: (1)
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`"tear deficient dry eye" – characterized by a deficiency in aqueous tear production;
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`and (2) "evaporative dry eye" – characterized by an increase in tear evaporation.
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`Exhibit 1036, p. 4. Symptoms of dry eye may include grittiness, foreign body
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`sensation, burning, soreness, stinging, scratchiness, dryness, blurred vision, a "film
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`over the eyes," paradoxical reflex tearing, and photophobia. Exhibit 1029, p. 6;
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`Exhibit 1004, p. 1.
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`29. Due to its multifactorial nature, multiple diagnostic tests were used to
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`clinically diagnose dry eye, such as fluorescein tear breakup time, Schirmer Tear
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`Test, and ocular surface staining. Exhibit 1028, p. 2. The National Dry Eye
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`Institute published global guidelines for dry eye diagnosis in 1995. Exhibit 1036, p.
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`2.
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`ii. Causes of dry eye
`30. Before September 15, 2003, the cause of dry eye was understood to be
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`multifactorial. See Exhibit 1002, at 1:49 ("The etiologies of dry eye are varied.") A
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`2001 publication by Albietz explains that Sjögren's syndrome, aging, menopause,
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`medicamentosa, neutrophic keratitis, meibomian gland disease, lid surface/blinking
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`anomalies, contact lens irritation, chronic allergy or toxicity, and cicatricial ocular
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`surface disorder were all considered possible causes of dry eye (including tear-
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`deficient and evaporative types of dry eye). Exhibit 1029, Table 1.
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`31. Before September 15, 2003, inflammation was known to be a
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`causative factor in dry eye. For example, U.S. Patent No. 5,981,607, which issued
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`in 1999, states, "[a] growing body of research suggests that dry eye is the result of
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`an underlying cytokine and receptor-mediated inflammatory process." Exhibit
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`1002, 1:53-55. Sall et al. reported in 2000, "there is now sufficient evidence to
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`suggest that dry eye disease is the result of an underlying cytokine and receptor-
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`mediated inflammatory process affecting both the lacrimal gland and the ocular
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`surface." Exhibit 1004, p. 1. Similarly, a 2000 publication by Stevenson et al.
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`stated, "[a] growing body of evidence suggests that chronic dry eye disease is the
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`result of an underlying cytokine and receptor-mediated inflammatory process that
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`affects the lacrimal gland acini and ducts, leading to abnormalities in the tear film
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`and ultimately disrupting the homeostasis of the ocular surface." Exhibit 1023, p.
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`1.
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`iii. Dry eye treatments were known before 2003
`32. Before September 15, 2003, dry eye was routinely treated with simple
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`therapies such as a warm compress, lid massage, and artificial tears. Exhibit 1037,
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`p. 6; Exhibit 1029, p. 8. Depending on the individual’s dry eye condition,
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`alternative or additional treatments such as topical steroids or oral tetracyclines
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`Declaration of Christopher N. Ta, M.D.
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`could be administered. Exhibit 1037, pp. 6-7; Exhibit 1028, p. 5.
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`33. Many different artificial
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`tear preparations were commercially
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`available before 2003, such as GenTeal® (CIBA Vision), Hypotears® PF (CIBA
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`Vision), Moisture Eyes® (Bausch & Lomb Pharmaceuticals), Refresh® Plus
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`(Allergan), Refresh® Tears (Allergan), Tears Naturale Free® (Alcon) and
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`TheraTears® (Advanced Vision Research). Exhibit 1020, p. 2; Exhibit 1028, p. 5.
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`Commercial artificial tear formulations ranged in electrolyte content, viscosity,
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`presence or absence of preservatives like benzalkonium chloride, and other
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`features, which provided several different treatment options for individual patient
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`needs. Exhibit 1020, p. 2. Artificial tears were referred to as a palliative therapy for
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`dry eye because they lubricate the eye and provide relief but do not necessarily
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`address the underlying cause of dry eye. Exhibit 1020, p. 2. Nonetheless,
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`depending on the specific dry eye symptoms, artificial tears were known to provide
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`complete or at least partial relief. See Exhibit 1002, 1:56-58. For example, a 1999
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`publication noted that "TheraTears has been shown to cure symptoms and restore
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`conjunctival goblet cells in dry eye patients following LASIK." Exhibit 1037, p. 6.
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`Artificial tears were (and still are) considered a first line of treatment for dry eye.
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`Exhibit 1037, p. 6; Exhibit 1020, p. 2.
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`34. Another common treatment of dry eye before 2003 was punctual
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`occlusion. Exhibit 1019, p. 2186, ¶ 4. Tears drain from our eyes through the
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`nasolacrimal duct (the "tear duct") into the nasal cavity. A technique used for
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`decades, punctal occlusion comprises inserting a "plug" into the lacrimal puncta of
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`the eyelid to slow or prevent tear drainage into the nasolacrimal duct – i.e., retain
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`moisture on the eye. See, e.g., Exhibit 1040, p. 1 ("[p]unctal plugs have offered a
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`safe and often reversible treatment option for aqueous-deficient dry eye for over
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`three decades." (citing Freeman, JM, Trans. Sect. Ophthalmol. Am. Acad.
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`Ophthalmol. Otaryngol. 79(6):874-879 (1975) (Exhibit 1014)). As Murphy stated
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`in 2000, "[p]unctal plugs can be effective for moderate to severe dry eye when
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`artificial tears alone don't bring relief." Exhibit 1020, pp. 2-3.
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`35. Before September 15, 2003, therapies for dry eye that targeted
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`underlying causes of the disease were also known. For example, anti-inflammatory
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`therapies such as topical steroids, oral tetracyclines (e.g., doxycycline), and topical
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`cyclosporine A (CsA) were known treatments for dry eye. Exhibit 1028, p. 5;
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`Exhibit 1022, pp. 2 and 13; Exhibit 1004; Exhibit 1023. In 2000, Stevenson et al.
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`reported the results of a Phase II clinical trial investigating topical ophthalmic
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`emulsions comprising CsA. Exhibit 1023. Stevenson et al. described the Phase II
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`trial as a dose-response study testing twice-daily administration of ophthalmic
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`emulsions comprising 0.05%, 0.1%, 0.2%, or 0.4% CsA for the treatment of
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`moderate-to-severe dry eye. Exhibit 1023, p. 2. Stevenson et al. also described a
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`vehicle control group using the vehicle of the 0.2% CsA formulation. Exhibit 1023,
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`p. 2. The authors concluded that all four concentrations of CsA were safe, but there
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`was a lack of any additional therapeutic benefit in the two higher concentrations of
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`CsA compared to the two lower concentrations. Exhibit 1023, p. 8. Stevenson et al.
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`recommended that subsequent studies focus on formulations comprising CsA
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`concentrations of 0.05% and 0.1%. Exhibit 1023, p. 8.
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`36.
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`In 2000, Sall et al. reported the results of a Phase III clinical trial
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`investigating ophthalmic emulsions comprising CsA. Exhibit 1004. Consistent
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`with the recommendation of Stevenson et al., the Phase III study of Sall et al.
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`compared twice-daily administration of two concentrations of CsA (0.05% CsA
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`and 0.1% CsA) to its vehicle (castor oil). Exhibit 1004, p. 2. The authors found that
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`both concentrations of CsA were effective in reducing corneal staining, increasing
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`tear production as measured by the Schirmer Tear Test, reducing blurred vision,
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`and reducing the use of artificial tears. Exhibit 1004, at Figures 1-4. The authors
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`also stated that there was no dose-response effect for the two different
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`concentrations of CsA tested. Exhibit 1004, Abstract.
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`37. Both the Phase II Stevenson study and the Phase III Sall study
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`acknowledged that the vehicle used in the CsA-containing emulsions provided
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`"substantial palliative benefits." Exhibit 1004, p. 8; Exhibit 1023, p. 7. Though
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`Stevenson et al. did not explicitly describe the vehicle used in the emulsions, Sall
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`et al. stated that the vehicle used in the Phase III study was castor oil. Exhibit
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`1004, p. 2. Thus, it was understood in the art before September 15, 2003, that
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`castor oil emulsions had beneficial properties for treating dry eye. For example,
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`U.S. Patent No. 5,981,607 ("the '607 patent"), which issued in 1999, describes
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`ophthalmic emulsions comprising castor oil for the treatment of dry eye. See
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`Exhibit 1002, at 3:42-49; 4:57-62; and 6:1-27. Further, a 2002 publication by Goto
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`et al. shows that castor oil eye drops were effective in treating meibomian gland
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`dysfunction (MGD), a major cause of lipid-deficiency dry eye. Exhibit 1033,
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`Abstract. Even Allergan itself commercially produced a castor-oil-based treatment
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`for dry eye as early as 2002. I understand from Allergan's 2002 Annual Report that
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`Refresh Endura®, an over-the-counter dry eye remedy sold by Allergan, was
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`launched in 2002. Exhibit 10392, p. 24. Refresh Endura is derived from the same
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`castor oil/water emulsion that serves as the vehicle for Restasis. See, e.g., Exhibit
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`1038, p. 1 ("Refresh Endura (Allergan) is derived from the ophthalmic emulsion
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`vehicle for Restasis.") Thus, even Allergan understood that castor oil could serve
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`2 Exhibit 1039 is a true and correct copy of a document entitled "Allergan's
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`2002 Annual Report," which I downloaded from Allergan's website,
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`http://agn.client.shareholder.com/financials.cfm.
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`as an active agent for treating dry eye.
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`38.
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`In addition to the reports of Stevenson and Sall, other publications
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`described ophthalmic emulsions comprising CsA and castor oil before September
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`15, 2003. For example, the '607 patent describes ophthalmic formulations
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`comprising ca