UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`
`ALCON RESEARCH, LTD
`Patent Owner
`
`U.S. PATENT NO. 8,791,154
`
`Inter Partes Review No. 2016-00544
`
`____________________________________________________________
`
`DECLARATION OF LEONARD BIELORY, MD
`
`APOTEX EX1003
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`Page 1
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`
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`
`ALCON RESEARCH, LTD
`Patent Owner
`
`U.S. PATENT NO. 8,791,154
`
`Inter Partes Review No. 2016-00544
`
`____________________________________________________________
`
`DECLARATION OF LEONARD BIELORY, MD
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`APOTEX EX1003
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`Page 1
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`Declaration of Leonard Bielory, MD
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`TABLE OF CONTENTS
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`I.
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`II.
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`III.
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`IV.
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`Introduction ........................................................................................... 3
`Background and Qualifications ............................................................. 4
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`Person of Ordinary Skill in the Art ....................................................... 7
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`The Technology Claimed in the ’154 Patent ....................................... 10
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`V. Claim Construction ............................................................................. 12
`V.
`State of the Art .................................................................................... 13
`VI.
`Summary of My Conclusions .............................................................. 28
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`A. Aqueous ophthalmic solutions containing higher
`concentrations of olopatadine were known in the art ............... 29
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`B.
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`Even at high concentrations, olopatadine did not exhibit
`the biphasic effect commonly known to be exhibited by
`antihistamines ............................................................................ 34
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`C. Olopatadine’s efficacy in treating both early and late
`phase ocular allergic conjunctivitis symptoms would not
`have been surprising ................................................................. 35
`
`D. Ground 1: Obviousness Based On Bhowmick In View Of
`Yanni And Castillo ................................................................... 38
`
`E. Ground 2: Obviousness Based On Schneider In View Of
`Hayakawa, Bhowmick And Castillo ......................................... 40
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`2
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`Declaration of Leonard Bielory, MD
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`I, Leonard Bielory, MD., hereby declare as follows.
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`I.
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`Introduction
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`1.
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`I have been retained as an expert witness on behalf of ARGENTUM
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`PHARMACEUTICALS, LLC, ("ARGENTUM") for the above-captioned inter
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`partes review (IPR). I am being compensated for my time by the hour in preparing
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`this declaration, but my compensation is not tied to the outcome of this matter.
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`2.
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`I understand that this Declaration accompanies a petition for IPR
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`involving U.S. Patent No. 8,791,154 ("the '154 patent"), Ex. 1001, which resulted
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`from U.S. Patent Application No. 13/475,607 ("the '607 application"), filed May
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`18, 2012. I also understand that the '154 patent claims priority to U.S. Provisional
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`Patent Application No. 61/548,957, filed Oct 19, 2011 and U.S. Provisional Patent
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`Application No. 61/487,789, filed May 19,2011.
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`3.
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`The '154 patent names Daniel A. Gamache, Laman Alani, Malay
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`Ghosh, Francisco Javier Galan, Núria Carreras Perdiguer, and Onkar N. Singh as
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`the inventors. The '154 patent issued on June 29, 2014 from the '607 application. I
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`understand that, according to the United States Patent and Trademark Office
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`("USPTO") records, the '154 patent is currently assigned to Alcon Research, Ltd.
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`("Alcon".)
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`Declaration of Leonard Bielory, MD
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`4.
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`In preparing this Declaration, I have reviewed the '154 patent, the
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`granted claims (1-27), and each of the documents cited herein, in light of general
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`knowledge in the art. In formulating my opinions, I have relied upon my
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`experience, education, and knowledge in the relevant art. In formulating my
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`opinions, I have also considered the viewpoint of a person of ordinary skill in the
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`art ("POSA") (i.e., a person of ordinary skill in the art of ophthalmic drug
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`formulations and treatment). Throughout this declaration, in rendering my
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`opinion, I have considered what the viewpoint of a POSA would have been prior to
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`May 19, 2011, the filing date of U.S. Provisional Patent Application No.
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`61/487,789, to which the challenged '154 patent claims priority. In the event that
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`the priority claim to the ‘789 patent is deemed invalid, I have also considered what
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`the viewpoint of a POSA would have been prior to October 11, 2011, the filing
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`date of U.S. Provisional Patent Application No. 61/548,957, to which the
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`challenged ‘154 patent also claims priority.
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`II. Background and Qualifications
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`5.
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`I am an expert in the field of Allergy and Immunology. I am
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`currently a Professor at Rutgers University, Center for Environmental Prediction,
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`and an affiliate Member, NIEHS Center for Environmental Health Sciences at the
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`Environmental and Occupational Health Sciences Institute, Rutgers University and
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`Robert Wood Johnson Medical School, Piscataway, New Jersey, as well as
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`Declaration of Leonard Bielory, MD
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`Professor of Medicine, Thomas Jefferson University. I am also currently the
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`Chair, Joint Council of Allergy and Immunology – Joint Task Force - Practice
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`Parameters of Allergic Eye Disease – Diagnosis and Management. Additionally, I
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`have private practice as an allergist at Springfield, New Jersey.
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`6.
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`I received a Bachelor’s Degree in Fundamental Science from Lehigh
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`University in 1976. I received a Doctor of Medicine (M.D.) degree from -
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`University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey
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`Medical School (now Rutgers University –New Jersey Medical School), Newark,
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`N.J. I completed postdoctoral training in Medicine at the University of Maryland
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`Hospitals, Baltimore, Maryland, and in Allergy and Immunology and Hematology
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`at the National Institutes of Health, National Heart, Lung and Blood Institute,
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`Bethesda, Maryland. Subsequent to my education, I joined UMDNJ – NJ Medical
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`School in 1985 as an Assistant Professor of Medicine and Pediatrics. I also
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`worked as Associate Professor of Medicine, Pediatrics and Ophthalmology before
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`being promoted to Professor of Medicine, Pediatrics, Ophthalmology and Visual
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`Sciences. I was also appointed to the positions of Director of the Division of
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`Allergy and Immunology, Department of Medicine, Co-Director Immuno-
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`Ophthalmology Service, Department of Ophthalmology, and Director, Division of
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`Allergy, Immunology & Rheumatology, Department of Medicine at UMDNJ – NJ
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`Medical School. In 2010, I joined the Center for Environmental Prediction,
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`Declaration of Leonard Bielory, MD
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`Rutgers University, as an Adjunct Professor.
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`7.
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`I have also held a number of other professional positions and
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`appointments, memberships and served on several Boards and Trustees including
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`the JCAAI, and as president of NJMS University Physician Associates Board of
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`Directors. From 2007-2012, I was a member of the American Academy of
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`Allergy, Asthma and Immunology, Rhinitis, Rhinosinusitis, Ocular Allergy
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`Committee. From 2008 to 2010, I served as the Chair of the Ocular Allergy
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`Committee at the American Academy of Allergy, Asthma and Immunology.
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`8.
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`I have received several honors in my career, including the Dean's
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`Award of Clinical Excellence - UMDNJ - New Jersey Medical School in 1986, the
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`American Academy of Ophthalmology Achievement Award in 1999 and the New
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`York Magazine – “Top Docs” in New York Metropolitan Area and the New Jersey
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`Magazine Best Doctors in New Jersey from 1996 to the present.
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`9.
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`I also have extensive experience related to ocular diseases and
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`ophthalmic pharmaceuticals. My major research interests have been immuno-
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`ophthalmology – ocular allergy, climate change and allergic airway disease,
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`asthma disease management and outcomes and complementary and alternative
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`medicine. I have given numerous presentations on the advances in the
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`management and treatment of ocular allergy as shown in my curriculum vitae, Ex.
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`Declaration of Leonard Bielory, MD
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`1025.
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`10.
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`I served as an expert witness in litigation concerning olopatadine
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`formulations, [Alcon Research, Ltd. v. Apotex Inc., 790 F. Supp. 2d 868 (2011); Ex
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`1031]. The validity of the claims of U.S. Patent No. 5,641,805 (herein referred to
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`as the Hayakawa reference; Ex. 1008) was, among other issues, considered in this
`
`litigation. In the litigation I testified concerning the prior-art that was cited during
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`the litigation and the antihistamine and mast cell inhibition activity of olopatadine.
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`The Federal Circuit ultimately found that claims 1-3 and 5-7 of U.S. Patent No.
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`5,641,805 to be invalid as obvious over various prior art references (Alcon
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`Research, Ltd. v. Apotex Inc., Appeal No. 2011-1455, Fed. Cir. August 8, 2012; Ex
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`1030).
`
`11.
`
`Accordingly, I am an expert in the field of anterior surface disease of
`
`the eye and ocular allergy. My full background is detailed in my curriculum vitae,
`
`Ex. 1025.
`
`III. Person of Ordinary Skill in the Art
`
`12.
`
`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 of the pertinent art, thinks
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`along conventional wisdom in the art, and is a person of ordinary creativity. A
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`POSA with respect to topical eye formulations would have had knowledge of the
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`Declaration of Leonard Bielory, MD
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`scientific literature regarding inflammatory eye disorders and useful therapies
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`including, e.g., topical aqueous solutions and their formulation into delivery
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`vehicles, as of May 19, 2010.
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`13. With respect to the subject matter of the '154 patent, at the time of
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`filing a POSA typically would have had: (i) an M.D., Pharm. D. or Ph.D. in
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`chemistry, biochemistry, pharmaceutics, or in a related field in the biological or
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`chemical sciences, and have at least about two years of experience in the treatment
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`ocular diseases and formulations used to treat ocular diseases, including topical
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`pharmaceuticals for use in the eye; or (ii) a Master's degree in chemistry,
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`biochemistry, pharmaceutics, or in a related field in the biological or chemical
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`sciences, and have at least about five years of experience in the treatment of ocular
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`diseases and formulations used to treat ocular diseases, including topical
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`pharmaceuticals for use in the eye; or (iii) a bachelor’s degree in pharmacy,
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`chemistry, biochemistry, pharmaceutics, or in a related field in the biological or
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`chemical sciences, and have at least about 10 years of experience in the treatment
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`of ocular diseases and formulations used to treat ocular diseases, including topical
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`pharmaceuticals for use in the eye. These descriptions are approximate, and a
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`higher level of education or specific skill might make up for less experience, and
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`vice-versa.
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`14. As shown by the scientific and patent literature cited herein, a POSA
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`would have an understanding of the basis of ocular allergy including knowledge of
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`the structure and constitution of conjunctiva of the eye, IgE antigen stimulated
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`histamine release, cell-based and animal models and assays for assessing
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`effectiveness of ophthalmic treatments, and knowledge of ophthalmic formulation
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`excipients. Furthermore, the ’154 Patent and much of the prior art discussed herein
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`involves the development of ophthalmic pharmaceutical compositions to treat
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`ocular allergic conjunctivitis. Ex. 1001 at 2:41-42. Thus, the POSA will also
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`have experience in developing ophthalmic pharmaceutical formulations for the
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`treatment of ocular allergic conjunctivitis.
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`15. 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 allergic disorders of the eye with topical
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`pharmaceuticals would be part of the team. A formulations chemist with
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`knowledge of a wide array of excipients suitable for use in ophthalmic
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`formulations and their properties would also be part of the team.
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`16.
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`I believe that I would qualify as a person of at least ordinary skill in
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`the art as of May 19, 2010.
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`IV. The Technology Claimed in the ’154 Patent
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`Declaration of Leonard Bielory, MD
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`17. The ’154 patent relates to ophthalmic aqueous solutions for the
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`treatment of ocular allergic conjunctivitis containing the drug olopatadine, and
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`methods of treating ocular allergy symptoms in human. Ex. 1001, Abstract, 2:41-
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`45, 3:1-2, claims 1, 4, 8, 12 and 21. These compositions contain “relatively high”
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`concentrations of olopatadine including at least 0.67% w/v, 0.7% w/v, and not
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`more than 1.0% w/v olopatadine. Id., 2:42-45; 4:1-2; claims 1, 4, 8 and 21. In
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`order to solubilize the relatively high concentrations of olopatadine in a stable
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`manner, the inventors purport to provide a unique set of excipients for solubilizing
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`the olopatadine. Id., 3:28-29. The excipients include a cyclodextrin derivative
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`selected from SAE-β-cyclodextrin, HP-γ-cyclodextrin, HP-β-cyclodextrin or
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`combinations thereof. Id., 2:45-52; claims 1, 4, 8 and 21. Typically, the solution
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`contains at least 0.5% w/v but no greater than 2.0% w/v HP-γ-cyclodextrin. Id.,
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`4:65-67; and claims 8 and 21. The composition also includes the common lactam
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`polymer polyvinylpyrrolidone (PVP) to aid in the solubilization of the olopatadine,
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`and a polyether (e.g., polyethylene glycol (PEG)) for enhancing solubility and/or
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`aiding in achieving the desired tonicity. Id., 2:52-57; claims 1, 4, 8 and 21. The
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`solutions typically contain 2.0% w/v to 6.0% w/v PVP and 2.0% w/v to 6.0% w/v
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`PEG having a molecular weight of 300 to 500. Id. claims 4, 8 and 21.
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`18. The compositions also include a common preservative such as
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`benzalkonium chloride (BAC), as well as borate and/or polyol to aid in achieving
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`desired preservation. Id., 2:60-67; claims 1, 2, 3, 4, 8 and 21. Typically, the
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`compositions contain greater than 0.003% w/v but less than 0.03% w/v BAC . Id.,
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`9:6-14; claim 21. In order to enhance the residence time of the composition upon
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`the cornea when the composition is topically administered, the compositions may
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`contain commonly used viscosity enhancing agents such as hydroxypropylmethyl
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`cellulose (HPMC) at a concentration of at least 0.15% w/v but no greater than
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`1.0% w/v. Id., 6: 41-50; 7: 9-14; claim 22. The compositions also include
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`water. Id., 4: 24-26; Examples 1-2; claims 1, 4, 8. and 21. The pH of the aqueous
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`solution is 6.0 to 7.8 and the osmolality of the solution is 200 to 400
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`mOsm/kg. Id., 10: 4-9; claim 21.
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`19. The aqueous solutions may be administered to a human to treat at
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`least one ocular allergy symptom such as ocular itching. Id., 3:1-5; claim 12. The
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`solution is topically applied to an eye by dispensing at least one drop of the
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`solution to the eye. Id., claim 13.
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`20. The ophthalmic compositions of the ’154 patent are also purported to
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`provide multiple advantages over previous olopatadine compositions. Among the
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`surprising advantages asserted for the claimed compositions are the
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`following. First, relatively high concentration solutions of olopatadine are alleged
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`Declaration of Leonard Bielory, MD
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`to provide significantly improved reduction of late phase ocular allergic
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`conjunctivitis symptoms in addition to relief from early phase symptoms. Id.,
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`1:35-39, 11:9-19, 23:33-45, 24:43-26:25. Second, significantly improved
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`reduction of redness in the early phase is claimed. Id., 1:39-42; 11:9-23; 23:33-45;
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`24:5-10. The ’154 patent alleges that the enhanced reduction of early phase
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`redness was surprising because “it was generally believed that itching and redness
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`would show similar responses to different concentrations of olopatadine.” Id.,
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`11:19-23. Third, the enhanced relief from the early and late phase symptoms can
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`be achieved through once a day dosing of a relatively high concentration
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`olopatadine solution rather than through greater dosing frequencies. Id., 1:42-46.
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`However, as discussed below, the olopatadine concentrations in the claimed
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`ophthalmic compositions as well as the compositions and methods of the ’154
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`patent would have been obvious to a POSA and do not provide any surprising
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`results or advantages.
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`V. Claim Construction
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`21.
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`I understand that terms of the claims are to be given their broadest
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`reasonable interpretation in light of the language of the claims and specification of
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`the '154 patent.
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`22.
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`“Sufficient to treat.” Claim 12 recites a method which includes
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`topically applying to an eye of a human an amount of the aqueous solution
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`“sufficient to treat” ocular allergy symptoms, such as ocular itching. Although the
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`‘154 patent does not explicitly define the phrase “sufficient to treat,” a POSA
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`would understand it to mean “at least one drop of the solution.” Id. at Claims 13,
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`26.
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`23. Any term I have not expressly interpreted above, I have given its plain
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`and ordinary meaning to a POSA consistent with the specification of the '154 patent.
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`V.
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`State of the Art
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`24. Allergic reactions of the eye to allergens such as pollen or pet dander
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`manifest with redness, watery eyes, and itching. They occur when the immune
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`system responds to allergens as if they were a threat to the body such as bacteria.
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`The allergens cause the body to produce specific allergy antibodies such as
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`Immunoglobulin E (IgE) which go on to bind to specialized cells, called mast cells.
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`Mast cells are the immune system cells responsible for allergic reactions and are
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`located throughout the body including in the membranes of the nose and on and
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`near the eye. Binding of the antibodies to the mast cells sensitizes them to the
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`allergen. When the mast cells are later exposed to the same allergen, the allergen
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`binds to antibodies on the surface of the cell and causes it to release a variety of
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`chemical mediators such as tryptase, prostaglandin D2, histamine, and many more.
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`The mediators subsequently bind to other receptors in the surrounding tissue and
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`stimulate the allergic reaction. In an allergic disorder such as allergic
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`conjunctivitis, mast cells in the conjunctiva of the eye release histamine and other
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`mediators, triggering the symptoms of allergy. Drugs for the treatment of such
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`allergic disorders are designed to block cell receptors for the mediators (primarily
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`histamine) and/or block the release of the mediators from the mast cells (i.e., mast
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`cell stabilizers). Proud, Ex. 1054, 902; Sharif, Ex. 1055, 1252.
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`25. The allergic mediator histamine exerts its broad range of biological
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`effects through binding to at least four receptor subtypes H1, H2, H3, and H4. Each
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`receptor is responsible for a suite of effects including two or more of
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`immunomodulatory, itching, swelling, erythema, vascular permeability, pain,
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`vasodilation (redness), and others. Ex. 1050, 511, Table 1; 512(1st col.)-513(1st
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`col.)(reviewing art prior to 2010, with one 2012 reference further supporting a
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`prior art finding). For example, binding of histamine to H1 and H4 receptors cause,
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`among others, itching and swelling, but not vasodilation, exhibited as redness. Id.,
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`511, Table 1; 512(1st col.); 512(2nd col.)-513(1st col.). Binding to H2 receptors
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`causes redness, but not itching and swelling. Id., 511, Table 1; 512(1st col.). Not
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`surprisingly since the effects are mediated by different receptors, the time course of
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`itching and redness differ, with the onset of redness being faster than itching. See
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`id., 511(1st col.)-(2nd col.). Anti-histamines are drugs that bind to and block one or
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`Declaration of Leonard Bielory, MD
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`more types of histamine receptors, providing relief from symptoms of allergy
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`mediated by the histamine receptors. See id., 510(2nd col.)- 511(1st col.).
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`26. The allergic reaction mediated by histamine receptors includes both
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`early and late phases. When a sensitized individual who comes in contact with an
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`allergen at a target site, e.g., the conjunctiva, the allergen binds to the mast cells as
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`discussed above and causes an immediate release of mediators from their storage
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`granules in the mast cells. (Choi, S. H., Bielory, L., Curr. Opin. Allergy. Clin.
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`Immunol. 8:438-44 (2008)) Ex. 1051, 439 (1st col.). This acute allergic response is
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`known the early phase reaction. Id. Release of the mediators leads, 6-24 hours
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`later, to the late phase reaction. Id. Early and late phase reactions differ to some
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`extent in the type and distribution of mediators released and the recruitment
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`(attraction) of eosinophils (a type of white blood cell) to the site of allergic
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`reaction. Id., 439 (1st col.), 439 (2nd col.)-440(2nd col.). Although less is released,
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`histamine is still released in both phases. Id., 442(2nd col.)-443(1st col.).
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`27. Olopatadine hydrochloride ([(Z)-3-(dimethylamino)propylidene]-
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`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride) is a selective
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`histamine H1-receptor antagonist (that nevertheless still retains some H2-receptor
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`binding activity (Sharif, Ex. 1055, Abstract, ) that is used for the treatment of
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`ocular symptoms of seasonal allergic conjunctivitis and has the following formula:
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`PATADAY® label; Ex. 1038, 6.
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`.
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`28. Olopatadine and its pharmaceutically acceptable salts are disclosed in
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`EP 0214779, U.S. Pat. No. 4,871,865, EP 0235796 and U.S. Pat. No. 5,116,863.
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`U.S. Pat. No. 5,116,863 discloses olopatadine (Z-11-[3-(dimethylamino)-
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`propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid) as a compound having
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`anti-allergic activity that is known to be an effective treatment for symptoms of
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`allergic rhinitis and urticaria (e.g., sneezing, nasal discharge and nasal congestion),
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`as well as in the treatment of various skin diseases, such as eczema and dermatitis.
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`Id., 2:1-14. The compound may be administered in a solid oral dosage form or as
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`an ophthalmic solution. Id., 1:18-19.
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`29. More than a year prior to May 19, 2011, topical ophthalmic
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`compositions comprising aqueous solutions of olopatadine were known to be
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`useful for treating allergic eye diseases such as allergic conjunctivitis. See, e.g.,
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`Declaration of Leonard Bielory, MD
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`U.S. Patent No. 5,641,805 (Hayakawa, published on June 24, 1997 and assigned to
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`Alcon Laboratories, Inc. and Kyowa Hakko Kogyo Co., Ltd.), Ex. 1008 at 1:5-14.
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`Hayakawa discloses that the topical formulations may be prepared as a topically
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`administrable solution that includes from about 0.0001% w/v to about 5% w/v
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`olopatadine. Ex. 1008 at 6:43-46 and claims 2, 6. Olopatadine is disclosed to have
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`significant antihistamine activity as well as human conjunctival mast cell
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`stabilizing activity that allows it to be administered as infrequently as once or twice
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`a day. Id., 3:18-20; see also Table 1. The effects of olopatadine on histamine
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`release from human conjunctival tissue mast cells upon anti-human IgE challenge
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`were predictive of the in vivo effect of 0.1 %w/v olopatadine on passive
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`conjunctival anaphylaxis in rats. Id., 5:57-6:29. This rat assay indicated that
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`topically applied olopatadine effectively reduced the local allergic response by
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`86% over control. Id., 6: 11-29.
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`30. Hayakawa indicates that olopatadine may be administered to the eye
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`by conventional ophthalmic formulations, including solutions, suspensions or gels.
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`Id., 6:31-33. Solutions for use as eye drops are preferred formulations. Id., 6:33-
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`35. Hayakawa goes on to disclose preparation of such eye drops, disclosing
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`concentrations of up to 5% w/v. Id., 6: 37-46. Hayakawa teaches applying one to
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`several drops to the eyes a few times a day. Id., 6: 63-67. Hayakawa does not
`17
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`mention any solubility or stability issues at any concentration of olopatadine and
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`Declaration of Leonard Bielory, MD
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`recommends the use of standard ophthalmic excipients such as glycerin, boric acid
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`and polyvinyl pyrrolidone among others. Id., 6:50-58.
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`31.
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`In the U. S, olopatadine hydrochloride is commercially available
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`under the brand names PATANOL® and PATADAY® as 0.1 % and 0.2% sterile
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`ophthalmic solutions, respectively, both marketed by Alcon. Exs. 1037 & 1038.
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`PATANOL® is indicated for the treatment of signs and symptoms of allergic
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`conjunctivitis and PATADAY® for the treatment of ocular itching associate with
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`eye allergy. Id. According to its labelling information, each mL of PATANOL®
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`contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01%
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`benzalkonium chloride, and unspecified amounts of sodium chloride, dibasic
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`sodium phosphate, hydrochloric acid and/or sodium hydroxide (to adjust pH) and
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`purified water. Ex. 1037. According to its labelling information, each mL of
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`PATADAY® solution contains olopatadine hydrochloride equivalent to 0.2%
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`olopatadine, and inactives such as 0.01% benzalkonium chloride and unspecified
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`amounts of povidone, dibasic sodium phosphate, sodium chloride, edentate
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`disodium, hydrochloric acid/sodium hydroxide (to adjust pH) and purified water.
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`Ex. 1038.
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`Declaration of Leonard Bielory, MD
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`32. Subsequently, in 2003, olopatadine was shown to be efficacious in
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`treating late phase allergic reaction. In a double-masked, randomized, placebo-
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`controlled clinical trial, where responses were measured 15 minutes (early phase)
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`and 5 hours (late phase) post challenge. It was shown that olopatadine
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`significantly reduced post challenge itching and redness in the early and late phase
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`compared to placebo. Leonardi, Ex. 1053, Abstract. Further, olopatadine also
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`reduced the number of eosinophils and other cellular infiltrate. Id.
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`33. Yanni. Yanni, J.M. et al. “The In Vitro and In Vivo Ocular
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`Pharmacology of olopatadine (AL-4943A), an Effective Anti-
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`Allergic/Antihistaminic Agent,” J. Ocular Pharma Ther. 1996, Vol. 12(4), 389 –
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`400 (“Yanni”, Ex. 1005) describes studies conducted to characterize the in vitro
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`and in vivo pharmacological profile of olopatadine relevant to its topical ocular
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`use. Both the inhibition of histamine at the cellular level and the reduction of
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`allergic response in the eye of an animal challenged with allergenic antigens were
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`studied.
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`34.
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` Olopatadine, referred to as AL-4943A by the Alcon researchers who
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`authored the Yanni reference, was found to inhibit histamine release in a
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`concentration-dependent fashion in both rat cells and human conjunctival mast
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`cells. Ex. 1005, Abstract, pp. 393-94 (including Figure 1). This result established
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`that inhibition of histamine release by olopatadine is not species dependent at least
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`Declaration of Leonard Bielory, MD
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`with respect to rodents and humans. At concentrations as high as 10 mM (0.34%
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`w/v1), olopatadine continued to inhibit rather than stimulate histamine release. Id.,
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`Abstract, p. 393, 397. In contrast, ketotifen, a more potent inhibitor of mast cell
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`mediator release than olopatadine, stimulated histamine release at concentrations
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`only slightly greater than effective inhibitory concentrations due to the cytotoxicity
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`of ketotifen. Id., 393-394. In other words, olopatadine, displayed a significantly
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`larger safety margin than ketotifen. Id., 397.
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`35. Yanni also examined the effect of olopatadine on passive anaphylaxis
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`in rat or guinea pig conjunctiva following intravenous or topical ocular antigen
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`challenge. Id., 393, 395 and 397-398. These experiments were designed to show
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`the extent to which olopatadine could reduce allergic reaction in animal
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`conjunctiva. In the both types of studies, 20 uL of an aqueous solution of 0.001 to
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`1.0 %w/v olopatadine were topically applied to eyes of the animal either after
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`intravenous antigen challenge or at a period of time before topical antigen
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`1 A POSA would know how to convert millimolar concentrations of olopatadine to
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`% w/v using the following formula: % w/v olopatadine = (No. of moles
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`olopatadine/liter)*(molecular weight olopatadine)/10 deciliters/liter. The
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`molecular weight of olopatadine is 337.412 g/mol.
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`challenge. Id., 391-92. The results of these studies are shown in Tables 1 and 2 of
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`Declaration of Leonard Bielory, MD
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`Yanni. Id., 395. The results following intravenous antigen challenge in rat show a
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`dose-dependent reduction in allergic response from .01 to 1.0% w/v in the rat. Id.
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`Likewise, in the topical antigen challenge studies, the reduction in allergic
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`response was, at the longer time periods of 4 and 8 hours, clearly dose dependent.
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`Id. At 8 hours pretreatment, the 1.0% w/v dose of olopatadine provided
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`substantially greater reduction of allergic reaction than the 0.1% w/v dose (i.e., -
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`77% versus -41%). Id. The authors conclude that olopatadine treats allergic
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`conjunctivitis by both inhibiting the release of histamine and stabilizing
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`conjunctival mast cells. Id., 398. On this basis, Alcon entered clinical trials (Id.)
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`and subsequently received FDA approval for PATANOL.
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`36. Schneider. U.S. Pat. Pub. No. 2011/0082145 (“Schneider”; Ex.
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`1007) published on April 7, 2011 and assigned to Alcon Research, Ltd., teaches
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`formulations of olopatadine and a Phosphodiesterase type-IV (PDE4) inhibitor (of
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`Formula I) for treating and/or preventing allergic or inflammatory disorders of the
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`eye, nose, skin, and ear. Ex. 1007, ¶2. In particular the formulations may be used
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`for treating ophthalmic allergic disorders such as allergic conjunctivitis, vernal
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`conjunctivitis, vernal keratoconjunctivits, and gian papillary conjunctivitis as well
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`as other. Id., ¶48. Schneider notes that PDE4 inhibitor compounds are known to
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`be useful as anti-inflammatory and anti-allergy agents. Id., ¶6. Schneider teaches
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`that, in general, it is more desirable for active ingredients to be in solution rather
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`Declaration of Leonard Bielory, MD
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`than in suspension in a pharmaceutical composition, and that pharmaceutical
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`solution formulations have a number of advantages over suspensions, such as ease
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`of manufacturing and handling, better penetration to a target site of action and
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`better dosage consistency. Id., ¶7. Concentrations of olopatadine in a solution
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`composition as described by Schneider can range from about 0.05% w/v to 0.60%
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`w/v, or higher, e.g., solution formulations containing 0.17-0.62% w/v. Id., ¶45.
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`Schneider teaches that the solution compositions can be administered topically to
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`the eye to treat allergic conjunctivitis and/or ocular inflammation in an effective
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`amount to reduce or eliminate allergic conjunctivitis and/or ocular inflammation.
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`Id., ¶ 50. Schneider teaches administering 1-2 drops of such compositions one or
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`more times per day or as directed by an eye care provider Id.
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`37. Schneider also suggests that formulation “comprising compounds that
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`enhance the solubility of olopatadine is desirable because it assures that the
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`olopatadine will not precipitate during a desired shelf life, and allows for an
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`increased concentration of solubilized olopatadine.” Id., ¶8. Schneider thus
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`suggests to a POSA that including solubilizing compounds in solution formulations
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`of olopatadine is desirable in the range of olopatadine concentrations disclosed.
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`While Schneider also suggests PDE4 inhibitors of Formula I may enhance
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`olopatadine solubility, it also implicitly acknowledges that there are other such
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`compounds. Id., ¶ 42. Schneider teaches the olopatadine-containing solutions
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`Declaration of Leonard Bielory, MD
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`may also contain a variety of other components such as tonicity agents,
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`preservatives (e.g., benzalkonium chloride), polymers that may act as lubricants or
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`viscosity agents, such as HPMC, PEG, and PVP, chelating agents (e.g., sodium
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`edetate), buffering agents (e.g., borates), surfactants, and antioxidants. Id., ¶ 52.
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`Schneider particularly notes mannitol, sorbitol, propylene glycol, or glycerol are
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`tonicity agents that may be added in amount
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