`_______________
`
`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
`
`ARGENTUM PHARM. 1003
`
`000001
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 1
`
`
`
`Declaration of Leonard Bielory, MD
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`V.
`
`VI.
`
`Introduction ........................................................................................... 3
`Background and Qualifications ............................................................. 4
`
`Person of Ordinary Skill in the Art ....................................................... 7
`
`The Technology Claimed in the ’154 Patent ....................................... 10
`
`Claim Construction ............................................................................. 12
`State of the Art .................................................................................... 13
`Summary of My Conclusions .............................................................. 28
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Aqueous ophthalmic solutions containing higher
`concentrations of olopatadine were known in the art ............... 29
`
`Even at high concentrations, olopatadine did not exhibit
`the biphasic effect commonly known to be exhibited by
`antihistamines ............................................................................ 34
`
`Olopatadine’s efficacy in treating both early and late
`phase ocular allergic conjunctivitis symptoms would not
`have been surprising ................................................................. 35
`
`Ground 1: Obviousness Based On Bhowmick In View Of
`Yanni And Castillo ................................................................... 38
`
`Ground 2: Obviousness Based On Schneider In View Of
`Hayakawa, Bhowmick And Castillo ......................................... 40
`
`2
`
`000002
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 2
`
`
`
`Declaration of Leonard Bielory, MD
`
`I, Leonard Bielory, MD., hereby declare as follows.
`
`I.
`
`Introduction
`
`1.
`
`I have been retained as an expert witness on behalf of ARGENTUM
`
`PHARMACEUTICALS, LLC, ("ARGENTUM") for the above-captioned inter
`
`partes review (IPR). I am being compensated for my time by the hour in preparing
`
`this declaration, but my compensation is not tied to the outcome of this matter.
`
`2.
`
`I understand that this Declaration accompanies a petition for IPR
`
`involving U.S. Patent No. 8,791,154 ("the '154 patent"), Ex. 1001, which resulted
`
`from U.S. Patent Application No. 13/475,607 ("the '607 application"), filed May
`
`18, 2012. I also understand that the '154 patent claims priority to U.S. Provisional
`
`Patent Application No. 61/548,957, filed Oct 19, 2011 and U.S. Provisional Patent
`
`Application No. 61/487,789, filed May 19,2011.
`
`3.
`
`The '154 patent names Daniel A. Gamache, Laman Alani, Malay
`
`Ghosh, Francisco Javier Galan, Núria Carreras Perdiguer, and Onkar N. Singh as
`
`the inventors. The '154 patent issued on June 29, 2014 from the '607 application. I
`
`understand that, according to the United States Patent and Trademark Office
`
`("USPTO") records, the '154 patent is currently assigned to Alcon Research, Ltd.
`
`("Alcon".)
`
`3
`
`000003
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 3
`
`
`
`Declaration of Leonard Bielory, MD
`
`4.
`
`In preparing this Declaration, I have reviewed the '154 patent, the
`
`granted claims (1-27), and each of the documents cited herein, in light of general
`
`knowledge in the art. In formulating my opinions, I have relied upon my
`
`experience, education, and knowledge in the relevant art. In formulating my
`
`opinions, I have also considered the viewpoint of a person of ordinary skill in the
`
`art ("POSA") (i.e., a person of ordinary skill in the art of ophthalmic drug
`
`formulations and treatment). Throughout this declaration, in rendering my
`
`opinion, I have considered what the viewpoint of a POSA would have been prior to
`
`May 19, 2011, the filing date of U.S. Provisional Patent Application No.
`
`61/487,789, to which the challenged '154 patent claims priority. In the event that
`
`the priority claim to the ‘789 patent is deemed invalid, I have also considered what
`
`the viewpoint of a POSA would have been prior to October 11, 2011, the filing
`
`date of U.S. Provisional Patent Application No. 61/548,957, to which the
`
`challenged ‘154 patent also claims priority.
`
`II.
`
`Background and Qualifications
`
`5.
`
`I am an expert in the field of Allergy and Immunology. I am
`
`currently a Professor at Rutgers University, Center for Environmental Prediction,
`
`and an affiliate Member, NIEHS Center for Environmental Health Sciences at the
`
`Environmental and Occupational Health Sciences Institute, Rutgers University and
`
`4
`
`000004
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 4
`
`
`
`Declaration of Leonard Bielory, MD
`
`Robert Wood Johnson Medical School, Piscataway, New Jersey, as well as
`
`Professor of Medicine, Thomas Jefferson University. I am also currently the
`
`Chair, Joint Council of Allergy and Immunology – Joint Task Force - Practice
`
`Parameters of Allergic Eye Disease – Diagnosis and Management. Additionally, I
`
`have private practice as an allergist at Springfield, New Jersey.
`
`6.
`
`I received a Bachelor’s Degree in Fundamental Science from Lehigh
`
`University in 1976. I received a Doctor of Medicine (M.D.) degree from -
`
`University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey
`
`Medical School (now Rutgers University –New Jersey Medical School), Newark,
`
`N.J. I completed postdoctoral training in Medicine at the University of Maryland
`
`Hospitals, Baltimore, Maryland, and in Allergy and Immunology and Hematology
`
`at the National Institutes of Health, National Heart, Lung and Blood Institute,
`
`Bethesda, Maryland. Subsequent to my education, I joined UMDNJ – NJ Medical
`
`School in 1985 as an Assistant Professor of Medicine and Pediatrics. I also
`
`worked as Associate Professor of Medicine, Pediatrics and Ophthalmology before
`
`being promoted to Professor of Medicine, Pediatrics, Ophthalmology and Visual
`
`Sciences. I was also appointed to the positions of Director of the Division of
`
`Allergy and Immunology, Department of Medicine, Co-Director Immuno-
`
`Ophthalmology Service, Department of Ophthalmology, and Director, Division of
`
`Allergy, Immunology & Rheumatology, Department of Medicine at UMDNJ – NJ
`5
`
`000005
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 5
`
`
`
`Declaration of Leonard Bielory, MD
`
`Medical School. In 2010, I joined the Center for Environmental Prediction,
`
`Rutgers University, as an Adjunct Professor.
`
`7.
`
`I have also held a number of other professional positions and
`
`appointments, memberships and served on several Boards and Trustees including
`
`the JCAAI, and as president of NJMS University Physician Associates Board of
`
`Directors.
`
`From 2007-2012, I was a member of the American Academy of
`
`Allergy, Asthma and Immunology, Rhinitis, Rhinosinusitis, Ocular Allergy
`
`Committee. From 2008 to 2010, I served as the Chair of the Ocular Allergy
`
`Committee at the American Academy of Allergy, Asthma and Immunology.
`
`8.
`
`I have received several honors in my career, including the Dean's
`
`Award of Clinical Excellence - UMDNJ - New Jersey Medical School in 1986, the
`
`American Academy of Ophthalmology Achievement Award in 1999 and the New
`
`York Magazine – “Top Docs” in New York Metropolitan Area and the New Jersey
`
`Magazine Best Doctors in New Jersey from 1996 to the present.
`
`9.
`
`I also have extensive experience related to ocular diseases and
`
`ophthalmic pharmaceuticals. My major research interests have been immuno-
`
`ophthalmology – ocular allergy, climate change and allergic airway disease,
`
`asthma disease management and outcomes and complementary and alternative
`
`medicine. I have given numerous presentations on the advances in the
`
`6
`
`000006
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 6
`
`
`
`management and treatment of ocular allergy as shown in my curriculum vitae, Ex.
`
`Declaration of Leonard Bielory, MD
`
`1025.
`
`10.
`
`I served as an expert witness in litigation concerning olopatadine
`
`formulations, [Alcon Research, Ltd. v. Apotex Inc., 790 F. Supp. 2d 868 (2011); Ex
`
`1031]. The validity of the claims of U.S. Patent No. 5,641,805 (herein referred to
`
`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
`
`the litigation and the antihistamine and mast cell inhibition activity of olopatadine.
`
`The Federal Circuit ultimately found that claims 1-3 and 5-7 of U.S. Patent No.
`
`5,641,805 to be invalid as obvious over various prior art references (Alcon
`
`Research, Ltd. v. Apotex Inc., Appeal No. 2011-1455, Fed. Cir. August 8, 2012; Ex
`
`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
`
`hypothetical person who is presumed to be aware of all of the pertinent art, thinks
`
`along conventional wisdom in the art, and is a person of ordinary creativity. A
`7
`
`000007
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 7
`
`
`
`
`POSA with respect to topical eye formulations would have had knowledge of the
`
`Declaration of Leonard Bielory, MD
`
`scientific literature regarding inflammatory eye disorders and useful therapies
`
`including, e.g., topical aqueous solutions and their formulation into delivery
`
`vehicles, as of May 19, 2010.
`
`13. With respect to the subject matter of the '154 patent, at the time of
`
`filing a POSA typically would have had: (i) an M.D., Pharm. D. or Ph.D. in
`
`chemistry, biochemistry, pharmaceutics, or in a related field in the biological or
`
`chemical sciences, and have at least about two years of experience in the treatment
`
`ocular diseases and formulations used to treat ocular diseases, including topical
`
`pharmaceuticals for use in the eye; or (ii) a Master's degree in chemistry,
`
`biochemistry, pharmaceutics, or in a related field in the biological or chemical
`
`sciences, and have at least about five years of experience in the treatment of ocular
`
`diseases and formulations used to treat ocular diseases, including topical
`
`pharmaceuticals for use in the eye; or (iii) a bachelor’s degree in pharmacy,
`
`chemistry, biochemistry, pharmaceutics, or in a related field in the biological or
`
`chemical sciences, and have at least about 10 years of experience in the treatment
`
`of ocular diseases and formulations used to treat ocular diseases, including topical
`
`pharmaceuticals for use in the eye. These descriptions are approximate, and a
`
`higher level of education or specific skill might make up for less experience, and
`
`vice-versa.
`
`
`
`8
`
`000008
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 8
`
`
`
`Declaration of Leonard Bielory, MD
`
`14. As shown by the scientific and patent literature cited herein, a POSA
`
`would have an understanding of the basis of ocular allergy including knowledge of
`
`the structure and constitution of conjunctiva of the eye, IgE antigen stimulated
`
`histamine release, cell-based and animal models and assays for assessing
`
`effectiveness of ophthalmic treatments, and knowledge of ophthalmic formulation
`
`excipients. Furthermore, the ’154 Patent and much of the prior art discussed herein
`
`involves the development of ophthalmic pharmaceutical compositions to treat
`
`ocular allergic conjunctivitis. Ex. 1001 at 2:41-42. Thus, the POSA will also
`
`have experience in developing ophthalmic pharmaceutical formulations for the
`
`treatment of ocular allergic conjunctivitis.
`
`15. A POSA typically would work as part of a multidisciplinary team and
`
`draw upon not only his or her own skills, but also take advantage of certain
`
`specialized skills of others in the team to solve a given problem. For example, a
`
`clinician having experience in treating allergic disorders of the eye with topical
`
`pharmaceuticals would be part of the team. A formulations chemist with
`
`knowledge of a wide array of excipients suitable for use in ophthalmic
`
`formulations and their properties would also be part of the team.
`
`16.
`
`I believe that I would qualify as a person of at least ordinary skill in
`
`the art as of May 19, 2010.
`
`9
`
`000009
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 9
`
`
`
`Declaration of Leonard Bielory, MD
`
`IV. The Technology Claimed in the ’154 Patent
`
`17.
`
`The ’154 patent relates to ophthalmic aqueous solutions for the
`
`treatment of ocular allergic conjunctivitis containing the drug olopatadine, and
`
`methods of treating ocular allergy symptoms in human. Ex. 1001, Abstract, 2:41-
`
`45, 3:1-2, claims 1, 4, 8, 12 and 21. These compositions contain “relatively high”
`
`concentrations of olopatadine including at least 0.67% w/v, 0.7% w/v, and not
`
`more than 1.0% w/v olopatadine. Id., 2:42-45; 4:1-2; claims 1, 4, 8 and 21. In
`
`order to solubilize the relatively high concentrations of olopatadine in a stable
`
`manner, the inventors purport to provide a unique set of excipients for solubilizing
`
`the olopatadine. Id., 3:28-29. The excipients include a cyclodextrin derivative
`
`selected from SAE-β-cyclodextrin, HP-γ-cyclodextrin, HP-β-cyclodextrin or
`
`combinations thereof. Id., 2:45-52; claims 1, 4, 8 and 21. Typically, the solution
`
`contains at least 0.5% w/v but no greater than 2.0% w/v HP-γ-cyclodextrin. Id.,
`
`4:65-67; and claims 8 and 21. The composition also includes the common lactam
`
`polymer polyvinylpyrrolidone (PVP) to aid in the solubilization of the olopatadine,
`
`and a polyether (e.g., polyethylene glycol (PEG)) for enhancing solubility and/or
`
`aiding in achieving the desired tonicity. Id., 2:52-57; claims 1, 4, 8 and 21. The
`
`solutions typically contain 2.0% w/v to 6.0% w/v PVP and 2.0% w/v to 6.0% w/v
`
`PEG having a molecular weight of 300 to 500. Id. claims 4, 8 and 21.
`
`10
`
`000010
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 10
`
`
`
`
`
`Declaration of Leonard Bielory, MD
`
`18. The compositions also include a common preservative such as
`
`benzalkonium chloride (BAC), as well as borate and/or polyol to aid in achieving
`
`desired preservation. Id., 2:60-67; claims 1, 2, 3, 4, 8 and 21. Typically, the
`
`compositions contain greater than 0.003% w/v but less than 0.03% w/v BAC . Id.,
`
`9:6-14; claim 21. In order to enhance the residence time of the composition upon
`
`the cornea when the composition is topically administered, the compositions may
`
`contain commonly used viscosity enhancing agents such as hydroxypropylmethyl
`
`cellulose (HPMC) at a concentration of at least 0.15% w/v but no greater than
`
`1.0% w/v. Id., 6: 41-50; 7: 9-14; claim 22. The compositions also include
`
`water. Id., 4: 24-26; Examples 1-2; claims 1, 4, 8. and 21. The pH of the aqueous
`
`solution is 6.0 to 7.8 and the osmolality of the solution is 200 to 400
`
`mOsm/kg. Id., 10: 4-9; claim 21.
`
`19. The aqueous solutions may be administered to a human to treat at
`
`least one ocular allergy symptom such as ocular itching. Id., 3:1-5; claim 12. The
`
`solution is topically applied to an eye by dispensing at least one drop of the
`
`solution to the eye. Id., claim 13.
`
`20. The ophthalmic compositions of the ’154 patent are also purported to
`
`provide multiple advantages over previous olopatadine compositions. Among the
`
`surprising advantages asserted for the claimed compositions are the
`
`
`
`11
`
`000011
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 11
`
`
`
`
`following. First, relatively high concentration solutions of olopatadine are alleged
`
`Declaration of Leonard Bielory, MD
`
`to provide significantly improved reduction of late phase ocular allergic
`
`conjunctivitis symptoms in addition to relief from early phase symptoms. Id.,
`
`1:35-39, 11:9-19, 23:33-45, 24:43-26:25. Second, significantly improved
`
`reduction of redness in the early phase is claimed. Id., 1:39-42; 11:9-23; 23:33-45;
`
`24:5-10. The ’154 patent alleges that the enhanced reduction of early phase
`
`redness was surprising because “it was generally believed that itching and redness
`
`would show similar responses to different concentrations of olopatadine.” Id.,
`
`11:19-23. Third, the enhanced relief from the early and late phase symptoms can
`
`be achieved through once a day dosing of a relatively high concentration
`
`olopatadine solution rather than through greater dosing frequencies. Id., 1:42-46.
`
`However, as discussed below, the olopatadine concentrations in the claimed
`
`ophthalmic compositions as well as the compositions and methods of the ’154
`
`patent would have been obvious to a POSA and do not provide any surprising
`
`results or advantages.
`
`V. Claim Construction
`
`21.
`
`I understand that terms of the claims are to be given their broadest
`
`reasonable interpretation in light of the language of the claims and specification of
`
`the '154 patent.
`
`
`
`12
`
`000012
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 12
`
`
`
`Declaration of Leonard Bielory, MD
`
`22.
`
`“Sufficient to treat.” Claim 12 recites a method which includes
`
`topically applying to an eye of a human an amount of the aqueous solution
`
`“sufficient to treat” ocular allergy symptoms, such as ocular itching. Although the
`
`‘154 patent does not explicitly define the phrase “sufficient to treat,” a POSA
`
`would understand it to mean “at least one drop of the solution.” Id. at Claims 13,
`
`26.
`
`23. Any term I have not expressly interpreted above, I have given its plain
`
`and ordinary meaning to a POSA consistent with the specification of the '154 patent.
`
`V.
`
`State of the Art
`
`24. Allergic reactions of the eye to allergens such as pollen or pet dander
`
`manifest with redness, watery eyes, and itching. They occur when the immune
`
`system responds to allergens as if they were a threat to the body such as bacteria.
`
`The allergens cause the body to produce specific allergy antibodies such as
`
`Immunoglobulin E (IgE) which go on to bind to specialized cells, called mast cells.
`
`Mast cells are the immune system cells responsible for allergic reactions and are
`
`located throughout the body including in the membranes of the nose and on and
`
`near the eye. Binding of the antibodies to the mast cells sensitizes them to the
`
`allergen. When the mast cells are later exposed to the same allergen, the allergen
`
`binds to antibodies on the surface of the cell and causes it to release a variety of
`
`13
`
`000013
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 13
`
`
`
`
`chemical mediators such as tryptase, prostaglandin D2, histamine, and many more.
`
`Declaration of Leonard Bielory, MD
`
`The mediators subsequently bind to other receptors in the surrounding tissue and
`
`stimulate the allergic reaction. In an allergic disorder such as allergic
`
`conjunctivitis, mast cells in the conjunctiva of the eye release histamine and other
`
`mediators, triggering the symptoms of allergy. Drugs for the treatment of such
`
`allergic disorders are designed to block cell receptors for the mediators (primarily
`
`histamine) and/or block the release of the mediators from the mast cells (i.e., mast
`
`cell stabilizers). Proud, Ex. 1054, 902; Sharif, Ex. 1055, 1252.
`
`25. The allergic mediator histamine exerts its broad range of biological
`
`effects through binding to at least four receptor subtypes H1, H2, H3, and H4. Each
`
`receptor is responsible for a suite of effects including two or more of
`
`immunomodulatory, itching, swelling, erythema, vascular permeability, pain,
`
`vasodilation (redness), and others. Ex. 1050, 511, Table 1; 512(1st col.)-513(1st
`
`col.)(reviewing art prior to 2010, with one 2012 reference further supporting a
`
`prior art finding). For example, binding of histamine to H1 and H4 receptors cause,
`
`among others, itching and swelling, but not vasodilation, exhibited as redness. Id.,
`
`511, Table 1; 512(1st col.); 512(2nd col.)-513(1st col.). Binding to H2 receptors
`
`causes redness, but not itching and swelling. Id., 511, Table 1; 512(1st col.). Not
`
`surprisingly since the effects are mediated by different receptors, the time course of
`
`itching and redness differ, with the onset of redness being faster than itching. See
`14
`
`
`
`000014
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 14
`
`
`
`
`id., 511(1st col.)-(2nd col.). Anti-histamines are drugs that bind to and block one or
`
`Declaration of Leonard Bielory, MD
`
`more types of histamine receptors, providing relief from symptoms of allergy
`
`mediated by the histamine receptors. See id., 510(2nd col.)- 511(1st col.).
`
`26. The allergic reaction mediated by histamine receptors includes both
`
`early and late phases. When a sensitized individual who comes in contact with an
`
`allergen at a target site, e.g., the conjunctiva, the allergen binds to the mast cells as
`
`discussed above and causes an immediate release of mediators from their storage
`
`granules in the mast cells. (Choi, S. H., Bielory, L., Curr. Opin. Allergy. Clin.
`
`Immunol. 8:438-44 (2008)) Ex. 1051, 439 (1st col.). This acute allergic response is
`
`known the early phase reaction. Id. Release of the mediators leads, 6-24 hours
`
`later, to the late phase reaction. Id. Early and late phase reactions differ to some
`
`extent in the type and distribution of mediators released and the recruitment
`
`(attraction) of eosinophils (a type of white blood cell) to the site of allergic
`
`reaction. Id., 439 (1st col.), 439 (2nd col.)-440(2nd col.). Although less is released,
`
`histamine is still released in both phases. Id., 442(2nd col.)-443(1st col.).
`
`27. Olopatadine hydrochloride ([(Z)-3-(dimethylamino)propylidene]-
`
`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride) is a selective
`
`histamine H1-receptor antagonist (that nevertheless still retains some H2-receptor
`
`
`
`15
`
`000015
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 15
`
`
`
`
`binding activity (Sharif, Ex. 1055, Abstract, ) that is used for the treatment of
`
`Declaration of Leonard Bielory, MD
`
`ocular symptoms of seasonal allergic conjunctivitis and has the following formula:
`
`PATADAY® label; Ex. 1038, 6.
`
`.
`
`28. Olopatadine and its pharmaceutically acceptable salts are disclosed in
`
`EP 0214779, U.S. Pat. No. 4,871,865, EP 0235796 and U.S. Pat. No. 5,116,863.
`
`U.S. Pat. No. 5,116,863 discloses olopatadine (Z-11-[3-(dimethylamino)-
`
`propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid) as a compound having
`
`anti-allergic activity that is known to be an effective treatment for symptoms of
`
`allergic rhinitis and urticaria (e.g., sneezing, nasal discharge and nasal congestion),
`
`as well as in the treatment of various skin diseases, such as eczema and dermatitis.
`
`Id., 2:1-14. The compound may be administered in a solid oral dosage form or as
`
`an ophthalmic solution. Id., 1:18-19.
`
`29. More than a year prior to May 19, 2011, topical ophthalmic
`
`compositions comprising aqueous solutions of olopatadine were known to be
`16
`
`
`
`000016
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 16
`
`
`
`
`useful for treating allergic eye diseases such as allergic conjunctivitis. See, e.g.,
`
`Declaration of Leonard Bielory, MD
`
`U.S. Patent No. 5,641,805 (Hayakawa, published on June 24, 1997 and assigned to
`
`Alcon Laboratories, Inc. and Kyowa Hakko Kogyo Co., Ltd.), Ex. 1008 at 1:5-14.
`
`Hayakawa discloses that the topical formulations may be prepared as a topically
`
`administrable solution that includes from about 0.0001% w/v to about 5% w/v
`
`olopatadine. Ex. 1008 at 6:43-46 and claims 2, 6. Olopatadine is disclosed to have
`
`significant antihistamine activity as well as human conjunctival mast cell
`
`stabilizing activity that allows it to be administered as infrequently as once or twice
`
`a day. Id., 3:18-20; see also Table 1. The effects of olopatadine on histamine
`
`release from human conjunctival tissue mast cells upon anti-human IgE challenge
`
`were predictive of the in vivo effect of 0.1 %w/v olopatadine on passive
`
`conjunctival anaphylaxis in rats. Id., 5:57-6:29. This rat assay indicated that
`
`topically applied olopatadine effectively reduced the local allergic response by
`
`86% over control. Id., 6: 11-29.
`
`30. Hayakawa indicates that olopatadine may be administered to the eye
`
`by conventional ophthalmic formulations, including solutions, suspensions or gels.
`
`Id., 6:31-33. Solutions for use as eye drops are preferred formulations. Id., 6:33-
`
`35. Hayakawa goes on to disclose preparation of such eye drops, disclosing
`
`concentrations of up to 5% w/v. Id., 6: 37-46. Hayakawa teaches applying one to
`
`several drops to the eyes a few times a day. Id., 6: 63-67. Hayakawa does not
`17
`
`
`
`000017
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 17
`
`
`
`
`mention any solubility or stability issues at any concentration of olopatadine and
`
`Declaration of Leonard Bielory, MD
`
`recommends the use of standard ophthalmic excipients such as glycerin, boric acid
`
`and polyvinyl pyrrolidone among others. Id., 6:50-58.
`
`31.
`
`In the U. S, olopatadine hydrochloride is commercially available
`
`under the brand names PATANOL® and PATADAY® as 0.1 % and 0.2% sterile
`
`ophthalmic solutions, respectively, both marketed by Alcon. Exs. 1037 & 1038.
`
`PATANOL® is indicated for the treatment of signs and symptoms of allergic
`
`conjunctivitis and PATADAY® for the treatment of ocular itching associate with
`
`eye allergy. Id. According to its labelling information, each mL of PATANOL®
`
`contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01%
`
`benzalkonium chloride, and unspecified amounts of sodium chloride, dibasic
`
`sodium phosphate, hydrochloric acid and/or sodium hydroxide (to adjust pH) and
`
`purified water. Ex. 1037. According to its labelling information, each mL of
`
`PATADAY® solution contains olopatadine hydrochloride equivalent to 0.2%
`
`olopatadine, and inactives such as 0.01% benzalkonium chloride and unspecified
`
`amounts of povidone, dibasic sodium phosphate, sodium chloride, edentate
`
`disodium, hydrochloric acid/sodium hydroxide (to adjust pH) and purified water.
`
`Ex. 1038.
`
`
`
`18
`
`000018
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 18
`
`
`
`
`
`Declaration of Leonard Bielory, MD
`
`32. Subsequently, in 2003, olopatadine was shown to be efficacious in
`
`treating late phase allergic reaction. In a double-masked, randomized, placebo-
`
`controlled clinical trial, where responses were measured 15 minutes (early phase)
`
`and 5 hours (late phase) post challenge. It was shown that olopatadine
`
`significantly reduced post challenge itching and redness in the early and late phase
`
`compared to placebo. Leonardi, Ex. 1053, Abstract. Further, olopatadine also
`
`reduced the number of eosinophils and other cellular infiltrate. Id.
`
`33. Yanni. Yanni, J.M. et al. “The In Vitro and In Vivo Ocular
`
`Pharmacology of olopatadine (AL-4943A), an Effective Anti-
`
`Allergic/Antihistaminic Agent,” J. Ocular Pharma Ther. 1996, Vol. 12(4), 389 –
`
`400 (“Yanni”, Ex. 1005) describes studies conducted to characterize the in vitro
`
`and in vivo pharmacological profile of olopatadine relevant to its topical ocular
`
`use. Both the inhibition of histamine at the cellular level and the reduction of
`
`allergic response in the eye of an animal challenged with allergenic antigens were
`
`studied.
`
`34.
`
` Olopatadine, referred to as AL-4943A by the Alcon researchers who
`
`authored the Yanni reference, was found to inhibit histamine release in a
`
`concentration-dependent fashion in both rat cells and human conjunctival mast
`
`cells. Ex. 1005, Abstract, pp. 393-94 (including Figure 1). This result established
`
`
`
`19
`
`000019
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 19
`
`
`
`Declaration of Leonard Bielory, MD
`
`that inhibition of histamine release by olopatadine is not species dependent at least
`
`with respect to rodents and humans. At concentrations as high as 10 mM (0.34%
`
`w/v1), olopatadine continued to inhibit rather than stimulate histamine release. Id.,
`
`Abstract, p. 393, 397. In contrast, ketotifen, a more potent inhibitor of mast cell
`
`mediator release than olopatadine, stimulated histamine release at concentrations
`
`only slightly greater than effective inhibitory concentrations due to the cytotoxicity
`
`of ketotifen. Id., 393-394. In other words, olopatadine, displayed a significantly
`
`larger safety margin than ketotifen. Id., 397.
`
`35. Yanni also examined the effect of olopatadine on passive anaphylaxis
`
`in rat or guinea pig conjunctiva following intravenous or topical ocular antigen
`
`challenge. Id., 393, 395 and 397-398. These experiments were designed to show
`
`the extent to which olopatadine could reduce allergic reaction in animal
`
`conjunctiva. In the both types of studies, 20 uL of an aqueous solution of 0.001 to
`
`1.0 %w/v olopatadine were topically applied to eyes of the animal either after
`
`intravenous antigen challenge or at a period of time before topical antigen
`
`1 A POSA would know how to convert millimolar concentrations of olopatadine to
`
`% w/v using the following formula: % w/v olopatadine = (No. of moles
`
`olopatadine/liter)*(molecular weight olopatadine)/10 deciliters/liter. The
`
`molecular weight of olopatadine is 337.412 g/mol.
`
`20
`
`000020
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 20
`
`
`
`
`challenge. Id., 391-92. The results of these studies are shown in Tables 1 and 2 of
`
`Declaration of Leonard Bielory, MD
`
`Yanni. Id., 395. The results following intravenous antigen challenge in rat show a
`
`dose-dependent reduction in allergic response from .01 to 1.0% w/v in the rat. Id.
`
`Likewise, in the topical antigen challenge studies, the reduction in allergic
`
`response was, at the longer time periods of 4 and 8 hours, clearly dose dependent.
`
`Id. At 8 hours pretreatment, the 1.0% w/v dose of olopatadine provided
`
`substantially greater reduction of allergic reaction than the 0.1% w/v dose (i.e., -
`
`77% versus -41%). Id. The authors conclude that olopatadine treats allergic
`
`conjunctivitis by both inhibiting the release of histamine and stabilizing
`
`conjunctival mast cells. Id., 398. On this basis, Alcon entered clinical trials (Id.)
`
`and subsequently received FDA approval for PATANOL.
`
`36. Schneider. U.S. Pat. Pub. No. 2011/0082145 (“Schneider”; Ex.
`
`1007) published on April 7, 2011 and assigned to Alcon Research, Ltd., teaches
`
`formulations of olopatadine and a Phosphodiesterase type-IV (PDE4) inhibitor (of
`
`Formula I) for treating and/or preventing allergic or inflammatory disorders of the
`
`eye, nose, skin, and ear. Ex. 1007, ¶2. In particular the formulations may be used
`
`for treating ophthalmic allergic disorders such as allergic conjunctivitis, vernal
`
`conjunctivitis, vernal keratoconjunctivits, and gian papillary conjunctivitis as well
`
`as other. Id., ¶48. Schneider notes that PDE4 inhibitor compounds are known to
`
`be useful as anti-inflammatory and anti-allergy agents. Id., ¶6. Schneider teaches
`21
`
`
`
`000021
`
`Novartis AG Exhibit 2004
`Ayla Pharma LLC v. Novartis AG
`IPR2020-00295
`Page 21
`
`
`
`
`that, in general, it is more desirable for active ingredients to be in solution rather
`
`Declaration of Leonard Bielory, MD
`
`than in suspension in a pharmaceutical composition, and that pharmaceutical
`
`solution formulations have a number of advantages over suspensions, such as ease
`
`of manufacturing and handling, better penetration to a target site of action and
`
`better dosage consistency. Id., ¶7. Concentrations of olopatadine in a solution
`
`composition as described by Schneider can range from about 0.05% w/v to 0.60%
`
`w/v, or higher, e.g., solution formulations containing 0.17-0.62% w/v. Id., ¶45.
`
`Schneider teaches that the solution compositions can be ad