IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`MYLAN PHARMACEUTICALS, INC.
`Petitioner,
`
`v.
`
`SENJU PHARMACEUTICAL CO., LTD.
`Patent Owner.
`
`U.S. Patent No. 8,784,789 to Higashiyama
`Issue Date: July 22, 2014
`Inter Partes Review No.: IPR2016-626
`Title: Aqueous Liquid Preparations and Light-Stabilized Aqueous Liquid
`Preparations
`
`_____________________
`
`DECLARATION OF MANSOOR M. AMIJI, PH.D., R.PH.
`
`MYLAN Ex. 1003, Page 1
`
`

`
`VI.
`
`I.
`II.
`III.
`IV.
`V.
`
`TABLE OF CONTENTS
`Introduction ................................................................................................. 4
`Background and Qualifications.................................................................... 5
`List of Materials Considered........................................................................ 9
`Legal Standards ......................................................................................... 11
`Summary of Opinions................................................................................ 15
`A.
`Claims 1-11 of the ’789 patent are obvious...................................... 15
`The ’789 Patent.......................................................................................... 16
`i.
`Claims of the ’789 Patent....................................................... 18
`VII. The Subject Matter of Claims 1-11 of the ’789 Patent is Unpatentable
`as Obvious ................................................................................................. 20
`A.
`Level of Skill in the Art ................................................................... 20
`B.
`Scope and Content of the Prior Art .................................................. 21
`a.
`Bepotastine Besilate was Considered in the Prior Art to be
`Suitable for Ophthalmic Preparations............................................... 21
`Sodium Chloride was Commonly Used as a Tonicity Agent............ 23
`Using Additives in Aqueous Liquid Preparations was Common ...... 26
`Sodium Chloride was Known to have Light-Stabilizing
`Properties and Testing for Light-Stability was Routine.................... 28
`Differences Between the Claims and the Prior Art........................... 30
`Ground 1A: Claims 1-11 of the ’789 Patent are Obvious Over
`Tanabe In View of Yanni................................................................. 31
`i.
`Claim 1 Would Have Been Obvious ...................................... 31
`ii.
`Claims 2 and 8 Would Have Been Obvious ........................... 41
`iii.
`Claims 3 and 4 Would Have Been Obvious ........................... 42
`iv.
`Claim 5 Would Have Been Obvious ...................................... 43
`v.
`Claim 6 Would Have Been Obvious ...................................... 43
`vi.
`Claim 7 Would Have Been Obvious ...................................... 44
`vii. Claim 9 Would Have Been Obvious ...................................... 45
`viii. Claim 10 Would Have Been Obvious .................................... 49
`ix.
`Claim 11 Would Have Been Obvious .................................... 53
`
`b.
`c.
`d.
`
`C.
`D.
`
`ii
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`MYLAN Ex. 1003, Page 2
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`

`
`E.
`
`ii.
`
`Ground 2A: Claims 1-11 of the ’789 Patent are Obvious Over
`Tanabe In View of Hecht................................................................. 53
`i.
`Claim 1 .................................................................................. 53
`ii.
`Claims 2 and 8 Would Have Been Obvious ........................... 60
`iii.
`Claims 3 and 4 Would Have Been Obvious ........................... 61
`iv.
`Claim 5 Would Have Been Obvious ...................................... 62
`v.
`Claim 6 Would Have Been Obvious ...................................... 62
`vi.
`Claim 7 Would Have Been Obvious ...................................... 63
`vii. Claim 9 Would Have Been Obvious ...................................... 64
`viii. Claim 10 Would Have Been Obvious .................................... 67
`ix.
`Claim 11 Would Have Been Obvious .................................... 71
`VIII. Secondary Considerations.......................................................................... 71
`A.
`No unexpected results...................................................................... 71
`i.
`The sodium chloride of the prior art formulation would
`have had the same properties that are the basis of the
`alleged unexpected results ..................................................... 72
`Sodium chloride was known to have light-stabilizing
`properties for compounds with cholorophenyl groups,
`thus such properties would not have been unexpected ........... 74
`It is not shown that the alleged unexpected results cover
`the entire claimed range ......................................................... 75
`No other evidence of nonobviousness.............................................. 77
`B.
`IX. Conclusion................................................................................................. 77
`
`iii.
`
`iii
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`MYLAN Ex. 1003, Page 3
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`

`
`I.
`
`Introduction
`1.
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Petitioner for the
`
`above captioned inter partes reviews (“IPRs”). I am being compensated for my time
`
`in connection with these IPRs at my standard consulting rate, which is $870 per hour.
`
`My compensation is in no way dependent on the outcome of these IPRs.
`
`3.
`
`I understand that the petition for inter partes review involves U.S.
`
`Patent No. 8,784,789 (“the ’789 patent”) (EX1001), issued on July 22, 2014 from
`
`U.S. Appl. No. 10/500,354 (“the ’354 application”). Both patents name Masayo
`
`Higashiyama as the sole inventor. The ’354 application was filed on June 30, 2004
`
`as
`
`a national phase
`
`application of PCT International Application No.
`
`PCT/JP03/09713 (“the ’713 application”), which was filed on July 30, 2003 and
`
`claims priority to Japanese Patent Application No. 2002-223804 (“JP 804
`
`application”), which was filed on July 31, 2002.
`
`It is my understanding that the
`
`earliest possible priority date of the ’789 patent is July 31, 2002, the filing date of
`
`the Japanese priority application.
`
`I further understand that the ’789 patent is
`
`assigned to Senju Pharmaceutical Co., Ltd. (“Senju,” “the Patentee,” or “the Patent
`
`Owner”).
`
`4
`
`MYLAN Ex. 1003, Page 4
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`

`
`II.
`
`Background and Qualifications
`4.
`I am an expert in the field of pharmaceutical sciences. Specifically, I
`
`specialize in drug formulation development and targeted delivery of therapeutics,
`
`including development of parenteral and ophthalmic products, and I have been an
`
`expert in this field since prior to 2002. Throughout this declaration, I will refer to
`
`the field of aqueous drug formulations which includes ophthalmic drug
`
`formulations, as the relevant field or the relevant art.
`
`I have relied upon my
`
`training, knowledge, and experience in the relevant art to form my opinions. A
`
`copy of my current curriculum vitae is provided as EX1018.
`
`5.
`
`As an expert in the relevant field since prior to 2002, I am qualified to
`
`provide an opinion as to what a person of ordinary skill in the art (“POSA”) would
`
`have understood, known, or concluded as of 2002. Since the 1990’s, I have
`
`accumulated significant training and experience in the relevant field and related
`
`fields.
`
`6.
`
`I received my Bachelor of Science degree in Pharmacy from the
`
`College of Pharmacy and Allied Health Professions at Northeastern University,
`
`Boston, MA in 1988 and my Ph.D. in Pharmaceutics/Biomaterial Science from the
`
`School of Pharmacy and Pharmaceutical Sciences at Purdue University, West
`
`Lafayette, IN in 1992.
`
`5
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`MYLAN Ex. 1003, Page 5
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`

`
`7.
`
`In January 1993, I joined the faculty at Northeastern University in the
`
`School of Pharmacy, Department of Pharmaceutical Sciences, as an Assistant
`
`Professor.
`
`8.
`
`In 1999, I was promoted to Associate Professor at Northeastern
`
`University in the School of Pharmacy, Department of Pharmaceutical Sciences.
`
`9.
`
`From June 2000 to December 2000, I served as a Visiting Research
`
`Scholar at
`
`the Massachusetts Institute of Technology in the Department of
`
`Chemical Engineering.
`
`10.
`
`In 2006, I was promoted to Full Professor at Northeastern University
`
`in the School of Pharmacy, Department of Pharmaceutical Sciences.
`
`11.
`
`Since 2010, I have served as a Bouvé College Distinguished Professor
`
`and as the Chairman of the Department of Pharmaceutical Sciences in the School
`
`of Pharmacy, Bouvé College of Health Sciences, at Northeastern University.
`
`12.
`
`The primary focus of my research is on the development of
`
`biocompatible materials from natural and synthetic polymers, target-specific drug
`
`and gene delivery systems for cancer, inflammatory, and infectious diseases, and
`
`nanotechnology applications for medical diagnosis, imaging, and therapy. We
`
`have made seminal contributions in pharmaceutical formulation development,
`
`especially in the area of target-specific delivery for cancer, inflammatory diseases,
`
`and brain disorders.
`
`6
`
`MYLAN Ex. 1003, Page 6
`
`

`
`13.
`
`I have served as the Pharmaceutics Section Leader of the Department
`
`of Pharmaceutical Sciences in the School of Pharmacy at Northeastern University;
`
`the Education and Outreach Coordinator for the Molecular Biotechnology Initiative
`
`at Northeastern University;
`
`the Co-Director of the NERC at Northeastern
`
`University; the Associate Chair of the Department of Pharmaceutical Sciences in
`
`the School of Pharmacy at Northeastern University; the Acting Chair of the
`
`Department of Pharmaceutical Sciences in the School of Pharmacy at Northeastern
`
`University; and I am currently the Chairman of the Department of Pharmaceutical
`
`Sciences in the School of Pharmacy, Bouvé College of Health Sciences, at
`
`Northeastern University.
`
`14.
`
`I have more than 22 years of experience, teaching both graduate and
`
`undergraduate students. As a tenured faculty member in the School of Pharmacy
`
`at Northeastern University, I have taught professional pharmacy students and
`
`graduate
`
`students
`
`in the Pharmaceutical Sciences, Biotechnology,
`
`and
`
`Nanomedicine Programs.
`
`I specifically lecture on the development of drug
`
`delivery systems for parenteral, ophthalmic, and oral routes of administration,
`
`including intravenous administration of aqueous drug formulations and site-
`
`specific nano-particulate dosage forms. During this time, I have had extensive
`
`experience researching and teaching parenteral and ophthalmic drug formulations.
`
`7
`
`MYLAN Ex. 1003, Page 7
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`

`
`15.
`
`I have experience in stabilization of pharmaceutical products,
`
`including those that are made in aqueous solutions.
`
`In these studies, we have
`
`examined the role of various excipients, such as buffers, photostabilizers, and
`
`antioxidants, in improving drug stability. In my role as a teacher, I also teach drug
`
`stability to pharmacy and graduate students at Northeastern University.
`
`16.
`
`I am the author or co-author on a large number of peer-reviewed
`
`articles, book chapters, and conference proceedings and have also authored and/or
`
`edited several books,
`
`including Applied Physical Pharmacy – 2nd Edition
`
`(McGraw-Hill, 2014). I am also the inventor or co-inventor on a number of issued
`
`United States and foreign patents and pending patent applications.
`
`17.
`
`I extensively lecture on various topics at the leading edge of modern
`
`pharmaceutical
`
`sciences,
`
`and
`
`I
`
`regularly
`
`attend
`
`numerous worldwide
`
`pharmaceutical conferences. I have submitted over 200 papers to conferences in
`
`the field of pharmaceutical sciences.
`
`18.
`
`I was appointed as a Fellow of American Association of
`
`Pharmaceutical Scientists (AAPS) in 2007 and served as a long-term member of
`
`the Association. I am also a Fellow and member of the Scientific Advisory Board
`
`of the Controlled Release Society.
`
`I am a permanent member of the National
`
`Institutes of Health’s grant review panel and many other public funding agencies
`
`8
`
`MYLAN Ex. 1003, Page 8
`
`

`
`in the U.S. and across the world. I am an Associate Editor of two peer-reviewed
`
`journals and on the editorial board of about a half dozen other scientific journals.1
`
`III. List of Materials Considered
`19.
`I have reviewed the ’789 patent, relevant portions of the prosecution
`
`history, and each of the documents cited herein, in consideration of general
`
`knowledge in the art as of July 2002. In forming my opinions, I have relied upon
`
`my experience in the relevant art. I have also considered the viewpoint of a POSA
`
`as defined below as of July 2002.
`
`I have considered all documents cited in this
`
`Declaration and all documents cited in the Petition for Inter Partes Review of the
`
`’789 patent, as well as the following documents:
`
`Petitioner
`Exhibit #
`1001
`
`1002
`
`1003
`1004
`1005
`
`1006
`
`Description
`Higashiyama, U.S. Patent No. 8,784,789, “Aqueous Liquid
`Preparations and Light-Stabilized Aqueous Liquid Preparations”
`(“the ’789 patent”)
`Higashiyama, U.S. Patent No. 8,877,168 “Aqueous Liquid
`Preparations and Light-Stabilized Aqueous Liquid Preparations”
`(“the ’168 patent”)
`Reserved for Declaration of Dr. Mansoor M. Amiji
`U.S. Patent No. 6,174,914 (“Yanni”)
`Remington: The Science and Practice of Pharmacy 20th Ed.
`(“Hecht”)
`Lloyd V. Allen Jr. et al. “Compounding Ophthalmic
`Preparations,” International Journal of Pharmaceutical
`Compounding 2(3) (1998) (“Allen”)
`
`1 I reserve the right to further explain my background and qualifications in deposition
`
`if needed.
`
`9
`
`MYLAN Ex. 1003, Page 9
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`

`
`1007
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`1015
`
`1016
`
`1017
`1018
`1019
`1020
`1021
`1022
`1023
`1024
`1025
`1026
`1027
`1028
`1029
`1030
`1031
`
`Chemical and Pharmaceutical Bulletin 50(2) (“Araki I”)
`Press Release “Tanabe Seiyaku Granted Rights for Bepotastine
`Besilate for Ophthalmic [sic] Use to Senju Seiyaku (Japan)”
`(“Tanabe”)
`PCT International Patent Publication No. WO 01/080858 (“Araki
`II”)
`Antihistamines: topical vs oral administration, Clinical and
`Experimental Allergy 26(3):11-17 (1996) (“Davies”)
`“Stability Testing: Photostability Testing of New Drug
`Substances and Products” (“ICH Guideline”)
`“Formulation of a Stable Parenteral Product; Clonidine
`Hydrochloride Injection,” PDA Journal of Pharmaceutical
`Science & Technology 56(6):320-325 (1998) (“Kostecka”)
`Photoreactivity of LY277359 Maleate, a 5- Hydroxytryptamine3
`(5-HT3) Receptor Antagonist, in Solution, Pharmaceutical
`Research 8(10):1215-1222 (1991) (“Mosher”)
`Reserved
`Press Release “Regarding Extended Indication for Selective
`Histamine H1 Receptor Antagonist/Anti-Allergic Agent Talion®
`Tablets 5 and Talion® Tablets 10 in Treating Pruritus/Itching
`Accompanying Urticaria and Other Skin Diseases” (“Talion Press
`Release”)
`Remington’s Pharmaceutical Sciences, pp. 1410-1419 (1980)
`(“Remington”).
`European Patent Publication No. EP 0 949 260 (“Kita”)
`CV of Dr. Mansoor M. Amiji
`Declaration of Higashiyama of Nov. 6, 2007
`Supplemental Amendment of Nov. 13, 2007
`Final Office Action dated of Feb. 8, 2008
`Declaration of Higashiyama of Dec. 22, 2008
`Amendment of Jan. 5, 2009
`Office Action of May 8, 2009
`Office Action of April 9, 2010
`Final Office Action of Dec. 20, 2010
`Declaration of Higashiyama of Sept., 11, 2012
`Supplemental Amendment of Sept. 14, 2012
`Office Action of Aug. 30, 2013
`Amendment of May 30, 2014
`Notice of Allowance of June 12, 2014
`
`10
`
`MYLAN Ex. 1003, Page 10
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`

`
`1032
`1033
`
`Amendment of April 24, 2012
`Final Office Action of Apr. 30, 2014
`
`IV. Legal Standards
`20.
`In this section I describe my understanding of certain legal standards. I
`
`have been informed of these legal standards by Petitioners’ attorneys. I am not an
`
`attorney, and I am relying only on instructions from Petitioners’ attorneys for these
`
`legal standards.
`
`I have applied these understandings in my analysis as detailed
`
`below.
`
`21.
`
`I understand that a patent claim is obvious if the claimed invention
`
`would have been obvious to a POSA at the time of the invention in view of the prior
`
`art, and in light of the general knowledge in the art.
`
`22.
`
`I understand that the first step in determining whether a patent claim is
`
`obvious is to properly construe the claims to determine claim scope and meaning.
`
`I understand that in inter partes review proceedings the claim terms are presumed
`
`to take on their ordinary and customary meaning based on the broadest reasonable
`
`interpretation of the claim language that a POSA would apply to the claim terms,
`
`when those terms are read in light of the teachings in the specification.
`
`23.
`
`I understand that a patent or other publication must first qualify as prior
`
`art before it can be used to invalidate a patent claim. I understand that documents
`
`and materials that qualify as prior art can be used to render a claim unpatentable as
`
`obvious under 35 U.S.C. § 103.
`
`11
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`MYLAN Ex. 1003, Page 11
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`

`
`24.
`
`I understand that the “priority date” of a patent is taken to be the date
`
`on which it is filed. I further understand information that is published or otherwise
`
`publicly available more than one year before the priority date of a patent is prior art
`
`that can render a patent claim unpatentable regardless of the purported date of
`
`invention.
`
`25.
`
`I understand that, once the claims of a patent have been properly
`
`construed, the second step in determining obviousness of a patent claim requires a
`
`comparison of the properly construed claim language to the prior art on a limitation-
`
`by-limitation basis.
`
`I have been instructed by counsel on the law regarding
`
`obviousness, and understand that a patent will be unpatentable if the differences
`
`between the claimed subject matter and the prior art are such that the subject matter
`
`as a whole would have been obvious at the time the invention was made to a POSA.
`
`26.
`
`I have been instructed by counsel that the priority date for the purposes
`
`of the ’789 patent is July 31, 2002, which is the earliest filing to which the patent
`
`claims priority.
`
`In forming my opinions and conclusions below, I consider the
`
`POSA’s understanding as of July 2002.
`
`27. When determining if a claimed invention would have been obvious, it
`
`is my understanding that this determination includes the consideration of various
`
`factors, including: (i) the scope and content of the prior art; (ii) differences between
`
`12
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`MYLAN Ex. 1003, Page 12
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`

`
`the prior art and the claims at issue; (iii) the level of ordinary skill in the pertinent
`
`art; (iv) the existence of secondary considerations of non-obviousness.
`
`28.
`
`I understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art to achieve the claimed invention. A claimed
`
`invention can be obvious when, for example, there is some teaching, suggestion, or
`
`motivation in the prior art that would have led a POSA to modify the prior art
`
`reference or to combine prior art reference teachings to arrive at the claimed
`
`invention.
`
`In other words, even if one reference does not show the whole of the
`
`invention, if it would have been obvious to a person of ordinary skill in the art at the
`
`relevant time to add the missing pieces to the invention, then a single reference can
`
`render a claim invalid as obvious even if it does not show the whole invention. I
`
`also understand that the prior art references themselves do not have to provide a
`
`specific hint or suggestion of the alteration needed to arrive at the claimed invention;
`
`the analysis may rely on a recourse to logic, judgment, and common sense available
`
`to a POSA. In other words, a combination of two or more references can render a
`
`claim invalid as obvious whether or not there is an explicit suggestion in one of the
`
`references to combine the two references, if as a matter of engineering skill or
`
`practice in the field it would be known to do so.
`
`29.
`
`I am informed that a combination of familiar elements according to
`
`known methods is likely to be obvious when it does no more than yield predictable
`
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`MYLAN Ex. 1003, Page 13
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`

`
`results. I also understand that when a person of ordinary skill would have reached
`
`the claimed invention through routine experimentation,
`
`the invention may be
`
`deemed obvious. I further understand that a key inquiry is whether any improvement
`
`alleged by a patent is more than the predictable use of prior art elements according
`
`to their established functions.
`
`30.
`
`I understand that various rationales are utilized to determine whether a
`
`claim is obvious, including, among others: (i) simple substitution of one known
`
`element for another to obtain predictable results; (ii) use of known techniques to
`
`improve similar methods or products in the same way; (iii) applying a known
`
`technique to a known method or product ready for improvement to yield predictable
`
`results; (iv) “obvious to try” – choosing from a finite number of identified,
`
`predictable solutions, with a reasonable expectation of success; and (v) known work
`
`in one field of endeavor may prompt variations of it for use in either the same field
`
`or a different one based on design incentives or other market forces if the variations
`
`would have been predictable to one of ordinary skill in the art.
`
`31. As stated above, I understand that secondary considerations of non-
`
`obviousness are part of the inquiry of determining the obviousness of an invention.
`
`I understand that these secondary considerations include failure of others, copying,
`
`unexpectedly superior results, perception in the industry, commercial success, and
`
`long-felt but unmet need.
`
`I also understand that
`
`in order
`
`for secondary
`
`14
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`MYLAN Ex. 1003, Page 14
`
`

`
`considerations of non-obviousness to be applicable, they must have some nexus to
`
`the subject matter in the claim that was not known in the prior art. I understand that
`
`this nexus includes a factual connection between the subject matter of the claim and
`
`the secondary considerations alleged.
`
`V.
`
`Summary of Opinions
`32. As described in detail below, I offer the following opinions in this
`
`declaration.
`
`A.
`33.
`
`Claims 1-11 of the ’789 patent are obvious
`It is my opinion that certain prior art references render obvious the
`
`claims of the ’789 patent.
`
`34.
`
`In particular, it would have been obvious for a POSA to combine the
`
`teachings of Tanabe with either the teachings of Yanni or Hecht to arrive at the
`
`subject matter of claims 1-11 of the ’789 patent,
`
`thus rendering the claims
`
`unpatentable. Tanabe discusses the use of bepotastine besilate tablets for allergic
`
`rhinitis and discusses further the expected effectiveness of bepotastine besilate in
`
`eye-drop form against symptoms of allergic conjunctivitis as a result of its known
`
`histimine antagonistic action. (EX1008, 1). Yanni discloses an aqueous ophthalmic
`
`solution formulation with a preferred solution including the salt of an active
`
`ingredient, sodium chloride, water, a buffer, a preservative, and pH adjusters.
`
`(EX1004, 3:36-54). Similarly, Hecht discusses several stock solutions for use in
`
`15
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`MYLAN Ex. 1003, Page 15
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`

`
`ophthalmic preparations, one of which is a phosphate buffer containing solution that
`
`contains 0.5 w/v % sodium chloride, phosphate buffers, a chelating agent, and a
`
`preservative, and further notes that the concentration of the active ingredient is
`
`generally less than 2.5 to 3.0% which facilitates drug dissolution within the vehicle.
`
`(EX1005, 827). A POSA would have found such combinations to be obvious and
`
`would expect such preparations to have suitable properties.
`
`VI. The ’789 Patent
`35.
`I have considered the disclosure of the ’789 patent and reviewed it in
`
`light of the knowledge of the POSA as of the earliest possible priority date of the
`
`’789 patent, which I understand to be July 31, 2002.
`
`36.
`
`The ’789 patent specification indicates that it is directed to an aqueous
`
`liquid
`
`preparation
`
`containing
`
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-
`
`pyridyl)methoxy]piperidino]butyric acid, more commonly known as bepotastine, or
`
`a pharmacologically acceptable acid addition salt thereof such as bepotastine
`
`besilate, which is an acid addition salt monobenzenesulfonate. (EX1001, Abstract,
`
`1:10-35). Bepotastine besilate has the following structure:
`
`16
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`MYLAN Ex. 1003, Page 16
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`

`
`The ’789 patent states the concentration of the active ingredient bepotastine besilate
`
`as follows:
`
`[A] lower limit of about 0.1 w/v %, preferably about 0.3 w/v %, more
`preferably about 0.5 w/v %, and an upper limit of about 2.0 w/v %,
`preferably about 1.5 w/v %, which are increased or decreased
`appropriately depending on the object of use and the degree of
`symptoms.
`
`(EX1001, 3:7-15).
`
`37.
`
`The ’789 patent states further that bepotastine is unstable to light in an
`
`aqueous solution.
`
`(EX1001, 36-41). The inventor of the ’789 patent purports to
`
`have found that adding a water-soluble metal chloride to the aqueous solution
`
`provided light-stability.
`
`(EX1001, 2:1-7). The ’789 patent discloses the water-
`
`soluble metal chloride is preferably “alkali metal chlorides such as sodium chloride,
`
`potassium chloride and the like, and alkaline earth metal chlorides such as calcium
`
`chloride and the like,” and that sodium chloride is particularly preferred.
`
`(EX1001,
`
`3:17-22).
`
`38.
`
`The ’789 patent states the desirable concentration of the water-soluble
`
`metal chloride as follows:
`
`[T]he content of the water-soluble metal chloride is generally shown by
`a lower limit of about 0.15 w/v % and an upper limit of about 1.5 w/v
`%, preferably a lower limit of about 0.2 w/v % and an upper limit of
`about 1.2 w/v %. Particularly, as sodium chloride, it is not less than
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`

`
`about 0.15 w/v %, about 0.2 w/v %, about 0.3 w/v %, and not more than
`about 1.0 w/v %, about 0.8 w/v %, about 0.6 w/v %. As potassium
`chloride, it is not less than about 0.15 w/v %, about 0.2 w/v %, about
`0.3 w/v %, and not more than about 1.0 w/v %, about 0.9 w/v %, about
`0.8 w/v %. As calcium chloride and as dihydrate, it is not less than
`about 0.2 w/v %, about 0.3 w/v %, and not more than about 1.5 w/v %,
`about 1.2 w/v %.
`
`(EX1001 3:23-35). The ’789 patent also states the amount of the water-soluble metal
`
`chloride takes into account the osmotic pressure of the resulting preparation.
`
`(EX1001, 3:37-43 (“[T]he osmotic pressure is generally about 230 mOsm-about 350
`
`mOsm . . . .”)).
`
`39.
`
`The ’789 patent also discloses common additives for aqueous
`
`formulations, such as buffers, preservatives, and chelating agents. (EX1001, 3:44-
`
`58). The ’789 patent also discloses adjusting the pH of the aqueous liquid
`
`preparation “to not less than about 4, 5, 6, and not more than about 8.5, 8.” (EX1001,
`
`3:59-61).
`
`Claims of the ’789 Patent
`i.
`40. Claim 1 of the ’789 patent is reproduced below:
`
`1. An aqueous liquid preparation consisting of, in an aqueous
`solution,
`an active
`ingredient
`consisting of
`(+)-(S)-4-[4-[(4-
`chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`or
`a
`pharmacologically acceptable acid addition salt
`thereof; a water-
`soluble metal chloride in a light-stabilizing effective amount; water;
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`

`
`and optionally at least one material selected from the group consisting
`of a buffer, a preservative, a chelating agent, and a flavor; wherein the
`metal chloride has a concentration selected from the range of a lower
`limit concentration of 0.2 w/v % and an upper limit concentration of
`1.2 w/v %.
`
`41. Claims 2-8 depend directly or indirectly from Claim 1. Claims 2-8
`
`recite the specific metal chloride, the form of the active ingredient, the pH range,
`
`and whether the preparation is an eye drop or nasal drop.
`
`42. Claim 9 is reproduced below:
`
`9. An aqueous eye drop consisting of: (a) an active ingredient
`consisting
`of
`(+)-(S)-4-[4-[(4-chlorophenyl)(2-
`pyridyl)methoxy]piperidino]butyric
`acid or a pharmacologically
`acceptable acid addition salt thereof; (b) a water-soluble metal chloride;
`(c) sodium dihydrogen phosphate buffer; (d) a preservative; (e) water;
`and optionally (f) disodium edetate; wherein the metal chloride has a
`concentration selected from the range of a lower limit concentration of
`0.2 w/v % and an upper limit concentration of 1.2 w/v %.
`
`43. Claim 10 is reproduced below:
`
`10. An aqueous liquid preparation consisting of, in an aqueous
`solution,
`an active
`ingredient
`consisting of
`(+)-(S)-4-[4-[(4-
`chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric
`acid
`or
`a
`pharmacologically acceptable acid addition salt thereof, a water-soluble
`metal chloride in a light-stabilizing effective amount, wherein the metal
`chloride has a concentration selected from the range of a lower limit
`concentration of 0.2 w/v % and an upper limit concentration of 1.2 w/v
`
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`

`
`%, benzalkonium chloride, sodium dihydrogenphosphate dihydrate,
`sodium hydroxide and water.
`
`44. Claim 11 depends from claim 9. Claim 11 recites that the active
`
`ingredient is a monobenzenesulfonate and the water-soluble metal chloride is
`
`sodium chloride with a particular concentration range.
`
`45. Claims 1, 9, and 10 of the ’789 patent recite the phrase “consisting of.”
`
`I have been informed that the transitional phrase “consisting of” is a closed term
`
`which excludes any ingredient not specified in the claim.
`
`VII. The Subject Matter of Claims 1-11 of the ’789 Patent is Unpatentable as
`Obvious
`A.
`Level of Skill in the Art
`46.
`I understand that a person of ordinary skill in the art (hereinafter
`
`“POSA”) is a hypothetical person who is presumed to be aware of all pertinent art,
`
`thinks along conventional wisdom in the art, and is a person of ordinary creativity.
`
`A POSA at the time of the alleged invention of the ’789 patent would have been an
`
`individual with a Ph.D. in pharmaceutical sciences or a related discipline and
`
`several years of formulation development or research experience in formulating
`
`chemical compounds in liquid aqueous pharmaceutical preparations, including
`
`ophthalmic preparations, in either an industrial or academic setting. A POSA would
`
`collaborate with others having expertise in formulation development, and take
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`

`
`advantage of certain specialized skills of others in a multi-disciplinary team, while
`
`drawing upon his or her own skills.
`
`47.
`
`In determining the qualifications of a POSA I considered, among other
`
`factors, the field of the alleged invention and use thereof described in the ’789
`
`patent, and my experience with the educational level of practitioners in related
`
`fields.
`
`In addition, my opinion is based upon my background, education, and
`
`personal experience in the field of liquid aqueous pharmaceutical formulation.
`
`48.
`
`I consider myself to be an expert in the art of the ’789 patent at the time
`
`of the alleged inventions claimed therein.
`
`B.
`
`49.
`
`Scope and Content of the Prior Art
`a. Bepotastine Besilate was Considered in the Prior Art to be
`Suitable for Ophthalmic Preparations
`Prior to the alleged inventions of the ’789 patent, bepotastine was
`
`known as an effective pharmaceutical agent. European Patent Publication No. EP 0
`
`949 260 (“Kita”) (EX1017), published on October 13, 1999, shows that a
`
`benzenesulfonic
`
`acid
`
`salt
`
`or
`
`benzoic
`
`acid
`
`salt
`
`of
`
`(S)-4-[4-[(4-
`
`chlorophenyl)(2pyridyl)methoxy]piperidino]butanoic acid (“(S)-bepotastine”) was
`
`known to have excellent antihistaminic activity and antiallergic activity. (EX1017,
`
`[0001]). Kita discloses that the particular class of compounds encompassing
`
`bepotastine is effective against various diseases and symptoms, including allergic
`
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`
`

`
`rhinitis and sneezing and coughing due to respiratory inflammation from a cold.
`
`(EX1017, [0002]).
`
`50. Bepotastine besilate, the acid addition salt of bepotastine, was known
`
`prior to July 2002. Tanabe Seiyaku Co., Ltd. issued a press release on July 17, 2001
`
`entitled, “Tanabe Seiyaku Granted Rights for Bepotastine Besilate for Ophtalmic
`
`[sic] Use to Senju Seiyaku (Japan)” (“Tanabe”) discussing generally the use of
`
`bepotastine besilate to treat allergic rhinitis and the expected effectiveness of
`
`bepotastine besilate in eye-drop form against symptoms of seasonal and perennial
`
`allergic conjunctivitis due to its strong histamine antagonistic action and good
`
`solubility in water. (EX1008, 1) (stating that bepotastine besilate “is expected to be
`
`effective against main symptoms such as itching in seasonal allergic conjunctivitis
`
`caused by pollens as well as perennial allergic conjunctivitis cause by house dusts
`
`etc.”). Accordingly, bepotastine and bepotastine besilate were well known as an
`
`effective antihistamine and also was recognized as being suitable for being prepared
`
`as an ophthalmic preparation. I understand Tanabe is prior art, but was not cited or
`
`considered during prosecution of the ’789 patent.
`
`51. Another press release from Tanabe Seiyaku Co., Ltd. issued on January
`
`25, 2002 entitled, “Regarding Extended Indication for Selective