UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC.,
`Petitioner,
`
`v.
`
`PFIZER INC.,
`Patent Owner.
`
`_____________________
`
`Inter Partes Review No.: IPR2021-01132
`_____________________
`
`U.S. Patent No. 6,890,927 to Bogle et al.
`Issued: May 10, 2005
`
`Title: TARTRATE SALTS OF 5,8, 14-
`TRIAZATERACYCLO[10.3.1.02,11.04.9]-
`HEXADECA-2(11),3,5,7,9-PENTAENE AND
`PHARMACEUTICAL COMPOSITIONS THEREOF
`_____________________
`
`EXPERT DECLARATION OF DR. PHILIP GOULD
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,890,927
`
`
`
`Apotex Exhibit 1002.001
`
`

`

`
`
`LIST OF EXHIBITS AND ABBREVIATIONS ...................................................... iv
`I.
`INTRODUCTION. .......................................................................................... 1
`II.
`QUALIFICATIONS AND BACKGROUND. ................................................ 1
`Education and Experience. .................................................................... 1
`Scope of Work and Compensation. ....................................................... 6
`Bases for Opinions and Materials Considered. ..................................... 6
`III. LEGAL STANDARDS. .................................................................................. 7
`IV. PERSON OF ORDINARY SKILL IN THE ART. ....................................... 11
`V.
`SUMMARY OF OPINIONS. ........................................................................ 12
`VI. RELEVANT CHEMISTRY AND TECHNOLOGY
`BACKGROUND. .......................................................................................... 15
` Acid-Base Chemistry, pH, and pKa. ................................................... 15
`Pharmaceutical Salts............................................................................ 18
`Basics of Pharmaceutical Salt Selection. ............................................ 20
` Varenicline and Salts. .......................................................................... 23
`VII. THE ‘927 PATENT. ...................................................................................... 28
`‘927 Patent Challenged Claims. .......................................................... 29
`‘927 Patent Prosecution History. ......................................................... 30
`Claim Construction.............................................................................. 36
`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES. ............. 40
`Coe (EX1005) and US ‘550 (EX1006). .............................................. 40
`Berge (EX1009). ................................................................................. 45
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`ii
`
`Apotex Exhibit 1002.002
`
`

`

`
`
`
`
`
`
`
`
`
`
`Gould (EX1010). ................................................................................. 48
`Tartrate Salt References. ..................................................................... 51
`1.
`Nyqvist (EX1016). .................................................................... 51
`2.
`Jessen (EX1017). ...................................................................... 53
`3.
`US ‘495 (EX1018). ................................................................... 55
`4.
`US ‘376 (EX1019). ................................................................... 56
`5.
`US ‘198 (EX1020). ................................................................... 56
`IX. UNPATENTABILITY OF THE ‘927 PATENT. ......................................... 57
`Claims 1-2 of the ‘927 Patent Are Anticipated by Each of Coe
`and US ‘550. ........................................................................................ 57
`1.
`Claim 1 of the ‘927 Patent Is Anticipated by Each of Coe
`and US ‘550. ............................................................................. 57
`Dependent Claim 2.................................................................... 65
`2.
`Claims 1-2 of the ‘927 Patent Are Made Obvious by Coe in
`View of Berge or Gould. ..................................................................... 68
`Claims 1-2 of the ‘927 Patent Are Made Obvious by Coe in
`View of Berge or Gould, in Further View of the Tartrate Salt
`References as Exemplified by Nyqvist. .............................................. 76
`There Is a Motivation to Combine Coe with Berge and/or
`Gould and Further with the Tartrate Salt References as
`Exemplified by Nyqvist. ..................................................................... 82
`There Was a Reasonable Expectation of Success Combining a
`Known Compound with a Common Salt. ........................................... 87
`LACK OF EVIDENCE OF SECONDARY CONSIDERATIONS .............. 89
`X.
`XI. CONCLUSION .............................................................................................. 92
`
`
`
`
`
`
`
`iii
`
`Apotex Exhibit 1002.003
`
`

`

`LIST OF EXHIBITS AND ABBREVIATIONS
`
`Exhibit Abbreviation
`1001
`‘927 patent
`1003
`
`Gould CV
`
`Description
`U.S. Patent No. 6,890,927 B2
`
`Dr. Philip Gould Curriculum Vitae
`
`1004
`
`‘927 patent PH
`
`File History for U.S. Patent Application No.
`10/139,730, issued as the ‘927 patent
`
`1005
`
`Coe
`
`International Patent Application No.
`WO 1999/035131, to Coe et al.
`
`1006
`
`US ‘550
`
`U.S. Patent No. 6,410,550
`
`1007
`
`US ‘550 PH
`
`File History for U.S. Patent Application No.
`09/402,010, issued as US ‘550
`
`1008
`
`CA ‘490
`
`Canadian Patent Application No. 2,467,490
`
`1009
`
`Berge
`
`1010
`
`Gould
`
`1011 Wells
`
`1012
`
`Bighley
`
`1013
`
`Paulekuhn
`
`Stephen M. Berge et al., Pharmaceutical Salts, 66 J.
`PHARM. SCIS. 1 (1977)
`
`Philip L. Gould, Salt Selection for Basic Drugs, 33
`INT’L J. PHARM. 201 (1986)
`
`James I. Wells, Pharmaceutical Preformulation: The
`Physicochemical Properties of Drug Substances 21
`(1988)
`
`Lyle D. Bighley et al., Salt Forms of Drugs and
`Absorption, in 13 ENCYCLOPEDIA OF
`PHARMACEUTICAL TECHNOLOGY 453 (James
`Swarbrick & James C. Boylan eds., 1996)
`
`G. Steffen Paulekuhn et al., Trends in Active
`Pharmaceutical Ingredient Salt Selection Based on
`Analysis of the Orange Book Database, 50 J.
`MEDICINAL CHEMISTRY 6665 (2007)
`
`iv
`
`Apotex Exhibit 1002.004
`
`

`

`1014 Morris
`
`1015
`
`Bastin
`
`1016
`
`Nyqvist
`
`1017
`
`Jessen
`
`1018
`1019
`1020
`1021
`
`US ‘495
`
`US ‘376
`
`US ‘198
`
`US ‘388
`
`1022
`
`Stahl
`
`1023
`
`Pharmeuropa 2000
`
`1024
`
`Aakeroy
`
`Kenneth R. Morris et al., An Integrated Approach to
`the Selection of Optimal Salt Form for a New Drug
`Candidate, 105 INT’L J. PHARM. 209 (1994)
`
`Richard J. Bastin et al., Salt Selection and
`Optimisation Procedures for Pharmaceutical New
`Chemical Entities, 4 ORGANIC PROCESS RSCH. &
`DEV. 427 (2000)
`
`International Patent Application No.
`WO 1998/054166, to Nyqvist et al.
`
`International Patent Application No.
`WO 2000/055131, to Jessen et al.
`
`U.S. Patent No. 5,834,495
`
`U.S. Patent No. 5,073,376
`
`U.S. Patent No. 2,870,198
`
`U.S. Patent No. 6,794,388
`
`HANDBOOK OF PHARMACEUTICAL SALTS 329 (P.
`Heinrich Stahl & Camille G. Wermuth eds., 1st ed.
`2002)
`
`European Directorate for the Quality of Medicines
`and Healthcare, Enquiry: Alkyl Mesilate
`(Methanesulphonate) Impurities in Mesilate Salts, 12
`PHARMEUROPA 27 (2000)
`
`Christer B. Aakeroy & Peter B. Hitchcock;
`Hydrogen-bonded Layers of Hydrogentartrate
`Anions: Two-dimensional Building Blocks for Crystal
`Engineering, 3 J. MATERIAL CHEMISTRY 1129
`(1993).
`
`
`
`v
`
`Apotex Exhibit 1002.005
`
`

`

`I.
`
`INTRODUCTION.
`1. My name is Dr. Philip Gould. I have been retained by counsel for
`
`Apotex Inc. (“Apotex” or “Petitioner”) to provide my opinion regarding U.S. Patent
`
`No. 6,890,927 to Bogle et al. (“the ‘927 patent”) (EX1001), which I understand is
`
`owned by Pfizer Inc. (“Patentee” or “Pfizer”).
`
`2.
`
`I also understand that Apotex intends to request that the United States
`
`Patent and Trademark Office (“USPTO”) cancel certain claims of the ‘927 patent as
`
`unpatentable in a petition for inter partes review—claims 1-2 (the “Challenged
`
`Claims”). I submit this expert declaration in support of Apotex’s request for inter
`
`partes review of the ‘927 patent, and the cancellation of the Challenged Claims.
`
`II. QUALIFICATIONS AND BACKGROUND.
` Education and Experience.
`I have over 30 years of experience in the research and development of
`3.
`
`pharmaceutical products, including the development of liquid, semi-solid, and solid
`
`dosage formulations of drug products.
`
`4.
`
`I am currently the Chief Executive of Jadara Pharma Ltd. Jadara
`
`Pharma Ltd. is a healthcare consultancy that focuses on assisting pharmaceutical
`
`companies with the technical aspects of their drug discovery, as well as
`
`pharmaceutical product development strategies and the technical and commercial
`
`aspects of new product introduction.
`
`5.
`
`I received a Bachelor of Science degree in Chemistry with Special
`
`Apotex Exhibit 1002.006
`
`

`

`Honours from the University of Hull in the United Kingdom (also known as Hull
`
`University) in 1975. I also received my Ph.D. in physical chemistry from Hull
`
`University in 1979. My thesis work, which was published in various publications
`
`from 1980-1985, related primarily to reactions of hot hydrogen atoms and covered
`
`a number of aspects of reaction kinetics and photochemistry.
`
`6.
`
`In 1978, prior to receiving my Ph.D., I became Section Leader of Drug
`
`Design at Reckitt & Colman’s Pharmaceutical Division. During my time at Reckitt
`
`& Colman, I assisted the company in establishing a structure-activity group to
`
`support the company’s drug discovery efforts and profiled the physico-chemical
`
`properties of a number of drug candidates. I advised on the important aspects of
`
`drug characteristics necessary to formulate products under development.
`
`7.
`
`In 1980, I left Reckitt & Colman to join Pfizer Central Research
`
`(“Pfizer”) where I later became a Principal Research Scientist working in
`
`formulations research and drug development. In my capacity as Principal Research
`
`Scientist, I formulated a large number of drug candidates for animal studies and
`
`human trials and studies. I was part of the team that discovered and developed the
`
`anti-fungal drug fluconazole (DIFLUCAN). I formulated solid oral, topical and
`
`sterile liquid (solution) parenteral dosage forms. During this time, I also assisted
`
`Pfizer drug discovery, both in the United Kingdom and United States, with salt form
`
`selection of drug candidates to aid in the drug development process and published
`
`2
`
`Apotex Exhibit 1002.007
`
`

`

`externally some of my findings and recommendations. (See, e.g., P.L. Gould, “Salt
`
`selection for basic drugs,” International Journal of Pharmaceutics, vol. 32, pp. 201-
`
`17 (1986)).
`
`8.
`
`In 1985, I left Pfizer to become Senior Manager of the Pharmaceutical
`
`Development Group at Lederle Laboratories (“Lederle”). At Lederle, I oversaw a
`
`team of 60 and was largely responsible for new chemical entity and product line
`
`extension developments, including the development of a wide range of dosage forms
`
`(e.g., solid oral dosage forms, such as tablets and capsules, and oral and parenteral
`
`solution and suspension dosage forms), as well as establishing Lederle Generic
`
`Products in the United States.
`
`9.
`
`During this time (i.e., between approximately 1980-1988), I published
`
`a number of papers on formulation science, including papers on aspects of the
`
`formulation of a number of dosage forms.
`
`10.
`
`In 1988, I left Lederle to join Glaxo Group (n/k/a GlaxoSmithKline)
`
`(“Glaxo”), leading one of its product development groups. In 1995, I was appointed
`
`Head of the New Product Introduction and Product Technology Division at Glaxo.
`
`In this capacity, I had a significant and international role in establishing new
`
`products (parenteral injectable formulations, topical formulations, tablets, capsules
`
`and respiratory products) for Glaxo, and often worked with the research and
`
`development, manufacturing, procurement, supply chain and commercial operation
`
`3
`
`Apotex Exhibit 1002.008
`
`

`

`entities on product development and introduction. At Glaxo, I regularly considered
`
`aspects of physical pharmaceutics for a wide range of developmental drug
`
`candidates and had to consider suitable formulation approaches, particularly for a
`
`wide range of tablet and capsule products.
`
`11.
`
`In 1998, following a period as R&D Director, which involved the oral
`
`formulation of peptide drugs, I became the Chief Executive Officer of Provalis PLC,
`
`a pharmaceuticals and diagnostic group. In 2003, I led Provalis PLC to its first profit
`
`and assisted the group in entering both the European and U.S. markets with both
`
`ethical pharmaceutical and medical diagnostic products. I left Provalis PLC in 2005
`
`to pursue a technical and business portfolio of activities with Jadara Pharma Ltd.
`
`12.
`
`I have continued to work with drug discovery/development companies
`
`in a consulting/advisory capacity. Most of my technical work involves assisting
`
`companies with understanding drug pharmaceutics, selecting the optimum solid API
`
`form for pharmaceutical development and designing suitable, bioavailable,
`
`commercial dosage forms.
`
`13. For a number of years (2003-2008), I was on the Scientific Board of
`
`Lectus Therapeutics Ltd., a company focused on ion channels research to develop
`
`new drugs for pain and other diseases. I assisted that company with its research
`
`strategy and drug development of its lead candidates. From 2007-2014, I was on the
`
`Board of RedX Pharma plc and chaired its Scientific Advisory Board, covering its
`
`4
`
`Apotex Exhibit 1002.009
`
`

`

`development of products in the areas of oncology and anti-infectives. Its oncology
`
`drug candidates are now in the clinic. From 2006-2012, I also worked part-time at
`
`the Liverpool School of Tropical Medicine, a charity, managing R&D collaborations
`
`with major pharmaceutical companies and providing an
`
`internal drug
`
`discovery/development consultancy role working with the neglected disease drug
`
`discovery teams in the areas of malaria and filariasis.
`
`14.
`
`I was a member of the IUPAC Sub-Committee on the Use of Salt Forms
`
`in Drug Development from 1995-1998. This Committee guided the establishment
`
`of a working group to provide a guidance text for this subject area and to scope out
`
`a series of monographs to aid pharmaceutical scientists.
`
`15.
`
`I have also been a member of the Royal Society of Chemistry since
`
`1980, where I am a Fellow and a Chartered Chemist. I am also an honorary Professor
`
`of Industrial Pharmacy from Liverpool John Moores University in the United
`
`Kingdom and give invited seminars on aspects of pharmaceutics and pharmaceutical
`
`product development. I have also been a research Member of the Royal
`
`Pharmaceutical Society. I continue from time to time to peer review scientific papers
`
`for pharmaceutical research journals.
`
`16. Additional details concerning my background, training and experience,
`
`and publications I have authored in the previous ten (10) years are contained in my
`
`Curriculum Vitae (EX1003).
`
`5
`
`Apotex Exhibit 1002.010
`
`

`

`
`17.
`
`Scope of Work and Compensation.
`I have been retained by Apotex as a technical expert in this matter to
`
`provide various opinions regarding the ‘927 patent. The opinions expressed in this
`
`Declaration are not exhaustive of my opinions on the patentability of the claims of
`
`the ‘927 patent. Therefore, the fact that I do not address a particular point should
`
`not be understood to indicate any opinion on my part that any claim otherwise
`
`complies with the patentability requirements.
`
`18.
`
`I am compensated at my normal rate of £700 GBP per hour. No part of
`
`my compensation is dependent upon my opinions given or the outcome of this
`
`matter. I have not had any affiliation with Pfizer since 1985 – over 35 years ago. I
`
`have not had at any time any affiliation with the named inventors on the ‘927 patent.
`
` Bases for Opinions and Materials Considered.
`19. Exhibit A to this Declaration includes a list of the materials I
`
`considered, in addition to my education, knowledge of the relevant published art,
`
`training, and experience, in forming the opinions I provide in this Declaration.
`
`20.
`
`I may rely upon these materials and/or additional materials to rebut
`
`arguments raised by the Pfizer. Further, I may also consider additional documents
`
`and information in forming any necessary opinions, including documents that I may
`
`not yet have reviewed and documents that have not yet been provided to me.
`
`21. My analysis of the materials related to this proceeding is ongoing, and
`
`6
`
`Apotex Exhibit 1002.011
`
`

`

`I will continue to review any new material as it is provided. This Declaration
`
`represents only those opinions I have formed as of the date of this Declaration.
`
`III. LEGAL STANDARDS.
`22. For my opinions in this declaration, I understand that it requires
`
`applying various legal principles. As I am not an attorney, I have been informed
`
`about various legal principles that govern my analysis. I have used my
`
`understanding of those principles in forming my opinions. I can summarise those
`
`principles as I understand them below.
`
`23. Burden of Proof. I understand that Apotex, as the Petitioner, bears the
`
`burden of proving unpatentability in this proceeding by a preponderance of the
`
`evidence. I am informed that this preponderance of the evidence standard means
`
`that Petitioner must show that unpatentability is more probable than not.
`
`Furthermore, I understand that each patent claim is considered separately. That is
`
`the standard I have considered in rendering the opinions in this Declaration.
`
`24. Claim Construction. I have also been told that when I review and
`
`consider the claims, the claim term(s) should be analysed under their ordinary and
`
`customary meaning as understood from the perspective of one of ordinary skill in
`
`the art, taking into account the claim language itself, specification, and prosecution
`
`history pertaining to the patent, as well as relevant extrinsic evidence. I have applied
`
`this standard in formulating my opinions, and set forth my understanding of the
`
`7
`
`Apotex Exhibit 1002.012
`
`

`

`scope of particular claim terms discussed below.
`
`25. Anticipation. I have been asked to consider the question of
`
`anticipation, namely, whether the claims cover something that is new, or novel. I
`
`am told that the concept of anticipation requires that each and every element of a
`
`challenged claim is present in or otherwise taught by a single reference. I also
`
`understand that an anticipatory reference does not need to explicitly describe each
`
`element because anticipation can occur when a claimed limitation is necessarily
`
`inherent or otherwise implicit in the relevant reference.
`
`26. Obviousness. I have been asked to consider the question of
`
`obviousness/non-obviousness. Again, I am told that this analysis must be from the
`
`perspective of the person of ordinary skill in the art, and whether the skilled artisan
`
`would consider any differences between the prior art and what is claimed to have
`
`been obvious. To make this assessment, I have been informed that the concept of
`
`patent obviousness involves four factual inquiries:
`
`• the scope and content of the prior art;
`
`• the differences between the claimed invention and the prior art;
`
`• the level of ordinary skill in the art; and
`
`• so-called objective indicia, also referred to as secondary considerations,
`
`of non-obviousness.
`
`27.
`
`I have further been instructed that one cannot use the challenged patent
`
`8
`
`Apotex Exhibit 1002.013
`
`

`

`itself (here, the ‘927 patent) as a guide from which to select prior art elements, or
`
`otherwise engage in hindsight. Rather, the better approach is to consider what the
`
`person of ordinary skill in the art knew, and what the art taught; suggested; or
`
`motivated the person of ordinary skill in the art to further pursue; and to differentiate
`
`between steps that were routinely done (such as in response to known problems,
`
`steps or obstacles), and those which, for example, may have represented a different
`
`way of solving existing or known problems.
`
`28.
`
`I am also informed that when there is some recognised reason to solve
`
`a problem, and there are a finite number of identified, predictable and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. In addition, when a patent simply arranges old elements with each performing
`
`its known function and yields no more than what one would expect from such an
`
`arrangement, the combination is obvious.
`
`29.
`
`I understand that before reaching any final conclusion on obviousness,
`
`the obviousness analysis requires consideration of objective indicia of non-
`
`obviousness, if it is offered. These must be considered to ensure that, for example,
`
`there were not some unanticipated problems, obstacles, or hurdles that may seem
`
`easy to overcome in hindsight, but which were not readily overcome prior to the
`
`9
`
`Apotex Exhibit 1002.014
`
`

`

`relevant invention date of the patents/claims at issue here. I understand that these
`
`objective indicia are also known as “secondary considerations of non-obviousness,”
`
`and may include long-felt but unmet need, commercial success, and unexpected
`
`results, among others. I also understand, however, that any offered evidence of
`
`secondary considerations of non-obviousness must be comparable with the scope of
`
`the challenged claims. This means that for any offered evidence of secondary
`
`considerations of non-obviousness to be given substantial weight, I understand the
`
`proponent of that evidence must establish a “nexus” or a sufficient connection or tie
`
`between that evidence and the merits of the claimed invention, which I understand
`
`specifically incorporates any novel element(s) of the claimed invention. If the
`
`secondary considerations evidence offered actually results from something other
`
`than the merits of the claim, then I understand that there is no nexus or tie to the
`
`claimed invention. I also understand it is the patentee that has the burden of proving
`
`that a nexus exists.
`
`30. With respect to unexpected results, I understand that any results upon
`
`which a patentee wishes to rely as an indicator of non-obviousness must be based on
`
`a comparison of the purported invention(s) with the closest prior art.
`
`31. However, I further understand that there also are instances where
`
`secondary considerations, even if available, do not overcome a strong showing of
`
`obviousness, such as when a prior art problem was already known in the art, and
`
`10
`
`Apotex Exhibit 1002.015
`
`

`

`where there was a known solution reasonably expected to work. Merely carrying
`
`out routine optimisation or experimental work to reasonably expected results is
`
`similarly something a person of ordinary skill would consider obvious.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART.
`32. As discussed above, I have been informed by counsel that my analysis
`
`is to be conducted from the perspective of a person of ordinary skill in the art (a
`
`“person of ordinary skill” or “POSA”) at the time of the invention – May 2001. I
`
`also understand that the person of ordinary skill in the art is assumed to know,
`
`understand and be familiar with all of the relevant prior art, and that such person is
`
`not an automaton, but rather a person of ordinary creativity.
`
`33.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill in the art the following factors may be considered: (1) the educational
`
`level of the inventor(s); (2) the type of problems encountered in the art; (3) prior art
`
`solutions to those problems; (4) rapidity with which innovations are made; and
`
`(5) sophistication of the technology and educational level of active workers in the
`
`field.
`
`34. After considering the above-mentioned factors, it is my opinion that a
`
`person of ordinary skill in the art would have an advanced degree in medicinal
`
`chemistry, industrial pharmacy and/or pharmaceutics, or related fields, such as a
`
`Ph.D., with several years of experience in that field. Such a person would have some
`
`11
`
`Apotex Exhibit 1002.016
`
`

`

`direct experience with or direct involvement with selecting suitable salts for drug
`
`development. Such a person would also be well versed in the world-wide literature,
`
`and aware of patent and non-patent literature. Such a person would understand that
`
`the salt selection process requires a multi-disciplinary approach, and would draw
`
`upon not only his or her own skills, but could also take advantage of certain
`
`specialised skills of a team that may include a pharmacologist, analytical chemist,
`
`toxicologist and/or clinician, to solve any given problem.
`
`V.
`
`SUMMARY OF OPINIONS.
`I have been asked to determine if certain claims of the ‘927 patent
`35.
`
`would have been known and/or obvious as of May 14, 2001 to a person having
`
`ordinary skill in the art, in light of the prior art.
`
`36.
`
`It is my opinion, as set forth in detail below, that U.S. Patent No.
`
`6,410,550 (“US ‘550”) discloses each and every element of claims 1-2 of the ‘927
`
`patent by putting a person of ordinary skill in the art in possession of varenicline and
`
`its tartrate salt (including the L-tartrate salt) and thus anticipates these claims. In
`
`particular, US ‘550: (1) discloses and claims varenicline; (2) discloses tartaric acid
`
`as a “pharmaceutically acceptable acid addition salt[]” of varenicline; and
`
`(3) teaches the preparation of an acid addition salt of varenicline in crystalline form
`
`in Example 26, which Pfizer admits – in CA ‘490 – may be used by a person of
`
`ordinary skill in the art to prepare crystalline varenicline tartrate (the L-tartrate salt).
`
`12
`
`Apotex Exhibit 1002.017
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`37.
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`It is further my opinion, as set forth in detail below, that International
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`Patent Application No. WO 1999/035131, to Coe et al. (“Coe”) discloses each and
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`every element of claims 1-2 of the ‘927 patent and thus anticipates these claims. In
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`particular, Coe: (1) discloses varenicline; (2) discloses
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`tartaric acid as a
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`“pharmaceutically acceptable acid addition salt[]” of varenicline; and (3) teaches the
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`preparation of an acid addition salt of varenicline in crystalline form in Example 26,
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`which Pfizer admits – in CA ‘490 – may be used by a person of ordinary skill in the
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`art to prepare crystalline varenicline tartrate (the L-tartrate salt). (See EX1008.021,
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`CA ‘490 (“[Varenicline] (L-tartrate salt) may be prepared by the methods described
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`in patent application[] WO9935131A1 [Coe].”); EX1008.004, 012).
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`38. Additionally, based on my review of the state of the art as it existed
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`prior to the priority date of the ‘927 patent, and putting myself in the frame of mind
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`of the person of ordinary skill in the art such as a pharmaceutical researcher, it is my
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`opinion that a person of ordinary skill as of May 2001, would have known or at the
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`very least found it known or obvious to prepare a salt of varenicline and in particular
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`the tartrate salt.
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`39. That person of ordinary skill in the art would have understood that there
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`were only a limited number of acids that were suitable as anions or counter-ions for
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`varenicline that gave salts suitable for pharmaceutical formulation. That person of
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`ordinary skill in the art would have been specifically motivated to first consider the
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`13
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`Apotex Exhibit 1002.018
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`hydrochloride salt, then consider the organic acid salts and then consider employing
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`salts that may have additional pharmaceutical or other benefits such as the tartrate
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`salt.
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`40. For at least these reasons, and as set forth in detail below, it is further
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`my opinion that the person of ordinary skill in the art, as of May 2001, would not
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`have found the subject matter of at least claims 1-2 of the ‘927 patent to be novel.
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`Independently, the person of ordinary skill in the art would have found the subject
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`matter obvious and at the very least obvious to try, for example in view of Coe in
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`combination with Stephen M. Berge et al., Pharmaceutical Salts, 66 J. PHARM. SCIS.
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`1 (1977) (“Berge”) or Philip L. Gould, Salt Selection for Basic Drugs, 33 INT’L J.
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`PHARM. 201 (1986) (“Gould”), and Coe in view of Berge and/or Gould in further
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`view of International Patent Application No. WO 1998/054166 (“Nyqvist”).
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`41.
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`It is also my opinion that there are no “secondary considerations” that
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`would support the patentability of the Challenged Claims of the ‘927 patent. First,
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`it is my understanding that secondary considerations are not relevant in the context
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`of anticipation and so should not be considered in connection with the anticipation
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`ground above. Second, in the context of obviousness, it is my opinion that the
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`arguments presented by Pfizer to the USPTO do not support a finding of unexpected
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`results or any other secondary consideration, especially given that the hydrochloride
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`salt can be more hygroscopic than other salts; tartrate salts were a known approach
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`14
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`Apotex Exhibit 1002.019
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`to addressing hydrochloride salt hygroscopicity; and there is no materially superior
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`performance outcome for the tartrate salt as compared to, e.g., other acid addition
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`salts listed in US ‘550 and Coe, such as succinic acid salts.
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`VI. RELEVANT CHEMISTRY AND TECHNOLOGY BACKGROUND.
` Acid-Base Chemistry, pH, and pKa.
`42. According to the Brønsted-Lowry (BL) theory, an acid is a substance
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`capable of donating a proton to another substance such as water. Put another way,
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`an acid is a species having a tendency to lose a proton, while a base is a species
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`having a tendency to accept a proton.
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`43. This process, in solution, represents the ionisation of the acid (HA), and
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`corresponds to the following chemical reaction:
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`HA + H2O  H3O+ + A-
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`44. The extent to which the ionisation (shown above) takes place is
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`determined by the strength of the acid and the ionisation constant of the acid (Ka), a
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`factor that is defined as:
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`Ka = [H3O+] [A-]
` [HA]
`where the square brackets correlate to the concentration of the various species in
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`solution.
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`45. Because the ionisation constants (Ka) of weak acids are very small,
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`practitioners in the field usually refer to the pKa value of the acid, which is defined
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`15
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`Apotex Exhibit 1002.020
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`by the ionisation constant as:
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`pKa = -log(Ka)
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`46. A base is a substance capable of accepting protons donated by another
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`substance, such as water, and corresponds to the following chemical process:
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`B + H2O  BH+ + OH-
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`47. The extent to which the ionisation process takes place is determined by
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`the magnitude of the ionisation constant of the base (Kb), a factor that is defined as:
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`Kb = [BH+] [OH-]
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` [B]
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`
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`48. As with weak acids, because the ionisation constants of weak bases are
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`small, practitioners in the field usually refer to the pKb value of the base, which is
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`defined from the ionisation constant by:
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`pKb = -log(Kb)
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`49.
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`It is often more useful to know the degree of ionisation of the conjugate
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`acid that was formed when the base accepted a proton:
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`BH+ + H2O  B + H3O+
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`50. The degree of ionisation of the conjugate acid process is determined by
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`the magnitude (strength) of the ionisation constant (Ka), which is defined as:
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`
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`Ka = [H3O+] [B]
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` [BH+]
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`51. For each acid, the pH at the half neutralisation is equal to the pKa value
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`16
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`Apotex Exhibit 1002.021
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`of the acid (or the base).
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`52. An ionisation centre is the atom on a molecule that donates a proton (an
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`acid) or accepts a proton (a base) in the scenarios described above. A basic
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`ionisation centre, as in the case of varenicline, which accepts a proton, is typically a
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`nitrogen atom. In the case of varenicline, it is the piperidinyl secondary amine
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`nitrogen atom that is the ionisation centre.
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`53. A typical organic acid is a mono-carboxylic acid (for example, acetic
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`acid below), which donates a proton to yield a carboxylic anion.
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`CH3CO2H  CH3CO2
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`- + H+

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`54. Taking the above example, the carboxylic acid group (CO2H) is the
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`ionisation centre donating the proton, and it is regarded as a weak organic acid with
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`a pKa value of ~4.76.
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`55. Tartaric acid is termed a di-carboxylic acid as it has two ca