`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________
`
`APOTEX INC. AND APOTEX CORP.,
`Petitioners
`
`v.
`
`AUSPEX PHARMACEUTICALS, INC.,
`Patent Owner
`_____________________
`
`Case IPR2021-01507
`U.S. Patent No. 8,524,733
`Issued: September 3, 2013
`
`Title:
`BENZOQUINOLINE INHIBITORS OF VESICULAR MONOAMINE TRANSPORTER 2
`
`DECLARATION OF JEFFREY P. JONES, PH.D.
`
`
`
`Doc # NY/17336110
`
`
`
`
`
`Apotex Ex. 1002
`
`Apotex v. Auspex
`IPR2021-01507
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`
`
`
`
`INTRODUCTION ......................................................................................... 1
`
`EXPERIENCE AND QUALIFICATIONS ................................................. 1
`
` LEGAL STANDARDS USED IN MY ANALYSIS.................................... 4
`
`A.
`
`B.
`
`C.
`
`Prior Art ................................................................................................. 4
`
`Person of Ordinary Skill in the Art ....................................................... 4
`
`Obviousness ........................................................................................... 5
`
` THE ’733 PATENT ....................................................................................... 8
`
`A.
`
`B.
`
`C.
`
`The Alleged Invention ........................................................................... 8
`
`The Challenged Claims ......................................................................... 8
`
`Claim Construction................................................................................ 9
`
`
`
`BACKGROUND ..........................................................................................10
`
`A.
`
`B.
`
`C.
`
`Tetrabenazine Was a Well-Known Therapeutic with Known
`Drawbacks ...........................................................................................11
`
`The Methoxy Groups of Tetrabenazine Were Known to Be
`Essential for Its Activity and Were Also Sites of Metabolism ...........13
`
`Strategic Deuteration Was Known to Slow Metabolism in
`Compounds Like Tetrabenazine..........................................................17
`
`D. Deuteration Was Known to Impart Other Therapeutic Benefits ........23
`
`E.
`
`The Patentee’s Arguments Made During Prosecution Were
`Incorrect ...............................................................................................23
`
`1.
`
`The Effects of Deuteration of Tetrabenazine’s Methoxy
`Groups Were Predictable ..........................................................24
`
`2.
`
`The Patentee Did Not Demonstrate Unexpected Results .........29
`
` OBVIOUSNESS ...........................................................................................34
`
`- ii -
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`
`
`A.
`
`Claims 1-3 of the ’733 Patent Would Have Been Obvious
`Based on Zheng in View of Naicker ’921 and Kohl ...........................34
`
`1.
`
`A POSITA Would Have Been Motivated to Combine
`Prior Art Teachings Regarding Tetrabenazine and
`Deuteration to Arrive at the Claimed Invention .......................35
`
`a.
`
`b.
`
`c.
`
`Zheng Would Have Motivated a POSITA to Select
`Tetrabenazine as a Lead Compound and Seek to
`Improve It .......................................................................35
`
`Naicker ’921 Would Have Motivated a POSITA to
`Deuterate Tetrabenazine in Order to Improve Its
`Activity and Highlights Methoxy Groups
`Specifically as Promising Sites for Deuteration .............36
`
`Kohl Discloses Benefits from Deuterating
`Methoxy Groups and Also Teaches the Other
`Claim Limitations ...........................................................40
`
`2.
`
`3.
`
`A POSITA Would Have Had a Reasonable Expectation
`of Arriving at the Claimed Compounds and
`Compositions ............................................................................43
`
`The Patentee Failed to Show Unexpected Results
`Sufficient to Rebut Obviousness ...............................................44
`
`B.
`
`Claims 1-3 of the ’733 Patent Would Have Been Obvious
`Based on Zheng in View of Foster AB and Kohl ...............................45
`
`1.
`
`A POSITA Would Have Been Motivated to Combine
`Prior Art Teachings Regarding Tetrabenazine and
`Deuteration to Arrive at the Claimed Invention .......................46
`
`a.
`
`b.
`
`Zheng Would Have Motivated a POSITA to Select
`Tetrabenazine as a Lead Compound and Seek to
`Improve It .......................................................................46
`
`Foster AB Would Have Motivated a POSITA to
`Deuterate Tetrabenazine in Order to Improve
`Tetrabenazine’s Activity and Highlights Methoxy
`Groups as Promising Sites for Deuteration ....................47
`
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`
`
`c.
`
`Kohl Discloses Benefits from Deuterating
`Methoxy Groups and Also Teaches Other
`Dependent Claim Limitations .........................................48
`
`2.
`
`3.
`
`A POSITA Would Have Had a Reasonable Expectation
`of Arriving at the Claimed Compounds and
`Compositions ............................................................................49
`
`The Patentee Failed to Show Unexpected Results
`Sufficient to Rebut Obviousness ...............................................50
`
`C.
`
`Claims 1-3 of the ’733 Patent Would Have Been Obvious
`Based on Gano in View of Schwartz and Gant ’991 ..........................50
`
`1.
`
`A POSITA Would Have Been Motivated to Combine
`Prior Art Teachings Regarding Tetrabenazine and
`Deuteration to Arrive at the Claimed Invention .......................51
`
`a.
`
`b.
`
`c.
`
`Gano Would Have Motivated a POSITA to Select
`Tetrabenazine as a Lead Compound and Seek to
`Improve It .......................................................................51
`
`Schwartz Teaches that the Methoxy Groups of
`Deutetrabenazine Were Sites of Metabolism .................52
`
`Gant ’991 Would Have Motivated a POSITA to
`Deuterate the Methoxy Groups of Tetrabenazine
`and Discloses the Other Claim Limitations ....................53
`
`2.
`
`3.
`
`A POSITA Would Have Had a Reasonable Expectation
`of Arriving at the Claimed Compounds and
`Compositions ............................................................................57
`
`The Patentee Has Not Shown Unexpected Results
`Sufficient to Rebut Obviousness ...............................................58
`
` CONCLUSIONS ..........................................................................................59
`
`
`
`
`
`- iv -
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`
`
`LIST OF EXHIBITS
`
`
`Exhibit No.
`
`Description
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`U.S. Patent No. 8,524,733, “Benzoquinoline Inhibitors of Vesicular
`Monoamine Transporter 2” (the “’733 patent”)
`
`Declaration of Jeffrey P. Jones, Ph.D. (the “Jones Decl.”)
`
`Zheng, G. et al., Vesicular Monoamine Transporter 2: Role as a
`Novel Target for Drug Development, THE AAPS JOURNAL,
`8(4):E682-E692 (2006) (“Zheng”)
`
`Naicker, S. et al., U.S. Patent No. 6,503,921, “Deuterated rapamycin
`compounds, methods and uses thereof” (“Naicker ’921”)
`
`Kohl, B. et al., WO 2007/012650, “Isotopically Substituted Proton
`Pump Inhibitors” (2007) (“Kohl”)
`
`Foster A.B. et al., Isotope effects in O- and N-demethylations
`mediated by rat liver microsomes: An application of direct insertion
`electron impact mass spectrometry, CHEM.-BIOL. INTERACTIONS,
`9:327-340 (1974) (“Foster AB”)
`
`Gano, K.W., U.S. Patent No. 8,039,627, “Substituted 3-isobutyl-
`9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-
`a]isoquinolin-2-ol compounds and methods relating thereto”
`(“Gano”)
`
`Schwartz, D.E. et al., Metabolic studies of tetrabenazine, a
`psychotropic drug in animals and man, BIOCHEMICAL
`PHARMACOLOGY, 15:645-655 (1966) (“Schwartz”)
`
`Gant, T.G. et al., U.S. Pat. Pub. No. 2008/0280991, “Substituted
`Naphthalenes” (2008) (“Gant ’991”)
`
`- v -
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`
`
`Exhibit No.
`
`Description
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`Huntington Study Group, Tetrabenazine as antichorea therapy in
`Huntington disease – A randomized controlled trial, NEUROLOGY,
`66(3):366-372 (2006) (“Huntington Study”)
`
`Gant, T.G. et al., U.S. Pat. Pub. No. 2007/0149622 “Substituted
`phenethylamines with serotoninergic and/or norepinephrinergic
`activity” (2007) (“Gant ’622”)
`
`Mitoba, C. et al., Effect of deuteration of the O-CH3 group on the
`enzymic demethylation of o-nitroanisole. BIOCHIM. BIOPHYS. ACTA,
`136: 566-567 (1967) (“Mitoba”)
`
`Naicker, S. et al., U.S. Patent No. 6,613,739, “Deuterated
`cyclosporine analogs and their use as immunomodulating agents”
`(“Naicker ’739”)
`
`Chou, D.T.H. et al., U.S. Pat. Pub. No. 2007/0088075, “Deuterated
`aminocyclohexyl ether compounds and processes for preparing
`same” (“Chou”)
`
`Jones, J.P. et al., Isotopically Sensitive Branching and Its Effect on
`the Observed Intramolecular Isotope Effects in Cytochrome P-450
`Catalyzed Reactions: A New Method for the Estimation of Intrinsic
`Isotope Effects, J. AM. CHEM. SOC. 1986, 108, 7074-7078 (“Jones
`1986”)
`
`Jones, J.P. et al., Computational Models for Cytochrome P450: A
`Predictive Electronic Model for Aromatic Oxidation and Hydrogen
`Atom Abstraction, DRUG METABOLISM AND DISPOSITION, 2002, Vol
`30, No. 1 (“Jones 2002”)
`
`Paleacu, D., Tetrabenazine in the treatment of Huntington’s disease,
`NEUROPSYCHIATRIC DISEASE AND TREATMENT, 3(5):545–551 (2007)
`(“Paleacu”)
`
`- vi -
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`
`
`Exhibit No.
`
`Description
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`Kilbourn, M.R. et al., Absolute Configuration of (+)-a-
`Dihydrotetrabenazine, an Active Metabolite of Tetrabenazine,
`CHIRALITY, 9(1):59-62 (1997) (“Kilbourn”)
`
`Foster, R. et al., WO 95/26325, “Enhancement of the efficacy of
`drugs by deuteration” (1995) (“Foster R”)
`
`Ondo, W.G. et al., Tetrabenazine Treatment for Huntington’s
`Disease-Associated Chorea, CLINICAL NEUROPHARMACOLOGY, Vol.
`25, No. 6, pp. 300-302 (2002) (“Ondo”)
`
`Burger’s Medicinal Chemistry and Drug Discovery, Volume 1, 5th
`edition, 1995, Ch. 6, pp. 129-180 (“Burger’s Ch. 6”).
`
`Burger’s Medicinal Chemistry and Drug Discovery, Volume 1, 5th
`edition, 1995, Ch. 9, pp. 251-300 (“Burger’s Ch.9”).
`
`Foster, A.B., Deuterium Isotope Effect in Studies of Drug
`Metabolism, TRENDS PHARMACOL. SCI., pp. 524-527, Dec. 1984
`(“Foster AB 1984”)
`
`Fisher, M.B. et al., The complexities inherent in attempts to decrease
`drug clearance by blocking sites of CYP-mediated metabolism,
`CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT 2006 Vol
`9, No. 1, pp. 101-109 (“Fisher”)
`
`Atkins, W.M. et al., Metabolic Switching in Cytochrome P-450cam:
`Deuterium Isotope Effects on Regiospecificity and the
`Monooxygenase/Oxidase Ratio, J. AM. CHEM. SOC. 1987, 109, 3754-
`3760 (“Atkins”)
`
`Higgins, L. & Jones, J.P. et al., Evaluation of Cytochrome P450
`Mechanism and Kinetics Using Kinetic Deuterium Isotope Effects,
`BIOCHEM., 1998, 37, 7039-7046 (“Higgins & Jones 1998”)
`
`- vii -
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`

`Exhibit No.
`
`1027
`
`
`
`Description
`
`Excerpts from the Application File History for the ’733 Patent, U.S.
`App. No. 12/562,621 (the “FH Excerpts”)
`
`- viii -
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`
`
`I, Jeffrey P. Jones, Ph.D., of Pullman, Washington declare that:
`
`
`
`INTRODUCTION
`
`1.
`
`I have been retained as an expert on behalf of Apotex, Inc.
`
`(“Apotex”). I have been asked to review U.S. Patent No. 8,524,733 (“the ’733
`
`patent”) (Ex. 1001) and opine on whether claims 1-3 would have been obvious as
`
`of September 18, 2008, its earliest possible priority date.
`
`2. My findings, as explained below, are based on my study, experience,
`
`and background in the field and review of the relevant references. The materials I
`
`have considered in connection with this report are attached as Exs. 1001-1027.
`
`3.
`
`I am being compensated for my work as an expert with respect to this
`
`inter partes review, but my compensation is not contingent in any way on the
`
`content of my opinions or the outcome of this proceeding.
`
` EXPERIENCE AND QUALIFICATIONS
`
`4.
`
`A true and correct copy of my curriculum vitae is attached to this
`
`declaration as Appendix 1.
`
`5.
`
`I am currently appointed as Ralph G. Yount Distinguished Professor
`
`of Chemistry (endowed chair) Department of Chemistry, Washington State
`
`University.
`
`6.
`
`I earned a Bachelor of Science degree from the University of
`
`Michigan, Ann Arbor in 1982 and my Ph.D. from the University of Washington,
`
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`Department of Medicinal Chemistry in 1987. I then completed postdoctoral
`
`fellowships under Professor William Trager in the Department of Medicinal
`
`Chemistry at the University of Washington and Professor W. W. Cleland in the
`
`Department of Biochemistry at the University of Wisconsin.
`
`7.
`
`I joined the faculty of University of Rochester in the Department of
`
`Pharmacology and Physiology in 1990. I was promoted to Associate Professor at
`
`University of Rochester 1996.
`
`8.
`
`In 1998, I joined Washington State University as an Associate
`
`Professor of Chemistry in the Department of Chemistry. I was promoted to full
`
`Professor in 2002 and was named to my first endowed chair in 2008 as the Don
`
`and Marianna Matteson Professor of Chemistry. I began in my current role as
`
`Ralph G. Yount Distinguished Professor of Chemistry in 2014 and continue
`
`through present as the Don and Marianna Matteson Professor of Chemistry.
`
`9.
`
`As well as being a Professor, I am Cofounder of Camitro Corporation.
`
`Camitro developed methodology to predict rates of drug metabolism. I reviewed
`
`grants for numerous granting agencies including the American Cancer Society
`
`Drug Discovery special emphasis panels for NCI (National Cancer Institute) and
`
`NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases). I was
`
`on the XNDA (Xenobiotic and Nutrient Disposition and Action) study section for
`
`7 years, which reviews grants related to drug metabolism, drug transport, and drugs
`
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`
`
`adverse effects. I have served on the editorial board of Drug Metabolism and
`
`Disposition. I was Chair Executive Committee for the Drug Metabolism Division
`
`of the American Society for Pharmacology and Experimental Therapeutics and
`
`was a programing officer for the Experimental Biology Annual meetings.
`
`10. Through my own research I have extensive knowledge and experience
`
`in medicinal chemistry and the study of drug metabolism, including the effects of
`
`isotopic substitution on pharmacologically active molecules. I began work on the
`
`use of deuterium isotope effects in graduate school, working on their use in
`
`exploring Cytochrome P450 mediated reactions.1 As an independent principal
`
`investigator, I have published numerous papers that use isotope effects to study
`
`rates of reactions, mainly on drug metabolizing enzymes.
`
`11.
`
`I have published more than 110 articles in peer-reviewed journals,
`
`including many relating to drug metabolism and isotopic substitution, including
`
`deuteration. I am the inventor on 3 issued patents and have numerous patent
`
`applications.
`
`
`1 Cytochromes P450, also referred to as “CYPs,” are a superfamily of enzymes
`
`that oxidize, inter alia, xenobiotics (substances that are foreign to the body),
`
`contributing to their metabolism and clearance.
`
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` LEGAL STANDARDS USED IN MY ANALYSIS
`
`12.
`
`I am not a patent attorney, nor have I independently researched patent
`
`law. Counsel for Petitioner have explained certain legal standards to me that I
`
`have relied upon in forming my opinions set forth in this Declaration.
`
`A.
`
`Prior Art
`
`13.
`
`I have been informed that the law provides certain categories of
`
`information, known as prior art, that may be used to render patent claims obvious.
`
`I understand that the reference materials I discuss in this declaration are prior art at
`
`least because they would have been considered available to members of the public
`
`as of September 18, 2008 and are relevant to the subject matter of the ’733 patent.
`
`The references I discuss herein are from the same field of endeavor as the claimed
`
`invention and/or are reasonably pertinent to the problem faced by the inventor.
`
`B.
`
`Person of Ordinary Skill in the Art
`
`14.
`
`I understand that “a person of ordinary skill in the art” (a “POSITA”)
`
`is a hypothetical person who is presumed to be aware of pertinent art including
`
`knowledge in the art, thinks along conventional wisdom in the art, and is a person
`
`of ordinary creativity. I understand that this hypothetical person of ordinary skill
`
`in the art is considered to have the normal skills and knowledge of a person in the
`
`technical field.
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`15. For the technology of the ’733 patent’s claims, a POSITA would
`
`typically have had a master’s degree or a Ph.D. in chemistry, biochemistry,
`
`pharmaceutics, pharmaceutical sciences, physical organic chemistry, or a related
`
`discipline. To the extent necessary, a POSITA may have collaborated with others
`
`of skill in the art, such that the individual and/or team collectively would have had
`
`experience in synthesizing and analyzing complex organic compounds and
`
`developing drugs for human use.
`
`16.
`
`I have had exposure to those who met the definition of a POSITA at
`
`and around the time of the alleged invention during my work as a faculty member
`
`at Washington State University.
`
`C. Obviousness
`
`17.
`
`I have been informed that the following four factors are considered
`
`when determining whether a patent claim would have been obvious to a POSITA:
`
`(a) the level of ordinary skill in the art; (b) the scope and content of the prior art;
`
`(c) the differences between the prior art and the claim; and (d) any “secondary
`
`considerations” tending to prove nonobviousness.
`
`18.
`
`I understand that the question of obviousness turns on whether a
`
`hypothetical person of ordinary skill in the art would have been motivated to
`
`combine prior art teachings to derive the claimed subject matter with a reasonable
`
`expectation of success. Further, I understand that obviousness does not require
`
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`
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`absolute predictability. Only a reasonable expectation that the invention will be
`
`achieved is necessary to show obviousness.
`
`19.
`
`I have been informed that a claimed invention can be rendered
`
`obvious by the combination of teachings in the prior art even if there is no explicit
`
`teaching to combine them. Instead, any problem known in the field at the time of
`
`the priority date can provide a sufficient rationale to combine the elements of the
`
`prior art in the manner claimed in the patent.
`
`20.
`
`I have been informed that examples of sufficient rationales for
`
`establishing obviousness include the following:
`
` combining prior art elements according to known methods to yield
`predictable results;
`
` substituting known elements for other known elements to obtain
`predictable results;
`
` using a known technique to improve similar devices, methods, or
`products in the same way;
`
` choosing from a finite number of identified, predictable solutions
`that would be obvious to try; and
`
` providing some teaching, suggestion, or motivation to modify the
`prior art reference or to combine teachings in prior art references to
`arrive at the claimed invention.
`
`21.
`
`I have been informed that obviousness analyses for chemical
`
`compounds such as deutetrabenazine generally follow a two-part inquiry. The first
`
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`question is whether a POSITA would have selected the asserted prior art
`
`compounds as lead compounds, or starting points, for further development efforts.
`
`The second question is whether there was a reason or motivation to modify the
`
`lead compound and reasonable expectation of success in arriving at the claimed
`
`invention.
`
`22.
`
`I have been informed that “secondary considerations,” which I
`
`understand are also called “objective indicia” or “objective evidence,” may also
`
`provide evidence that claimed subject matter is not obvious. I further understand
`
`that such secondary considerations may include factors such as: (i) the invention’s
`
`satisfaction of a long-felt unmet need in the art; (ii) unexpected results of the
`
`invention; (iii) skepticism of the invention by experts; (iv) teaching away from the
`
`invention in the prior art; (v) commercial success of an embodiment of the
`
`invention; and (vi) praise by others for the invention. I have been informed that
`
`there must be an adequate nexus or connection between the evidence that is the
`
`basis for an asserted secondary consideration and the scope of the invention
`
`claimed in the patent.
`
`23. Regarding unexpected results, I understand that differences between a
`
`claimed subject matter and the prior art may be expected to result in some
`
`differences in properties, and the issue is whether the properties differ to such an
`
`extent that the difference is really unexpected. I also understand that it is not
`
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`
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`sufficient that the difference is one of degree, but that there must be a difference in
`
`kind in order for unexpected results to evidence nonobviousness.
`
`24.
`
`In my opinion, claims 1-3 of the ’733 patent would have been obvious
`
`as of its priority date.
`
` THE ’733 PATENT
`
`A. The Alleged Invention
`
`25. The ’733 patent is entitled “Benzoquinoline Inhibitors of Vesicular
`
`Monoamine Transporter 2,” and generally claims a deuterated derivative of
`
`tetrabenazine with certain levels of deuterium enrichment and related
`
`compositions.
`
`B.
`
`The Challenged Claims
`
`26. Claims 1-3 of the ’733 patent recite as follows:
`
`1.
`
`A compound having the structural formula:
`
`
`
`or a salt thereof, wherein each position represented as D has
`deuterium enrichment of no less than about 90%.
`
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`
`
`2.
`
`The compound as recited in claim 1 wherein each position
`represented as D has deuterium enrichment of no less than
`about 98%.
`
`3. A pharmaceutical composition comprising a compound as
`recited in claim 1 together with a pharmaceutically acceptable
`carrier.
`
`(Ex. 1001 at 50:40-67.)
`
`C. Claim Construction
`
`27.
`
`I understand that “claim construction” is the interpretation of the
`
`meaning of patent claims. I understand that claims in this inter partes review
`
`proceeding are given their broadest reasonable construction.
`
`28.
`
`I understand that many sources can be used to assist in understanding
`
`the meaning of a claim including the claims themselves, the specification, the
`
`prosecution history, and extrinsic evidence concerning scientific principles, the
`
`meaning of technical terms, and the state of the art.
`
`29.
`
`I have been asked to review the claims and ascertain the meaning of
`
`the claims from the perspective of one of ordinary skill in the art. I have reviewed
`
`the claims themselves, the specification, the prosecution history, and relevant
`
`technical papers from the time of the invention. Any opinions on claim
`
`construction expressed in this declaration are from the perspective of a person of
`
`ordinary skill in the art as of September 2008, and are consistent with my
`
`understanding as stated above with regards to this inter partes review.
`
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`
`
`30.
`
`In my opinion, the meaning of the ’733 patent claims can be
`
`ascertained by referring to the language of the claims themselves and do not
`
`require any special redefinition. In other words, the ordinary meaning of the terms
`
`in the ’733 patent claims would be understood by a POSITA by reading the claims
`
`in view of the specification.
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` BACKGROUND
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`31.
`
`I provide the following description of the state of the art as of
`
`September 18, 2008, which I understand is the ’733 patent’s earliest possible
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`priority date. Therefore, I understand that September 18, 2008 is the date as of
`
`which the obviousness of ’733 patent’s claims should be judged. As of that date,
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`the following fundamental concepts/components were well established in the art:
`
`(A) tetrabenazine was a well-known therapeutic with known drawbacks; (B) the
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`methoxy groups of tetrabenazine were known to be essential for its activity and
`
`were also sites of metabolism; (C) strategic deuteration was known to slow the
`
`metabolism in compounds like tetrabenazine; and (D) deuteration was also known
`
`to impart other therapeutic benefits. I also address (E) my disagreement with the
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`patentee’s arguments during prosecution that effects of deuteration in
`
`deutetrabenazine were in any way unpredictable or led to any unexpected results.
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`Apotex Ex. 1002
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`A. Tetrabenazine Was a Well-Known Therapeutic with Known
`Drawbacks
`
`32. Tetrabenazine was introduced in 1956 as an antipsychotic drug. (Ex.
`
`1003 (Zheng) at E683.) By September 18, 2008, tetrabenazine had been “used to
`
`treat hyperkinetic movement disorders, such as chorea associated with
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`Huntington’s disease, tics in Tourette’s syndrome, and movement stereotypes in
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`tardive dyskinesia.” (Ex. 1003 (Zheng) at E683; see also Ex. 1017 (Paleacu) 2007
`
`at 545; Ex. 1007 (Gano) at 1:31-32; Ex. 1010 (Huntington Study) at 366; Ex. 1001
`
`at 1:16-19.) Tetrabenazine was reported to provide effects by reversibly inhibiting
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`vesicular monoamine transporter-2 (VMAT2).2 (Ex. 1007 (Gano) at 1:27-32; Ex.
`
`1003 (Zheng) at E682, E683.)
`
`
`2 VMAT2 is a neurotransmitter transporter that was reported to be responsible for
`
`the translocation of monoamines (serotonin, dopamine, norepinephrine, and
`
`histamine) from the cytoplasm into synaptic vesicles in the central nervous system.
`
`(See, e.g., Ex. 1003 (Zheng) at E682-E684.) Inhibiting VMAT2, therefore,
`
`decreases the concentration of monoamines in neural matter. (Id.) This was
`
`thought to provide therapeutic benefits by reducing the concentration of toxic
`
`products of monoamine metabolism in the brain. (Id.)
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`Apotex Ex. 1002
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`33. Tetrabenazine has a relatively short half-life. (Ex. 1010 (Huntington
`
`Study) at 371; Ex. 1007 (Gano) at 1:58-59, 7:66-8:1.) Tetrabenazine’s short half-
`
`life necessitated administration of high and/or multiple (2-3) doses per day. (Id.)
`
`A POSITA would have understood that lengthening tetrabenazine’s half-life would
`
`have allowed for the administration of a lower dose or fewer doses per day. (Ex.
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`1007 (Gano) at 7:64-66.)
`
`34. Lowering the dose would also mitigate side effects because there
`
`would be less pharmacologically active material in the body. One of the axioms of
`
`drug design is that more potent compounds, with lower doses, are less likely to
`
`have off-target effects. Thus, medicinal chemists strive to make ligands (potential
`
`drugs) with the highest affinity to decrease side effects. This is in fact the origin of
`
`the term “side effect,” which normally results from off-target pharmacodynamics
`
`effects. Acute toxicity studies in drug development are performed with
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`“exaggerated doses” in recognition of the connection between dose and toxicity.
`
`(Ex. 1022 (Burger’s Ch. 9) at 265.) This is significant since tetrabenazine was
`
`associated with serious side effects, such as “sedation, depression, akathisia, and
`
`parkinsonism.” (Ex. 1007 (Gano) at 1:32-34; see also Ex. 1003 (Zheng) at E683;
`
`Ex. 1001 at 1:41-46.)
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`Apotex Ex. 1002
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`B.
`
`The Methoxy Groups of Tetrabenazine Were Known to Be
`Essential for Its Activity and Were Also Sites of Metabolism
`
`35.
`
`It was known that tetrabenazine’s methoxy groups, located at the C-9
`
`and C-10 positions, are “essential” for its activity. (Ex. 1003 (Zheng) at E685.) I
`
`prepared the following figure to show the location of the C-9 and C-10 methoxy
`
`groups on tetrabenazine.
`
`
`
`36. Because the prior art taught that the C-9 and C-10 methoxy groups
`
`were “essential” to tetrabenazine’s activity, a POSITA would have focused on
`
`modifying these positions in any attempt to lengthen tetrabenazine’s half-life or
`
`otherwise improve the molecule.
`
`37. A POSITA also would have focused on protecting the methoxy
`
`groups based on what was known about metabolism of tetrabenazine in the body.
`
`(See, e.g., Ex. 1008 (Schwartz) at 650.) Tetrabenazine’s metabolic pathways were
`
`disclosed by Schwartz in 1966. (Id.) These metabolic pathways can be divided
`
`into those that are productive and those that are destructive. A productive pathway
`
`is one that enhances or maintains the pharmacological efficacy. A destructive
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`Apotex Ex. 1002
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`pathway eliminates or lowers pharmacological efficacy. I have highlighted these
`
`pathways in the figure below taken from Schwartz at 650. The productive
`
`pathways are indicated in green and the destructive pathways in red and orange.
`
`
`
`38. The productive pathway involves reduction of the keto-group (the
`
`C=O) to the alcohol (C–OH)—compounds I & II in Schwartz (green annotations in
`
`the figure above). (Ex. 1008 (Schwartz) at 650; Ex. 1003 (Zheng) at E683-E684;
`
`Ex. 1018 (Kilbourn) at 59; Ex. 1001 at 1:34-37.) The reduced (C–OH) products
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`Apotex Ex. 1002
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`are called dihydrotetrabenazine, which is abbreviated HTBZ (used here) or DTBZ.3
`
`(Ex. 1003 (Zheng) at E683-E684; Ex. 1018 (Kilbourn) at 59.) The reduction
`
`pathway is productive because HTBZ provides therapeutic effects. (Ex. 1018
`
`(Kilbourn) at 59; Ex. 1020 (Ondo) at 302; Ex. 1003 (Zheng) at E684; Ex. 1001 at
`
`1:34-37.) HTBZ binds to the VMAT2 receptor and depletes cerebral monoamine
`
`neurotransmitters, providing the benefits of tetrabenazine. (Ex. 1018 (Kilbourn) at
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`59; Ex. 1003 (Zheng) at E683-84.)
`
`39. The destructive metabolic pathways involve (1) O-demethylation, also
`
`called O-dealkylation, which involves removal of the methyl group from the
`
`methoxy to form a phenol and (2) hydroxylation of the isobutyl group, which
`
`involves overall insertion of an oxygen to form an alcohol group in the
`
`hydrocarbon chain. (Ex. 1008 (Schwartz) at 650; Ex. 1001 at 1:34-37.)
`
`40. A POSITA would have understood that the pathways involving O-
`
`demethylation—compounds VI-IX in Schwartz (red in the figure above)—were the
`
`most significant of the destructive pathways. It was well known that O-
`
`demethylation was energetically more favorable, i.e., faster, than hydroxylation of
`
`
`3 HTBZ is a mixture of two sets of enantiomers, identified as α-HTBZ and β-
`
`HTBZ, divided according to the relative stereochemistry of the alcohol group. (Ex.
`
`1003 (Zheng) at E684.)
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`Apotex Ex. 1002
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`a hydrocarbon, and therefore it would produce the predominant set of metabolites.
`
`(Ex. 1016 (Jones 2002) at 7-11.)
`
`41. By the priority date it was known that both of the methoxy groups (at
`
`the C-9 and C-10 positions) would be subject to demethylation, as shown in the
`
`figure below.
`
`
`
`The ’733 patent itself cites to Schwartz for the proposition that “metabolic
`
`pathways [of tetrabenazine] involve O-demethylation of the methoxy groups.”
`
`(Ex. 1001 at 1:38-40.) Similarly, the patentee during prosecution admitted that the
`
`combination of Schwartz (Ex. 1008) and Zheng (Ex. 1003) taught “that
`
`tetrabenazine is metabolized at the O-methyl groups.” (Ex. 1027 (FH Excerpts) at
`
`022.) A POSITA would have known to be concerned with O-demethylation at
`
`both methoxy groups because the enzymes responsible for metabolism of
`
`compounds like tetrabenazine were capable of “branching,” also referred to as
`
`“metabolic switching,” where the same destructive metabolic reaction could
`
`alternately be catalyzed at proximate chemically similar bonds, such as the C–H
`
`bonds of the two adjacent methoxy groups in tetrabenazine. (Ex. 1015 (Jones
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`Apotex Ex. 1002
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`1986) at 7074-75; Ex. 1014 (Chou) ¶ 0010; Ex. 1004 (Naicker ’921) at 3:13-18.)
`
`Also, it is synthetically simpler and easier to deuterate both methoxy groups, as
`
`opposed to only one. (See, e.g., Ex. 1001 at cols. 17-19 (Scheme 1, especially the
`
`reaction of compounds 3 & 4 to form compound 5); see also id. at 23:55-24:15.)
`
`In addition, failure to deuterate the two adjacent methoxy groups would have been
`
`understood to increase the likelihood of undesirable production of an ortho-
`
`quinone, a known toxophore. (Ex. 1021 (Burger’s Ch. 6) at 177 (“A drug designer
`
`worthy of the name must be conversant with toxication reactions and toxophoric
`
`groups, which include [s]ome aromatic systems that can be oxidized to epoxides,
`
`quin