UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`MERCK PATENTGESELLSCHAFT
`Patent Owner
`
`Patent No. 8,673,921
`Issue Date: March 18, 2014
`Title: POLYMORPHIC FORMS OF
`1-[4-(5-CYANOINDOL-3-YL)BUTYL]-4-
`(2-CARBAMOYLBENZOFURAN-5-YL)
`PIPERAZINE HYDROCHLORIDE
`
`Inter Partes Review No.: Unassigned
`
`DECLARATION OF DR. SANJAY J. MATHEW, M.D.
`
`Argentum EX1003
`
`

`

`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
`
`
`
`
`
`I. 
`I. 
`II. 
`II. 
`
`TABLE OF CONTENTS
`Introduction ....................................................................................................... 1 
`My Background and Qualifications .................................................................. 1 
`The Basis for My Opinion ................................................................................ 2 
`Legal Principles ................................................................................................ 3 
`A.  Anticipation ............................................................................................ 3 
`B. 
`Obviousness ............................................................................................ 3 
`Summary of Opinions ....................................................................................... 4 
`III. 
`IV.  Person of Ordinary Skill in the Art ................................................................... 5 
`V. 
`The ’921 Patent ................................................................................................. 6 
`VI.  Claim Construction ......................................................................................... 10 
`VII.  State of the Prior Art ....................................................................................... 11 
`A.  U.S. Patent No. 5,532,241 (’241 Patent) (Ex. 1004) ............................ 11 
`B. 
`Bartoszyk (Ex. 1005) ............................................................................ 14 
`C. 
`Byrn (Ex. 1012) .................................................................................... 15 
`D. 
`Pavia (Ex. 1032) ................................................................................... 17 
`VIII.  Ground 1: Claim 14 is Anticipated by the ’241 Patent as Characterized by
`Patent Owner Admissions .............................................................................. 17 
`IX.  Ground 2: Claim 14 is Obvious over ’241 Patent and Bartoszyk .................. 20 
`X.  Ground 4: Claims 12 and 14 are Obvious Over ’241 Patent as Characterized
`by Patent Owner Admissions, Bartoszyk, Byrn, and Pavia ........................... 24 
`XI.  Absence of Secondary Considerations of Nonobviousness ........................... 29 
`A.  Unexpected Results .............................................................................. 29 
`XII.  Conclusion ...................................................................................................... 32 
`
`
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`-ii-
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`
`
`I, Sanjay Mathew, do declare as follows:
`
`
`
`
`
`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 Argentum
`
`Pharmaceuticals LLC for a inter partes review (IPR) for U.S. Patent No. 8,673,921
`
`(“’921 patent”) (Ex. 1001). I am being compensated for my time in connection with
`
`this IPR at my standard consulting rate, which is $700 per hour. I understand that my
`
`declaration accompanies a petition for inter partes review involving the above-
`
`mentioned U.S. Patent.
`
`I.
`
`My Background and Qualifications
`
`3.
`
`I am currently Professor of Psychiatry with Tenure at the Menninger
`
`Department of Psychiatry at Baylor College of Medicine. In addition, I am also Staff
`
`Physician at the Michael E. Debakey VA Medical Center since 2010. Since 2010, I
`
`have also been the Director of the Mood and Anxiety Disorders Program. As of
`
`2014, I am also the Johnson Family Chair for Research in Psychiatry. I have
`
`authored numerous original research articles, reviews, book chapters, and abstracts
`for meetings.
`
`4.
`
`I received a B.A. in Biology in 1991 from Dartmouth College in
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`
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`Hanover, New Hampshire and a M.D. in 1997 from Baylor College of Medicine in
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`
`
`Houston, Texas. From 1997-1998, I was an intern at Columbia-Presbyterian Hospital
`
`in New York. During the period of 1998–2001, I completed my Residency at New
`
`York State Psychiatric Institute (NYSPI). I also completed a National Institute of
`
`Mental Health (NIMH)-funded T32 Research Fellowship in Mood/Anxiety
`Disorders at Columbia University from 2001-2004.
`5.
`I was re-certified to the American Board of Psychiatry and Neurology
`in 2012.
`
`6.
`
`I am a member of the American Psychiatric Association, the American
`
`Medical Association, Anxiety and Depression Association of America, International
`
`Society of Magnetic Resonance in Medicine, Society of Biological Psychiatry,
`
`Society for Neuroscience, American College of Neuropsychopharmacology,
`
`European College of Neuropsychopharmacology, American Society of Clinical
`
`Psychopharmacology, and the National Network of Depression Centers.
`
`7. My area of expertise is in the psychopharmacological management of
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`adult patients with difficult-to-treat depressive and anxiety disorders. Accordingly, I
`
`believe that I am more than competent to express the opinions set forth below.
`
`8. My curriculum vitae is attached as an appendix to this document.
`
`II.
`
`The Basis for My Opinion
`
`9.
`
`In formulating my opinion, I considered the documents listed in
`2
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`

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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`Appendix A.
`
`
`
`
`
`
`
`II. Legal Principles
`A. Anticipation
`10.
`I understand from counsel that a patent claim is “anticipated” if all
`
`elements of the claim are disclosed in a single prior art reference in the same way the
`
`elements are arranged in the claim. I further understand that where a reference
`
`provides broad disclosure of a larger group of, e.g., combinations, as well as specific
`
`preferences for the combinations, the reference still anticipates so long as all claim
`
`elements are disclosed as arranged in the claim. I am also told that the prior art
`
`reference must be enabling (i.e., allowing a Person of Ordinary Skill in the Art
`
`(“POSA”) to make and use the claimed invention without undue experimentation) in
`order to anticipate the claim.
`B. Obviousness
`
`11.
`
`I understand that an obviousness analysis involves comparing a claim to
`
`the prior art to determine whether the claimed invention would have been obvious to
`
`a POSA in view of the prior art, and in light of the general knowledge in the art. I
`
`also understand that when a POSA would have reached the claimed invention
`
`through routine experimentation, the invention may be deemed obvious. I understand
`
`that a finding of obviousness for a specific range or ratio in a patent can be overcome
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`
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`3
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`if the claimed range or ratio is proven to be critical to the performance or use of the
`
`
`
`claimed invention.
`
`12.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art to achieve the claimed invention. It is also
`
`my understanding that where this is a reason to modify or combine the prior art to
`
`achieve the claimed invention, there must also be a reasonable expectation of success
`
`in so doing. I understand that the reason to combine prior art references can come
`
`from a variety of sources, not just the prior art itself or the specific problem the
`
`patentee was trying to solve. And I understand that the references themselves need
`
`not provide a specific hint or suggestion of the alteration needed to arrive at the
`
`claimed invention; the analysis may include recourse to logic, judgment, and
`
`common sense available to a person of ordinary skill that does not necessarily
`
`require explication in any reference.
`
`13.
`
`I understand that when considering the obviousness of an invention, one
`
`should also consider whether there are any secondary considerations that support the
`
`nonobviousness of the invention. I understand that secondary considerations of
`
`nonobviousness include failure of others, copying, unexpectedly superior results,
`
`perception in the industry, commercial success, and long-felt but unmet need.
`
`III.
`
`Summary of Opinions
`
`14. Based on my investigation and analysis and for the reasons set forth
`4
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
`
`
`below, it is my opinion that claim 14 of the ’921 patent would have been anticipated
`
`by U.S. Patent No. 5,532,241 (“’241 patent”) as characterized by Patent Owner’s
`
`Admissions in the ’921 patent.
`
`15.
`
`In addition, it is my opinion that claim 14 would have been obvious to
`
`one of ordinary skill in the art at the time of the alleged invention in view of the
`
`combined teachings of the ’241 patent and WO 00/72832 (“Bartoszyk”).
`
`16. Lastly, claim 12 would have been obvious to one of ordinary skill in the
`
`art in view of the combined teachings of the ’241 patent, Bartoszyk, Pavia, D et al.,
`
`INTRODUCTION TO ORGANIC LABORATORY TECHNIQUES A CONTEMPORARY
`
`APPROACH, 3d. edition (1988) (“Pavia”), and Byrn et al., Solid-State Chemistry of
`
`Drugs, Chapter 10, “Polymorphs,” 143-231 (2d ed. 1999) (“Byrn”).
`
`IV.
`
`Person of Ordinary Skill in the Art
`
`17.
`
`I understand that as of June 19, 2001, a hypothetical POSA would “be
`
`aware all the pertinent prior art” at the time of the alleged invention. A hypothetical
`
`POSA would be part of a multidisciplinary team including a solid-state chemist and
`
`a clinician/scientist.
`
`18. A person of ordinary skill in the art would have an M.D. with extensive
`
`experience in the study and treatment of mood disorders. A person of ordinary skill
`
`in the art would understand the references referred to herein and have the capability
`
`to draw inferences from them. These descriptions are approximate, and a higher
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`level of education or specific skill might make up for less experience, and vice-versa.
`
`
`
`V.
`
`The ’921 Patent
`
`19.
`
`I understand that the ’921 patent (Ex. 1001) is listed in the FDA’s
`
`Orange Book as covering the Viibryd® product. The Orange Book states that the
`
`’921 patent will expire on June 5, 2022.
`
`20. The ’921 patent issued from U.S. Patent Application No. 14/032,183
`
`(“’183 Application”), filed September 19, 2013, which purports to claim priority to a
`
`series of continuation and divisional applications.
`
`21. The ’183 Application claims priority to a series of continuation and
`
`divisional applications, of which European Patent No. 01113674, filed on June 19,
`
`2001, is the earliest possible priority date for the ’921 patent.
`
`22. The ’921 patent is directed to crystalline modifications of the
`
`hydrochloride salt of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`
`5yl)-piperazine (“vilazodone”), amorphous vilazodone hydrochloride, and a
`
`crystalline modification of the dihydrochloride of vilazodone. Ex. 1001 at Abstract.
`
`23. The ’921 patent also states that the ’241 patent discloses 1-[4-(5-
`
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-piperazine and its
`
`physiologically acceptable salts. Ex. 1001 at 1:35-37. The ’921 patent also states that
`
`the ’241 patent discloses a process by which vilazodone and its physiologically
`
`acceptable salts can be prepared. Ex. 1001 at 1:37-41. Further, the ‘921 patent states
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`that the use of vilazodone and its physiologically acceptable salts in treating certain
`
`
`
`medical disorders was well known. Id.
`
`24.
`
`In more detail, the ’921 patent states that Example 4 discloses the
`
`conversion of the vilazodone free base to the hydrochloride salt of vilazodone. Ex.
`
`1001 at 1:35-57. Specifically, the ’921 patent states that Example 4 of the ’241
`
`patent yielded the active ingredient vilazodone as a mixture of crystalline vilazodone
`
`hydrochloride, amorphous vilazodone hydrochloride, and vilazodone free base. Ex.
`
`1001 at 1:65-2:5.
`
`25. The Background section further states:
`
`Certain crystalline, i.e. morphological forms of pharmaceutical
`compounds may be of interest to those involved in the development
`of a suitable dosage form because if the morphological form is not
`held constant during clinical and stability studies, the exact dosage
`used or measured may not be comparable from one lot to the next.
`Once a pharmaceutical compound is produced for use, it is important
`to recognize the morphological form delivered in each dosage form
`to assure that the production process use the same form and that the
`same amount of drug is included in each dosage. Therefore, it is
`imperative to assure that either a single morphological form or some
`known combination of morphological forms is present. In addition,
`certain morphological forms may exhibit enhanced
`thermodynamic stability and may be more suitable than other
`
`
`
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`
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`morphological forms for inclusion in pharmaceutical
`formulations.
`
`Ex. 1001 at 2:6-21 (emphases added)
`
`26. The ’921 patent discloses that the vilazodone crystalline modifications
`
`are suitable to treat or prevent a wide-range of disorders, including depressive
`
`disorders, anxiety disorders, bipolar disorders, mania, dementia, substance-related
`
`disorders, sexual dysfunctions, eating disorders, obesity, fibromyalgia, sleeping
`
`disorders, psychiatric disorders, cerebral infract, tension, and provide therapy for the
`
`side effects of hypertension, cerebral disorders, chronic pain, acromegaly,
`
`hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired
`
`puerperal lactation. Ex. 1001 at Abstract.
`
`27.
`
`Independent claim 1 of the ’921 patent recites:
`
`“A compound which is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride in its
`crystalline modification, wherein the compound is an anhydrate,
`hydrate, solvate or dihydrochloride.”
`
`28.
`
`Independent claim 11 of the ’921 patent recites:
`
`“A pharmaceutical composition comprising a compound which is 1-
`[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-
`piperazine hydrochloride anhydrate in its crystalline modification
`
`
`
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`
`
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`IV, and one or more conventional auxiliary substances and/or
`carriers.”
`
`29. Dependent claim 12 recites a method of treating the same list of
`
`disorders using the composition disclosed in claim 11. Claim 12 recites:
`
`“A method of treating a patient suffering from a depressive disorder,
`an anxiety disorder, a bipolar disorder, mania, dementia, a
`substance-related disorder, a sexual dysfunction, an eating disorder,
`obesity, fibromyalgia, a sleeping disorder, a psychiatric disorder,
`cerebral infarct, tension, side-effects in the treatment of
`hypertension, a cerebral disorder, chronic pain, acromegaly,
`hypogonadism, secondary amenorrhea, premenstrual syndrome and
`undesired puerperal lactation, or combinations thereof, comprising
`administering to the patient in need thereof the pharmaceutical
`composition of claim 11.”
`
`30. Dependent claim 14 recites a method of treating a patient with disorders
`
`listed in the Abstract of the ’921 patent using the compound disclosed in claim 1.
`
`Claim 14 recites:
`
`“A method of treating a patient suffering from a depressive disorder,
`an anxiety disorder, a bipolar disorder, mania, dementia, a
`substance-related disorder, a sexual dysfunction, an eating disorder,
`obesity, fibromyalgia, a sleeping disorder, a psychiatric disorder,
`cerebral infarct, tension, side-effects in the treatment of
`hypertension, a cerebral disorder, chronic pain, acromegaly,
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`
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`hypogonadism, secondary amenorrhea, premenstrual syndrome and
`undesired puerperal lactation, or combinations thereof, comprising
`administering to the patient in need thereof an effective amount of a
`compound of claim 1.”
`
`31. Throughout the ‘921 patent, the use of the term “Form” is synonymous
`
`with “modification” or “crystalline modification.” Ex. 1001 at 2:41-43.
`
`32. The ’921 patent does not provide any in vitro or in vivo data, on humans
`
`or animals, regarding the efficacy and activity of vilazodone hydrochloride in
`
`treating the disorders that are claimed in the patent.
`
`33. The ’921 patent also discloses that Form IV “has superior properties
`
`over other crystalline forms and is more suitable for inclusion in pharmaceutical
`
`formulations.” Ex. 1001 at 12:38-41. However, the ’921 patent does not say how
`
`Form IV is more suitable for pharmaceutical formulations, nor does it provide any
`
`data to support this assertion.
`
`VI.
`
`Claim Construction
`
`34.
`
`I have been advised that, in the present proceeding, the ’921 patent
`
`claims are to be given their broadest reasonable interpretation (BRI) in view of the
`
`specification as understood by one of ordinary skill in the art. I understand that claim
`
`language is read in light of the while patent, including the other claims, the
`
`specification, and the prosecution history as it would be interpreted by one of
`
`
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
`
`ordinary skill in the art. I also understand that, absent some reason to the contrary,
`
`
`
`claim terms are typically given their ordinary and customary meaning, as they would
`
`have been understood by one of ordinary skill in the art. I have followed these
`
`principles in my analysis described throughout this declaration.
`
`35. The ’921 patent provides definitions for certain claim terms, but other
`
`claim terms are not defined in the patent. I discuss a few terms below and what I
`
`understand these terms to mean.
`
`36. Claim 12 and 14 contain the term “administering.” It is my opinion that
`
`a person of ordinary skill in the art would understand “administering” to mean
`
`“delivering to the body” of a patient.
`
`VII.
`
`State of the Prior Art
`A. U.S. Patent No. 5,532,241 (’241 Patent) (Ex. 1004)
`
`37.
`
`I understand from counsel that U.S. Patent No. 5,532,241 qualifies as
`
`prior art under 35 U.S.C. § 102(b), pre-AIA, because it issued on July 2, 1996, which
`
`is more than 1 year before the priority date of the ’921 patent. Ex. 1004.
`
`38. The ’241 patent issued from Application No. 08/314,734, which was
`
`filed on September 29, 1994 by Henning Boettcher as the lead inventor.
`
`39. The ’241 patent discloses piperidine and piperazine derivatives and
`
`their physiologically acceptable salts. Ex. 1004 at 1:5-29. The ’241 patent also
`
`discloses that the compounds of formula I as claimed in the patent possess “valuable
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`pharmacological properties” and “are active on the central nervous system.” Id. at
`
`
`
`1:35-39. The ’241 patent discloses that the compounds claimed can be “used as
`
`active ingredients for anxiolytics, antidepressants, antipsychotics, neuroleptics,
`
`and/or antihypertensives, and also as intermediates for the preparation of other
`
`pharmaceutical active ingredients.” Id. at 1:56-61. Furthermore, the ’241 patent
`
`discloses that the “compounds of the formula I and their physiologically acceptable
`
`salts can be used for the therapeutic treatment of the human or animal body and for
`
`controlling diseases.” Id. at 8:24-26. Additionally, these compounds can be used to
`
`treat acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome
`
`and undesired puerperal lactation, cerebral disorders, including migraine, cerebral
`
`infarction, stroke, and cerebral ischemia. Id. at 8:30-38.
`
`40. The ’241 patent also discloses that the substances of the invention
`
`should be “normally administered analogously to known, commercially available
`
`preparations,” “preferably in dosages of about 0.2-500 mg, especially 0.2-50 mg per
`
`dosage unit.” Id. at 8:39-43. The ’241 patent further discloses the daily dosage as
`
`preferably about 0.001-10 mg/kg of body weight, with low dosages particularly
`
`suitable for anti-migraine preparations and dosages of about 10-50 mg per dosage
`
`unit as preferred for the other indications. Id. at 8:44-48.
`
`41. The ’241 patent discloses several Examples where substances of the
`
`
`
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`invention are prepared and worked up in a conventional manner. Ex. 1004 at 9:15-
`
`
`
`28, 10:28-35, 10:57-67, 12:30-41, 12:54-62, 13:23-34, 14:29-39, and 14:59-67. The
`
`‘241 patent specifies that “‘working up in conventional manner’ means: [w]ater is
`
`added if necessary, extraction is carried out with methylene chloride, the organic
`
`phase is separated off, dried over sodium sulfate and filtered, the filtrate is
`
`evaporated and the residue is purified by chromatography on silica gel and/or by
`
`crystallization.” Ex. 1004 at 9:3-10.
`
`42. Example 4 of the ’241 patent specifically discloses “1-[4-(5-cyanoindol-
`
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-piperazine, m.p. 269-272°
`
`(hydrochloride).” Id. at 11:19-26.
`
`43. The ’241 patent specifically claims vilazodone as the third compound
`
`listed in Claim 2. Claim 2 recites:
`
`“A compound according to claim 1, wherein said compound is
`
`(a) 1-[4-(5-methoxyindol-3-yl)butyl]-4-(2-
`hydroxymethylbenzofuran-5-yl)piperazine or a physiologically
`acceptable salt thereof;
`
`(b) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-ethoxycarbonylbenzofuran-
`5-yl ) piperazine or a physiologically acceptable salt thereof; or
`
`(c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)
`piperazine or a physiologically acceptable salt thereof.”
`
`
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`Patent No. 8,673,921
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`44. Claim 16 of the ’241 patent discloses “A pharmaceutical composition
`
`comprising a compound according to claim 1 and a pharmaceutically acceptable
`
`carrier.”
`
`B.
`
`Bartoszyk (Ex. 1005)
`
`45. Bartoszyk is a WIPO publication published on December 7, 2000 based
`
`on International Application No. PCT/EP00/04376, filed on May 16, 2000. Ex. 1005
`
`at cover. I understand from counsel that Bartoszyk qualifies as prior art under 35
`
`U.S.C. §102(b) because it was published more than 1 year before the earliest U.S.
`
`filing date for the ’921 patent of June 5, 2002.
`
`46. Bartoszyk discloses 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`benzofuran-5yl)-piperazine or a physiologically acceptable salt thereof. Bartoszyk
`
`also discloses that the preferred salt is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride. Id. at Abstract.
`
`47. Bartoszyk discloses the use of vilazodone for the treatment of sub-type
`
`anxiety disorders chosen from the sub-types panic disorder with or without
`
`agoraphobia, agoraphobia, obsessive-compulsive spectrum disorders, social phobia,
`
`posttraumatic stress disorder, acute stress indication or generalized-anxiety disorder,
`
`bipolar disorders, mania, dementia, substance-related disorders, sexual dysfunctions,
`
`eating disorders, obesity, anorexia and fibromyalgia. Id.; Claims 1-10.
`
`48. Bartoszyk discloses several examples, which all relate to
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`Patent No. 8,673,921
`Declaration in Support of Inter Partes Review
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`pharmaceutical products. Examples A through I disclose several pharmaceutical
`
`
`
`preparations of the active ingredient vilazodone or its physiologically acceptable salt,
`
`including vials, suppositories, solutions, ointments, tablets, sugar-coated tablets,
`
`capsules, ampoules, and sprays for inhalation. Id. at 32-34.
`
`49. Claim 1 of Bartoszyk recites:
`
`“Use of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5-yl)piperazine or a physiologically acceptable salt thereof, for the
`manufacture of a medicament for the treatment of sub-type anxiety
`disorders chosen from the sub-types panic disorder with or without
`agoraphobia, agoraphobia, obsessive-compulsive spectrum
`disorders, social phobia, posttraumatic stress disorder, acute stress
`indication and/or generalized-anxiety disorder.”
`
`50. Claim 2 of Bartoszyk discloses a “pharmaceutical preparation for the
`
`treatment of sub-type anxiety disorders according to claim 1 characterized in that it
`
`contains at least 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-
`
`piperazine or one of its pharmaceutically acceptable salts. Id. at cl. 2.
`
`51. Claims 3-10 of Bartoszyk disclose the use of vilazodone or a
`
`physiologically acceptable salt thereof for the manufacture of a medicament for the
`
`treatment of the disorders listed in the Abstract. Id. at cls. 3-10.
`
`C. Byrn (Ex. 1012)
`
`52. Bryn, a textbook titled Solid-State Chemistry of Drugs was published in
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`1999.
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`53. Byrn is an authoritative source on the solid-state chemistry of drugs and
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`provides detailed information regarding methods of analysis, polymorphs, solvates,
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`and amorphous forms, and the physical and chemical transformations of crystalline
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`solids.
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`54. Byrn discloses basic information regarding the forces responsible for
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`crystal packing, how crystal forms, and the solubility of a solid substance. Id. at 3-
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`15. Byrn also states the importance of using X-ray Powder Diffraction (“PXRD”) to
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`distinguish solid phases having different internal structures. Id. at 59. Byrn also
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`discusses how to compare PXRD diffraction data obtained from different samples
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`and on the same instrumentation. Id. at 63.
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`55. Byrn discloses that interconversion between different crystal forms is
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`common. Id. at 169-170. The different crystal forms often have differences in
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`hygroscopicity and can interconvert in the presence of high humidity. In the case of
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`succinylsulfathiazole, Byrn disclosed that the differences in solubility among the
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`anhydrate crystal forms is as large as a factor of 4 and differences in solubility
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`between anhydrate and hydrate crystal forms are as large as a factor of 12. Byrn
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`further disclosed that succinylsulfathiazole is one of “many cases where anhydrate
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`crystal forms have significantly higher solubilities than the hydrate.” Id. at 170.
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`56. Byrn also discloses that because polymorphs have different physical
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`properties, it is “often advantageous to choose the proper polymorph for the desired
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`pharmaceutical application.” Id. at 225. Byrn further discloses that the physical
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`stability of each form can be determined using the solution phase transformation
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`method. Id. This method involves placing two polymorphs in a drop of saturated
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`solution under the microscope. Id. Stable crystals will grow until only the most
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`stable form remains. Byrn also states that varying the temperature can also be used to
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`determine which metastable form is the most stable. Id.
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`D.
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`Pavia (Ex. 1032)
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`57. Pavia is a 3rd edition textbook titled Introduction to Organic Laboratory
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`Techniques: A Contemporary Approach published in 1988. Pavia discloses the use
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`of crystallization as a technique to purify solids. Ex. 1032 at 522. Pavia also teaches
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`step-by-step how to perform a crystallization experiment starting with choosing the
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`right solvent. Id. at 522-525.
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`58. Pavia also discloses how to dissolve the solid, filter, crystallize, and
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`isolate the crystals collected. Id. at 526-529. Pavia further teaches how to oven-dry
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`a solid substance. Id. at 530.
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`VIII.
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`Ground 1: Claim 14 is Anticipated by the ’241 Patent as Characterized by
`Patent Owner Admissions
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`59. Claim 14 depends from Claim 1 and recites a method of treating a
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`patient and administering to said patient in need of an effective amount of the
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`compound in claim 1. The disorders claimed in Claim 14 include “a depressive
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`disorder, an anxiety disorder, a bipolar disorder, mania, dementia, a substance-
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`related disorder, a sexual dysfunction, an eating disorder, obesity, fibromyalgia, a
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`sleeping disorder, a psychiatric disorder, cerebral infarct, tension, side-effects in the
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`treatment of hypertension, a cerebral disorder, chronic pain, acromegaly,
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`hypogonadism, secondary amenorrhea, premenstrual syndrome and undesired
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`puerperal lactation, or combinations thereof.” Ex. 1001, cl. 14.
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`60.
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`I understand that Patent Owner’s Admissions and the ’241 patent can be
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`considered in evaluating the validity of the claims of the ’921 patent. Based upon
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`my review of the declaration submitted by Dr. Robin Rogers (Ex. 1002), I
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`understand his opinion to be that Patent Owner’s Admissions disclose vilazodone
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`hydrochloride as recited in Claim 1, and that the ’241 patent discloses the same
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`compound in its crystal form, which can be used for the “therapeutic treatment of
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`human or animal body and for controlling diseases.” Ex. 1001 at 1:35-41; Ex. 1004
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`at 8:24-26. Additionally, the ’241 patent discloses that its claimed compounds can be
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`used to treat disorders of the central nervous system, endocrinology, gynecology,
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`and also for the prophylaxis and therapy of cerebral disorders. Id. at 8:26-38.
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`Specifically, vilazodone hydrochloride is claimed in the ’241 patent. Id. at cl. 2(c).
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`As discussed in detail below, the use of vilazodone hydrochloride in its crystalline
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`
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`modification to treat the conditions recited in Claim 14 is anticipated by the ’241
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`patent as characterized by Patent Owner’s Admissions.
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`61.
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`In fact, the disorders listed in both the ’241 patent and Claim 14,
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`include depression, hypertension, acromegaly, hypogonadism, secondary
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`amenorrhea, premenstrual syndrome, undesired puerperal lactation, and cerebral
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`infarction. A POSA would recognize that Example 4 of the ’241 patent would be
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`effective in treating at least these disorders.
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`62. A POSA would also appreciate that preferable dosage amounts for the
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`compounds are also disclosed in the ’241 patent. Ex. 1004 at 8:39-46. The ’241
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`patent discloses that “the substances of the invention are normally administered…,
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`preferably in dosages of about 0.2 to 500 mg, especially 0.2-50 mg per dosage unit.”
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`Id. Therefore, a POSA would recognize what constitutes an “effective amount” of
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`the compound, vilazodone hydrochloride in its crystalline form.
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`63. Moreover, the ‘921 patent does not disclose any additional information
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`on the preferred dosage amounts for the claimed compounds. In fact, the ‘921 patent
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`states that the dose for the products of the claimed invention should “correspond to
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`that mentioned in U.S. Pat. No. 5,532,241.” Ex. 1001 at 15:33-34.
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`64. Accordingly, the ’241 patent discloses every limitation of claim 14 of
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`Patent No. 8,673,921
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`the ’921 patent.
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`IX.
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`Ground 2: Claim 14 is Obvious over ’241 Patent and Bartoszyk
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`65. Claim 14 recites a method of treating a patient and administering to said
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`patient in need an effective amount of the compound in Claim 1 suffering from a
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`long list of disorders, including “depressive disorder, an anxiety disorder, a bipolar
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`disorder, mania, dementia, a substance-related disorder, a sexual dysfunction, an
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`eating disorder, obesity, fibromyalgia, a sleeping disorder, a psychiatric disorder,
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`cerebral infarct, tension, side-effects in the treatment of hypertension, a cerebral
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`disorder, chronic pain, acromegaly, hypogonadism, secondary amenorrhea,
`premenstrual syndrome and undesired puerperal lactation.”
`66. As discussed above, I understand that the ’241 patent and Bartoszyk can
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`be considered in evaluating the validity of the claims of the ’921 patent. Based upon
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`my review of the declaration of Dr. Rogers, I understand his opinion to be that the
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`’241 patent, as characterized by Patent Owner’s Admissions in the ’921 patent,
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`discloses a crystalline modification of vilazodone hydrochloride. Dr. Roge