IPR2018-00423
`Patent Owner’s Preliminary Response
`
`Filed on behalf of Patent Owner Merck Patentgesellschaft by:
`
`Emily R. Whelan (Reg. No. 50,391)
`
`Deric X. Geng (Reg. No. 73,434)
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`60 State Street
`Boston, MA 02109
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`v.
`MERCK PATENTGESELLSCHAFT,
`Patent Owner.
`____________________________________________
`Case IPR2018-00423
`Patent 8,673,921
`____________________________________________
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`

`

`IPR2018-00423
`Patent Owner’s Preliminary Response
`
`TABLE OF CONTENTS
`
`I. 
`II. 
`
`Page
`INTRODUCTION ........................................................................................... 1 
`TECHNOLOGY BACKGROUND ................................................................. 3 
`A.  Antidepressant Drugs .................................................................................... 3 
`B.  Solid Forms of Pharmaceutical Compounds ................................................. 4 
`1. 
`Crystalline and Amorphous Forms ....................................................... 4 
`
`2. 
`
`Polymorphism Is Unpredictable ............................................................ 5 
`
`C.  Melting Point ................................................................................................. 6 
`III.  THE ’921 PATENT ......................................................................................... 6 
`A.  Challenged Claims ........................................................................................ 6 
`B. 
`’921 Patent Specification ............................................................................... 7 
`C.  File History .................................................................................................... 8 
`IV.  PERSON OF ORDINARY SKILL IN THE ART .......................................... 9 
`V. 
`CLAIM CONSTRUCTION ............................................................................ 9 
`VI.  PRIMARY REFERENCES ASSERTED BY PETITIONER ....................... 11 
`A.  The ’241 Patent ........................................................................................... 11 
`B.  Bartoszyk ..................................................................................................... 13 
`VII.  THE PETITION SHOULD BE DENIED BECAUSE NO GROUND
`HAS A REASONABLE LIKELIHOOD OF SUCCESS .............................. 13 
`A.  Ground 1: Claims 1, 14, and 15 Are Not Anticipated by the ’241
`Patent and the So-Called Patent Owner Admissions ............................... 13 
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`1. 
`
`2. 
`
`3. 
`
`4. 
`
`The ’241 Patent Examples Do Not Disclose Crystalline
`Vilazodone HCl ................................................................................... 14 
`
`Example 4’s Melting Point Range Does Not Disclose Any Solid
`Form Information About Vilazodone HCl .......................................... 17 
`
`The Petition Does Not Establish Inherent Disclosure of Form
`VIII ...................................................................................................... 19 
`
`The Petition Improperly Relies on So-Called Patent Owner
`Admissions .......................................................................................... 21 
`
`B.  Ground 2: Claims 1, 14, and 15 Are Not Obvious Over the ’241
`Patent, the So-Called Patent Owner Admissions, and Bartoszyk ............ 27 
`Ground 2 Fails for the Same Reasons as Ground 1 ............................ 28 
`
`1. 
`
`2. 
`
`3. 
`
`Bartoszyk Does Not Remedy the Deficiencies of the ’241
`Patent ................................................................................................... 28 
`
`The Petition Fails to Establish a Motivation to Modify the Prior
`Art to Achieve the Claimed Invention, or a Reasonable
`Expectation of Success in Doing So ................................................... 29 
`
`C.  Ground 3: Claims 1 and 11 Are Not Obvious Over the ’241 Patent,
`the So-Called Patent Owner Admissions, Pavia, and Byrn ..................... 34 
`The ’241 Patent, Pavia, and Byrn Do Not Teach or Suggest
`Crystalline Forms of Vilazodone HCl ................................................. 34 
`
`1. 
`
`2. 
`
`3. 
`
`Courts and the Board Consistently Have Rejected Petitioner’s
`“General Motivation,” “Obvious to Try,” and “Known Method
`to Improve a Prior Art Product” Arguments ....................................... 36 
`
`Dr. Rogers’ Alleged “Routine” Experiments Do Not Support
`Petitioner’s Obviousness Challenge .................................................... 39 
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`D.  Ground 4: Claims 1, 12, 14, and 15 Are Not Obvious In View of the
`’241 Patent as Characterized by “Patent Owner’s Admissions,”
`Bartoszyk, Pavia, and Byrn ...................................................................... 48 
`VIII.  OBJECTIVE INDICIA OF NON-OBVIOUSNESS ..................................... 50 
`IX.  THE PETITION SHOULD BE DENIED UNDER 35 U.S.C. § 325(d) ....... 51 
`X. 
`IPRS ARE UNCONSTITUTIONAL AS APPLIED TO THE ’921
`PATENT ........................................................................................................ 53 
`XI.  CONCLUSION .............................................................................................. 53 
`
`
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`TABLE OF AUTHORITIES
`
`
`
`Page(s)
`
`Federal Cases
`
`In re Armodafinil Patent Litig.,
`939 F. Supp. 2d 456 (D. Del. 2013) ................................................................................. passim
`
`Commvault Sys., Inc. v. Realtime Data LLC,
`IPR2017-02007, 2018 WL 1364025 (Mar. 15, 2018) .............................................................46
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) .............................................................................................................10
`
`In re Depomed,
`No. 13-cv-4507, 2016 WL 7163647 (D. N.J. Sept. 30, 2016) .....................................30, 31, 37
`
`In re Ehrreich,
`590 F.2d at 910 ............................................................................................................24, 25, 26
`
`In re Hellsund,
`474 F.2d 1307 (C.C.P.A. 1973) ...............................................................................................24
`
`King Pharm., Inc. v Eon Labs, Inc.,
`616 F.3d 1267 (Fed Cir. 2010).................................................................................................14
`
`Kowa Co. v. Amneal Pharm.,
`No. 14-cv-2758 (PAC), ECF No. 168 (S.D.N.Y. Sept. 19, 2017) .....................................31, 45
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................................................38
`
`In re Lee,
`277 F.3d 1338 (Fed. Cir. 2002)................................................................................................41
`
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017)................................................................................................42
`
`Par Pharm., Inc. v. TWi Pharm., Inc.,
`No. CIV. CCB-11-2466, 2014 WL 694976 (D. Md. Feb. 21, 2014), vacated on
`other grounds, 773 F.3d 1186 (Fed. Cir. 2014) .......................................................................23
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007)................................................................................................26
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) ................................................................................10
`
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`Riverwood Int’l Corp. v. R.A. Jones & Co.,
`324 F.3d 1346 (Fed. Cir. 2003)................................................................................................25
`
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017)....................................................................................29, 40, 41
`
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002)..........................................................................................14, 18
`
`ViiV Healthcare UK Ltd. v. Lupin Ltd.,
`6 F. Supp. 3d 461 (D. Del. 2013) .............................................................................................24
`
`Federal Statutes
`
`35 U.S.C. § 103 ............................................................................................................34, 39, 40, 48
`
`35 U.S.C. § 325(d) ...........................................................................................................1, 3, 51, 53
`
`America Invents Act ......................................................................................................................53
`
`Regulations
`
`37 C.F.R. § 42.24(d) ......................................................................................................................55
`
`37 C.F.R. § 42.100(b) ....................................................................................................................10
`
`37 C.F.R. § 42.104(b)(4) ................................................................................................................14
`
`Constitutional Provisions
`
`US Constitution ..............................................................................................................................53
`
`Other Authorities
`
`Ex Parte Bush,
`APL 2009-010640, 2010 WL 321356 (B.P.A.I. Jan. 27, 2010) ..........................................5, 16
`
`Coalition for Affordable Drugs VII LLC v. Pozen Inc.,
`No. IPR2015-01344, 2015 .......................................................................................................30
`
`Lupin Ltd. v. Janssen Scis. Ireland UC,
`No. IPR2015-01030, 2015 .........................................................................................................2
`
`Unified Patents Inc. v. Berman,
`No. IPR2016-01571, 2016 .......................................................................................................52
`
`v
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`IPR2018-00423
`Patent Owner’s Preliminary Response
`
`I.
`
`INTRODUCTION
`The Petition must be denied because it is based on mischaracterizations of
`
`U.S. Patent No. 5,532,241 (the “’241 patent”) and on an improper attempt to create
`
`prior art from a disclosure in the challenged U.S. Patent No. 8,673,921 (the “’921
`
`patent”) itself. The alleged anticipation ground must fail because it rests on these
`
`errors along with insufficient and internally inconsistent inherency arguments. The
`
`alleged obviousness grounds also fail because they rest on these same errors and
`
`“general motivation” and “obvious to try” type arguments that have been rejected
`
`consistently by courts and the Board, and they do not establish any reasonable
`
`expectation of success in view of the well-recognized unpredictability of
`
`crystalline forms. The Board also should deny institution under 35 U.S.C. § 325(d)
`
`because substantially the same prior art and arguments were before the examiner
`
`during prosecution, and the Petition does not add any new evidence or argument to
`
`support reconsideration.
`
`The challenged claims in the ’921 patent relate to crystalline vilazodone
`
`hydrochloride including vilazodone hydrochloride Form IV. The ’241 patent, the
`
`key reference relied upon by Petitioner, does not teach crystalline vilazodone
`
`hydrochloride or even any specific method to synthesize vilazodone hydrochloride,
`
`and thus cannot anticipate the claimed crystalline compounds or associated
`
`compositions and methods. The Board should reject Petitioner’s improper attempt
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`to overcome this fundamental deficiency by using alleged “Patent Owner
`
`Admissions” to read in disclosure that clearly is not present in the prior art.
`
`These same basic flaws defeat Petitioner’s obviousness grounds, which are
`
`further deficient because they rest on “general motivation” and “obvious to try”
`
`type arguments that have been rejected consistently. Specifically, courts and the
`
`Board have concluded that because polymorphism is a “decidedly unpredictable
`
`field” involving “unpredictable trial and error experimentation,” arguments
`
`premised on “general motivation to find new crystal forms” or “obvious to try”
`
`theories fail to render new crystalline forms obvious. See, e.g., In re Armodafinil
`
`Patent Litig., 939 F. Supp. 2d 456, 502-3 (D. Del. 2013); Lupin Ltd. v. Janssen
`
`Scis. Ireland UC, No. IPR2015-01030, 2015 Pat. App. LEXIS 12746, at *28-29
`
`(P.T.A.B. Oct. 16, 2015). None of Petitioner’s obviousness grounds establishes
`
`the requisite reasonable expectation of success for a person of ordinary skill in the
`
`art (“POSA”) to arrive at the claimed crystalline vilazodone hydrochloride based
`
`on the teachings of the prior art.
`
`Finally, Petitioner relies on substantially the same prior art and arguments
`
`presented during prosecution and has not established any reason to revisit the
`
`Examiner’s determination of patentability. The ’921 patent was expressly allowed
`
`over the ’241 patent. Ex. 1006 at 8 (stating that the ’241 patent “does not teach the
`
`claimed crystalline forms”). WO 00/72832 (“Bartoszyk”) was considered by the
`
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`Examiner and is also cited on the face of the ’921 patent. See Ex. 2001 at 3; Ex.
`
`1001. Moreover, Petitioner’s alleged “admissions” are contained in the ’921
`
`specification and thus were also considered by the Examiner. Pavia and Byrn, two
`
`additional references cited by Petitioner, are both general textbooks that provide no
`
`teachings about vilazodone hydrochloride and in fact emphasize the
`
`unpredictability of crystallization. As a result, they undermine Petitioner’s own
`
`obviousness challenges. Ex. 1032 at 525; Ex. 1012 at 179, 234, 489. Therefore, it
`
`is appropriate for the Board to reject the Petition pursuant to 35 U.S.C. § 325(d).
`
`II. TECHNOLOGY BACKGROUND
`A. Antidepressant Drugs
`Major Depressive Disorder (MDD) is one of the most common mental
`
`disorders linked to the normal human emotional responses to grief and
`
`disappointment. See Ex. 2002 at 187-216. When the application leading to the
`
`’921 patent was filed in June 2001, then-available antidepressant drugs were
`
`ineffective for a large proportion of MDD patients and also led to various side
`
`effects. Ex. 2003 at 43-64. Thus, as of June 2001, there was an unmet need for
`
`additional therapies, both for patients who did not respond to traditional
`
`antidepressants and for those who experienced unacceptable side effects.
`
`Vilazodone hydrochloride, the active ingredient in VIIBRYD®, has been
`
`shown to possess a novel dual mechanism of action, as both a serotonin reuptake
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`inhibitor and 5-HT1A receptor partial agonist. Ex. 2004 at 5-6. This combined
`
`mechanism offers a pharmacologic means to intensify the effects of the serotonin
`
`neurotransmission that is thought to underlie the efficacy of the selective serotonin
`
`reuptake inhibitors. Id. Since FDA approval in 2011, VIIBRYD® has proved to be
`
`a useful treatment option for doctors and patients, due to its efficacy and
`
`potentially more favorable sexual side-effect profile compared to other
`
`antidepressants. Ex. 2005 at 1957-65.
`
`B.
`
`Solid Forms of Pharmaceutical Compounds
`1.
`Crystalline and Amorphous Forms
`An active pharmaceutical ingredient (“API”) may exist in solid state forms
`
`including crystalline and amorphous forms. A crystalline solid has a regular
`
`arrangement of atoms or molecules that repeats in three dimensions, also referred
`
`to as three-dimensional long-range order.1 See Ex. 1028 at 1. A compound may be
`
`capable of crystallizing in more than one crystal structure—a phenomenon known
`
`as “polymorphism.” The different crystalline forms that a compound can take are
`
`known as “polymorphs.” See id. Some compounds may also crystallize in
`
`different “solvated” forms, wherein one or more molecules of a solvent become
`
`incorporated into the crystal structure. See id at 1, 7. Different solid forms of a
`
`
`1 An amorphous solid lacks such three-dimensional long-range order.
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`compound often exhibit different properties due to the intimate relationship
`
`between a compound’s three-dimensional structure and its properties. Crystalline
`
`solids can provide physical and chemical stability, as well as other advantageous
`
`properties for pharmaceutical manufacturing and formulation. See, e.g., Ex. 1001
`
`at 5:4-21. Different crystalline compounds can be identified experimentally, for
`
`instance by X-ray diffraction (XRD). See, e.g., Ex. 1001, Figs. 12-26.
`
`2.
`Polymorphism Is Unpredictable
`While many pharmaceutical compounds have been found to exist in
`
`amorphous and crystalline forms, each compound provides a unique situation. By
`
`2001, it was well-recognized that ‘“there are no failsafe methods to predict the
`
`extent of polymorphism of a given compound,’” and that ‘“the existence and
`
`identity of … polymorphs have defied prediction.”’ In re Armodafinil Patent
`
`Litig., 939 F. Supp. 2d at 491 (internal citations omitted). Accordingly, it was well
`
`understood that the crystallization art is inherently unpredictable. Ex Parte Bush,
`
`APL 2009-010640, 2010 WL 321356, at *2 (B.P.A.I. Jan. 27, 2010) (reversing
`
`obviousness determination where the “Examiner fail[ed] to take into account the
`
`unpredictability of the crystallization art, such that the structure of any allegedly
`
`obvious new form, or its associated properties, cannot be determined by theory”).
`
`Even today, there is simply “no way of predicting if a molecule will crystallize, let
`
`alone in what forms or under what conditions.” Ex. 2006 at 14.
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`C. Melting Point
`Melting point refers to the “temperature at which, under a specified pressure,
`
`liquid and solid coexist in equilibrium.” Ex. 2007 at 185. As of 2001, there were
`
`many different methods for evaluating a solid’s melting point, including open
`
`capillary method; softening point method; DSC methods; and automated
`
`techniques. See Ex. 2008 at 16, 20-21. These methods could provide variable
`
`results. Thus, even for the same compound, the literature often reports various
`
`melting point values. For instance, fluorene’s melting point has been reported as
`
`114-116 oC (Ex. 2009 at 805); 116-117 oC (Ex. 2010 at 159); and 112-115 oC (Ex.
`
`2011 at 428).
`
`III. THE ’921 PATENT
`A. Challenged Claims
`Petitioner challenges claims 1, 11, 12, 14, and 15 of the ’921 patent.
`
`Independent claims 1 and 11 read as follows:
`
`1. A compound which is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride in its
`crystalline modification, wherein the compound is an anhydrate,
`hydrate, solvate or dihydrochloride.
`11. A pharmaceutical composition comprising a compound which
`is 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride anhydrate in its crystalline
`modification IV, and one or more conventional auxiliary
`substances and/or carriers.
`
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`Claim 12 recites a method of treating a patient suffering from certain recited
`
`disorders, comprising administering to the patient in need thereof the
`
`pharmaceutical composition of claim 11. Claim 14 recites a method of treating a
`
`patient suffering from certain recited disorders, comprising administering to the
`
`patient in need thereof an effective amount of a compound of claim 1. Claim 15
`
`recites a pharmaceutical composition comprising a compound according to claim
`
`1, and one or more conventional auxiliary substances and/or carriers.
`
`B.
`’921 Patent Specification
`The ’921 patent describes the invention of crystalline forms of vilazodone
`
`hydrochloride, along with pharmaceutical compositions and methods of using the
`
`same to treat conditions including depressive disorders. See Ex. 1001, Abstract;
`
`1:29-31; 2:44-3:35; 14:58-16:15. The specification further describes crystalline
`
`vilazodone hydrochloride forms including solvates (see e.g., id. at 4:21-49),
`
`anhydrates (see e.g., id. at 11:37-42), hydrates (see e.g., id. at 9:13-22), and
`
`dihydrochloride (see e.g., id. at 13:60-65). The specification includes experimental
`
`data for numerous crystalline forms, including IR absorption spectra, X-ray
`
`diffractograms, thermal analysis diagrams, and Raman spectra. See id., Figs. 1-46;
`
`21:14 to 27:11. The specification also describes advantages of the vilazodone
`
`hydrochloride crystalline forms. Id. at 5:4-25.
`
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`In the background section of the specification, the ’921 patent discusses the
`
`’241 patent and Bartoszyk (PCT Publication WO 00/72832). Ex. 1001 at 1:35-48.
`
`The background section goes on to describe experimental details and evaluation of
`
`“former” vilazodone hydrochloride material, which are not described in the ’241
`
`patent. See, e.g., Ex. 1001 at 1:50-2:5 (“700 mg of the base are dissolved in 30 ml
`
`2-propanol under heating and then treated with 0.1 n 2-propanolic HCl solution
`
`(Merck-Art. No. 1.00326) until precipitation of hydrochloride is complete.”).
`
`C.
`File History
`During prosecution, a set of claims substantially corresponding to the
`
`allowed claims of the ’921 patent was submitted in a Preliminary Amendment and
`
`subsequently allowed without any Office Action. Ex. 2012 at 3-5. The Notice of
`
`Allowance states that “[t]he instantly claimed crystalline compounds,
`
`compositions, and methods for using the same, are novel and nonobvious over the
`
`prior art. The closest prior art is U.S. Patent no. 5,532,241, which does not teach
`
`the claimed crystalline forms. This reference does not encompass the scope of the
`
`instant application. This reference lacks identical or obvious crystalline forms of
`
`1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine.” Ex.
`
`1006 at 2 (emphasis added).
`
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`A POSA of the ’921 patent would have had at least a bachelor’s degree in
`
`chemistry, pharmaceutical sciences, or a related discipline, along with several
`
`years of experience working in pharmaceutical solid product development and/or
`
`solid-state chemistry. A POSA also would have had knowledge and experience
`
`(and/or access to others with knowledge and experience) in treating patients for
`
`depression or other conditions identified in the ’921 patent and evaluating the
`
`effects of such treatment.
`
`The Petition sets forth a similar definition of a POSA, but also identifies a
`
`POSA as including an individual with an “M.D. with extensive experience in the
`
`study and treatment of mood disorders.” Petition at 11-12. This definition is
`
`flawed because it does not require any experience in solid-state chemistry, which is
`
`the primary focus of the ’921 patent claims. Thus, a medical doctor treating mood
`
`disorders is not a POSA unless she also has the requisite experience in solid-state
`
`chemistry outlined above.
`
`However, for the reasons described below, the claims are patentable even
`
`under Petitioner’s proposed definition.
`
`V. CLAIM CONSTRUCTION
`In an IPR proceeding, the terms of the challenged claims are to be given
`
`their broadest reasonable interpretation in light of the specification as commonly
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`understood by those of ordinary skill in the art. See 37 C.F.R. § 42.100(b); Cuozzo
`
`Speed Techs., LLC v. Lee, 136 S. Ct. 2131 (2016).2 Petitioner proposes to construe
`
`the term “crystalline modification” as “crystalline form,” and the term
`
`“administering” as “delivering into the body” of a patient. Petition at 9-11. For
`
`purposes of this preliminary response, Patent Owner does not advance
`
`constructions for any other terms in the challenged claims, but notes that several
`
`claim terms were interpreted in district court proceedings involving the ’921
`
`patent.3
`
`
`2 On May 8, 2018, the United States Patent and Trademark Office announced its
`
`proposed rulemaking to replace the broadest reasonable interpretation standard for
`
`construing unexpired patent claims in an IPR proceeding with the standard under
`
`Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc) that is applied in
`
`federal district courts and International Trade Commission proceedings. Patent
`
`Owner reserves all rights with respect to any claim construction issue that may be
`
`impacted by this proposed rule change.
`
`3 During district court litigation involving the ’921 patent, Forest Laboratories,
`
`LLC et al. v. Accord Healthcare, Inc. et al., No. 15-cv-272-GMS (consolidated) (D.
`
`Del. 2015), the parties agreed upon the construction of certain claim terms and
`
`additional claim terms were construed by the court. See Ex. 2013; Ex. 2014.
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`VI. PRIMARY REFERENCES ASSERTED BY PETITIONER
`A. The ’241 Patent
`The ’241 patent to Boettcher et al. is assigned to Merck Patent Gesellschaft
`
`mit beschraenkter Haftung and describes a compound of formula I:
`
`, where the various substituents are defined therein. Ex.
`
`1004 at 1:5-29. This chemical genus includes vilazodone, which is identified as l-
`
`[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine. Ex. 1004
`
`at 11:16-24.
`
`Example 3 of the ’241 patent teaches a method to synthesize a different
`
`compound, l-[4-(5-carbamoylindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)-
`
`piperazine:
`
`2.8 g of l-[4-(5-carboxyindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-
`yl)piperazine are suspended in 100 ml of N-methylpyrrolidine. 3.2 g of
`2-chloro-1-methylpyridinium methanesulfonate are then added and the
`mixture is stirred at room temperature for 12 hours. Dried NH3 gas is
`then passed into the resulting solution until it is saturated and the
`mixture is stirred again for 10 hours. Customary working up gives 1-[4-
`(5-carbamoylindol-3-yl)butyl]-4-(2,3-dihydrobenzofuran-5-yl)-
`piperazine.
`
`
`Id. at 10:57-67. The Example 3 procedure uses excess base (N-
`
`methylpyrrolidine and NH3 gas) and no acid, such that the free base compound is
`
`synthesized. The ’241 patent states that three other free base (amine) compounds
`
`were prepared “analogously” to the procedure in Example 3. Id. at 11:1-16.
`
`11
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`The ’241 patent states that “[i]n the following Examples, ‘working-up in
`
`conventional manner’ means: … the filtrate is evaporated and the residue is
`
`purified by chromatography on silica gel and/or by crystallization.” Id. at 9:3-8.
`
`Thus, the ’241 patent indicates that if the phrase “working-up in conventional
`
`manner” is used in an example, then this includes that “the residue is purified by
`
`chromatography on silica gel and/or crystallization.” However, Example 3 does
`
`not use the term “working-up in conventional manner.”
`
`Example 4 of the ’241 patent describes the synthesis of vilazodone
`
`hydrochloride:
`
`Analogously to Example 3, starting from 1-[4-(5-cyanoindol-3-yl)butyl]-
`4-(2-carboxybenzofuran-5-yl)piperazine reaction with 2-chloro-l-
`methyl-pyridinium methane sulfonate gives 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoylbenzofuran-5-yl)piperazine, m.p. 269-272°
`(hydrochloride).
`
`
`Id. at 11:17-24. In Example 4, the procedure analogous to Example 3 would
`
`produce the vilazodone free base, which then was converted to its hydrochloride
`
`salt. Example 4 does not describe any particular method for preparing vilazodone
`
`hydrochloride from vilazodone free base, nor does it (or any other part of the ’241
`
`patent) describe any crystalline vilazodone hydrochloride. Like Example 3,
`
`Example 4 does not use the term “working-up in conventional manner.” Id.
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`B.
`Bartoszyk
`Bartoszyk is a PCT application by Merck Patent GmbH directed to the use
`
`of vilazodone and its physiologically acceptable salts. Ex. 1005 at 2, ll. 4-7.
`
`Bartoszyk teaches the treatment of various disorders, including “the sub-types
`
`panic disorder with and/or without agoraphobia, agoraphobia, obsessive-
`
`compulsive spectrum disorders, social phobia, posttraumatic stress disorder, acute
`
`stress indication and/or generalized-anxiety disorder.” Id. at 3, ll. 9-14. Bartoszyk
`
`refers to Example 4 of the ’241 patent for the preparation of vilazodone
`
`hydrochloride. Id. at 2, ll. 9-12.
`
`VII. THE PETITION SHOULD BE DENIED BECAUSE NO GROUND
`HAS A REASONABLE LIKELIHOOD OF SUCCESS
`A. Ground 1: Claims 1, 14, and 15 Are Not Anticipated by the ’241
`Patent and the So-Called Patent Owner Admissions
`Petitioner’s Ground 1 must fail because the ’241 patent does not disclose,
`
`expressly or inherently, crystalline vilazodone hydrochloride as recited in the
`
`challenged claims. Petitioner cannot use the so-called Patent Owner Admissions to
`
`import into the prior art non-existent disclosure that simply is not present in the
`
`’241 patent.
`
`Claims 1, 14, and 15 of the ’921 patent recite, inter alia, crystalline
`
`vilazodone hydrochloride. Thus, for the ’241 patent to anticipate any of the
`
`challenged claims, it must disclose “each and every limitation”—including
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`IPR2018-00423
`Patent Owner’s Preliminary Response
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`crystalline vilazodone hydrochloride—“expressly or inherently.” See King
`
`Pharm., Inc. v Eon Labs, Inc., 616 F.3d 1267, 1274 (Fed Cir. 2010) (citation
`
`omitted); see also 37 C.F.R. § 42.104(b)(4) (“The petition must specify where each
`
`element of the claim is found in the prior art patents or printed publications relied
`
`upon.”). To establish inherency, Petitioner must show that the allegedly inherent
`
`claim limitation is “‘necessarily present,’ not merely probably or possibly present,
`
`in the prior art.” Trintec Indus., Inc. v. Top-U.S.A. Corp., 295 F.3d 1292, 1295
`
`(Fed. Cir. 2002) (citation omitted). The Petition includes several arguments in
`
`Ground 1, none of which can establish anticipation.
`
`1.
`
`The ’241 Patent Examples Do Not Disclose Crystalline
`Vilazodone HCl
`The Petition first alleges that the ’241 patent teaches crystalline vilazodone
`
`hydrochloride because “[t]he ’241 patent teaches that the Examples disclosed in
`
`the ’241 patent were ‘work[ed]-up in [a] conventional manner,’” which includes
`
`“purifi[cation] by chromatography on silica gel and/or by crystallization.” Petition
`
`at 20. The disclosure of the ’241 patent regarding “working-up in [a] conventional
`
`manner” does not establish disclosure of crystalline vilazodone hydrochloride for
`
`at least three reasons.
`
`First, Petitioner’s argument that the Examples disclosed in the ’241 patent
`
`were “work[ed]-up in [a] conventional manner” is incorrect. The ’241 patent at
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`IPR2018-00423
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`most teaches that if the phrase “working-up in conventional manner” is used in an
`
`example, then this includes that “the residue is purified by chromatography on
`
`silica gel and/or crystallization.” Ex. 1004 at 9:3-8; see also Section VI.A.
`
`Neither Example 4 (production of vilazodone hydrochloride) nor Example 3
`
`(referenced in Example 4) includes “working-up in conventional manner.”
`
`Therefore, the ’241 patent simply does not teach that the compounds of these
`
`examples were “work[ed]-up in conventional manner” or purified by
`
`“chromatography on silica gel and/or crystallization.”
`
`Second, although Example 3 teaches the use of “[c]ustomary working up” in
`
`the preparation of a free base amine (id. at 10:65-67), the ’241 patent does not
`
`equate “customary working up” with “working-up in conventional manner,” and
`
`Petitioner does not argue otherwise. Thus, Examples 3 and 4 do not teach, and
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`IPR2018-00423
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`certainly do not necessarily teach, the use of “working