`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`MERCK PATENTGESELLSCHAFT,
`Patent Owner.
`
`
`
`Case No. Unassigned
`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
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,673,921
`
`
`
`
`
`
`
`
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`
`
`TABLE OF CONTENTS
`
`GROUNDS FOR STANDING UNDER 37 C.F.R. §§ 42.101
`
`I. MANDATORY NOTICES (37 C.F.R. § 42.8)............................................. 1
`A.
`Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1) ......................... 1
`B.
`Related Matters under 37 C.F.R. § 42.8(b)(2) .................................... 1
`C.
`Lead and Backup Counsel .................................................................. 2
`D.
`Service Information ........................................................................... 2
`II.
`AND 42.104 ................................................................................................ 3
`A. Grounds for Standing under 37 C.F.R. § 42.104(a) ............................ 3
`B.
`Identification of Challenge under 37 C.F.R. § 42.104(b) .................... 3
`III. THE ‘921 PATENT ..................................................................................... 4
`A.
`Brief Description ............................................................................... 4
`B.
`Summary of Prosecution History ....................................................... 7
`IV. CLAIM CONSTRUCTION ......................................................................... 8
`A.
`Legal Principles ................................................................................. 8
`B.
`Construction of the Term “Crystalline modification” ......................... 9
`C.
`Construction of the Term “Administering” .......................................11
`LEVEL OF SKILL IN THE ART ...............................................................11
`V.
`VI. TECHNOLOGY BACKGROUND.............................................................12
`A.
`Crystals .............................................................................................12
`B.
`Characterizing crystals ......................................................................14
`C.
`Crystallization techniques .................................................................14
`D. Vilazodone hydrochloride (VHCl) ....................................................16
`VII. CLAIM-BY-CLAIM EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ...............................................................................17
`A. Ground 1: Claims 1, 14, and 15 Are Anticipated By the
`‘241 Patent as Characterized by Patent Owner’s Admissions ............17
`
`Page
`
`
`
`
`i
`
`

`

`B.
`C.
`
`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`Ground 2: Claims 1, 14, and 15 are Obvious over the
`‘241 Patent as characterized by Patent Owner’s Admissions
`
`Ground 3: Claims 1 and 11 are Obvious Over the
`‘241 Patent as Characterized by Patent Owner’s Admissions,
`
`a.
`
`b.
`
`Experiments showing crystalline forms present in
`Example 4 of the ‘241 patent ........................................35
`
`The Second and Fifth Experiments Would Create
`Form IV Even If Form VIII Was Not the Starting
`Material ........................................................................43
`
`and Bartoszyk ...................................................................................23
`Pavia, and Byrn .................................................................................31
`1.
`Claim 11 .................................................................................32
`2.
`Crystallization .........................................................................44
`Obvious to Try ........................................................................45
`3.
`Known Method to Improve a Prior Art Product ......................47
`4.
`Claim 1 ...................................................................................48
`5.
`D. Ground 4: Claim 1, 12, 14, and 15 are Obvious in View of
`Admissions, Bartoszyk, Pavia, and Byrn ...........................................50
`1.
`Claim 12 .................................................................................50
`2.
`Claim 1 ...................................................................................54
`3.
`Claim 14 .................................................................................56
`4.
`Claim 15 .................................................................................59
`VIII. NO SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS ........63
`A. No Unexpected Results Compared to the Closest Prior Art ...............63
`No Required Nexus ...........................................................................65
`B.
`IX. NO BASIS TO DENY THE PETITION UNDER 35 U.S.C. § 325(D) .......66
`CONCLUSION ..........................................................................................67
`X.
`
`Teaching, Suggestion, Motivation to Purify Via
`
`the ‘241 Patent, as Characterized by Patent Owner’s
`
`
`
`
`
`ii
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`TABLE OF EXHIBITS
`
`
`Exhibit
`
`United States Patent No. 8,673,921 (“’921 patent)
`
`Declaration of Robin Rogers, Ph.D.
`
`Declaration of Sanjay Mathew, M.D.
`
`United States Patent No. 5,532,241 (“‘241 patent”)
`
`WO 00/72832 to Bartoszyk (“Bartoszyk”)
`
`Notice of Allowance in U.S. Patent No. 8,673,921
`
`Defendants’ Claim Construction Opening Brief, Forest
`Laboratories et al. v. Accord Healthcare Inc., Case No. 1:15-cv-
`00272 (D. Del.)
`
`Defendants’ Answering Claim Construction Brief, Forest
`Laboratories et al. v. Accord Healthcare Inc., Case No. 1:15-cv-
`00272 (D. Del.)
`
`Stipulation and Order, Forest Laboratories et al. v. Accord
`Healthcare Inc., Case No. 1:15-cv-00272 (D. Del.)
`
`Polymorphism in Pharmaceutical Solids, (Brittain, H., ed.), Drugs
`and the Pharmaceutical Sciences, Vol. 95 (1999) (“Brittain”)
`
`Gould, P. et al., Salt Selection for Basic Drugs, Int’l J. of
`Pharmaceutics, Vol. 33 (1986) (“Gould”)
`
`Byrn et al., Solid-State Chemistry of Drugs, Chapter 10,
`“Polymorphs,” 143-231 (2d ed. 1999)
`
`Pharmaceutical Dosage Forms: Tablets, (Lieberman, H. et al. ed.),
`Vol. 1 (2d ed. 1989) (“Lieberman”)
`
`Claims Charts
`
`Claim Construction Order, Forest Laboratories et al. v. Accord
`Healthcare Inc., Case No. 1:15-cv-00272 (D. Del.)
`
`Intentionally omitted
`
`Intentionally omitted
`
`Byrn et al., Solid-State Chemistry of Drugs (1d ed. 1982)
`
`Ex #
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`
`
`iii
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`Intentionally omitted
`
`VIIBRYD® (vilazodone), Full Prescribing Information,
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/02256
`7s000lbl.pdf
`
`File History of U.S. Patent Application No. 14/032,183
`
`File History of U.S. Patent No. 5,532,241
`
`Curriculum Vitae of Dr. Robin D. Rogers
`
`Curriculum Vitae of Dr. Sanjay Mathew
`
`Intentionally omitted
`
`Intentionally omitted
`
`Vippagunta, S. et al., Crystalline Solids, Advanced Drug Delivery
`Reviews, Vol. 48, pg. 3-26 (2001) (“Vippagunta”)
`
`Hancock B. & Zografi G., Characteristics and Significance of the
`Amorphous State in Pharmaceutical Systems, J. Pharm. Sci., Vol.
`86, pg. 1-12 (1997) (“Hancock”)
`
`Beckmann, W. & Budde U., Crystallization, Encyclopedia of
`Separation Science, 1999, Vol. 3 (“Beckmann”)
`
`United States Patent No. 4,132,792 (“Zinnes”)
`
`Armarego, W.L.F. & Perrin, D.D., PURIFICATION OF LABORATORY
`CHEMICALS, 4th Edition (1996) (“Armarego”)
`
`Pavia, D et al., INTRODUCTION TO ORGANIC LABORATORY
`TECHNIQUES A CONTEMPORARY APPROACH, 3d. edition (1988)
`(“Pavia”)
`
`Intentionally omitted
`
`Scanned Pages of the Laboratory Notebook of Dr. Gabriela Gurau,
`Ph.D. from October 23, 2017 to December 12, 2017
`
`United States Application No. 2014/071,930 (“’930 Application”)
`
`Wang, S et al., Vilazodone for the Treatment of Depression: An
`Update, Chonnam Med. J., Vol. 52, pg. 91-100 (2016)
`
`
`
`iv
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`Deardorff, W. & Grossberg, G., A review of the clinical efficacy,
`safety and tolerability of the antidepressants vilazodone,
`levomilnacipran and vortioxetine, Vol. 15, pg. 2525-2542 (2014)
`
`Aerde, P. et al., Polymorphic Behaviour of Chloroquine
`Diphosphate, J. Pharm. Pharmacol., Vol. 36, pg. 190-191 (1984)
`
`Declaration of Dr. Gabriela Gurau, Ph.D.
`
`United States Pharmacopeia <941>, (24th ed. 2000)
`
`Data from experiments performed in Ex. 1034
`
`Terence L. Threlfall, Analysis of Organic Polymorphs, A Review,
`120 Analyst 2435-60 (Oct. 1995)
`
`David D. Kendall, Identification of Polymorphic Forms of
`Crystals by Infrared Spectroscopy, 25 Analytical Chemistry 382-
`89 (1953)
`
`1044
`
`United States Pharmacopeia <197>, (29th ed. 2006)
`
`
`
`v
`
`
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`Argentum Pharmaceuticals LLC (“Petitioner”) petitions for inter partes
`
`review (“IPR”) of claims 1, 11, 12, 14, and 15 of U.S. Patent No. 8,673,921 (“the
`
`‘921 patent”) (Ex. 1001), which is assigned to Merck Patentgesellschaft (“Merck”
`
`or “Patent Owner”) per an assignment recorded at reel/frame 031966/0799.
`
`This Petition is filed in accordance with 37 C.F.R. § 42.106(a). Filed
`
`herewith is a power of attorney and exhibit list per §§ 42.10(b) and 42.63(e).
`
`Pursuant to 37 C.F.R. § 42.103, the fee set forth in § 42.15(a) accompanies this
`
`Petition.
`
`I. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1)
`
`The real parties in interest are Argentum Pharmaceuticals LLC, Intelligent
`
`Pharma Research LLC, APS GP LLC, and APS GP Investors LLC.
`
`B. Related Matters under 37 C.F.R. § 42.8(b)(2)
`
`The ‘921 patent has been the subject of the following proceedings: Forest
`
`Laboratories, Inc. et al v. InvaGen Pharmaceuticals Inc., Civ. Action No. 15-cv-
`
`272; Forest Laboratories, Inc. et al v. Alembic Pharmaceuticals Ltd. et al., Civ.
`
`Action No. 15-cv-273; Forest Laboratories, Inc. et al v. Apotex Inc. et al., Civ.
`
`Action No. 15-cv-274; Forest Laboratories, Inc. et al v. Teva Pharmaceuticals
`
`USA Inc., Civ. Action No. 15-cv-275; Forest Laboratories, Inc. et al v. InvaGen
`
`Pharmaceuticals Inc., Civ. Action No. 15-cv-277; and Forest Laboratories, Inc. et
`
`
`
`1
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`al v. InvaGen Pharmaceuticals Inc., Civ. Action No. 15-cv-1078.
`
`C. Lead and Backup Counsel
`
`Lead Counsel
`
`Teresa Stanek Rea, Reg. No. 30,427
`Crowell & Moring LLP
`Intellectual Property Group
`1001 Pennsylvania Ave, NW
`Washington, DC 20004-2595
`(202) 624-2620
`TRea@Crowell.com
`
`Back-Up Counsel
`
`
`
`Tyler C. Liu, Reg. No. 72,126
`Argentum Pharmaceuticals LLC
`25 Massachusetts Avenue, NW
`Suite 450
`Washington, DC 20001
`tliu@agpharm.com
`
`
`Karla I. Arias, Reg. No. 72,679
`Crowell & Moring LLP
`Intellectual Property Group
`1001 Pennsylvania Ave, NW
`Washington, DC 20004-2595
`(202) 624-2899
`KArias@Crowell.com
`
`Deborah Yellin, Reg. No. 45,904
`Crowell & Moring LLP
`Intellectual Property Group
`1001 Pennsylvania Ave, NW
`Washington, DC 20004-2595
`(202) 624-2947
`DYellin@Crowell.com
`
`
`
`D.
`
`Service Information
`
`Please direct all correspondence regarding this Petition to lead counsel and
`
`back-up counsel at the above address. Petitioner consents to service by email at the
`
`email addresses listed above.
`
`
`
`2
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`II. GROUNDS FOR STANDING UNDER 37 C.F.R. §§ 42.101 AND 42.104
`
`A. Grounds for Standing under 37 C.F.R. § 42.104(a)
`
`Petitioner certifies that the ‘921 patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting inter partes review on
`
`the grounds identified in this petition.
`
`B.
`
`Identification of Challenge under 37 C.F.R. § 42.104(b)
`
`Petitioner requests cancellation of claims 1, 11, 12, 14, and 15 of the ‘921
`
`patent on the following grounds:
`
`Ground
`
`Claims
`
`Basis
`
`Reference(s)
`
`1
`
`2
`
`3
`
`4
`
`1, 14, 15
`
`§ 102
`
`1, 14, 15
`
`§ 103
`
`1 and 11
`
`§ 103
`
`1, 12, 14, and
`15
`
`§ 103
`
`5,532,241 (“‘241 patent”) (Ex. 1004) as
`characterized by Patent Owner’s
`Admissions (Ex. 1001)
`
`‘241 patent (Ex. 1004) as characterized
`by Patent Owner’s Admissions (Ex.
`1001) in view of Bartoszyk (Ex. 1005)
`
`‘241 patent (Ex. 1004) as characterized
`by Patent Owner’s Admissions (Ex.
`1001) in view of Pavia (Ex. 1032), and
`Byrn (Ex. 1012)
`
`‘241 patent (Ex. 1004) as characterized
`by Patent Owner’s Admissions (Ex.
`1001) in view of Bartoszyk (Ex. 1005),
`Pavia (Ex. 1032), and Byrn (Ex. 1012)
`
`
`
`
`
`3
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`III. THE ‘921 PATENT
`
`A. Brief Description
`
`The ‘921 patent is listed in the FDA’s Orange Book as covering the
`
`vilazodone hydrochloride product Viibryd®. The ‘921 patent issued from U.S.
`
`Patent Application No. 14/032,183 (“‘183 Application”), filed September 19,
`
`2013, which purports to claim priority through a series of continuation and
`
`divisional applications to European Patent No. 01113674, filed June 19, 2001. Ex.
`
`1002, ¶¶28-30.
`
`The ‘921 patent is directed to crystalline modifications of vilazodone
`
`hydrochloride, amorphous vilazodone hydrochloride, a crystalline modification of
`
`vilazodone dihydrochloride. Ex. 1002, ¶31; Ex 1003, ¶22.
`
`The background section of the ‘921 patent makes several admissions
`
`(“Patent Owner’s Admissions” or “POAs”) regarding the ‘241 patent, including:
`
`(1) The ‘241 patent teaches 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`benzofuran-5yl)-piperazine (“vilazodone”) and its physiologically acceptable salts.
`
`Ex. 1001, 1:35-57.
`
`(2) Example 4 of the ‘241 patent teaches how to make vilazodone
`
`hydrochloride (“VHCl”), and that the product achieved is a mixture of crystalline
`
`HCl salt, amorphous HCl salt, and free base. Ex. 1001, 1:65-2:5.
`
`(3) The product of Example 4 of the ‘241 patent was a mixture of crystalline
`
`
`
`4
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`VHCl, amorphous VHCl, and vilazodone free base. Ex. 1001, 1:65-2:5.
`
`(4) The ‘241 patent discloses the use of VHCl in treating certain medical
`
`disorders. Ex. 1001, 1:35-57; Ex. 1002, ¶33; Ex. 1003, ¶23.
`
`Additionally, the Background section of the ‘921 patent discusses the
`
`motivation to discover certain crystalline forms of compounds like vilazodone:
`
`“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 uses 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
`
`morphological
`
`forms
`
`for
`
`inclusion
`
`in pharmaceutical
`
`formulations.”
`
`Id., 2:6-21 (emphases added). Throughout the ‘921 patent, the use of the term
`
`“form” is synonymous with “modification” or “crystalline modification.” Id., 2:41-
`
`43; Ex. 1002, ¶¶34, 41, 278; Ex. 1003, ¶31.
`
`
`
`5
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`The claims of the ‘921 patent are directed to crystalline modifications of
`
`VHCl. The ‘921 patent discloses that these crystalline modifications are suitable to
`
`treat or prevent a wide range of disorders, including depressive, anxiety, and
`
`bipolar disorders, mania, dementia, sexual dysfunctions, substance-related and
`
`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. Id.,
`
`Abstract; Ex. 1002, ¶35; Ex. 1003, ¶26.
`
`Claim 1 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.
`
`Ex. 1001, cl. 1.
`
`Dependent claim 14 recites a method of treating a patient with
`
`certain disorders using the compound of claim 1. Dependent
`
`claim 15 additionally recites a pharmaceutical composition
`
`comprising the compound of claim 1 and one or more
`
`conventional auxiliary substances and/or carriers. Ex. 1001, cl.
`
`14.
`
`Claim 11 recites:
`
`
`
`6
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`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 IV, and one or more conventional auxiliary
`
`substances and/or carriers.
`
`Dependent claim 12 recites a method of treating the same list of disorders as in
`
`claim 14, using the composition of claim 11. Ex 1001, cls. 11-12.
`
`
`
`The ’921 patent does not provide any in vitro or in vivo data, on humans or
`
`animals, regarding the efficacy and activity of VHCl in treating the disorders that
`
`are claimed in the patent. Ex. 1003, ¶32. The ’921 patent states that Form IV “has
`
`superior properties over other crystalline forms and is more suitable for inclusion
`
`in pharmaceutical formulations,” but provides no data or explanation to support
`
`either of these assertions. Ex. 1001, 12:38-41; Ex. 1002, ¶¶42-43; Ex. 1003, ¶33.
`
`B.
`
`Summary of Prosecution History
`
`No claim of the ‘921 patent faced a single rejection during examination. A
`
`Notice of Allowability was mailed on December 13, 2013, stating the following:
`
`The instantly claimed crystalline compounds, compositions,
`
`and methods for using the same are novel and non-obvious 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
`
`
`
`7
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`
`forms of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`benzofuran-5yl)-piperazine. A person of ordinary skill in the art
`
`would not have expected that making modifications would
`
`retain identical activity as disclosed in the prior art.
`
`Ex. 1006, 2 (emphases added).
`
`
`In the Reasons for Allowability, the Examiner stated that the closest prior art
`
`was the ‘241 patent. Id. However, the Examiner incorrectly stated that the ‘241
`
`patent did not teach the claimed crystalline forms.1
`
`IV. CLAIM CONSTRUCTION
`
`A. Legal Principles
`
`In an inter partes review, claim terms in an unexpired patent are interpreted
`
`according to their broadest reasonable construction in light of the specification of
`
`the patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC
`
`v Lee, 136 S. Ct. 2131, 2133-46 (2016). To be clear, any claim terms not included
`
`in the following discussion should be given their broadest reasonable construction
`
`in light of the specification of the ‘921 patent.
`
`The claims of the ‘921 Patent were previously construed by the U.S. District
`
`
`1 As discussed supra at III.A., Patent Owner’s Admissions in the ’921 patent
`
`clearly show that Example 4 of the ‘241 patent contained a crystallized form of
`
`VHCl.
`
`
`
`8
`
`

`

`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
`
`Court for the District of Delaware in Forest Laboratories, LLC et al. v. Accord
`
`Healthcare, et al., No. 15-272-GMS (D. Del.). That claim construction was based
`
`on the narrower “Phillips standard” under Phillips v. AWH Corp., 415 F.3d 1303
`
`(Fed. Cir. 2005) (en banc).
`
`B. Construction of the Term “Crystalline modification”
`
`The broadest reasonable interpretation of the term “crystalline modification”
`
`is “crystalline form.” This may include the categories of crystalline forms that
`
`VHCl can take. This interpretation follows directly from the plain meaning of the
`
`term, and the intrinsic evidence provides no reason to diverge from the plain
`
`meaning. Indeed, the ‘921 patent states that “form” is generally used as a synonym
`
`for the term “modification” or “crystalline modification.” Ex. 1001, 2:41-43; Ex.
`
`1002, ¶46.
`
`This construction is identical to the one proposed by Patent Owner in the
`
`‘921 litigation under the Phillips standard. Ex. 1015, 3.2 In the ‘921 litigation, the
`
`
`2 The District Court agreed with Patent Owner’s proposed construction,
`
`finding that “crystalline modification” would be construed as crystalline form,
`
`which referred “broadly to the categories of crystalline forms that 1-[4-(5-
`
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`
`can take.” Ex. 1015 at 6, footnote 5.
`
`(Continued...)
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`
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`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
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`plaintiffs (in this petition, the Patent Owner) proposed that the term “crystalline”
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`does not require construction and “crystalline modification” should be construed as
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`“crystalline form.” Ex. 1015, 6. Having argued for that construction in the ‘921
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`litigation, Patent Owner cannot now argue for a narrower claim construction, as the
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`broadest reasonable interpretation of this phrase cannot be narrower than the
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`construction of the phrase under the Phillips standard. Facebook, Inc. v.
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`Pragmatus AV, LLC, 582 F. App’x 864, 869 (Fed. Cir. 2014).
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`The broadest reasonable interpretation of “crystalline” and “crystalline
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`modification” should not be interpreted to mean that Forms I to XVI must be
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`“entirely crystalline” and no particular level of purity should be attributed to the
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`crystalline compound recited in claims 1, 11, 12, 14, and 15. There is no support
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`in the claims, specification, or prosecution history to support such a construction.
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`Indeed, neither the claim terms nor the specification of the ’921 patent mentions
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`the purity of the crystalline compound recited in claims 1, 11, 12, 14, and 15. See
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`generally EX 1001; Ex. 1002, ¶47. When a patent recites a compound comprising
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`a specific polymorphic form, that recitation does not foreclose the possibility that
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`other active ingredients are also present. See In re Armodafinil Patent Litig., Inc.,
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`939 F. Supp. 2d 456, 474 (D. Del. 2013) (explaining that the claim term
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`U.S. Patent No. 8,673,921
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`“comprising” allows for other forms of armodafinil to be present in the recited
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`composition); see also Ex Parte Reddy, 2010 Pat. App. LEXIS 13975, at *9-10
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`(B.P.A.I. Mar. 31, 2010) (“The claims do not require a specific amount of
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`crystalline compound or purity of the compound. If the solids or crystals of [the
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`prior art] have even a small portion of the claimed compound in the product, the
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`product is anticipated”).
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`C. Construction of the Term “Administering”
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`The broadest reasonable interpretation of “administering” is “delivering into
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`the body” of a patient, which is consistent with the ordinary meaning of the term in
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`the context of the ’921 patent. Ex. 1002, ¶48; Ex. 1003, ¶3. This construction is
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`identical to the one proposed by Patent Owner under the Phillips standard. Ex.
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`1015, 1. Patent Owner cannot now argue for a narrower claim construction, as the
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`broadest reasonable interpretation of this phrase cannot be narrower than the
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`construction of the phrase under the Phillips standard.
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`V. LEVEL OF SKILL IN THE ART
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`A person of ordinary skill in the art (“POSA”) at the time of the alleged
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`invention of the ‘921 patent would have at least a bachelor’s degree in chemistry,
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`pharmaceutical sciences, or related discipline, and several years of experience
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`working in pharmaceutical solid product development and/or solid-state chemistry.
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`The POSA would have expertise and experience in synthesis, crystallization, and
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`Petition for Inter Partes Review
`U.S. Patent No. 8,673,921
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`characterization of salts and polymorphic forms. A POSA could have a lower
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`level of formal education if such a person had a higher degree of relevant working
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`experience. Ex. 1002, ¶¶25-27.
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`A POSA would collaborate with others having expertise in methods of
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`treating mood disorders, including depression. Such a POSA would have an M.D.
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`with extensive experience in the study and treatment of mood disorders. A POSA
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`would understand the references referred to herein and would be able to draw
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`inferences from them. Ex. 1002, ¶27; Ex. 1003, ¶¶17-18.
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`VI. TECHNOLOGY BACKGROUND
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`A. Crystals
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`Prior to June 19, 2001, it was well known that many pharmaceutical solids
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`exhibit polymorphism, the ability of a substance to exist as two or more crystalline
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`phases that have different arrangements and/or conformations. Ex. 1010, 1-2; Ex.
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`1013, 34, 38; Ex. 1002, ¶¶115-119. The different crystal forms are called
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`“polymorphs.” Ex. 1010, 1; Ex. 1002, ¶¶49-50. The importance of screening for
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`polymorphs was known, as different forms have different physical properties. Ex.
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`1027, 14; Ex. 1002, ¶¶124, 127; see also Ex. 1003, ¶¶55-56.
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`Crystals are solids made up of highly organized molecules arranged in a
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`regularly repeating three-dimensional array. Id., ¶¶51-53. These arrangements of
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`regularly repeating molecules form what are known as crystal lattices. Id. The
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`smallest repeating unit of the crystalline lattice is known as the unit cell. Ex. 1027,
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`4; Ex. 1002, ¶¶54-56. Molecules of a compound may arrange themselves in more
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`than one way, giving rise to different crystalline structures or “forms.” Ex. 1010, 2;
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`Ex. 1027, 4; Ex. 1002, ¶¶57, 121. Many substances, including pharmaceutical
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`compounds, can exist in more than one crystal form, each form having a different
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`crystalline lattice and unit cell. Ex. 1010, 1-2; Ex. 1002, ¶57.
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`Pharmaceutical solids can also exist in amorphous form; however, these are
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`not considered crystalline structures because they possess no distinguishable
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`crystal lattice or unit cell. Ex. 1010, 8; Ex. 1002, ¶61.
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`When crystals of a compound are forming, i.e. crystallizing from a solution,
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`molecules may become entrapped within the crystal lattice. Ex. 1010, 205; Ex.
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`1002, ¶58. Solvates are crystalline solids that contain amounts of a solvent
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`incorporated within the crystal structure. Id. If the solvent is water, the solvates are
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`known as “hydrates.” Ex. 1027, 4; Ex. 1002, ¶¶58-59. Unsolvated crystals are
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`termed “anhydrous crystal forms.” Id.; Ex. 1002, ¶¶122-123.
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`A compound that is initially prepared as one crystal form may convert to
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`another, such as when exposed to heat, pressure, solvents, or time. Ex. 1002, ¶60.
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`It is also possible for a compound to exist as a mixture of different crystal forms.
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`Ex. 1010, 187; Ex. 1002, ¶60. This mixture is caused by the method by which the
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`substance is made and isolated, and the subsequent conditions to which the
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`U.S. Patent No. 8,673,921
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`substance is exposed. Id.
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`B. Characterizing crystals
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`Because each polymorph has its own unique unit cell and three-dimensional
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`lattice, a crystal form can be identified by characteristics associated with that
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`crystal lattice and unit cell. Ex. 1002, ¶¶62-75. For example, different polymorphs
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`diffract X-rays differently. Ex. 1010, 229-231; Ex. 1002, ¶¶62-63. One technique is
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`X-ray diffraction (“XRD”).Id.; Ex. 1010, 235; Ex. 1002, ¶62. The X-ray diffraction
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`pattern can act as a fingerprint for that polymorph. Id., 236; Ex. 1002, ¶¶64-67.
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`When a diffraction is carried out on a crystalline compound in powder form, the
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`technique is called powder X-Ray diffraction (PXRD). Ex. 1010, 235; Ex. 1002,
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`¶¶65-68.
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`Differential scanning calorimetry (DSC) is another method of analysis that
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`allows tracking of changes in physical state of a sample as it is heated. Ex. 1010,
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`251-254; Ex. 1002, ¶¶70-71.
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`A sample’s melting point is another way to differentiate crystal forms. Ex.
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`1002, ¶¶69, 72-73.
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`C. Crystallization techniques
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`Crystallization is commonly used throughout the production process of the
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`active ingredient of a pharmaceutical product. Ex. 1002, ¶76. Crystallization is
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`routinely performed in the field of solid-state chemistry to purify organic
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`compounds. Ex. 1031, 15; Ex. 1032, 522; Ex. 1002, ¶79.
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`The techniques used to crystallize drug substances are well known. Ex.
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`1029, 3729; Ex. 1031, 14; Ex. 1032, 522; Ex. 1002, ¶76, 95-105, 106-111; Ex.
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`1003, ¶57-58. Crystallization determines many of the important properties of the
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`drug substance, including the purity, residual solvent content, the polymorphic
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`form, crystal size, size distribution, as well the techniques used to obtain the final
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`drug product, such as drying, ease of comminution and formulation. Ex. 1029,
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`3729; Ex. 1002, ¶76. Accordingly, crystallization steps for oral dosage forms are
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`well understood in the field. Ex. 1002, ¶77.
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`Known crystallization steps include dissolution in the crystallization solvent,
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`filtration, crystallization, solid-liquid separation, drying, homogenization,
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`comminution, and formulation. Ex. 1029, 3729; Ex. 1002, ¶¶76-79, 126.
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`Recrystallization is the process of allowing crystals to reform in a compound. Ex.
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`1002, ¶281. Prior to 2001, a POSA would have been aware that recrystallization
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`was commonly performed in the field, and understood how to perform such a
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`recrystallization experiment. Ex. 1002, ¶¶135-136. Pavia discloses the use of
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`recrystallization to purify solids. Ex. 1002, ¶136. Pavia teaches how to recrystallize
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`a solid, providing guidance for choosing a solvent and how to dissolve, filter,
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`crystallize, isolate, and oven-dry a solid substance. Id., 522-530 Ex. 1002, ¶137;
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`see also Ex. 1031, 15; Ex. 1029, 3729. Thus, a POSA would have known how to
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`Petition for Inter Partes Review
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`purify a compound by recrystallization prior to 2001.
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`D. Vilazodone hydrochloride (VHCl)
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`Vilazodone and its hydrochloride salt were known in the art before 2001.
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`For example, vilazodone and its physiologically acceptable salts and a process by
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`which they could be prepared were disclosed in the ‘241 patent. See, e.g., Ex. 1004
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`1:5-29, 7:31-37, and 11:19-24; Ex. 1002, ¶32. The ‘241 patent states that all
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`examples disclosed in the patent, including Example 4, were purified by
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`chromatography and/or by crystallization. Ex. 1004, 9:3-11. Bartoszyk teaches
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`hydrochloride as the preferred salt of vilazodone. Id., abstract; Ex. 1002, ¶88.
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`Moreover, it was known in the art that “there is clear precedent…to immediately
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`progress to the hydrochloride salt. Ex. 1011, 203; Ex. 1002, ¶¶112-114.
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`Before 2001, the pharmacological activity of vilazodone and VHCl, and
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`consequently its utility in the treatment of various diseases, was well known. Ex.
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`1002, ¶¶88, 91-93. Bartoszyk teaches that VHCl served as a combined selective
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`serotonin reuptake inhibitor and 5-HT1A agonist. Ex. 1005, 1:12-14 and 8:7-11:17.
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`Bartoszyk found VHCl to be useful in treating depressive disorders (e.g., major
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`depressive disorder and dysthymic disorder); anxiety disorders; psychiatric
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`disorders (e.g., psychose