Filed on behalf of Lupin Limited
`By: Deanne M. Mazzochi
`
`
`Tara M. Raghavan
`
`RAKOCZY MOLINO MAZZOCHI SIWIK LLP
`6 West Hubbard Street, Suite 500
`Chicago, IL 60654
`Tel.: 312-222-6305
`Fax: 312-222-6325
`Email: dmazzochi@rmmslegal.com
`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________
`
`LUPIN LIMITED
`Petitioner
`v.
`JANSSEN SCIENCES IRELAND UC
`Patent Owner, based on Public Filings
`JANSSEN R&D IRELAND
`Patent Owner, based on Electronic Records of PTO
`U.S. Patent No. 8,518,987 B2 to Vermeersch et al.
`Issue Date: August 27, 2013
`Title: Pseudopolymorphic Forms of a HIV Inhibitor
`________________________________
`
`Inter Partes Review Trial No. TBD
`________________________________
`
`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`TABLE OF CONTENTS
`
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND
`TABLE OF ABBREVIATIONS ........................................................... iii 
`
`I. 
`
`INTRODUCTION. ................................................................................. 1 
`
`II.  MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)). ............................ 4 
`
`A.  Notice of Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)). .......... 5 
`
`B. 
`
`C. 
`
`Notice of Related Matters (37 C.F.R. § 42.8(b)(2)). .................... 5 
`
`Notice of Lead and Back-Up Counsel (37 C.F.R. §
`42.8(b)(3)). ................................................................................... 6 
`
`D.  Notice of Service Information (37 C.F.R. § 42.8(b)(4)). ............. 6 
`
`III.  GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)). ....................... 7 
`
`IV.  SPECIFIC IDENTIFICATION OF CHALLENGE (37 C.F.R. §
`42.104(b)). .............................................................................................. 7 
`
`V.  OVERVIEW OF THE ‘987 PATENT AND THE
`PROSECUTION HISTORY THEREOF. .............................................. 8 
`
`A. 
`
`B. 
`
`C. 
`
`The ‘987 Patent. ........................................................................... 8 
`
`The ‘987 Patent Prosecution History. ........................................ 12 
`
`The ‘987 Patent Is Not Entitled to a Priority Benefit to EP
`‘929. ............................................................................................ 13 
`
`VI.  PERSON OF SKILL IN THE ART AND STATE OF THE ART. ..... 14 
`
`VII.  CLAIM CONSTRUCTION. ................................................................ 16 
`
`VIII.  EXPLANATION OF GROUNDS FOR UNPATENTABILITY. ....... 19 
`
`‘987 Patent Are
`the
`A.  Ground 1: Claims 1-19 of
`Unpatentable Under 35 U.S.C. § 102 in View of the
`Enabling Disclosure of Ghosh 1998. ......................................... 19 
`i
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`B. 
`
`C. 
`
`‘987 Patent Are
`the
`Ground 2: Claims 1-19 of
`Unpatentable Under 35 U.S.C. § 102 in View of the
`Enabling Disclosure of the ‘775 Patent. ..................................... 32 
`
`‘987 Patent Are
`the
`Ground 3: Claims 1-19 of
`Unpatentable Under 35 U.S.C. § 103 Over Ghosh 1998
`and the ‘775 patent in View of Byrn 1995, Desiraju 1991
`and the Knowledge of a Person of Ordinary Skill in the
`Art. .............................................................................................. 41 
`
`IX.  THE CHALLENGED PATENT CLAIMS WOULD HAVE
`BEEN OBVIOUS EVEN ASSUMING PATENT OWNER
`OFFERS ANY ALLEGATIONS OF OBJECTIVE INDICIA. ........... 55 
`
`A. 
`
`B. 
`
`C. 
`
`Praise in the Industry. ................................................................. 55 
`
`Copying. ..................................................................................... 56 
`
`Commercial Success. ................................................................. 57 
`
`D.  Unexpected Results. ................................................................... 58 
`
`X. 
`
`CONCLUSION ..................................................................................... 60 
`
`
`
`
`
`
`
`ii
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND
`TABLE OF ABBREVIATIONS
`
`
`Lupin
`Exhibit
`No.
`1001
`1002
`
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`1009
`1010
`1011
`1012
`1013
`1014
`
`1015
`1016
`1017
`1018
`1019
`1020
`
`
`
`Description of Exhibit
`
`U.S. Patent No. 8,518,987 B2 (“the ‘987 patent”)
`Arun K. Ghosh et al., Potent HIV Protease Inhibitors Incorporating
`High-Affinity P2-Ligands and (R)-(Hydroxyethylamino)sulfonamide
`Isostere, 8 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 687
`(1998) (“Ghosh 1998”)
`U.S. Patent No. 6,248,775 B1 (“the ‘775 patent”)
`Stephen Byrn et al., Pharmaceutical Solids: A Strategic Approach to
`Regulatory Considerations, 12 PHARMACEUTICAL RES. 945 (1995)
`(“Byrn 1995”)
`Gautam R. Desiraju, Hydration in Organic Crystals: Prediction from
`Molecular Structure, 6 J. CHEMICAL SOC’Y CHEMICAL COMM. 426
`(1991) (“Desiraju 1991”)
`Elke Van Gyseghem et al., Solid State Characterization of the Anti-
`HIV Drug TMC114: Interconversion of Amorphous TMC114
`Ethanolate and Hydrate, 38 EUR. J. PHARMACEUTICAL SCI. 489
`(2009) (“Van Gyseghem”)
`U.S. Application Serial No. 12/536,807 (“the ‘807 application”)
`Prosecution History (“PH”), 8/6/2009 Transmittal of New
`Application
`‘807 application PH, 7/2/2010 Preliminary Amendment
`‘807 application PH, 9/12/2011 Office Action
`‘807 application PH, 3/12/2012 Reply
`‘807 application PH, 5/22/2012 Final Office Action
`‘807 application PH, 7/20/2012 Reply
`‘807 application PH, 9/17/2012 Pre-Appeal Brief Request for Review
`‘807 application PH, 10/25/2012 Notice of Panel Decision from Pre-
`Appeal Brief Review
`‘807 application PH, 1/25/2013 Appeal Brief
`European Patent Application No. EP 02076929.5 (“EP ‘929”)
`International Publication No. WO 95/06030 A1 (“WO ‘030”)
`European Patent No. 1 567 529 B1(“EP ‘529”)
`EP ‘529 PH, 12/3/2004 Entry into European Phase Request
`EP ‘529 PH, 1/29/2013 Communication to EPO
`iii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`1021
`1022
`1023
`
`1024
`
`1025
`
`1026
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`EP ‘529 PH, 1/29/2013 Experimental Report
`U.S. Patent No. 7,700,645 B2 (“the related ‘645 patent”)
`3/12/2014 Summ. J. Op. (public version), Janssen Prods., L.P. et al.
`v. Lupin Ltd. et al., No. 10-cv-5954 (D.N.J. Sept. 23, 2014), ECF No.
`997 (“Summ. J. Op.”)
`Excerpts of Trial Transcripts from March 18, 2014 – April 2, 2014
`trial proceedings in Janssen Products, L.P. et al. v. Lupin Ltd. et al.,
`Consolidated Case No. 10-5954 (D.N.J.) (“Trial Tr.”)
`Declaration of Terence L. Threlfall, Ph.D. in Support of Lupin
`Limited’s Petition for Inter Partes Review of U.S. Patent No.
`8,518,987 B2 (“Threlfall Decl.”)
`Curriculum Vitae of Terence L. Threlfall, Ph.D.
`List of Documents Reviewed and Relied Upon by Terence L.
`Threlfall, Ph.D.
`Guideline for Submitting Supporting Documentation in Drug
`Applications for the Manufacture of Drug Substances, FOOD & DRUG
`ADMINISTRATION (1987) (“FDA Guidelines”)
`Preface, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS iii (Harry G.
`Brittain ed., 1999) (“Brittain”)
`David J.W. Grant, Theory and Origin of Polymorphism, in
`POLYMORPHISM IN PHARMACEUTICAL SOLIDS 8 (Harry G. Brittain ed.,
`1999) (“Grant”)
`John Haleblian & Walter McCrone, Pharmaceutical Applications of
`Polymorphism, 58 J. PHARMACEUTICAL SCI. 911 (1969) (“McCrone”)
`J. Keith Guillory, Generation of Polymorphs, Hydrates, Solvates, and
`Amorphous Solids, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS
`183 (Harry G. Brittain ed., 1999) (“Guillory”)
`Örn Almarsson & Michael J. Zaworotko, Crystal Engineering of the
`Composition of Pharmaceutical Phases. Do Pharmaceutical Co-
`crystals Represent a New Path to Improved Medicines?, CHEMICAL
`COMM. 1889 (2004) (“Almarsson”)
`Stephen R. Byrn et al., Hydrates and Solvates, in SOLID-STATE
`CHEMISTRY OF DRUGS 233 (2d ed. 1999) (“Byrn 1999”)
`Steven S. Zumdahl, CHEMISTRY 31-59, 295-347, 383-433, 559-613
`(1986) (“Zumdahl”)
`R. Docherty, The Application of Computational Chemistry to the
`Study of Molecular Materials, in CRYSTAL GROWTH OF ORGANIC
`MATERIALS 2 (Allan S. Myerson et al. eds., 1996) (“Docherty”)
`Terence L. Threlfall, Analysis of Organic Polymorphs: A Review, 120
`
`
`
`iv
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`ANALYST 2435 (1995) (“Threlfall”)
`Gregory A. Stephenson et al., Formation of Isomorphic Desolvates:
`Creating a Molecular Vacuum, 87 J. PHARMACEUTICAL SCI. 536
`(1998) (“Stephenson”)
`Sherry L. Morissette et al., High Throughput Crystallization:
`Polymorphs, Salts, Co-crystals and Solvates of Pharmaceutical
`Solids, 56 ADVANCED DRUG DELIVERY REVIEWS 275 (2004)
`(“Morissette”)
`Stephen R. Byrn et al., Solid-State Pharmaceutical Chemistry, 6
`CHEMISTRY MATERIALS 1148 (1994) (“Byrn 1994”)
`P. Heinrich Stahl, The Problems of Drug Interactions with Excipients,
`in TOWARDS BETTER SAFETY OF DRUGS AND PHARMACEUTICAL
`PRODUCTS 265 (D.D. Breimer ed., 1980) (“Stahl 1980”)
`Bruno C. Hancock & Michael Parks, What is the True Solubility
`Advantage for Amorphous Pharmaceuticals?, 17 PHARMACEUTICAL
`RES. 397 (2000) (“Hancock”)
`Harry G. Brittain & Eugene F. Fiese, Effects of Pharmaceutical
`Processing on Drug Polymorphs and Solvates, in POLYMORPHISM IN
`PHARMACEUTICAL SOLIDS 331 (Harry G. Brittain ed., 1999) (“Brittain
`& Fiese”)
`Joel Bernstein, Polymorphism of Pharmaceuticals, in POLYMORPHISM
`IN MOLECULAR CRYSTALS 240 (2002) (“Bernstein”)
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS xv-xvi (Arthur H.
`Kibbe ed., 3d ed. 2000) (“HPE”)
`Sudha R. Vippagunta et al., Crystalline Solids, 48 ADVANCE DRUG
`DELIVERY REVIEWS 3 (2001)
`U.S. Application Serial No. 10/514,352 (“the ‘352 application”) PH,
`11/12/2004 Transmittal of New Application
`1048
`‘352 application PH, 1/14/2008 Office Action
`1049
`‘352 application PH, 7/14/2008 Response & Amendment
`1050
`‘352 application PH, 11/3/2008 Office Action
`1051 Matti U.A. Ahlqvist & Lynne S. Taylor, Water Dynamics in Channel
`Hydrates Investigated Using H/D Exchange, 241 INT’L J.
`PHARMACEUTICS 253 (2002) (“Ahlqvist”)
`Rajendra K. Khankari & David J.W. Grant, Pharmaceutical
`Hydrates, 248 THERMOCHIMICA ACTA 61 (1995) (“Khankari”)
`Kenneth R. Morris & Nair Rodríguez-Hornedo, Hydrates, in
`ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY 393 (James
`Swarbrick & James C. Boylan eds., 1993) (“Morris 1993”)
`
`1044
`
`1045
`
`1046
`
`1047
`
`1052
`
`1053
`
`
`
`v
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`1054
`
`1055
`
`1056
`
`1057
`
`Albert J. Fry, Solvents and Supporting Electrolytes, in LABORATORY
`TECHNIQUES IN ELECTROANALYTICAL CHEMISTRY 469 (Peter T.
`Kissinger & William R. Heineman eds., 2d ed. 1996) (“Fry”)
`Charles Cougnon & Jacques Simonet, Cathodic Reactivity of
`Platinum and Palladium in Electrolytes in Superdry Conditions, 46
`PLATINUM METALS REV. 94 (2002) (“Cougnon”)
`Dian J. Gaffen et al., Annual Cycles of Tropospheric Water Vapor, 97
`J. GEOPHYSICAL RES. 18185 (1992) (“Gaffen”)
`Svante Arrhenius, On the Influence of Carbonic Acid in the Air Upon
`the Temperature of the Ground, in CLIMATE CHANGE: CRITICAL
`CONCEPTS IN THE ENVIRONMENT 11 (Frank Chambers & Michael
`Ogle eds., 2002) (“Arrhenius”)
`1058 Mihaly V. Toth & Garland R. Marshall, A Simple, Continuous
`Fluorometric Assay for HIV Protease, 36 INT’L J. PEPTIDE & PROTEIN
`RES. 544 (1990) (“Toth & Marshall”)
`Agenerase® Prescribing Information (April 1999) (“1999 Agenerase®
`PI”)
`Kenneth R. Morris, Structural Aspects of Hydrates and Solvates, in
`POLYMORPHISM IN PHARMACEUTICAL SOLIDS 125 (Harry G. Brittain
`ed., 1999) (“Morris 1999”)
`Frank H. Allen et al., Systematic Analysis of Structural Data as a
`Research Technique in Organic Chemistry, 16 ACCOUNTS CHEMICAL
`RES. 146 (1983)
`Declaration of Keith B. Leffler, Ph.D. in Support of Lupin Limited’s
`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`(“Leffler Decl.”)
`Curriculum Vitae of Keith B. Leffler, Ph.D.
`Prezista® Prescribing Information (Revised: March 2015) (“2015
`Prezista® PI”)
`8/14/2014 Trial Op. (public version), Janssen Prods., L.P. et al. v.
`Lupin Ltd. et al., No. 10-cv-5954 (D.N.J. Sept. 23, 2014), ECF No.
`998 (“Trial Op.”)
`Consolidated Guidelines on the Use of Antiretroviral Drugs for
`Treating and Preventing HIV Infection, WORLD HEALTH
`ORGANIZATION (June 2013) (“WHO Guidelines”)
`Panel on Antiretroviral Guidelines for Adults and Adolescents,
`Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected
`Adults and Adolescents., DEPARTMENT OF HEALTH AND HUMAN
`SERVICES (Nov. 13, 2014), available at
`
`1059
`
`1060
`
`1061
`
`1062
`
`1063
`1064
`
`1065
`
`1066
`
`1067
`
`
`
`vi
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`1068
`
`1069
`
`1070
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`
`1077
`
`1078
`
`1079
`
`1080
`
`http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
`(“DHHS Guidelines”)
`Press Release, Lupin Pharmaceuticals, Inc., Lupin Receives Tentative
`Approval for Generic Prezista® Tablets, (Dec. 30, 2014), available
`at http://www.lupinpharmaceuticals.com/30dec2014.htm
`Declaration of Frederick J. Northrup, Ph.D. in Support of Lupin
`Limited’s Petition for Inter Partes Review of U.S. Patent No.
`8,518,987 B2 (“Northrup Decl.”)
`Curriculum Vitae of Frederick J. Northrup, Ph.D.
`REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 173-77, 649-
`50, 702-10 (20th ed. 2000) (“Remington”)
`Eric D. Carlson et al., An Integrated High Throughput Workflow for
`Pre-formulations: Polymorph and Salt Selection Studies, DRUG DEV.
`10 (2003) (“Carlson”)
`Printout of Data File of Dr. Northrup’s Powder X-Ray Diffraction
`testing on “Compound 13” (Apr. 8, 2015) (“PXRD on Compound 13
`sample”)
`Printout of Data File of Dr. Northrup’s Powder X-Ray Diffraction
`testing on “Compound 13 EtOH recrystallized” (Apr. 8, 2015)
`(“PXRD on Compound 13 EtOH recrystallized sample”)
`Printout of Data File of Dr. Northrup’s Powder X-Ray Diffraction
`testing on “Compound 13 iPrOH recrystallized” (Apr. 8, 2015)
`(“PXRD on Compound 13 iPrOH recrystallized sample”)
`Printout of Data File of Dr. Northrup’s Thermogravimetric Analysis
`sample mass testing on “Compound 13” (Apr. 8, 2015) (“TGA on
`Compound 13 sample”)
`Printout of Data File of Dr. Northrup’s Thermogravimetric Analysis
`sample mass testing on “Compound 13 EtOH recrystallized” (Apr. 8,
`2015) (“TGA on Compound 13 EtOH recrystallized sample”)
`Printout of Data File of Dr. Northrup’s Thermogravimetric Analysis
`sample mass testing on “Compound 13 iPrOH recrystallized” (Apr. 8,
`2015) (“TGA on Compound 13 iPrOH recrystallized sample”)
`Printout of Data File of Dr. Northrup’s Thermogravimetric Analysis /
`Mass Spectrometry testing on “Compound 13” (Apr. 8, 2015)
`(“TGA/MS on Compound 13 sample”)
`Printout of Data File of Dr. Northrup’s Thermogravimetric Analysis /
`Mass Spectrometry testing on “Compound 13 EtOH recrystallized”
`(Apr. 8, 2015) (“TGA/MS on Compound 13 EtOH recrystallized
`sample”)
`
`
`
`vii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`1081
`
`1082
`
`1083
`1084
`
`1085
`
`1086
`
`1087
`
`1088
`
`1089
`1090
`
`1091
`
`1092
`
`Printout of Data File of Dr. Northrup’s Thermogravimetric Analysis /
`Mass Spectrometry testing on “Compound 13 iPrOH recrystallized”
`(Apr. 8, 2015) (“TGA/MS on Compound 13 iPrOH recrystallized
`sample”)
`Declaration of Aristotle G. Kalivretenos, Ph.D. in Support of Lupin
`Limited’s Petition for Inter Partes Review of U.S. Patent No.
`8,518,987 B2 (“Kalivretenos Decl.”)
`Curriculum Vitae of Aristotle G. Kalivretenos, Ph.D.
`Arun K. Ghosh et al., Potent HIV Protease Inhibitors: The
`Development of Tetrahydrofuranylglycines as Novel P2-Ligands and
`Pyrazine Amides as P3-Ligands, 36 J. MEDICINAL CHEMISTRY 2300
`(1993) (“Ghosh 1993”)
`Arun K. Ghosh et al., Nonpeptidal P2 Ligands for HIV Protease
`Inhibitors: Structure-Based Design, Synthesis, and Biological
`Evaluation, 39 J. MEDICINAL CHEMISTRY 3278 (1996) (“Ghosh
`1996”)
`Arun K. Ghosh et al., N,N’-Disuccinimidyl Carbonate: A Useful
`Reagent for Alkoxycarbonylation of Amines, 33 TETRAHEDRON
`LETTERS 2781 (1992) (“Ghosh 1992”)
`Dieter Seebach et al., Diastereoselective α-Alkylation of β-
`Hydroxycarboxylic Esters Through Alkoxide Enolates: Diethyl (2S,
`3R)-(+)-3-Allyl-2-Hydroxysuccinate from Diethyl (S)-( – )-Malate, 63
`ORGANIC SYNTHESES 109 (1985) (“Seebach”)
`Packing Slip from Aurora Analytics, LLC to Frederick Northrup,
`Ph.D. (Apr. 4, 2015)
`Certificate of Analysis of “Compound 13 Darunavir” (Apr. 8, 2015)
`Certificate of Analysis of “Compound 13 Darunavir, ethanol
`recrystallized” (Apr. 8, 2015)
`Certificate of Analysis of “Compound 13 Darunavir, isopropyl
`recrystallized” (Apr. 8, 2015)
`Oral Argument Hearing Transcript from June 3, 2014 in In re
`Armodafinil Patent Litig., Appeal No. 2013-1360 (Fed. Cir. June 3,
`2014) (“Oral Hrg. Tr.”)
`
`
`
`
`
`viii
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`
`Lupin Limited (“Lupin” or “Petitioner”) petitions for Inter Partes Review
`
`(“Petition”) under 35 U.S.C. § 312 and 37 C.F.R. § 42.108, seeking cancellation of
`
`claims 1-19 of U.S. Patent No. 8,518,987 B2 (Exhibit (“Ex.”) 1001), which issued
`
`on August 27, 2013, to Vermeersch et al. (“the ‘987 patent”). Concurrently filed is
`
`a Power of Attorney and an Exhibit List pursuant to 37 C.F.R. §§ 42.10(b) and
`
`42.63(e), respectively. Required fee under 37 C.F.R. § 42.15(a) of $24,600 is paid
`
`via online credit card payment. The Office is authorized to charge fee deficiencies
`
`and credit overpayments to Deposit Acct. No. 50-3626 (Customer ID No. 60024).
`
`I.
`
`INTRODUCTION.
`
`The ‘987 patent purports to cover any darunavir substance (including an
`
`amorphous or solvate mixture) provided that it has acquired some association with
`
`darunavir “hydrate.” (See, e.g., Ex. 1001 at claims 1, 3, 19). Such “hydrate”
`
`purportedly includes: (1) an incredibly expansive scope of water associations; (2)
`
`trace quantities (even if undetectable); and (3) substances resulting spontaneously
`
`from exposure of darunavir to humidity in the air. (See id. at col. 4, ll. 61-62
`
`(defining “hydrates” as “substances that are formed by adding water molecules”);
`
`col. 31, ll. 1-13 (e.g., claim 2); col. 18, l. 44 – col. 19, l. 16 (Example 5, exposing
`
`Form A to humidity produced Form A-hydrate mix)).
`
`During prosecution, the ‘987 patent Applicants consistently relied upon the
`
`“non-limiting” definition of hydrates set forth in the specification. (Ex. 1013 at 3;
`
`
`
`1
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`see also Ex. 1015 at 6). From this premise, Applicants responded to repeated
`
`enablement rejections by insisting that “[t]he specification sets forth several
`
`examples describing the claimed compound and water” and citing Examples
`
`where water is added to a darunavir solution or where darunavir is exposed to
`
`relative humidities. (See, e.g., Ex. 1012 at 8-9 (emphasis added)). Thus,
`
`Applicants indisputably considered merely disclosing the compound + water
`
`exposure, including from relative humidity, sufficient to enable producing the
`
`claimed hydrates. Patent Owner, in Van Gyseghem, has also conceded darunavir
`
`hydrate can function as a channel structure that necessarily forms upon exposure of
`
`any form of darunavir to various relative humidities. (See Ex. 1006 at 490, 497).
`
`Anticipation. Darunavir was a known, potent protease inhibitor (“PI”)
`
`independently disclosed in the scientific literature (Ghosh 1998) and patented (the
`
`‘775 patent) prior to the effective filing date (“EFD”) of the ‘987 patent. (See, e.g.,
`
`Ex. 1002 at 689; Ex. 1003 at col. 221, ll. 1-18 (claim 7)). The ‘987 patent
`
`expressly concedes such prior art disclosed darunavir and enabling “processes for
`
`its preparation.” (Ex. 1001 at col. 1, ll. 35-65). Such processes necessarily occur
`
`in the presence of water molecules. (Ex. 1025 ¶¶ 141-45, 152, 153, 156).
`
`Further, in prior litigation involving related U.S. Patent No. 7,700,645 B2
`
`(“the related ‘645 patent”), Patent Owner’s expert conceded a lack of novelty and
`
`obviousness to incorporating darunavir in a pharmaceutical composition with an
`
` 2
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
`
`inert carrier. (Ex. 1024 at 1874:23-1875:9 (Myerson)). With such additional
`
`elements not conferring separate patentability, the only issue is whether the prior
`
`art enabled the skilled artisan to, e.g., expose darunavir to water. It plainly did.
`
`Ghosh 1998 and the ‘775 patent each anticipate claims 1-19 of the ‘987
`
`patent by expressly disclosing darunavir, and enabling the skilled artisan to reach
`
`claimed darunavir “hydrates” and compositions thereof. Repeating Ghosh 1998
`
`further confirms the inherent presence of the hydrates as claimed. (Ex. 1025 ¶¶
`
`168-70, 172; Ex. 1069 ¶¶ 7-8, 28-29; Ex. 1082 ¶¶ 5-45).
`
`Obviousness. Darunavir was a known, potent PI by the EFD. The skilled
`
`artisan would have been motivated by regulatory guidelines (as well as the general
`
`understood preference for crystalline drugs), to evaluate as a matter of routine
`
`practice whether the darunavir in Ghosh 1998 and the ‘775 patent possessed
`
`different solid-state forms. (Ex. 1004 at 945; Ex. 1025 ¶¶ 17-18, 197-200). Byrn
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`1995 discloses a step-by-step flowchart for a skilled artisan to follow, using
`
`standard, preferred solvents
`
`(including ethanol and water),
`
`to prompt
`
`crystallization. (Ex. 1004 at 945-46, 949). Evaluation of darunavir’s structure
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`independently would have signaled the compound was likely to have more than
`
`one solid-state form—and was amenable to hydrate formation according to
`
`Desiraju 1991—given the known imbalance of hydrogen bond donors to acceptors.
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`(Ex. 1005 at 427; Ex. 1025 ¶¶ 19, 212-16). Thus, a skilled artisan would have
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`reasonably expected the formation of a hydrate of darunavir by following Byrn
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`1995’s crystallization procedures. (Ex. 1004 at 946, 949; Ex. 1025 ¶¶ 19, 212-16).
`
`Routine crystallization studies confirm this. (Ex. 1025 ¶¶ 171, 173, 220; Ex. 1069
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`¶¶ 7-8, 28-29; Ex. 1082 ¶¶ 46-48). That such a hydrate may possess a compound
`
`to water ratio between 1:0.5 and 1:3 is reasonably expected and obvious, as most
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`common pharmaceutical hydrates fall within that range. (Ex. 1025 ¶¶ 20, 221-26).
`
`The additional composition elements recited in claims 3-8 and 14-19 do not
`
`further distinguish the claims from the prior art, and also would have been obvious.
`
`The use of a carrier in a formulation comprising a compound (including a hydrate)
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`is ubiquitous in formulation sciences. (Ex. 1025 ¶¶ 21, 43; Ex. 1024 at 1830:18 –
`
`1831:5, 1874:23-1875:9 (Myerson)). Ghosh 1998 and the ‘775 patent further
`
`enable or disclose these elements. (Ex. 1002 at 688-89; Ex. 1003 at col. 218, l. 11
`
`– col. 220, l. 13 (claims 1-3); col. 221, ll. 1-17 (claim 7); col. 222, ll. 33-34 (claim
`
`13)). Thus, claims 1-19 are obvious.
`
`For the reasons set forth herein, pursuant to 37 C.F.R. § 42.22(A), Petitioner
`
`requests Inter Partes Review and cancellation of claims 1-19. Petitioner’s detailed
`
`statement of the reasons for the relief is set forth in Sections IV and VIII below.
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)).
`
`As set forth below and pursuant to 37 C.F.R. §§ 42.8(a)(1) and 42.8(b), the
`
`following mandatory notices are provided as part of this Petition.
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`A. Notice of Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)).
`
`Petitioner Lupin Limited has no parent corporation, no publicly-held
`
`corporation owns 10% or more of its stock, and is a real party of interest. Lupin
`
`Pharmaceuticals, Inc. is a wholly-owned subsidiary of Lupin Limited, no publicly-
`
`held corporation owns 10% or more of its stock, and is also a real party of interest.
`
`B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)).
`
`The ‘987 patent is the subject of a patent infringement suit filed by Janssen
`
`Products, L.P. and Janssen R&D Ireland (collectively “Janssen”) against Petitioner
`
`and Lupin Pharmaceuticals, Inc. on Mar. 4, 2014. Janssen Prods., L.P. et al. v.
`
`Lupin Ltd. et al., C.A. No. 14-1370 (D.N.J.), Doc. 1. Waiver of service was
`
`executed and filed on Apr. 11, 2014. Id., Docs. 6-7. This case is consolidated
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`with Janssen Products, L.P. et al. v. Lupin Ltd. et al., C.A. No. 13-3891 (D.N.J.)
`
`and stayed pending the related ‘645 patent appeal. Id., Doc. 28.
`
`The ‘987 patent was also the subject of a patent infringement suit filed by
`
`Janssen against Teva Pharmaceutical Industries, Ltd. and Teva Pharmaceuticals,
`
`USA, Inc. on Nov. 27, 2013. Janssen Prods., L.P. et al. v. Teva Pharm. USA, Inc.
`
`et al., C.A. No. 13-7576 (D.N.J.), Doc. 1. Pursuant to a Settlement Agreement, the
`
`parties agreed to terminate the litigation. Id., Docs. 12-13.
`
`The ‘987 patent and the related ‘645 patent are the subject of pending patent
`
`infringement suits filed by Janssen against Cipla Ltd. and Cipla USA Inc. on Aug.
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`13, 2014 (D.N.J.) and Aug. 15, 2014 (D. Del). Janssen Prods., L.P. et al. v. Cipla
`
`Ltd. et al., C.A. No. 14-5093 (D.N.J.), Doc. 1; C.A. No. 14-1056 (D. Del.), Doc. 1.
`
`The related ‘645 patent is also the subject of the following actions: Janssen
`
`Prods., L.P. et al. v. Lupin Ltd. et al., Lead Consolidated C.A. No. 10-5954
`
`(D.N.J.) (pending Consolidated Appeal No. 14-1842 (Fed. Cir.)); Tibotec Inc. et al.
`
`v. Lupin Ltd. et al., C.A. No. 11-4027 (D.N.J.) (consolidated with 10-5954 action,
`
`pending 14-1842 appeal); Janssen Prods., L.P. et al. v. Lupin Ltd. et al., C.A. No.
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`13-3891 (D.N.J.) (consolidated with 14-1370 action, stayed pending 14-1842
`
`appeal); Tibotec Inc. et al. v. Teva Pharm. USA, Inc. et al., C.A. No. 11-1509
`
`(D.N.J.) (consolidated with 10-5954 action and dismissed).
`
`C. Notice of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)).
`
`Lead Counsel
`Deanne M. Mazzochi (Reg. No. 50,158)
`RAKOCZY MOLINO MAZZOCHI SIWIK LLP
`6 West Hubbard, Suite 500
`Chicago, IL
`(312) 222-6305 (telephone)
`(312) 222-6325 (facsimile)
`dmazzochi@rmmslegal.com
`
`Back-Up Counsel
`Tara M. Raghavan (Reg. No. 55,557)
`RAKOCZY MOLINO MAZZOCHI SIWIK LLP
`6 West Hubbard, Suite 500
`Chicago, IL
`(312) 222-6340 (telephone)
`(312) 222-6341 (facsimile)
`traghavan@rmmslegal.com
`
`D. Notice of Service Information (37 C.F.R. § 42.8(b)(4)).
`
`Please direct all correspondence regarding this Petition to lead and back-up
`
`
`
`counsel at the above address. Petitioner also consents to service by email at:
`
`dmazzochi@rmmslegal.com and traghavan@rmmslegal.com.
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)).
`
`Petitioner certifies that the ‘987 patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting an inter partes review
`
`challenging the patent claims on the grounds identified in this Petition. Neither
`
`Petitioner nor any other real party of interest has filed a civil action challenging the
`
`validity of the ‘987 patent. Nor has the petitioner or any other real party of interest
`
`been served with a complaint alleging infringement of the ‘987 patent, more than
`
`one year prior to the filing of this Petition. See Paper 20 at 6, Motorola Mobility
`
`LLC v. Arnouse, Case IPR2013-00010 (MT) (P.T.A.B. Jan. 30, 2013) (“[I]n the
`
`situation where the petitioner waives service of a summons, the one-year time
`
`period begins on the date in which such a waiver is filed.”).
`
`IV. SPECIFIC IDENTIFICATION OF CHALLENGE (37 C.F.R. §
`42.104(b)).
`
`Petitioner respectfully requests inter partes review and cancellation of
`
`claims 1-19 of the ‘987 patent based on the grounds set forth in the table below:
`
`Ground Challenged
`Claims
`1-19
`1-19
`1-19
`
`1
`2
`3
`
`Statutory Basis Reference(s)
`
`§ 102
`§ 102
`§ 103
`
`Ghosh 1998 (Ex. 1002)
`The ‘775 patent (Ex. 1003)
`Ghosh 1998 (Ex. 1002) and the ‘775
`patent (Ex. 1003) in view of Byrn 1995
`(Ex. 1004), Desiraju 1991 (Ex. 1005),
`and the knowledge of one of ordinary
`skill in the art
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`Sections VII and VIII below set forth the detailed explanation as to how
`
`terms of the ‘987 patent claims are to be construed and how these claims, as
`
`properly construed, are unpatentable under the grounds set forth above. In support
`
`of the proposed grounds for unpatentability, this Petition is accompanied by a
`
`declaration of technical expert Dr. Terence L. Threlfall, Ph.D. (Ex. 1025), who
`
`explains what the prior art would have conveyed to a person of ordinary skill in the
`
`art. This Petition is also accompanied by the declaration of pharmacoeconomics
`
`expert, Dr. Keith B. Leffler, Ph.D. (Ex. 1062). The petitioner further relies on
`
`other Exhibits set forth on the Exhibit List filed concurrently herewith, including
`
`the Declaration of Aristotle G. Kalivretenos, Ph.D. (Ex. 1082) and the Declaration
`
`of Frederick J. Northrup. Ph.D. (Ex. 1069).
`
`V. OVERVIEW OF THE ‘987 PATENT AND THE PROSECUTION
`HISTORY THEREOF.
`
`A. The ‘987 Patent.
`
`The ‘987 patent, titled Pseudopolymorphic Forms of a HIV Protease
`
`Inhibitor, issued on or about August 27, 2013, from U.S. Patent Application Serial
`
`No. 12/536,807 (“the ‘807 application”), filed on or about August 6, 2009. The
`
`‘807 application was filed as a divisional of U.S. Application Serial No.
`
`10/514,352 (“the ‘352 application”), filed as International Patent Application No.
`
`PCT/EP03/50176 on or about May 16, 2003, which issued as the related ‘645
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`patent on or about April 20, 2010. The ‘987 patent also makes a priority claim to
`
`European Patent Application No. EP 02076929.5 (“EP ‘929”), filed on or about
`
`May 16, 2002, but as set forth in Section V(C) below is not so entitled.
`
`According to the electronic records of the PTO at Reel/Frame 30292-8, the
`
`‘987 patent is assigned to Janssen R&D Ireland. However, based on public filings,
`
`the ‘987 patent has been assigned to Janssen Sciences Ireland UC. See, e.g.,
`
`Janssen Prods., L.P. et al. v. Lupin Ltd. et al., C.A. No. 14-1370 (D.N.J.), Doc. 27.
`
`Accordingly, both are collectively identified as Patent Owner herein.
`
`While discussed more specifically below in connection with the grounds
`
`upon which Petitioner relies, the challenged claims of the ‘987 patent are directed
`
`to a purported “hydrate” of darunavir with various degrees of hydration (claims 1,
`
`2, and 9-13), as well as compositions comprising the same (claims 3-8 and 14-19).
`
`The compound darunavir. As noted above, the ‘987 patent’s specification
`
`concedes the prior art discloses darunavir, “and processes for its preparation,”
`
`including in Ghosh 1998 and the ‘775 patent. (Ex. 1001 at col. 1, ll. 35-65).
`
`Drug forms. The specification asserts certain (unidentified) modifications
`
`to darunavir’s solid state “unexpectedly” positively influenced its suitability for
`
`use as a pharmaceutical, including in terms of the compound’s stability,
`
`bioavailability, and purity. (Ex. 1001 at col. 2, ll. 54-67). Pseudopolymorphs
`
`asserted as “preferred” include “hydrate and ethanolate,” with Form A labeled an
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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`ethanolate and Form B labeled a hydrate. (Id. at col. 3, ll. 5-21; col. 5, ll. 45-54).
`
`The specification further states numerous possible hydrates result from different
`
`hydration levels. (Id. at col. 6, ll. 3-18). Yet, comparative bioavailability, stability
`
`or purity assessments of any “hydrate” to forms disclosed in the closest prior art
`
`are absent. (Ex. 1025 ¶ 261). The specification never assigns any “unexpected”
`
`positive influences to any particular solid state modification. (Id.).
`
`Amorphous, hydrate. The specification expressly defines “amorphous
`
`form” and “hydrates.” “[A]m