IN THE UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD

Transcription

1 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 Tel.: Fax: 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

2 TABLE OF CONTENTS EXHIBIT LIST PURSUANT TO 37 C.F.R (e) AND TABLE OF ABBREVIATIONS... iii I. INTRODUCTION II. MANDATORY NOTICES (37 C.F.R. 42.8(a)(1)) A. Notice of Real Party-In-Interest (37 C.F.R. 42.8(b)(1)) B. Notice of Related Matters (37 C.F.R. 42.8(b)(2)) C. Notice of Lead and Back-Up Counsel (37 C.F.R. 42.8(b)(3)) D. Notice of Service Information (37 C.F.R. 42.8(b)(4)) III. GROUNDS FOR STANDING (37 C.F.R (a)) IV. SPECIFIC IDENTIFICATION OF CHALLENGE (37 C.F.R (b)) V. OVERVIEW OF THE 987 PATENT AND THE PROSECUTION HISTORY THEREOF A. The 987 Patent B. The 987 Patent Prosecution History C. The 987 Patent Is Not Entitled to a Priority Benefit to EP VI. PERSON OF SKILL IN THE ART AND STATE OF THE ART VII. CLAIM CONSTRUCTION VIII. EXPLANATION OF GROUNDS FOR UNPATENTABILITY A. Ground 1: Claims 1-19 of the 987 Patent Are Unpatentable Under 35 U.S.C. 102 in View of the Enabling Disclosure of Ghosh i

3 B. Ground 2: Claims 1-19 of the 987 Patent Are Unpatentable Under 35 U.S.C. 102 in View of the Enabling Disclosure of the 775 Patent C. Ground 3: Claims 1-19 of the 987 Patent Are 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 IX. THE CHALLENGED PATENT CLAIMS WOULD HAVE BEEN OBVIOUS EVEN ASSUMING PATENT OWNER OFFERS ANY ALLEGATIONS OF OBJECTIVE INDICIA A. Praise in the Industry B. Copying C. Commercial Success D. Unexpected Results X. CONCLUSION ii

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

5 1021 EP 529 PH, 1/29/2013 Experimental Report 1022 U.S. Patent No. 7,700,645 B2 ( the related 645 patent ) /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. ) 1024 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 (D.N.J.) ( Trial Tr. ) 1025 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. ) 1026 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 ) 1029 Preface, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS iii (Harry G. Brittain ed., 1999) ( Brittain ) 1030 David J.W. Grant, Theory and Origin of Polymorphism, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS 8 (Harry G. Brittain ed., 1999) ( Grant ) 1031 John Haleblian & Walter McCrone, Pharmaceutical Applications of Polymorphism, 58 J. PHARMACEUTICAL SCI. 911 (1969) ( McCrone ) 1032 J. Keith Guillory, Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS 183 (Harry G. Brittain ed., 1999) ( Guillory ) 1033 Örn Almarsson & Michael J. Zaworotko, Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Cocrystals Represent a New Path to Improved Medicines?, CHEMICAL COMM (2004) ( Almarsson ) 1034 Stephen R. Byrn et al., Hydrates and Solvates, in SOLID-STATE CHEMISTRY OF DRUGS 233 (2d ed. 1999) ( Byrn 1999 ) 1035 Steven S. Zumdahl, CHEMISTRY 31-59, , , (1986) ( Zumdahl ) 1036 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 ) 1037 Terence L. Threlfall, Analysis of Organic Polymorphs: A Review, 120 iv

6 ANALYST 2435 (1995) ( Threlfall ) 1038 Gregory A. Stephenson et al., Formation of Isomorphic Desolvates: Creating a Molecular Vacuum, 87 J. PHARMACEUTICAL SCI. 536 (1998) ( Stephenson ) 1039 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 ) 1040 Stephen R. Byrn et al., Solid-State Pharmaceutical Chemistry, 6 CHEMISTRY MATERIALS 1148 (1994) ( Byrn 1994 ) 1041 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 ) 1042 Bruno C. Hancock & Michael Parks, What is the True Solubility Advantage for Amorphous Pharmaceuticals?, 17 PHARMACEUTICAL RES. 397 (2000) ( Hancock ) 1043 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 ) 1044 Joel Bernstein, Polymorphism of Pharmaceuticals, in POLYMORPHISM IN MOLECULAR CRYSTALS 240 (2002) ( Bernstein ) 1045 HANDBOOK OF PHARMACEUTICAL EXCIPIENTS xv-xvi (Arthur H. Kibbe ed., 3d ed. 2000) ( HPE ) 1046 Sudha R. Vippagunta et al., Crystalline Solids, 48 ADVANCE DRUG DELIVERY REVIEWS 3 (2001) 1047 U.S. Application Serial No. 10/514,352 ( the 352 application ) PH, 11/12/2004 Transmittal of New Application application PH, 1/14/2008 Office Action application PH, 7/14/2008 Response & Amendment 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 ) 1052 Rajendra K. Khankari & David J.W. Grant, Pharmaceutical Hydrates, 248 THERMOCHIMICA ACTA 61 (1995) ( Khankari ) 1053 Kenneth R. Morris & Nair Rodríguez-Hornedo, Hydrates, in ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY 393 (James Swarbrick & James C. Boylan eds., 1993) ( Morris 1993 ) v

7 1054 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 ) 1055 Charles Cougnon & Jacques Simonet, Cathodic Reactivity of Platinum and Palladium in Electrolytes in Superdry Conditions, 46 PLATINUM METALS REV. 94 (2002) ( Cougnon ) 1056 Dian J. Gaffen et al., Annual Cycles of Tropospheric Water Vapor, 97 J. GEOPHYSICAL RES (1992) ( Gaffen ) 1057 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 ) 1059 Agenerase Prescribing Information (April 1999) ( 1999 Agenerase PI ) 1060 Kenneth R. Morris, Structural Aspects of Hydrates and Solvates, in POLYMORPHISM IN PHARMACEUTICAL SOLIDS 125 (Harry G. Brittain ed., 1999) ( Morris 1999 ) 1061 Frank H. Allen et al., Systematic Analysis of Structural Data as a Research Technique in Organic Chemistry, 16 ACCOUNTS CHEMICAL RES. 146 (1983) 1062 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. ) 1063 Curriculum Vitae of Keith B. Leffler, Ph.D Prezista Prescribing Information (Revised: March 2015) ( 2015 Prezista PI ) /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. ) 1066 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection, WORLD HEALTH ORGANIZATION (June 2013) ( WHO Guidelines ) 1067 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 vi

8 ( DHHS Guidelines ) 1068 Press Release, Lupin Pharmaceuticals, Inc., Lupin Receives Tentative Approval for Generic Prezista Tablets, (Dec. 30, 2014), available at 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. ) 1070 Curriculum Vitae of Frederick J. Northrup, Ph.D REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY , , (20th ed. 2000) ( Remington ) 1072 Eric D. Carlson et al., An Integrated High Throughput Workflow for Pre-formulations: Polymorph and Salt Selection Studies, DRUG DEV. 10 (2003) ( Carlson ) 1073 Printout of Data File of Dr. Northrup s Powder X-Ray Diffraction testing on Compound 13 (Apr. 8, 2015) ( PXRD on Compound 13 sample ) 1074 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 ) 1075 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 ) 1076 Printout of Data File of Dr. Northrup s Thermogravimetric Analysis sample mass testing on Compound 13 (Apr. 8, 2015) ( TGA on Compound 13 sample ) 1077 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 ) 1078 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 ) 1079 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 ) 1080 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

9 1081 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 ) 1082 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. ) 1083 Curriculum Vitae of Aristotle G. Kalivretenos, Ph.D Arun K. Ghosh et al., Potent HIV Protease Inhibitors: The Development of Tetrahydrofuranylglycines as Novel P 2 -Ligands and Pyrazine Amides as P 3 -Ligands, 36 J. MEDICINAL CHEMISTRY 2300 (1993) ( Ghosh 1993 ) 1085 Arun K. Ghosh et al., Nonpeptidal P 2 Ligands for HIV Protease Inhibitors: Structure-Based Design, Synthesis, and Biological Evaluation, 39 J. MEDICINAL CHEMISTRY 3278 (1996) ( Ghosh 1996 ) 1086 Arun K. Ghosh et al., N,N -Disuccinimidyl Carbonate: A Useful Reagent for Alkoxycarbonylation of Amines, 33 TETRAHEDRON LETTERS 2781 (1992) ( Ghosh 1992 ) 1087 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 ) 1088 Packing Slip from Aurora Analytics, LLC to Frederick Northrup, Ph.D. (Apr. 4, 2015) 1089 Certificate of Analysis of Compound 13 Darunavir (Apr. 8, 2015) 1090 Certificate of Analysis of Compound 13 Darunavir, ethanol recrystallized (Apr. 8, 2015) 1091 Certificate of Analysis of Compound 13 Darunavir, isopropyl recrystallized (Apr. 8, 2015) 1092 Oral Argument Hearing Transcript from June 3, 2014 in In re Armodafinil Patent Litig., Appeal No (Fed. Cir. June 3, 2014) ( Oral Hrg. Tr. ) viii

10 Lupin Limited ( Lupin or Petitioner ) petitions for Inter Partes Review ( Petition ) under 35 U.S.C. 312 and 37 C.F.R , 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 (b) and 42.63(e), respectively. Required fee under 37 C.F.R (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 (Customer ID No ). 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 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 (defining hydrates as substances that are formed by adding water molecules ); col. 31, ll (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 at 3; 1

11 see also Ex 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 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 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 at 689; Ex at col. 221, ll (claim 7)). The 987 patent expressly concedes such prior art disclosed darunavir and enabling processes for its preparation. (Ex at col. 1, ll ). Such processes necessarily occur in the presence of water molecules. (Ex , 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

12 inert carrier. (Ex at 1874: :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 , 172; Ex , 28-29; Ex ). 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 at 945; Ex , ). Byrn 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 at , 949). Evaluation of darunavir s structure 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. (Ex at 427; Ex , ). Thus, a skilled artisan would have 3

13 reasonably expected the formation of a hydrate of darunavir by following Byrn 1995 s crystallization procedures. (Ex at 946, 949; Ex , ). Routine crystallization studies confirm this. (Ex , 173, 220; Ex , 28-29; Ex ). 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 common pharmaceutical hydrates fall within that range. (Ex , ). The additional composition elements recited in claims 3-8 and 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) is ubiquitous in formulation sciences. (Ex , 43; Ex at 1830: :5, 1874: :9 (Myerson)). Ghosh 1998 and the 775 patent further enable or disclose these elements. (Ex at ; Ex at col. 218, l. 11 col. 220, l. 13 (claims 1-3); col. 221, ll (claim 7); col. 222, ll (claim 13)). Thus, claims 1-19 are obvious. For the reasons set forth herein, pursuant to 37 C.F.R (A), Petitioner requests Inter Partes Review and cancellation of claims 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. 4

14 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 publiclyheld 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, Janssen Prods., L.P. et al. v. Lupin Ltd. et al., C.A. No (D.N.J.), Doc. 1. Waiver of service was executed and filed on Apr. 11, Id., Docs This case is consolidated with Janssen Products, L.P. et al. v. Lupin Ltd. et al., C.A. No (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, Janssen Prods., L.P. et al. v. Teva Pharm. USA, Inc. et al., C.A. No (D.N.J.), Doc. 1. Pursuant to a Settlement Agreement, the parties agreed to terminate the litigation. Id., Docs 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. 5

15 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 (D.N.J.), Doc. 1; C.A. No (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 (D.N.J.) (pending Consolidated Appeal No (Fed. Cir.)); Tibotec Inc. et al. v. Lupin Ltd. et al., C.A. No (D.N.J.) (consolidated with action, pending appeal); Janssen Prods., L.P. et al. v. Lupin Ltd. et al., C.A. No (D.N.J.) (consolidated with action, stayed pending appeal); Tibotec Inc. et al. v. Teva Pharm. USA, Inc. et al., C.A. No (D.N.J.) (consolidated with 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) (telephone) (312) (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) (telephone) (312) (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 at: dmazzochi@rmmslegal.com and traghavan@rmmslegal.com. 6

16 III. GROUNDS FOR STANDING (37 C.F.R (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 IPR (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 (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 Statutory Basis Reference(s) 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 7

17 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, 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 8

18 patent on or about April 20, The 987 patent also makes a priority claim to European Patent Application No. EP ( 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 , 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 (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 at col. 1, ll ). 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 at col. 2, ll ). Pseudopolymorphs asserted as preferred include hydrate and ethanolate, with Form A labeled an 9

19 ethanolate and Form B labeled a hydrate. (Id. at col. 3, ll. 5-21; col. 5, ll ). 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 ). 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]morphous form is defined as a form in which a threedimensional long-range order does not exist. In the amorphous form the position of the molecules relative to one another are essentially random, i.e. without regular arrangement of the molecules on a lattice structure. (Ex at col. 4, ll ). This is consistent with the plain and ordinary meaning of an amorphous drug material. (Ex ). However, the specification broadly defines hydrates as substances that are formed by adding water molecules, and [h]ydration as the process of adding water molecules to a substance that occurs in a particular form. (Ex at col. 4, ll ). Such definitions do not coincide with the plain and ordinary meaning of hydrate, as Section VII below discusses. Patent examples. Example 2 asserts it generated Form B (a hydrate) in admixture with Form D (an acetonate) where Form B impliedly resulted from 10

20 incorporating water into the darunavir solution. (Ex at col. 16, ll ). Example 4 purports to characterize Form B (hydrate) prepared from an undisclosed process using thermogravimetric analysis, but the data discloses weight loss associated with both water and ethanol, indicating the existence of a solvatedhydrate. (Id. at col. 16, l. 60 col. 17, l. 6; col. 17, ll ; Ex , 72). Table 10 discloses approximate expected mass loss for different Forms in thermogravimetric (TG) experiments but such theoretical data fails to account for the expected weight loss of the Example 2 and 4 solvate-hydrate mix. (Ex at col. 17, l. 55 col. 18, l. 22; Ex ). Example 5 states exposing Form A to humidity in an Adsorption/Desorption test produced a Form A and hydrated form B mix. (Ex at col. 18, l. 44 col. 19, l. 16). Example 7 similarly asserts Form A s humidity exposure in an Adsorption/Desorption test purportedly resulted in a mixture of ethanolate form and hydrated form. (Id. at col. 19, l. 37 col. 20, l. 35). Examples disclose characterization, Adsorption/Desorption, solubility, stability and chemical stability testing on Form B, but none describe how the original Form B was prepared and isolated. (Id. at col. 23, l. 34 col. 25, l. 53; Ex ). Additional disclosures. The 987 specification further discusses general processes asserted to prepare compound (X) [darunavir] pseudopolymorphs, including the claimed hydrates. (Ex at col. 3, ll ). The processes 11

21 include those as simple as combining darunavir with water and applying any suitable technique to induce crystallization. (Id. at col. 3, l. 27). No particular conditions are identified as necessary to obtain the claimed hydrates. B. The 987 Patent Prosecution History. The 807 application was filed as a divisional of the 352 application. The original claims directed to pseudopolymorphs of darunavir were cancelled and new claims substantively similar to the 987 patent claims were added. (Ex at 2-3). While the Examiner never rejected the claims under 35 U.S.C. 102 or 103, the Examiner repeatedly rejected the claims for indefiniteness, lack of written description support and lack of enablement. The examiner noted the specification (i) failed to describe how to prepare the claimed hydrates, giving only descriptions on solvate-hydrate forms (which included ethanol); (ii) failed to provide support for any product with the water loss in Table 10 or the indefinite continuous range of the claimed hydrates; and (iii) the expected mass loss of Table 10 does not match the experimental loss of the claimed hydrates, which happened to show loss of water+solvent, not water alone. (Ex at 3-7; Ex at 2, 4-7). During prosecution, Applicants argued against such rejections asserting (i) the entirety of the specification s disclosure supports the claimed hydrates of various ratios of compound to water; (ii) Examples 2, 4, and 7 provide methods of making the claimed hydrates where water was added under routine 12

22 crystallization conditions or relative humidity; (iii) the Examples provide experimental mass loss data aligning with Table 10 s expected mass loss for the claimed hydrates; (iv) the claimed hydrates could readily be formed by subjecting a sample to various relative humidities ; (v) written description of the water ratios existed because a skilled artisan would envision the claimed subject matter ; (vi) the specification clearly defines hydrates in a non-limiting way; (vii) those skilled in the art frequently use continuous ranges to describe phenomena known to occur in fixed intervals; and (viii) it is well known that hydrates can exist in a non-stoichiometric form. (Ex at 5-7; Ex at 5-9; Ex at 2-5; Ex at 4-7). The Examiner allowed the claims on April 10, C. The 987 Patent Is Not Entitled to a Priority Benefit to EP 929. The 987 patent makes a priority claim to EP 929. To receive such benefit, the earlier disclosure must meet the requirements of 35 U.S.C. 112, 1 with respect to patent claims at issue. See, e.g., Cross v. Iizuka, 753 F.2d 1040, (Fed. Cir. 1985). The 987 patent contains substantial new, additional disclosure not found in the May 16, 2002-filed EP 929. (Compare Ex with Ex. 1016). EP 929 lacks, e.g., critical elements of Example 5, along with Examples 7-24 and Figures 9-26 in their entirety. (Ex ). Examples 7, 11 and 12 and 13

23 associated figures (not found in EP 929) were cited by Applicants during prosecution of the 987 patent in response to the Examiner s written description rejection of the claims. (See, e.g., id. 123). Because Patent Owner relied on information missing from EP 929 to argue written description support for the claimed hydrates, the 987 patent claims cannot benefit from priority of EP 929. The EFD is thus no earlier than May 16, 2003, the filing date of the 352 application. VI. PERSON OF SKILL IN THE ART AND STATE OF THE ART. The person of ordinary skill. For the 987 patent, a person of ordinary skill in the art would have had a high level of education (e.g., a Ph.D. in chemistry or a related field), several years of training or experience in his or her pertinent field, and an understanding of various aspects of drug development, including crystallization methods, screening, and characterization. Alternatively, he or she would have held at least a Bachelor s or Master s degree in chemistry or a related discipline with several addiitonal years of experience in his or her pertinent field and a similar understanding of crystallization. (Ex ). Because the drug development process requires a multi-disciplinary approach, the skilled artisan could also take advantage of certain specialized skills of others. (Id. 49). Patent Owner, in the prior litigation involving the related 645 patent, has offered a 14

24 slightly different definition. (Ex at 1780:9-23 (Myerson)). The challenged claims are unpatentable under either definition. The state of the art. As of May 16, 2003, the compound now known as darunavir was well known as evidenced by the disclosures of Ghosh 1998 and the 775 patent. (Ex at 689; Ex at col. 221, ll (claim 7)). As of May 16, 2003, it was also recognized that any drug compound being considered for further development must undergo certain routine evaluations under regulatory guidelines. (Ex at 945). The art recognized that drug molecules frequently existed in more than one solid state form (whether polymorphic, hydrated, amorphous, etc.), and encouraged identifying and characterizing such forms during the early stages of drug development. (Id.). The art set forth a step by step process for conducting crystallization screens to do so. (Id. at 946, 949). Such crystallization screens invariably employed water. (Id.). There was a general understanding in the art, as of May 16, 2003, that larger drug molecules with an imbalance in proton donors and acceptors had the greatest propensity to form hydrates. (Ex at 427). Crystalline forms of drugs were generally preferred based on their handling properties. (Ex , 44-45). Hydrates had long been employed in pharmaceutical drug products. (Id. 44). Darunavir, compositions thereof, and standards for identifying, characterizing and envisioning the likelihood of it forming hydrates was envisioned and known. 15

25 VII. CLAIM CONSTRUCTION. In accordance with 37 C.F.R (b), claim terms of a challenged patent are presumed to take on their ordinary and customary meaning based on the broadest reasonable interpretation ( BRI ) of the claim language in light of the specification. With the exception of hydrate, Petitioner believes that Applicants have not attempted to apply any special meanings to the terms of the 987 patent. Thus, when BRI is applied: The term the compound (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3- yl(1s,2r)-3-[[(4-aminophenyl)sulfonyl](isobutyl)amino]-1-benzyl-2- hydroxypropylcarbamate (claims 1, 3-5 and 9-19) is at least broad enough to read on any existing form of the compound now known as darunavir. The term composition (claims 3-8 and 14-19) is itself at least broad enough to read on any formulation, including, as the specification references, solid, liquid, oral, subcutaneous, intravenous, aerosol, spray or alternative dosage forms. The terms inert carrier, pharmaceutically acceptable carrier, and solid inert carrier (claims 3-19) are at least broad enough to read on additives that are chemically inactive including those suitable for solid oral dosage forms. The term the ratio of compound to water is about or the ratio of the compound to water is about (claims 1, 3-5 and 9-19) refers to the amount of compound to water in in the claimed hydrate as that term is purportedly defined 16

26 in the specification. Given the nature of the Examples and the specification s hydration description, these water molecules may be added via exposure to ambient humidity as well as routine crystallization conditions. The term (claims 2, 6-8) is at least broad enough to read on any form of darunavir that may be characterized as a 1:1 hydrate as that latter term is defined in the specification. As discussed in Section V(A) above, the term amorphous form and thus amorphous (claim 19) is defined in the specification. (Ex at col. 4, ll ). This is in line with the plain and ordinary meaning of the term wherein threedimensional long-range order doesn t exist. (Ex ). The plain and ordinary meaning of hydrate (Claims 1-19) typically refers to a crystalline form of a compound in which water is bound in a specific manner within a three-dimensional lattice structure. (Ex ). As noted above, however, the 987 patent specification defines hydrates as substances that are formed by adding water molecules and hydration as the process of adding water molecules to a substance that occurs in a particular form. (Ex at col. 4, ll ). As Dr. Threlfall confirms, these definitions are far broader than the plain and ordinary meaning. (Ex ). 17

27 During prosecution of the 987 patent, Applicants repeatedly invoked the specification s non-limiting hydrates definition in response to rejections. (Ex at 2 ( [t]he instant specification expressly defines hydrates as substances formed by adding water molecules ); id. at 3 (stating there is no basis for the Examiner s restrictive definition of the term hydrate. As noted above, for example, the Specification clearly defines hydrates, in a non-limiting way.... ); see also Ex at 5-7). Applicants also repeatedly argued that the Examiner was applying a restrictive definition of hydrate that is at odds with the definition that Applicants provide in their specification. (Ex at 3; Ex at 7). Because even Applicants argued that the hydrate term should be given the non-restrictive definitional meaning in the specification, the term hydrate under the BRI is at least broad enough to read on any darunavir substance that is formed by adding water molecules, including those formed in the presence of water molecules (Example 2); by exposure to ambient humidity (Examples 5 and 7); or via the process of hydration. (Ex at col. 16, ll ; col. 18, l. 44 col. 19, l. 16; col. 19, 37 col. 20, l. 35; col. 4, ll ). Moreover, in the prior litigation on the related 645 patent, Patent Owner argued that ethanolates and hydrates of darunavir are equivalent because they are isostructural. (Ex at 39:11-19 (Pls. Opening); id. at 649:21-650:7 (Myerson)). As such, under the BRI, hydrate can also be understood to include trace, undetectable quantities that may not even be 18

28 deliberately made, but are allowed to come into existence via spontaneous action, including from purportedly equivalent isostructural solvates. (Note: Petitioner s proposed constructions should not be taken as an assertion regarding proper claim scope where a different claim construction standard applies.) VIII. EXPLANATION OF GROUNDS FOR UNPATENTABILITY. A petition for inter partes review must demonstrate a reasonable likelihood that the petitioner would prevail with respect to at least 1 of the claims challenged in the petition. 35 U.S.C. 314(a). Petitioner undoubtedly should prevail here because each of the elements of claims 1-19 of the 987 patent is taught or sufficiently enabled by the Ghosh 1998 and 775 patent processes and disclosures respectively. Moreover, the subject matter encompassed within claims 1-19 of the 987 patent are taught by or obvious over Ghosh 1998 and the 775 patent in combination with other art discussed for Ground 3 below. For the obviousness Ground 3, motivational bases and reasonable expectation of success are expressly explained. A. Ground 1: Claims 1-19 of the 987 Patent Are Unpatentable Under 35 U.S.C. 102 in View of the Enabling Disclosure of Ghosh The Ghosh disclosures. Ghosh 1998, published by at least March 17, 1998, more than one year prior to the EFD, and qualifies as prior art under 35 U.S.C. 102(b) and 103. Additional supporting evidence is provided by the Patent Owner s 19

29 admissions during prosecution of the 987 patent (e.g., Exs. 1010, , 1015), Van Gyseghem (Ex. 1006), the Threlfall Declaration (Ex. 1025), the Kalivretenos Declaration (Ex. 1082), the Northrup Declaration (Ex. 1069) and exhibits thereto. Ghosh 1998 discloses darunavir amongst a series of very potent and nonpeptidal HIV protease inhibitors and provides test results demonstrating a composition comprising darunavir and an inert carrier was, in fact, made and used. (Ex at ). Ghosh 1998 shows darunavir (compound 13) functions as a PI at a lower concentration than most of the other nine PIs specifically identified. (Id. at 689 (Table 1 showing potency data, compound 13)). Ghosh 1998 also discloses an enabling darunavir process. The 987 patent specification concedes that darunavir, the [c]ompound of formula (X) and processes for its preparation, are disclosed in Ghosh (Ex at col. 1, ll ). Ghosh 1998 s Scheme 1 and the accompanying description set forth this process. (Ex at ). While Ghosh 1998 was of record before the PTO, the reference was never applied by the Examiner in connection with an anticipation or obviousness rejection during prosecution of the 987 patent or of the related 645 patent. Discussion of Ground. For at least the following reasons, Petitioner establishes a reasonable likelihood of prevailing with respect to anticipation of claims 1-19 over Ghosh

30 A claim is inherently anticipated when it encompasses subject matter the prior art enabled an ordinarily skilled artisan to make. See SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1344 (Fed. Cir. 2005). The skilled artisan need not recognize the inherent disclosure in the prior art. Id. at Applying the above and as discussed in more detail below, Ghosh 1998 discloses in an enabling manner the production of the claimed hydrates encompassed by claims 1-19 of the 987 patent and thus anticipates those hydrates. Moreover, a prior art reference preferably omits from the disclosure any routine technology that is well known at the time of application. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1254 (Fed. Cir. 2004). Ghosh 1998 did not need to disclose known formulation information to prepare compositions satisfying claims 3-8 and Ghosh 1998 disclosed a composition comprising darunavir with an inert carrier; noted the compound was pharmaceutically active; taught it was designed to be orally bioavailable; and noted its structural similarity to Vertex s VX-478 (later known as amprenavir) which was an oral anti-hiv drug in advanced clinical use at the time of Ghosh (Ex at ; see also Ex at ; Ex at 1). The skilled artisan was thus enabled to make the compositions claimed. Independent claims 1 and 2 and Dependent claims 9-13 specify a hydrate of the compound darunavir. Claim 1 further specifies a hydrate in 21

31 which the ratio of the compound to water is about 1:0.5 to about 1:3. Claim 2 specifies, by virtue of chemical structure designation, a ratio of the compound to water of 1:1. Claims 9-13 respectively specify a hydrate of claim 1, wherein the ratio of compound to water is about 1:1 to about 1:2 (claim 9), about 1:0.5 (claim 10), about 1:1 (claim 11), about 1:2 (claim 12), and about 1:3 (claim 13). A hydrate of the compound darunavir. As set forth in Section VII above, the specification defines hydrates as substances formed by adding water molecules, which under the BRI standard at least includes any darunavir substance formed in the presence of water molecules, by exposure to ambient humidity or via the process of hydration (including isostructural solvates). Ghosh 1998 s process necessarily occurs in the presence of water molecules. Specifically, as Scheme 1 and the accompanying description notes, one solvent employed is aqueous NaHCO 3. (Ex at 688; Ex ). As water is accepted as a universal contaminant, one or more of the other solvents employed in the process (e.g., 2-proponol, methylene chloride, etc.), including in the final reaction step that produces darunavir, will also contain water molecules. (Ex at 688; Ex , 142 (as confirmed by Fry (Ex at )). Thus, water molecules necessarily are added to a darunavir substance through this process (even if in trace/contaminate quantities), yielding an enabling disclosure 22

32 for the claimed hydrates. See SmithKline, 403 F.3d at (prior art process anticipated where it prepared trace, undetectable contaminate quantities). Furthermore, Ghosh 1998 discloses that the authors of the reference were at institutions in the Chicago area when synthesizing darunavir. (Ex at 687). Dr. Threlfall confirms the atmosphere s relative humidity in such temperate climates is commonly between at least 30 and 70%, and even in desert conditions is around 5%. (Ex , 142, 166 (as further confirmed by Gaffen (Ex at & tbl. 2, figs. 2 & 3) and Arrhenius (Ex at 31-32)). For this additional reason, a skilled artisan would have understood that Ghosh 1998 discloses a process wherein water molecules are necessarily added to darunavir via exposure to humidity. (Ex at 688; Ex , 166). Moreover, because Ghosh 1998 discloses that at least one sample of darunavir was tested in an enzyme inhibitor assay, a skilled artisan would recognize that the sample was in fact exposed to or associated with water for this additional reason. (Ex at ; see also Ex at ; Ex ). For at least these reasons, Ghosh 1998 by virtue of its enabling disclosure inherently discloses the claimed hydrates. But Ghosh s enabling disclosure is further confirmed given Patent Owner s arguments during prosecution of the 987 patent. For example, in response to an enablement rejection of the claimed hydrates, Applicants, relying on their broad definition of hydrates, argued: 23

33 Compositions wherein water molecules have been added to the claimed compound are clearly enabled by the specification, as originally filed. The specification sets forth several examples describing the claimed compound and water. As noted above, Example 2 describes the preparation of a mixture of Form D (acetonate) and Form B. As stated in Example 2, the starting compound was stirred in acetone and heated until the compound dissolved. Water was then added and the solution was cooled. The resulting crystals were a mixture of the acetonate (Form D) and the hydrate (Form B). Various Form B hydrates were also formed by subjecting Form A to adsorption/desorption tests, as described at Example 7. Form B hydrates were also formed by subjecting a sample of Form B to adsorption/desorption. See, e.g., Example 12. (Ex at 8-9 (emphasis added)). Applicants argued examples producing hydrates derived via exposing amorphous material to relative humidity met the claims under their self-proclaimed non-limiting definition of hydrate. (Ex at 4-5; Ex at 6-7). Thus, Applicants repeatedly argued that their own patent enabled the claimed hydrates preparation because the examples had darunavir (or a solution of darunavir), to which water was added either deliberately or via atmospheric humidity. As Ghosh 1998 samples and processes necessarily generated such conditions, it too is enabling. See SmithKline, 403 F.3d at Petitioner directs the Board s attention to Van Gyseghem, which insists that, as channel structures, darunavir hydrates necessarily form in the presence of water 24