Filed on behalf of Lupin Limited By: Deanne M. Mazzochi ...fishpostgrant.com/wp-content/uploads/IPR2015-01030.pdf1039 Sherry L. Morissette et al., High Throughput Crystallization:

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: [email protected]

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


i

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. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)). .................... 5

C. 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. The ‘987 Patent. ........................................................................... 8

B. The ‘987 Patent Prosecution History. ........................................ 12

C. 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

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 1998. ......................................... 19


ii

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. ..................................... 32

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. .............................................................................................. 41

IX. THE CHALLENGED PATENT CLAIMS WOULD HAVE BEEN OBVIOUS EVEN ASSUMING PATENT OWNER OFFERS ANY ALLEGATIONS OF OBJECTIVE INDICIA. ........... 55

A. Praise in the Industry. ................................................................. 55

B. Copying. ..................................................................................... 56

C. Commercial Success. ................................................................. 57

D. Unexpected Results. ................................................................... 58

X. CONCLUSION ..................................................................................... 60


iii

EXHIBIT LIST PURSUANT TO 37 C.F.R. § 42.63(e) AND TABLE OF ABBREVIATIONS

Lupin

Exhibit No.

Description of Exhibit

1001 U.S. Patent No. 8,518,987 B2 (“the ‘987 patent”) 1002 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”)

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

1008 ‘807 application PH, 7/2/2010 Preliminary Amendment 1009 ‘807 application PH, 9/12/2011 Office Action 1010 ‘807 application PH, 3/12/2012 Reply 1011 ‘807 application PH, 5/22/2012 Final Office Action 1012 ‘807 application PH, 7/20/2012 Reply 1013 ‘807 application PH, 9/17/2012 Pre-Appeal Brief Request for Review 1014 ‘807 application PH, 10/25/2012 Notice of Panel Decision from Pre-

Appeal Brief Review 1015 ‘807 application PH, 1/25/2013 Appeal Brief 1016 European Patent Application No. EP 02076929.5 (“EP ‘929”) 1017 International Publication No. WO 95/06030 A1 (“WO ‘030”) 1018 European Patent No. 1 567 529 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


iv

1021 EP ‘529 PH, 1/29/2013 Experimental Report 1022 U.S. Patent No. 7,700,645 B2 (“the related ‘645 patent”) 1023 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.”)

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. 10-5954 (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. 1027 List of Documents Reviewed and Relied Upon by Terence L.

Threlfall, Ph.D. 1028 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 Co-crystals Represent a New Path to Improved Medicines?, CHEMICAL

COMM. 1889 (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, 295-347, 383-433, 559-613

(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


v

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 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”)

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”)


vi

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. 18185 (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. 1064 Prezista® Prescribing Information (Revised: March 2015) (“2015

Prezista® PI”) 1065 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.”)

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


vii

http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf (“DHHS Guidelines”)

1068 Press Release, Lupin Pharmaceuticals, Inc., Lupin Receives Tentative Approval for Generic Prezista® Tablets, (Dec. 30, 2014), available at http://www.lupinpharmaceuticals.com/30dec2014.htm

1069 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. 1071 REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 173-77, 649-

50, 702-10 (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”)


viii

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. 1084 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”)

1085 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”)

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. 2013-1360 (Fed. Cir. June 3, 2014) (“Oral Hrg. Tr.”)


1

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;


2

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


3

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

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

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. 1005 at 427; Ex. 1025 ¶¶ 19, 212-16). Thus, a skilled artisan would have


4

reasonably expected the formation of a hydrate of darunavir by following Byrn

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

¶¶ 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

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)

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.


5

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

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.


6

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.

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 Back-Up 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) [email protected]

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) [email protected]

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:

[email protected] and [email protected].


7

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

Statutory Basis Reference(s)

1 1-19 § 102 Ghosh 1998 (Ex. 1002) 2 1-19 § 102 The ‘775 patent (Ex. 1003) 3 1-19 § 103 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


8

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


9

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


10

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]morphous form” is “defined as a form in which a three-

dimensional 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. 1001 at col. 4, ll. 50-54).

This is consistent with the plain and ordinary meaning of an amorphous drug

material. (Ex. 1025 ¶¶ 57-58).

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. 1001

at col. 4, ll. 59-62). 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


11

incorporating water into the darunavir solution. (Ex. 1001 at col. 16, ll. 35-47).

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 solvated-

hydrate. (Id. at col. 16, l. 60 – col. 17, l. 6; col. 17, ll. 13-16; Ex. 1025 ¶¶ 13, 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. 1001 at

col. 17, l. 55 – col. 18, l. 22; Ex. 1025 ¶ 66).

Example 5 states exposing Form A to humidity in an Adsorption/Desorption

test produced a Form A and “hydrated form B” mix. (Ex. 1001 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 11-15 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. 1025 ¶¶ 68-70).

Additional disclosures. The ‘987 specification further discusses general

processes asserted to prepare compound (X) [darunavir] pseudopolymorphs,

including the claimed hydrates. (Ex. 1001 at col. 3, ll. 22-28). The processes


12

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. 1008 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. 1009 at 3-7; Ex. 1011 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


13

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. 1010 at 5-7; Ex. 1012 at 5-9;

Ex. 1013 at 2-5; Ex. 1015 at 4-7). The Examiner allowed the claims on April 10,

2013.

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, 1051-52

(Fed. Cir. 1985).

The ‘987 patent contains substantial new, additional disclosure not found in

the May 16, 2002-filed EP ‘929. (Compare Ex. 1001 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. 1025 ¶¶ 116-22). Examples 7, 11 and 12 and


14

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. 1025 ¶ 48). 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


15

slightly different definition. (Ex. 1024 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. 1002 at 689; Ex. 1003 at col. 221, ll. 1-17 (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. 1003 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. 1005 at 427). Crystalline forms of drugs were

generally preferred based on their handling properties. (Ex. 1025 ¶ 41-42, 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.


16

VII. CLAIM CONSTRUCTION.

In accordance with 37 C.F.R. § 42.100(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


17

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. 1001 at col. 4, ll. 50-

54). This is in line with the plain and ordinary meaning of the term wherein three-

dimensional long-range order doesn’t exist. (Ex. 1025 ¶ 58).

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. 1025 ¶ 127). 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. 1001 at col.

4, ll. 59-62). As Dr. Threlfall confirms, these definitions are far broader than the

plain and ordinary meaning. (Ex. 1025 ¶ 129).


18

During prosecution of the ‘987 patent, Applicants repeatedly invoked the

specification’s “non-limiting” “hydrates” definition in response to rejections. (Ex.

1013 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. 1015 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. 1013 at 3; Ex. 1015 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. 1001 at col. 16, ll. 35-47; col. 18, l. 44 – col. 19,

l. 16; col. 19, 37 – col. 20, l. 35; col. 4, ll. 59-62). 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. 1024 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


19

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 1998.

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


20

admissions during prosecution of the ‘987 patent (e.g., Exs. 1010, 1012-13, 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. 1002 at 688-89). 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 1998. (Ex. 1001 at col. 1, ll.

59-64). Ghosh 1998’s Scheme 1 and the accompanying description set forth this

process. (Ex. 1002 at 688-89). 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 1998.


21

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 1343. 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 14-19. 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 1998. (Ex. 1002 at 687-89; see also Ex.

1058 at 545-47; Ex. 1059 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


22

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 NaHCO3. (Ex. 1002 at 688; Ex. 1025 ¶ 142). 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. 1002

at 688; Ex. 1025 ¶¶ 74, 142 (as confirmed by Fry (Ex. 1054 at 478-79)). Thus,

water molecules necessarily are added to a darunavir substance through this

process (even if in trace/contaminate quantities), yielding an enabling disclosure


23

for the claimed hydrates. See SmithKline, 403 F.3d at 1344-45 (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. 1002 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. 1025 ¶¶ 139, 142, 166 (as further confirmed by Gaffen (Ex.

1056 at 18187 & tbl. 2, 18188-89 figs. 2 & 3) and Arrhenius (Ex. 1057 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. 1002 at 688; Ex. 1025 ¶¶ 142, 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. 1002 at

688-89; see also Ex. 1058 at 545-47; Ex. 1025 ¶¶ 143-44).

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:


24

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. 1012 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. 1013

at 4-5; Ex. 1015 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 1344-45.

Petitioner directs the Board’s attention to Van Gyseghem, which insists that,

as channel structures, darunavir hydrates necessarily form in the presence of water


25

at various relative humidities, irrespective of starting form. (Ex. 1006 at 489). The

figure from Van Gyseghem below confirms that even under ambient conditions as

set forth in Ghosh 1998, conversion to hydrate likely occurs:

(Id.).

Repetition of the Ghosh 1998 process and subsequent testing confirms the

presence of the claimed hydrates of darunavir as set forth in the challenged claims.

(Ex. 1082 ¶¶ 5-45 (describing synthesis); Ex. 1069 ¶¶ 7-8, 28-29 (describing

testing and results); Ex. 1025 ¶¶ 168-69, 171-72 (confirming synthesis and testing

establish Ghosh 1998 inherently discloses the claimed hydrates by disclosing at

least amorphous darunavir with added water molecules)).

Further, in prior litigation regarding the related ‘645 patent, Patent Owner

argued, and the Court held, that “trace amounts” or even “a single undetectable

[molecule]” infringes similarly-structured claims. (Ex. 1023 at 44-45 (quoting


26

SmithKline, 403 F.3d at 1335, 1339-40)). That which infringes later, anticipates if

earlier; further, any assertion by Patent Owner that the test results do not

conclusively establish inherency must fail. See SmithKline, 403 F.3d at 1344-

45 (emphasizing enabling disclosure versus prior art detection when analyzing

anticipation of hemihydrate claim because “existence and detection are not the

same thing” and hemihydrate “may have existed in undetectable amounts”).

Ratio of compound to water elements. In analyzing the compound to water

elements of claims 1, 2 and 9-13, Ghosh 1998 must be found to disclose in an

enabling manner the production of a hydrate within the claimed ratios by enabling

the hydrates in the first instance, for several reasons.

First, the Patent Owner’s own admissions during prosecution support

concluding that Ghosh 1998’s disclosure is sufficiently enabling. In response to a

written description rejection, Applicants argued that “[w]hen the entirety of

Applicants’ disclosure is considered, including the specification, figures, and

examples, it is clear that adequate written description has been provided, not only

for the monohydrate, but for hydrates comprising the claimed ratios of compound

to water.” (Ex. 1010 at 6). Applicants insisted that “hydrates of the claimed

compound (referred throughout the specification as ‘Form B’) were made using

several methods,” citing Examples 2, 4 and 7. (Id.). After pointing to the

disclosures of Table 10 disclosing expected thermogravimetric mass losses and


27

comparing the same to the data set forth in those examples, which were

purportedly consistent to the hemi-, mono-, and di-hydrate forms, Applicants

critically argued:

Not only does the specification describe actual samples of the hemi-,

mono- and di-hydrate of the claimed compound, it teaches that

hydrates can be prepared by subjecting Form A or Form B to

adsorption-desorption, that is, by subjecting Form A to Form B to

various relative humidities. See, e.g., Examples 7 and 12. As such,

the claimed hydrates could readily be formed by subjecting a sample

to various relative humidities.

(Id. at 6-7 (emphasis added)). In so arguing, Applicants conceded (1) claimed

hydrates with the required ratios of compound to water necessarily form by

subjecting a sample of darunavir, regardless of form, to various relative humidities;

and (2) that the ratio claimed need not be actually demonstrated but may be

assumed to exist in a sample. Thus, applying Applicants’ analysis of their own

patent disclosures, because Ghosh 1998 necessarily discloses a process of

preparing darunavir, wherein darunavir is necessarily exposed to water at various

relative humidities, the reference enables ordinary skilled artisans to produce a

hydrate within the claimed ratios. (Ex. 1025 ¶ 174).

Applicants also argued during prosecution of the ‘987 patent that the range

of the compound to water ratio (i.e., about 1:0.5 to about 1:3) is enabled despite the


28

lack of specificity in the specification as “[i]t is well known . . . that hydrates can

exist in a non-stoichiometric form that does not have an integer ratio of water to

host molecule.” (Ex. 1015 at 6). Van Gyseghem explains that varying compound

to water ratios result from darunavir existing as a channel structure where any

amount of water (including within the ranges set forth in the challenged claims)

will be present depending on the ambient environmental conditions. (Ex. 1006 at

494). Because the skilled artisan preparing Ghosh 1998 darunavir would have

unquestionably exposed it to the very ambient environmental conditions

Applicants insisted give rise to these ratio of water to compound elements, for this

independent reason, hydrates satisfying the claimed compound to water ratios of

claims 1, 2 and 9-13 are inherently disclosed in Ghosh 1998. (Ex. 1025 ¶ 175).

Moreover, because hemi-, mono-, di- and trihydrates are the most common

stoichiometric ratios of water, with monohydrate being the most common, a person

of ordinary skill in the art noting the darunavir structure disclosed in Table 1 of

Ghosh 1998, and understanding inherent water exposure, would envisage only a

limited number of fixed integer hydrates. (Ex. 1002 at 689; Ex. 1025 ¶ 176).

Under Federal Circuit precedent, this also demonstrates that Ghosh 1998

anticipates the disclosure of the claimed ratios. In re Gleave, 560 F.3d 1331, 1338

(Fed. Cir. 2009) (“[W]hen the class of compounds that falls within the genus is so

limited that a person of ordinary skill in the art can ‘at once envisage each member


29

of this limited class.’ . . . [A] reference describing the genus anticipates every

species within the genus.” (citation omitted)).

Applicants’ admissions during prosecution of the ‘987 patent further confirm

inherency on this basis. Specifically, in response to a written description rejection

with respect to claims directed to a hydrate wherein the ratio of compound is about

1:0.5 to about 1:3, Applicants argued that “[a]dequate written description is

provided if a skilled artisan, upon review of a patent specification in light of the

properties and features of what is described, would envision the claimed subject

matter.” (Ex. 1012 at 6). Pointing to the general description of the possible and

preferable compound to water ratios disclosed in the specification as well as the

prophetic disclosures of Table 10 on the expected ratios of hemi-, mono-, and

dihydrates, Applicants argued that this “reasonably conveys to persons skilled in

the art that Applicants had possession of the claimed subject matter.” (Id. at 6-7).

Under Applicants’ interpretation, being able to envision a hemi-, mono-, di- and

trihydrate of a particular compound is sufficient to provide sufficient written

description support to enable the ratios claimed. A skilled artisan reviewing Ghosh

1998 would have known the same. (Ex. 1025 ¶ 176).

For the reasons set forth above, Ghosh 1998 discloses in an enabling manner

the production of the claimed hydrates of and anticipates claims 1, 2 and 9-13.


30

Independent claims 3 and 6 and Dependent claims 14-18 differ from

claims 1, 2 and 9-13, respectively, merely by prefacing “hydrate” and structure

elements with “A composition comprising” such hydrate/structure, and further

requiring an “inert carrier.” Because Ghosh 1998 actually made a composition

with an inert carrier (glycerol and water), and indeed prepared it for use in

biological testing (see Ex. 1002 at 688-89; see also Ex. 1058 at 545-47), the skilled

artisan would have been likewise enabled to prepare the claimed compositions of

claims 3, 6 and 14-18, including with an inert carrier (which could be water itself,

glycerol or any other vehicle) for the same reasons stated for claims 1, 2 and 9-13.

(Ex. 1025 ¶ 178).

Dependent claims 4-5 and 7-8 require the composition to include a

pharmaceutically acceptable carrier or a solid inert carrier. Given that Ghosh 1998

actually prepared a darunavir composition to demonstrate its biological activity

and touted the disclosed compounds as being developed to have oral bioavailability

(Ex. 1002 at 687-89), the skilled artisan is enabled to include a pharmaceutically

acceptable and/or solid inert carrier with darunavir because such will necessarily

be present in oral dosage forms. (Ex. 1025 ¶ 179). This enabling disclosure, given

the existing skill set of the person of ordinary skill, is sufficient to anticipate these

claim elements. See Chiron, 363 F.3d at 1254. (Ex. 1024 at 1830:18 – 1831:5,

1874:23-1875:9 (Myerson) (Patent Owner’s expert in related ‘645 litigation


31

conceding that such formulation elements did not confer separate patentability

where it was part of the skilled artisan’s general knowledge).

Dependent claim 19 specifies the composition of claim 3 further

comprising “amorphous” darunavir. As noted above, Ghosh 1998 anticipates the

composition of claim 3. The ‘987 patent never exemplifies a composition

comprising both darunavir hydrate and amorphous darunavir. In fact, the only

disclosure of a purported mixture of hydrated and amorphous form is in Example

12 which asserts after Adsorption/Resorption Testing of Form B hydrate, a mixture

of hydrated and amorphous forms remained. (Ex. 1001 at col. 23, l. 59 – col. 24,

l. 3). Example 12 explains that by drying a hydrated product, an amorphous form

results, which picks up water upon exposure to increasing relative humidity and

forms a mixture of hydrated and amorphous forms. (Id.). During prosecution,

Applicants relied on this Example in arguing that claims (including that which

eventually issued as claim 19) were enabled. (See, e.g., Ex. 1013 at 4-5).

Ghosh 1998 discloses in an enabling manner the production of hydrate in

conjunction with amorphous material under virtually the same process. For

example, as confirmed by Dr. Threlfall, the Ghosh 1998 darunavir necessarily

lacked long-range order in the assay test solution when combined with water. (Ex.

1002 at 688-89; Ex. 1025 ¶ 180). The Ghosh 1998 material should behave

similarly when dried as did the ‘987 patent Example 12 product; there is no


32

suggestion the skilled artisan is not able to dry a sample. (Ex. 1025 ¶ 180). Van

Gyseghem also confirms that darunavir hydrate converts to amorphous darunavir

under such drying conditions. (Ex. 1006 at 497). For these reasons, Ghosh 1998

provides an enabling disclosure for the composition of claim 19 as well. As further

support, repetition of the Ghosh 1998 process and subsequent testing of the product

of this process establish the presence of at least amorphous darunavir along with

darunavir with added water molecules. (Ex. 1082, Kalivretenos Decl. ¶¶ 5-45; Ex.

1069, Northrup Decl. ¶¶ 7-8, 28-29; Ex. 1025, Threlfall Decl. ¶ 180).

For the reasons set forth above, Ghosh 1998 anticipates claims 1-19 of the

‘987 patent.

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.

The ‘775 patent disclosures. The ‘775 patent, titled “α- And β-Amino Acid

Hydroxyethylamino Sulfonamides Useful As Retroviral Protease Inhibitors,”

issued on or about June 19, 2001, 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 Patent Owner’s Admissions during prosecution of the ‘987

patent (e.g., Exs. 1010, 1012-13, 1015) and during prosecution before the

European Patent Office (“EPO”) regarding related EP 1567529 (“EP ‘529”) (Ex.

1020), Van Gyseghem (Ex. 1006), and the Threlfall Declaration (Ex. 1025).


33

The ‘775 patent discloses a genus of retroviral PIs, including darunavir

specifically. (See, e.g., Ex. 1003 at col. 2, l. 35 – col. 3, l. 44). Darunavir is

disclosed and claimed multiple times by identification of its structure. (Ex. 1003 at

cols. 161-162 (disclosing in Table 16K, the darunavir structure (as confirmed by

foreign equivalent Ex. 1017, WO ‘030 at 204)); see also Ex. 1003 at col. 218, l. 66

– col. 220, l. 13 (claim 3); col. 221, ll. 1-17 (claim 7)).

The ‘775 patent discloses processes for making darunavir. Example 22

notes, that “[f]ollowing the procedures of Examples 1-21, the compounds shown in

Tables 3, 5A and 5B were prepared and in Tables 4 through 17 can be prepared.”

(Ex. 1003 at col. 96, ll. 33-36). The procedures set forth in Examples 1-21 disclose

water molecules are added throughout the processes to prepare darunavir. (Ex.

1003 at col. 24, l. 45 – col. 25, 26; col. 64, l. 47 – col. 65, l. 8; col. 81, l. 38 – col.

82, l. 7; col. 82, ll. 27-67).

Claim 13 of the ‘775 patent recites “[a] pharmaceutical composition

comprising a compound of claim 1” and a “pharmaceutically acceptable carrier.”

(Ex. 1003 at col. 222, ll. 33-34). Claim 7 recites “[a] compound of claim 3” which

is darunavir. (Id. at col. 221, ll. 1-17). Claim 3 is directed to “[a] compound of

claim 1” and sets forth additional limitations. (Id. at col. 218, l. 66 – col. 220, l.

13). As darunavir satisfies the claim 1 genus, the ‘775 patent claims a

pharmaceutical composition comprising darunavir and a pharmaceutically


34

acceptable carrier. (Ex. 1025 ¶ 190). The ‘775 patent also notes that the active

compound can be mixed with lactose or starch. (Ex. 1003 at col. 217, ll. 36-40).

While the ‘775 patent was of record before the PTO, the Examiner never

applied the reference 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 of the ‘987 patent over the ‘775 patent. Specifically, the ‘775 patent

discloses in an enabling manner the production of the claimed hydrates as well as

compositions comprising such claimed hydrates as set forth in claims 1-19 and

thus anticipates those claims.

Independent claims 1 and 2 and Dependent claims 9-13 require a

“hydrate” of the compound now known as darunavir, which under the BRI

standard discussed in Section VII above includes any darunavir substance formed

in the presence of water molecules, by exposure to ambient humidity or via the

process of hydration including of its isostructural equivalents.

The ‘775 patent discloses processes for making darunavir. (Ex. 1003 at cols.

161-162 (disclosing in Table 16K, the darunavir structure); col. 96, ll. 33-36

(disclosing the products of Table 16K can be prepared by use of Examples 1-21)).

As a prior art patent, the ‘775 patent is presumed to enable everything in its


35

disclosure, including the processes disclosed. In re Antor Media Corp., 689 F.3d

1282, 1287 (Fed. Cir. 2012). To the extent Patent Owner asserts that there is no

evidence that darunavir was actually made and tested in the ‘775 patent, as set

forth in Gleave, it is not “necessary that an invention disclosed in a publication

shall have actually been made in order to satisfy the enablement requirement” so as

to find anticipation. Gleave, 560 F.3d at 1338. Also, the ‘987 patent concedes the

‘775 patent process makes darunavir. (Ex. 1001 at col. 1, ll. 59-61).

This ‘775 patent process, by use of solvents and solutions comprising water,

necessarily involves the addition of water molecules to a darunavir substance. (Ex.

1003 at col. 24, l. 45 – col. 25, l. 26; col. 64, l. 47 – col. 65, l. 8; col. 81, l. 38 – col.

82, l. 7; col. 82, ll. 27-67; Ex. 1025 ¶¶ 152, 153, 156). The final coupling step

required to produce darunavir in the ‘775 patent involves “stirring at-room

temperature for 72 hours, ethyl acetate was added, washed with 5% citric acid,

saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and

concentrated to afford 550 mg of crude product.” (Ex. 1003 at col. 82, ll. 28-

62). As confirmed by Dr. Threlfall, water is used throughout the process and is

specifically employed in the final reaction step required to produce darunavir; thus,

the ‘775 patent necessarily discloses a darunavir substance formed with the

addition of water molecules and inherently discloses the claimed hydrates. (Ex.

1025 ¶ 153). Further, Dr. Threlfall also confirms, given the relative humidity in


36

the atmosphere, a person of ordinary skill in the art would understand that the ‘775

patent process necessarily adds water to darunavir at various relative humidities.

(Ex. 1025 ¶ 183 (as confirmed by Ex. 1056 at 18187 & tbl. 2, 18188-89 figs. 2 & 3

and Ex. 1057 at 31-32)). For at least these reasons, and inherency rationales

expressed above for Ground 1 in the context of the Ghosh 1998 discussion, the

‘775 patent, based on its enabling disclosure alone, inherently discloses the

claimed hydrates.

This inherent disclosure is further confirmed by the Patent Owner’s

arguments during prosecution of the ‘987 patent. As discussed for Ground 1

above, applying the specification’s “non-limiting” “hydrate” definition, Applicants

repeatedly argued in response to lack of enablement rejections of claims virtually

identical to claims 1, 2 and 9-13, that it could be assumed that the specification’s

examples provided an enabling disclosure of the claimed hydrates simply because

water was added to a solution of the compound and because the compound (in

some form) was exposed to relative humidity. (See, e.g., Ex. 1012 at 7-8). Patent

Owner’s admissions compel the conclusion that the ‘775 patent process, which

necessarily places darunavir in the presence of water and further involves exposure

of darunavir in a final coupling reaction to room temperature relative humidity

conditions, “inevitably results in the production of at least trace amounts of

anticipating [hydrates].” SmithKline, 403 F.3d at 1344.


37

Moreover, as noted for Ground 1 above, Van Gyseghem confirms that

hydrates of darunavir necessarily form in the presence of water at various relative

humidities. (Ex. 1006 at 489-90). As the ‘775 patent process, like Van Gyseghem,

necessarily occurs under these conditions, the ‘775 patent enables the production

of the claimed hydrates for this additional reason. (Ex. 1025 ¶ 186).

Furthermore, Patent Owner also alleged, during prosecution before the EPO

regarding the related EP ‘529, that the WO ‘030 equivalent to the ‘775 patent

provides for preparing at least amorphous darunavir. (Ex. 1020 at 5). Even

accepting this allegation as true for the ‘775 patent, because Van Gyseghem

confirms amorphous darunavir converts to a channel hydrated form under

moderate to high relative humidity conditions resulting from ambient exposure, the

skilled artisan has an enabling disclosure via the ‘775 patent for this additional

reason. (Ex. 1006 at 497; Ex. 1025 ¶¶ 154, 157).

With respect to the ratio of compound to water limitations of claims 1, 2 and

9-13, the ‘775 patent discloses in an enabling manner the production of a hydrate

within the claimed ratios by enabling hydrates in the first instance.

Again, applying Applicants’ arguments during prosecution, the ‘775 patent

process necessarily produces the claimed hydrates within the claimed ratios of

compound to water. During prosecution, Applicants expressly argued that “the

claimed hydrates,” (i.e., hemi-, mono-, dihydrates) “could readily be formed by


38

subjecting a sample to various relative humidities.” (Ex. 1010 at 6-7). Thus,

Applicants conceded the claimed hydrates, including within the claimed ratios of

compound to water set forth in claims 1, 2 and 9-13, form by subjecting a sample

of darunavir to various relative humidities. (Id.). Because the ‘775 patent

necessarily discloses a process of preparing darunavir, wherein darunavir is

exposed to water at various relative humidities, the ‘775 patent discloses in an

enabling manner hydrates meeting the ratio of compound to water limitations.

Further, as noted above for Ground 1, Applicants argued that “[i]t is well

known . . . that hydrates can exist in a non-stoichiometric form that does not have

an integer ratio of water to host molecule.” (Ex. 1015 at 6). Van Gyseghem also

confirms that darunavir can exist as a channel structure where any amount of water

(including within the ranges in the challenged claims) is present depending on the

environmental conditions. (Ex. 1006 at 494). For this independent reason,

hydrates within the claimed ratios of claims 1, 2 and 9-13 are inherently disclosed

and presumed enabled in the ‘775 patent. (Ex. 1025 ¶ 186).

Because 1:0.5, 1:1, 1:2 and 1:3 are the most common stoichiometric ratios,

with 1:1 the most common (Ex. 1025 ¶ 187), a skilled artisan identifying the

darunavir structure disclosed in claims 3 and 7 of the ‘775 patent can actually

envisage only limited number of fixed integer hydrates. (Id.). During prosecution,

Applicants argued the skilled artisan’s existing ability to envision such ratios


39

adequately supported and enabled the claimed hydrates. (Ex. 1012 at 6). The

‘775 patent’s disclosure similarly enables such ratios. Gleave, 560 F.3d at 1338.

Thus, the ‘775 patent discloses an enabling manner of producing the claimed

hydrates and thus anticipates claims 1, 2 and 9-13.


composition comprising the same hydrate as specified in claim 1 or as specified in

claim 2 above, or as specified in claims 9-13, along with an inert carrier. As

discussed for Ground 1 above, the ‘987 patent does not exemplify a composition

comprising the claimed hydrates and an inert carrier, but claims the same based on

general disclosures. The ‘775 patent provides these same disclosures. For

example, claim 13 of the ‘775 patent, by virtue of disclosing a pharmaceutical

composition comprising a compound of claim 1 and a pharmaceutically acceptable

carrier, expressly discloses the “composition” and “carrier” limitations of claims 3

and 6. (Ex. 1003 at col. 222, ll. 33-34). The ‘775 patent also inherently discloses

the hydrate and ratio of compound to water elements for the same reasons as set

forth for claims 1, 2 and 9-13, and thereby anticipates the claims.

Dependent claims 4, 5, 7, and 8 require a composition comprising the same

hydrate as specified in claim 3 or the same hydrate as specified in claim 6, further

requiring a pharmaceutically acceptable carrier or a solid inert carrier. As noted

for claims 3 and 6 above, claim 13 of the ‘775 patent identifies a composition


40

comprising a pharmaceutically acceptable carrier. (Ex. 1003 at col. 222, ll. 33-34).

The ‘987 patent identifies suitable inert carriers for solid oral dosage forms, such

as tablets to include lactose and starch. (Ex. 1001 at col. 15, ll. 13-21). The ‘775

patent similarly identifies lactose and starch as inert diluents for solid oral dosage

forms comprising the compounds of the invention. (Ex. 1003 at col. 217, ll. 36-

40). Thus, the ‘775 patent discloses in an enabling manner the production of

compositions comprising a hydrate of darunavir in combination with a carrier of

claims 4, 5, 7, and 8 for the same reasons as set forth for claims 3 and 6,

respectively, and thereby anticipates these dependent claims.

Dependent claim 19 requires a composition of claim 3 further comprising

amorphous darunavir. As noted above for this claim in Ground 1 above, the ‘987

patent never exemplifies a composition comprising both darunavir hydrate and

amorphous darunavir. Example 12 indicates amorphous results from routine

testing of hydrates. (Ex. 1001 at col. 23, l. 59 – col. 24, l. 3). Applicants relied on

Example 12 to insist their claims (including the claim eventually issuing as claim

19) were enabled. (Ex. 1013 at 4-5).

The ‘775 patent discloses a very similar process to Example 12 by virtue of

disclosing in the final coupling step required to prepare darunavir, the addition of

water molecules at room temperature and subsequent formation of the claimed

hydrates by washing with 5% citric acid, saturated sodium bicarbonate and brine,


41

followed by a drying step. (Ex. 1003 at col. 82, ll. 28-67; Ex. 1025 ¶ 191).

Because the ‘775 patent product is necessarily produced by a very similar process

of preparing the claimed mixture of hydrated and amorphous forms set forth in the

‘987 patent, the ‘775 patent’s process conditions will necessarily result in a

mixture of hydrated and amorphous forms. See In re Best, 562 F.2d 1252, 1255

(C.C.P.A. 1977). Van Gyseghem confirms that applying process conditions

similar to those in the ‘775 patent does in fact result in such a mixture of forms.

(Ex. 1006 at 497; see also Ex. 1025 ¶ 192). For the same reason, even accepting

Patent Owner’s allegation during EPO prosecution of the related EP ‘529, that the

WO ‘030 equivalent to the ‘775 patent prepares amorphous darunavir, in view of

Van Gyseghem, exposure to ambient humidity too results in a mixture of forms.

(Ex. 1020 at 5). Thus, the ‘775 patent inherently discloses the composition of

claim 19.

For the reasons set forth above, the ‘775 patent anticipates claims 1-19.

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.

Prior Art Disclosures. As described for Grounds 1 and 2 above, Ghosh

1998 and the ‘775 patent are prior art under 35 U.S.C. §§ 102(b) and 103(b). Byrn

1995 published more than one year prior to the EFD and qualifies as prior art under


42

35 U.S.C. §§ 102(b) and 103. Similarly, Desiraju 1991, published more than one

year prior to the EFD and qualifies as prior art 35 U.S.C. §§ 102(b) and 103.

While Ghosh 1998, the ‘775 patent and Byrn 1995 were of record before the PTO,

none of these references were applied by the Examiner in connection with an

anticipation or obviousness rejection during prosecution of the ‘987 patent or of

the related ‘645 patent. Desiraju 1991 was not submitted to or cited by the PTO.

Additional supporting evidence for the obviousness 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 is provided by the Threlfall Declaration (Ex. 1025), Patent

Owner’s Admissions during prosecution of the ‘987 patent (e.g., Exs. 1010, 1012-

13, 1015) and EP ‘529 (Ex. 1020), Van Gyseghem (Ex.1006), the Kalivretenos

Declaration (Ex. 1082), the Northrup Declaration (Ex. 1069) and exhibits thereto.

Discussion of Ground. As discussed for Grounds 1 and 2 above, Ghosh

1998 and the ‘775 patent disclose in an enabling manner the production of the

claimed hydrates of claims 1-19 of the ‘987 patent and thus anticipate those claims.

To the extent that the Board does not agree that Ghosh 1998 or the ‘775 patent

anticipates, Petitioner establishes a reasonable likelihood of prevailing with respect

to obviousness of claims 1-19 of the ‘987 patent over Ghosh 1998 and the ‘775

patent in view of Byrn 1995, Desiraju 1991 and the knowledge of the person of

ordinary skill in the art.


43

Independent claims 1, 2 and Dependent claims 9-13. Claims 1, 2 and 9-

13 (as well as claims 3-8 and 14-19) each require a “hydrate” of darunavir, within

a range or specific ratio of compound to water. As noted above, under the BRI

standard set forth in Section VII above, the claimed “hydrate” includes any

darunavir substance formed in the presence of water molecules, by exposure to

ambient humidity or via the process of hydration.

As discussed for Grounds 1 and 2 above, Ghosh 1998 and the ‘775 patent

disclose, amongst other things, the compound darunavir, its structure, and

processes of preparing the same. (Ex. 1002 at 688-89; Ex. 1003 at cols. 161-162;

col. 218, l. 66 – col. 220, l. 13 (claim 3); col. 221, ll. 1-17 (claim 7); col. 96, ll. 33-

36 (Example 22)).

Ghosh 1998 discloses that darunavir is one of only four compounds

expressly synthesized in the reference that had demonstrated extraordinary

potency. (Ex. 1002 at 689). Ghosh 1998 also notes that the selected PIs are the

subject of ongoing biological investigation. (Id.). Similarly, while the ‘775 patent

discloses many compounds, it only claims eight. (Ex. 1003 at col. 218, l. 11 – col.

220, l. 13 (claims 1-3); col. 221, ll. 1-17 (claim 7)). As Dr. Threlfall confirms

based on the ‘775 patent, Ghosh 1998, as well as the general knowledge in the art,

darunavir would have been considered as a candidate suitable for at the very least

preformulation studies. (Ex. 1025 ¶¶ 194-96).


44

During the Prior Litigation and trial on the related ‘645 patent, Patent Owner

applied a lead compound analysis (“LCA”) in arguing that nothing in Ghosh 1998

or the ‘775 patent indicates darunavir should be pursued for clinical studies

because millions of other compounds exist; darunavir is a complex compound; and

it is purportedly hard to synthesize. First, LCA generally applies to the

development phase of designing a new drug molecule, not with respect to an old

molecule with a known structure like darunavir. Compare Otsuka Pharm. Co. v.

Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012), with Aventis Pharma

Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1300-01 (Fed. Cir. 2007) (no

“lead compound” analysis applied to question of whether there was a motivation to

pursue a single isomer of an existing drug). Second, as discussed above, Ghosh

1998 and the ‘775 patent provide ample motivation to pursue darunavir clinically

(even if such motivation is unnecessary). (Ex. 1002 at 689; Ex. 1003 at col. 218, l.

11 – col. 220, l. 13 (claims 1-3); col. 221, ll. 1-17 (claim 7)). Third, the existence

of complexity in structure or processing would not deter a party from evaluating a

promising compound like darunavir. (Ex. 1024 at 777:9-19 (Marshall)).

Motivation to Combine with Byrn 1995. Motivation to combine and

modify “may be derived from the prior art reference itself, from the knowledge of

one of ordinary skill in the art, or from the nature of the problem to be solved.”

SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp., 225 F.3d 1349, 1356 (Fed. Cir.


45

2000). Here, Ghosh 1998 expressly discloses that “recent research efforts have

been devoted to the design and synthesis of nonpeptidal protease inhibitors that are

potent against mutant strains resistant to the current approved protease inhibitors”

and further discloses that “in-depth biological studies of the selected protease

inhibitors are the subject” of ongoing investigation. (Ex. 1002 at 687, 689). In the

field of the invention section, the ‘775 patent similarly identifies “[t]his invention,

in particular, relates to sulfonamide- containing hydroxyethylamine protease

inhibitor compounds, a composition and method for inhibiting retroviral proteases

such as human immunodeficiency virus (HIV) protease and for treating a retroviral

infection, e.g., an HIV infection.” (Ex. 1003 at col. 1, ll. 25-30). As confirmed by

Dr. Threlfall, based on these disclosures, a person of ordinary skill in the art would

have been motivated to evaluate darunavir and address routine regulatory issues

that would arise in connection with the in-depth ongoing investigation of the

compound. (Ex. 1025 ¶ 197).

This evaluation would have placed the person of ordinary skill in the art

squarely on the path to Byrn 1995 which explains that during the course of product

development, regulatory guidelines direct an applicant to investigate whether a

new chemical entity can exist in different solid-state forms, including polymorphs,

hydrates and solvates. (Ex. 1004 at 945). Byrn 1995 stresses the importance of

routinely screening for these solid-state forms, during the preformulation stage of


46

drug development and most certainly before pivotal clinical trials, so as to avoid

conversion problems during latter stages. (Id. at 945, 949).

According to Byrn 1995, the regulatory guidelines “suggest the importance

of controlling the crystal form of the drug substance.” (Ex. 1004 at 945). As noted

above, Patent Owner has alleged, during prosecution before the EPO of EP ‘529,

that the closest prior art, as set forth in the WO ‘030 foreign equivalent to the ‘775

patent, is amorphous darunavir. (Ex. 1020 at 5). As Dr. Threlfall confirms,

crystalline materials are generally desired in the pharmaceutical industry because

of their ease of handling, compatibility with excipients, and long term chemical

and physical stability amongst other factors. (Ex. 1025 ¶ 198). In other words, not

only would regulatory guidelines have motivated the person of ordinary skill in the

art to assess the crystallinity of darunavir, but accepting that the closest prior art

was amorphous, the general desire for crystalline materials over amorphous

independently would have done so.

Byrn 1995 discloses routine procedures for assessing crystallinity.

Specifically, Byrn 1995 provides a sequence of decision trees and flowcharts to be

followed in order to investigate the existence of crystalline forms of a drug, as

instructed by FDA Guidelines. (Ex. 1004 at 945-46). According to Byrn 1995, the

first step in complying with FDA’s directive is to crystallize the substance from a

very limited selection of solvents. (Id. at 946). Byrn 1995 further notes that one of


47

the solvents that should be used in these crystallization screens is water as well as

ethanol. (Id.). As confirmed by Dr. Threlfall, such a crystallization screening is

routine, would just take a few days to complete, and could be purchased in the

relevant time frame from a number of different companies. (Ex. 1025 ¶¶ 203, 206-

08). In fact, as confirmed in the prior litigation regarding the related ‘645 patent,

Patent Owner admitted that it used a third-party company to conduct such a screen

utilizing water as one of the solvents to confirm the existence of solid-state forms.

(Ex. 1024 at 466:14-17, 468:6-9 (Wigerinck); 2374:15-17, 2389:2-4 (Janssens)).

This also confirms that such screening is routine and obvious. See Pfizer, Inc. v.

Apotex, Inc., 480 F.3d 1348, 1367 (Fed. Cir. 2007) (salt selection was routine;

Pfizer scientists merely verified the product of a process that was routine in the

art); see also Ex. 1092, Oral Hrg. Tr. at 13:6-12, 16:4-17:17, In re Armodafinil

Patent Litig., No. 2013-1360 (Fed. Cir. June 3, 2014) (Patent Owner challenged to

explain why routine crystallization with ethanol which resulted in claimed form a

majority of the time was not obvious).

Byrn 1995 also provides an entirely separate flow chart relating specifically

to screening for hydrates and counsels that the steps outlined in this second flow

chart pertaining to hydrates should be “applied after the preliminary

crystallizations have been completed.” (Ex. 1004 at 949). As Dr. Threlfall


48

confirms, the fact that Byrn 1995 singles out hydrate screening underscores the

ubiquitous nature with which hydrate formation is observed. (Ex. 1025 ¶ 211).

Thus, a person of ordinary skill in the art, following the teachings discussed

above, would have certainly been directed to crystallize darunavir from water or

water-containing mixtures.

Reasonable Expectation of Success of Forming Hydrate. The person of

ordinary skill in the art would also have reasonably expected the formation of a

hydrate in such routine crystallization efforts. First, as Dr. Threlfall confirms,

because darunavir is a complex molecule, a person of ordinary skill in the art

would recognize that without a solvent to fill in the gaps, the compound would not

crystallize. (Ex. 1025 ¶ 202).

Further, prior to May 16, 2003, Desiraju 1991 specifically taught that

compounds like darunavir, in which there is an imbalance in the ratio of hydrogen

bond donors to hydrogen bond acceptors, are more likely to form hydrates. (Ex.

1005 at 427). Dr. Threlfall confirms that this theory was accepted in the field by

persons of ordinary skill in the art. (Ex. 1025 ¶ 212). For at least these reasons, a

person of ordinary skill in the art would have had a reasonable expectation of

preparing a hydrated form of darunavir.

Should Patent Owner rely on general statements in the literature regarding

unpredictability in the art, the Federal Circuit has long cautioned that “general


49

statements regarding the unpredictability” do not establish absence of reasonable

expectation of success. See, e.g., Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286,

1292 (Fed. Cir. 2013); see also Pfizer, 480 F.3d at 1364 (“[O]bviousness cannot be

avoided simply by a showing of some degree of unpredictability in the art.”).

Moreover, even setting aside crystallization procedures, as discussed for

Grounds 1 and 2 above, Patent Owner’s admissions during prosecution confirm the

reasonable likelihood of success in forming the claimed hydrates. As noted above,

Applicants admitted that the claimed hydrates can readily be formed under routine

crystallization conditions as well as by subjecting darunavir forms to various

relative humidities, i.e., in the presence of water. (See, e.g., Ex. 1010 at 7). Van

Gyseghem further confirms darunavir will convert from an amorphous form, for

example, to a channel hydrated form under moderate to high relative humidity.

(Ex. 1006 at 497). Van Gyseghem confirms that a solvated form will also convert

to the hydrate “under ambient conditions.” (Id.). Thus, should the Patent Owner

argue that the prior art fails to disclose specific crystallization conditions to

produce the claimed hydrates, such arguments fail in view of these very

admissions.

Reasonable Expectation of Success of Forming Hydrate Within Claimed

Ratios of Compound to Water. With respect to the additional ratio of compound

to water elements of claims 1, 2 and 9-13, the relevant question is not whether one


50

of ordinary skill in the art had an absolute guarantee of success, see Pfizer, 480

F.3d at 1364, or a perfect correlation between the use of water as a recrystallization

solvent and the formation of a hydrate exhibiting the claimed ratio of compound to

water. Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1295 (Fed. Cir. 2006)

(holding that a “general, albeit imperfect, correlation between a drug’s

lipophilicity and its colonic absorptivity” was adequate to establish a “reasonable

likelihood of success” even though colonic absorption was not “guaranteed”

(emphasis added)). Rather, the appropriate question is whether the skilled person

would have reasonably expected that, if he or she crystallized a darunavir sample

from water or exposed a sample to relative humidity, it would also be reasonable to

predict that a hydrate exhibiting the claimed ratios of compound to water would

result. See Pfizer, 480 F.3d at 1364.

As a preliminary matter, during prosecution of the ‘987 patent, Patent Owner

failed to demonstrate the criticality of any degree of hydration. Instead, Applicants

pointed to the disclosures of Table 10 disclosing expected thermogravimetric mass

losses and compared the same to the data set forth in Examples 2, 4, and 7, which

they argued were consistent with the hemi-, mono-, and dihydrate forms. (Ex.

1010 at 5). Moreover, Applicants argued that even without such data, the claimed

hydrates “could readily be formed by subjecting a sample to various relative

humidities.” (Id. at 6-7 (emphasis added)).


51

Furthermore, as confirmed by Dr. Threlfall, the person of ordinary skill in

the art would have understood from the ample data available regarding other

compounds that about 90% of known hydrated forms of pharmaceutical

compounds occur as hemi-, mono-, di- and trihydrates with a monohydrate being

the most common. (Ex. 1025 ¶¶ 222-25). In other words, because a hydrate of

darunavir is reasonably expected, the fact that it has a degree of hydration between

0.5 and 3 water molecules per darunavir molecule is entirely expected based on the

historical data. (Id.). Indeed, during prosecution of the ‘987 patent claims,

Applicants applied and relied on this general understanding in response to

rejections. (Ex. 1012 at 6). Thus, a person of ordinary skill in the art would have

reasonably expected a degree of hydration ranging from about 1:0.5 to about 1:3

(darunavir:water) would result in such a routine crystallization.

Routine crystallizations of the Ghosh 1998 reproduction product using

ethanol and isopropanol further confirm that there was a reasonable expectation of

success that Byrn 1995’s crystallization studies would have resulted in the

preparation of the claimed hydrates. (Ex. 1082, Kalivretenos Decl. ¶¶ 46-48; Ex.

1069, Northrup Decl. ¶¶ 7-8, 28-29). Specifically, such results demonstrate that at

least one isostructural solvate of darunavir was produced which, based on Van

Gyseghem, converts to the claimed hydrates under ambient conditions. (Ex. 1082,


52

Kalivretenos Decl. ¶¶ 46-48; Ex. 1069, Northrup Decl. ¶¶ 7-8, 28-29; Ex. 1025,

Threlfall Decl. ¶ 220; Ex. 1006 at 497).

For at least these reasons, claims 1, 2 and 9-13 are obvious over Ghosh 1998

and the ‘775 patent in view of Byrn 1995, Desiraju 1991 and the knowledge of the

person of ordinary skill in the art.


composition comprising the same hydrates as specified in claim 1 or as specified in

claim 2, respectively, or as specified in claims 9-13, respectively, and an inert

carrier. As discussed above, claims 1, 2 and 9-13 are obvious over Ghosh 1998

and the ‘775 patent in view of Byrn 1995, Desiraju 1991 and the knowledge of the

person of ordinary skill in the art. For the same reasons, the same claim elements

in claims 3, 6 and 14-18 are obvious as well.

With respect to the “composition” comprising an “inert carrier” limitations

as required by claims 3, 6 and 14-18, such additions are well within the knowledge

of a person of ordinary skill in the art because hydrates have universally been

accepted as appropriate for pharmaceutical products, including those comprising a

pharmaceutically acceptable carrier. (Ex. 1025 ¶¶ 238-40, 245, 253; Ex. 1024 at

1830:18 – 1831:5, 1874:23-1875:9 (Myerson)) As discussed for Ground 1 above,

Ghosh 1998, by its disclosure of enzymatic assay testing of darunavir, also

discloses a composition comprising an inert carrier. (Ex. 1002 at 688-89


53

(incorporating Ex. 1058 at 545-47); Ex. 1025 ¶ 238). Moreover, as noted in

Ground 2 above, the ‘775 patent expressly discloses a composition and teaches that

it can incorporate compounds including darunavir along with a pharmaceutically

acceptable carrier. (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); Ex. 1025 ¶ 239). By virtue of

these disclosures, Ghosh 1998 and the ‘775 patent in view of Byrn 1995, Desiraju

1991 and the knowledge of the person of ordinary skill in the art disclose or render

obvious all limitations of claims 3 and 6. Motivation to combine and reasonable

expectation of success are the same as noted for claims 1, 2 and 9-13 above.

Dependent claims 4, 5, 7 and 8 require a composition comprising the same

hydrate as specified in claim 1 or the same hydrate as specified in claim 6, further

requiring a pharmaceutically acceptable carrier or a solid inert carrier. Ghosh 1998

discloses a composition comprising darunavir and an inert carrier and also notes

that the design goal is an orally bioavailable product. (Ex. 1002 at 687-88; Ex.

1025 ¶ 238). Furthermore, the claims of the ‘775 patent confirm that darunavir can

be combined with a pharmaceutically acceptable carrier. (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); Ex. 1025 ¶ 239). The ‘987 patent identifies suitable inert carriers for

solid oral dosage forms, such as tablets to include lactose and starch. (Ex. 1001 at

col. 15, ll. 13-21). The ‘775 patent similarly identifies lactose and starch as inert


54

diluents for solid oral dosage forms comprising the compounds of the invention

(including darunavir). (Ex. 1003 at col. 217, ll. 36-40). The motivation to

combine and reasonable expectation of success are the same as noted for claims 1,

2 and 9-13 above. Thus, the references discussed for claims 1, 2 and 9-13 above

disclose or render obvious each and every limitation of claims 4, 5, 7 and 8 as well.

Dependent claim 19 requires a composition of claim 3 further comprising

amorphous darunavir. To the extent that the Board does not agree that Ghosh 1998

or the ‘775 patent fully anticipates the amorphous limitation of claim 19, it would

at least be obvious. Specifically, Byrn 1995 expressly discusses the concern over

conversion of forms in formulations, and also provides a step-by-step method of

identifying such mixtures in both hydrate and amorphous screening. (Ex. 1004 at

949, 952). Accordingly, a person of ordinary skill in the art would have not only

been motivated to identify mixtures of hydrated and amorphous darunavir in

compositions, but would have had a reasonable expectation of success in view of

the routine methodology provided in Byrn 1995. (Ex. 1025 ¶ 257). Moreover,

Van Gyseghem confirms that darunavir mixtures necessarily result from the

conversion studies set forth in Byrn 1995. (Ex. 1006 at 493, 497). For at least

these reasons, claim 19 is rendered obvious over Ghosh 1998 in view of Byrn

1995, Desiraju 1991 and the knowledge of a person of ordinary skill in the art.


55

IX. THE CHALLENGED PATENT CLAIMS WOULD HAVE BEEN OBVIOUS EVEN ASSUMING PATENT OWNER OFFERS ANY ALLEGATIONS OF OBJECTIVE INDICIA.

Patentee bears the initial burden of coming forth with a nexus between the

evidence presented and the allegedly novel aspects of the claimed invention. See

Rolls-Royce, PLC v. United Techs. Corp., 603 F.3d 1325, 1340 (Fed. Cir. 2010).

During prosecution of the ‘987 patent, Applicants did not present a single

argument nor an iota of data in support of any secondary consideration of

nonobviousness, let alone with respect to nexus. The scope of the following

discussion regarding secondary considerations is thus premised on Patent Owner’s

arguments during trial on the related ‘645 patent and EPO prosecution of EP ‘529.

Should the Patent Owner proffer any additional secondary considerations

and/or nexus evidence, such evidence would need to be fully consonant with the

full scope of the ‘987 patent’s claims. Allergan, Inc. v. Apotex Inc., 754 F.3d 952,

965 (Fed. Cir. 2014). Given under BRI, the claims must be construed broadly to

include trace quantities of hydrate in the prior art product that achieve nothing of

pharmaceutical or commercial value, there simply is no secondary considerations

evidence that can render the claims non-obvious. Id.

A. Praise in the Industry.

In the Prior Litigation, Patent Owner generally asserted that Prezista® is the

subject of praise and has experienced a high level of sales and prescriptions. (Ex.


56

1024 at 33:5-21 (Pls. Opening); 104:12-16 (Stoffels)). The Patent Owner has not

disputed, however, that Prezista®’s clinical effects are inherent properties of the

darunavir molecule itself (apart from solid-state form considerations), which the

Patent Owner admits was in the prior art, or otherwise emanate from factors

unrelated to the ‘987 patent. (Ex. 1024 at 121:1-9, 129:6-12 (Stoffels); 1832:6-21

(Myerson); 861:9-15 (Zingman); 2481:9-21 (Falcon); 193:11-21 (Wigerinck);

2091:15-18 (Reider)). There is also simply no basis for arguing that any praise and

use of Prezista® result from the presence of darunavir hydrate that meets the

requirements of the ‘987 patent claims. In fact, darunavir ethanolate is the form of

the API that the Patent Owner has contended is used in the Patent Owner’s

commercial darunavir product in the United States, Prezista®. (Ex. 1062 ¶¶ 26-27).

Under such circumstances, there is an insufficient nexus between the alleged praise

and the allegedly novel aspects of the claims. See Tokai Corp. v. Easton Enters.,

Inc., 632 F.3d 1358, 1369-70 (Fed. Cir. 2011).

B. Copying.

In the context of pharmaceutical cases, the Federal Circuit has deemed

evidence of copying to be “not probative of nonobviousness because a showing of

bioequivalence is required for FDA approval.” Bayer Healthcare Pharm., Inc. v.

Watson Pharm., Inc., 713 F.3d 1369, 1377 (Fed. Cir. 2013). In any event, as

reflected in the public record, Patent Owner has conceded that neither Lupin


57

Limited’s ANDA Products, nor those of ANDA-filer Mylan Pharmaceuticals Inc.,

use darunavir hydrate as the API. (Ex. 1024 at 39:17-23 (Pls. Opening)). There is

no probative evidence of widespread copying.

C. Commercial Success.

The particular solid-state form of a drug does not guide physicians’

prescribing decisions. (Ex. 1024 at 889:17-890:12 (Zingman)). Further, the Patent

Owner has admitted that Prezista® does not contain significant amounts of any of

the hydrated forms of darunavir claimed in the ‘987 patent. (Ex. 1064 at 23). As

confirmed by Dr. Leffler, there is also no evidence that any sales of Prezista® are

due to any inter-conversion between the claimed hydrate forms and the ethanolate

form utilized in Prezista®. (Ex. 1062, Leffler Decl. ¶¶ 33-34). Thus, there is no

evidence of a nexus between the claims of the ‘987 patent and Prezista® sales.

Even assuming for the sake of argument that some nexus exists (it does not),

other factors contributing to Prezista® sales (e.g., the products Prezista® is co-

administered with; other patents, including the blocking patents directed to the

darunavir molecule as well as other ancillary patents relating to darunavir such as

those that the district court in the Prior Litigation held contributed to Prezista®

sales; the influence of treatment guidelines) would need to be analyzed in order to

ensure the proper weight is accorded to each contributing factor. (Ex. 1062,

Leffler Decl. ¶¶ 30-36). Patent Owner cannot properly do so here. (Id. ¶ 39).


58

D. Unexpected Results.

There is no discussion or evidence in the specification of the ‘987 patent or

the prosecution history of the patent relating to unexpected results as allegedly

relevant to darunavir hydrate. (Ex. 1025 ¶¶ 261-62). For example, there is no data

in the specification that describes any unexpected benefit of employing a hydrate

over what was disclosed in the prior art. (Id. ¶ 261).

Should Patent Owner argue that darunavir hydrate resulted in a better safety

profile than prior art darunavir, Prezista®’s side effect profile has nothing to do

with the form of the drug material or tablets used. (Ex. 1024 at 893:4-11

(Zingman)). By the time darunavir is absorbed into the bloodstream, it is no longer

in any crystalline form; a point that the Patent Owner has never disputed. (Id. at

1895:6-10 (Myerson)). Moreover, while darunavir hydrate, may be employed in

commercial products, the same is true for other forms. There is no evidence that

darunavir hydrate is extraordinary. (Ex. 1025 ¶ 276).

While the Patent Owner has presented data to the EPO regarding EP ‘529

that purports to show that darunavir hydrate exhibits unexpectedly superior

properties relative to darunavir amorphous (Exs. 1020-21), this data falls short.

(Ex. 1025 ¶¶ 264-67). First, Patent Owner did not demonstrate that the subject

prior art (i.e., WO ‘030, counterpart to the ‘775 patent) produces darunavir

amorphous. (Id. ¶ 268). Rather, Patent Owner assumed, reasoning by analogy,


59

that because the product of Example 18B of WO ‘030 occurred as a white foam,

darunavir would only occur in like form. (Id.). As discussed in Section VIII(B)

above, the ‘775 patent in fact enables production of the claimed hydrates.

Even assuming that the closest prior art is amorphous darunavir, any

purported benefits of darunavir hydrate relative to amorphous darunavir, including,

for example, in terms of dissolution, solubility, bioavailability, and stability, would

not have been unexpected to the skilled artisan. As discussed in Section VIII, the

skilled artisan looking to improve upon certain attributes of an amorphous drug

would routinely seek to isolate a crystalline product with an expectation of

realizing one or more of such improvements. (Ex. 1025 ¶¶ 269-70).

Moreover, as confirmed by Dr. Threlfall, the data submitted stems from a

test method conducted at very high relative humidity which improperly skews

stability in favor of hydrated forms. (Ex. 1025 ¶¶ 271, 273). Further, the absence

of data showing uniform particle size as between the darunavir amorphous and

darunavir hydrate samples being tested further supports a finding that different

dissolution and solubility would be expected. (Id. ¶ 272). Moreover, Patent

Owner’s data submitted to the EPO lacks probative value because the particular

hydrate form is not characterized and, therefore, cannot be tied to any particular

hydrate. (Id. ¶ 274). Trying to do so, results in unfounded speculation.


60

For the reasons stated above, there is no evidence of any secondary

consideration that supports a finding of nonobviousness of the ‘987 patent.

X. CONCLUSION

Claims 1-19 of U.S. Patent No. 8,518,987 B2 are anticipated as described

above and rendered obvious over the prior art combination cited herein. None of

these arguments were considered by the Patent Examiner during the prosecution of

the ‘987 patent. Pursuant to 35 U.S.C. § 314(a), petitioner has established a

reasonable likelihood of prevailing on each ground presented herein, and prompt

and favorable consideration of this Petition is respectfully requested.

Respectfully Submitted,

RAKOCZY MOLINO MAZZOCHI SIWIK LLP

Dated: April 9, 2015. /Deanne M. Mazzochi/ Deanne M. Mazzochi

Registration No. 50,158 6 West Hubbard, Suite 500

Chicago, IL (312) 222-6305 (telephone) (312) 222-6325 (facsimile) [email protected]

Attorneys for Petitioner Lupin Limited

CERTIFICATE OF SERVICE

Pursuant to 37 C.F.R. §§ 42.6(e) and 42.105, I, Deanne M. Mazzochi,

hereby certify that on this 9th day of April, 2015, I caused to be served a true and

correct copy of the foregoing Petition for Inter Partes Review of U.S. Patent No.

8,518,987 B2 (and accompanying exhibits 1001 - 1092) in its entirety by Federal

Express®, which is a means at least as fast and reliable as U.S. Express Mail, on the

following:

Baker & Hostetler LLP ATTN: Stephanie A. Lodise Cira Centre, 12th Floor 2929 Arch Street Philadelphia, PA 19104-2891 Patent owner’s correspondence address of record for U.S. Patent No. 8,518,987

I also caused to be served a courtesy copy of the foregoing via Electronic Mail,

upon the following litigation counsel for Janssen R&D Ireland and Janssen

Sciences Ireland UC:

Gregory L. Diskant ([email protected]) Irena Royzman ([email protected]) Patterson Belknap Webb & Tyler LLP 1133 Avenue of the Americas New York, New York 10036 Telephone: (212) 336-2000

2

Fax: (212) 336-2222 Dated: April 9, 2015. /Deanne M. Mazzochi/

Deanne M. Mazzochi Registration No. 50,158 6 West Hubbard, Suite 500 Chicago, IL (312) 222-6305 (telephone) (312) 222-6325 (facsimile) [email protected] Attorney for Petitioner Lupin Limited