You Oughta Know Uma História Oral de Jagged Little Pill de Alanis Morissette
Filed on behalf of Lupin Limited By: Deanne M. Mazzochi...
Transcript of Filed on behalf of Lupin Limited By: Deanne M. Mazzochi...
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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”)
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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”)
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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.”)
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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;
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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reasonably expected the formation of a hydrate of darunavir by following Byrn
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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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A. Notice of Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)).
Petitioner Lupin Limited has no parent corporation, no publicly-held
corporation owns 10% or more of its stock, and is a real party of interest. Lupin
Pharmaceuticals, Inc. is a wholly-owned subsidiary of Lupin Limited, no publicly-
held corporation owns 10% or more of its stock, and is also a real party of interest.
B. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)).
The ‘987 patent is the subject of a patent infringement suit filed by Janssen
Products, L.P. and Janssen R&D Ireland (collectively “Janssen”) against Petitioner
and Lupin Pharmaceuticals, Inc. on Mar. 4, 2014. Janssen Prods., L.P. et al. v.
Lupin Ltd. et al., C.A. No. 14-1370 (D.N.J.), Doc. 1. Waiver of service was
executed and filed on Apr. 11, 2014. Id., Docs. 6-7. This case is consolidated
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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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13, 2014 (D.N.J.) and Aug. 15, 2014 (D. Del). Janssen Prods., L.P. et al. v. Cipla
Ltd. et al., C.A. No. 14-5093 (D.N.J.), Doc. 1; C.A. No. 14-1056 (D. Del.), Doc. 1.
The related ‘645 patent is also the subject of the following actions: Janssen
Prods., L.P. et al. v. Lupin Ltd. et al., Lead Consolidated C.A. No. 10-5954
(D.N.J.) (pending Consolidated Appeal No. 14-1842 (Fed. Cir.)); Tibotec Inc. et al.
v. Lupin Ltd. et al., C.A. No. 11-4027 (D.N.J.) (consolidated with 10-5954 action,
pending 14-1842 appeal); Janssen Prods., L.P. et al. v. Lupin Ltd. et al., C.A. No.
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:
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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Sections VII and VIII below set forth the detailed explanation as to how
terms of the ‘987 patent claims are to be construed and how these claims, as
properly construed, are unpatentable under the grounds set forth above. In support
of the proposed grounds for unpatentability, this Petition is accompanied by a
declaration of technical expert Dr. Terence L. Threlfall, Ph.D. (Ex. 1025), who
explains what the prior art would have conveyed to a person of ordinary skill in the
art. This Petition is also accompanied by the declaration of pharmacoeconomics
expert, Dr. Keith B. Leffler, Ph.D. (Ex. 1062). The petitioner further relies on
other Exhibits set forth on the Exhibit List filed concurrently herewith, including
the Declaration of Aristotle G. Kalivretenos, Ph.D. (Ex. 1082) and the Declaration
of Frederick J. Northrup. Ph.D. (Ex. 1069).
V. OVERVIEW OF THE ‘987 PATENT AND THE PROSECUTION HISTORY THEREOF.
A. The ‘987 Patent.
The ‘987 patent, titled Pseudopolymorphic Forms of a HIV Protease
Inhibitor, issued on or about August 27, 2013, from U.S. Patent Application Serial
No. 12/536,807 (“the ‘807 application”), filed on or about August 6, 2009. The
‘807 application was filed as a divisional of U.S. Application Serial No.
10/514,352 (“the ‘352 application”), filed as International Patent Application No.
PCT/EP03/50176 on or about May 16, 2003, which issued as the related ‘645
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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patent on or about April 20, 2010. The ‘987 patent also makes a priority claim to
European Patent Application No. EP 02076929.5 (“EP ‘929”), filed on or about
May 16, 2002, but as set forth in Section V(C) below is not so entitled.
According to the electronic records of the PTO at Reel/Frame 30292-8, the
‘987 patent is assigned to Janssen R&D Ireland. However, based on public filings,
the ‘987 patent has been assigned to Janssen Sciences Ireland UC. See, e.g.,
Janssen Prods., L.P. et al. v. Lupin Ltd. et al., C.A. No. 14-1370 (D.N.J.), Doc. 27.
Accordingly, both are collectively identified as Patent Owner herein.
While discussed more specifically below in connection with the grounds
upon which Petitioner relies, the challenged claims of the ‘987 patent are directed
to a purported “hydrate” of darunavir with various degrees of hydration (claims 1,
2, and 9-13), as well as compositions comprising the same (claims 3-8 and 14-19).
The compound darunavir. As noted above, the ‘987 patent’s specification
concedes the prior art discloses darunavir, “and processes for its preparation,”
including in Ghosh 1998 and the ‘775 patent. (Ex. 1001 at col. 1, ll. 35-65).
Drug forms. The specification asserts certain (unidentified) modifications
to darunavir’s solid state “unexpectedly” positively influenced its suitability for
use as a pharmaceutical, including in terms of the compound’s stability,
bioavailability, and purity. (Ex. 1001 at col. 2, ll. 54-67). Pseudopolymorphs
asserted as “preferred” include “hydrate and ethanolate,” with Form A labeled an
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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ethanolate and Form B labeled a hydrate. (Id. at col. 3, ll. 5-21; col. 5, ll. 45-54).
The specification further states numerous possible hydrates result from different
hydration levels. (Id. at col. 6, ll. 3-18). Yet, comparative bioavailability, stability
or purity assessments of any “hydrate” to forms disclosed in the closest prior art
are absent. (Ex. 1025 ¶ 261). The specification never assigns any “unexpected”
positive influences to any particular solid state modification. (Id.).
Amorphous, hydrate. The specification expressly defines “amorphous
form” and “hydrates.” “[A]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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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).
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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.
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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:
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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).
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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.
Independent claims 3 and 6 and Dependent claims 14-18 require a
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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,
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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).
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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)).
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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,
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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.
Independent claims 3 and 6 and Dependent claims 14-18 require a
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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).
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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,
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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.
Petition for Inter Partes Review of U.S. Patent No. 8,518,987 B2
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