Petition for Inter Partes Review of USP 5,665,772
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`In re Inter Partes Review of:
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`U.S. Patent No. 5,665,772
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`Issued: Sep. 9, 1997
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`Application No.: 08/416,673
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`U.S. Filing Date: April 7, 1995
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`For: O-alkylated rapamycin derivatives and their use, particularly as immu-
`nosuppressants
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`FILED VIA PRPS
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`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 5,665,772
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`For ease of reference, Petitioner refers to this petition as the “’772 Petition” chal-
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`lenging claims 1-3 and 8-10.
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`Table of Contents
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`Petition for Inter Partes Review of USP 6,455,518
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`I.
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`REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW .......... 1
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`A. Grounds for Standing (37 C.F.R. § 42.104(a)) ..................................... 1
`B.
`Notice of Lead and Backup Counsel and Service Information ............. 1
`C.
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................. 2
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 3
`Fee for Inter Partes Review .................................................................. 3
`E.
`F.
`Proof of Service ..................................................................................... 3
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`II.
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`III.
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`IV.
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`SUMMARY OF ISSUE PRESENTED ........................................................... 3
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`INTRODUCTION ........................................................................................... 4
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`IDENTIFICATION OF CLAIMS BEING CHALLENGED
`(§ 42.104(B)) ................................................................................................. 10
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`V. DESCRIPTION OF THE PURPORTED INVENTION ............................... 11
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`VI. CLAIM CONSTRUCTION .......................................................................... 13
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`A. Applicable Law ................................................................................... 13
`B.
`Construction of Claim Terms .............................................................. 15
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`VII. PERSON HAVING ORDINARY SKILL IN THE ART ............................. 16
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`VIII. TECHNICAL BACKGROUND AND STATE OF THE ART .................... 16
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`A.
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`B.
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`C.
`D.
`E.
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`F.
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`Rapamycin Was Known as a Powerful Immunosuppressant
`with Limited Solubility ....................................................................... 16
`Rapamycin Derivatives at C40 Had Been Synthesized and
`Shown to Have Immunosuppressant Activity ..................................... 18
`Rapamycin’s Interactions With Its Targets Were Known .................. 19
`Solubility-Enhancing Modifications Were Well-Known ................... 23
`Standard Assays Were Available to Evaluate
`Immunosuppressant Activity of Rapamycin Derivatives ................... 24
`Computer-Aided Drug Design Provided Quantitative
`Assessment of Modifications to Known Compounds ......................... 25
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`IX. THE SCOPE AND CONTENT OF THE PRIOR ART ................................ 26
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`i
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`Petition for Inter Partes Review of USP 5,665,772
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`B.
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`C.
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`D.
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`E.
`F.
`G.
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`A. Morris Teaches that Rapamycin Is a Promising Lead
`Compound with Limited Solubility .................................................... 26
`Rossmann Teaches How to Obtain Three-Dimensional
`Coordinates from Stereo Diagrams ..................................................... 27
`Van Duyne Revealed the Structural Interactions Between
`Rapamycin and FKBP-12 .................................................................... 27
`The Full Coordinates of the Van Duyne Structure Show that
`C40 of Rapamycin Is the Optimal Position for Modification ............. 31
`Flexible Side Chains Were Known to Improve Solubility ................. 32
`The Addition of Solubilizing Substituents Was Well-Known ............ 33
`Rapamycin Derivatives at C40 Were Shown to Have
`Immunosuppressant Activity and Were Evaluated in Standard
`Assays .................................................................................................. 34
`Computer-Aided Design Allowed For the Screening of
`Potential Modifications to Determine Promising Derivatives to
`Synthesize and Evaluate ...................................................................... 35
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`H.
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`X. MOTIVATIONS TO COMBINE THE PRIOR ART REFERENCES ......... 37
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`XI. PRECISE REASONS FOR THE RELIEF REQUESTED ........................... 38
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`C.
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`B.
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`A. Ground 1: Claims 1-3 and 10 are Invalid under 35 U.S.C. § 103
`on the Ground That They Are Rendered Obvious in View of
`Morris, Van Duyne, Rossmann, Lemke, and Yalkowsky ................... 40
`Ground 2: Claims 8 and 9 are Invalid under 35 U.S.C. § 103 on
`the Ground That They Are Rendered Obvious in View of
`Morris, Van Duyne, Rossmann, Lemke, Yalkowsky, and in
`further view of Hughes ........................................................................ 48
`Ground 3: Claims 1-3 and 10 of the ’772 Patent Would Have
`Been Obvious Over Routine Use of Computer-Aided Drug
`Design Software In View of Morris, Van Duyne, Lemke, and
`Yalkowsky ........................................................................................... 51
`D. Ground 4: Claims 8 and 9 are Invalid under 35 U.S.C. § 103 on
`the Ground That They Are Rendered Obvious Over Routine
`Use of Computer-Aided Drug Design Software In View of
`Morris, Van Duyne, Lemke, and Yalkowsky, and in further
`view of Hughes .................................................................................... 54
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`XII. Secondary Considerations Do Not Render Claims 1-3 and 8-10
`Nonobvious .................................................................................................... 54
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`ii
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`XIII. CONCLUSION .............................................................................................. 55
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`Petition for Inter Partes Review of USP 5,665,772
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`iii
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`Petition for Inter Partes Review of USP 5,665,772
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`
`Exhibit List
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`1001 U.S. Patent No. 5,665,772 (“the ’772 Patent”)
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`1002 File History for the ’772 Patent
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`1003 Declaration of William L. Jorgensen, Ph.D. in Support of Petition for In-
`ter Partes Review of U.S. Patent No. 5,665,772
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`1004 Curriculum Vitae of William L. Jorgensen
`
`1005 Randall Ellis Morris, Rapamycins: Antifungal, Antitumor, Antiprolifera-
`tive, and Immunosuppressive Macrolides, 6 TRANSPLANTATION REVIEWS
`39 (1992) (“Morris”)
`
`1006 Gregory D. Van Duyne et al., Atomic Structure of the Rapamycin Human
`Immunophilin FKBP-12 Complex, 113 J. AM. CHEMICAL SOC’Y 7433
`(1991) (“Van Duyne”)
`
`1007 Samuel H. Yalkowsky, Estimation of Entropies of Fusion of Organic
`Compounds, 18 INDUS. & ENG’G CHEMISTRY FUNDAMENTALS 108 (1979)
`(“Yalkowsky”)
`
`1008 Thomas L. Lemke, Chapter 16: Predicting Water Solubility, REVIEW OF
`ORGANIC FUNCTIONAL GROUPS 113 (2d ed. 1988)
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`1009 U.S. Patent No. 5,233,036 (“Hughes”)
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`1010 U.S. Patent No. 4,650,803 (“Stella”)
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`1011 U.S. Patent No. 5,100,883 (“Scheihser”)
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`1012 Stuart L. Schreiber, Chemistry and Biology of the Immunophilins and
`Their Immunosuppressive Ligands, 251 SCI. 283 (1991) (“Schreiber”)
`
`1013
`
`Joseph B. Moon & W. Jeffrey Howe, Computer Design of Bioactive Mol-
`ecules: A Method for Receptor-Based de Novo Ligand Design, 11 PRO-
`TEINS: STRUCTURE, FUNCTION, & GENETICS 314 (1991) (“Moon”)
`
`iv
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`Petition for Inter Partes Review of USP 5,665,772
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`
`1014 Hans-Joachim Böhm, LUDI: rule-based automatic design of new substit-
`uents for enzyme inhibitor leads, 6 J. COMPUTER-AIDED MOLECULAR DE-
`SIGN 593 (1992) (“Böhm”)
`
`1015 Silverman, Chapter 2: Drug Discovery, Design, and Development, THE
`ORGANIC CHEMISTRY OF DRUG DESIGN & ACTION 4 (1992) (“Silverman”)
`
`1016
`
`Julianto Pranata & William L. Jorgensen, Computational Studies on
`FK506: Conformational Search and Molecular Dynamics Simulation in
`Water, 113 J. AM. CHEMICAL SOC’Y 9483 (1991)
`
`1017 William L. Jorgensen, Rusting of the Lock and Key Model for Protein-
`Ligand Binding, 254 SCI. 954 (1991)
`
`1018 Modesto Orozco et al., Mechanism for the Rotamase Activity of FK506
`Binding Protein from Molecular Dynamics Simulations, 32 BIOCHEMIS-
`TRY 12864 (1993)
`
`1019 Michelle L. Lamb & William L. Jorgensen, Investigations of Neu-
`rotrophic Inhibitors of FK506 Binding Protein via Monte Carlo Simula-
`tions, 41 J. MED. CHEMISTRY 3928 (1998)
`
`1020 Michelle L. Lamb et al., Estimation of Binding Affinities of FKBP12 In-
`hibitors Using a Linear Response Method, 7 BIOORGANIC & MEDICINAL
`CHEMISTRY 851 (1999)
`
`1021 Thomas W. Bell, Construction of a Soluble Heptacyclic Terpyridine, 51 J.
`ORGANIC CHEMISTRY 764 (1986) (“Bell”)
`
`1022 M. Ballauff, Phase Equilibria in Rodlike Systems with Flexible Side
`Chains, 19 MACROMOLECULES 1366 (1986) (“Ballauff”)
`
`1023 R. Stern et al., Rigid rod polymers with flexible side chains, 32 POLYMER
`2096 (1991) (“Stern”)
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`1024 Michael G. Rossmann et al., Three-Dimensional Coordinates from Ste-
`reodiagrams of Molecular Structures, B36 ACTA CRYSTALLOGRAPHICA
`819 (1980) (“Rossmann”)
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`Petition for Inter Partes Review of USP 5,665,772
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`
`1025 William L. Jorgensen & Julian Tirado-Rives, The OPLS Potential Func-
`tions for Proteins. Energy Minimizations for Crystals of Cyclic Peptides
`and Crambin, 110 J. AM. CHEMICAL SOC’Y 1657 (1988)
`
`1026
`
`Julian Tirado-Rives & William L. Jorgensen, Molecular Dynamics of Pro-
`teins with the OPLS Potential Functions. Simulation of the Third Domain
`of Silver Pheasant Ovomucoid in Water, 112 J. AM. CHEMICAL SOC’Y
`2773 (1990)
`
`1027 Michael L. Connolly, Solvent-Accessible Surfaces of Proteins and Nucleic
`Acids, 221 SCI. 709 (1983)
`
`1028 Yoshihiko Nisibata et al., Automatic Creation of Drug Candidate Struc-
`tures Based on Receptor Structure. Starting Point for Artificial Lead
`Generation., 47 TETRAHEDRON 8985 (1991)
`
`1029 Stephen W. Michnick et al., Solution Structure of FKBP, a Rotamase En-
`zyme and Receptor for FK506 and Rapamycin, 252 SCI. 836 (1991)
`
`
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`vi
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`Petition for Inter Partes Review of USP 5,665,772
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`Par Pharmaceutical, Inc. (“Petitioner”), in accordance with 35 U.S.C. § 311
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`and 37 C.F.R. § 42.100, hereby requests inter partes review of claims 1-3 and 8-10
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`of United States Patent No. 5,665,772, titled “O-alkylated rapamycin derivatives
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`and their use, particularly as immunosuppressants” (the “’772 Patent”). According
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`to USPTO records, the ’772 Patent is assigned to Novartis Ag (“Novartis”). A
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`copy of the ’772 Patent is provided as Ex. 1001.
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`I.
`REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Petitioner certifies that the ’772 Patent is available for inter partes review
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`and that Petitioner is not barred or estopped from requesting inter partes review of
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`the challenged claims of the ’772 Patent on the grounds identified herein.
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`B. Notice of Lead and Backup Counsel and Service Information
`Pursuant to 37 C.F.R. §§ 42.8(b)(3), 42.8(b)(4), and 42.10(a), Petitioner pro-
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`vides the following designation of Lead and Back-Up counsel.
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`LEAD COUNSEL
`Daniel G. Brown (Reg. No. 54,005)
`(dan.brown@lw.com)
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`885 Third Avenue
`New York, NY 10022-4834
`T: 212-906-1742; F: 212-751-4864
`
`
`BACKUP COUNSEL
`Robert Steinberg (Reg. No. 33,144)
`(bob.steinberg@lw.com)
`Latham & Watkins LLP
`355 South Grand Avenue
`Los Angeles, CA 90071-1560
`T: 213-485-1234; F: 213-891-8763
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`1
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`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney for the Petitioner is at-
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`Petition for Inter Partes Review of USP 5,665,772
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`tached.
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`C. Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`Petitioner Par Pharmaceutical, Inc. (“Par”) is a real-party-in-interest for this
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`proceeding. Out of an abundance of caution, and as a result of ongoing integration
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`and reorganization activities, Petitioner identifies the following additional entities
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`as real-parties-in-interest who, going forward, may have control over this proceed-
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`ing: Endo International PLC; Endo DAC; Endo Management Limited; Endo Lux-
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`embourg Holding Company S.a.r.l.; Endo Luxembourg Finance Company I S.a.r.l.;
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`Endo U.S. Inc.; Endo US Holdings Luxembourg I S.a.r.l.; Endo US Holdings Lux-
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`embourg II S.a.r.l.; Endo Health Solutions Inc.; Hawk Acquisition Ireland Limited;
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`and Par Pharmaceutical Companies, Inc.1 No other parties exercised or could have
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`exercised control over this petition; no other parties funded or directed this peti-
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`1 As a result of Endo International PLC’s acquisition of Par Pharmaceutical, Inc.,
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`Petitioner states that: Sky Growth Intermediate Holdings Corporation I, Sky
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`Growth Intermediate Holdings Corporation II and Par Pharmaceutical Companies,
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`Inc. were merged into and reorganized with Par Pharmaceutical Holdings, Inc.,
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`which was immediately thereafter re-named Par Pharmaceutical Companies, Inc.
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`For clarity, the newly reorganized Par Pharmaceutical Companies, Inc. is not iden-
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`tical to the entity previously known by the same name.
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`2
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`tion. See Office Patent Trial Practice Guide, 77 Fed. Reg. 48759-60.
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`Petition for Inter Partes Review of USP 5,665,772
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`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:14-cv-1289-RGA
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`(D. Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:14-cv-1494-
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`RGA (D. Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:15-cv-78-
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`RGA (D. Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:15-cv-
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`475-RGA (D. Del.). Petition for Inter Partes Review of U.S. Patent No.
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`6,455,518, No. IPR2016-00078 (to be filed concurrently). Petition for Inter Partes
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`Review of U.S. Patent No. 7,741,338, No. IPR2016-00074 (to be filed concurrent-
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`ly). Petition for Inter Partes Review of U.S. Patent No. 7,297,703, IPR2016-
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`00075 (to be filed concurrently). According to USPTO records, no patent claims
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`priority to the ’772 Patent .
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`E.
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`Fee for Inter Partes Review
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`The Director is authorized to charge the fee specified by 37 C.F.R.
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`§ 42.15(a) to Deposit Account No. 506269.
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`F.
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`Proof of Service
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`Proof of service of this petition on the patent owner at the correspondence
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`address of record for the ’772 Patent is attached.
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`II.
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`SUMMARY OF ISSUE PRESENTED
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`This petition presents the Patent Trial and Appeal Board with the following
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`issue: The ’772 Patent claims certain alkylated derivatives of rapamycin, a well-
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`known immunosuppressant. It was well-known that rapamycin’s poor solubility
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`Petition for Inter Partes Review of USP 5,665,772
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`limited its use in drug formulations. The prior art taught that rapamycin could be
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`modified at the C40 position without sacrificing the compound’s immunosuppres-
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`sant activity. The prior art also taught that the routine addition of solubility-
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`enhancing substituents could improve a compound’s solubility. Would the certain
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`alkylated derivatives of rapamycin and their use claimed in claims 1-3 and 8-10 of
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`the ’772 Patent have been obvious to a person of ordinary skill in the art at the time
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`of the claimed invention?
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`III.
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`INTRODUCTION
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`The ’772 Patent describes and claims certain derivatives of the compound
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`rapamycin, compositions including those derivatives, and their use as immunosup-
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`pressants. According to the ’772 Patent, the claimed rapamycin derivatives im-
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`prove on rapamycin’s properties. (Ex. 1001, ’772 Patent at 1:33-36.) Claim 1 of
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`the ’772 Patent reads as follows:
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`A compound of the formula2
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`2 The structural formula shown in claim 1 of the ’772 Patent depicts a bond be-
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`tween C3 and C35. Novartis has filed a Request for Certificate of Correction with
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`the Patent Office to clarify that there is no bond between C3 and C35 but rather
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`that there is a methyl (CH3) group at C35. (Ex. 1002, ’772 Patent File History at
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`Certificate of Correction (stamped pages 630-633.) The Patent Office has not yet
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`Petition for Inter Partes Review of USP 5,665,772
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`R1O
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`40
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`O
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`O
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`O
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`28
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`OH
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`O
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`O
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`N
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`O
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`10
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`O
`OH
`O
`
`O
`
`O
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`wherein R1 is hydroxyl(C1-6)alkyl or hydroxyl(C1-3)alkoxy(C1-3)alkyl.
`Claim 1 of the ’772 Patent, and the claims that depend from Claim 1, are in-
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`valid as obvious under 35 U.S.C. § 103. Claim 1 includes derivatives of rapamy-
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`cin which have been modified at C40. (Ex. 1003, Jorgensen Decl. at ¶ 27.) Claims
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`2 and 3 depend from claim 1 and narrow the scope of R1. (Ex. 1001, ’772 Patent at
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`22:4-7; Ex. 1003, Jorgensen Decl. at ¶¶ 32-35.) Claim 10 depends from claim 1
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`and recites one specific rapamycin derivative, 40-O-(2-hydroxyethyl)-rapamycin.
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`(Ex. 1001, ’772 Patent at 22:28-29, Certificate of Correction; Ex. 1003, Jorgensen
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`Decl. at ¶ 38.) Claim 10 falls within the scope of claims 1, 2, and 3. (Ex. 1003,
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`Jorgensen Decl. at ¶¶ 38-39.) The prior art suggested modifying rapamycin to ob-
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`tain rapamycin derivatives with improved solubility, including the compound of
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`issued a response. This petition construes the chemical compounds included in the
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`scope of the claims of the ’772 Patent as though the Certificate of Correction has
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`been implemented.
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`claim 10, which necessarily falls within the scope of claims 1, 2, and 3.
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`Petition for Inter Partes Review of USP 5,665,772
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`“In drug development, it is common to modify a lead compound in an effort
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`to ‘obtain a compound with better’” properties. Bristol-Myers Squibb Co. v. Teva
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`Pharm. USA, Inc., 752 F.3d 967, 974 (Fed. Cir. 2014) (citation omitted). A com-
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`pound is obvious if the selection of the position to modify and determination of
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`how to modify “equate to a small, finite number of changes to try.” Id. at 976. A
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`person of ordinary skill in the art would have been motivated to select rapamycin
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`as a lead compound to modify in order to improve its solubility. Morris summariz-
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`es the significant amount of information available as of October 1992 regarding the
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`remarkable immunosuppressant activity of rapamycin, making it an ideal candidate
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`for further investigation. (Ex. 1005, Morris at 39-42, 52-64; Ex. 1003, Jorgensen
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`Decl. at ¶¶ 72-74, 132-137.) Additionally, Morris teaches that rapamycin is mini-
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`mally soluble in water, and indeed, the ’772 Patent expressly admits this well-
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`known limitation of rapamycin. (Ex. 1005, Morris at 46; Ex. 1001, ’772 Patent at
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`1:36-40; Ex. 1003, Jorgensen Decl. at ¶¶ 75-76, 138-140.) See KSR Int'l Co. v. Te-
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`leflex Inc., 550 U.S. 398, 420 (2007) (“[A]ny need or problem known in the field
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`of endeavor at the time of invention and addressed by the patent can provide a rea-
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`son for combining the elements in the manner claimed.”); In re Beattie, 974 F.2d
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`1309, 1312 (Fed. Cir. 1992) (“As long as some motivation or suggestion to com-
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`bine the references is provided by the prior art taken as a whole, the law does not
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`require that the references be combined for the reasons contemplated by the inven-
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`Petition for Inter Partes Review of USP 5,665,772
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`tor.”).
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`A person of ordinary skill in the art would have been motivated to modify
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`rapamycin to improve its solubility without disrupting its biological activity. In
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`order to achieve this, a person of ordinary skill in the art would have modified ra-
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`pamycin’s C40 hydroxyl group because the structure showing rapamycin’s binding
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`to its biological target FKBP-12 taught that the C40 hydroxyl was the best position
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`for modification. (Ex. 1006, Van Duyne at 7434; Ex. 1003, Jorgensen Decl. at
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`¶¶ 101-123, 141-145.)
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`Yalkowsky (Ex. 1007) and Lemke (Ex. 1008) teach how to improve the sol-
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`ubility of chemical compounds by adding flexible side chains with solubilizing
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`substituents. (Ex. 1003, Jorgensen Decl. at ¶¶ 77-88.) Such solubilizing substitu-
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`ents include the 2-hydroxyethoxy substituent at the C40 position of the compound
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`of claim 10. (Id. at ¶¶ 146-161.)
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`Additionally, prior researchers had synthesized rapamycin derivatives by
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`modifying rapamycin at the C40 position and reported that such derivatives dis-
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`played immunosuppressant activity in standard pharmacological assays, including
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`preventing allograft rejection. (Ex. 1009, Hughes at 2:62-65, 3:51-4:12; Ex. 1003,
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`Jorgensen Decl. at ¶¶ 125-126.) As such a person of ordinary skill in the art would
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`have a reasonable expectation that modifying rapamycin at its C40 position would
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`result in a compound with immunosuppressant activity. (Ex. 1003, Jorgensen
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`Petition for Inter Partes Review of USP 5,665,772
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`Decl. at ¶¶ 166-172.) Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d
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`1293, 1301 (Fed. Cir. 2007) (“[I]t is sufficient to show that the claimed and prior
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`art compounds possess a ‘sufficiently close relationship . . . to create an expecta-
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`tion,’ in light of the totality of the prior art, that the new compound will have ‘simi-
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`lar properties’ to the old.”) (citations omitted); Pfizer, Inc. v. Apotex, Inc., 480 F.3d
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`1348, 1364 (Fed. Cir. 2007) (simply because the properties of a compound must be
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`verified through testing does not mean that the compound lack an expection for
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`success “since the expectation of success need only be reasonable, not absolute”);
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`In re Wilder, 563 F.2d 457, 460 (C.C.P.A. 1977) (“[O]ne who claims a compound,
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`per se, which is structurally similar to a prior art compound must rebut the pre-
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`sumed expectation that the structurally similar compounds have similar proper-
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`ties.”). Therefore, claims 8 and 9, which recite methods of using the compounds of
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`claim 1 as immunosuppressants or to prevent allograft rejection, would also have
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`been obvious.
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`Furthermore, because the structure of rapamycin bound to its biological tar-
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`get FKBP-12 was known, computer-aided design allowed a person of ordinary
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`skill in the art to screen potential modifications by quantifying favorable arrange-
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`ments for hydrogen bonds and hydrophobic contacts to identify those modifica-
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`tions that would not interfere with FKBP-12 binding and thus would not disrupt
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`8
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`rapamycin’s biological activity. This additional tool would have been used by a
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`Petition for Inter Partes Review of USP 5,665,772
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`person of ordinary skill in the art to quantitatively evaluate modifications at ra-
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`pamycin’s C40 position and to identify those modifications that would increase
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`solubility while not interfering with rapamycin’s ability to bind to FKBP-12. (See
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`Ex. 1003, Jorgensen Decl. at ¶¶ 173-193.) Using such a tool, a person of ordinary
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`skill in the art would have identified modifications at C40 that included the 2-
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`hydroxyethyl group of the compound of claim 10 of the ’772 Patent. (See id.)
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`In summary, claims 1-3 and 8-10 of the ’772 Patent would have been obvi-
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`ous to a person of ordinary skill in the art in view of the prior art disclosing at least
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`the following: (1) rapamycin was a well-known and significant immunosuppres-
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`sant with known limited solubility; (2) the known information regarding the inter-
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`actions between rapamycin and its biological targets taught that C40 was the opti-
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`mal position for making modifications without disrupting biological activity;
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`(3) known strategies for improving solubility of chemical compounds taught add-
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`ing flexible side chains with solubilizing substituents; and (4) prior rapamycin de-
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`rivatives modified at C40 had been shown to have immunosuppressant activity, in-
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`cluding the ability to prevent allograft rejection. And, to the extent a person of or-
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`dinary skill in the art chose to utilize computer-aided drug design, that tool would
`
`have provided additional reason to modify rapamycin at C40 to arrive at the com-
`
`pounds claimed in the ’772 Patent.
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`9
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`Petition for Inter Partes Review of USP 5,665,772
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`Par provides below a detailed comparison of the claimed subject matter and
`
`the prior art. Par respectfully submits that Claims 1-3 and 8-10 would have been
`
`obvious in view of the prior art presented herein and therefore requests that the
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`Board institute an inter partes review and determine that these claims are un-
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`patentable.
`
`IV.
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`IDENTIFICATION OF CLAIMS BEING CHALLENGED
`(§ 42.104(B))
`
`Par respectfully requests that the Board cancel claims 1-3 and 8-10 of the
`
`’772 Patent (Ex. 1001) (the “challenged claims”) based on the following grounds
`
`for unpatentability:
`
`Ground 1. Claims 1-3 and 10 are unpatentable under 35 U.S.C. § 103 as
`
`obvious over Morris (Ex. 1005), Van Duyne (Ex. 1006), Rossmann (Ex. 1024),
`
`Yalkowsky (Ex. 1007), and Lemke (Ex. 1008).
`
`Ground 2. Claims 8 and 9 are unpatentable under 35 § 103 as obvious over
`
`Morris (Ex. 1005), Van Duyne (Ex. 1006), Rossmann (Ex. 1024), Yalkowsky (Ex.
`
`1007), and Lemke (Ex. 1008) in further view of Hughes (Ex. 1009).
`
`Ground 3. Claims 1-3 and 10 are unpatentable under 35 U.S.C. § 103 as
`
`obvious over routine use of computer-aided design software in view of Morris (Ex.
`
`1005), Van Duyne (Ex. 1006), Yalkowsky (Ex. 1007), and Lemke (Ex. 1008).
`
`Ground 4. Claims 8 and 9 are unpatentable under 35 § 103 as obvious over
`
`routine use of computer-aided design software in view of Morris (Ex. 1005), Van
`
`10
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`

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`Duyne (Ex. 1006), Yalkowsky (Ex. 1007), and Lemke (Ex. 1008) in further view
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`Petition for Inter Partes Review of USP 5,665,772
`
`of Hughes (Ex. 1009).
`
`V. DESCRIPTION OF THE PURPORTED INVENTION
`The ’772 Patent discloses certain alkylated derivatives of rapamycin. It
`
`discloses that rapamycin is “an extremely potent immunosuppressant” that also
`
`demonstrates antitumor and antifungal activity. (Ex. 1001, ’772 Patent at 1:33-36.)
`
`However, the ’772 Patent also explains that rapamycin has shortcomings, including
`
`relatively poor solubility, which created difficulty in making pharmaceutic
`
`formulations. (Id. at 1:36-40.)
`
`The ’772 Patent states that the disclosed alkylated derivatives of rapamycin
`
`have improved pharmacologic profiles over rapamycin. Specifically, the ’772
`
`Patent states that alkylated derivatives demonstrate “an improved pharmacologic
`
`profile over rapamycin, exhibit greater stability and bioavailability, and allow for
`
`greater ease in producing galenic formulations.” (Id. at 1:41-45.) The ’772 Patent
`
`further discloses that these alkylated derivatives having improved pharmacologic
`
`profiles were obtained by modifying rapamycin at the C-40 position.
`
`
`
`Claim 1 of the ’772 Patent claims a genus of compounds of the following
`
`formula, as modified by the pending Certificate of Correction (see n.1, supra):
`
`11
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`Petition for Inter Partes Review of USP 5,665,772
`
`
`
`R1O
`
`40
`
`O
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`(highlighted
`
`emphasis
`
`added), where R1
`
`is
`
`hydroxyl(C1-6)alkyl
`
`or
`
`hydroxyl(C1-3)alkoxy(C1-3)alkyl. Claim 2 claims a subset of the compounds of
`
`claim 1 where the alkyl group can only contain between one and three carbon
`
`atoms. Claim 3 depends from claim 1 and requires that R1 is hydroxy(C1-3)alkyl.
`
`Claim 10 depends from claim 1 and recites the specific compound 40-O-
`
`(2-hydroxyethyl)-rapamycin, the compound shown in the figure below. (Ex. 1003,
`
`Jorgensen Decl. at ¶ 38.)
`
`40
`
`O O
`
`HO
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`12
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`

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`Petition for Inter Partes Review of USP 5,665,772
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`Claim 8 recites a method of inducing an immunosuppressant effect in a sub-
`
`ject in need of immunosuppression, which comprises administering to said subject
`
`an immunosuppressant effective amount of a compound according to claim 1.
`
`Claim 9 recites a method of preventing allograft rejection in a subject in
`
`need of such treatment, which comprises administering to said subject a compound
`
`according to claim 1 in an amount effective to prevent allograft rejection.
`
`VI. CLAIM CONSTRUCTION3
`A. Applicable Law
`In deciding whether to institute inter partes review, “[a] claim in an unex-
`
`pired patent shall be given its broadest reasonable construction in light of the speci-
`
`fication of the patent in which it appears.”4 37 C.F.R. § 42.100(b). This claim
`
`3 Petitioners expressly reserve the right to challenge one or more claims (and claim
`
`terms) of the ’772 Patent for failure to satisfy the requirements of 35 U.S.C. § 112,
`
`which cannot be raised in these proceedings. See 35 U.S.C. § 311(b). Nothing in
`
`this Petition, or the constructions provided herein, shall be construed as a waiver of
`
`such challenge, or agreement that the requirements of 35 U.S.C. § 112 are met with
`
`for any claim of the ’772 Patent.
`
`4 The district court, in contrast, affords a claim term its “ordinary and customary
`
`meaning . . . to a person of ordinary skill in the art in question at the time of the in-
`
`vention.” Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005) (en banc).
`
`13
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`construction standard is different from—and broader than—that applied in district
`
`Petition for Inter Partes Review of USP 5,665,772
`
`court. Versata Dev. Group v. SAP Am., Inc., 793 F.3d 1306, 1327-28 (Fed. Cir.
`
`2015). Under the broadest reasonable interpretation, “claims should always be
`
`read in light of the specification and teachings in the underlying patent.” Microsoft
`
`Corp. v. Proxyconn, Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015). The “PTO should
`
`also consult the patent’s prosecution history in proceedings in which the patent has
`
`been brought back to the agency for a second review.” Id. In addition, “[e]ven
`
`under the broadest reasonable interpretation, the Board’s construction cannot be
`
`divorced from the specification and the record evidence and must be consistent
`
`with the one that those skilled in the art would reach.” Id.
`
`To the extent there is any ambiguity regarding the “broadest reasonable con-
`
`struction” of a claim term, the ambiguity should be resolved in favor of the broader
`
`construction absent amendment by the patent owner. Final Rules, 77 Fed. Reg. at
`
`48699 (“[T]he broader standard serves to identify ambiguities in the claims that
`
`can then be clarified through claim amendments.”). Consistent with the patent
`
`owner’s responsibility to clarify ambiguous terms, “the Office may take into con-
`
`sideration inconsistent statements made by a patent owner about a claim, such as
`
`those submitted under 35 U.S.C. § 301(a), when applying the ‘broadest reasonable
`
`Petitioners expressly reserve the right to argue different or additional claim con-
`
`struction positions under this standard in district court.
`
`14
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`

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`interpretation’ standard.” Id. Thus, while not controlling, claim constructions of-
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`Petition for Inter Partes Review of USP 5,665,772
`
`fered by a patent owner in related litigation (under the narrower standard applica-
`
`ble in district court) are relevant to the “broadest reasonable construction” applica-
`
`ble here. See, e.g., SAP Am., Inc. v. Versata Dev. Group, Inc., CBM2012-00001,
`
`Paper 36 at 8-9 (Jan. 9, 2013) (adopting petitioner’s proposed construction, in part,
`
`because it was “consistent with [patentee’s] proposed construction in the related
`
`district court proceeding”).
`
`B. Construction of Claim Terms
`All claim terms have been accorded their broadest reasonable interpretation
`
`as understood by one of ordinary skill in the art and consistent with the specifica-
`
`tion of the ’772 Patent. Additionally, Novartis has submitted a Certificate of Cor-
`
`rection, which has not been accepted by the Patent Office as of yet, stating that the
`
`chemical structure presented in claim 1 is an error. (Ex. 1002, ’772 File History at
`
`Certificate of Correction (stamped pages 630-633).) Novartis asserts that the prop-
`
`er chemical structure for the claimed compounds does not have a bond between the
`
`C3 and C35 carbons, but rather that there is a methyl group (CH3) group on the
`
`C35 carbon. (Id.) This proposed corrected structure aligns with the structure pre-
`
`sented in the ’772 Patent specification. (Ex. 1001, ’772 Patent at 1:45-67.) Par
`
`therefore has assumed that the broadest reasonable construction for the chemical
`
`compounds included within the scope of the challenged claims is the proposed cor-
`
`15
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`

`
`rected structure contained in Novartis’s submitted Certificate of Correction.
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`Petition for Inter Partes Review of USP 5,665,772
`
`VII. PERSON HAVING ORDIN