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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`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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`II.
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`III.
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`IV.
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`V.
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`OVERVIEW .................................................................................................... 1
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`REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW .......... 3
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`A. Grounds for Standing (37 C.F.R. § 42.104(a)) ..................................... 3
`B.
`Notice of Lead and Backup Counsel and Service Information ............. 4
`C.
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................. 4
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 5
`Fee for Inter Partes Review .................................................................. 6
`E.
`F.
`Proof of Service ..................................................................................... 6
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`SUMMARY OF ISSUE PRESENTED ........................................................... 6
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`INTRODUCTION ........................................................................................... 7
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`IDENTIFICATION OF CLAIMS BEING CHALLENGED
`(§ 42.104(B)) ................................................................................................. 12
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`VI. DESCRIPTION OF THE PURPORTED INVENTION ............................... 12
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`VII. CLAIM CONSTRUCTION .......................................................................... 15
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`A. Applicable Law ................................................................................... 15
`B.
`Construction of Claim Terms .............................................................. 17
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`VIII. PERSON HAVING ORDINARY SKILL IN THE ART ............................. 18
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`IX. TECHNICAL BACKGROUND AND STATE OF THE ART .................... 19
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`A.
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`B.
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`C.
`D.
`E.
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`Rapamycin Was Known as a Powerful Immunosuppressant
`with Limited Solubility ....................................................................... 19
`Rapamycin Derivatives at C40 Had Been Synthesized and
`Shown to Have Immunosuppressant Activity ..................................... 20
`Rapamycin’s Interactions With Its Targets Were Known .................. 21
`Solubility-Enhancing Modifications Were Well-Known ................... 25
`Standard Assays Were Available to Evaluate
`Immunosuppressant Activity of Rapamycin Derivatives ................... 27
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`X.
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`THE SCOPE AND CONTENT OF THE PRIOR ART ................................ 27
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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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`A. Morris Teaches that Rapamycin Is a Promising Lead
`Compound with Limited Solubility .................................................... 27
`Rossmann Teaches How to Obtain Three-Dimensional
`Coordinates from Stereo Diagrams ..................................................... 29
`Van Duyne Revealed the Structural Interactions Between
`Rapamycin and FKBP-12 .................................................................... 29
`The Full Coordinates of the Van Duyne Structure Show that
`C40 of Rapamycin Is the Optimal Position for Modification ............. 33
`Flexible Side Chains Were Known to Improve Solubility ................. 34
`The Addition of Solubilizing Substituents Was Well-Known ............ 35
`Rapamycin Derivatives at C40 Were Shown to Have
`Immunosuppressant Activity and Were Evaluated in Standard
`Assays .................................................................................................. 36
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`D.
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`E.
`F.
`G.
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`XI. MOTIVATIONS TO COMBINE THE PRIOR ART REFERENCES ......... 38
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`XII. PRECISE REASONS FOR THE RELIEF REQUESTED ........................... 39
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`A. Ground 1: Claim 7 Is 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 Hughes ................. 41
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`XIII. Secondary Considerations Do Not Render Claim 7 Nonobvious ................. 53
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`XIV. CONCLUSION .............................................................................................. 54
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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
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`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”)
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`iii
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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
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`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)
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`1018 Modesto Orozco et al., Mechanism for the Rotamase Activity of FK506
`Binding Protein from Molecular Dynamics Simulations, 32 BIOCHEMIS-
`TRY 12864 (1993)
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`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)
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`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)
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`1021 Thomas W. Bell, Construction of a Soluble Heptacyclic Terpyridine, 51 J.
`ORGANIC CHEMISTRY 764 (1986) (“Bell”)
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`1022 M. Ballauff, Phase Equilibria in Rodlike Systems with Flexible Side
`Chains, 19 MACROMOLECULES 1366 (1986) (“Ballauff”)
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`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
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`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)
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`1027 Michael L. Connolly, Solvent-Accessible Surfaces of Proteins and Nucleic
`Acids, 221 SCI. 709 (1983)
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`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)
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`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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`Petition for Inter Partes Review of USP 5,665,772
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`Petitioner Par Pharmaceutical, Inc. (“Par”), in accordance with 35 U.S.C.
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`§ 311 and 37 C.F.R. § 42.100, hereby requests inter partes review of dependent
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`claim 7 of United States Patent No. 5,665,772, titled “O-alkylated rapamycin de-
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`rivatives and their use, particularly as immunosuppressants” (“the ’772 Patent”).
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`According to USPTO records, the ’772 Patent is assigned to Novartis Ag (“Novar-
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`tis”). A copy of the ’772 Patent is provided as Ex. 1001.
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`On April 29, 2016, the Board granted Par’s previous petition seeking review
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`of claims 1-3 and 8-10 of the ’772 Patent. (IPR2016-00084, Paper 8.) This petition
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`seeks review of dependent claim 7, which Par has not previously challenged, and is
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`filed concurrently with a motion for joinder to the -00084 proceeding.
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`I.
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`OVERVIEW
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`Dependent claim 7 of the ’772 Patent is not patentable for the same reasons
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`that independent claim 1 is not patentable. It is broadly drawn to a “pharmaceuti-
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`cal composition comprising a therapeutically effective amount of a compound ac-
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`cording to claim 1 and a pharmaceutically acceptable carrier therefor.” Such a
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`pharmaceutical composition is obvious over the prior art. Because Par is reasona-
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`bly likely to prevail in showing unpatentability, this Petition should be granted and
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`trial instituted on the challenged claim.
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`In its institution decision in the -00084 proceeding, the Board found that Par
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`demonstrated a reasonable likelihood of demonstrating that claims 1-3 and 8-10 are
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`obvious over the prior art. (IPR2016-00084, Paper 8.) As relevant here, Par set
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`Petition for Inter Partes Review of USP 5,665,772
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`forth in that petition (and repeats herein with the exact same prior art, testimony,
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`and other evidence already submitted), the broad genus of compounds recited in
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`claim 1 of the ’772 Patent are obvious over Morris (Ex. 1005), Van Duyne (Ex.
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`1006), Yalkowsky (Ex. 1007), Lemke (Ex. 1008), and Rossmann (Ex. 1024).
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`IPR2016-00084, Paper 2 at 7-15. Par also explained in its previous petition (also
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`repeated herein with the exact same evidence) a reasonable likelihood that claims 8
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`and 9, which recite methods of administering effective amounts of the compound
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`of claim 1, would have been obvious. (Id. at 15-16.)
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`The Board agreed, instituting the -00084 petition. Likewise, the Board
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`should find that this petition demonstrates a reasonable likelihood of prevailing on
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`claim 7 of the ’772 Patent. Claim 7 recites pharmaceutical compositions compris-
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`ing a compound of claim 1. On indistinguishable facts, the Federal Circuit held
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`that the validity of such claims “rise or fall with the validity of” the compound
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`claim. Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d 1293, 1303
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`(Fed. Cir. 2007) (finding that when the prior art described using ACE inhibitors in
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`combination with pharmaceutical excipients, a dependent pharmaceutical composi-
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`tion claim was obvious because the independent compound claim was obvious).
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`Further, pharmaceutical composition claims (such as claim 7 of the ’772 Patent)
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`are patentably indistinct from methods of using those same compounds for thera-
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`peutic effect (such as claims 8 and 9 of the ’772 Patent). Geneva Pharm., Inc. v.
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`Petition for Inter Partes Review of USP 5,665,772
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`Glaxosmithkline PLC, 189 F. Supp. 2d 377, 384-85 (E. D. Va. 2002), aff’d 349
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`F.3d 1373 (Fed. Cir. 2003) (finding pharmaceutical composition claim containing a
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`compound and a carrier to be patentably indistinct from method claims of adminis-
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`tering effective amounts of the compound). As such, the same arguments, refer-
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`ences, and testimony presented in IPR2016-00084 and credited by the Board as
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`demonstrating a reasonable likelihood of prevailing as to claims 1, 8, and 9 should
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`result in an identical conclusion with respect to the pharmaceutical compositions of
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`claim 7. Indeed, the public interest in consistent resolution of claims of similar pa-
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`tent scope and subject matter compels the institution of this petition to allow for
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`the complete analysis of these claims of the ’772 Patent. See, e.g., Samsung Elecs.
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`Co. v. Va. Innovation Scis., Inc., No. IPR2014-00557 (P.T.A.B. June 13, 2014),
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`Paper 10 at 16-18.
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`II. REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Par certifies that the ’772 Patent is available for inter partes review. Alt-
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`hough more than one year has passed since Par was served with a complaint alleg-
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`ing infringement of the ’772 Patent, this petition is not barred because it is filed
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`concurrently with a motion for joinder. 35 U.S.C. § 315(b); 37 C.F.R. § 42.122(b).
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`If the Board grants joinder, Par is not barred or estopped from requesting inter
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`partes review of the challenged claim of the ’772 Patent on the grounds identified
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`Petition for Inter Partes Review of USP 5,665,772
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`herein. This Petition is filed in accordance with 37 C.F.R. § 42.106(a).
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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), Par provides
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`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
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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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`BACKUP COUNSEL
`Robert Steinberg (Reg. No. 33,144)
`(bob.steinberg@lw.com)
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`355 South Grand Avenue
`Los Angeles, CA 90071-1560
`T: 213-485-1234; F: 213-891-8763
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`tached.
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`C. Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`Par Pharmaceutical, Inc. is a real-party-in-interest for this proceeding. Out
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`of an abundance of caution, and as a result of ongoing integration and reorganiza-
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`tion activities, Par identifies the following additional entities as real-parties-in-
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`interest who, going forward, may have control over this proceeding: Endo Interna-
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`tional PLC; Endo DAC; Endo Management Limited; Endo Luxembourg Holding
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`Company S.a.r.l.; Endo Luxembourg Finance Company I S.a.r.l.; Endo U.S. Inc.;
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`Endo US Holdings Luxembourg I S.a.r.l.; Endo US Holdings Luxembourg II
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`Petition for Inter Partes Review of USP 5,665,772
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`S.a.r.l.; Endo Health Solutions Inc.; Hawk Acquisition Ireland Limited; and Par
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`Pharmaceutical Companies, Inc.1 No other parties exercised or could have exer-
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`cised control over this petition; no other parties funded or directed this petition.
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`See Office Patent Trial Practice Guide, 77 Fed. Reg. 48759-60.
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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.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., No. 1:15-
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`cv-1050-RGA (D. Del.). Petition for Inter Partes Review of U.S. Patent No.
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`5,665,772, No. IPR2016-00084. According to USPTO records, no patent claims
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`1 As a result of Endo International PLC’s acquisition of Par Pharmaceutical, Inc.,
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`Par states that: Sky Growth Intermediate Holdings Corporation I, Sky Growth In-
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`termediate Holdings Corporation II and Par Pharmaceutical Companies, Inc. were
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`merged into and reorganized with Par Pharmaceutical Holdings, Inc., which was
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`immediately thereafter re-named Par Pharmaceutical Companies, Inc. For clarity,
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`the newly reorganized Par Pharmaceutical Companies, Inc. is not identical to the
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`entity previously known by the same name.
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`priority to the ’772 Patent .
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`Petition for Inter Partes Review of USP 5,665,772
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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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`III. SUMMARY OF ISSUE PRESENTED
`This petition presents the Board with the following sole issue: The ’772 Pa-
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`tent claims certain alkylated derivatives of rapamycin, a well-known immunosup-
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`pressant, and pharmaceutical compositions comprising such derivatives in combi-
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`nation with a pharmaceutically acceptable carrier. It was well-known that rapamy-
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`cin’s poor solubility limited its use in drug formulations. The prior art taught that
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`rapamycin could be modified at the C40 position without sacrificing the com-
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`pound’s immunosuppressant activity. The prior art also taught that the routine ad-
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`dition of solubility-enhancing substituents could improve a compound’s solubility.
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`Would a pharmaceutical composition comprising the certain alkylated derivatives
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`of rapamycin with a pharmaceutically acceptable carrier claimed in Claim 7 of the
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`’772 Patent, as dependent from Claim 1, have been obvious to a person of ordinary
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`skill in the art at the time of the claimed invention?
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`IV.
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`INTRODUCTION
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`Petition for Inter Partes Review of USP 5,665,772
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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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`R1O
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`40
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`O
`
`O
`
`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
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`O
`
`O
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`wherein R1 is hydroxyl(C1-6)alkyl or hydroxyl(C1-3)alkoxy(C1-3)alkyl.
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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 recently
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`granted the request.
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`Petition for Inter Partes Review of USP 5,665,772
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`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. ¶ 27.) Claims 2
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`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. ¶¶ 32-35.) Claim 10 depends from claim 1 and
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`recites one specific rapamycin derivative, 40-O-(2-hydroxyethyl)-rapamycin. (Ex.
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`1001, ’772 Patent at 22:28-29, Certificate of Correction; Ex. 1003, Jorgensen Decl.
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`¶ 38.) Claim 10 falls within the scope of claims 1, 2, and 3. (Ex. 1003, Jorgensen
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`Decl. ¶¶ 38-39.) The prior art suggested modifying rapamycin to obtain rapamycin
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`derivatives with improved solubility, including the compound of claim 10, which
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`necessarily falls within the scope of claims 1, 2, and 3.
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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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`Petition for Inter Partes Review of USP 5,665,772
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`Decl. ¶¶ 72-74, 132-137.) Additionally, Morris teaches that rapamycin is minimal-
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`ly soluble in water, and indeed, the ’772 Patent expressly admits this well-known
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`limitation of rapamycin. (Ex. 1005, Morris at 46; Ex. 1001, ’772 Patent at 1:36-40;
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`Ex. 1003, Jorgensen Decl. ¶¶ 75-76, 138-140.) See KSR Int'l Co. v. Teleflex Inc.,
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`550 U.S. 398, 420 (2007) (“[A]ny need or problem known in the field of endeavor
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`at the time of invention and addressed by the patent can provide a reason for com-
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`bining the elements in the manner claimed.”); In re Beattie, 974 F.2d 1309, 1312
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`(Fed. Cir. 1992) (“As long as some motivation or suggestion to combine the refer-
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`ences is provided by the prior art taken as a whole, the law does not require that the
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`references be combined for the reasons contemplated by the inventor.”).
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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.
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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. ¶¶ 77-88.) Such solubilizing substituents
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`Petition for Inter Partes Review of USP 5,665,772
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`include the 2-hydroxyethoxy substituent at the C40 position of the compound of
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`Claim 10. (Id. ¶¶ 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. ¶¶ 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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`Decl. ¶¶ 166-172.) Aventis, 499 F.3d at 1301 (“[I]t is sufficient to show that the
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`claimed and prior art compounds possess a ‘sufficiently close relationship . . . to
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`create an expectation,’ in light of the totality of the prior art, that the new com-
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`pound will have ‘similar properties’ to the old.”) (citations omitted); Pfizer, Inc. v.
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`Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (simply because the properties
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`of a compound must be verified through testing does not mean that the compound
`
`lack an expectation for success “since the expectation of success need only be rea-
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`sonable, not absolute”); In re Wilder, 563 F.2d 457, 460 (C.C.P.A. 1977) (“[O]ne
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`who claims a compound, per se, which is structurally similar to a prior art com-
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`pound must rebut the presumed expectation that the structurally similar compounds
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`10
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`have similar properties.”). Therefore, Claims 8 and 9, which recite methods of us-
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`Petition for Inter Partes Review of USP 5,665,772
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`ing the compounds of claim 1 as immunosuppressants or to prevent allograft rejec-
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`tion, would also have been obvious.
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`In addition, because a person of ordinary skill in the art would have been
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`motivated to modify rapamycin in order to make a compound with improved
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`pharmaceutical properties, a person of ordinary skill in the art would have been
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`motivated to make a pharmaceutical composition containing a therapeutically ef-
`
`fective amount of the rapamycin derivatives and a pharmaceutically acceptable car-
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`rier. In fact, Hughes (Ex. 1009) explicitly teaches rapamycin derivatives modified
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`at the C40 position as useful immunosuppressants that “may be administered neat
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`or with a pharmaceutical carrier to a mammal in need thereof.” (Hughes, Ex.
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`1009, at 4:57-59.)
`
`In summary, Claim 7, depending from claim 1, of the ’772 Patent would
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`have been obvious to a person of ordinary skill in the art in view of the prior art
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`disclosing at least the following: (1) rapamycin was a well-known and significant
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`immunosuppressant with known limited solubility; (2) the known information re-
`
`garding the interactions between rapamycin and its biological targets taught that
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`C40 was the optimal position for making modifications without disrupting biologi-
`
`cal activity; (3) known strategies for improving solubility of chemical compounds
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`taught adding flexible side chains with solubilizing substituents; (4) prior rapamy-
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`cin derivatives modified at C40 had been shown to have immunosuppressant activ-
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`Petition for Inter Partes Review of USP 5,665,772
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`ity, including the ability to prevent allograft rejection; and (5) prior art teaching
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`that rapamycin derivatives modified at the C40 position may be combined with
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`pharmaceutically acceptable carriers in order to administer as useful immunosup-
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`pressants
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`Par provides below a detailed comparison of the claimed subject matter and
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`the prior art. Par respectfully submits that Claim 7 would have been obvious in
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`view of the prior art presented herein for the same reasons concerning claims 1, 8,
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`and 9 and therefore requests that the Board institute an inter partes review and de-
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`termine that this claim is unpatentable.
`
`V.
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`IDENTIFICATION OF CLAIMS BEING CHALLENGED
`(§ 42.104(B))
`
`Par respectfully requests that the Board cancel Claim 7 of the ’772 Patent
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`(Ex. 1001) (the “challenged claim”) based on the following grounds for unpatenta-
`
`bility:
`
`Ground 1. Claim 7 is unpatentable under 35 U.S.C. § 103 as obvious over
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`Morris (Ex. 1005), Van Duyne (Ex. 1006), Rossmann (Ex. 1024), Yalkowsky (Ex.
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`1007), Lemke (Ex. 1008), and Hughes (Ex. 1009).
`
`VI. DESCRIPTION OF THE PURPORTED INVENTION
`The ’772 Patent discloses certain alkylated derivatives of rapamycin. It
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`discloses that rapamycin is “an extremely potent immunosuppressant” that also
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`demonstrates antitumor and antifungal activity. (Ex. 1001, ’772 Patent at 1:34-36.)
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`Petition for Inter Partes Review of USP 5,665,772
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`However, the ’772 Patent also explains that rapamycin has shortcomings, including
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`relatively poor solubility, which created difficulty in making pharmaceutic
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`formulations. (Id. at 1:36-40.) The ’772 Patent states that the “Novel Compounds
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`are administered by any conventional route, in particular enterally, e.g., orally, for
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`example in the form of solutions for drinking, tablets or capsules or parenterally,
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`for example in the form of injectable solutions or suspensions.” (Id. at 5:4-8.)
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`The ’772 Patent states that the disclosed alkylated derivatives of rapamycin
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`have improved pharmacologic profiles over rapamycin. Specifically, the ’772
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`Patent states that alkylated derivatives demonstrate “an improved pharmacologic
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`profile over rapamycin, exhibit greater stability and bioavailability, and allow for
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`greater ease in producing galenic formulations.” (Id. at 1:41-45.) The ’772 Patent
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`further discloses that these alkylated derivatives having improved pharmacologic
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`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
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`formula, as modified by the pending Certificate of Correction (see n.2, supra):
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`Petition for Inter Partes Review of USP 5,665,772
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`
`
`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
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`claim 1 where the alkyl group can only contain between one and three carbon
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`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-
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`(2-hydroxyethyl)-rapamycin, the compound shown in the figure below. (Ex. 1003,
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`Jorgensen Decl. ¶ 38.)
`
`40
`
`O O
`
`HO
`
`O
`
`O
`
`28
`
`OH
`
`O
`
`N
`
`O
`
`10
`
`O
`OH
`O
`
`O
`
`O
`
`O
`
`
`
`14
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`Petition for Inter Partes Review of USP 5,665,772
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`Claim 7 recites a pharmaceutical composition comprising a therapeutically
`
`effective amount of a compound according to claim 1 and a pharmaceutically ac-
`
`ceptable carrier therefor.
`
`Claim 8 recites a method of inducing an immunosuppressant effect in a sub-
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`ject in need of immunosuppression, which comprises administering to said subject
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`an immunosuppressant effective amount of a compound according to claim 1.
`
`Claim 9 recites a method of preventing allograft rejection in a subject in
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`need of such treatment, which comprises administering to said subject a compound
`
`according to claim 1 in an amount effective to prevent allograft rejection.
`
`VII. 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-
`
`
`3 Par expressly reserves 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
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`cannot be raised in these proceedings. See 35 U.S.C. § 311(b). Nothing in this Pe-
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`tition, 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.
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`fication of the patent in which it appears.”4 37 C.F.R. § 42.100(b). This claim
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`Petition for Inter Partes Review of USP 5,665,772
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`construction standard is different from—and broader than—that applied in district
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`court. Versata Dev. Grp., Inc. v. SAP Am., Inc., 793 F.3d 1306, 1327-28 (Fed. Cir.
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`2015). Under the broadest reasonable interpretation, “claims should always be
`
`read in light of the specification and teachings in the underlying patent.” Microsoft
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`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. (citation omitted).
`
`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
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`48699 (“[T]he broader standard serves to identify ambiguities in the claims that
`
`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).
`
`Par expressly reserves the right to argue different or additional claim construction
`
`positions under this standard in district court.
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`can then be clarified through claim amendments.”). Consistent with the patent
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`Petition for Inter Partes Review of USP 5,665,772
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`owner’s responsibility to clarify ambiguous terms, “the Office may take into con-
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`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
`
`interpretatio