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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ROXANE LABORATORIES, INC.
`Petitioner
`
`
`v.
`
`
`NOVARTIS AG
`Patent Owner
`
`
`
`
`Case No. To Be Assigned
`Patent No. 5,665,772
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`5,665,772 UNDER 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq.
`
`
`

`

`
`EXHIBIT LIST ........................................................................................................ iv 
`TABLE OF AUTHORITIES .................................................................................. vii 
`I. 
`OVERVIEW .................................................................................................... 1 
`II. 
`INTRODUCTION ........................................................................................... 2 
`III.  MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8 ..................... 9 
`A. 
`Real Party-In-Interest ............................................................................ 9 
`B. 
`Related Matters ...................................................................................... 9 
`C. 
`Lead and Backup Counsel ................................................................... 10 
`D. 
`Service Information ............................................................................. 11 
`IV.  PAYMENT OF FEES ................................................................................... 11 
`V. 
`REQUIREMENTS UNDER 37 C.F.R. § 42.104 .......................................... 12 
`A.  Grounds for Standing .......................................................................... 12 
`B. 
`Identification of Challenge and Precise Relief Requested .................. 12 
`Claims for Which Inter Partes Review is Requested ............... 12 
`1. 
`2. 
`Statutory Grounds on Which the Challenge is Based ............... 13 
`3. 
`Evidence Relied Upon to Support the Challenge ..................... 13 
`4. 
`How the Challenged Claims Are to be Construed .................... 14 
`VI.  DESCRIPTION OF THE PURPORTED INVENTION ............................... 14 
`VII.  PERSON HAVING ORDINARY SKILL IN THE ART ............................. 16 
`VIII.  TECHNICAL BACKGROUND AND STATE OF THE ART .................... 17 
`A. 
`Rapamycin Was Known as a Powerful Immunosuppressant with
`Limited Solubility................................................................................ 17 
`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 ................... 25 
`
`C. 
`D. 
`E. 
`
`B. 
`
`TABLE OF CONTENTS
`
`i
`
`

`

`F. 
`
`B. 
`
`C. 
`
`D. 
`
`E. 
`F. 
`G. 
`
`Computer-Aided Drug Design Provided Quantitative
`Assessment of Modifications to Known Compounds ......................... 25 
`IX.  THE SCOPE AND CONTENT OF THE PRIOR ART ................................ 26 
`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 ..................................................... 28 
`Van Duyne Revealed the Structural Interactions Between
`Rapamycin and FKBP-12 .................................................................... 28 
`The Full Coordinates of the Van Duyne Structure Show that C40
`of Rapamycin Is the Optimal Position for Modification ..................... 32 
`Flexible Side Chains Were Known to Improve Solubility ................. 33 
`The Addition of Solubilizing Substituents Was Well-Known ............ 34 
`Rapamycin Derivatives at C40 Were Shown to Have
`Immunosuppressant Activity and Were Evaluated in Standard
`Assays .................................................................................................. 35 
`Computer-Aided Design Allowed For the Screening of Potential
`Modifications to Determine Promising Derivatives to Synthesize
`and Evaluate ........................................................................................ 37 
`X.  MOTIVATIONS TO COMBINE THE PRIOR ART REFERENCES ......... 39 
`XI.  PRECISE REASONS FOR THE RELIEF REQUESTED ........................... 40 
`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 ................... 43 
`1. 
`A Person of Ordinary Skill in The Art Would Have
`Selected Rapamycin as a Lead Compound and Would
`Have Been Motivated to Improve Rapamycin’s Solubility ...... 43 
`Van Duyne Teaches that Modifications of Rapamycin at
`the C40 Position Should Not Interfere with Activity ............... 45 
`Yalkowsky and Lemke teach that solubility can be
`improved with the addition of small, flexible side chains
`containing solubilizing groups .................................................. 47 
`Ground 2: Claims 7-9 are Invalid under 35 U.S.C. § 103 on the
`Ground That They Are Rendered Obvious in View of Morris,
`
`H. 
`
`2. 
`
`3. 
`
`B. 
`
`ii
`
`

`

`2. 
`
`Van Duyne, Rossmann, Lemke, Yalkowsky, and in further view
`of Hughes ............................................................................................ 51 
`1. 
`Ground 2 (With Respect to Claims 8 and 9): 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 ......................................................................... 52 
`Ground 2 With Respect to Claim 7: Claim 7 is Invalid
`under 35 U.S.C. § 103 on the Ground That It Is Rendered
`Obvious in View of Morris, Van Duyne, Rossmann,
`Lemke, Yalkowsky, and in further view of Hughes ................. 55 
`XII.  SECONDARY CONSIDERATIONS DO NOT RENDER CLAIMS 1-
`3 AND 7-10 NONOBVIOUS ........................................................................ 57 
`XIII.  CONCLUSION .............................................................................................. 58 
`
`
`
`
`
`
`
`
`iii
`
`

`

`EXHIBIT LIST
`
`1001 U.S. Patent No. 5,665,772 (“the ’772 Patent”)
`
`1002 File History for the ’772 Patent
`
`1003 Declaration of William L. Jorgensen, Ph.D. in Support of Petition for Inter
`Partes Review of U.S. Patent No. 5,665,772
`
`1004 Curriculum Vitae of William L. Jorgensen
`
`1005 Randall Ellis Morris, Rapamycins: Antifungal, Antitumor,
`Antiproliferative, 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)
`
`1009 U.S. Patent No. 5,233,036 (“Hughes”)
`
`1010 U.S. Patent No. 4,650,803 (“Stella”)
`
`1011 U.S. Patent No. 5,100,883 (“Schiehser”)
`
`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
`Molecules: A Method for Receptor-Based de Novo Ligand Design, 11
`PROTEINS: STRUCTURE, FUNCTION, & GENETICS 314 (1991)
`(“Moon”)
`
`
`
`
`iv
`
`

`

`1014 Hans-Joachim Böhm, LUDI: rule-based automatic design of new
`substituents for enzyme inhibitor leads, 6 J. COMPUTER-AIDED
`MOLECULAR DESIGN 593 (1992) (“Böhm”)
`
`1015 Silverman, Chapter 2: Drug Discovery, Design, and Development, THE
`ORGANIC CHEMISTRY OF DRUG DESIGN & ACTION 4 (1992)
`(“Silverman”)
`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)
`
`1016
`
`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
`BIOCHEMISTRY 12864 (1993)
`
`1019 Michelle L. Lamb & William L. Jorgensen, Investigations of Neurotrophic
`Inhibitors of FK506 Binding Protein via Monte Carlo Simulations, 41 J.
`MED. CHEMISTRY 3928 (1998)
`
`1020 Michelle L. Lamb et al., Estimation of Binding Affinities of FKBP12
`Inhibitors 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”)
`
`1024 Michael G. Rossmann et al., Three-Dimensional Coordinates from
`Stereodiagrams of Molecular Structures, B36 ACTA
`CRYSTALLOGRAPHICA 819 (1980) (“Rossmann”)
`
`v
`
`

`

`1025 William L. Jorgensen & Julian Tirado-Rives, The OPLS Potential
`Functions 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
`Proteins 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
`Structures 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
`Enzyme and Receptor for FK506 and Rapamycin, 252 SCI. 836 (1991)
`
`1030 Certificate of Correction for U.S. Patent No. 5,665,772
`
`
`
`vi
`
`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott GmbH v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171 (D. Mass. 2013) ..................................................... 43, 55, 57
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ...................................................................passim
`
`In re Beattie,
`974 F.2d 1309 (Fed. Cir. 1992) ...................................................................passim
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ............................................................................ 39
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .................................................................. 4, 40, 50
`
`In re Fout,
`675 F.2d 297 (C.C.P.A. 1982) ...................................................................... 48, 53
`
`Geneva Pharm., Inc. v. Glaxosmithkline PLC,
`189 F. Supp. 2d 377 (E. D. Va. 2002) .......................................................... 42, 57
`
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .....................................................................................passim
`
`Leapfrog Enters. Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 58
`
`In re Mayne,
`104 F.3d 1339 (Fed. Cir. 1997) .................................................................... 48, 53
`
`Newell Co. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 57
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................... 6, 41, 47, 54
`
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) ...................................................................... 48, 53
`
`vii
`
`

`

`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .......................................................................... 40
`
`In re Wilder,
`563 F.2d 457 (C.C.P.A. 1977) ............................................................ 6, 42, 47, 54
`
`Statutes
`
`35 U.S.C. § 102 .................................................................................................passim
`
`35 U.S.C. § 103 .................................................................................................passim
`
`35 U.S.C. §§ 311-319 ............................................................................................ 1, 2
`
`35 U.S.C. § 318(a) ................................................................................................... 12
`
`Other Authorities
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 9
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 9
`
`37 C.F.R. § 42.8(b)(3) .............................................................................................. 10
`
`37 C.F.R. § 42.8(b)(4) .............................................................................................. 10
`
`37 C.F.R. § 42.10(a) ................................................................................................. 10
`
`37 C.F.R. § 42.10(b) ................................................................................................ 10
`
`37 C.F.R. § 42.15(a) ................................................................................................. 11
`
`37 C.F.R. § 42.100(b) .............................................................................................. 14
`
`37 C.F.R. § 42.100 et seq. ...................................................................................... 1, 2
`
`37 C.F.R. § 42.104(a) ............................................................................................... 12
`
`37 C.F.R. § 42.104(b) .............................................................................................. 12
`
`77 Fed. Reg. 48759-60 ............................................................................................... 9
`
`
`
`
`
`viii
`
`

`

`I.
`
`OVERVIEW
`
`Roxane Laboratories, Inc. (“Roxane” or the “Petitioner”) respectfully
`
`requests an inter partes review (“IPR”) of claims 1-3 and 7-10 of U.S. Patent
`
`No. 5,665,772, issued on September 9, 1997, to Cottens et al. (“the ’772 Patent”)
`
`(Ex. 1001) in accordance with 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq.
`
`In Par Pharmaceutical, Inc. v. Novartis AG, No. IPR2016-00084, the Board
`
`previously instituted an IPR on claims 1-3 and 8-10 on the same grounds (Grounds
`
`1 and 2) upon which Roxane relies below. Claims 1-3 and 10 claim compounds,
`
`and claims 8 and 9 methods of using a compound of claim 1.
`
`On May 17, 2016, Par Pharmaceutical, Inc. (“Par”) filed a petition for IPR of
`
`claim 7 of the ’772 Patent and filed a motion to join the IPR on claim 7 with the
`
`previously instituted IPR2016-00084 on claims 1-3 and 8-10. Claim 7 claims a
`
`pharmaceutical composition containing a compound of claim 1 and a carrier. In
`
`support of its petition and motion, Par notes that Par has been sued by Novartis AG
`
`(“Novartis”) for infringement of claim 7 of the ’772 Patent and asserts that claim 7
`
`is invalid on the same grounds as claims 1, 8 and 9 on which an IPR has already
`
`been instituted.
`
`Roxane, like Par, has been sued by Novartis for infringement of, inter alia,
`
`claim 7 of the ’772 Patent. Roxane, like Par, contends that claim 7 is invalid on the
`
`same grounds as claims 8 and 9 of the ’772 Patent, on which an IPR has already
`
`1
`
`

`

`been instituted. The validity of claim 7 of the ’772 Patent should rise or fall with
`
`the validity of the compound and method claims of the ’772 Patent. Accordingly,
`
`Roxane further requests an IPR on claim 7 of the ’772 Patent in accordance with 35
`
`U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq. based on the same prior art,
`
`evidence and grounds as Roxane relies upon for its request to institute an IPR on
`
`claims 1-3 and 8-10 and that the Board considered when instituting IPR2016-
`
`00084 on claims 1-3 and 8-10.
`
`II.
`
`INTRODUCTION
`
`The ’772 Patent describes and claims certain derivatives of the compound
`
`rapamycin, compositions including those derivatives, and their use as
`
`immunosuppressants. According to the ’772 Patent, the claimed rapamycin
`
`derivatives improve on rapamycin’s properties. (Ex. 1001, ’772 Patent at 1:41-45.)
`
`Claim 1 of the ’772 Patent1 reads as follows:
`
`1.
`
`A compound of the formula
`
`
`1
`Claim 1 reflects a certificate of correction that the Patent Office entered on
`
`February 9, 2016. (Ex. 1030, ’772 Patent Certificate of Correction.)
`
`2
`
`

`

`wherein R1 is hydroxy(C1-6)alkyl or hydroxy(C1-
`
`3)alkoxy(C1-3)alkyl.
`
`
`
`Claims 2, 3, and 10 depend from claim 1. Claims 8 and 9 recite methods of using
`
`the compounds of claim 1. There is a reasonable likelihood that at least one of
`
`claims 1-3 and 8-10 is unpatentable because it would have been obvious to a
`
`person of ordinary skill in the art.
`
`Claim 7 of the ’772 Patent recites a pharmaceutical composition comprising
`
`a compound of claim 1. For the same reasons as pertain to claims 1 and 8-9, there
`
`is a reasonable likelihood that claim 7 is unpatentable as obvious.
`
`Claim 1 includes derivatives of rapamycin that have been modified at C40.
`
`(Ex. 1003, Jorgensen Decl. at ¶ 27.) Claims 2 and 3 depend from claim 1 and
`
`narrow the scope of R1. (Ex. 1001, ’772 Patent at 22:4-7; Ex. 1003, Jorgensen
`
`Decl. at ¶¶ 32-35.) Claim 10 depends from claim 1 and recites one specific
`
`rapamycin derivative, 40-O-(2-hydroxyethyl)-rapamycin. (Ex. 1001, ’772 Patent at
`
`3
`
`

`

`22:28-29, Certificate of Correction dated June 30, 1998; Ex. 1003, Jorgensen Decl.
`
`at ¶ 38.) Claim 10 falls within the scope of claims 1, 2, and 3. (Ex. 1003,
`
`Jorgensen Decl. at ¶¶ 38-39.) The prior art suggested modifying rapamycin to
`
`obtain rapamycin derivatives with improved solubility, including the compound of
`
`claim 10, which necessarily falls within the scope of claims 1, 2, and 3.
`
`“In drug development, it is common to modify a lead compound in an effort
`
`to ‘obtain a compound with better’” properties. Bristol-Myers Squibb Co. v. Teva
`
`Pharm. USA, Inc., 752 F.3d 967, 974 (Fed. Cir. 2014) (citation omitted). A
`
`compound is obvious if the selection of the position to modify and determination of
`
`how to modify “equate to a small, finite number of changes to try.” Id. at 976. A
`
`person of ordinary skill in the art would have been motivated to select rapamycin
`
`as a lead compound to modify in order to improve its solubility. Morris
`
`summarizes the significant amount of information available as of October 1992
`
`regarding the remarkable immunosuppressant activity of rapamycin, making it an
`
`ideal candidate for further investigation. (Ex. 1005, Morris at 39-42, 52-64; Ex.
`
`1003, Jorgensen Decl. at ¶¶ 72-74, 132-137.) Additionally, Morris teaches that
`
`rapamycin is minimally soluble in water, and indeed, the ’772 Patent expressly
`
`admits this well-known limitation of rapamycin. (Ex. 1005, Morris at 46; Ex.
`
`1001, ’772 Patent at 1:36-40; Ex. 1003, Jorgensen Decl. at ¶¶ 75-76, 138-140.) See
`
`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007) (“[A]ny need or problem
`
`4
`
`

`

`known in the field of endeavor at the time of invention and addressed by the patent
`
`can provide a reason for combining the elements in the manner claimed.”); In re
`
`Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992) (“As long as some motivation or
`
`suggestion to combine the references is provided by the prior art taken as a whole,
`
`the law does not require that the references be combined for the reasons
`
`contemplated by the inventor.”).
`
`A person of ordinary skill in the art would have been motivated to modify
`
`rapamycin to improve its solubility without disrupting its biological activity. In
`
`order to achieve this, a person of ordinary skill in the art would have modified
`
`rapamycin’s C40 hydroxyl group because the structure showing rapamycin’s
`
`binding to its biological target FKBP-12 taught that the C40 hydroxyl was the best
`
`position for modification. (Ex. 1006, Van Duyne at 7434; Ex. 1003, Jorgensen
`
`Decl. at ¶¶ 101-123, 141-145.)
`
`Yalkowsky (Ex. 1007) and Lemke (Ex. 1008) teach how to improve the
`
`solubility of chemical compounds by adding flexible side chains with solubilizing
`
`substituents. (Ex. 1003, Jorgensen Decl. at ¶¶ 77-88.) Such solubilizing
`
`substituents include the 2-hydroxyethoxy substituent at the C40 position of the
`
`compound of claim 10. (Id. at ¶¶ 146-161.)
`
`Additionally, prior researchers had synthesized rapamycin derivatives by
`
`modifying rapamycin at the C40 position and reported that such derivatives
`
`5
`
`

`

`displayed immunosuppressant activity in standard pharmacological assays,
`
`including preventing allograft rejection. (Ex. 1009, Hughes at 2:62-4:12; Ex. 1003,
`
`Jorgensen Decl. at ¶¶ 125-126.) As such, a person of ordinary skill in the art would
`
`have a reasonable expectation that modifying rapamycin at its C40 position would
`
`result in a compound with immunosuppressant activity. (Ex. 1003, Jorgensen
`
`Decl. at ¶¶ 166-172.) Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499 F.3d
`
`1293, 1301 (Fed. Cir. 2007) (“[I]t is sufficient to show that the claimed and prior
`
`art compounds possess a ‘sufficiently close relationship . . . to create an
`
`expectation,’ in light of the totality of the prior art, that the new compound will
`
`have ‘similar properties’ to the old.”) (citations omitted); Pfizer, Inc. v. Apotex,
`
`Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (simply because the properties 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
`
`reasonable, not absolute”); In re Wilder, 563 F.2d 457, 460 (C.C.P.A. 1977)
`
`(“[O]ne who claims a compound, per se, which is structurally similar to a prior art
`
`compound must rebut the presumed expectation that the structurally similar
`
`compounds have similar properties.”). Therefore, claims 8 and 9, which recite
`
`methods of using the compounds of claim 1 as immunosuppressants or to prevent
`
`allograft rejection, would also have been obvious.
`
`6
`
`

`

`Furthermore, because the structure of rapamycin bound to its biological
`
`target FKBP-12 was known, computer-aided design allowed a person of ordinary
`
`skill in the art to screen potential modifications to identify those modifications that
`
`would not interfere with FKBP-12 binding and thus would not disrupt rapamycin’s
`
`biological activity. This common tool would have been used by a person of
`
`ordinary skill in the art to identify those modifications that would increase
`
`solubility while not interfering with rapamycin’s ability to bind to FKBP-12. (See
`
`Ex. 1003, Jorgensen Decl. at ¶¶ 173-193.) Using such a tool, a person of ordinary
`
`skill in the art would have identified modifications at C40 that included the 2-
`
`hydroxyethyl group of the compound of claim 10 of the ’772 Patent. (See id. at
`
`150-165.)
`
`In summary, claims 1-3 and 8-10 of the ’772 Patent would have been
`
`obvious to a person of ordinary skill in the art in view of the prior art disclosing at
`
`least the following: (1) rapamycin was a well-known and significant
`
`immunosuppressant with known limited solubility; (2) the known information
`
`regarding the interactions between rapamycin and its biological targets taught that
`
`C40 was the optimal position for making modifications without disrupting
`
`biological activity; (3) known strategies for improving solubility of chemical
`
`compounds taught adding flexible side chains with solubilizing substituents; and
`
`7
`
`

`

`(4) prior rapamycin derivatives modified at C40 had been shown to have
`
`immunosuppressant activity, including the ability to prevent allograft rejection.
`
`Claim 7 recites a pharmaceutically composition comprising a therapeutically
`
`effective amount of a compound of claim 1 and a carrier. Claim 7 would have
`
`been obvious for the same reasons as set forth above with respect to claims 1-3 and
`
`8-10, and the validity of claim 7 should rise or fall with the validity of claims 1-3
`
`and 8-10. As explained above, and in more detail below, a person of ordinary skill
`
`in the art would have been motivated to modify rapamycin to make a rapamycin
`
`derivative with improved pharmaceutical properties. A person of ordinary skill in
`
`the art likewise would have been motivated to make a pharmaceutical composition
`
`containing a therapeutically effective amount of such a rapamycin derivative and to
`
`include a pharmaceutically acceptable carrier in the composition. Hughes (Ex.
`
`1009) explicitly teaches rapamycin derivatives modified at the C40 position as
`
`useful immunosuppressants that “may be administered neat or with a
`
`pharmaceutical carrier to a mammal in need thereof.” (Hughes, Ex. 1009, at 4:57-
`
`58.)
`
`Roxane provides below a detailed comparison of the claimed subject matter
`
`and the prior art. Roxane respectfully submits that claims 1-3 and 7-10 would have
`
`been obvious in view of the prior art presented herein and therefore requests that
`
`the Board institute an IPR on this basis.
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`8
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`III. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8
`A. Real Party-In-Interest
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Roxane is a real-
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`party-in-interest for this proceeding. Out of an abundance of caution, and as a
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`result of ongoing integration and reorganization activities, Petitioner identifies the
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`following additional entity as a real-party-in-interest who, going forward, may have
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`control over this proceeding: Hikma Pharmaceuticals PLC and its U.S. subsidiary
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`West-Ward Pharmaceuticals Corp. No other parties exercised or could have
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`exercised 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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`B. Related Matters
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is aware of the following
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`matters: Novartis Pharmaceuticals Corp. v. Breckenridge Pharmaceutical, Inc.,
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`C.A. No. 14-1043-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane
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`Laboratories, Inc., C.A. No. 14-1196-RGA (D. Del.); Novartis Pharmaceuticals
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`Corp. v. Par Pharmaceutical, Inc., C.A. No. 14-1289-RGA (D. Del.); Novartis
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`Pharmaceuticals Corp. v. Par Pharmaceutical, Inc., C.A. No. 14-1494-RGA (D.
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`Del.); Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc., C.A. No. 15-
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`78-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
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`9
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`

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`C.A. No. 14-1508-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane
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`Laboratories, Inc., C.A. No. 15-128-RGA (D. Del.); and, Par Pharmaceutical,
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`Inc. v. Novartis AG, IPR2016-00084.
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`Lead and Backup Counsel
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`C.
`Pursuant to 37 C.F.R. §§ 42.8(b)(3), 42.8(b)(4) and 42.10(a), Roxane
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`provides the following designation of Lead and Back-Up counsel.
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`
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`LEAD CONSEL
`Keith A. Zullow (Reg. No. 37,975)
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`BACKUP COUNSEL
`Marta E. Delsignore (Reg. No. 32,689)
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`(kzullow@goodwinprocter.com)
`
`(mdelsignore@goodwinprocter.com)
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`GOODWIN PROCTER LLP
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`GOODWIN PROCTER LLP
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`The New York Times Building
`
`The New York Times Building
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`620 Eighth Avenue
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`620 Eighth Avenue
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`New York, NY 10018-1405
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`New York, NY 10018-1405
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`T: 212-813-8846; F: 646-558-4226
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`T: 212-813-8822; F: 646-558-4079
`
`
`
`
`
`A Power of Attorney is being filed concurrently herewith in accordance with
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`37 C.F.R. § 42.10(b).
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`10
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`

`

`Service Information
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`D.
`Papers concerning this matter should be served by EXPRESS MAIL, hand-
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`delivery, or electronic mail at the following address:
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`Mailing Address:
`
`Keith A. Zullow, Esq.
`
`
`
`
`
`
`
`GOODWIN PROCTER LLP
`
`The New York Times Building
`
`620 Eighth Avenue
`
`
`
`New York, NY 10018-1405
`
`Electronic Mail:
`
`kzullow@goodwinprocter.com
`
`Telephone:
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`Facsimile:
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`212-813-8846
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`646-558-4226
`
`
`IV. PAYMENT OF FEES
`The undersigned authorizes payment of $23,000.00 for the fees set forth in
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`37 C.F.R. § 42.15(a) for this Petition to be charged to Deposit Account No. 50-
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`6989. The undersigned further authorizes payment for any additional fees that
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`might be due in connection with this Petition to be charged to Deposit Account No.
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`50-6989.
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`11
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`

`

`V. REQUIREMENTS UNDER 37 C.F.R. § 42.104
`A. Grounds for Standing
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ’772
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`Patent is available for inter partes review. Although more than one year has
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`passed since Roxane was served with a complaint alleging infringement of the ’772
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`Patent, Petitioner is not barred or estopped from joining inter partes review of the
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`challenged claims of the ’772 Patent on the grounds identified in this Petition.
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`Neither Petitioner nor any privy of Petitioner has received a final written decision
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`under 35 U.S.C. § 318(a) with respect to any claim of the ’772 Patent on any
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`ground that was raised or could have been raised by Petitioner or its privies in any
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`inter partes review, post grant review, or covered business method patent review.
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`Identification of Challenge and Precise Relief Requested
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`B.
`Pursuant to 37 C.F.R. § 42.104(b), Petitioner challenges claims 1-3 and 7-10
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`of the ’772 Patent and requests that these claims be found unpatentable over the
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`prior art for the reasons given herein.
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`Claims for Which Inter Partes Review is Requested
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`1.
`Petitioner requests inter partes review of claims 1-3 and 8-10 of the ’772
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`Patent. Claims 1 of the ’772 Patent, and claims 2, 3 and 10 which depend directly
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`therefrom, are directed to compounds. Claims 8 is directed to a method of
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`inducing an immunosuppressant effect by administering a compound of claim 1.
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`12
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`Claim 9 is directed to a method of preventing allograft rejection by administering a
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`compound of claim 1.
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`Petitioner also requests inter partes review of claim 7, which is directed to a
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`pharmaceutical composition comprising a compound of claim 1 and a carrier.
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`Statutory Grounds on Which the Challenge is Based
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`2.
`Claims 1-3 and 10 are unpatentable because they are obvious under 35
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`U.S.C. § 103(a) in view of the combined teachings of Morris (Ex. 1005), Van
`
`Duyne (Ex. 1006), Rossmann (Ex. 1024), Yalkowsky (Ex. 1007) and Lemke (Ex.
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`1008). Claims 8 and 9 are unpatentable because they are obvious under 35 U.S.C.
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`§ 103(a) in view of the combined teachings of Morris (Ex. 1005), Van Duyne (Ex.
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`1006), Rossmann (Ex. 1024), Yalkowsky (Ex. 1007), Lemke (Ex. 1008), and
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`Hughes (Ex. 1009). Claim 7 is also unpatentable because it is obvious under 35
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`U.S.C. § 103(a) in view of the same combined teachings of Morris (Ex. 1005), Van
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`Duyne (Ex. 1006), Rossmann (Ex. 1024), Yalkowsky (Ex. 1007), Lemke (Ex.
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`1008), and Hughes (Ex. 1009).
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`Evidence Relied Upon to Support the Challenge
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`3.
`Petitioner relies upon each of the publications cited herein. Petitioner also
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`relies upon the Declaration of William L. Jorgensen, Ph.D. (Ex. 1003) and Exhibits
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`1001-1002 and 1004-1030.
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`13
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`

`

`How the Challenged Claims Are to be Construed
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`4.
`The terms of the claims of the ’772 Patent are to be given their broadest
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`reasonable interpretation in light of the specification, as understood by a person of
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`ordinary skill in the art. See 37 C.F.R. § 42.100(b). All claim terms have been
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`accorded their broadest reasonable interpretation as understood by one of ordinary
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`skill in the art and consistent with the specification of the ’772 Patent.
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`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 1:33-36.)
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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, tabl