`
`
`By: B. Jefferson Boggs, Esq.
`Matthew L. Fedowitz, Esq.
`Daniel R. Evans, Esq.
`MERCHANT & GOULD P.C.
`1701 Duke Street, Suite 310
`Alexandria, VA 22314
`Main Telephone: (703) 684-2500
`Main Facsimile: (703) 684-2501
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`BRECKENRIDGE PHARMACEUTICAL, 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.
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`I.
`
`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8 ..................... 6
`
`A.
`
`B.
`
`C.
`
`D.
`
`Real Party-In-Interest ............................................................................ 6
`
`Related Matters ...................................................................................... 7
`
`Lead and Backup Counsel ..................................................................... 7
`
`Service Information ............................................................................... 8
`
`III.
`
`PAYMENT OF FEES ..................................................................................... 8
`
`IV. REQUIREMENTS UNDER 37 C.F.R. § 42.104 ............................................ 9
`
`A. Grounds for Standing ............................................................................ 9
`
`B.
`
`Identification of Challenge and Precise Relief Requested .................... 9
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claims for Which Inter Partes Review is Requested ................. 9
`
`Statutory Grounds on Which the Challenge is Based ............... 10
`
`Evidence Relied Upon to Support the Challenge ..................... 10
`
`How the Challenged Claims Are to be Construed .................... 10
`
`V. DESCRIPTION OF THE PURPORTED INVENTION ............................... 11
`
`VI. PERSON HAVING ORDINARY SKILL IN THE ART ............................. 13
`
`VII. TECHNICAL BACKGROUND AND STATE OF THE ART .................... 14
`
`A.
`
`B.
`
`Rapamycin Was Known as a Powerful Immunosuppressant
`with Limited Solubility ....................................................................... 14
`
`Rapamycin Derivatives at C40 Had Been Synthesized and
`Shown to Have Immunosuppressant Activity ..................................... 15
`
`C.
`
`Rapamycin’s Interactions With Its Targets Were Known .................. 16
`
`
`
`ii
`
`
`
`D.
`
`E.
`
`F.
`
`Solubility-Enhancing Modifications Were Well-Known ................... 20
`
`Standard Assays Were Available to Evaluate
`Immunosuppressant Activity of Rapamycin Derivatives ................... 23
`
`Computer-Aided Drug Design Provided Quantitative
`Assessment of Modifications to Known Compounds ......................... 23
`
`VIII. THE SCOPE AND CONTENT OF THE PRIOR ART ................................ 24
`
`A. Morris Teaches that Rapamycin Is a Promising Lead
`Compound with Limited Solubility .................................................... 24
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`Rossmann Teaches How to Obtain Three-Dimensional
`Coordinates from Stereo Diagrams ..................................................... 25
`
`Van Duyne Revealed the Structural Interactions Between
`Rapamycin and FKBP-12 .................................................................... 26
`
`The Full Coordinates of the Van Duyne Structure Show that
`C40 of Rapamycin Is the Optimal Position for Modification ............. 30
`
`Flexible Side Chains Were Known to Improve Solubility ................. 31
`
`The Addition of Solubilizing Substituents Was Well-Known ............ 32
`
`Rapamycin Derivatives at C40 Were Shown to Have
`Immunosuppressant Activity and Were Evaluated in Standard
`Assays .................................................................................................. 33
`
`Computer-Aided Design Allowed For the Screening of
`Potential Modifications to Determine Promising Derivatives to
`Synthesize and Evaluate ...................................................................... 34
`
`IX. MOTIVATIONS TO COMBINE THE PRIOR ART REFERENCES ......... 36
`
`X.
`
`PRECISE REASONS FOR THE RELIEF REQUESTED ........................... 37
`
`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 ................... 39
`
`1.
`
`A Person of Ordinary Skill in The Art Would Have
`iii
`
`
`
`
`
`Selected Rapamycin as a Lead Compound and Would
`Have Been Motivated to Improve Rapamycin’s Solubility ...... 40
`
`Van Duyne Teaches that Modifications of Rapamycin at
`the C40 Position Should Not Interfere with Activity ................ 41
`
`Yalkowsky and Lemke teach that solubility can be
`improved with the addition of small, flexible side chains
`containing solubilizing groups .................................................. 44
`
`2.
`
`3.
`
`B.
`
`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
`
`XI. SECONDARY CONSIDERATIONS DO NOT RENDER CLAIMS
`1-3 AND 8-10 NONOBVIOUS .................................................................... 50
`
`XII. CONCLUSION .............................................................................................. 51
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`iv
`
`
`
`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”)
`
`
`
`v
`
`
`
`
`
`
`
`
`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”)
`
`vi
`
`
`
`
`
`
`
`
`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 Declaration of Steven W. Baldwin, Ph.D. in Support of Petition for Inter
`Partes Review of U.S. Patent No. 5,665,772
`
`1031 Curriculum Vitae of Steven W. Baldwin
`
`1032 U.S. Patent No. 5,258,389
`
`vii
`
`
`
`
`
`TABLE OF AUTHORITIES
`
`
`CASES
`Abbott GmbH v. Centocor Ortho Biotech, Inc.,
`971 F. Supp. 2d 171 (D. Mass 2013), aff’d sub. nom. AbbVie
`Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed.
`Cir. 2014) ..................................................................................................... 39, 50
`
`Page(s)
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ......................................................... 4, 39, 43, 50
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ........................................................................... 37
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .................................................................. 2, 37, 47
`
`In re Beattie,
`974 F.2d 1309 (Fed. Cir. 1992) ..................................................................passim
`
`In re Deuel,
`51 F.3d 1552 (Fed. Cir. 1995) .......................................................................... 37
`
`In re Fout,
`675 F.2d 297 (C.C.P.A. 1982) ...................................................................... 45, 49
`
`In re Mayne,
`104 F.3d 1339 (Fed. Cir. 1997) .................................................................... 45, 49
`
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) ...................................................................... 45, 49
`
`In re Wilder,
`563 F.2d 457 (C.C.P.A. 1977) ............................................................ 5, 39, 43, 50
`
`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) ........................................................................... 51
`
`
`
`viii
`
`
`
`
`
`Newell Co. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 50
`
`Novartis Pharmaceuticals Corp. v. Breckenridge Pharmaceutical, Inc.,
`C.A. No. 14-1043-RGA (D. Del.) ........................................................................ 7
`
`Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc.,
`C.A. No. 14-1289-RGA (D. Del.) ........................................................................ 7
`
`Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc.,
`C.A. No. 14-1494-RGA (D. Del.) ........................................................................ 7
`
`Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc.,
`C.A. No. 15-78-RGA (D. Del.) ............................................................................ 7
`
`Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`C.A. No. 14-1196-RGA (D. Del.) ........................................................................ 7
`
`Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`C.A. No. 14-1508-RGA (D. Del.) ........................................................................ 7
`
`Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`C.A. No. 15-128-RGA (D. Del.) .......................................................................... 7
`
`Par Pharmaceutical, Inc. v. Novartis AG,
`IPR2016-00084 ..................................................................................................... 7
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................... 4, 39, 43, 50
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) ........................................................................ 37
`
`STATUTES
`
`35 U.S.C. § 102(a) .................................................................................................. 24
`
`35 U.S.C. § 102(b) ............................................................................................passim
`
`35 U.S.C. § 102(e) .................................................................................................. 33
`
`35 U.S.C. § 103 ...................................................................................... 39, 45, 48, 49
`
`35 U.S.C. § 103(a) ................................................................................................... 10
`
`
`
`ix
`
`
`
`
`
`35 U.S.C. §§ 311-319 ................................................................................................ 1
`35 U.S.C. §§ 311-319 .............................................................................................. ..1
`
`35 U.S.C. § 318(a) ..................................................................................................... 9
`35 U.S.C. § 318(a) ................................................................................................... ..9
`
`OTHER AUTHORITIES
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.8 ......................................................................................................... 6
`37 C.F.R. § 42.8 ....................................................................................................... ..6
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 6
`37 C.F.R. § 42.8(b)(1) .............................................................................................. ..6
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 7
`37 C.F.R. § 42.8(b)(2) .............................................................................................. ..7
`
`37 C.F.R. § 42.10(b) .................................................................................................. 8
`37 C.F.R. §42.10(b) ................................................................................................ ..8
`
`37 C.F.R. § 42.15(a)(1-4) ........................................................................................... 8
`37 C.F.R. § 42.15(a)(1-4) ......................................................................................... ..8
`
`37 C.F.R. § 42.100(b) .............................................................................................. 10
`37 C.F.R. § 42.100(b) ............................................................................................ ..10
`
`37 C.F.R. § 42.100 et seq. .......................................................................................... 1
`37 C.F.R. § 42.100 et seq. ........................................................................................ ..1
`
`37 C.F.R. § 42.104 ..................................................................................................... 9
`37 C.F.R. §42.104 ................................................................................................... ..9
`
`37 C.F.R. § 42.104(a) ................................................................................................. 9
`37 C.F.R. §42.104(a) ............................................................................................... ..9
`
`37 C.F.R. § 42.104(b) ................................................................................................ 9
`37 C.F.R. §42.104(b) .............................................................................................. ..9
`
`
`
`x
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`Breckenridge Pharmaceutical, Inc. (“Breckenridge” or the “Petitioner”)
`
`respectfully requests an inter partes (“IPR”) review for claims 1-3 and 8-10 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.
`
`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 Patent reads as follows:
`
`A compound of the formula
`
`
`
`
`
`1
`
`
`
`
`
`wherein R1 is hydroxy(C1-6)alkyl or hydroxy(C1-3)alkoxy(C1-3)alkyl. Claims 2, 3,
`and 8-10 depend from 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 1 includes derivatives of rapamycin which have been modified at
`
`C40. (Ex. 1030, Baldwin Decl. at ¶ 26.) Claims 2 and 3 depend from claim 1
`
`and narrow the scope of R1. (Ex. 1001, ’772 Patent at 22:4-7; Ex. 1030, Baldwin
`
`Decl. at ¶¶ 31-34.) Claim 10 depends from claim 1 and recites one specific
`
`rapamycin derivative, 40-O-(2-hydroxyethyl)-rapamycin. (Ex. 1001, ’772 Patent
`
`at 22:28-29, Certificate of Correction dated June 30, 1998; Ex. 1030, Baldwin
`
`Decl. at ¶ 37.) Claim 10 falls within the scope of claims 1, 2, and 3. (Ex. 1030,
`
`Baldwin Decl. at ¶¶ 37-38.) 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
`
`Pharms. USA, Inc., 752 F.3d 967, 975 (Fed. Cir. 2014) (citation omitted). A
`
`com- pound 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
`
`
`
`2
`
`
`
`
`
`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. 1030, Baldwin Decl. at ¶¶ 75-77, 136-141.)
`
`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. 1030,
`
`Baldwin Decl. at ¶¶ 78-79, 142-144.) See KSR Int'l Co. v. Teleflex Inc., 550 U.S.
`
`398, 420 (2007) (“[A]ny need or problem 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
`
`
`
`3
`
`
`
`
`
`position for modification. (Ex. 1006, Van Duyne at 7434; Ex. 1030, Baldwin
`
`Decl. at ¶¶ 104-126, 145-149.)
`
`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. 1030, Baldwin Decl. at ¶¶ 80-91.) Such
`
`solubilizing substituents include the 2-hydroxyethoxy substituent at the C40
`
`position of the compound of claim 10. (Id. at ¶¶ 150-165.)
`
`Additionally, prior researchers had synthesized rapamycin derivatives by
`
`modifying rapamycin at the C40 position and reported that such derivatives dis-
`
`played immunosuppressant activity in standard pharmacological assays, including
`
`preventing allograft rejection. (Ex. 1009, Hughes at 2:62-4:12; Ex. 1030, Baldwin
`
`Decl. at ¶¶ 92-103.) 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. 1030, Baldwin Decl. at
`
`¶¶ 170-176.) 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
`
`
`
`4
`
`
`
`
`
`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.
`
`Furthermore, because the structure of rapamycin bound to its biological tar-
`
`get 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 additional 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. 1030, Baldwin Decl. at ¶¶ 130-132, 145.) 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.)
`
`
`
`5
`
`
`
`
`
`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
`
`(4) prior rapamycin derivatives modified at C40 had been shown to have
`
`immunosuppressant activity, including the ability to prevent allograft rejection.
`
`Breckenridge provides below a detailed comparison of the claimed subject
`
`matter and the prior art. Breckenridge 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 Board institute an IPR on this basis.
`
`II. 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 Breckenridge,
`
`Pensa Pharma S.A., Corporacion Quimico Farmaceutica Esteve, S.A., and Natco
`
`Pharma Ltd. are the real parties-in-interest.
`
`
`
`6
`
`
`
`
`
`B. Related Matters
`
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is aware of the following
`
`matters: Novartis Pharmaceuticals Corp. v. Breckenridge Pharmaceutical, Inc.,
`
`C.A. No. 14-1043-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane
`
`Laboratories, Inc., C.A. No. 14-1196-RGA (D. Del.); Novartis Pharmaceuticals
`
`Corp. v. Par Pharmaceutical, Inc., C.A. No. 14-1289-RGA (D. Del.); Novartis
`
`Pharmaceuticals Corp. v. Par Pharmaceutical, Inc., C.A. No. 14-1494-RGA (D.
`
`Del.); Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc., C.A. No. 15-
`
`78-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`
`C.A. No. 14-1508-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane
`
`Laboratories, Inc., C.A. No. 15-128-RGA (D. Del.); and, Par Pharmaceutical, Inc.
`
`v. Novartis AG, IPR2016-00084.
`
`C. Lead and Backup Counsel
`
`Lead Counsel:
`B. Jefferson Boggs, Esq.
`Registration No. 32,344
`Merchant & Gould P.C.
`1701 Duke Street
`Suite 310
`Alexandria, VA 22314
`Main Telephone: (703) 684-2500
`Main Facsimile: (703) 684-2501
`jboggs@merchantgould.com
`
`
`Backup Counsel:
`Matthew L. Fedowitz, Esq.
`Registration No. 61,386
`Merchant & Gould P.C.
`1701 Duke Street
`Suite 310
`Alexandria, VA 22314
`Main Telephone: (703) 684-2500
`Main Facsimile: (703) 684-2501
`mfedowitz@merchantgould.com
`
`
`
`
`
`
`
`7
`
`
`
`
`
`Backup Counsel:
`Daniel R. Evans, Esq.
`Registration No. 55,868
`Merchant & Gould P.C.
`191 Peachtree Street, NE
`Suite 3800
`Atlanta, GA 30303
`Main Telephone: (404) 954-5100
`Main Facsimile: (404) 954-5099
`devans@merchantgould.com
`
`A Power of Attorney is being filed concurrently herewith in accordance with
`
`37 C.F.R. § 42.10(b).
`
`D.
`
`Service Information
`
`Papers concerning this matter should be served by EXPRESS MAIL, hand-
`
`delivery, or electronic mail at the following address:
`
`Mailing Address: Matthew L. Fedowtiz, Esq.
`
`
`
`Merchant & Gould P.C.
`
`
`
`1701 Duke Street, Suite 310
`
`
`
`Alexandria, VA 22314
`Electronic Mail: mfedowitz@merchantgould.com
`Main Telephone: 703-684-2500
`Main Facsimile: 703-684-2501
`
`
`
`
`
`
`
`
`
`III. PAYMENT OF FEES
`
`Payment of $23,000.00 for the fees set forth in 37 C.F.R. § 42.15(a)(1-4)
`
`accompanies this Petition by way of credit card payment. The undersigned further
`
`authorizes payment for any additional fees that might be due in connection with
`
`this Petition to be charged to Deposit Account No. 13-2725.
`
`
`
`8
`
`
`
`
`
`IV. 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
`
`Patent is available for inter partes review, and that the Petitioner is not barred or
`
`estopped from requesting inter partes review of the challenged claims of the ’772
`
`Patent on the grounds identified in this Petition. Neither Petitioner nor any privy
`
`of Petitioner has received a final written decision under 35 U.S.C. § 318(a) with
`
`respect to any claim of the ’772 Patent on any ground that was raised or could have
`
`been raised by Petitioner or its privies in any inter partes review, post grant
`
`review, or covered business method patent review.
`
`B.
`
`Identification of Challenge and Precise Relief Requested
`
`Pursuant to 37 C.F.R. § 42.104(b), Petitioner challenges claims 1-3 and 8-10
`
`of the ’772 Patent and requests that these claims be found unpatentable over the
`
`prior art for the reasons given herein.
`
`1.
`
`Claims for Which Inter Partes Review is Requested
`
`Petitioner requests inter partes review of claims 1-3 and 8-10 of the ’772
`
`Patent. The claims of the ’772 patent at issue are directed to compounds (claims 1-
`
`3 and 10), a method of inducing an immunosuppressant effect (claim 8), and a
`
`method of preventing allograft rejection (claim 9). Claim 1 is independent.
`
`Claims 2, 3, and 8-10 all depend directly from claim 1.
`
`
`
`9
`
`
`
`
`
`2.
`
`Statutory Grounds on Which the Challenge is Based
`
`Claims 1-3 and 10 are unpatentable because they are obvious under 35
`
`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.
`
`1008). Claims 8 and 9 are unpatentable because they are obvious under 35 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), Lemke (Ex. 1008), and
`
`Hughes (Ex. 1009).
`
`3.
`
`Evidence Relied Upon to Support the Challenge
`
`Petitioner relies upon each of the publications cited herein. Petitioner also
`
`relies upon the Declaration of Steven W. Baldwin, Ph.D. (Ex. 1030) and Exhibits
`
`1001-1029, 1031, and 1032.
`
`4. How the Challenged Claims Are to be Construed
`
`The terms of the claims of the ’772 Patent are to be given their broadest
`
`reasonable interpretation in light of the specification, as understood by a person of
`
`ordinary skill in the art. See 37 C.F.R. § 42.100(b). All claim terms have been
`
`accorded their broadest reasonable interpretation as understood by one of ordinary
`
`skill in the art and consistent with the specification of the ’772 Patent.
`
`
`
`10
`
`
`
`
`
`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 the 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:
`
`
`
`11
`
`
`
`
`
`
`(highlighted emphasis added), where R1 is hydroxy(C1-6)alkyl or hydroxy(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.
`
`1030, Baldwin Decl. at ¶ 37.)
`
`
`
`12
`
`
`
`
`
`
`
`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 effe