`
`
`By: B. Jefferson Boggs, Esq.
`Matthew L. Fedowitz, Esq.
`Daniel R. Evans, Esq.
`MERCHANT & GOULD P.C.
`1900 Duke Street, Suite 600
`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 ................... 10 
`
`A. 
`
`B. 
`
`C. 
`
`D. 
`
`Real Party-In-Interest .......................................................................... 10 
`
`Related Matters .................................................................................... 10 
`
`Lead and Backup Counsel ................................................................... 11 
`
`Service Information ............................................................................. 12 
`
`III. 
`
`PAYMENT OF FEES ................................................................................... 12 
`
`IV.  REQUIREMENTS UNDER 37 C.F.R. § 42.104 .......................................... 12 
`
`A.  Grounds for Standing .......................................................................... 12 
`
`B. 
`
`Identification of Challenge and Precise Relief Requested .................. 13 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`Claims for Which Inter Partes Review is Requested ............... 13 
`
`Statutory Grounds on Which the Challenge is Based ............... 13 
`
`Evidence Relied Upon to Support the Challenge ..................... 14 
`
`How the Challenged Claims Are to be Construed .................... 14 
`
`V.  DESCRIPTION OF THE PURPORTED INVENTION ............................... 15 
`
`VI.  PERSON HAVING ORDINARY SKILL IN THE ART ............................. 18 
`
`VII.  TECHNICAL BACKGROUND AND STATE OF THE ART .................... 19 
`
`A. 
`
`B. 
`
`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 
`
`C. 
`
`Rapamycin’s Interactions With Its Targets Were Known .................. 21 
`
`i
`
`

`

`D. 
`
`E. 
`
`Solubility-Enhancing Modifications Were Well-Known ................... 25 
`
`Standard Assays Were Available to Evaluate
`Immunosuppressant Activity of Rapamycin Derivatives ................... 27 
`
`VIII.  THE SCOPE AND CONTENT OF THE PRIOR ART ................................ 28 
`
`A.  Morris Teaches that Rapamycin Is a Promising Lead
`Compound with Limited Solubility .................................................... 28 
`
`B. 
`
`C. 
`
`D. 
`
`E. 
`
`F. 
`
`G. 
`
`Rossmann Teaches How to Obtain Three-Dimensional
`Coordinates from Stereo Diagrams ..................................................... 29 
`
`Van Duyne Revealed the Structural Interactions Between
`Rapamycin and FKBP-12 .................................................................... 30 
`
`The Full Coordinates of the Van Duyne Structure Show that
`C40 of Rapamycin Is the Optimal Position for Modification ............. 34 
`
`Flexible Side Chains Were Known to Improve Solubility ................. 35 
`
`The Addition of Solubilizing Substituents Was Well-Known ............ 36 
`
`Rapamycin Derivatives at C40 Were Shown to Have
`Immunosuppressant Activity and Were Evaluated in Standard
`Assays .................................................................................................. 37 
`
`IX.  MOTIVATIONS TO COMBINE THE PRIOR ART REFERENCES ......... 39 
`
`X. 
`
`PRECISE REASONS FOR THE RELIEF REQUESTED ........................... 40 
`
`A.  Ground 1: 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 Hughes ......................... 42 
`
`1. 
`
`2. 
`
`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 ............... 44 
`
`ii
`
`

`

`3. 
`
`4. 
`
`Yalkowsky and Lemke teach that solubility can be
`improved with the addition of small, flexible side chains
`containing solubilizing groups .................................................. 47 
`
`Hughes Teaches the Use of C40-Modified Rapamycin
`Derivatives in Pharmaceutical Compositions for Use as
`Immunosuppressants ................................................................. 51 
`
`XI.  SECONDARY CONSIDERATIONS DO NOT RENDER THE
`CLAIMS NONOBVIOUS ............................................................................. 55 
`
`XII.  CONCLUSION .............................................................................................. 56 
`
`
`
`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)
`
`
`
`
`
`vi
`
`
`
`
`
`
`
`
`

`

`TABLE OF AUTHORITIES
`
`
`CASES
`
`
`
`Page(s)
`
`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) ............................................................................................................. 42, 54
`
`Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
`499 F.3d 1293 (Fed. Cir. 2007) ...................................................................passim
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ............................................................................ 39
`
`Breckenridge Pharmaceutical, Inc. v. Novartis AG,
`IPR2016-01023 ................................................................................................... 11
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................ 6, 40, 50, 51
`
`Geneva Pharm., Inc. v. Glaxosmithkline PLC,
`189 F. Supp. 2d 377 (E. D. Va. 2002), aff’d 349 F.3d 1373 (Fed. Cir.
`2003) ............................................................................................................... 3, 52
`
`In re Beattie,
`974 F.2d 1309 (Fed. Cir. 1992) ...................................................................passim
`
`In re Deuel,
`51 F.3d 1552 (Fed. Cir. 1995) ............................................................................ 40
`
`In re Fout,
`675 F.2d 297 (C.C.P.A. 1982) ...................................................................... 48, 53
`
`In re Mayne,
`104 F.3d 1339 (Fed. Cir. 1997) .................................................................... 48, 53
`
`In re Siebentritt,
`372 F.2d 566 (C.C.P.A. 1967) ...................................................................... 48, 53
`
`In re Wilder,
`563 F.2d 457 (C.C.P.A. 1977) ............................................................ 8, 42, 46, 54
`
`
`
`vii
`
`

`

`
`
`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) .......................................................................... 55
`
`Newell Co. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 55
`
`Novartis Pharmaceuticals Corp. v. Breckenridge Pharmaceutical, Inc.,
`C.A. No. 14-1043-RGA (D. Del.) ...................................................................... 10
`
`Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc.,
`C.A. No. 14-1289-RGA (D. Del.) ...................................................................... 10
`
`Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc.,
`C.A. No. 14-1494-RGA (D. Del.) ...................................................................... 10
`
`Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc.,
`C.A. No. 15-78-RGA (D. Del.) .......................................................................... 11
`
`Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`C.A. No. 14-1196-RGA (D. Del.) ...................................................................... 10
`
`Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`C.A. No. 14-1508-RGA (D. Del.) ...................................................................... 11
`
`Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
`C.A. No. 15-128-RGA (D. Del.) ........................................................................ 11
`
`Par Pharmaceutical, Inc. v. Novartis AG,
`IPR2016-00084 ................................................................................................... 11
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................... 8, 41, 46, 54
`
`Samsung Elecs. Co. v. Va. Innovation Scis., Inc.,
`No. IPR2014-00557 (P.T.A.B. June 13, 2014) ..................................................... 3
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .......................................................................... 40
`
`
`
`viii
`
`

`

`
`
`STATUTES
`STATUTES
`
`35 U.S.C. § 102(a) ................................................................................................... 28
`35 U.S.C. § 102(a) ................................................................................................. ..28
`
`35 U.S.C. § 102(b) ............................................................................................passim
`35 U.S.C. § 102(b) .......................................................................................... ..passim
`
`35 U.S.C. § 102(e) ................................................................................................... 37
`35 U.S.C. § 102(e) ................................................................................................. ..37
`
`35 U.S.C. § 103 ............................................................................................ 42, 48, 53
`35 U.S.C. § 103 .......................................................................................... ..42, 48, 53
`
`35 U.S.C. § 103(a) ................................................................................................... 13
`35 U.S.C.§103(a) ................................................................................................. ..13
`
`35 U.S.C. §§ 311-319 ................................................................................................ 1
`35 U.S.C. §§311-319 .............................................................................................. ..1
`
`35 U.S.C. § 318(a) ................................................................................................... 13
`35 U.S.C. § 318(a) ................................................................................................. ..13
`
`OTHER AUTHORITIES
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.8 ................................................................................................ 10, 58
`37 C.F.R. § 42.8 .............................................................................................. ..10, 58
`
`37 C.F.R. § 42.8(b)(1) .............................................................................................. 10
`37 C.F.R. § 42.8(b)(1) ............................................................................................ ..10
`
`37 C.F.R. § 42.8(b)(2) .............................................................................................. 10
`37 C.F.R. § 42.8(b)(2) ............................................................................................ ..10
`
`37 C.F.R. § 42.10(b) ................................................................................................ 12
`37 C.F.R. § 42.10(b) .............................................................................................. ..12
`
`37 C.F.R. § 42.15(a)(1-4) ......................................................................................... 12
`37 C.F.R. §42.15(a)(1-4) ....................................................................................... ..12
`
`37 C.F.R. § 42.24(d) ................................................................................................ 58
`37 C.F.R. § 42.24(d) .............................................................................................. ..58
`
`37 C.F.R. § 42.100(b) .............................................................................................. 14
`37 C.F.R. § 42.100(b) ............................................................................................ ..14
`
`37 C.F.R. § 42.100 et seq. .......................................................................................... 1
`37 C.F.R. § 42.100 et seq. ........................................................................................ ..1
`
`37 C.F.R. § 42.104 .................................................................................................. 12
`37 C.F.R. § 42.104 ................................................................................................ ..12
`
`37 C.F.R. § 42.104(a) ............................................................................................... 12
`37 C.F.R. § 42.104(a) ............................................................................................. ..12
`
`37 C.F.R. § 42.104(b) .............................................................................................. 13
`37 C.F.R. § 42.104(b) ............................................................................................ ..13
`
`
`
`ix
`
`ix
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Petition for Inter Partes Review of USP 5,665,772
`
`Breckenridge Pharmaceutical, Inc. (“Breckenridge” or the “Petitioner”)
`
`respectfully requests an inter partes (“IPR”) review for dependent claim 7 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.
`
`On April 29, 2016, the Board granted Par Pharmaceutical, Inc.’s (“Par”)
`
`petition seeking review of claims 1-3 and 8-10 of the ’772 Patent. (IPR2016-
`
`00084, Paper 8.) This petition seeks review of dependent claim 7, which
`
`Breckenridge has not previously challenged, and is filed concurrently with a
`
`motion for joinder to the IPR2016-00084 proceeding.
`
`Moreover, because the instant petition presents the same grounds – the exact
`
`same prior art, expert testimony, and other evidence – relied on by PAR in pending
`
`IPR2016-01059 seeking inter partes review of claim 7, to the extent IPR2016-
`
`01059 petition is granted, Breckenridge’s instant petition seeking inter partes
`
`review of claim 7 should also be granted.
`
`Dependent claim 7 of the ’772 Patent is not patentable for the same reasons
`
`that independent claim 1 is not patentable. It is broadly drawn to a “pharmaceutical
`
`composition comprising a therapeutically effective amount of a compound
`
`according to claim 1 and a pharmaceutically acceptable carrier therefor.” Such a
`
`
`
`1
`
`

`

`
`
`Petition for Inter Partes Review of USP 5,665,772
`
`pharmaceutical composition is obvious over the prior art. Because the instituted
`
`IPR is reasonably likely to prevail in showing unpatentability, this Petition should
`
`also be granted and trial instituted on the challenged claim.
`
`In its institution decision in the IPR2016-00084 proceeding, the Board found
`
`that Par demonstrated a reasonable likelihood of demonstrating that claims 1-3 and
`
`8-10 are obvious over the prior art. (IPR2016-00084, Paper 8.) As relevant here,
`
`Par set forth in that petition (and Breckenridge repeats herein with the exact same
`
`prior art, testimony, and other evidence already submitted), the broad genus of
`
`compounds recited in claim 1 of the ’772 Patent are obvious over Morris (Ex.
`
`1005), Van Duyne (Ex. 1006), Yalkowsky (Ex. 1007), Lemke (Ex. 1008), and
`
`Rossmann (Ex. 1024). IPR2016-00084, Paper 2 at 7-15. Par also explained in its
`
`previous petition (also repeated herein by Breckenridge with the exact same
`
`evidence) a reasonable likelihood that claims 8 and 9, which recite methods of
`
`administering effective amounts of the compound of claim 1, would have been
`
`obvious. (Id. at 15-16.)
`
`The Board agreed, instituting the IPR2016-00084 petition. Likewise, the
`
`Board should find that this petition demonstrates a reasonable likelihood of
`
`prevailing on claim 7 of the ’772 Patent. Claim 7 recites pharmaceutical
`
`compositions comprising a compound of claim 1. On indistinguishable facts, the
`
`Federal Circuit held that the validity of such claims “rise or fall with the validity
`
`
`
`2
`
`

`

`
`
`
`
`Petition for Inter Partes Review of USP 5,665,772
`
`of” the compound claim. Aventis Pharma Deutschland GmbH v. Lupin, Ltd., 499
`
`F.3d 1293, 1303 (Fed. Cir. 2007) (finding that when the prior art described using
`
`ACE inhibitors in combination with pharmaceutical excipients, a dependent
`
`pharmaceutical composition claim was obvious because the independent
`
`compound claim was obvious). Further, pharmaceutical composition claims (such
`
`as claim 7 of the ’772 Patent) are patentably indistinct from methods of using
`
`those same compounds for therapeutic effect (such as claims 8 and 9 of the ’772
`
`Patent). Geneva Pharm., Inc. v. Glaxosmithkline PLC, 189 F. Supp. 2d 377, 384-
`
`85 (E. D. Va. 2002), aff’d 349 F.3d 1373 (Fed. Cir. 2003) (finding pharmaceutical
`
`composition claim containing a compound and a carrier to be patentably indistinct
`
`from method claims of administering effective amounts of the compound). As
`
`such, the same arguments, references, and testimony presented in IPR2016-00084
`
`and credited by the Board as demonstrating a reasonable likelihood of prevailing
`
`as to claims 1, 8, and 9 should result in an identical conclusion with respect to the
`
`pharmaceutical compositions of claim 7. Indeed, the public interest in consistent
`
`resolution of claims of similar patent scope and subject matter compels the
`
`institution of this petition to allow for the complete analysis of these claims of the
`
`’772 Patent. See, e.g., Samsung Elecs. Co. v. Va. Innovation Scis., Inc., No.
`
`IPR2014-00557 (P.T.A.B. June 13, 2014), Paper 10 at 16-18.
`
`3
`
`

`

`
`
`Petition for Inter Partes Review of USP 5,665,772
`
`Accordingly, this petition presents the Board with the following sole issue:
`
`The ’772 Patent claims certain alkylated derivatives of rapamycin, a well-known
`
`immunosuppressant, and pharmaceutical compositions comprising such derivatives
`
`in combination with a pharmaceutically acceptable carrier. It was well-known that
`
`rapamycin’s poor solubility limited its use in drug formulations. The prior art
`
`taught that rapamycin could be modified at the C40 position without sacrificing the
`
`compound’s immunosuppressant activity. The prior art also taught that the routine
`
`addition of solubility-enhancing substituents could improve a compound’s
`
`solubility. Would a pharmaceutical composition comprising the certain alkylated
`
`derivatives of rapamycin with a pharmaceutically acceptable carrier claimed in
`
`Claim 7 of the ’772 Patent, as dependent from Claim 1, have been obvious to a
`
`person of ordinary skill in the art at the time of the claimed invention?
`
`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 1:33-36.)
`
`Claim 1 of the ’772 Patent reads as follows:
`
`A compound of the formula1
`
`1 The structural formula shown in claim 1 of the ’772 Patent depicts a bond
`
`between C3 and C35. Novartis has filed a Request for Certificate of Correction
`
`
`
`4
`
`

`

`
`
`Petition for Inter Partes Review of USP 5,665,772
`
`
`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. 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
`
`
`with the Patent Office to clarify that there is no bond between C3 and C35 but
`
`rather that there is a methyl (CH3) group at C35. (Ex. 1002, ’772 Patent File
`
`History at Certificate of Correction. The Patent Office recently granted the
`
`request.
`
`
`
`
`
`5
`
`

`

`
`
`Petition for Inter Partes Review of USP 5,665,772
`
`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 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
`
`Pharms. USA, Inc., 752 F.3d 967, 975 (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.
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`A person of ordinary skill in the art would have been motivated to select
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`rapamycin as a lead compound to modify in order to improve its solubility. Morris
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`summarizes the significant amount of information available as of October 1992
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`regarding the remarkable immunosuppressant activity of rapamycin, making it an
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`ideal candidate for further investigation. (Ex. 1005, Morris at 39-42, 52-64; Ex.
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`1003, Jorgensen Decl. at ¶¶ 72-74, 132-137.) Additionally, Morris teaches that
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`rapamycin is minimally soluble in water, and indeed, the ’772 Patent expressly
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`admits this well-known limitation of rapamycin. (Ex. 1005, Morris at 46; Ex.
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`6
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`Petition for Inter Partes Review of USP 5,665,772
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`1001, ’772 Patent at 1:36-40; Ex. 1003, Jorgensen Decl. at ¶¶ 75-76, 138-140.)
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`See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007) (“[A]ny need or
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`problem known in the field of endeavor at the time of invention and addressed by
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`the patent can provide a reason for combining the elements in the manner
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`claimed.”); In re Beattie, 974 F.2d 1309, 1312 (Fed. Cir. 1992) (“As long as some
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`motivation or suggestion to combine the references is provided by the prior art
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`taken as a whole, the law does not require that the references be combined for the
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`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. To
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`achieve this, a person of ordinary skill in the art would have modified rapamycin’s
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`C40 hydroxyl group because the structure showing rapamycin’s binding to its
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`biological target FKBP-12 taught that the C40 hydroxyl was the best position for
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`modification. (Ex. 1006, Van Duyne at 7434; Ex. 1003, Jorgensen Decl. at ¶¶ 101-
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`123, 141-145.)
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`Yalkowsky (Ex. 1007) and Lemke (Ex. 1008) teach how to improve the
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`solubility of chemical compounds by adding flexible side chains with solubilizing
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`substituents. (Ex. 1003, Jorgensen Decl. at ¶¶ 77-88.) Such solubilizing
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`substituents include the 2-hydroxyethoxy substituent at the C40 position of the
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`compound of claim 10. (Id. at ¶¶ 146-161.)
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`7
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`Petition for Inter Partes Review of USP 5,665,772
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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
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`displayed immunosuppressant activity in standard pharmacological assays,
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`including preventing allograft rejection. (Ex. 1009, Hughes at 2:62-4:12; Ex.
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`1003, Jorgensen Decl. at ¶¶ 125-126.) As such, a person of ordinary skill in the art
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`would have a reasonable expectation that modifying rapamycin at its C40 position
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`would result in a compound with immunosuppressant activity. (Ex. 1003,
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`Jorgensen Decl. at ¶¶ 166-172.) Aventis Pharma Deutschland GmbH v. Lupin,
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`Ltd., 499 F.3d 1293, 1301 (Fed. Cir. 2007) (“[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
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`compound will have ‘similar properties’ to the old.”) (citations omitted); Pfizer,
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`Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (simply because the
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`properties of a compound must be verified through testing does not mean that the
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`compound lack an expectation for success “since the expectation of success need
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`only be reasonable, not absolute”); In re Wilder, 563 F.2d 457, 460 (C.C.P.A.
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`1977) (“[O]ne who claims a compound, per se, which is structurally similar to a
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`prior art compound must rebut the presumed expectation that the structurally
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`similar compounds have similar properties.”). Therefore, claims 8 and 9, which
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`8
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`Petition for Inter Partes Review of USP 5,665,772
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`recite methods of using the compounds of claim 1 as immunosuppressants or to
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`prevent allograft rejection, 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 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
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`effective amount of the rapamycin derivatives and a pharmaceutically acceptable
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`carrier. In fact, Hughes (Ex. 1009) explicitly teaches rapamycin derivatives
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`modified at the C40 position as useful immunosuppressants that “may be
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`administered neat or with a pharmaceutical carrier to a mammal in need thereof.”
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`(Hughes, Ex. 1009, at 4:57-59.)
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`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
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`regarding the interactions between rapamycin and its biological targets taught that
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`C40 was the optimal position for making modifications without disrupting
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`biological activity; (3) known strategies for improving solubility of chemical
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`compounds taught adding flexible side chains with solubilizing substituents; (4)
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`prior rapamycin derivatives modified at C40 had been shown to have
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`9
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`Petition for Inter Partes Review of USP 5,665,772
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`immunosuppressant activity, including the ability to prevent allograft rejection;
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`and (5) prior art teaching that rapamycin derivatives modified at the C40 position
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`may be combined with pharmaceutically acceptable carriers to administer as useful
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`immunosuppressants.
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`Breckenridge provides below a detailed comparison of the claimed subject
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`matter and the prior art. Breckenridge respectfully submits that Claim 7 would
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`have been obvious in view of the prior art presented herein for the same reasons
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`concerning claims 1, 8, and 9, and, therefore, requests that the Board institute an
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`inter partes review and determine that this claim is unpatentable.
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`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8
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`A. Real Party-In-Interest
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`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Breckenridge,
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`Pensa Pharma S.A., Corporacion Quimico Farmaceutica Esteve, S.A., and Natco
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`Pharma Ltd. are the real parties-in-interest.
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`B. Related Matters
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`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is aware of the following
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`matters: Novartis Pharmaceuticals Cor