Paper No. ____
`Date Filed: September 16, 2016
`
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-00084
`
`Patent No. 5,665,772
`
`
`
`
`
`NOVARTIS’S PATENT OWNER RESPONSE
`
`
`
`
`
`
`Date Filed: September 16, 2016
`
`
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-00084
`
`Patent No. 5,665,772
`
`
`
`
`
`NOVARTIS’S PATENT OWNER RESPONSE
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`Argument Overview ........................................................................................ 2
`
`III. Ground 1: Claims 1-3 And 10 ......................................................................... 6
`
`A. A POSA With Par’s Goals Would Not Have Been
`Motivated To Modify Rapamycin To Make Everolimus
`Nor Have Had A Reasonable Expectation Of Achieving
`Those Goals ........................................................................................... 6
`
`1.
`
`Lemke And Yalkowsky Do Not Provide A
`Motivation To Make Everolimus Nor A
`Reasonable Expectation Of Increasing Water
`Solubility ..................................................................................... 7
`
`a.
`
`b.
`
`c.
`
`d.
`
`e.
`
`Par Focuses On Lemke’s Teachings About
`Adding Hydroxyl Groups, But Adding
`Hydroxyl Groups To Rapamycin Would Not
`Lead To Everolimus ......................................................... 7
`
`Lemke Would Not Have Motivated A POSA
`To Add An Ethyleneoxy Because A POSA
`Would Not Have Reasonably Expected
`Everolimus To Have Increased Water
`Solubility ........................................................................... 9
`
`Lemke Would Have Suggested Other
`Modifications To Rapamycin, Not The
`Addition Of An Ethyleneoxy .......................................... 12
`
`Dr. Jorgensen’s New Deposition Arguments
`Do Not Reflect How A POSA Would Have
`Interpreted Lemke ........................................................... 14
`
`Dr. Jorgensen’s New Deposition Argument
`That Primary Alcohols Would Have Been
`Reasonably Expected To Impart Greater
`Solubility Than Secondary Alcohols Is
`Unsupported .................................................................... 16
`
`
`
`i
`
`
`
`f.
`
`Yalkowsky’s Teachings Are Inapplicable To
`Rapamycin’s Or Everolimus’s Water
`Solubility ......................................................................... 17
`
`i.
`
`ii.
`
`Everolimus Is Not A Long-Chain
`Derivative Of A Rigid Molecule
`Under Yalkowsky ................................................. 20
`
`Dr. Jorgensen’s New Deposition
`Argument Is Unsupported As Figure 2
`Only Applies To Long-Chain
`Derivatives ............................................................ 23
`
`2.
`
`3.
`
`g. Water Solubility Is Unpredictable .................................. 25
`
`Dr. Jorgensen’s Reliance On Polyethyleneoxy
`(PEG) Groups Is Not Supported Nor Relevant To
`The Addition Of A Single Ethyleneoxy Group To
`Rapamycin ................................................................................ 26
`
`Par Has Not Established A Reasonable
`Expectation Of Increasing Rapamycin’s Water
`Solubility Sufficiently To Provide A Practical
`Benefit ....................................................................................... 29
`
`4.
`
`Conclusion ................................................................................ 31
`
`B.
`
`Par Has Not Established That A POSA Would Have
`Been Motivated To Make Only The Three Specific
`Compounds Par Proposes, With A Reasonable
`Expectation That They Would Maintain Rapamycin’s
`Immunosuppressive Activity ............................................................... 31
`
`1.
`
`2.
`
`Prior Art Rapamycin Derivatives Were Not
`Limited To Those With Small C40 Groups .............................. 32
`
`The Structure Of Rapamycin Bound To FKBP-12
`Would Not Have Led A POSA To Consider Only
`Small Substituents ..................................................................... 36
`
`ii
`
`
`
`
`
`
`
`3.
`
`4.
`
`5.
`
`The Art As A Whole Would Have Taught A
`POSA To Synthesize Ester And Amide
`Derivatives, Not Avoid Them ................................................... 38
`
`Par’s List Of Possible C40-Substituents Ignores
`Numerous Options A POSA Would Have
`Considered ................................................................................ 40
`
`A POSA Would Not Have Expected Everolimus
`To Have Immunosuppressant Activity Comparable
`To Rapamycin With Improved Solubility As Par
`Suggests .................................................................................... 42
`
`In Selecting Its Lead Compound, Par Ignored The Prior
`Art As A Whole ................................................................................... 47
`
`Par Fails To Show A Motivation To Modify Rapamycin
`To Increase Water Solubility, Let Alone A Motivation To
`Do So By Chemical Synthesis Of Everolimus .................................... 50
`
`1.
`
`2.
`
`Contrary To Par’s Allegation, Morris Does Not
`Provide A Motivation To Improve Rapamycin’s
`Water Solubility ........................................................................ 51
`
`Par Ignores Preferred Methods Of Addressing
`Water Solubility ........................................................................ 53
`
`Par Fails To Show A Sufficient Motivation To Modify
`Rapamycin’s C40 Position Over Other Positions ............................... 55
`
`Par Fails To Show That A POSA Would Have
`Reasonably Expected Everolimus To Have Its Unique
`Combination Of Properties .................................................................. 56
`
`1.
`
`2.
`
`A POSA Would Not Have Reasonably Expected
`Everolimus’s Combination Of Immunosuppressive
`Properties .................................................................................. 56
`
`A POSA Also Would Not Have Reasonably
`Expected Everolimus’s Observed Antitumor
`Activity ...................................................................................... 58
`
`C.
`
`D.
`
`E.
`
`F.
`
`iii
`
`
`
`
`
`
`
`G.
`
`Compelling Objective Indicia Further Support Non-
`Obviousness ......................................................................................... 60
`
`1.
`
`Everolimus’s Antitumor Properties Provide
`Evidence That Claims 1-3 And 10 Are Non-
`Obvious ..................................................................................... 61
`
`
`
`a.
`
`b.
`
`c.
`
`d.
`
`Everolimus Satisfied Long-Felt But Unmet
`Medical Needs In RCC And Breast Cancer ................... 61
`
`Others Tried And Failed To Develop
`Effective Therapies For Advanced RCC
`And Breast Cancer .......................................................... 62
`
`Everolimus Unexpectedly Has FDA
`Approval For Six Antitumor Indications ........................ 63
`
`Everolimus Has Achieved Significant
`Commercial Success ....................................................... 66
`
`e.
`
`Everolimus Has Received Industry Praise ..................... 66
`
`2.
`
`Everolimus’s Immunosuppressant Properties
`Provide Evidence Of Non-Obviousness Of Claims
`1-3 And 10 ................................................................................ 67
`
`a.
`
`b.
`
`c.
`
`Others Tried And Failed To Develop
`Rapamycin Derivatives For Preventing
`Transplant Rejection ....................................................... 67
`
`Everolimus Met A Long Felt Need For An
`Immunosuppressive Regimen For Liver
`Transplant Recipients ..................................................... 68
`
`Everolimus Has A Significantly Shorter Half-
`Life Than Rapamycin And Can Be Safely Co-
`Administered With Cyclosporin A ................................. 68
`
`IV. Ground 2: Claims 8 And 9 ............................................................................. 69
`
`V.
`
`Conclusion ..................................................................................................... 71
`
`
`
`
`
`iv
`
`
`
`TABLE OF AUTHORITIES
`
`
`
`
`
`Cases
`
`AstraZeneca Pharm. LP v. Anchen Pharm., Inc.,
`No. 10-CV-1835 JAP TJB, 2012 WL 1065458 (D.N.J.
`Mar. 29, 2012) ............................................................................................... 64
`
`Circuit Check Inc. v. QXQ Inc.,
`795 F.3d 1331 (Fed. Cir. 2015) ..................................................................... 17
`
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) ..................................................................... 66
`
`Demaco Corp. v. F. von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .............................................................. 61, 66
`
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) ..................................................................... 63
`
`In re Cyclobenzaprine Hydrochloride Extended-Release
`Capsule Patent Litig.,
`No. 09-MD-2118-SLR, 2010 WL 3766530 (D. Del. Sept.
`21, 2010) ........................................................................................................ 67
`
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) ..................................................................... 62
`
`In re Rosuvastatin Calcium Patent Litig.,
`703 F.3d 511 (Fed. Cir. 2012) ............................................................ 6, 50, 56
`
`In re Wertheim,
`541 F.2d 257 (C.C.P.A. 1976) ....................................................................... 52
`
`Janssen Pharm. N.V. v. Mylan Pharms., Inc.,
`456 F. Supp. 2d 644 (D.N.J. 2006) ................................................................ 52
`
`Knoll Pharm. Co. v. Teva Pharms. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004) ........................................................ 62, 63, 67
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................... 3, 60, 65
`
`
`
`v
`
`
`
`
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ..................................................................... 63
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ............................................................. passim
`
`Pfizer Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ..................................................................... 70
`
`Pfizer Inc. v. Mylan Pharms. Inc.,
`71 F. Supp. 3d 458 (D. Del. 2014) ................................................... 45, 63, 70
`
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`555 Fed. App’x 961 (Fed. Cir. 2014) ............................................................ 50
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) .................................................................. 3, 62
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .................................................... 6, 17, 31, 47
`
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ..................................................................... 15
`
`Yamanouchi Pharm Co., Ltd. v. Danbury Pharmacal, Inc.,
`231 F.3d 1339 (Fed. Cir. 2000) .............................................................. 30, 43
`
`
`
`vi
`
`
`
`
`
`
`
`LIST OF EXHIBITS
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2001
`
`2010
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`2011
`
`2012
`
`2023
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`2033
`
`2034
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`Rosen
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`Fagiuoli
`
`Keeffe
`
`Sollinger
`
`Silverman
`
`Ansel
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2035 U.K. Patent Application GB 2 222 770 A
`
`GB 770
`
`2037 U.S. Patent No. 4,916,138
`
`’138 patent
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`2045
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`Goldin
`
`Marsoni
`
`Merck Index
`
`Rapamune® PI
`
`Kahan
`
`viii
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2055
`
`Zortress® Package Insert
`(Revised 11/2015)
`
`Zortress® PI
`
`2057
`
`GB Application 9221220 (October 9,
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`
`ix
`
`GB 220
`
`Motzer
`
`Yardley
`
`Wersäll
`
`Stahl
`
`Merimsky
`
`Sledge
`
`
`
`
`
`
`
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`
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`
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`2068
`
`2069
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`
`2071
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`
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`Everolimus ‘Biggest Advance in Years,’”
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`2072
`
`2073
`
`2074
`
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`
`Yagoda
`
`
`
`
`
`Adams
`
`Chustecka
`
`Fedele
`
`2075 U.S. Patent No. 5,194,447
`
`’447 patent
`
`x
`
`
`
`
`
`
`
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`
`Description
`
`Abbreviation
`
`2079
`
`Pfizer Inc. v. Teva Pharms. USA, Inc.,
`555 F. App’x 961 (Fed. Cir. 2014)
`
`2081
`
`2082
`
`2083
`
`2086
`
`2091
`
`2092
`
`2093
`
`2095
`
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`Inc., 456 F. Supp. 2d 644 (D.N.J. 2006),
`aff’d, 223 Fed. App’x 999 (Fed. Cir.
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`
`Pfizer Inc. v. Mylan Pharms. Inc., 71 F.
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`
`AstraZeneca Pharms. LP v. Anchen
`Pharms., Inc., No. 10-CV-1835 JAP TJB,
`2012 WL 1065458 (D.N.J. Mar. 29,
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`2013)
`
`Janssen Pharm. N.V. v. Mylan Pharms.,
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`
`Transcript of the August 9, 2016
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`
`Declaration of Professor Alexander M.
`Klibanov
`
`Expert Declaration of William R. Roush,
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`
`Declaration of Howard A. Burris, III,
`M.D.
`
`
`
`
`
`
`
`
`
`
`
`Jorgensen
` Dep.
`
`Klibanov
`
`Roush
`
`Burris
`
`xi
`
`
`
`
`
`
`
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`
`Description
`
`Abbreviation
`
`2097
`
`2098
`
`The Merck Index, 11th Edition
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`The Merck Index, 10th Edition
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`Merck Index, 11th
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`
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`
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`
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`Szász
`
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`Carey
`
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`
`2108 U.S. Patent No. 4,388,307
`
`’307 Patent
`
`xii
`
`
`
`
`
`
`
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`
`Description
`
`Abbreviation
`
`2109
`
`2112
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`Venkataramanan, R. et al.,
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`
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`
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`2121 U.S. Patent No. 5,221,670
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`2122 U.S. Patent No. 5,260,299
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`
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`
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`
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`
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`
`2130 U.S. Patent No. 5,118,678
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`2132
`
`2133
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`xiii
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`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2134
`
`2135
`
`De Simone, P., “Everolimus With
`Reduced Tacrolimus Improves Renal
`Function in De Novo Liver Transplant
`Recipients: A Randomized Controlled
`Trial,” Am. J. Transplant. 12:3008-20
`(2012)
`
`Fischer, L., “Three-year Outcomes in De
`Novo Liver Transplant Patients
`Receiving Everolimus With Reduced
`Tacrolimus: Follow-up Results From a
`Randomized Multicenter Study,”
`Transplantation 99(7):1455-62 (2015)
`
`De Simone
`
`Fischer
`
`2136 U.S. Patent No. 5,130,307
`
`’307 patent
`
`2138
`
`2139
`
`Merck Manual of Diagnosis and Therapy,
`16th Edition (Berkow, R. & Fletcher, A.J.
`eds., 1992)
`
`Merck Manual
`
`Sollinger H.W. et al., “RS-61443—A
`Phase I Clinical Trial and Pilot Rescue
`Study,” Transplantation 53:428-32
`(1992)
`
`Sollinger 1992(a)
`
`2142 U.S Patent No. 5,233,036 File History
`
`2143 U.S. Patent No. 5,023,263
`
`2145
`
`Excerpts of Transcript of Trial Testimony
`of M. Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA)
`(D. Del. August 31, 2016), Pages 769-72,
`957-58, 967, 971, 990-1003, 1010-15
`
`Hughes File
`History
`
`’263 patent
`
`Ratain Trial
`
`xiv
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2149
`
`Skillings, J., et al. “A Phase II Study of
`Recombinant Tumor Necrosis Factor in
`Renal Cell Carcinoma: A Study of the
`National Cancer Institute of Canada
`Clinical Trials Group.” J. of Immunology
`11:67-70 (1992)
`
`Skillings
`
`2151
`
`Afinitor® Package Insert
`(Revised: 02/2016)
`
`2152
`
`2154
`
`2157
`
`2174
`
`Excerpts of Transcript of Deposition of
`M. Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-RGA)
`(D. Del. Apr. 11, 2016) (with errata
`sheet)
`
`Macheledt, J., et al., “Phase II evaluation
`of interferon added to tamoxifen in the
`treatment of metastatic breast cancer,”
`Breast Cancer Research and Treatment
`18:165-70 (1991)
`
`Houchens, D.P. et al., “Human Brain
`Tumor Xenografts In Nude Mice as a
`Chemotherapy Model,” Eur. J. Cancer
`Clin. Oncol. 19(6):799-805 (1983)
`
`Duran, I. et al., “A phase II clinical and
`pharmacodynamic study of temsirolimus
`in advanced neuroendocrine carcinomas,”
`Br. J. Cancer 95(9):1148-54 (2006)
`
`Afinitor®
`February 2016
`Label
`
`Ratain Dep.
`
`Macheledt
`
`Houchens
`
`Duran
`
`xv
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2176
`
`Wolff, A.C. et al., “Randomized Phase III
`Placebo-Controlled Trial of Letrozole
`Plus Oral Temsirolimus As First-Line
`Endocrine Therapy in Postmenopausal
`Women With Locally Advanced or
`Metastatic Breast Cancer,” J. of Clin.
`Oncol. 31(2):195-202 (2013)
`
`2183
`
`Abuchowski, A. & Davis, F.F., Chapter
`13, “Soluble Polymer-Enzyme Adducts,”,
`Enzymes as Drugs, (Holcenberg, J.S. &
`Roberts, J. eds.,1981)
`
`Wolff
`
`Abuchowski
`
`xvi
`
`
`
`
`
`
`
`Introduction
`
`Novartis AG (“Novartis”) respectfully submits this Response to Par’s
`
`
`
`I.
`
`
`
`Petition seeking inter partes review of claims 1-3 and 8-10 of U.S. Patent No.
`
`5,665,772 (“the ’772 patent”), which claim, among other things, everolimus, the
`
`novel rapamycin derivative 40-O-(2-hydroxyethyl)-rapamycin and its use.
`
`Everolimus is the active ingredient in two Novartis products, Zortress®, approved
`
`to prevent liver and kidney transplant rejection, and Afinitor®, approved to treat
`
`breast and kidney cancers, pancreatic, gastrointestinal or lung neuroendocrine
`
`tumors, and brain and kidney tumors caused by Tuberous Sclerosis Complex
`
`(“TSC”), a life-threating genetic disease.
`
`
`
`Par’s hindsight-based approach does not reflect how a person of ordinary
`
`skill in the art (“POSA”) would have discovered a new immunosuppressant in
`
`October 1992. Par worked backwards from everolimus by naming rapamycin, the
`
`most structurally similar compound in the prior art, as its lead, and then asserting
`
`that a POSA would have focused on making the specific chemical modification
`
`necessary to convert rapamycin to everolimus, as one of only three possible
`
`options, with a reasonable expectation of increasing rapamycin’s water solubility
`
`and maintaining its immunosuppressive activity.
`
`Par’s approach suffers from two fundamental flaws. First, Par ignores the
`
`foundational principles of patent law that require a POSA to consider the prior art
`
`1
`
`
`
`
`
`
`
`as a whole and references in their entirety. Instead, Par focuses on only select
`
`hindsight-picked references and specific passages within those references allegedly
`
`supporting its position. Second, Par fails to consider everolimus as a whole,
`
`including all of its properties. This ignores the well-established principle that “a
`
`claimed compound and its properties are inseparable.”
`
`These two flaws led Par to draw conclusions that a POSA would not draw.
`
`When the art as a whole is properly considered from the POSA’s perspective, there
`
`is no basis to conclude that the challenged ’772 patent claims are obvious.
`
`II. Argument Overview
`
`The Board instituted review of claims 1-3 and 8-10 on Grounds 1 and 2.
`
`Paper 8. Everolimus is covered by claims 1-3 and 10, and falls within the scope of
`
`the compounds in method claims 8 and 9. Id. 5, 12.
`
`To succeed on Ground 1, directed to compound claims 1-3 and 10, Par has
`
`the burden of showing that a POSA,1 considering the art as a whole would have:
`
`
`
` 1
`
` Novartis disputes Par’s POSA definition (Pet. 16) because a POSA would have
`
`had access to and consult with others having training and expertise with
`
`immunosuppressive agents, antitumor agents and drug formulation. Ex. 2093,
`
`Roush ¶¶47-48; Ex. 2092, Klibanov ¶22.
`
`2
`
`
`
`
`
`
`
`(a) selected rapamycin as a “lead compound” (based on Morris (Ex. 1005)
`
`and Van Duyne (Ex. 1006));
`
`(b) had a motivation to modify rapamycin to increase its water solubility
`
`while retaining immunosuppressive activity (based on Morris), by
`
`specifically modifying the C40 (i.e., carbon 40) position (based on Van
`
`Duyne and Rossmann (Ex. 1024)) to insert an ethyleneoxy group (based
`
`on Lemke (Ex. 1008) and Yalkowsky (Ex. 1007)) to arrive at
`
`everolimus; and
`
`(c) had a reasonable expectation that everolimus would have its unique
`
`combination of properties.
`
`Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012); Procter
`
`& Gamble Co. v. Teva Pharms. USA, Inc., 566 F.3d 989, 998 (Fed. Cir. 2009).
`
`Par’s burden also includes showing the absence of objective indicia of non-
`
`obviousness. Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir.
`
`2013).
`
`In Ground 2, directed to method claims 8 and 9, Par has the additional
`
`burden of showing that Hughes (Ex. 1009) would have provided a POSA with a
`
`reasonable expectation that everolimus would have immunosuppressive activity,
`
`including preventing allograft rejection.
`
`3
`
`
`
`
`
`
`
`Par cannot meet its burden under Ground 1 or 2. Its approach is deficient in
`
`numerous respects, most notably with respect to motivation to modify and
`
`reasonable expectation of success concerning Par’s stated goals of increasing
`
`rapamycin’s water solubility while maintaining its immunosuppressive activity. In
`
`particular, Par’s Lemke and Yalkowsky references would not have provided a
`
`motivation to modify rapamycin by inserting an ethyleneoxy group, nor a
`
`reasonable expectation of increasing rapamycin’s water solubility.
`
`Lemke, properly considered, would not have led a POSA to modify
`
`rapamycin by inserting an ethyleneoxy group because this modification would not
`
`have been expected to impact water solubility: the solubilizing effect of the ether is
`
`canceled out by the two carbons.
`
`Yalkowsky is similarly unhelpful. Par’s declarant Dr. Jorgensen admits that
`
`Yalkowsky’s teachings about ideal solubility are inapplicable to rapamycin’s
`
`solubility in water. Moreover, Yalkowsky teaches that side chains having five or
`
`fewer atoms, such as everolimus’s 4-atom long C40 group, would not have been
`
`expected to increase ideal solubility.
`
`Rather than pursuing everolimus, a POSA seeking to increase rapamycin’s
`
`water solubility while maintaining immunosuppressive activity would have first
`
`pursued approaches that would have been reasonably expected to meaningfully
`
`impact water solubility, such as formulation, prodrugs, and water-soluble salts.
`
`4
`
`
`
`
`
`
`
`Par’s suggestion that a POSA would limit potential options to only three
`
`specific compounds is unsupported and contrary to art disclosing the types of
`
`modifications Par says a POSA would avoid. And, Par’s suggestion that
`
`everolimus would be reasonably expected to maintain rapamycin’s
`
`immunosuppressive activity ignores the art showing the unpredictability of
`
`chemical modification and is contradicted by the deposition admissions of Par’s
`
`declarant.
`
`In addition, Par’s analysis is deficient for numerous other reasons.
`
`(i)
`
`Par improperly identifies rapamycin as its lead without considering
`
`the art as a whole, or comparing the properties of the known
`
`immunosuppressants in October 1992 to rapamycin’s.
`
`(ii) Par fails to establish that rapamycin’s water solubility was a problem
`
`that a POSA would try to solve.
`
` (iii) Par improperly suggests a POSA would have been motivated to
`
`modify only the C40 position of rapamycin, ignoring the art showing
`
`that others were modifying elsewhere.
`
`(iv) Par fails to establish that a POSA would have reasonably expected
`
`everolimus to have its unique combination of immunosuppressive and
`
`antitumor properties.
`
`5
`
`
`
`
`
`
`
`(v)
`
`Par does not address compelling objective indicia of non-obviousness
`
`concerning both everolimus’s immunosuppressive and antitumor
`
`properties.
`
`(vi) Concerning Ground 2, Par’s key reference (Hughes) fails to support
`
`Par’s assertion that everolimus’s method of treatment was obvious.
`
`Put simply, Par’s Grounds do not provide sufficient basis for finding obviousness.
`
`III. Ground 1: Claims 1-3 And 10
`
`A. A POSA With Par’s Goals Would Not
`Have Been Motivated To Modify Rapamycin
`To Make Everolimus Nor Have Had A
`Reasonable Expectation Of Achieving Those Goals
`
`To support obviousness, the prior art must provide a reason or motivation to
`
`modify a lead compound to arrive at the claimed compound with a reasonable
`
`expectation of success. In re Rosuvastatin Calcium Patent Litig., 703 F.3d 511,
`
`517-18 (Fed. Cir. 2012); Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492
`
`F.3d 1350, 1356-57, 1360 (Fed. Cir. 2007).
`
`Even accepting Par’s arguments that a POSA would have selected
`
`rapamycin as a lead, been motivated to modify it to increase water solubility and
`
`maintain immunosuppressive activity, and selected C40 for modification (points
`
`Novartis disputes (see Sections III.C.-III.E.)), Par cannot succeed under Ground 1.
`
`Par’s references do not establish that a POSA would have been motivated to make
`
`the specific chemical modification to arrive at everolimus, nor provide a
`
`6
`
`
`
`
`
`
`
`reasonable expectation that everolimus would have increased water solubility or
`
`maintained rapamycin’s immunosuppressive activity, let alone satisfied both goals.
`
`1.
`
`Lemke And Yalkowsky Do Not Provide A Motivation
`To Make Everolimus Nor A Reasonable
`Expectation Of Increasing Water Solubility
`
`Par relies on Lemke to support a POSA’s motivation to modify rapamycin
`
`by adding an alcohol, amine, or carboxylic acid. Pet. 45-47. As Lemke alone is
`
`insufficient, Par also relies on Yalkowsky’s alleged teachings concerning flexible
`
`chains. Id. Neither Lemke nor Yalkowsky, alone or in combination, supports a
`
`motivation to modify rapamycin to arrive at everolimus with a reasonable
`
`expectation that it will have increased solubility.
`
`a.
`
`Par Focuses On Lemke’s Teachings About Adding
`Hydroxyl Groups, But Adding Hydroxyl Groups
`To Rapamycin Would Not Lead To Everolimus
`
`Par’s reliance on Lemke is fatally flawed because it is premised on a
`
`mischaracterization of the chemical similarities and differences between rapamycin
`
`and everolimus.
`
`According to Par, Lemke teaches that the addition of a hydroxyl (alcohol)
`
`group would be expected to improve rapamycin’s water solubility. See Pet. 23-24,
`
`33-34, 45-47; Ex. 1003, Jorgensen ¶¶77, 82-84, 152-153; Ex. 2092, Klibanov
`
`¶¶33-34. But it is undisputed that rapamycin and everolimus have the same
`
`7
`
`
`
`
`
`
`
`number of hydroxyl groups. Ex. 2091, Jorgensen Dep. 126:24-127:5; Ex. 2092,
`
`Klibanov ¶¶30-31.
`
`
`
`As shown above, both compounds have a single hydroxyl (alcohol) (HO-)
`
`(see blue circle) at C40. Rapamycin has a hydroxyl (HO-) attached directly to
`
`C40, and everolimus has a hydroxyl within its 2-hydroxyethyl ether
`
`(HOCH2CH2O-) C40 substituent. Thus, as Dr. Jorgensen admits, everolimus does
`
`not have an additional hydroxyl (HO-) compared to rapamycin. E
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