`Paper No. ______
`Date Original Version Filed: April 4, 2018
`Date Corrected Version Filed: April 24, 2018
`
`
`Filed On Behalf Of:
`Novartis Pharmaceuticals Corporation
`
`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
`
`
`
`BRECKENRIDGE PHARMACEUTICAL, INC., AND
`WEST-WARD PHARMACEUTICALS INTERNATIONAL LIMITED,
`Petitioners,
`
`v.
`
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner.
`
`
`
`
`Case IPR2017-015921
`
`Patent No. 8,410,131
`
`
`
`CORRECTED NOVARTIS’S PATENT OWNER RESPONSE
`
`
`
`
`
` IPR2018-00507 has been joined to this proceeding.
`
`
`
` 1
`
`
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II.
`
`POSA ............................................................................................................... 3
`
`III. THE ’131 PATENT ......................................................................................... 5
`
`IV. GROUND 1: WASIK DOES NOT ANTICIPATE ........................................ 7
`
`A.
`
`Read As A Whole, Wasik Disclosed Liquid, Not Solid,
`Tumors ................................................................................................... 8
`
`B.
`
`In Wasik, “Tumor” Referred Exclusively To Lymphomas ................ 10
`
`C. Wasik Did Not Incorporate By Reference Any Solid
`Kidney Tumor Teaching ..................................................................... 17
`
`D. Ambiguous Disclosures Do Not Anticipate ........................................ 17
`
`V. GB’072 DESCRIBES THE CLAIMED INVENTIONS .............................. 18
`
`A. GB’072 Describes Solid Excretory System Tumors And
`Solid Kidney Tumors .......................................................................... 19
`
`B.
`
`GB’072 Describes Advanced Solid Excretory System
`Tumors ................................................................................................. 21
`
`VI. STATE OF THE ART IN 2001 ..................................................................... 22
`
`A. Advanced RCC Was Notoriously Difficult To Treat .......................... 22
`
`B.
`
`The Intracellular Signaling Pathways Reportedly
`Involved In Tumor Cell Proliferation Were Not
`Reasonably Predictable ....................................................................... 23
`
`C. mTOR Inhibitor Development For Cancer Therapy Was
`In Very Early Stages............................................................................ 25
`
`1.
`
`2.
`
`Rapamycin’s In Vivo Anti-Tumor Activity Was
`Not Reasonably Predictable ...................................................... 25
`
`Everolimus Had Not Demonstrated In Vivo Anti-
`Tumor Activity Against Any Solid Tumor ............................... 28
`
`
`
`
`
`i
`
`

`

`
`
`
`
`3.
`
`There Were Only Preliminary Phase I Data For
`Temsirolimus In Cancer Patients .............................................. 31
`
`4.
`
`mTOR Inhibitors Had Known Differences ............................... 32
`
`D. What Role PTEN Played In RCC, If Any, Was Not Well-
`Understood Or Reasonably Predictable .............................................. 34
`
`VII. STATE OF THE ART IN 2002 ..................................................................... 36
`
`A. mTOR Inhibitor Development For Cancer Therapy Was
`Still In Very Early Stages .................................................................... 36
`
`B. What Role PTEN Played In RCC, If Any, Was Still Not
`Well-Understood Or Reasonably Predictable ..................................... 40
`
`VIII. GROUND 2: THE CHALLENGED CLAIMS ARE NOT
`OBVIOUS OVER WASIK AND NAVARRO ............................................. 41
`
`IX. GROUND 3: THE CHALLENGED CLAIMS ARE NOT
`OBVIOUS OVER WASIK, NAVARRO, CROWE, AND
`LUAN ............................................................................................................ 45
`
`A.
`
`Petitioners Have Not Established That Luan Is Prior Art ................... 45
`
`1.
`
`Luan Was Not Published Before The February
`2001 Priority Date ..................................................................... 45
`
`2.
`
`GB’072 Antedates Luan ........................................................... 46
`
`B.
`
`C.
`
`A POSA Would Not Have Had A Motivation To
`Combine .............................................................................................. 47
`
`A POSA Would Not Have Had A Reasonable
`Expectation Of Success ....................................................................... 50
`
`X. GROUND 4: THE CHALLENGED CLAIMS ARE NOT
`OBVIOUS OVER HIDALGO, ALEXANDRE, CROWE,
`SCHULER, NEUMAYER, AND NAVARRO ............................................. 53
`
`A. A POSA Would Not Have Had A Motivation To
`Combine .............................................................................................. 53
`
`
`
`
`
`ii
`
`

`

`
`
`B.
`
`A POSA Would Not Have Had A Reasonable
`Expectation Of Success ....................................................................... 55
`
`
`
`1.
`
`2.
`
`3.
`
`4.
`
`Crowe, Schuler, Neumayer, And Navarro Did Not
`Reasonably Suggest That Everolimus Was
`Therapeutically Effective Against Solid Kidney
`Tumors ...................................................................................... 55
`
`Hidalgo And Alexandre Did Not Reasonably
`Suggest That Temsirolimus Was Therapeutically
`Effective Against Advanced RCC ............................................ 56
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective
`Against Advanced RCC Based On Molecular
`Biology ...................................................................................... 63
`
`A POSA Would Not Have Reasonably Expected
`An Immunosuppressant To Be Therapeutically
`Effective Against Solid Kidney Tumors, Like
`Advanced RCC ......................................................................... 64
`
`XI. GROUND 5: THE CHALLENGED CLAIMS ARE NOT
`OBVIOUS OVER HIDALGO, ALEXANDRE, CROWE,
`SCHULER, NEUMAYER, NAVARRO, AND LUAN................................ 65
`
`XII. A POSA WOULD NOT HAVE SELECTED EVEROLIMUS
`FOR THE CLAIMED METHODS ............................................................... 66
`
`XIII. CONSTITUTIONALITY OF INTER PARTES REVIEW ............................ 70
`
`XIV. CONCLUSION .............................................................................................. 70
`
`
`
`
`
`
`
`iii
`
`

`

`
`
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
` 320 F.3d 1339 (Fed. Cir. 2003) ............................................................. 42, 64
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
` 800 F.3d 1375 (Fed. Cir. 2015) ....................................................................45
`
`Eli Lilly & Co. v. Actavis Elizabeth LLC,
` 435 F. App’x 917 (Fed. Cir. 2011) ...............................................................61
`
`Eli Lilly & Co. v. Sicor Pharms., Inc.,
` 705 F. Supp. 2d. 971 (S.D. Ind. 2010) ................................................... 46, 47
`
`Ex Parte Saito,
` Appeal 2008-5777 (B.P.A.I. Dec. 22, 2008) ................................................46
`
`Falkner v. Inglis,
` 448 F.3d 1357 (Fed. Cir. 2006) ....................................................................20
`
`Genzyme Corp. v. Dr. Reddy’s Labs., Ltd.,
` Nos. 2016-2206, U.S. App. LEXIS 25454 (Fed. Cir. 2017) ................. 42, 64
`
`ICN Photonics, Ltd. v. Cynosure, Inc.,
` 73 F. App’x 425 (Fed Cir. 2003) ..................................................................20
`
`In re Bigio,
`381 F.3d. 1320 (Fed. Cir. 2004) ....................................................................49
`
`In re Clay,
` 966 F.2d 656 (Fed. Cir. 1992) ............................................................... 48, 54
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Patent
`Litig.,
` 676 F.3d 1063 (Fed. Cir. 2012) ....................................................................66
`
`In re Hedges,
` 783 F.2d 1038 (Fed. Cir. 1986) ...................................................................... 8
`
`In re Hughes,
` 345 F.2d 184 (C.C.P.A. 1965) ......................................................................17
`
`
`
`
`
`iv
`
`

`

`
`
`
`
`In re Klein,
` 647 F.3d 1343 (Fed. Cir. 2011) ....................................................... 49, 54, 65
`
`In re Mulder,
` 716 F.2d 1542 (Fed. Cir. 1983) ....................................................................46
`
`In re Nat. Alts, LLC,
` 659 F. App’x 608 (Fed. Cir. 2016) ...............................................................54
`
`In re Stempel,
` 241 F.2d 755 (C.C.P.A. 1957) ............................................................... 46, 47
`
`Innogenetics N.V. v. Abbott Labs.,
` 512 F.3d 1363 (Fed. Cir. 2008) ....................................................................48
`
`Insite Vision Inc. v. Sandoz, Inc.,
` 783 F.3d 853 (Fed. Cir. 2015) ......................................................................66
`
`L.A. Biomedical Research Inst. at Harbor-UCLA Med. Ctr. v. Eli Lilly &
`Co.,
` 849 F.3d 1049 (Fed. Cir. 2017) ............................................................. 18, 42
`
`Mahurkar v. C.R. Bard, Inc.,
` 79 F.3d 1572 (Fed. Cir. 1996) ......................................................................45
`
`Medtronic, Inc. v. Norred,
`640 F. App’x 994 (Fed. Cir. 2016) ................................................................46
`
`Monarch Knitting Mach. Corp. v. Sulzer Morat GmbH,
` 139 F.3d 877 (Fed. Cir. 1998) ......................................................................66
`
`Novartis Pharms. Corp. v. West-Ward Pharms Int’l Ltd.,
`No. 15-cv-474-RGA, 2017 U.S. Dist. LEXIS 205600 (D. Del. Dec.
`14, 2017) ................................................................................................ passim
`
`Oil States Energy Servs., LLC v. Greene’s Energy Grp., LLC,
` 137 S. Ct. 2239 (June 12, 2017) ...................................................................70
`
`Pozen Inc. v. Par Pharm., Inc.,
` 696 F.3d 1151 (Fed. Cir. 2012) ....................................................................18
`
`
`
`
`
`v
`
`

`

`
`
`
`
`Smith & Nephew, Inc. v. Hologic, Inc.,
` No. 2017-1008, 2018 U.S. App. LEXIS 2535 (Fed. Cir. Jan. 30,
`2018) ................................................................................................................ 4
`
`Unigene Labs., Inc. v. Apotex, Inc.,
` 655 F.3d 1352 (Fed. Cir. 2011) ....................................................................47
`
`Union Oil Co. of Cal. v. Atl. Richfield Co.,
` 208 F.3d 989 (Fed. Cir. 2000) ......................................................................21
`
`Vas-Cath Inc. v. Mahurkar,
` 935 F.2d 1555 (Fed. Cir. 1991) ....................................................................18
`
`Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc.,
` 853 F.3d 1272 (Fed. Cir. 2017) ................................................................7, 17
`
`P.T.A.B. Cases
`
`Coal. for Affordable Drugs VIII, LLC v. Trs. of the Univ. of Penn.,
`IPR2015-01835 (P.T.A.B. Mar. 6, 2017) ............................................... 45, 65
`
`Costco Wholesale Corp. v. Robert Bosch LLC,
` IPR2016-00041 (P.T.A.B. April 12, 2017) .................................................... 3
`
`Fitbit, Inc. v. BodyMedia, Inc.,
` IPR2016-00707 (P.T.A.B. Sept. 8, 2016) .....................................................18
`
`Medtronic, Inc. v. Norred,
` IPR2014-00111 (P.T.A.B. Apr. 23, 2015) ...................................................46
`
`Schott Gemtron Corp. v. SSW Holding Co. Inc.,
`IPR2014-00367 (P.T.A.B. May 26, 2015) ............................................. 49, 54
`
`Valeo N. Am., Inc. v. Magna Elecs. Inc.,
` IPR2015-01410 (P.T.A.B. Dec. 22, 2016) ...................................................46
`
`Vizio, Inc. v. Nichia Corp.,
`IPR2017-00558 (P.T.A.B. July 7, 2017) .......................................................49
`
`Statutory Authorities
`
`35 U.S.C. § 112 ........................................................................................................46
`
`35 U.S.C. § 316(e) ....................................................................................................45
`
`
`
`
`
`vi
`
`

`

`
`
`LIST OF ABBREVIATIONS
`
`U.S. Patent No. 8,410,131 (Ex.1001)
`Great Britain Application No. 0104072.4 (Ex.1012)
`Great Britain Application No. 0124957.2 (Ex.1013)
`Decision Institution of Inter Partes Review (IPR2017-01592,
`Paper 12)
`mammalian target of rapamycin
`National Cancer Institute
`Novartis Pharms. Corp. v. West-Ward Pharms Int’l Ltd.,
`No. 15-cv-474-RGA, 2017 U.S. Dist. LEXIS 205600 (D. Del.
`Dec. 14, 2017)
`Petition for Inter Partes Review of U.S. Patent No. 8,410,131
`(IPR2017-01592, Paper 1)
`Phosphatase and Tensin homolog deleted on chromosome Ten
`Post-transplant lymphoproliferative disorder
`Person of ordinary skill in the art
`Renal Cell Carcinoma
`Internal cross-reference to another Section(s) of Novartis’s
`Patent Owner Response
`A citation to page number(s) in brackets refers to the stamped
`exhibit page number
`
`
`
`vii
`
`
`
`
`’131 Patent
`GB’072
`
`GB’957
`
`Inst. Dec.
`
`
`
`
`
`
`
`
`
`mTOR
`NCI
`Novartis
`
`Pet.
`
`PTEN
`PTLD
`POSA
`RCC
`Section __
`
`[__]
`
`
`
`
`
`
`
`
`

`

`LIST OF EXHIBITS
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1001 U.S. Patent No. 8,410,131 ("the ’131 patent")
`
`’131 Patent
`
`1002
`
`PCT Published Application No. WO 01/51049 A1,
`OMethylated
`Rapamycin Derivatives for Alleviation and
`Inhibition of Lymphoproliferative Disorders, to
`Wasik
`et al. ("Wasik")
`
`Wasik
`
`1003
`
`PCT Published Application No. WO 00/33878 A2,
`Macrolides, to Navarro et al. ("Navarro")
`
`Navarro
`
`1004
`
`Crowe et al., Absorption and Intestinal Metabolism
`of SDZ-RAD and Rapamycin in Rats, Drug Metab.
`Disp. (1999), 27(5): 627-632 ("Crowe")
`
`1005
`
`1006
`
`Luan et al., Sirolimus Prevents Tumor Progression:
`mTOR Targeting for the Inhibition of Neoplastic
`Progression, Am. J. Transplant. (2001) 1 Suppl 1,
`243 (Abstr. No. 428) ("Luan")
`
`Hidalgo et al., The Rapamycin-sensitive Signal
`Transduction Pathway as a Target for Cancer
`Therapy, Oncogene (2000) 19(56): 6680-6686
`("Hidalgo")
`
`Crowe
`
`Luan
`
`Hidalgo
`
`viii
`
`
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1007
`
`Alexandre et al., CCI-779, A new Rapamycin
`Analog, Has Antitumor Activity at Doses Including
`Only Mild Cutaneous Effects and Mucositis: Early
`Results of an Ongoing Phase I Study, Clin. Cancer
`Res. Suppl. (1999) 5: 3730s, Abstr. No. 7 (AACR-
`NCI-EORTC International Conference, November
`16-19, 1999 held in Washington, DC) ("Alexandre")
`
`Alexandre
`
`1008
`
`Schuler et al., SDZ RAD, A New Rapamycin
`Derivative, Transplantation (1997) 64(1): 36-42
`("Schuler")
`
`Schuler
`
`1009
`
`Neumayer et al., Entry-into-human Study with the
`Novel Immunosuppressant SDZ RAD in Stable
`Renal Transplant Patients, Br. J. Clin. Pharmacol.
`(1999) 48(5): 694-703 ("Neumayer")
`
`Neumayer
`
`1010
`
`Declaration of Allan J. Pantuck, M.D. in Support of
`Petition for Inter Partes Review of U.S. Patent No.
`8,410,131
`
`1012
`
`Great Britain patent application (GB 0104072.4,
`"GB '072" or "the '072 priority application")
`
`1013
`
`Great Britain patent application (GB0124957.2,
`"GB '957" or "the '957 priority application")
`
`1016
`
`Dancey, J. E., Rapamycin-Sensitive Signal-
`Transduction Pathways: Protein Translation Control
`of Cell Proliferation, ASCO Educational Book
`(2000) 68-75 ("Dancey")
`
`Pantuck
`
`GB ‘072
`
`GB ‘957
`
`Dancey
`
`ix
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1017
`
`Sorbera et al, SDZ-RAD, Drugs of the Future
`(1999) 24(1): 22-29 ("Sorbera")
`
`1020
`
`Sedrani et al., Chemical Modification of
`Rapamycin: The Discovery of SDZ RAD,
`Transplantation Proc.(1998) 30(5): 2192-2194
`("Sedrani")
`
`Sorbera
`
`Sedrani
`
`1021
`
`PCT Published Application No. WO 97/47317 A1,
`Combination of a Somatostatin Analogue and a
`Rapamycin, to G. Weckbecker ("Weckbecker")
`
`Weckbecker
`
`1022
`
`1023
`
`1024
`
`U.S. Patent No. 6,331,547, Water Soluble SDZ
`RAD Esters, which issued to Zhu et al. on
`December 18, 2001 from U.S. Provisional Patent
`Application No. 60/183,035 filed on August 18,
`1999 to Zhu ("Zhu '547 patent")
`
`U.S. Patent Application Publication No.
`2002/0183239 A1, Antineoplastic Combinations,
`which published on December 5, 2002 from an
`application filed on April 6, 2001, to Gibbons
`("Gibbons US '239")
`
`Zhu ‘547
`
`Gibbons ‘239
`
`U.S. Patent Application Publication No.
`2003/0008923 A1, Antineoplastic Combinations,
`which published on January 9, 2003 from an
`application filed on June 1, 2001 to Dukart ("Dukart
`US '923")
`
`Dukart ‘932
`
`x
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1026
`
`Published Application No. WO 94/09010 A1,
`OAlkylated Rapamycin Derivatives and their use,
`particularly as immunosuppressants, to Cottens et
`al. ("Cottens WO '010")
`
`Cottens WO
`‘010
`
`1027
`
`Selected portions of Prosecution History Documents
`("May 10, 2010 Amendment re. Cottens WO '010")
`
`May 10, 2010
`Amendment
`
`Boni et al., Pharmacokinetics of escalating doses of
`CCI-779 in Combination with 5-Fluorouracil and
`Leucovorin in Patients with Advanced Solid
`Tumors, Eur. J. Cancer (2001) 37(Suppl. 6): S68
`(Abstr. No. 242) (The 11th ECCO October 21-25,
`2001 meeting held in Lisbon, Portugal) ("Boni")
`
`Motzer et al., Survival and Prognostic Stratification
`of 670 Patients with Advanced Renal Cell
`Carcinoma, J. Clin. Oncol. (1999) 17(8): 2530-2540
`("Motzer et al.")
`
`Boni
`
`Motzer
`
`Perez-Atayde et al., Spectrum of Tumor
`Angiogenesis in the Bone Marrow of Children with
`Acute Lymphoblastic Leukemia, Am. J. Pathol.
`(1997) 150(3): 815-821 ("Perez-Atayde")
`
`Perez-Atayde
`
`1031
`
`1035
`
`1041
`
`1042
`
`True et al., Pathology of Renal Cancers (799-811),
`in Principles and Practice of Genitourinary
`Oncology (Raghavan et al. eds., 1997) ("True")
`
`True
`
`xi
`
`
`
`
`
`
`
`

`

`Exhibit
`
`Description
`
`Abbreviation
`
`
`
`Jennings et al., Renal, Perirenal and Ureteral
`Neoplasms (643-694), In Adult and Pediatric
`Urology; Third Edition. (Gillenwater et al. eds., 3rd
`ed. 1996, Volume 1), Grayhack, Howards, and
`Duckett Eds. Mosby-Year Book, Inc. 1996
`("Jennings")
`
`Robert R. Bahnson, Renal and Urinary Tract
`Neoplasia (371-379), In Primer on Kidney Diseases
`(Greenberg, A. et al. eds., 2nd ed. 1998)
`("Bahnson")
`
`Eng et al., Activity of Rapamycin (AY-22,989)
`against Transplanted Tumors, J. Antibiotics (1984)
`37(10): 1231-1237 ("Eng")
`
`Garber, K., Rapamycin's Resurrection: A New Way
`to Target the Cancer Cell Cycle, J Natl Cancer Inst.
`(2001) 93(2): 1517-1519 ("Garber")
`
`Jennings
`
`Bahnson
`
`Eng
`
`Garber
`
`Breitenbach et al., Rapamycin Inhibits Tumor
`Growth and Metastasis in Mice by
`Antiangiogenesis, Am. J. Transplant. (2001) 1
`Suppl 1, 250 (Abstr. No. 459) ("Breitenbach")
`
`Breitenbuch
`
`Guba et al, Rapamycin inhibits Tumor Growth and
`Metastasis by Antiangiogenesis, Chirugicshes
`Forum 2001 für experimentelle und klinsche
`Forschung (2001) 30: 37-39 ("Guba")
`
`Guba
`
`Hosoi
`
`1043
`
`1044
`
`1050
`
`1059
`
`1060
`
`1061
`
`
`
`
`
`
`
`1062
`
`Hosoi et al., Studies on the Mechanism of
`Resistance toRapamycin in Human Cancer Cells,
`Mol. Pharmacol., (1998) 54 815-824 ("Hosoi")
`
`xii
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1063
`
`Zhang et al., Differences in Phosphorylation of the
`IL-2R Associated JAK/STAT Proteins between
`HTLV-I (+), IL-2-independent and IL-2-dependent
`Cell Lines and Uncultured Leukemic Cells from
`Patients with Adult T-cell Lymphoma/Leukemia,
`Leukemia Res. (1999) 23(4): 373-384 ("Zhang")
`
`Zhang
`
`1073
`
`U.S. Patent No. 7,297,703 to Navarro et al.
`("Navarro '703 patent")
`
`Navarro ‘703
`Patent
`
`1075
`
`Majewski et al., The Immunosuppresive Macrolide
`RAD inhibits Growth of Human Epstein-Barr
`Virustransformed B Lymphocytes in vitro and in
`vivo: A Potential Approach to Prevention and
`Treatment of Postrransplant Lymphoproliferative
`Disorders, Proc. Natl. Acad. Sci. (2000) 97(8):
`4285-4290 ("Majewski")
`
`1076
`
`Huang et al., Mechanisms of Resistance to
`Rapamycin, Drug Resistance Updates, (2001) 4:
`378-392 ("Huang")
`
`1077
`
`Beuvink et al., Antitumor Activity of RAD001, an
`Orally Active Rapamycin Derivative, Proc. Amer.
`Assoc. Cancer Res. (2001) 42, 366, Abstr. No. 1972
`("Beuvink")
`
`Majewski
`
`Huang
`
`Beuvink
`
`xiii
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1080
`
`Hidalgo et al., A Phase I and Pharmacological
`Study of CCI-779, a Rapamycin Ester Cell Cycle
`Inhibitor, Ann. Oncol. (2000) 11 (Suppl. 4) 133,
`Abstr. No. 606O (25th ESMO Congress, October
`13-17, 2000 held in Hamburg, DE) ("Hidalgo
`ESMO Abstract")
`
`Hidalgo ESMO
`Abstract
`
`1081
`
`December 1, 2000 issue of The Lancet Oncology,
`CCI-779: A New Targeted Anticancer Agent, by
`Ezzie Hutchinson ("Hutchinson")
`
`Hutchinson
`
`1082
`
`1083
`
`Hidalgo et al., Phase I and Pharmacological Study
`of CCI-779, a Cell Cycle Inhibitor, Clinical Cancer
`Research (2000), Supplement 6: 4548s-4549s,
`Abstr. No. 413 (11th NCI-EORTC-AACR
`November 7-10, 2000 meeting held in Amsterdam,
`NL) ("Hidalgo NCI Abstract")
`
`Raymond et al., CCI-779, an ester analogue of
`rapamycin that interacts with PTEN/PI3
`KinasePathways: A Phase I Study utilizing a
`Weekly Intravenous Schedule, Clinical Cancer Res.
`(2000) Supplement 6: 4549s, Abstr. No. 414 (11th
`NCIEORTC-AACR November 7-10, 2000 meeting
`held in Amsterdam, The Netherlands) ("Raymond
`NCI Abstract")
`
`Hidalgo NCI
`Abstract
`
`Raymond NCI
`Abstract
`
`xiv
`
`
`
`
`
`
`
`

`

`Exhibit
`
`Description
`
`Abbreviation
`
`
`
`1085
`
`1086
`
`1087
`
`1090
`
`1091
`
`Gibbons et al., The Effect of CCI-779, a Novel
`Macrolide Anti-Tumor Agent, on the Growth of
`Human Tumor Cells In Vitro and in Nude Mouse
`Xenographs In Vivo, Proc. Amer. Assoc. Cancer
`Res. (1999) 40: 301, Abstr. No. 2000 ("Gibbons
`Abstract")
`
`Geoerger et al., Rapamycin analog CCI 779 inhibits
`growth of Human Medulloblastoma Xenographs,
`Proc. Amer. Assoc. Cancer Res. (1999) 40: 603a,
`Abstr. No. 3978 (90th Annual Meeting of the
`AACR, April 10-14, 1999 held in Philadelphia, PA)
`("Geoerger Abstract")
`
`Geoerger et al., Antitumor Activity of the
`Rapamycin Analog CCI-779 in Human Primitive
`Neuroectodermal Tumor/Medulloblastoma Models
`as Single Agent and in Combination Chemotherapy,
`Cancer Res. (2001) 61(4): 1527-1532 ("Geoerger")
`
`Cowan et al., Sirolimus: Mammalian Target of
`Rapamycin Inhibitor to Prevent Kidney Rejection,
`Nephrol. Nursing Journal (2000) 27(6): 623-625
`("Cowan")
`
`Serkova et al., Tissue Distribution and Clinical
`Monitoring of the Novel Macrolide
`Immunosuppressant SDZ-RAD and its Metabolites
`in Monkey Lung Transplant Recipient: Interaction
`with Cyclosporine, J. Pharmacol. Exper. Therap.
`(2000) 294(1): 323-332 ("Serkova")
`
`Gibbons
`Abstract
`
`Georger
`Abstract
`
`Georger
`
`Cowan
`
`Serkova
`
`xv
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1092
`
`U.S. Patent No. 6,432,973, to Zhu et al. ("Zhu '973
`patent")
`
`Zhu ‘973 patent
`
`1093
`
`1094
`
`1095
`
`1096
`
`1097
`
`Neshat et al., Enhanced Sensitivity of PTEN-
`deficient Tumors to Inhibition of FRAP/mTOR,
`Proc. Natl. Acad. Sci. USA (2001) 98(18) 10314-
`10319 ("Neshat")
`
`Neshat
`
`Podsypanina et al., An Inhibitor of mTOR reduces
`Neoplasia and Normalizes p70/S6 Kinase Activity
`in PTEN+/- Mice, Proc. Natl. Acad. Sci. (2001)
`98(18): 10320-10325 ("Podsypanina")
`
`Podsypanina
`
`Yu et al., Deregulated P13k/AKT/TOR Pathway in
`PTEN-Deficient Tumor Cells Correlates with an
`Increased Growth Inhibition Sensitivity to a TOR
`Kinase Inhibitor CCI-779, Proc. Amer. Assoc.
`Cancer Res. (2001) 42: 802 (Abstr. No. 4305)
`("Yu")
`
`Wen et al., PTEN controls Tumor-induced
`Angiogenesis, Proc. Natl. Acad. Sci. USA (2001)
`98(8): 4622-4627 (92nd Annual Meeting of the
`AACR, March 24-28, 2001 held in New Orleans,
`LA) ("Wen")
`
`Yu
`
`Wen
`
`Cantley et al., New Insights into Tumor
`Suppression: PTEN suppresses Tumor Formation
`by restraining the Phosphoinositide 3-Kinase / AKT
`Pathway, Proc. Natl. Acad. Sci. USA, (1999) 96 (8):
`4240-4245 ("Cantley")
`
`Cantley
`
`xvi
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1098
`
`1100
`
`1101
`
`Kondo et al., PTEN/MMAC1/TEP1 Mutations in
`Human Primary Renal-Cell Carcinomas and Renal
`Carcinoma Cell Lines, Intl. J. Cancer (2001) 91(2):
`219–224 ("Kondo")
`
`Sokoloff et al., Systemic Immunotherapy for
`Genitourinary Neoplasms (869-883), in Principles
`and Practice of Genitourinary Oncology (Raghavan
`et al. eds., 1997) ("Sokoloff")
`
`Motzer et al., Chemotherapy for Renal Cell
`Carcinoma (885-896) in Principles and Practice of
`Genitourinary Oncology (Raghavan et al. eds.,
`1997) ("Motzer")
`
`Kondo
`
`Sokoloff
`
`Motzer
`
`1112
`
`Declaration of Daniel Chang Cho, M.D., in Support
`of the Petition for Inter Partes Review of U.S.
`Patent No. 8,410,131, (IPR2018-00507, Ex. 1112)
`
`
`
`1113
`
`Morel, Inhibitors of mTOR and FTY 720, Special
`Transcript 2001 ("Morel")
`
`Morel
`
`2003
`
`Laughlin, E.H., Coming To Terms With Cancer: A
`Glossary Of Cancer-Related Terms, pages 4, 126,
`140, 173-174, 188-190 (2002)
`
`Laughlin
`
`2004 Altman, R. & Sarg, M.J., The Cancer Dictionary,
`51-52, 278 (1992)
`
`Altman
`
`2005
`
`Sutcliffe, S.B. & Gospodarowicz, M.K., Chapter 25,
`“Primary Extranodal Lymphomas,” The
`Lymphomas (Canellos, G.P. et al. eds., 1998)
`
`Sutcliffe 1998
`
`xvii
`
`
`
`
`
`
`
`

`

`Exhibit
`
`Description
`
`Abbreviation
`
`
`
`2006
`
`2007
`
`Molina, A. & Pezner, R.D., Chapter 30, “Non-
`Hodgkin’s Lymphoma,” Cancer Management: A
`Multidisciplinary Approach: Medical, Surgical, &
`Radiation Oncology, 4th Edition (Pazdur, R. et al.
`eds., 2000)
`
`Sutcliffe, S.B. & Gospodarowicz, M.K., “Clinical
`Features And Management Of Localized Extranodal
`Lymphomas,” Haematological Oncology, Volume 2
`pages 189-222 (Keating, A. et al. eds., 1992)
`
`2008
`
`Lynch, C.F. & Cohen, M.B., “Urinary System,”
`Cancer 75(1 Suppl.): 316-329 (1995)
`
`2009
`
`2010
`
`2011
`
`2012
`
`Ligato, S. et al., “Benign Tumors And Tumor-Like
`Lesions Of The Adult Kidney Part I: Benign Renal
`Epithelial Neoplasms,” Adv. Anat. Pathol. 6(1): 1-
`11 (1999)
`
`Glenn, G.M. et al., Chapter 75, “The Molecular
`Genetics Of Renal Cell Carcinoma,” Principles And
`Practice Of Genitourinary Oncology (Raghavan, D.
`et al. eds., 1997)
`
`Hyland, S. & Wilkinson, D., Chapter 14, “The
`Nurse Practitioner And The Organization Of
`Support Services For The Patient With
`Genitourinary Cancer,” Principles And Practice Of
`Genitourinary Oncology (Raghavan, D. et al. eds.,
`1997)
`
`Vasey, P.A., “Immunotherapy For Renal
`Carcinoma: Theoretical Basis And Current Standard
`Of Care,” Br. J. Clin. Pharmacol. 50: 521-529
`(2000)
`
`Pazdur
`
`Sutcliffe
`
`Lynch
`
`Ligato
`
`Glenn
`
`Hyland
`
`Vasey
`
`xviii
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2013
`
`2014
`
`2015
`
`Kawai, K. et al., “Ex Vivo Gene Therapy Using
`Granulocyte-Macrophage Colony-Stimulating
`Factor-Transduced Tumor Vaccines,” Mol. Urol.
`4(2): 43-46 (2000)
`
`Adjei, A.A., “Signal Transduction Pathway Targets
`For Anticancer Drug Discovery,” Cur. Pharm.
`Design 6: 361-378 (2000)
`
`Gordon, M.S. et al., “Phase I Safety And
`Pharmacokinetic Study Of Recombinant Human
`Anti-Vascular Endothelial Growth Factor In
`Patients With Advanced Cancer,” J. Clin. Oncol.
`19(3): 843-850 (2001)
`
`Kawai
`
`Adjei
`
`Gordon
`
`2016
`
`Penn, I. & Starzl, T.E., “Immunosuppression And
`Cancer,” Transplant Proc. 5(1): 943-947 (1973)
`
`Penn
`
`2023
`
`Kozlowski, J.M. et al., Chapter 78, “Renal Cell
`Carcinoma, Tumor Markers,” Principles And
`Practice Of Genitourinary Oncology (Raghavan, D.
`et al. eds., 1997)
`
`Kozlowski
`
`2025
`
`Physicians’ Desk Reference, 55th Edition (2001),
`pages 3443-3448 (Entry for Rapamune® Oral
`Solution (Sirolimus))
`
`Rapamune®
`PDR
`
`2027
`
`March 13, 2018 Deposition Testimony of Dr. Allan
`J. Pantuck
`
`Pantuck
`
`2028
`
`Truong, L. et al., “The Diagnostic and Therapeutic
`Roles of Fine-Needle Aspiration,” Am. J. Clin.
`Pathol. 115:18-31 (2001)
`
`Truong
`
`2029 Hanahan, D. & R.A. Weinberg, “The Hallmarks of
`Cancer,” Cell 100:57-70 (2000)
`
`Hanahan
`
`xix
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2030
`
`Abbas, Z. et al., “Renal lymphoma: an unusual
`cause of extrahepatic biliary obstruction,”
`Postgraduate Med. J. 617-18 (1996)
`
`Abbas
`
`2031
`
`“Genitourinary,” Stedman’s Medical Dictionary
`738-39 (27th ed. 2000)
`
`Stedman’s
`
`2032
`
`Braybrooke, J.P. et al., “A Phase II Study of
`Razoxane, an Antiangiogenic Topoisomerase II
`Inhibitor, in Renal Cell Cancer with Assessment of
`Potential Surrogate Markers of Angiogenesis,” Clin.
`Cancer Res. 6:4697-4704 (2000)
`
`Braybrooke
`
`2033
`
`“Proleukin®,” Physicians’ Desk Reference®, 874-78
`(47th ed. 1993)
`
`Proleukin®
`PDR
`
`
`
`
`
`
`
`2035
`
`2036
`
`2037
`
`2034
`
`Yagoda, A. et al., “Chemotherapy for Advanced
`Renal-Cell Carcinoma: 1983-1993,” Seminars
`Oncol. 22(1):42-60 (1995)
`
`Figlin, R.A. et al., “Multicenter, Randomized, Phase
`III Trial of CD8+ Tumor-Infiltrating Lymphocytes
`in Combination With Recombinant Interleukin-2 in
`Metastatic Renal Cell Carcinoma,” J. Clin. Oncol.
`17(8):2521-29 (1999)
`
`Motzer, R.J. et al., “Phase III Trial of Interferon
`Alfa-2a With or Without 13-cis-Retinoic Acid for
`Patients With Advanced Renal Cell Carcinoma,” J.
`Clin. Oncol. 18(16):2972-80 (2000)
`
`Yagoda
`
`Figlin
`
`Motzer 2000
`
`Pagliaro, L. et al., “A Phase II Trial of Bryostatin-1
`for Patients with Metastatic Renal Cell Carcinoma,”
`Cancer 89(3):615-18 (2000)
`
`Pagliaro
`
`xx
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`Gollob, J. et al., “Phase I Trial of Twice-Weekly
`Intravenous Interleukin 12 in Patients with
`Metastatic Renal Cell Cancer or Malignant
`Melanoma: Ability to Maintain IFN-γ Induction Is
`Associated with Clinical Response,” Clin. Cancer
`Res. 6:1678-92 (2000)
`
`Gollob
`
`Motzer, R.J. et al., “Phase I Trial of Subcutaneous
`Recombinant Human Interleukin-12 in Patients with
`Advanced Renal Cell Carcinoma,” Clin. Cancer
`Res. 4:1183-91 (1998)
`
`Motzer 1998
`
`Kandel, E.S. & N. Hay, “The Regulation and
`Activities of the Multifunctional Serine/Theonine
`Kinase Akt/PKB,” Exper. Cell Res. 253:210-29
`(1999)
`
`Kandel
`
`Downward, J. “Mechanisms and consequences of
`activation of protein kinase B/Akt,” Current Op.
`Cell Biol. 10(2):262-67 (1998)
`
`Downward
`
`Sekulic, A. et al., “A Direct Linkage between the
`Phosphoinositide 3-Kinase-AKT Signaling Pathway
`and the Mammalian Target of Rapamycin in
`Mitogen-stimulated and Transformed Cells,”
`Cancer Res. 60:3504-13 (2000)
`
`Sekulić
`
`2043 Alexandre, J. et al., “Rapamycin and CCI-779,”
`Bull. Cancer 86(10):808-11 (1999)
`
`Alexandre 1999
`
`2044
`
`Douros, J. & M. Suffness, “New Natural Products
`Under Development at the National Cancer
`Institute,” in 76 Recent Results in Cancer Research,
`153-75 (S.K. Carter et al., eds., 1981)
`
`Douros I
`
`xxi
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Screening Data Summary, DEVELOPMENTAL
`THERAPEUTICS PROGRAM, DIVISION OF CANCER
`TREATMENT, NATIONAL CANCER INSTITUTE, 1983
`(available at
`https://wiki.nci.nih.gov/download/attachments/2117
`14065/Instruction_14.pdf?version=1&modification
`Date=1403007070000&api=v2, accessed 4/3/2018)
`
`Douros, J. & M. Suffness, “New antitumor
`substances of natural origin,” Cancer Treatment
`Revs. 8:63-87 (1981)
`
`Marsoni, S. & Wittes, R., “Clinical Development of
`Anticancer Agents – A National Cancer Institute
`Perspective,” Cancer Treatment Reports 68(1):77-
`85 (1984)
`
`Goldin, A. et al., “Current Results of the Screening
`Program at the Division of Cancer Treatment,
`National Cancer Institute,” Europ. J. Cancer
`17:129-42 (1981)
`
`Houchens, D. et al., “Human Brain Tumor
`Xenografts in Nude Mice as a Chemotherapy
`Model,” Eur. J. Cancer Clin. Oncol. 19(6):799-805
`(1985)
`
`Stadler, W. et al., “Flavopiridol, a Novel Cyclin-
`Dependent Kinase Inhibitor, in Metastatic Renal
`Cancer: A University of Chicago Phase II
`Consortium Study,” J. Clin. Oncol. 18(2):371-75
`(2000)
`
`NCI
`
`Douros II
`
`Marsoni
`
`Goldin
`
`Houchens
`
`Stadler 2000
`
`Lummen, G. et al., “Granulocyte-Macrophage
`Colony-Stimulating Factor and Interferon-Alpha 2B
`in Patients with Advanced Renal Cell Carcinoma,”
`Urol. Int. 61:215-19 (1998)
`
`Lümmen
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`2050
`
`2051
`
`xxii
`
`
`
`
`
`
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2052
`
`2053
`
`Tabernero, J. et al., “Dose- and Schedule-
`Dependent Inhibition of the Mammalian Target of
`Rapamycin Pathway With Everolimus: A Phase I
`Tumor Pharmacodynamic Study in Patients With
`Advanced Solid Tumors,” J. Clin. Oncol.
`26(10):1603-10 (2008)
`
`O’Donnell, A. et al., “A phase