`Date Filed: April 4, 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
`
`NOVARTIS’S PATENT OWNER RESPONSE
`
`1 IPR2018-00507 has been joined to this proceeding.
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ...........................................................................................1
`
`POSA ...............................................................................................................3
`
`III.
`
`THE ’131 PATENT.........................................................................................5
`
`IV. GROUND 1: WASIK DOES NOT ANTICIPATE ........................................7
`
`A.
`
`B.
`
`Read As A Whole, Wasik Disclosed Liquid, Not Solid,
`Tumors...................................................................................................8
`
`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.
`
`B.
`
`GB’072 Describes Solid Excretory System Tumors And
`Solid Kidney Tumors ..........................................................................19
`
`GB’072 Describes Advanced Solid Excretory System
`Tumors.................................................................................................21
`
`VI.
`
`STATE OF THE ART IN 2001.....................................................................22
`
`A.
`
`B.
`
`C.
`
`Advanced RCC Was Notoriously Difficult To Treat..........................22
`
`The Intracellular Signaling Pathways Reportedly
`Involved In Tumor Cell Proliferation Were Not
`Reasonably Predictable .......................................................................23
`
`mTOR Inhibitor Development For Cancer Therapy Was
`In Very Early Stages............................................................................25
`
`1.
`
`Rapamycin’s In Vivo Anti-Tumor Activity Was
`Not Reasonably Predictable......................................................25
`
`i
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`2.
`
`3.
`
`4.
`
`Everolimus Had Not Demonstrated In Vivo Anti-
`Tumor Activity Against Any Solid Tumor...............................28
`
`There Were Only Preliminary Phase I Data For
`Temsirolimus In Cancer Patients..............................................31
`
`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.
`
`2.
`
`Luan Was Not Published Before The February
`2001 Priority Date.....................................................................45
`
`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
`
`ii
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`A.
`
`B.
`
`A POSA Would Not Have Had A Motivation To
`Combine ..............................................................................................53
`
`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
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`TABLE OF AUTHORITIES
`
`Cases
`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
`
`iv
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`In re Hughes,
`345 F.2d 184 (C.C.P.A. 1965)......................................................................17
`
`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
`
`v
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`Pozen Inc. v. Par Pharm., Inc.,
`696 F.3d 1151 (Fed. Cir. 2012) ....................................................................18
`
`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
`
`vi
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`Statutory Authorities
`
`35 U.S.C. § 112........................................................................................................46
`
`35 U.S.C. § 316(e)....................................................................................................45
`
`vii
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`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
`
`’131 Patent
`GB’072
`GB’957
`Inst. Dec.
`
`mTOR
`NCI
`Novartis
`
`Pet.
`
`PTEN
`PTLD
`POSA
`RCC
`Section __
`
`[__]
`
`viii
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`LIST OF EXHIBITS
`
`Exhibit
`
`Description
`
`1001
`
`U.S. Patent No. 8,410,131 ("the ’131 patent")
`
`Abbreviation
`
`’131 Patent
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`PCT Published Application No. WO 01/51049 A1,
`OMethylated
`Rapamycin Derivatives for Alleviation and
`Inhibition of Lymphoproliferative Disorders, to
`Wasik
`et al. ("Wasik")
`
`PCT Published Application No. WO 00/33878 A2,
`Macrolides, to Navarro et al. ("Navarro")
`
`Crowe et al., Absorption and Intestinal Metabolism
`of SDZ-RAD and Rapamycin in Rats, Drug Metab.
`Disp. (1999), 27(5): 627-632 ("Crowe")
`
`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")
`
`Wasik
`
`Navarro
`
`Crowe
`
`Luan
`
`Hidalgo
`
`ix
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`1007
`
`1008
`
`1009
`
`1010
`
`1012
`
`1013
`
`1016
`
`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")
`
`Schuler et al., SDZ RAD, A New Rapamycin
`Derivative, Transplantation (1997) 64(1): 36-42
`("Schuler")
`
`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")
`
`Declaration of Allan J. Pantuck, M.D. in Support of
`Petition for Inter Partes Review of U.S. Patent No.
`8,410,131
`
`Great Britain patent application (GB 0104072.4,
`"GB '072" or "the '072 priority application")
`
`Great Britain patent application (GB0124957.2,
`"GB '957" or "the '957 priority application")
`
`Dancey, J. E., Rapamycin-Sensitive Signal-
`Transduction Pathways: Protein Translation Control
`of Cell Proliferation, ASCO Educational Book
`(2000) 68-75 ("Dancey")
`
`x
`
`Alexandre
`
`Schuler
`
`Neumayer
`
`Pantuck
`
`GB ‘072
`
`GB ‘957
`
`Dancey
`
`
`
`Exhibit
`
`1017
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`Description
`
`Sorbera et al, SDZ-RAD, Drugs of the Future
`(1999) 24(1): 22-29 ("Sorbera")
`
`Sedrani et al., Chemical Modification of
`Rapamycin: The Discovery of SDZ RAD,
`Transplantation Proc.(1998) 30(5): 2192-2194
`("Sedrani")
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`Abbreviation
`
`Sorbera
`
`Sedrani
`
`PCT Published Application No. WO 97/47317 A1,
`Combination of a Somatostatin Analogue and a
`Rapamycin, to G. Weckbecker ("Weckbecker")
`
`Weckbecker
`
`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")
`
`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")
`
`Zhu ‘547
`
`Gibbons ‘239
`
`Dukart ‘932
`
`xi
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`Exhibit
`
`1026
`
`Description
`
`Published Application No. WO 94/09010 A1,
`OAlkylated Rapamycin Derivatives and their use,
`particularly as immunosuppressants, to Cottens et
`al. ("Cottens WO '010")
`
`Abbreviation
`
`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.")
`
`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")
`
`Boni
`
`Motzer
`
`Perez-Atayde
`
`True et al., Pathology of Renal Cancers (799-811),
`in Principles and Practice of Genitourinary
`Oncology (Raghavan et al. eds., 1997) ("True")
`
`True
`
`1031
`
`1035
`
`1041
`
`1042
`
`xii
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`1043
`
`1044
`
`1050
`
`1059
`
`1060
`
`1061
`
`1062
`
`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")
`
`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")
`
`Guba et al, Rapamycin inhibits Tumor Growth and
`Metastasis by Antiangiogenesis, Chirugicshes
`Forum 2001 für experimentelle und klinsche
`Forschung (2001) 30: 37-39 ("Guba")
`
`Hosoi et al., Studies on the Mechanism of
`Resistance toRapamycin in Human Cancer Cells,
`Mol. Pharmacol., (1998) 54 815-824 ("Hosoi")
`
`xiii
`
`Jennings
`
`Bahnson
`
`Eng
`
`Garber
`
`Breitenbuch
`
`Guba
`
`Hosoi
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`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
`
`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")
`
`Huang et al., Mechanisms of Resistance to
`Rapamycin, Drug Resistance Updates, (2001) 4:
`378-392 ("Huang")
`
`Beuvink et al., Antitumor Activity of RAD001, an
`Orally Active Rapamycin Derivative, Proc. Amer.
`Assoc. Cancer Res. (2001) 42, 366, Abstr. No. 1972
`("Beuvink")
`
`1075
`
`1076
`
`1077
`
`Majewski
`
`Huang
`
`Beuvink
`
`xiv
`
`
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`Exhibit
`
`Description
`
`Abbreviation
`
`1080
`
`1081
`
`1082
`
`1083
`
`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
`
`December 1, 2000 issue of The Lancet Oncology,
`CCI-779: A New Targeted Anticancer Agent, by
`Ezzie Hutchinson ("Hutchinson")
`
`Hutchinson
`
`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
`
`xv
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Paper No. ______
`Date Filed: April 4, 2018
`
`1085
`
`1086
`
`1087
`
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`
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`Exhibit
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`1092
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`1093
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`1095
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`1096
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`2031
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`2032
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