`
`
`
`
`
`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 EXPERT DECLARATION OF DR. HOWARD A. BURRIS,
`III
`
`
`1 IPR2018-00507 has been joined to this proceeding.
`
`
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`NOVARTIS EXHIBIT 2092
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`Contents
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`Qualifications ................................................................................................... 8
`
`III. Legal Principles ............................................................................................. 12
`
`IV. POSA ............................................................................................................. 15
`
`V.
`
`Tumor Background ........................................................................................ 20
`
`A. Advanced Tumors ............................................................................... 22
`
`B.
`
`C.
`
`Solid Excretory System Tumors ......................................................... 23
`
`Lymphomas ......................................................................................... 24
`
`VI. Summary Of The ’131 Patent ........................................................................ 26
`
`VII. Ground 1: The Challenged Claims Of The ’131 Patent Are Not
`Anticipated Because Wasik Disclosed Only Liquid Tumors,
`Not Solid Tumors .......................................................................................... 31
`
`VIII. The Challenged Claims Of The ’131 Patent Are Entitled To A
`February 2001 Priority Date .......................................................................... 50
`
`IX. Luan Is Not Prior Art Because The ’131 Patent Inventors
`Previously Invented As Much Of The Claimed Invention As
`Luan Disclosed .............................................................................................. 57
`
`X.
`
`State Of The Art As Of February 2001 ......................................................... 58
`
`A.
`
`Solid Kidney Tumor And RCC Background ...................................... 58
`
`1.
`
`2.
`
`In February 2001, Advanced RCC Was
`Associated With A Poor Prognosis ........................................... 59
`
`In February 2001, Advanced RCC Was
`Notoriously Difficult To Treat .................................................. 60
`
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`B.
`
`C.
`
`D.
`
`Intracellular Signaling Pathways Background .................................... 65
`
`In February 2001, The Role Of mTOR In The
`Intracellular Signaling Pathways Reportedly Involved In
`Cell Proliferation Was Not Well Understood Or
`Reasonably Predictable ....................................................................... 68
`
`In February 2001, The Development Of An mTOR
`Inhibitor For Cancer Treatment Was In Very Early
`Stages ................................................................................................... 72
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`In February 2001, The In Vivo Anti-Tumor
`Activity Of Rapamycin Was Not Reasonably
`Predictable ................................................................................. 74
`
`In February 2001, Only One mTOR Inhibitor Was
`In Development For Cancer Treatment .................................... 80
`
`In February 2001, Everolimus Had Not
`Demonstrated In Vivo Anti-Tumor Activity
`Against Any Solid Tumor ......................................................... 81
`
`In February 2001, There Was Only Preliminary
`Phase I Data For Temsirolimus In Cancer Patients .................. 93
`
`In February 2001, There Were Known Differences
`Between mTOR Inhibitors ...................................................... 103
`
`In February 2001, What Role PTEN Played In
`RCC, If Any, Was Not Well Understood Or
`Reasonably Predictable ........................................................... 110
`
`E.
`
`A POSA Would Not Have Selected Everolimus For The
`Development Of A New Treatment For Solid Kidney
`Tumors, Such As Advanced RCC, In February 2001 ....................... 117
`
`1.
`
`2.
`
`A POSA Would Not Have Selected Everolimus
`Over Immunotherapy For The Development Of A
`New Treatment For Solid Kidney Tumors, Such
`As Advanced RCC .................................................................. 120
`
`A POSA Would Not Have Selected Everolimus
`Over Temsirolimus For The Development Of A
`
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`New Treatment For Solid Kidney Tumors, Such
`As Advanced RCC .................................................................. 126
`
`XI. State Of The Art As Of February 2002 ....................................................... 127
`
`A.
`
`In February 2002, The Development Of An mTOR
`Inhibitor For Cancer Treatment Was Still In Very Early
`Stages ................................................................................................. 129
`
`1.
`
`2.
`
`3.
`
`In February 2002, The In Vivo Anti-Tumor
`Activity Of Rapamycin And Temsirolimus Was
`Not Reasonably Predictable And There Was Only
`Preliminary Phase I Data For Temsirolimus In
`Cancer Patients ........................................................................ 129
`
`In February 2002, The Preclinical Anti-Tumor
`Activity Of Everolimus Was Not Reasonably
`Predictable ............................................................................... 137
`
`In February 2002, What Role PTEN Played In
`RCC, If Any, Was Not Well Understood Or
`Reasonably Predictable ........................................................... 141
`
`B.
`
`A POSA Would Not Have Selected Everolimus For The
`Development Of A New Treatment For Solid Kidney
`Tumors, Such As Advanced RCC, In February 2002 ....................... 143
`
`XII. Ground 2: The Challenged Claims Of The ’131 Patent Are Not
`Obvious Over Wasik Alone Or In Combination With Navarro .................. 144
`
`A. A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC In
`February 2001 .................................................................................... 145
`
`B.
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2002 .................................................................................... 150
`
`XIII. Ground 3: The Challenged Claims Of The ’131 Patent Are Not
`Obvious Over Wasik, Navarro, Crowe, And Luan ..................................... 152
`
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`A. A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2001 .................................................................................... 153
`
`B.
`
`C.
`
`A POSA Would Not Have Been Motivated To Combine
`Luan And The Everolimus References In February 2002 ................ 154
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2002 .................................................................................... 155
`
`XIV. Ground 4: The Challenged Claims Of The ’131 Patent Are Not
`Obvious Over Hidalgo, Alexandre, Crowe, Schuler, Neumayer,
`And Navarro ................................................................................................ 159
`
`A. A POSA Would Not Have Been Motivated To Combine
`The Temsirolimus And Everolimus References In
`February 2001 .................................................................................... 160
`
`B.
`
`C.
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2001 .................................................................................... 164
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2002 .................................................................................... 172
`
`XV. Ground 5: The Challenged Claims Of The ’131 Patent Are Not
`Obvious Over Hidalgo, Alexandre, Crowe, Schuler, Neumayer,
`Navarro, And Luan ...................................................................................... 173
`
`A. A POSA Would Not Have Been Motivated To Combine
`Luan And The Everolimus References In February 2002 ................ 174
`
`B.
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2002 .................................................................................... 175
`
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`XVI. Conclusion ................................................................................................... 176
`
`
`
`
`
`
`
`
`
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`
`
`LIST OF EXHIBITS CITED
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1001
`
`U.S. Patent No. 8,410,131 (“the
`‘131 patent”)
`
`‘131 Patent
`
`63, 64, 65, 66, 70
`
`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
`
`73, 74, 75, 76, 77, 78, 79,
`80, 81, 82, 83, 87, 88, 89,
`90, 91, 92, 162, 169, 253,
`255, 261, Fn. 5
`
`1003
`
`PCT Published Application No.
`WO 00/33878 A2, Macrolides,
`to Navarro et al. ("Navarro")
`
`Navarro
`
`161, 258, 284, 291
`
`1004
`
`1005
`
`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")
`
`Crowe
`
`Luan
`
`194, 269, 270, 284, 304
`
`224, 226, 227, 231, 248,
`264, 273, Fn. 10
`
`vi
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`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1006
`
`Hidalgo et al., The Rapamycin-
`sensitive Signal Transduction
`Pathway as a Target for Cancer
`Therapy, Oncogene (2000)
`19(56): 6680-6686 ("Hidalgo")
`
`Hidalgo
`
`133, 138, 142, 143, 145,
`181, 182, 193, 194, 198,
`212, 218, 271, 282, 283,
`288, 296, 304
`
`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")
`
`1008
`
`Schuler et al., SDZ RAD, A
`New Rapamycin Derivative,
`Transplantation (1997) 64(1):
`36-42 ("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")
`
`174, 175, 180, 276, 277,
`283
`
`Alexandre
`
`Schuler
`
`156, 157, 191, 194, 223,
`261, 271, 275, 283, 284,
`296, 299, 304
`
`158, 159, 191, 284, 291,
`296, 304
`
`Neumayer
`
`vii
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`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1010
`
`Declaration of Allan J. Pantuck,
`M.D. in Support of Petition for
`Inter Partes Review of U.S.
`Patent No. 8,410,131
`
`Pantuck Dec.
`
`1012
`
`1013
`
`1016
`
`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")
`
`GB ‘072
`
`GB ‘957
`
`Dancey
`
`2, 44, 46, 50, 71, 89, 95,
`98, 103, 115, 117, 119,
`137, 145, 146, 153, 155,
`156, 158, 160, 161, 162,
`166, 166, 169, 174, 181,
`185, 186, 193, 194, 195,
`197, 198, 200, 215, 223,
`224, 236, 237, 238, 239,
`241, 252, 270, 274, 281,
`291, 292, 294, 304, Fn. 7,
`Fn. 10, Fn. 12, Fn. 13
`
`100, 101, 102, 103, 106,
`107, 108, 109, 111, 112,
`113, 114, 116
`
`114
`
`140, 141, 142, 143, 175,
`177, 193, 194, 198, 218,
`271, 275, 282, 283, 288,
`296, 304
`
`1017
`
`Sorbera et al, SDZ-RAD, Drugs
`of the Future (1999) 24(1): 22-
`29 ("Sorbera")
`
`Sorbera
`
`154, 194
`
`viii
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`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`U.S. Patent No. 5,362,718, to
`Skotnicki et al. ("Skotnichi
`'718")
`
`U.S. Patent No. 5,665,772 to
`Cottens et al. ("Cottens '772
`patent")
`
`Sedrani et al., Chemical
`Modification of Rapamycin: The
`Discovery of SDZ RAD,
`Transplantation Proc.(1998)
`30(5): 2192-2194 ("Sedrani")
`
`PCT Published Application No.
`WO 97/47317 A1, Combination
`of a Somatostatin Analogue and
`a Rapamycin, to G. 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")
`
`Skotnicki
`
`154, 173
`
`Cottens ‘772
`
`154, 155, Fn. 8
`
`156, 157, 194
`
`162, 163, 164, 165, 168
`
`191, 195
`
`Sedrani
`
`Weckbecker
`
`Zhu ‘547
`Patent
`
`ix
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`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`224, 238
`
`224, 238
`
`95, 155
`
`95, 124
`
`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")
`
`Published Application No. WO
`94/09010 A1, OAlkylated
`Rapamycin Derivatives and their
`use, particularly as
`immunosuppressants, to Cottens
`et al. ("Cottens WO '010")
`
`Gibbons ‘239
`
`Dukart ‘932
`
`Cottens WO
`‘010
`
`Selected portions of Prosecution
`History Documents ("May 10,
`2010 Amendment re. Cottens
`WO '010")
`
`May 10, 2010
`Amendment
`
`1023
`
`1024
`
`1026
`
`1027
`
`x
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`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`224, 237, 264, Fn. 14
`
`107, 112
`
`224
`
`224
`
`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.")
`
`PCT Published Application No.
`WO 02/40000 A2, Use of CCI-
`779 as an Antineoplastic Agent,
`to Dukart et al. ("Dukart WO
`'000")
`
`PCT Published Application No.
`WO 02/080975 A1,
`Antineoplastic Combinations
`such as Rapamycin together
`with Gemcitabine or
`Fluorouracil, to Gibbons et al.
`("Gibbons WO '975")
`
`1031
`
`1035
`
`1036
`
`1037
`
`Boni
`
`Motzer
`
`Dukart WO
`‘000
`
`Gibbons WO
`‘975
`
`xi
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`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1038
`
`1039
`
`1040
`
`1041
`
`PCT Published Application No.
`WO 02/098416 A2,
`Antineoplastic Combinations, to
`Dukart et al. ("Dukart WO
`'416")
`
`U.S. Patent Application
`Publication No. 2002/0091137
`A1, Use of CCI-779 as an
`Antineoplastic Agent, which
`published on July 11, 2002, to
`Dukart ("Dukart '137")
`
`U.S. Patent No. 7,781,446, Use
`of CCI-779 as an Antineoplastic
`Agent, which issued to Dukart et
`al. on August 24, 2010 ("Dukart
`'446"), and which claims priority
`to U.S. Provisional Patent
`Application No. 60/249,077
`("Dukart")
`
`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")
`
`224
`
`186
`
`181, 186, Fn. 15
`
`Dukart WO
`‘416
`
`Dukart ’137
`
`Dukart
`
`50
`
`Perez-Atayde
`
`xii
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`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1042
`
`True et al., Pathology of Renal
`Cancers (799-811), in Principles
`and Practice of Genitourinary
`Oncology (Raghavan et al. eds.,
`1997) ("True")
`
`True
`
`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")
`
`Vézina et al., Rapamycin (AY-
`22,989), A New Antifungal
`Antibiotic I. Taxonomy of the
`Producing Streptomycete and
`Isolation of the Active Principle,
`J. Antibiot. (1975) 28 (10): 721-
`726 ("Vézina")
`
`1043
`
`1044
`
`1045
`
`Jennings
`
`Bahnson
`
`Vezina
`
`59, 106, 111
`
`103, 106, 111, 201
`
`55, 106, 107, 111, 222
`
`Fn. 7
`
`xiii
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`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1046
`
`1047
`
`Sehgal et al., Rapamycin (AY-
`22,989), a New Antifungal
`Antibiotic II. Fermentation,
`Isolation, and Characterization,
`J. Antibiotics (1975) 28(10):
`727-732
`
`Baker et al., Rapamycin (AY-
`22,989), A New Antifungal
`Antibiotic III. In Vitro and In
`Vivo Evaluation, J. Antibiotics
`(1978) 31(6): 539-545 ("Baker")
`
`Seghal
`
`Baker
`
`1048
`
`U.S. Patent No. 3,929,992 to
`Sehgal ("Sehgal '992 patent")
`
`Sehgal ‘992
`
`1049
`
`1050
`
`Martel et al. Inhibition of the
`Immune Response by
`Rapamycin, a New Antifungal
`Antibiotic, Can. J. Physiol.
`Pharmacol. (1977) 55(1): 48-51
`("Martel")
`
`Eng et al., Activity of
`Rapamycin (AY-22,989) against
`Transplanted Tumors, J.
`Antibiotics (1984) 37(10): 1231-
`1237 ("Eng")
`
`Martel
`
`Eng
`
`Fn. 7
`
`Fn. 7
`
`Fn. 7
`
`Fn. 7
`
`145, 150, 151, Fn. 11
`
`1051
`
`U.S. Patent No. 5,066,493 to
`Sehgal et al. ("Sehgal '493
`patent")
`
`Sehgal ‘493
`patent
`
`145, 150, Fn. 11
`
`xiv
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`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1052
`
`U.S. Patent No. 5,206,018 to
`Sehgal et al. ("Sehgal '018
`patent")
`
`Sehgal ‘018
`patent
`
`145, 150, Fn. 11
`
`1059
`
`1060
`
`1061
`
`1062
`
`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.
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`Tumor Growth and Metastasis
`by Antiangiogenesis,
`Chirugicshes Forum 2001 für
`experimentelle und klinsche
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`
`Hosoi et al., Studies on the
`Mechanism of Resistance
`toRapamycin in Human Cancer
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`54 815-824 ("Hosoi")
`
`197, 198, 210, 224, 236
`
`Garber
`
`224, 232, 233, 235
`
`Breitenbuch
`
`224, 232, 233, 235
`
`141, 146, 147
`
`Guba
`
`Hosoi
`
`xv
`
`NOVARTIS EXHIBIT 2092
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`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`91, 146, 162, 171
`
`1063
`
`Zhang et al., Differences in
`Phosphorylation of the IL-2R
`Associated JAK/STAT Proteins
`between HTLV-I (+), IL-2-
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`Leukemic Cells from Patients
`with Adult T-cell
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`Leukemia Res. (1999) 23(4):
`373-384 ("Zhang")
`
`Zhang
`
`1065
`
`U.S. Patent No. 5,260,300 to Hu
`("Hu '300 patent")
`
`Hu ‘300 patent
`
`154
`
`1066
`
`U.S. Patent No. 5,221,670 to
`Caufield ("Caufield '670 patent")
`
`Caufield ‘670
`patent
`
`154, Fn. 18
`
`1067
`
`U.S. Patent No. 5,434,260 to
`Skotnicki et al. ("Skotnicki '260
`patent")
`
`Skotnicki ‘260
`patent
`
`1069
`
`PRNewswire, August 30, 2000
`press release, Novartis
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`Press Release
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`154
`
`160, 217
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`1073
`
`U.S. Patent No. 7,297,703 to
`Navarro et al. ("Navarro '703
`patent")
`
`Navarro ‘703
`Patent
`
`161
`
`xvi
`
`NOVARTIS EXHIBIT 2092
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`Page 17 of 218
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`57, 92, 93, 94, 162, 170
`
`141, 193, 198, 224, 239,
`244, 245, 265, 271, 275,
`283, 296, 304, Fn. 13,
`Fn. 19, Fn. 21
`
`224, 239, 240, 241, 244,
`249, 265, 274, Fn. 13
`
`Fn. 14
`
`Majewski et al., The
`Immunosuppresive Macrolide
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`Huang et al., Mechanisms of
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`Beuvink et al., Antitumor
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`Proc. Amer. Assoc. Cancer Res.
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`
`Wall Street Journal, Drug
`Progress on Hard-to-Treat
`Cancers is Cited, by Robert
`Langreth and Michael Waldholz
`in the November 17, 1999
`edition ("Langreth")
`
`1075
`
`1076
`
`1077
`
`1079
`
`Majewski
`
`Huang
`
`Beuvink
`
`Langreth
`
`xvii
`
`NOVARTIS EXHIBIT 2092
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`Page 18 of 218
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1080
`
`Hidalgo et al., A Phase I and
`Pharmacological Study of CCI-
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`held in Hamburg, DE) ("Hidalgo
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`
`1081
`
`December 1, 2000 issue of The
`Lancet Oncology, CCI-779: A
`New Targeted Anticancer
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`1082
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`Hidalgo et al., Phase I and
`Pharmacological Study of CCI-
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`Clinical Cancer Research
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`4549s, Abstr. No. 413 (11th
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`Abstract")
`
`174, 180
`
`Hidalgo
`ESMO
`Abstract
`
`183, 198, 295, Fn. 14
`
`Hutchinson
`
`174, 175, 180
`
`Hidalgo NCI
`Abstract
`
`xviii
`
`NOVARTIS EXHIBIT 2092
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`Page 19 of 218
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`174, 180
`
`185
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`185
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`Raymond et al., CCI-779, an
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`
`1083
`
`1085
`
`1086
`
`Raymond NCI
`Abstract
`
`Gibbons
`Abstract
`
`Georger
`Abstract
`
`xix
`
`NOVARTIS EXHIBIT 2092
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`Page 20 of 218
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`147, 243, 277, 305
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`194
`
`191, 194
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`1087
`
`1090
`
`1091
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`Geoerger et al., Antitumor
`Activity of the Rapamycin
`Analog CCI-779 in Human
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`Serkova et al., Tissue
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`323-332 ("Serkova")
`
`Georger
`
`Cowan
`
`Serkova
`
`1092
`
`U.S. Patent No. 6,432,973, to
`Zhu et al. ("Zhu '973 patent")
`
`Zhu ‘973
`patent
`
`195, Fn. 20
`
`xx
`
`NOVARTIS EXHIBIT 2092
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`Page 21 of 218
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1093
`
`1094
`
`1095
`
`1096
`
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`Sensitivity of PTEN-deficient
`Tumors to Inhibition of
`FRAP/mTOR, Proc. Natl. Acad.
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`10319 ("Neshat")
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`Podsypanina et al., An Inhibitor
`of mTOR reduces Neoplasia and
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`Wen et al., PTEN controls
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`March 24-28, 2001 held in New
`Orleans, LA) ("Wen")
`
`224, 243, 246, 247, 277,
`305
`
`Neshat
`
`139, 224, 247, 288
`
`Podsypanina
`
`224, 247
`
`224, 246, 247, 250, 265
`
`Yu
`
`Wen
`
`xxi
`
`NOVARTIS EXHIBIT 2092
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`Page 22 of 218
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`1097
`
`1098
`
`1099
`
`1100
`
`Cantley et al., New Insights into
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`Kondo et al.,
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`(Raghavan et al. eds., 1997)
`("Sokoloff")
`
`Cantley
`
`Kondo
`
`Morita
`
`Sokoloff
`
`138, 139, 197, 206, 207,
`208, 209, 221
`
`201, 202, 204
`
`208
`
`122, 215, 216
`
`xxii
`
`NOVARTIS EXHIBIT 2092
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`Page 23 of 218
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`Exhibit
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`Description
`
`Abbreviation
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`Citation (Para. Nos.)
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`1101
`
`2003
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`Motzer et al., Chemotherapy for
`Renal Cell Carcinoma (885-896)
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`Genitourinary Oncology
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`Laughlin, E.H., Coming To
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`44, 45, 59, 85, 123, 125,
`126, 127, 132, 177, 179,
`228, 255, 298
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`Motzer
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`44, 50, 51, 52, 56, 57, 86
`
`Laughlin
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`49, 51, 103
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`58, 83, 90
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`44, 58, 59, 85, 164
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`2004
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`Altman, R. & Sarg, M.J., The
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`Exhibit
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`Abbreviation
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`2007
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`Sutcliffe, S.B. &
`Gospodarowicz, M.K., “Clinical
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`Glenn, G.M. et al., Chapter 75,
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`Abbreviation
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`Citation (Para. Nos.)
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`Hyland, S. & Wilkinson, D.,
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`2012
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`2013
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`2014
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`Raghavan-
`Hyland
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`Vasey
`
`Kawai
`
`Adjei
`
`121, 210
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`215, 221
`
`216
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`130, 133, 134, 136, 212,
`218
`
`xxv
`
`NOVARTIS EXHIBIT 2092
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`Page 26 of 218
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`Citation (Para. Nos.)
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`2016
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`2023
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`Gordon
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`Penn & Starzl
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`Kozlowski
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`45, 121, 177
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`Pantuck Deposition Transcript,
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`Citation (Para. Nos.)
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