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
`
`EXPERT DECLARATION OF DR. HOWARD A. BURRIS, III
`
`1 IPR2018-00507 has been joined to this proceeding.
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 217
`
`

`

`TABLE OF CONTENTS
`
`Contents
`I.
`Introduction ..................................................................................................1
`
`II.
`
`III.
`
`IV.
`
`V.
`
`Qualifications ...............................................................................................8
`
`Legal Principles ..........................................................................................12
`
`POSA..........................................................................................................15
`
`Tumor Background.....................................................................................20
`
`A.
`
`B.
`
`C.
`
`Advanced Tumors.............................................................................22
`
`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
`
`i
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 2 of 217
`
`

`

`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
`
`ii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 217
`
`

`

`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.
`
`B.
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC In
`February 2001.................................................................................145
`
`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
`
`iii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 217
`
`

`

`A.
`
`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.................................................................................153
`
`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.
`
`B.
`
`C.
`
`A POSA Would Not Have Been Motivated To Combine
`The Temsirolimus And Everolimus References In
`February 2001.................................................................................160
`
`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.
`
`B.
`
`A POSA Would Not Have Been Motivated To Combine
`Luan And The Everolimus References In February 2002................174
`
`A POSA Would Not Have Reasonably Expected
`Everolimus To Be Therapeutically Effective Against
`Solid Kidney Tumors, Such As Advanced RCC, In
`February 2002.................................................................................175
`
`iv
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 217
`
`

`

`XVI. Conclusion................................................................................................176
`
`v
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 6 of 217
`
`

`

`LIST OF EXHIBITS CITED
`
`Exhibit
`
`1001
`
`Description
`U.S. Patent No. 8,410,131 (“the
`‘131 patent”)
`
`Abbreviation
`
`‘131 Patent
`
`Citation (Para. Nos.)
`63, 64, 65, 66, 70
`
`1002
`
`1003
`
`1004
`
`1005
`
`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")
`
`73, 74, 75, 76, 77, 78, 79,
`80, 81, 82, 83, 87, 88, 89,
`90, 91, 92, 162, 169, 253,
`255, 261, Fn. 5
`
`161, 258, 284, 291
`
`194, 269, 270, 284, 304
`
`224, 226, 227, 231, 248,
`264, 273, Fn. 10
`
`Wasik
`
`Navarro
`
`Crowe
`
`Luan
`
`vi
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 7 of 217
`
`

`

`Exhibit
`
`1006
`
`Description
`Hidalgo et al., The Rapamycin-
`sensitive Signal Transduction
`Pathway as a Target for Cancer
`Therapy, Oncogene (2000)
`19(56): 6680-6686 ("Hidalgo")
`
`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")
`
`1007
`
`1008
`
`1009
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`133, 138, 142, 143, 145,
`181, 182, 193, 194, 198,
`212, 218, 271, 282, 283,
`288, 296, 304
`
`174, 175, 180, 276, 277,
`283
`
`Hidalgo
`
`Alexandre
`
`Schuler
`
`156, 157, 191, 194, 223,
`261, 271, 275, 283, 284,
`296, 299, 304
`
`158, 159, 191, 284, 291,
`296, 304
`
`Neumayer
`
`vii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 8 of 217
`
`

`

`Exhibit
`
`Description
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`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
`
`154, 194
`
`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
`
`1017
`
`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")
`
`Sorbera et al, SDZ-RAD, Drugs
`of the Future (1999) 24(1): 22-
`29 ("Sorbera")
`
`GB ‘072
`
`GB ‘957
`
`Dancey
`
`Sorbera
`
`viii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 9 of 217
`
`

`

`Exhibit
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`Description
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`154, 173
`
`154, 155, Fn. 8
`
`156, 157, 194
`
`162, 163, 164, 165, 168
`
`191, 195
`
`Skotnicki
`
`Cottens ‘772
`
`Sedrani
`
`Weckbecker
`
`Zhu ‘547
`Patent
`
`ix
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 10 of 217
`
`

`

`Exhibit
`
`1023
`
`1024
`
`1026
`
`1027
`
`Description
`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")
`
`Selected portions of Prosecution
`History Documents ("May 10,
`2010 Amendment re. Cottens
`WO '010")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`224, 238
`
`224, 238
`
`95, 155
`
`95, 124
`
`Gibbons ‘239
`
`Dukart ‘932
`
`Cottens WO
`‘010
`
`May 10, 2010
`Amendment
`
`x
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 11 of 217
`
`

`

`Exhibit
`
`1031
`
`1035
`
`1036
`
`1037
`
`Description
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`224, 237, 264, Fn. 14
`
`107, 112
`
`224
`
`224
`
`Boni
`
`Motzer
`
`Dukart WO
`‘000
`
`Gibbons WO
`‘975
`
`xi
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 12 of 217
`
`

`

`Exhibit
`
`1038
`
`Description
`PCT Published Application No.
`WO 02/098416 A2,
`Antineoplastic Combinations, to
`Dukart et al. ("Dukart WO
`'416")
`
`1039
`
`1040
`
`1041
`
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`224
`
`186
`
`181, 186, Fn. 15
`
`Dukart WO
`‘416
`
`Dukart ’137
`
`Dukart
`
`50
`
`Perez-Atayde
`
`xii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 13 of 217
`
`

`

`Exhibit
`
`1042
`
`Description
`True et al., Pathology of Renal
`Cancers (799-811), in Principles
`and Practice of Genitourinary
`Oncology (Raghavan et al. eds.,
`1997) ("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
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`59, 106, 111
`
`103, 106, 111, 201
`
`55, 106, 107, 111, 222
`
`Fn. 7
`
`True
`
`Jennings
`
`Bahnson
`
`Vezina
`
`xiii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 14 of 217
`
`

`

`Abbreviation
`
`Citation (Para. Nos.)
`
`Exhibit
`
`1046
`
`Description
`Sehgal et al., Rapamycin (AY-
`22,989), a New Antifungal
`Antibiotic II. Fermentation,
`Isolation, and Characterization,
`J. Antibiotics (1975) 28(10):
`727-732
`
`1047
`
`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
`
`Fn. 7
`
`Fn. 7
`
`Fn. 7
`
`Fn. 7
`
`145, 150, 151, Fn. 11
`
`1048
`
`U.S. Patent No. 3,929,992 to
`Sehgal ("Sehgal '992 patent")
`
`Sehgal ‘992
`
`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
`
`1049
`
`1050
`
`1051
`
`U.S. Patent No. 5,066,493 to
`Sehgal et al. ("Sehgal '493
`patent")
`
`Sehgal ‘493
`patent
`
`145, 150, Fn. 11
`
`xiv
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 15 of 217
`
`

`

`Exhibit
`
`1052
`
`Description
`U.S. Patent No. 5,206,018 to
`Sehgal et al. ("Sehgal '018
`patent")
`
`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.
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`145, 150, Fn. 11
`
`197, 198, 210, 224, 236
`
`224, 232, 233, 235
`
`Sehgal ‘018
`patent
`
`Garber
`
`Breitenbuch
`
`224, 232, 233, 235
`
`141, 146, 147
`
`Guba
`
`Hosoi
`
`xv
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 16 of 217
`
`

`

`Exhibit
`
`1063
`
`1065
`
`1066
`
`1067
`
`1069
`
`1073
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`91, 146, 162, 171
`
`Zhang
`
`Description
`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")
`
`U.S. Patent No. 5,260,300 to Hu
`("Hu '300 patent")
`
`Hu ‘300 patent
`
`U.S. Patent No. 5,221,670 to
`Caufield ("Caufield '670 patent")
`
`Caufield ‘670
`patent
`
`U.S. Patent No. 5,434,260 to
`Skotnicki et al. ("Skotnicki '260
`patent")
`
`Skotnicki ‘260
`patent
`
`PRNewswire, August 30, 2000
`press release, Novartis
`Announces Positive Trial
`Results for Two Novel
`Transplantation Drugs ("Press
`Release")
`
`Press Release
`
`154
`
`154, Fn. 18
`
`154
`
`160, 217
`
`U.S. Patent No. 7,297,703 to
`Navarro et al. ("Navarro '703
`patent")
`
`Navarro ‘703
`Patent
`
`161
`
`xvi
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 17 of 217
`
`

`

`Exhibit
`
`1075
`
`1076
`
`1077
`
`1079
`
`Description
`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")
`
`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")
`
`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
`
`Huang
`
`Beuvink
`
`Langreth
`
`xvii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 18 of 217
`
`

`

`Exhibit
`
`1080
`
`1081
`
`1082
`
`Description
`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")
`
`December 1, 2000 issue of The
`Lancet Oncology, CCI-779: A
`New Targeted Anticancer
`Agent, by Ezzie 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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`174, 180
`
`183, 198, 295, Fn. 14
`
`174, 175, 180
`
`Hidalgo
`ESMO
`Abstract
`
`Hutchinson
`
`Hidalgo NCI
`Abstract
`
`xviii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 19 of 217
`
`

`

`Exhibit
`
`1083
`
`1085
`
`1086
`
`Description
`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")
`
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`174, 180
`
`185
`
`185
`
`Raymond NCI
`Abstract
`
`Gibbons
`Abstract
`
`Georger
`Abstract
`
`xix
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 20 of 217
`
`

`

`Exhibit
`
`1087
`
`1090
`
`1091
`
`Description
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`147, 243, 277, 305
`
`Georger
`
`Cowan
`
`Serkova
`
`194
`
`191, 194
`
`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
`Breckenridge v. Novartis, IPR 2017-01592
`Page 21 of 217
`
`

`

`Exhibit
`
`1093
`
`1094
`
`1095
`
`1096
`
`Description
`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")
`
`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")
`
`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")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`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
`Breckenridge v. Novartis, IPR 2017-01592
`Page 22 of 217
`
`

`

`Exhibit
`
`1097
`
`Description
`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")
`
`1098
`
`1099
`
`1100
`
`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")
`
`Morita et al., Common Regions
`of Deletion on Chromosomes
`5q, 6q, and 10q in Renal Cell
`Carcinoma, Cancer Res. (1991)
`51(21): 5817-5820 ("Morita")
`
`Sokoloff et al., Systemic
`Immunotherapy for
`Genitourinary Neoplasms (869-
`883), in Principles and Practice
`of Genitourinary Oncology
`(Raghavan et al. eds., 1997)
`("Sokoloff")
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`138, 139, 197, 206, 207,
`208, 209, 221
`
`201, 202, 204
`
`208
`
`122, 215, 216
`
`Cantley
`
`Kondo
`
`Morita
`
`Sokoloff
`
`xxii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 23 of 217
`
`

`

`Exhibit
`
`1101
`
`2003
`
`2004
`
`2005
`
`2006
`
`Description
`Motzer et al., Chemotherapy for
`Renal Cell Carcinoma (885-896)
`in Principles and Practice of
`Genitourinary Oncology
`(Raghavan et al. eds., 1997)
`("Motzer")
`
`Laughlin, E.H., Coming To
`Terms With Cancer: A Glossary
`Of Cancer-Related Terms, pages
`4, 126, 140, 173-174, 188-190
`(2002)
`
`Altman, R. & Sarg, M.J., The
`Cancer Dictionary, pages 51-52,
`278 (1992)
`
`Sutcliffe, S.B. &
`Gospodarowicz, M.K., Chapter
`25, “Primary Extranodal
`Lymphomas,” The Lymphomas
`(Canellos, G.P. et al. eds. 1998)
`
`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)
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`44, 45, 59, 85, 123, 125,
`126, 127, 132, 177, 179,
`228, 255, 298
`
`44, 50, 51, 52, 56, 57, 86
`
`49, 51, 103
`
`58, 83, 90
`
`44, 58, 59, 85, 164
`
`Motzer
`
`Laughlin
`
`Altman
`
`Sutcliffe 1998
`
`Pazdur
`
`xxiii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 24 of 217
`
`

`

`Exhibit
`
`2007
`
`2008
`
`2009
`
`2010
`
`Description
`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)
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`58
`
`Sutcliffe 1992
`
`Lynch, C.F. & Cohen, M.B.,
`“Urinary System,” Cancer 75(1
`Suppl.): 316-329 (1995)
`
`Lynch &
`Cohen
`
`55, 56, 106, 111
`
`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)
`
`Ligato
`
`Raghavan-
`Glenn
`
`56, 111
`
`205
`
`xxiv
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 25 of 217
`
`

`

`Exhibit
`
`2011
`
`2012
`
`2013
`
`2014
`
`Description
`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)
`
`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)
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`121, 210
`
`215, 221
`
`216
`
`130, 133, 134, 136, 212,
`218
`
`Raghavan-
`Hyland
`
`Vasey
`
`Kawai
`
`Adjei
`
`xxv
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 26 of 217
`
`

`

`Exhibit
`
`2015
`
`2016
`
`2023
`
`Description
`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)
`
`Penn, I. & Starzl, T.E.,
`“Immunosuppression And
`Cancer,” Transplant Proc. 5(1):
`943-947 (1973)
`
`Kozlowski, J.M. et al., Chapter
`78, “Renal Cell Carcinoma,
`Tumor Markers,” Principles And
`Practice Of Genitourinary
`Oncology (Raghavan, D., et al.
`eds. 1997)
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`213
`
`221
`
`45, 121, 177
`
`Gordon
`
`Penn & Starzl
`
`Kozlowski
`
`2027
`
`Pantuck Deposition Transcript,
`March 13, 2018
`
`Pantuck Tr.
`
`44, 119
`
`2028
`
`Truong, L., “The Diagnostic and
`Therapeutic Roles of Fine-
`Needle Aspiration,” Am. J. Clin.
`Pathol. 115:18-31 (2001)
`
`Truong
`
`44, 57, 59, 60, 85
`
`2029
`
`Hanahan, D., “The Hallmarks of
`Cancer,” Cell 100:57-70 (2000)
`
`Hanahan
`
`53, 135, 136
`
`xxvi
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 27 of 217
`
`

`

`Exhibit
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`Description
`Abbas, Z, “Renal lymphoma: an
`unusual cause of extrahepatic
`biliary obstruction,”
`Extrahepatic Biliary
`Obstruction, 617-618 (1996)
`
`“Genitourinary,” Steadman’s
`Medical Dictionary 738-739
`(27th ed. 2000)
`
`Braybrooke, J. “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)
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`60, 86
`
`106
`
`121, 126, 129
`
`Abbas
`
`Stedman’s
`
`Braybrooke
`
`“Proleukin® ,” Physicians’ Desk
`Reference® ,874-878 (47th ed.
`1993)
`
`Proleukin®
`PDR
`
`Yagoda, A., “Chemotherapy for
`Advanced Renal-Cell
`Carcinoma: 1983-1993,”
`Seminars Oncol. 22:42-60 1995
`
`Yagoda
`
`122
`
`126
`
`xxvii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 28 of 217
`
`

`

`Exhibit
`
`2035
`
`2036
`
`2037
`
`2038
`
`Description
`Figlin, R., “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):2521-2529 (1999)
`
`Motzer, R., “Phase III Trial of
`Interferon Alfa-2a With or
`Without 13-cis-Retinoic Acid
`for Patients With Advanced
`Renal Cell Carcinoma,” J Clin
`Oncol 18:2972-2980 (2000)
`
`Pagliaro, L., “A Phase II Trial of
`Bryostatin-1 for Patients with
`Metastatic Renal Cell
`Carcinoma,” Cancer 89:615-618
`(2000)
`
`Gollob, J., “Phase I Trial of
`Twice-Weekly Intravenous
`Interleukin 12 in Patients with
`Metastatic Renal Cell Cancer or
`Malignant Melanoma: Ability to
`Maintain IFN-y Induction Is
`Associated with Clinical
`Response,” Clin Cancer Res.
`6:1678-1692 (2000)
`
`Abbreviation
`
`Citation (Para. Nos.)
`
`128
`
`128
`
`130, 152, 184
`
`131, 179
`
`Figlin
`
`Motzer 2000
`
`Pagliaro
`
`Gollob
`
`xxviii
`
`NOVARTIS EXHIBIT 2092
`Breckenridge v. Novartis, IPR 2017-01592
`Page 29 of 217
`
`

`

`Exhibit
`
`2039
`
`Description
`Motzer, R., “Phase I Trial of
`Subcutaneous Recombinant
`Human Interleukin-12 in
`Patients with Advanced Renal
`Cell Carcinoma,” Clin Cancer
`Res. 4:1183-1191 (1998)
`
`2040
`
`2041
`
`2042
`
`Kandel, E., “The Regulation and
`Activities of the Multifunctional
`Serine/Theonine Kinase
`Akt/PKB,” Experimental Cell
`Research 253:210-229 (1999)
`
`Downward, J., “Mechanisms
`and consequences of activation
`of protein kinase B/Akt.” Curr.
`Opin. Cell Biol 10:262-267
`(1998)
`
`Se