`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01479
`
`Patent No. 9,006,224
`
`
`
`
`
`EXPERT DECLARATION OF DR. MATTHEW H. KULKE
`
`
`
`
`
`NOVARTIS EXHIBIT 2041
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`

`
`
`TABLE OF CONTENTS
`
`I.
`
`Qualifications ................................................................................................... 1
`
`II.
`
`Legal Principles ............................................................................................... 4
`
`III.
`
`Person Of Ordinary Skill In The Art ............................................................... 7
`
`IV. Summary Of Opinions ................................................................................... 10
`
`V.
`
`State Of The Art ............................................................................................. 14
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`In November 2005, PNETs And Carcinoid Tumors Were
`Known To Be Distinct Types Of Neuroendocrine Tumors ................ 14
`
`In November 2005, PNETs And Pancreatic
`Adenocarcinomas Were Known To Be Distinct Types Of
`Tumors Of The Pancreas ..................................................................... 22
`
`In November 2005, Advanced PNETs Were Known To
`Be More Aggressive And Harder To Treat After Failure
`Of Cytotoxic Chemotherapy ............................................................... 27
`
`In November 2005, Intracellular Signaling Pathways
`Were Known To Be Complex And Incompletely
`Understood .......................................................................................... 31
`
`In November 2005, The Role Of mTOR Inhibition In
`Cancer Treatment Was Uncertain ....................................................... 35
`
`In November 2005, It Was Not Reasonably Predictable
`Whether A Tumor Would Respond To mTOR Inhibition .................. 39
`
`In November 2005, The Etiology Of PNETs Was Poorly
`Understood .......................................................................................... 42
`
`1.
`
`2.
`
`Alterations To PTEN Would Not Have Suggested
`That PNETs Would Be Responsive To mTOR
`Inhibition ................................................................................... 45
`
`The PTEN Expression Data Reported In Wang
`Would Not Have Taught Or Suggested That
`
`i
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`
`
`PNETs Would Be Responsive To mTOR
`Inhibition ................................................................................... 47
`
`3.
`
`4.
`
`Dr. Ratain Has Provided No Evidence That PNETs
`Lacked Functional PTEN Expression ....................................... 48
`
`The Prior Art Suggested That Other Unknown
`Tumor-Suppressor Genes Could Be Involved In
`PNET Oncogenesis And Progression ....................................... 49
`
`VI. The ’224 Patent .............................................................................................. 51
`
`VII. Ground 1: Claims 1–3 Of The ’224 Patent Are Not Obvious
`Over Öberg 2004 In View Of Boulay 2004 And O’Donnell ........................ 56
`
`A. A POSA Would Have Considered Multiple Different
`Agents In Developing A Potential New PNET Therapy .................... 58
`
`B.
`
`Öberg 2004 Would Not Have Motivated A POSA To
`Select Rapamycin, Much Less Everolimus, To Treat
`Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy ..................................................................................... 63
`
`1.
`
`2.
`
`Öberg 2004 Would Not Have Motivated A POSA
`To Select Rapamycin ................................................................ 64
`
`Öberg 2004 Also Would Not Have Motivated A
`POSA To Select Everolimus ..................................................... 72
`
`C.
`
`Boulay 2004 Would Not Have Motivated A POSA To
`Select Everolimus Or Provided A Reasonable
`Expectation That Everolimus Would Be Effective To
`Treat Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy ..................................................................................... 74
`
`1.
`
`2.
`
`3.
`
`CA20948 Is Not A PNET Cell Line ......................................... 75
`
`CA20948 Is Not A Model For The Efficacy Of
`Everolimus To Treat PNETs ..................................................... 81
`
`Boulay 2004 Did Not Suggest That All mTOR
`Inhibitors Are Interchangeable ................................................. 89
`
`ii
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`
`
`D. O’Donnell Would Not Have Motivated A POSA To
`Select Everolimus Or Provided A Reasonable
`Expectation That Everolimus Would Be Effective To
`Treat Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy ..................................................................................... 91
`
`1.
`
`2.
`
`3.
`
`4.
`
`O’Donnell Did Not Teach Or Suggest That
`Everolimus Was Used To Treat Advanced PNETs
`After Failure Of Cytotoxic Chemotherapy ............................... 92
`
`O’Donnell Did Not Teach Or Suggest That
`Everolimus Was Effective To Treat All Tumors
`Disclosed ................................................................................... 93
`
`O’Donnell Did Not Teach Or Suggest That
`Everolimus Would Be Effective To Treat
`Advanced PNETs .................................................................... 100
`
`O’Donnell Did Not Teach Or Suggest That
`Everolimus Would Be Effective To Treat
`Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy ......................................................................... 107
`
`E.
`
`Claims 1–3 Of The ’224 Patent Are Not Obvious Over
`The Combination Of Öberg 2004, Boulay 2004, And
`O’Donnell .......................................................................................... 108
`
`VIII. Ground 2: Claim 2 Of The ’224 Patent Is Not Obvious Over
`Öberg 2004, Boulay 2004, And O’Donnell In View Of
`Tabernero ..................................................................................................... 111
`
`A.
`
`B.
`
`Tabernero Would Not Have Motivated A POSA Select
`Everolimus Or Provided A Reasonable Expectation That
`Everolimus Would Be Effective To Treat Advanced
`PNETs After Failure Of Cytotoxic Chemotherapy ........................... 113
`
`Claim 2 Of The ’224 Patent Is Not Obvious Over The
`Combination Of Öberg 2004, Boulay 2004, O’Donnell,
`And Tabernero ................................................................................... 120
`
`IX. Ground 3: Claims 1–3 Of The ’224 Patent Are Not Obvious
`Over Boulay 2004In View Of O’Donnell And Duran ................................ 121
`
`iii
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`
`
`A. Duran Did Not Teach Or Suggest That Temsirolimus
`Was Used To Treat Advanced PNETs After Failure Of
`Cytotoxic Chemotherapy ................................................................... 123
`
`B.
`
`C.
`
`Duran Did Not Teach Or Suggest That Temsirolimus
`Was Effective To Treat Advanced PNETs After Failure
`Of Cytotoxic Chemotherapy ............................................................. 126
`
`Duran Did Not Teach Or Suggest That Everolimus
`Would Be Effective To Treat Advanced PNETs After
`Failure Of Cytotoxic Chemotherapy ................................................. 131
`
`D. No Other Reference Cited In Connection With Ground 3
`Taught Or Suggested That Everolimus Would Be
`Effective To Treat Advanced PNETs After Failure Of
`Cytotoxic Chemotherapy ................................................................... 134
`
`E.
`
`F.
`
`Dr. Ratain’s Other Prior Art References Did Not Teach
`Or Suggest That Rapamycin And Its Derivatives Would
`Have Similar Anticancer Activity ..................................................... 137
`
`Claims 1–3 Of The ’224 Patent Are Not Obvious Over
`The Combination Of Boulay 2004, O’Donnell, And
`Duran ................................................................................................. 143
`
`X. Ground 4: Claim 2 Of The ’224 Patent Is Not Obvious Over
`Boulay 2004, O’Donnell, And Duran In View Of Tabernero ..................... 146
`
`XI. Claims 1–3 Of The ’224 Patent Are Not Obvious Over The
`Remaining Prior Art Relied On By Dr. Ratain............................................ 147
`
`XII. The Methods In Claims 1–3 Of The ’224 Patent Have
`Demonstrated Unexpected Results .............................................................. 156
`
`XIII. The Methods In Claims 1–3 Of The ’224 Patent Satisfied A
`Long-Felt Unmet Need For A New, Safe And Effective Method
`Of Treating Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy .............................................................................................. 164
`
`A.
`
`In November 2005, There Was A Long-Felt Unmet Need
`For A New, Safe And Effective Method Of Treating
`
`iv
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`
`
`Advanced PNETs After Failure Of Cytotoxic
`Chemotherapy ................................................................................... 165
`
`1.
`
`2.
`
`Therapies Were Available To Reduce Symptoms
`But These Therapies Were Rarely Effective To
`Treat Advanced PNETs .......................................................... 166
`
`Cytotoxic Chemotherapy Had Demonstrated
`Efficacy In Advanced PNETs But Was Toxic And
`Tumors Eventually Progressed ............................................... 167
`
`B.
`
`The Methods In Claims 1–3 Of The ’224 Patent Satisfied
`A Long-Felt Unmet Need For A New, Safe And
`Effective Method Of Treating Advanced PNETs After
`Failure Of Cytotoxic Chemotherapy ................................................. 172
`
`XIV. Others Tried And Failed To Develop New Methods Of Treating
`Advanced PNETs After Failure Of Cytotoxic Chemotherapy .................... 174
`
`XV. Conclusion ................................................................................................... 177
`
`
`
`
`
`v
`
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`
`
`LIST OF EXHIBITS
`
`Exhibit
`
`Description
`
`Abbreviation Paragraph(s)
`
`U.S. Patent No. 9,006,224, titled
`“Neuroendocrine Tumor Treatment”
`
`1001
`
`’224 Patent
`
`10, 20, 25, 32,
`38, 100-109,
`180, 185, 186,
`204, 205, 224,
`240, 245, 246,
`248, 261, 263,
`267, 279, 286
`
`1002
`
`File History for the ’224 patent
`
`
`
`137
`
`Declaration of Mark J. Ratain, M.D.
`in Support of Petition for Inter Partes
`Review of U.S. Patent No. 9,006,224
`
`1003
`
`Ratain
`
`20, 22, 23, 34,
`35, 38, 40, 41,
`52, 53, 70, 79,
`87, 88, 89 n.9,
`92, 95, 103
`n.10, 105,
`109, 110, 114-
`117, 122-126,
`129, 131, 135,
`136 n.13, 137,
`138, 142, 146-
`148, 153, 156,
`172, 174, 176,
`186, 187, 202,
`205, 206, 213,
`214, 220, 224-
`231, 235, 238,
`246, 248-251
`(n. 24, n.25),
`255, 257, 263,
`268, 270
`
`1004 Curriculum Vitae of Mark J. Ratain,
`M.D.
`
`
`
`
`
`vi
`
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`

`
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`Boulay, A., et al., “Antitumor Efficacy
`Of Intermittent Treatment Schedules
`With The Rapamycin Derivative
`RAD001 Correlates With Prolonged
`Inactivation Of Ribosomal Protein S6
`Kinase 1 In Peripheral Blood
`Mononuclear Cells,” Cancer Res. 64:
`252-261 (2004)
`
`Brown, E., et al., “A Mammalian
`Protein Targeted By G1-Arresting
`Rapamycin-Receptor Complex,”
`Nature 369: 756-758 (1994)
`
`Buetow, P. et al., “Islet Cell Tumors
`Of The Pancreas: Pathologic-Imaging
`Correlation Among Size, Necrosis and
`Cysts, Calcification, Malignant
`Behavior, And Functional Status,”
`Am. J. Roentgenology 165: 1175-1179
`(1995)
`
`“Center For Drug Evaluation &
`Research, Approval Package For NDA
`021083 (Rapamune),” Food & Drug
`Administration (Sept. 15, 1999)
`
`Dancey, J., “Clinical Development Of
`Mammalian Target Of Rapamycin
`Inhibitors,” Hematology/Oncology
`Clinics Of N. Am. 16: 1101-1114
`(2002)
`
`De Jong, M., et al., “Therapy Of
`Neuroendocrine Tumors With
`Radiolabeled Somatostatin-
`Analogues,” Q. J. Nuclear Med. &
`Molecular Imaging 43: 356-366
`(1999)
`
`vii
`
`Boulay
`
`28, 70, 79,
`109, 124, 131,
`135, 147, 148,
`153-155, 174,
`179, 180, 182-
`186, 204, 205,
`239-246, 251,
`264
`
`Brown
`
`231, 251
`
`Buetow
`
`34
`
`
`
`250
`
`Dancey
`
`De Jong
`
`89 n.9, 174,
`222, 235, 238,
`251, 252, 259
`n.28
`
`109, 131, 138-
`144 (n. 15),
`146, 147, 182,
`241
`
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`

`
`
`1011
`
`Duran, I., et al., “A Phase II Trial Of
`Temsirolimus In Metastatic
`Neuroendocrine Carcinomas
`(NECs),” Suppl. J. Clin. Oncol.
`23:3096 (2005)
`
`Duran
`
`30, 79, 205,
`206, 208-214,
`216-220, 223,
`239, 240, 243-
`246, 252, 264
`
`1012 Dutcher, J.P., “Mammalian Target Of
`Rapamycin Inhibition, “Clin. Cancer
`Res. 10: 6382s-6387s (2004)
`
`Dutcher
`
`251, 252, 259
`n.28
`
`1013
`
`1014
`
`1015
`
`1016
`
`Eng, C.P., et al., “Activity Of
`Rapamycin (AY-22,989) Against
`Transplanted Tumors,” J. Antibiotics
`37: 1231-1237 (1984)
`
`Grewe, M., et al., “Regulation Of
`Cell Growth And Cyclin D1
`Expression By The Constitutively
`Active FRAP-p70s6K Pathway In
`Human Pancreatic Cancer Cells,”
`Cancer Res. 59: 3581-3587 (1999)
`
`Guba, M. et al., “Rapamycin Inhibits
`Primary And Metastatic Tumor
`Growth By Antiangiogenesis:
`Involvement Of Vascular Endothelial
`Growth Factor,” Nature Med. 8(2):
`128-134 (2002)
`
`Hidalgo, M. et al., “The Rapamycin-
`Sensitive Signal Transduction
`Pathway As A Target For Cancer
`Therapy,” Oncogene 19: 6680-6686
`(2000)
`
`Eng
`
`74, 251
`
`Grewe
`
`136 n.13, 251
`
`Guba
`
`251
`
`Hidalgo
`
`68, 69, 73, 75,
`111, 174, 175,
`251-255
`
`viii
`
`NOVARTIS EXHIBIT 2041
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`

`

`
`
`1017
`
`1018
`
`1019
`
`1020
`
`Huang, S. et al., “Inhibitors Of
`Mammalian Target Of Rapamycin As
`Novel Antitumor Agents: From
`Bench To Clinic,” Current Opinion In
`Investigational Drugs 3(2): 295-304
`(2002)
`
`Huang, S. et al., “Rapamycins:
`Mechanism Of Action And Cellular
`Resistance,” Cancer Biol. & Ther.
`2(3): 222-232 (2003)
`
`Levy, M. & Wiersema, M.,
`“Pancreatic Neoplasms,”
`Gastrointestinal Endoscopy Clin. N.
`Am. 15: 117-142 (2005)
`
`Huang 2002
`
`76, 77, 80,
`249, 251, 252
`
`Huang 2003
`
`70, 76, 80,
`129, 174, 231,
`232, 251
`
`Levy
`
`53
`
`Kaltsas, G., et al., “The Diagnosis
`And Medical Management Of
`Advanced Neuroendocrine Tumors,”
`Endocrine Rev. 25(3): 458-511 (2004)
`
`Kaltsas
`
`35, 39, 40, 41,
`43, 45, 214,
`265 n.29
`
`1021 Martel, R., et al., “Inhibition Of The
`Immune Response By Rapamycin, A
`New Antifungal Antibiotic,” Can. J.
`Physiol. Pharmacol. 55: 48-51 (1977)
`
`1022 Morris, R., “Rapamycins: Antifungal,
`Antitumor, Antiproliferative, And
`Immunosuppressive Macrolides,”
`Transplantation Rev. 6: 39-87 (1992)
`
`1023
`
`Moertel, C., et al., “Streptozocin-
`Doxorubicin, Streptozocin-
`Fluorouracil, Or Chlorozotocin In
`The Treatment of Advanced Islet-Cell
`Carcinoma,” New Eng. J. Med.
`326(8): 519-523 (1992)
`
`Martel
`
`250
`
`Morris
`
`250
`
`Moertel
`
`37, 60, 61,
`107, 272, 274,
`276, 281
`
`ix
`
`NOVARTIS EXHIBIT 2041
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`

`
`
`1024
`
`1025
`
`1026
`
`Neshat, M., et al., “Enhanced
`Sensitivity Of PTEN-Deficient
`Tumors To Inhibition Of
`FRAP/mTOR,” PNAS 98(18): 10314-
`319 (2001)
`
`Öberg, K., “Chemotherapy And
`Biotherapy In The Treatment Of
`Neuroendocrine Tumours,” Ann.
`Oncol. 12(Suppl. 2): S111-S114
`(2001)
`
`Öberg, K., “Management Of
`Neuroendocrine Tumors,” Ann.
`Oncol. 15(Suppl. 4): iv293-iv298
`(2004)
`
`Neshat
`
`80, 251
`
`Öberg 2001
`
`45, 224, 226
`
`Öberg 2004b 116 n.12, 284
`
`1027
`
`Öberg, K., “Treatment Of
`Neuroendocrine Tumors Of The
`Gastrointestinal Tract,” Oncologia
`27(4): 57-61 (2004)
`
`Öberg 2004
`
`27, 42, 44, 46,
`109, 115-124,
`128-130, 179,
`180-186, 204,
`224, 225, 228,
`250
`
`1028
`
`Öberg, K. & Eriksson, B, “Endocrine
`Tumours Of The Pancreas,” Best
`Practice & Res. Clin. Gastroent.
`19(5): 753-781 (2005)
`
`Öberg &
`Eriksson
`
`86, 88-90, 96-
`98, 118, 120,
`224, 225, 276
`
`1029
`
`O’Donnell, A., et al., “A Phase I
`Study Of The Oral mTOR Inhibitor
`RAD001 As A Monotherapy To
`Identify The Optimal Biologically
`Effective Dose Using Toxicity,
`Pharmacokinetic (PK) And
`Pharmacodynamics (PD) Endpoints
`In Patients With Solid Tumors,”
`Proc. Am. Soc’y Of Clinical
`Oncology 22: 200(803ab) (2003)
`
`O’Donnell
`
`29, 79, 109,
`122, 124, 156-
`162 (n.16),
`165, 166, 169-
`172, 176-180,
`183-186, 202,
`204, 205, 235,
`240, 242-246,
`252, 264
`
`x
`
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`

`
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`O’Reilly, T., et al., “In Vivo Activity
`Of RAD001, An Orally Active
`Rapamycin Derivative, In
`Experimental Tumor Models,” Proc.
`Am. Ass’n Of Cancer Res. 43: 71
`(Abstract #359) (2002)
`
`Perren, A., et al., “Mutation And
`Expression Analyses Reveal
`Differential Subcellular
`Compartmentalization Of PTEN In
`Endocrine Pancreatic Tumors
`Compared To Normal Islet Cells,”
`Am. J. Pathology 157(4): 1097-1103
`(2000)
`
`Plöckinger, U., et al., “Guidelines For
`The Diagnosis And Treatment Of
`Neuroendocrine Gastrointestinal
`Tumours,” Neuroendocrinology 80:
`394-424 (2004)
`
`Rao, R.D., et al., “Mammalian Target
`Of Rapamycin (mTOR) Inhibitors As
`Anti-Cancer Agents,” Curr. Cancer
`Drug Targets 4(8): 621-635 (2004)
`
`Sawyers, C., “Will mTOR Inhibitors
`Make It As Cancer Drugs?,” Cancer
`Cell 4: 343-348 (2003)
`
`Schreiber, S., “Chemistry And
`Biology Of The Immunophilins And
`Their Immunosuppressive Ligands,”
`Science 251: 283-287 (1991)
`
`Schuler, W., et al., “SDZ RAD, A
`New Rapamycin Derivative:
`Pharmacological Properties In Vitro
`And In Vivo,” Transplantation 64(1):
`36-42 (1997)
`
`xi
`
`O’Reilly
`
`137, 252
`
`Perren
`
`86, 88-91, 95,
`97
`
`NET
`Guidelines
`
`45
`
`Rao
`
`76, 77, 82,
`251, 252
`
`Sawyers
`
`251
`
`Schreiber
`
`231, 232
`
`Schuler
`
`233, 238, 250
`
`NOVARTIS EXHIBIT 2041
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`

`
`
`1037
`
`1038
`
`Tolcher, A., “Novel Therapeutic
`Molecular Targets For Prostate
`Cancer: The mTOR Signaling
`Pathway And Epidermal Growth
`Factor Receptor,” J. Urology 171:
`S41-S44 (2004)
`
`Tabernero, J., et al., “A Phase I Study
`With Tumor Molecular
`Pharmacodynamic (MPD) Evaluation
`Of Dose And Schedule Of The Oral
`mTOR-Inhibitor Everolimus
`(RAD001) In Patients (pts) With
`Advanced Solid Tumors,” J. Clin.
`Oncol. 23:3007 (2005)
`
`Tolcher
`
`113, 251, 259
`n.28
`
`Tabernero
`
`29, 186-198
`(n.21), 200,
`202-204, 246,
`252, 264
`
`1039
`
`Vignot, S., et al., “mTOR-Targeted
`Therapy Of Cancer With Rapamycin
`Derivatives,” Ann. Oncol. 16: 525-
`537 (2005)
`
`Vignot
`
`75, 76, 80, 81,
`85, 113, 174,
`231, 232, 251,
`252
`
`1040 U.S. Patent No. 3,929,992
`
`’992 Patent
`
`250
`
`1041 U.S. Patent No. 4,650,803
`
`’803 Patent
`
`250
`
`1042 U.S. Patent No. 4,885,171
`
`’171 Patent
`
`251
`
`1043 U.S. Patent No. 5,100,883
`
`’883 Patent
`
`250
`
`1044 U.S. Patent No. 5,206,018
`
`’018 Patent
`
`251
`
`1045 U.S. Patent No. 5,233,036
`
`’036 Patent
`
`250
`
`1046 U.S. Patent No. 5,362,718
`
`’718 Patent
`
`250 (n.25)
`
`xii
`
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`

`
`
`1047 U.S. Patent No. 5,391,730
`
`’730 Patent
`
`250
`
`1048 U.S. Patent No. 5,665,772
`
`’772 Patent
`
`250
`
`1049 U.S. Patent No. 7,091,213
`
`’213 Patent
`
`250
`
`1050 U.S. Patent No. 8,410,131
`
`’131 Patent
`
`251
`
`1051
`
`1052
`
`Wang, L., et al., “Differential
`Expression Of The PTEN Tumor
`Suppressor Protein In Fetal And
`Adult Neuroendocrine Tissues And
`Tumors: Progression Loss Of PTEN
`Expression In Poorly Differentiated
`Neuroendocrine Neoplasms,” Applied
`Immunohistochemistry & Molecular
`Morphology 10(2): 139-146 (2002)
`
`Wiedenmann, B. & Pape, U., “From
`Basic To Clinical Research In
`Gastroenteropancreatic
`Neuroendocrine Tumor Disease—The
`Clinician-Scientist Perspective,”
`Neuroendocrinology 80(Suppl. 1): 94-
`98 (2004)
`
`Wang
`
`41, 42, 92, 93,
`211
`
`Wiedenmann
`
`22, 40, 46,
`111, 115, 116,
`124-129
`
`1053 WO 97/47317
`
`Weckbecker
`
`251
`
`WO 02/40000
`
`1054
`
`Dukart
`
`211 (n.22),
`251, 252, 255-
`257, 259
`(n.27)
`
`1055 WO 02/066019
`
`Lane
`
`251
`
`xiii
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 14 of 216
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Clements
`
`O’Toole
`
`224, 227, 276,
`282
`
`
`
`1056
`
`1057
`
`1058
`
`Excerpt From The File History Of
`U.S. Application No. 14/608,644,
`Information Disclosure Statement
`(April 1, 2015)
`
`Excerpt From The File History Of
`U.S. Application No. 14/608,644,
`Office Action (December 18, 2015)
`
`Dr. Kjell Öberg, Web Bio, Uppsala
`University, available at
`http://katalog.uu.se/empinfo?language
`Id=1&id=n96-5147, visited June 26,
`2015
`
`
`
`
`
`Öberg
`Biography
`
`1059
`
`“What is ENETS?,” available at
`http://www.enets.org/what_is_enets.h
`tml, visited June 26, 2015
`
`ENETS Info
`
`1060
`
`Sandostatin LAR® Prescribing Label
`(November 1998)
`
`1061 Declaration Of Scott Bennett, Ph.D.
`
`
`
`
`
`1062
`
`1063
`
`Clements, D., et al., “Regression Of
`Metastatic Vipoma With Somatostatin
`Analogue SMS 201-995,” Lancet 874-
`875 (1985)
`
`O’Toole, D., et al., “Chemotherapy
`For Gastro-Enteropancreatic
`Endocrine Tumours”
`Neuroendocrinology 80(Suppl. 1):
`79-84 (2004)
`
`xiv
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 15 of 216
`
`

`

`Jimeno
`
`252 n.26
`
`1064
`
`Jimeno, A., et al.,
`“Pharmacodynamic-Guided,
`Modified Continuous Reassessment
`Method (mCRM)-Based, Dose
`Finding Study Of Rapamycin In
`Adult Patients With Solid Tumors,” J.
`Clin. Oncol. 24(18S): 3020 (2006)
`
`
`
`
`
`
`
`xv
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 16 of 216
`
`

`

`
`
`Exhibit
`
`Description
`
`Abbreviation Paragraph(s)
`
`2001
`
`Expert Declaration Of Matthew H.
`Kulke, M.D., M.M.Sc. (November
`18, 2016)
`
`Kulke Decl.
`
`2002
`
`Curriculum Vitae of Matthew H.
`Kulke, M.D., M.M.Sc. (May 20,
`2016)
`
`Kulke C.V.
`
`
`
`
`
`2003
`
`Seeley, R. R., Stephens, T.D., & Tate,
`P., Anatomy & Physiology, 3rd
`Edition, pages 585 – 586 (1995)
`
`Seeley
`
`50
`
`2004
`
`Reserved
`
`
`
`2005
`
`Laughlin, E.H., Coming To Terms
`With Cancer: A Glossary Of Cancer-
`Related Terms, page 4 (2002)
`
`Laughlin
`Cancer
`Glossary
`
`2006
`
` Reserved
`
`2007
`
` Reserved
`
`2008
`
`Motzer, R.J. & Russo, P., “Systemic
`Therapy For Renal Cell Carcinoma,”
`J. Urology 163:408-417 (2000)
`
`2009
`
` Reserved
`
`
`
`
`
`Motzer
`
`
`
`
`
`38
`
`
`
`
`
`191
`
`
`
`xvi
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 17 of 216
`
`

`

`
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`Pazdur, R., et al. (eds.), Chapters 6,
`11, 14-16, 19, 25, Cancer
`Management: A Multidisciplinary
`Approach: Medical, Surgical, &
`Radiation Oncology, 9th Edition
`(2005)
`
`Kouvaraki, M.A. et al., “Fluorouracil,
`Doxorubicin, And Streptozocin In
`The Treatment Of Patients With
`Locally Advanced And Metastatic
`Pancreatic Endocrine Carcinomas,” J.
`Clin. Oncol. 22(23):4762-4771
`(2004)
`
`Delaunoit, Th., et al., “The
`Doxorubicin-Streptozotocin
`Combination For The Treatment Of
`Advanced Well-Differentiated
`Pancreatic Endocrine Carcinoma: A
`Judicious Option?,” Eur. J. Cancer
`40:515-520 (2004)
`
`Kulke, M.H., Chapter 110,
`“Neuroendocrine Cancer,” Clinical
`Hematology and Oncology:
`Presentation, Diagnosis and
`Treatment (Furie, B., et al. eds. 2003)
`
`Pazdur
`
`45, 56, 158,
`170, 199, 270,
`271, 272
`
`Kouvaraki
`
`54, 63 (n.6),
`107, 161 n.18,
`271 n.31, 273,
`274, 281
`
`Delaunoit
`
`62, 107, 281
`
`Kulke 2003a
`
`35, 43, 213,
`270
`
`Kulke, M.H. et al., “A Phase II Trial
`Of Gemcitabine For Metastatic
`Neuroendocrine Tumors,” Cancer
`101(5): 934-939 (2004)
`
`Kulke 2004
`
`56, 168, 215,
`216, 270, 272-
`274, 282, 284
`
`xvii
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 18 of 216
`
`

`

`
`
`2015
`
`2016
`
`Margolin, K. et al., “CCI-779 In
`Metastatic Melanoma: A Phase II
`Trial Of The California Cancer
`Consortium,” Cancer 104(5): 1045-
`1048 (2005)
`
`“Novartis Drug Afinitor Is First
`Treatment For Advanced Pancreatic
`NET To Provide Overall Survival Of
`More Than 3.5 Years In Phase III
`Trial,” Novartis Institutes For
`Biomedical Research (September 27,
`2014)
`
`Margolin
`
`71, 83, 162,
`
`Novartis
`Press Release
`
`261
`
`2017
`
`Ritschel, W.A., Handbook of Basic
`Pharmacokinetics, 4th Edition, pages
`6-7, 264-267 (1992)
`
`Ritschel
`
`221, 235
`
`2018
`
`Heitz, Ph.U., et al., Chapter 4,
`“Tumours Of The Endocrine
`Pancreas,” World Health
`Organization Classification of
`Tumours, Pathology and Genetics,
`Tumours of Endocrine Organs, pages
`177-182 (DeLellis, R.A. et al., eds.
`2004)
`
`WHO 2004
`
`34, 53, 55, 86,
`97
`
`2019
`
`Physicians’ Desk Reference, 59th
`Edition (2005), pages 1844-1849
`(Entry for Gemzar® (Gemcitabine
`HCl))
`
`Gemzar®
`Prescribing
`Information
`2005
`
`
`
`2020
`
`Kulke, M.H. & Mayer, R.J.,
`“Carcinoid Tumors,” N. Eng. J. Med.
`340(11): 858-868 (1999)
`
`Kulke 1999
`
`41
`
`xviii
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 19 of 216
`
`

`

`
`
`2021
`
`Gennaro, A.R. (Ed.), Remington’s,
`18th Edition, pages 726-730 (1990)
`
`Remington’s
`
`221, 235
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`Yao, J.C. et al., “Everolimus For
`Advanced Pancreatic Neuroendocrine
`Tumors,” N. Eng. J. Med. 364(6):
`514-523 (2011)
`
`Yao 2011
`
`260-263, 265
`n.30
`
`Kola, I. & Landis, J., “Can The
`Pharmaceutical Industry Reduce
`Attrition Rates?,” Nat. Rev. Drug
`Discov., 3:711-715 (2004)
`
`Kola &
`Landis
`
`164, 266
`
`Excerpts of Transcript of Trial
`Testimony of M. Ratain, Pfizer Inc. et
`al. v. Mylan Pharms. Inc., (C.A. No.
`10-528-GMS), (D. Del. November
`29, 2012), Pages 778-79, 950, 995
`
`Ratain Trial
`Tr. I
`
`Excerpts of Transcript of Trial
`Testimony of M. Ratain, Novartis v.
`Breckenridge, Roxane and Par (C.A.
`Nos. 14-1043-RGA, 14-1196-RGA
`and 14-1289-RGA) (D. Del. August
`31, 2016), Pages 769-772, 957, 993-
`94, 1003, 1010, 1012, 1014
`
`Excerpts of Transcript of Deposition
`of M. Ratain, Novartis v.
`Breckenridge, Roxane and Par (C.A.
`Nos. 14-1043-RGA, 14-1196-RGA
`and 14-1289-RGA) (D. Del. Apr. 11,
`2016), Pages 1-5, 34, 156, 340
`
`Ratain Trial
`Tr. II
`
`Ratain Dep.
`Tr. I
`
`
`
`
`
`
`
`xix
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 20 of 216
`
`

`

`
`
`2027
`
`Dancey, J.E., “Inhibitors Of The
`Mammalian Target Of Rapamycin,”
`Expert Opin. Investig. Drugs 14(3):
`313-328 (2005)
`
`Dancey 2005
`
`69, 70, 73, 74,
`175, 221, 222,
`235
`
`Duran, I, et al., “A Phase II Clinical
`And Pharmacodynamic Study Of
`Temsirolimus In Advanced
`Neuroendocrine Carcinomas,” British
`J. of Cancer 95(9): 1148-1154
`(2006)
`
`Declaration of Nicholas N. Kallas
`Regarding Exhibits 2016, 2022, And
`2028
`
`2028
`
`2029
`(served
`but not
`filed)
`
`2030
`(served
`but not
`filed)
`
`The New England Journal of
`Medicine, Publication Process,
`available at
`http://www.nejm.org/page/media-
`center/publication-process
`
`2031
`(served
`but not
`filed)
`
`British Journal of Cancer, Aims and
`Scope, available at
`http://www.nature.com/bjc/about/aim
`s_scope.html
`
`2032
`(served
`but not
`filed)
`
`Transcript of Trial Testimony of M.
`Ratain, Pfizer Inc. et al. v. Mylan
`Pharms. Inc., (C.A. No. 10-528-
`GMS), (D. Del. November 29, 2012)
`
`Duran 2006
`
`219, 265
`(n.29, n.30)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`xx
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 21 of 216
`
`

`

`
`
`2033
`(served
`but not
`filed)
`
`Transcript of Trial Testimony of M.
`Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-
`RGA) (D. Del. August 31, 2016)
`
`2034
`(served
`but not
`filed)
`
`Transcript of Deposition of M.
`Ratain, Novartis v. Breckenridge,
`Roxane and Par (C.A. Nos. 14-1043-
`RGA, 14-1196-RGA and 14-1289-
`RGA) (D. Del. Apr. 11, 2016)
`
`Declaration Of Julie Masow Pursuant
`to Fed. R. Evid. 902(11)
`
`2035
`(served
`but not
`filed)
`
`2036
`
`
`
`
`
`
`
`
`
`
`
`
`
`Physicians’ Desk Reference, 58th
`Edition (2004), pages 1812-1817
`(Entry for Gemzar®(Gemcitabine
`HCl))
`
`2004 PDR
`
`56, 168
`
`2037
`
`2038
`
`Declaration in Support of Patent
`Owner
`Novartis’s Motion for Pro Hac Vice
`Admission of Charlotte Jacobsen
`Under
`37 C.F.R. § 42.10
`
`Longnecker, D.S. et al.,
`“Transplantation of Azaserine-
`Induced Carcinomas Of Pancreas In
`Rats,” Cancer Letters, 7:197-202
`(1979)
`
`
`
`
`
`Longnecker
`1979
`
`132, 133, 139
`
`xxi
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 22 of 216
`
`

`

`
`
`2039
`
`Longnecker, D.S. & Curphey,T.J.,
`“Adenocarcinoma Of The Pancreas In
`Azaserine-Treated Rats,” Cancer
`Res., 35:2249-2258 (1975)
`
`Longnecker
`1975
`
`134-136
`
`2040
`
`Transcript Of The April 17, 2017
`Deposition Of Mark J. Ratain
`
`Ratain Tr.
`
`
`
`
`
`Kulke
`
`Kulke 2017
`C.V.
`
`24
`
`Adjei
`
`66, 67, 69,
`111-113
`
`Expert Declaration Of Matthew H.
`Kulke, M.D., M.M.Sc. (May 11,
`2017)
`
`Curriculum Vitae of Matthew H.
`Kulke, M.D., M.M.Sc. (February 1,
`2017)
`
`Adjei, A.A., “Signal Transduction
`Pathway Targets For Anticancer Drug
`Discovery,” Current Pharm. Design
`6(4): 361-378 (2000)
`
`2041
`
`2042
`
`2043
`
`2044
`
`2045
`
`2046
`
`Afinitor® FDA Supplemental
`Approval Letter To Novartis
`Pharmaceuticals Corporation, dated
`May 5, 2011
`
`Afinitor®
`Supp.
`Approval
`Letter
`
`260
`
`Ansell, S.M., et al., “A Phase II Study
`Of High-Dose Paclitaxel In Patients
`With Advanced Neuroendocrine
`Tumors,” Cancer 91(8): 1543-48
`(2001)
`
`Ansell, S.M., et al., “Topotecan In
`Patients With Advanced
`Neuroendocrine Tumors: A Phase II
`Study With Significant Hematologic
`Toxicity,” Am. J. Clin. Oncol. 27(3):
`232-235 (2004)
`
`Ansell 2001
`
`45, 47, 168,
`215, 276, 283
`
`Ansell 2004
`
`47, 215, 275,
`276, 283
`
`xxii
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 23 of 216
`
`

`

`
`
`2047
`
`2048
`
`2049
`
`2050
`
`2051
`
`2052
`
`Bajetta, E., et al., “Treatment Of
`Metastatic Carcinoids And Other
`Neuroendocrine Tumors With
`Recombinant Interferon-Alpha-2a,”
`Cancer 72(10): 3099-3105 (1993)
`
`Bakker, W.H., et al., “In Vivo
`Application Of [111In-DTPA-D-Phe1]-
`Octreotide For Detection Of
`Somatostatin Receptor-Positive
`Tumors In Rats,” Life Sciences
`49(22): 1593-1601 (1991)
`
`Carr, K., et al., “A Phase II Trial Of
`Imatinib In Patients With Advanced
`Carcinoid Tumor,” J. Clin. Oncol.,
`ASCO Procs. 22: 14S (Abs. 4124)
`(July 15 Supplement) (2004)
`
`Chang, S.M., et al., “Phase II Study
`Of CCI-779 In Patients With
`Recurrent Gliobstaoma Multiforme,”
`Investig. New Drugs 23(4): 357-361
`(2005)
`
`Cheng, J.Q., et al., “The Akt/PKB
`Pathway: Molecular Target For
`Cancer Drug Discovery,” Oncogene
`24: 7482-7492 (2005)
`
`Creaven, P.J. & Raghavan, D.,
`Chapter 8, “Principles Of
`Chemotherapy For Genitourinary
`Cancer: Implications For
`Development Of New Anticancer
`Drugs,” Principles And Practice Of
`Genitourinary Oncology (Raghavan,
`D., et al. eds. 1997)
`
`xxiii
`
`Bajetta
`
`41
`
`Bakker
`
`150
`
`Carr
`
`123
`
`Chang
`
`69, 71, 72, 76,
`82, 167
`
`Cheng
`
`111
`
`Creaven
`
`160 n.17, 221
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 24 of 216
`
`

`

`
`
`2053
`
`2054
`
`2055
`
`2056
`
`2057
`
`Doran, H., et al., Chapter 1,
`“Epidemiology Of Pancreatic
`Neuroendocrine Tumours,”
`Pancreatic Disease: Basic Science
`And Clinical Management (Johnson,
`C.D. & Imrie, C.W. eds. 2004)
`
`Guidance For Industry: Clinical Trial
`Endpoints For The Approval Of
`Cancer Drugs And Biologics, US
`Department Of Health And Human
`Services, FDA 1-19 (May 2007),
`available at
`http://www.fda.gov/downloads/Drugs/
`.../Guidances/ucm071590.pdf
`(accessed 12/9/2016)
`
`Foster, B.J., et al., “A Strategy For
`The Development Of Two Clinically
`Active Cisplatin Analogs: CBDCA
`And CHIP,” Cancer Chemotherapy
`Pharmacology 25: 395-404 (1990)
`
`Hidalgo, M., et al., “A Phase I And
`Pharmacokinetic Study Of
`Temsirolimus (CCI-779)
`Administered Intravenously Daily For
`5 Days Every 2 Weeks To Patients
`With Advanced Cancer,” Clinical
`Cancer Res. 12(19): 5755-5763
`(2006)
`
`Jacobsen, W., et al., “Comparison Of
`The In Vitro Metabolism Of The
`Macrolide Immunosuppressants
`Sirolimus And RAD,” Transplant.
`Procs. 33: 514-515 (2001)
`
`xxiv
`
`Doran
`
`34, 43, 52, 54,
`85, 86
`
`FDA
`Guidance
`
`265 n.29
`
`Foster
`
`62, 223
`
`Hidalgo 2006
`
`259 n.27
`
`Jacobsen
`
`236
`
`NOVARTIS EXHIBIT 2041
`Par v. Novartis, IPR2016-01479
`Page 25 of 216
`
`

`

`
`
`2058
`
`2059
`
`Kokkinakis, D.M., et al., “Role Of
`O6-Methylguanine-DNA
`Methyltransferase In The Resistance
`Of Pancreatic Tumors To DNA
`Alkylating Agents,” Cancer Research
`57: 5360-5368 (1997)
`
`Kulke, M.H., “Recent Developments
`In The Pharmacological Treatment Of
`Advanced Pancreatic Cancer,” Expert
`Opin. Investig. Drugs 12(6): 983-992
`(2003)
`
`Kokkinakis
`
`52, 136 n.13
`
`Kulke 2003b
`
`56
`
`2060
`
`Laughlin, E.H., Coming To Terms
`With Cancer: A Glossary Of Cancer-
`Related Terms, pages 157-159 (2002)
`
`Laughlin
`Cancer
`Glossary
`
`81 n.7
`
`2061
`
`2062
`
`2063
`
`2064
`
`Marx, J., “Encouraging Results For
`Second-Generation Antiangiogenesis
`Drugs,” Science 308: 1248-1249
`(2005)
`