Paper No. __
`Date Filed: October 27, 2017
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`PAR PHARMACEUTICAL, INC.,
`ARGENTUM PHARMACEUTICAL LLC, AND
`WEST-WARD PHARMACEUTICALS
`INTERNATIONAL LIMITED,
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`
`
`Case IPR2016-014791
`Patent No. 9,006,224
`
`
`
`PATENT OWNER’S DEMONSTRATIVE
`EXHIBITS FOR ORAL HEARING
`
`
`1 Argentum Pharmaceutical LLC was joined as a party to this proceeding via a
`Motion for Joinder in IPR2017-01063; West-Ward Pharmaceuticals International
`Limited was joined as a party via a Motion for Joinder in IPR2017-01078.
`
`
`
`
`
`
`Date Filed: October 27, 2017
`
`Filed On Behalf Of:
`Novartis AG
`
`By:
`Nicholas N. Kallas
`NKallas@fchs.com
`ZortressAfinitorIPR@fchs.com
`(212) 218-2100
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`PAR PHARMACEUTICAL, INC.,
`ARGENTUM PHARMACEUTICAL LLC, AND
`WEST-WARD PHARMACEUTICALS
`INTERNATIONAL LIMITED,
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`Patent Owner.
`
`
`
`Case IPR2016-014791
`Patent No. 9,006,224
`
`
`
`PATENT OWNER’S DEMONSTRATIVE
`EXHIBITS FOR ORAL HEARING
`
`
`1 Argentum Pharmaceutical LLC was joined as a party to this proceeding via a
`Motion for Joinder in IPR2017-01063; West-Ward Pharmaceuticals International
`Limited was joined as a party via a Motion for Joinder in IPR2017-01078.
`
`
`
`
`
`
`
``
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`PAR PHARMACEUTICAL, INC.,
`ARGENTUM PHARMACEUTICAL LLC, AND
`WEST-WARD PHARMACEUTICALS
`INTERNATIONAL LIMITED
`Petitioners,
`
`v.
`
`NOVARTIS AG
`Patent Owner.
`
`
`IPR2016-01479
`
`U.S. Patent No. 9,006,224
`
`PATENT OWNER’S DEMONSTRATIVE
`EXHIBITS FOR ORAL HEARING
`
`November 1, 2017
`
`1
`
`
`
`Claims 1-3 Are Limited To Treating Advanced
`PNETs After Failure Of Cytotoxic Chemotherapy
`Paper 17 at 10
`
`Neuroendocrine
`tumors (NETs)
`
`Carcinoid tumors
`
`PNETs
`
`Benign carcinoid
`tumors
`
`Malignant
`carcinoid tumors
`(carcinomas)
`
`Benign PNETs
`
`Malignant
`PNETs
`(carcinomas)
`
`Localized
`carcinoid tumors
`
`Advanced
`carcinoid tumors
`(i.e., locally
`advanced,
`metastatic or
`unresectable)
`
`Localized PNETs
`
`Advanced
`PNETs (i.e.,
`locally
`advanced,
`metastatic or
`unresectable)
`
`Prior to failure of
`cytotoxic
`chemotherapy
`
`After failure of
`cytotoxic
`chemotherapy
`
`Prior to failure of
`cytotoxic
`chemotherapy
`
`After failure of
`cytotoxic
`chemotherapy
`
`Ex. 1001 at 26:66-27:8
`
`2
`
`
`
`Petitioners’ Prior Art Combinations
`
`Paper 17 at 1-4
`
`Ground
`
`References
`
`Challenged
`Claims
`
`1
`
`2
`
`3
`
`4
`
`Öberg 2004, Boulay 2004, and
`O’Donnell
`
`Öberg 2004, Boulay 2004, O’Donnell,
`and Tabernero
`
`Boulay 2004, O’Donnell, and Duran
`
`Boulay 2004, O’Donnell, Duran, and
`Tabernero
`
`1-3
`
`2
`
`1-3
`
`2
`
`Paper 8 at 4-5; see also Paper 1 at 4
`
`3
`
`
`
`Petitioners’ Grounds 1-4 Rely On Boulay 2004
`
`Paper 17 at 42-48, 56-59
`
`Ground
`
`References
`
`Challenged
`Claims
`
`1
`
`2
`
`3
`
`4
`
`Öberg 2004, Boulay 2004, and
`O’Donnell
`
`Öberg 2004, Boulay 2004, O’Donnell,
`and Tabernero
`
`Boulay 2004, O’Donnell, and Duran
`
`Boulay 2004, O’Donnell, Duran, and
`Tabernero
`
`1-3
`
`2
`
`1-3
`
`2
`
`Paper 8 at 4-5; see also Paper 1 at 4
`
`4
`
`
`
`The Petition Wrongly Claimed CA20948 Was A PNET
`
`Paper 17 at 30-32; Paper 26 at 1
`
`“Specifically, Boulay 2004 reported that administering
`everolimus as a monotherapy to rats injected with
`pancreatic NET tumor cells showed statistically
`significant antitumor activity….”
`
`Paper 1, Petition at 9.
`
`“Boulay 2004 also disclosed the use of everolimus as a
`monotherapy in treating rats with CA20948 tumors, which
`are a specific line of pancreatic NETs used in laboratory
`studies.”
`
`Paper 1, Petition at 32-33.
`
`5
`
`
`
`The Petition Wrongly Claimed CA20948 Was A PNET
`
`Paper 17 at 31; Paper 26 at 1
`
`Dr. Ratain:
`
`Q. … So we’re agreeing that there’s no indication in
`[Longnecker 1979] that [CA20948] arose from a
`pancreatic neuroendocrine tumor cell, correct?
`
`A. I never said that it did.
`
`Ex. 2040, Ratain Tr. at 329:7-11.
`
`See also Ex. 2041, Kulke ¶¶ 132-134
`
`6
`
`
`
`CA20948 Was Not A Model For
`Drugs Against The Claimed PNETs
`Paper 17 at 30-38; Paper 26 at 1-2; Paper 35 at 6-8; Paper 43 at 4-5
`
`
`
`1. A POSA would not extrapolate results from the CA20948
`pancreatic adenocarcinoma cell line to PNETs.
`
`2. Petitioners’ assertion that CA20948 was a model for PNETs
`is procedurally improper and unsupported by the record.
`
`3. CA20948 was not a model for advanced PNETs after failure
`of cytotoxic chemotherapy.
`
`Ex. 2041, Kulke ¶ 131
`
`7
`
`
`
`CA20948 Was A Pancreatic Adenocarcinoma Cell Line
`
`Paper 17 at 31
`
`“Two pancreatic adenocarcinomas which had been
`induced in Wistar/Lewis rats by azaserine treatment were
`transplanted into rats….”
`
`Ex. 2038, Longnecker 1979 at Summary.
`
`Ex. 2041, Kulke ¶ 132; Ex. 2040, Ratain Tr. at 325:15-326:16
`
`8
`
`
`
`CA20948 Was Not A PNET Model
`
`Paper 17 at 30-32
`
`“These results demonstrate that RAD001 is a well-
`tolerated antitumor agent in a rat model of pancreatic
`cancer….”
`
`Ex. 1005, Boulay 2004 at 254.
`
`Ex. 2041, Kulke ¶ 131; Ex. 2040, Ratain Tr. at 42:3-18
`
`9
`
`
`
`The Prior Art Did Not Reasonably
`Suggest That CA20948 Was A PNET Model
`Paper 17 at 31, 33
`
`Tumor Type CA20948 was a pancreatic adenocarcinoma
`(exocrine), not a PNET (endocrine)
`
`Biology
`
`Origin
`
`CA20948 expressed enzymes secreted by exocrine
`cells, not hormones secreted by PNETs
`
`CA20948 tumor was induced by azaserine treatment
`in rats, not a spontaneously occurring tumor in humans
`
`Predictive
`Value
`
`CA20948 did not simulate most spontaneously
`occurring human tumors of the pancreas
`
`“[I]t is clear that [azaserine-induced] carcinogenesis in rat
`pancreas does not simulate the majority of
`spontaneously occurring human neoplasms, which
`appear to be ductal.”
`
`Ex. 2039, Longnecker 1975 at 2253.
`
`Ex. 2038 at 197, 201; Ex. 2039 at 2253; Ex. 2041, Kulke ¶¶ 132-136; Ex. 2040, Ratain Tr. at 17:13-15, 37:15-19, 39:9-12, 324:4-15
`
`10
`
`
`
`A POSA Would Not Reasonably Predict Efficacy In
`PNETs Based On Pancreatic Adenocarcinoma Results
`Paper 17 at 11-12, 32
`
`Differences
`
`PNETs
`
`Pancreatic Adenocarcinomas
`
`Origin
`
`Endocrine pancreas cells
`(Ex. 2053, Doran at 5)
`
`Exocrine pancreas cells
`(Ex. 2095, WHO 2000 at 220-21)
`
`Incidence Uncommon: 1-2% of tumors
`of the pancreas
`(Ex. 2018, WHO 2004 at 177)
`
`Vast majority of tumors of the
`pancreas (Ex. 2040, Ratain Tr. at
`39:19-23, 40:5-11)
`
`Clinical
`Behavior
`
`Indolent or slow-growing
`(Ex. 2011, Kouvaraki at 4763)
`
`Aggressive, fast-growing
`(Ex. 2095, WHO 2000 at 219, 243)
`
`Molecular
`Genetics
`
`Response
`To
`Therapies
`
`“[T]he common genetic mutations identified in pancreatic ductal
`adenocarcinomas ... [were] not found in [PNETs].”
`(Ex. 2018, WHO 2004 at 181)
`
`“[L]ittle evidence of
`efficacy” of gemcitabine in a
`Phase II study
`(Ex. 2014, Kulke 2004 at 937)
`
`Treated with cytotoxic
`chemotherapy gemcitabine
`(Ex. 2036, 2004 PDR at 1814)
`
`Ex. 2041, Kulke ¶¶ 50-56, 135
`
`11
`
`
`
`A POSA Would Not Reasonably Predict Efficacy In
`PNETs Based On Pancreatic Adenocarcinoma Results
`Paper 17 at 32
`
`Dr. Ratain:
`
`Q. And would a person of ordinary skill in the art have expected
`the different diseases to respond differently to drugs?
`
`A. I think that one would not extrapolate results from one
`disease to the other.
`
`Q. And when you say “one disease to the other,” you mean
`pancreatic adenocarcinoma to PNET or PNET to pancreatic
`adenocarcinoma?
`
`A. Yes.
`
`Ex. 2040, Ratain Tr. at 51:10-21.
`
`See also Ex. 2041, Kulke ¶¶ 135-136
`
`12
`
`
`
`De Jong Used CA20948 To Test The Effect Of
`Radiation On A Somatostatin Receptor-Positive Cell Line
`Paper 17 at 33
`
`“[De Jong 1999] investigated the radiotherapeutic effect
`of [radioactive somatostatin analogs] in Lewis rats bearing
`the somatostatin receptor-positive rat pancreatic tumor
`CA20948….”
`
`Ex. 1010, De Jong at Abstract.
`
`“The success of the therapeutic strategy relies upon the
`amount of radioligand, which can be concentrated
`within tumor cells….”
`
`Ex. 1010, De Jong at 357.
`
`Ex. 2041, Kulke ¶¶ 138-139; Ex. 2040, Ratain Tr. at 113:12-16
`
`13
`
`
`
`Contrary To Dr. Ratain’s Opinion, A POSA
`Could Interpret De Jong’s Preclinical Results
`Paper 17 at 34
`
`Dr. Ratain:
`
`Q. … Can you read the flank model and tell me whether or not a
`person of ordinary skill in the art would understand that they compared
`the effects of radioactive somatostatin analog with unlabeled
`somatostatin analog.
`
`A. I think a person of ordinary skill, as I’ve defined it, wouldn’t have
`any opinion on the details of what was done here.
`
`A person of ordinary skill could interpret the clinical results, but
`not the preclinical results, and their interpretation of the preclinical
`results would be limited to whatever the authors wrote….
`
`Ex. 2040, Ratain Tr. at 159:5-160:2.
`
`See also Ex. 2041, Kulke ¶ 140
`
`14
`
`
`
`Contrary To Dr. Ratain’s Opinion, A POSA
`Could Interpret De Jong’s Preclinical Results
`Paper 17 at 4-5, 34-35
`
`“[A] a person of ordinary skill in the art in November 2005 would
`have had, at a minimum:
`
`“a. a medical degree (e.g., MD) with several years of specific
`experience in medical oncology, which generally includes
`board certification, as well as knowledge of oncology drug
`development and clinical pharmacology; or
`
`“b. a Ph.D. in cancer biology, molecular biology, medicinal
`chemistry, or a related field with several years of experience in
`oncology drug development and clinical pharmacology,
`including evaluating cancer therapeutics in in vitro and/or in
`vivo assays, as well as familiarity with the practice of medical
`oncology.”
`
`Ex. 1003, Ratain ¶ 21.
`
`See also Ex. 2041, Kulke ¶¶ 21-22, 140
`
`15
`
`
`
`De Jong’s Preclinical Results Demonstrated That The
`Radioactivity Was Responsible For The Observed Effect
`Paper 17 at 34-35
`
`Preclinical
`Testing
`
`Treatment
`
`Control Group
`
`Therapeutic Groups
`
`“[C]ontrol group
`received … unlabeled
`[somatostatin analog]
`….”
`
`
`
`“[T]herapeutic groups
`received … [radiolabeled
`somatostatin analog]….”
`
`
`
`Ex. 1010, De Jong at 358.
`
`Ex. 1010, De Jong at 358.
`
`Results
`
`“[T]umors … grew
`excessively.”
`
`
`
`
`
`
`
`“[P]artial tumor remission”
`and “complete tumor
`remission.”
`
`
`
`
`Ex. 1010, De Jong at 359.
`
`Ex. 1010, De Jong at 359-60.
`
`Ex. 2041, Kulke ¶ 140
`
`16
`
`
`
`Many Tumor Types Expressed Somatostatin Receptors
`
`Paper 17 at 35, 42-43
`
`Human Cancers
`Reported To Express
`Somatostatin Receptors
`
`Prior Art Studies
`
`Pancreatic adenocarcinoma Ex. 2100 at 665
`
`Carcinoid tumors
`
`Ex. 2086 at 668; Ex. 2087 at S224
`
`PNETs
`
`Lymphomas
`
`Ex. 2086 at 668; Ex. 2087 at S224
`
`Ex. 2086 at 668
`
`Small cell lung cancer
`
`Ex. 2084 at 69; Ex. 2086 at 668
`
`Nervous system cancer
`
`Ex. 2086 at 668
`
`Prostate cancer
`
`Breast cancer
`
`Ovarian cancer
`
`Ex. 2100 at 666
`
`Ex. 2084 at 69; Ex. 2086 at 668
`
`Ex. 2100 at 666
`
`Ex. 2041, Kulke ¶ 143
`
`17
`
`
`
`Somatostatin Receptors And Their
`Signaling Were Not Relevant To mTOR Inhibition
`Paper 26 at 1-2; see also Paper 17 at 34-35, 43
`
`Dr. Ratain:
`
`Q. … You’re not asserting that the mTOR pathway is
`involved in somatostatin receptor signaling, are you?
`
`A. No.
`
`Ex. 2111, Ratain Tr. at 80:5-8.
`
`See also Ex. 2041, Kulke ¶¶ 145-147
`
`18
`
`
`
`AR42J Would Not Reasonably
`Suggest That CA20948 Was A PNET Model
`Paper 17 at 60; Paper 26 at 2
`
`“The AR42J (AR4-2J) rat pancreatic tumor cell line is
`derived from an azaserine-induced exocrine pancreatic
`tumor….”
`
`Ex. 1053, Weckbecker at 15.
`
`Ex. 2041, Kulke ¶ 251
`
`19
`
`
`
`Petitioners’ Grounds 3 And 4 Rely On Duran
`
`Paper 17 at 56-59
`
`Ground
`
`References
`
`Challenged
`Claims
`
`1
`
`2
`
`3
`
`4
`
`Öberg 2004, Boulay 2004, and
`O’Donnell
`
`Öberg 2004, Boulay 2004, O’Donnell,
`and Tabernero
`
`Boulay 2004, O’Donnell, and Duran
`
`Boulay 2004, O’Donnell, Duran, and
`Tabernero
`
`1-3
`
`2
`
`1-3
`
`2
`
`Paper 8 at 4-5; see also Paper 1 at 4
`
`20
`
`
`
`Duran Reported Interim Observations From An
`Unfinished And Uncontrolled Phase II Trial In NETs
`Paper 17 at 48
`
`“A phase II trial of temsirolimus in metastatic
`neuroendocrine carcinomas (NECs),” i.e., advanced
`NETs.
`
`“[S]tudy accrual is ongoing.”
`
`Ex. 1011, Duran.
`
`Ex. 1011, Duran.
`
`Ex. 2041, Kulke ¶ 208
`
`21
`
`
`
`Duran Would Not Reasonably Suggest That
`Everolimus Would Effectively Treat The Claimed PNETs
`Paper 17 at 48-55; Paper 26 at 3-4; Paper 34 at 5-7
`
`“Conclusions: [4] Temsirolimus [2] appears to have
`antitumor activity in [1] NECs, [3] study accrual is ongoing.”
`Ex. 1011, Duran.
`
`1. Duran disclosed no patients with the claimed PNETs, which
`were known to respond to drugs differently from other NETs.
`
`2. Duran, an unfinished and uncontrolled Phase II study, had
`interim observations consistent with natural history of NETs.
`
`3. Duran’s interim observations were subject to change.
`
`4. Duran tested only temsirolimus.
`
`Ex. 2041, Kulke ¶ 206
`
`22
`
`
`
`Duran Did Not Disclose That
`Any Enrolled Patients Had PNETs
`Paper 17 at 8, 48-49
`
`Dr. Ratain:
`
`Q. A person of ordinary skill in the art as of November 2005 would know
`that carcinoid tumors are three to six times more common than
`PNETs, is that right?
`
`A. That's right.
`
`Dr. Ratain:
`
`Ex. 2040, Ratain Tr. at 61:16-20.
`
`Q. And so a person of ordinary skill in the art as of November 2005
`would understand that PNETs are rare tumors?
`
`A. Yes.
`
`Ex. 2040, Ratain Tr. at 28:16-19.
`
`See also Ex. 2041, Kulke ¶¶ 42, 208-209
`
`23
`
`
`
`Duran Did Not Disclose That
`Any Patients With Stable Disease Had PNETs
`Paper 17 at 49; Paper 34 at 5
`
`Dr. Ratain:
`
`Q. Duran does not disclose the type of neuroendocrine
`carcinoma that the [10] patients with stable disease had,
`correct?
`
`A. That's correct.
`
`Ex. 2040, Ratain Tr. at 194:8-11.
`
`See also Ex. 2041, Kulke ¶ 212; Ex. 2111, Ratain Tr. at 131:7-16
`
`24
`
`
`
`A POSA Would Not Reasonably Predict Efficacy
`In PNETs Based On Carcinoid Tumor Results
`Paper 17 at 9-10, 49-50
`
`Dr. Ratain:
`
`Q. A person … of ordinary skill in the art in November of
`2005 would have reasonably expected carcinoids and
`PNETs to respond in the same way to a new therapy?
`
`A. I don’t think I can quite go that far. I think that a
`person of ordinary skill would understand that they could
`respond similarly and they could respond differently.
`It would be one or the other.
`
` Ex. 2040, Ratain Tr. at 59:7-18.
`
`See also Ex. 2041, Kulke ¶ 213
`
`25
`
`
`
`PNETs Were Distinct From Other Types Of NETs
`
`Paper 17 at 8-9
`
`“Based on their diverse primary tumor localizations, NETs of
`the gastroenteropancreatic (GEP) system [i.e., carcinoids and
`PNETs] encompass a family of distinct or even individual
`tumors…. NET cells also exhibit, in relation to their primary
`origin, distinct cell biological features, such as distinct
`secretory as well as growth and differentiation properties.”
`
` Ex. 1052, Wiedenmann at 94.
`
`“NE tumours exhibit substantial differences in terms of
`genotype and phenotype.”
`
` Ex. 1027, Öberg 2004 at 57.
`
`Ex. 2041, Kulke ¶¶ 40, 43-44; Ex. 1003, Ratain ¶ 93
`
`26
`
`
`
`PNETs Were Distinct From Other Types Of NETs
`
`Paper 17 at 8
`
`“Neuroendocrine tumors (NETs) are a heterogeneous
`group of tumors or neoplasms originating from various
`glands and organs….”
`
` Ex. 1003, Ratain ¶ 93.
`
`See also Ex. 2041, Kulke ¶ 40
`
`27
`
`
`
`PNETs And Carcinoid Tumors Were Often Evaluated
`Separately Due To Anticipated Differences In Responses
`Paper 17 at 9
`
`“NETs have been diagnosed and treated as separate diseases,
`i.e. according to their primary location….”
`
` Ex. 1052, Wiedenmann at 95.
`
`“Patients were classified as having carcinoid, islet cell [i.e.,
`PNETs], or anaplastic carcinoma. Due to the anticipated
`difference in the responses of these patient populations to
`the chemotherapy regimens, we designed the current study as
`three sub-Phase II studies with the same primary endpoint of
`therapeutic activity (i.e., response rate).”
`Ex. 2045, Ansell 2001 at 1545.
`
`Ex. 2041, Kulke ¶¶ 46-47; see also Ex. 2046, Ansell 2004 at 233
`
`28
`
`
`
`A POSA Would Not Reasonably Predict Efficacy
`In PNETs Based On Carcinoid Tumor Results
`Paper 17 at 7-10, 49
`
`Differences
`
`PNETs
`
`Carcinoid Tumors
`
`Origin
`
`Clinical
`Behavior
`
`Incidence
`
`Pancreas
`
`(Ex. 2013, Kulke 2003a at 1133)
`
`Lungs, stomach, small
`intestine, appendix, colon
`(Ex. 2020, Kulke 1999 at 858)
`
`“[D]iverse clinical presentations of patients with carcinoid and
`pancreatic endocrine tumors.”
`(Ex. 2013, Kulke 2003a at 1133)
`
`0.4-0.8/100,000 (at least 3x
`less)
`(Ex. 1027, Öberg 2004 at 57)
`
`2.5/100,000
`
`(Ex. 1027, Öberg 2004 at 57)
`
`Molecular
`Genetics
`
`“NE tumors exhibit substantial differences in terms of genotype
`and phenotype.” (Ex. 1027, Öberg 2004 at 57)
`
`Response
`To Therapies
`
`“PETs [i.e., PNETs] are more sensitive to chemotherapy than are
`carcinoid tumors.” (Ex. 2010, Pazdur at 311)
`
`Ex. 2041, Kulke ¶¶ 34-35, 41-47, 213
`
`29
`
`
`
`Duran’s Uncontrolled (Single-Arm)
`Study Design Was Fundamentally Flawed
`Paper 17 at 48, 50-51
`
`Dr. Ratain:
`
`Q. [Duran] was a single-arm trial, correct?
`
`A. Yes.
`
`Q. So there was no placebo control arm, correct?
`
`A. That’s correct.
`
`Q. There was no randomization in this clinical trial, correct?
`
`A. That’s right.
`
`Dr. Ratain:
`
` Ex. 2040, Ratain Tr. at 187:11-19.
`
`Q. And you’d agree with me that single-arm Phase II trials have fundamental
`flaws leading to greater uncertainty in their outcomes than in randomized [i.e.,
`controlled] studies…, correct?
`
`A. Yes.
`
` Ex. 2105, Ratain Dep. Tr. I at 350:2-9.
`
`See also Ex. 2041, Kulke ¶¶ 208, 212-218, 265 n.29
`
`30
`
`
`
`Duran Observed Only Stable Disease
`
`Paper 34 at 5-6; see also Paper 17 at 49
`
`Dr. Ratain:
`
`Q. Okay. And under the RECIST criteria the 24 percent tumor
`shrinkage in one patient that’s mentioned in Duran 2005 does
`not qualify as a partial response, correct?
`
`A. That’s right.
`
`Q. So that patient with 24 percent tumor shrinkage would be
`considered to have stable disease?
`
`A. It’s one of the 10 patients with prolonged stable disease.
`
` Ex. 2111, Ratain Tr. at 131:7-16.
`
`See also Ex. 2041, Kulke ¶ 212
`
`31
`
`
`
`Duran’s Interim Observations Were
`Consistent With The Natural History Of NETs
`Paper 17 at 51; Paper 34 at 6
`
`“V. Natural History of Neuroendocrine Tumors
`
`“Natural history is defined as the spontaneous course of a
`disease…. The behavior of GEP NETs is rather
`heterogeneous, with the majority exhibiting long periods
`of relatively small growth, spontaneous standstill, or
`even tumor regression….”
`
` Ex. 1020, Kaltsas at 463.
`
`Ex. 2041, Kulke ¶ 214; Ex. 2040 Ratain Tr. at 48:25-49:11
`
`32
`
`
`
`Duran’s Interim Observations Were
`Consistent With The Natural History Of NETs
`Paper 17 at 51-52; Paper 34 at 5-6
`
`Dr. Ratain:
`
`Q. And neuroendocrine carcinomas [i.e., advanced NETs] are
`an example of an indolent disease for which one…would
`expect a high rate of stable disease in the absence of
`treatment that you referred to in the second sentence; is that
`right?
`
`A. Yes.
`
`Q. And that would have been known as of November 2005
`also?
`
`A. Yes.
`
` Ex. 2111, Ratain Tr. at 147:15-23.
`
`See also Ex. 2040, Ratain Tr. at 48:25-49:11; Ex. 2041, Kulke ¶¶ 214-217
`
`33
`
`
`
`Stable Disease Would Not Reasonably Suggest Efficacy Due
`To Uncontrolled Study Design And Indolent Nature Of NETs
`Paper 17 at 13, 51, 67
`
`Patients With
`Stable Disease
`
`Ex. 2014, Kulke 2004
`
`Ex. 1011, Duran
`
`65% stable disease: “[Stable
`disease] rate was substantial
`(65%) [11 of 18 patients]”
`
`
`Ex. 2014 at 937.
`
`67% stable disease: “[Of] 15
`pts evaluable for response
`thus far, 10 have achieved
`prolonged stable disease”
`Ex. 1011.
`
`Duration Of
`Stable Disease
`
`“[T]ime to tumor
`progression was 8.5 months
`[about 36 weeks]”
`
`“3-11 cycles” or 12 to 44
`weeks
`
`
`Ex. 2014 at 937.
`
`Ex. 1011.
`
`Kulke 2004:
`
`“[T]he relevance of these observations in patients with neuroendocrine
`tumors is uncertain, given the often indolent course of this disease.”
`
`“The current study adds gemcitabine to [the] list of inactive agents….”
`
`Ex. 2014, Kulke 2004 at 937, 938.
`
`Ex. 2041, Kulke ¶¶ 215, 284
`
`34
`
`
`
`Stable Disease Would Not Reasonably Suggest Efficacy Due
`To Uncontrolled Study Design And Indolent Nature Of NETs
`Paper 17 at 51-52; Paper 34 at 6
`
`Ex. 1112, Shah 2004
`
`Ex. 1011, Duran
`
`Patients With
`Stable Disease
`
`“[S]table disease was noted in
`11 of 16 patients, which was
`equivalent to … 69%”
`
`Ex. 2111 at 14:22-15:5 (citing
`Ex. 1112 at 6115).
`
`Duration Of
`Stable Disease
`
`“[M]edian evaluation time of 12
`weeks, range, 3 to 24 weeks”
`
`Ex. 2111 at 14:22-15:5 (citing
`Ex. 1112 at 6115).
`
`“Among 15 pts evaluable for
`response thus far, 10 [67%]
`have achieved prolonged
`stable disease”
`
`Ex. 1011.
`
`“3-11 cycles” or 12 to 44
`weeks
`
`
`Ex. 1011.
`
`Shah 2004:
`
`“We cannot attribute stable disease to the antitumor effect of bortezomib in
`our single-arm study” because of “the slow growing nature of these tumors.”
`
`“[S]ingle-agent bortezomib does not have activity in patients with metastatic
`neuroendocrine tumors.”
`
` Ex. 2111 at 15:15-24 (citing Ex. 1112 at 6116); Ex. 1112, Shah 2004 at 6117.
`
`Ex. 2111, Ratain Tr. at 14:22-15:24
`
`35
`
`
`
`Dr. Ratain’s Contrary Prior Art Position: Stable Disease
`Was Not Evidence Of Efficacy In Uncontrolled Study
`Paper 17 at 49-51
`
`Ratain 2004:
`
`“In the study by Rinehart et al, the hypothesized effect was
`either a partial response, or stable disease of at least 3 months
`duration. No partial responses were observed, but stable
`disease was observed in eight patients. However, it is not
`possible to ascertain from this uncontrolled trial whether the
`stable disease was the result of a drug effect or was due to
`the inherent growth characteristics of the disease.”
`
` Ex. 2104, Ratain 2004 at 4444.
`
`See also Ex. 2041, Kulke ¶ 265 n.29
`
`36
`
`
`
`A POSA Would Understand That Duran’s
`Interim Observations Were Subject To Change
`Paper 17 at 50-52
`
`“Conclusions: [4] Temsirolimus [2] appears to have
`antitumor activity in [1] NECs, [3] study accrual is
`ongoing.”
`
`Ex. 1011, Duran.
`
`Ex. 2041, Kulke ¶¶ 218, 259
`
`37
`
`
`
`A POSA Would Understand That Duran’s
`Interim Observations Were Subject To Change
`Paper 17 at 50
`
`Interim Observations:
`
`“6 [patients] with disease stabilization ranging from 12%
`increase to 39% decrease of the tumor size… [including]
`1 neuroendocrine tumor of the lung….”
`Ex. 2076, Raymond 2000a.
`
`Final Results:
`
`No stabilization or response in NET reported.
`Ex. 2078, Raymond 2004 at 2342.
`
`Ex. 2041, Kulke ¶¶ 218, 259
`
`38
`
`
`
`Everolimus And Rapamycin Had Different Properties
`
`Paper 17 at 28, 54
`
`Property
`
`Half-life
`
`Everolimus
`
`Rapamycin
`
`26-38 hours
`
`
`About 62 hours
`
`
`Ex. 2027, Dancey 2005 at 320.
`
`Ex. 2027, Dancey 2005 at 318.
`
`Bioavailability ~ 30%
`
`
`~15%
`
`
`Ex. 2027, Dancey 2005 at 319.
`
`Ex. 2027, Dancey 2005 at 318-19.
`
`Metabolism
`
`“[A]lthough structurally similar, in vitro metabolism of
`[everolimus] and [rapamycin] shows significant
`differences.”
`
`Ex. 2057, Jacobsen at 514.
`
`Protein
`Binding
`
`“[B]inding of [everolimus] to FKBP12 is about threefold
`weaker than that of [rapamycin].”
`
`Ex. 2041, Kulke ¶¶ 233-236
`
`39
`
`Ex. 1036, Schuler at 38 & Table 1.
`
`
`
`A POSA Would Not Reasonably Predict
`Efficacy Of Everolimus Based On Temsirolimus
`Paper 17 at 54-55
`
`“[T]here are differences in the pharmacology of
`[temsirolimus and everolimus] that may influence drug
`exposures obtainable in patients and result in differences
`in clinical activity and toxicity profiles.”
`Ex. 2027, Dancey 2005 at 319.
`
`Ex. 2041, Kulke ¶¶ 221-223
`
`40
`
`
`
`A POSA Would Not Reasonably Predict
`Efficacy Of Everolimus Based On Temsirolimus
`Paper 17 at 54-55
`
`“Differences in drug dose, schedule and pharmacokinetics,
`as well as possible but as yet unidentified differences in
`intracellular uptake and effects on target and pathway
`signaling, may explain any apparent differences in toxicity
`profiles of the agents seen in [everolimus and temsirolimus]
`clinical trials.”
`
`Ex. 2027, Dancey 2005 at 319.
`
`Ex. 2041, Kulke ¶¶ 221-223
`
`41
`
`
`
`Petitioners’ Grounds 1 And 2 Rely On Öberg 2004
`
`Paper 17 at 42-48
`
`Ground
`
`References
`
`Challenged
`Claims
`
`1
`
`2
`
`3
`
`4
`
`Öberg 2004, Boulay 2004, and
`O’Donnell
`
`Öberg 2004, Boulay 2004, O’Donnell,
`and Tabernero
`
`Boulay 2004, O’Donnell, and Duran
`
`Boulay 2004, O’Donnell, Duran, and
`Tabernero
`
`1-3
`
`2
`
`1-3
`
`2
`
`Paper 8 at 4-5; see also Paper 1 at 4
`
`42
`
`
`
`Öberg 2004 Would Not Reasonably Suggest That
`Everolimus Would Effectively Treat The Claimed PNETs
`Paper 17 at 26-30, 42; Paper 34 at 7
`
`1. Öberg 2004 did not disclose any rapamycin preclinical or
`clinical data.
`
`2. Öberg 2004 did not disclose that the “planned” rapamycin
`trial would be in NETs or PNETs.
`
`3. Numerous “planned” clinical trials failed.
`
`4. Öberg 2004 mentioned only rapamycin.
`
`Ex. 2041, Kulke ¶¶ 115-116
`
`43
`
`
`
`No Evidence That The Öberg 2004 Rapamycin
`“Planned” Study Would Be In NETs Or PNETs
`Paper 34 at 7; see also Paper 17 at 29-30
`
`Dr. Ratain:
`
`Q. And you say [Ex. 1064] was the first clinical trial of rapamycin
`administered to human cancer patients. Do you see that?
`
`A. That’s correct.
`
`Q. And that was a Phase I study, correct?
`
`A. Yes.
`
`Dr. Ratain:
`
`Ex. 2111, Ratain Tr. at 95:9-18.
`
`Q. … But this wasn’t a study that was directed to the treatment
`of NETs, correct?
`
`A. That’s right.
`
`Ex. 2111, Ratain Tr. at 97:6-8.
`
`See also Ex. 2041, Kulke ¶ 122
`
`44
`
`
`
`Numerous Other “Planned” Clinical Trials Failed
`
`Paper 17 at 15-16, 46, 67; Paper 34 at 1-2, 6, 8
`
`Failed Phase II
`Trials In NETs
`
`Failed Phase II Trials With
`Molecularly Targeted Drugs
`
`Ex. 1112, Shah 2004
`(Bortezomib in NETs)
`
`Ex. 1071, Mathy 2005
`(Gleevec® in mesothelioma)
`
`Ex. 2014, Kulke 2004
`(Gemcitabine in NETs)
`
`Ex. 1073, Verweij 2003
`(Gleevec® in soft-tissue sarcoma)
`
`Ex. 2045, Ansell 2001
`(Paclitaxel in NETs)
`
`Ex. 2046, Ansell 2004
`(Topotecan in NETs)
`
`Ex. 1112, Shah 2004
`(Bortezomib in NETs)
`
`Ex. 2015, Margolin 2005
`(Temsirolimus in melanoma)
`
`Ex. 2050, Chang 2005
`(Temsirolimus in glioblastoma)
`
`Ex. 2041, Kulke ¶¶ 71, 168, 215-217, 283-284
`
`45
`
`
`
`Öberg 2004 Only Disclosed Rapamycin, Not Everolimus,
`As An Experimental Therapy In NETs, Not PNETs
`Paper 17 at 26-28
`
`Ex. 2041, Kulke ¶¶ 117, 119
`
`46
`
`Ex. 1027, Oberg 2004 at 60.
`
`
`
`Everolimus And Rapamycin Had Different Properties
`
`Paper 17 at 28, 54
`
`Property
`
`Half-life
`
`Everolimus
`
`Rapamycin
`
`26-38 hours
`
`
`About 62 hours
`
`
`Ex. 2027, Dancey 2005 at 320.
`
`Ex. 2027, Dancey 2005 at 318.
`
`Bioavailability ~ 30%
`
`
`~ 15%
`
`
`Ex. 2027, Dancey 2005 at 319.
`
`Ex. 2027, Dancey 2005 at 318-19.
`
`Metabolism
`
`“[A]lthough structurally similar, in vitro metabolism of
`[everolimus] and [rapamycin] shows significant
`differences.”
`
`Ex. 2057, Jacobsen at 514.
`
`Protein
`Binding
`
`“[B]inding of [everolimus] to FKBP12 is about threefold
`weaker than that of [rapamycin].”
`
`Ex. 2041, Kulke ¶¶ 233-236
`
`47
`
`Ex. 1036, Schuler at 38 & Table 1.
`
`
`
`Different Properties Could Determine Whether
`Analogs Had Efficacy In The Same Tumor Types
`Paper 17 at 28
`
`“The amount of cytotoxic agent available at the tumor
`target and the length of time during which it is present
`determine its level of efficacy.”
`
`Ex. 2052, Creaven at 91.
`
`“The elimination half-life may be influenced by: dose size,
`variation in urinary excretion (pH), intersubject variation,
`age, protein binding, other drugs and diseases….”
`Ex. 2017, Ritschel at 7.
`
`“[T]he elimination half-life of a drug is a complex function
`of drug distribution, biotransformation and elimination.”
`Ex. 2021, Remington’s at 729.
`
`Ex. 2041, Kulke ¶ 235
`
`48
`
`
`
`Petitioners’ Grounds 1-4 Rely On O’Donnell
`And Grounds 2 And 4 Rely On Tabernero
`Paper 17 at 38-48, 56-59
`
`Ground
`
`References
`
`Challenged
`Claims
`
`1
`
`2
`
`3
`
`4
`
`Öberg 2004, Boulay 2004, and
`O’Donnell
`
`Öberg 2004, Boulay 2004, O’Donnell,
`and Tabernero
`
`Boulay 2004, O’Donnell, and Duran
`
`Boulay 2004, O’Donnell, Duran, and
`Tabernero
`
`1-3
`
`2
`
`1-3
`
`2
`
`Paper 8 at 4-5; see also Paper 1 at 4
`
`49
`
`
`
`O’Donnell And Tabernero Would Not Reasonably Suggest
`That Everolimus Would Effectively Treat The Claimed PNETs
`Paper 17 at 38-41, 46-48
`
`1. O’Donnell and Tabernero were Phase I dose finding studies
`not designed to test efficacy.
`
`2. O’Donnell and Tabernero disclosed no patients with PNETs.
`
`3. O’Donnell and Tabernero mentioned other tumors that
`responded to different drugs from PNETs.
`
`Ex. 2041, Kulke ¶¶ 156, 188
`
`50
`
`
`
`Temsirolimus Was Not Effective
`In Some Finished Phase II Trials
`Paper 17 at 15-17
`
`Phase II study of temsirolimus found “no evidence of
`efficacy [of temsirolimus] in patients with recurrent
`[glioblastoma multiforme].”
`
`Ex. 2050, Chang at Abstract.
`
`“The results of our [Phase II] clinical trial demonstrated that
`[temsirolimus] given at the dose and schedule supported by
`Phase I … studies did not have sufficient antitumor activity
`in melanoma to warrant further evaluation as a single agent.”
`Ex. 2015, Margolin at 1047.
`
`Ex. 2040, Kulke ¶¶ 71, 81, 167
`
`51
`
`
`
`O’Donnell Tested Other Tumors That
`Responded To Different Drugs From PNETs
`Paper 17 at 12, 40, 67
`
`Hepatocellular
`Cancer
`
`Retinoid therapy, hormone therapy, and
`biochemotherapy, but cytotoxic chemotherapy had
`been “disappointing” in these patients
`(Ex. 2010, Pazdur at 327-31)
`
`Fibrosarcoma Combinations of doxorubicin, epirubicin, ifosfamide,
`mensa, gemcitabine, docetaxel, and dacarbazine
`(Ex. 2010, Pazdur at 591-612)
`
`Non-Small Cell
`Lung Cancer
`
`Platinum-based adjuvant chemotherapy with
`paclitaxel, docetaxel, gemcitabine, or vinorelbine
`(Ex. 2010, Pazdur at 126-38)
`
`PNETs
`
`Streptozocin-based chemotherapy
`(Ex. 2010, Pazdur at 309-11)
`Gemcitabine and paclitaxel had little efficacy in
`PNETs (Ex. 2014, Kulke 2004 at 937; Ex. 2045, Ansell
`2001 at 1548)
`
`Ex. 2040, Kulke ¶¶ 56, 169-171, 283
`
`52
`
`
`
`Grounds 1 And 2 Would Not
`Provide A Reasonable Expectation Of Success
`Paper 17 at 42-48; Paper 34 at 7-8
`
`Claim Elements
`
`Öberg 2004
`
`Boulay 2004
`
`Everolimus?
`
`No (rapamycin)
`
`Yes
`
`In Humans?
`
`Yes
`
`Advanced
`PNETs?
`
`No (advanced NETs
`generally)
`
`No (preclinical,
`in vivo in rats)
`
`No (CA20948,
`pancreatic
`adenocarcinoma)
`
`O’Donnell/
`Tabernero
`
`Yes
`
`Yes
`
`Not indicated
`(advanced solid tumors)
`
`Prior
`Chemotherapy?
`
`Yes
`
`No
`
`Not indicated
`
`Therapeutically
`Effective?
`
`Not applicable
`(no rapamycin data;
`no evidence “planned”
`rapamycin trial would
`be in NETs or PNETs;
`numerous other
`“planned” trials failed)
`
`Not applicable
`(growth of CA20948
`inhibited, but would
`not extrapolate in
`vivo results to human
`PNETs)
`
`Not applicable
`(preliminary results of
`Phase I studies not
`designed to measure
`efficacy)
`
`See Ex. 2041, Kulke ¶¶ 180-188, 204
`
`53
`
`
`
`Grounds 3 And 4 Would Not
`Provide A Reasonable Expectation Of Success
`Paper 17 at 56-59
`
`Claim
`Elements
`
`Boulay 2004
`
`Duran
`
`O’Donnell/
`Tabernero
`
`Everolimus?
`
`Yes
`
`No (temsirolimus)
`
`In Humans?
`
`No (preclinical,
`in vivo in rats)
`
`Yes
`
`Yes
`
`Yes
`
`Advanced
`PNETs?
`
`No (CA20948,
`pancreatic
`adenocarcinoma)
`
`Not indicated
`(advanced NETs
`generally)
`
`Not indicated
`(advanced solid
`tumors)
`
`Prior
`Chemotherapy?
`
`No
`
`Not indicated for PNETs Not indicated
`
`Therapeutically
`Effective?
`
`Not applicable
`(growth of CA20948
`inhibited, but would
`not extrapolate in
`vivo results to
`human PNETs)
`
`Not applicable
`(interim data in single-
`arm Phase II: only
`“appear[ed]” to have
`activity in NETs, but
`results were consistent
`with natural history)
`
`Not applicable
`(preliminary results of
`Phase I studies not
`designed to measure
`efficacy)
`
`See Ex. 2041, Kulke ¶¶ 240-247
`
`54
`
`
`
`PNETs Were Harder To Treat After
`Failure Of Cytotoxic Chemotherapy
`Paper 17 at 13-14; Paper 34 at 3
`
`Study Drug
`
`Streptozocin + Doxorubicin
`Streptozocin + Fluorouracil
`Chlorozotocin
`
`Ex. 1023, Moertel at 521-22.
`
`Streptozocin + Doxorubicin
`
`
`
`
`Ex. 2012, Delaunoit at 517-18.
`
`Chemotherapy-
`Naïve PNETs
`
`30-69% response
`rates
`
`PNETs After Failure Of
`Other Cytotoxic
`Chemotherapy
`
`Only 17% response rate
`after patients crossed-over
`to a different regimen
`
`22.4 month median
`survival
`
`Only 5.5 month median
`survival after streptozocin +
`fluorouracil or cisplatin +
`fluorouracil
`
`Dacarbazine
`
`
`50% patients
`responded
`
`
`Ex. 2074, Ramanathan
`at 1139, 1141.
`
`Only 13.6% patients
`responded after various
`prior regimens
`
`Ex. 2041, Kulke ¶¶ 60-64
`
`55
`
`
`
`Moertel Tested Cytotoxic Chemotherapies
`With Different Mechanisms Of Action
`Paper 17 at 14; Paper 34 at 3
`
`First-Line
`Therapy
`
`Second-Line
`Therapy
`
`Different Mechanisms Of Action
`With Second-Line Therapy?
`
`Streptozocin
`+ Fluorouracil
`
`Chlorozotocin
`
`Yes (Ex. 2041, Kulke ¶ 61; Ex. 2111,
`Ratain Tr. at 117:17-24; 120:11-121:21)
`
`Streptozocin
`+ Doxorubicin
`
`Chlorozotocin
`
`Yes (Ex. 2041, Kulke ¶ 61; Ex. 2111,
`Ratain Tr. at 117:17-24; 121:22-122:19)
`
`Chlorozotocin
`
`Streptozocin
`+ Fl
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