Paper No. _______
`Date Filed: November 18, 2016
`
`
`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.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01479
`
`Patent No. 9,006,224
`
`
`
`
`
`PATENT OWNER’S PRELIMINARY
`RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`Date Filed: November 18, 2016
`
`
`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.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-01479
`
`Patent No. 9,006,224
`
`
`
`
`
`PATENT OWNER’S PRELIMINARY
`RESPONSE UNDER 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`I.
`
`Introduction ...................................................................................................... 1
`
`II.
`
`The Person Of Ordinary Skill In The Art And Invention Date ....................... 4
`
`III. Background On Neuroendocrine Tumors, Including Advanced
`PNETs .............................................................................................................. 4
`
`IV. Claim Construction .......................................................................................... 7
`
`A.
`
`B.
`
`“Advanced” Tumors Are “Metastatic Or Unresectable” ...................... 7
`
`The Ordinary And Customary Meaning Of “Advanced”
`Is Not “After Failure Of Cytotoxic Chemotherapy” ............................. 9
`
`V.
`
`The Board Should Deny Grounds 3 And 4 Because No
`Reference Teaches Or Suggests The Claim Element “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ................................... 11
`
`A.
`
`Boulay 2004 ........................................................................................ 12
`
`B. O’Donnell ............................................................................................ 14
`
`C. Duran ................................................................................................... 15
`
`D.
`
`Tabernero ............................................................................................. 17
`
`VI. The Board Should Deny Grounds 1-4 Because One Of Ordinary
`Skill Would Not Have Had A Reasonable Expectation That
`Everolimus Would Effectively Treat “Advanced [PNETs] After
`Failure Of Cytotoxic Chemotherapy” ........................................................... 19
`
`Par’s Reasonable Expectation Of Success Arguments
`Ignore That Tumors That Had Failed Cytotoxic
`Chemotherapy Generally Were More Resistant To
`Treatment And More Difficult To Treat ............................................. 20
`
`A.
`
`
`
`
`
`i
`
`
`
`
`
`B.
`
`The Art Cited In Grounds 1 And 2 Fails To Establish A
`Reasonable Expectation That Everolimus Would Be
`Effective In A Method Of Treating “Advanced [PNETs]
`After Failure Of Cytotoxic Chemotherapy” ........................................ 23
`
`1.
`
`2.
`
`3.
`
`4.
`
`Oberg 2004 ................................................................................ 24
`
`Boulay 2004 .............................................................................. 25
`
`O’Donnell .................................................................................. 26
`
`Tabernero .................................................................................. 29
`
`C.
`
`The Art Cited In Par’s Grounds 3 And 4 Fail To
`Establish A Reasonable Expectation That Everolimus
`Would Be Effective In A Method Of Treating “Advanced
`[PNETs] After Failure Of Cytotoxic Chemotherapy” ........................ 33
`
`1.
`
`2.
`
`3.
`
`Boulay 2004, O’Donnell And Tabernero ................................. 34
`
`Duran ......................................................................................... 34
`
`Additional Art Referenced In Connection With
`Grounds 3 And 4 ....................................................................... 38
`
`VII. The Methods Of Claims 1-3 Of The ’224 Patent Have
`Demonstrated Unexpected Results ................................................................ 40
`
`VIII. Conclusion ..................................................................................................... 45
`
`
`
`ii
`
`
`
`
`
`
`
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`
`10X Genomics, Inc. v. Univ. of Chicago,
`IPR2015-01163 (Patent Tr. & App. Bd. Nov. 16, 2015),
`Paper 14 .................................................................................................. 20, 23
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ................................................................ 22, 36
`
`Coalition for Affordable Drugs V LLC v. Hoffman-LaRoche
`Inc., IPR2015-01792 (Patent Tr. & App. Bd. March 11,
`2016), Paper 14 ....................................................................................... 40, 45
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ..................................................................................... 7
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) ....................................................................... 7
`
`InSite Vision Inc. v. Sandoz, Inc.,
`783 F.3d 853 (Fed. Cir. 2015) ................................................................ 20, 23
`
`IntelGenX Corp. v. ICOS Corp.,
`IPR2016-00678 (Patent Tr. & App. Bd. Sept. 1, 2016),
`Paper 13 .........................................................................................................12
`
`Janssen Pharmaceutica, N.V. v. Eon Labs. Mfg., Inc.,
`134 Fed. Appx. 425 (Fed. Cir. 2005) .............................................................. 9
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01633 (Patent Tr. & App. Bd. Jan. 4, 2016),
`Paper 10 .................................................................................................. 22, 36
`
`NetApp Inc. v. Crossroads Sys., Inc.,
`IPR2014-01233, 2015 WL 996342 (Patent Tr. & App.
`Bd. Feb. 10, 2015) .........................................................................................11
`
`Par Pharm., Inc. v. Novartis AG,
`IPR2016-00078, 2016 WL 2849201 (Patent Tr. & App.
`Bd. Apr. 28, 2016) .........................................................................................12
`
`
`
`iii
`
`
`
`
`
`Praxair Distrib., Inc. v. INO Therapeutics, Inc.,
`IPR2015-00522, -00524, -00525, -00526 (Patent Tr. &
`App. Bd. July 29, 2015), Paper 12.......................................................... 41, 45
`
`
`
`Regulations
`
`37 C.F.R. § 42.100(b) ................................................................................................ 7
`
`37 C.F.R. § 42.104(b)(4) ......................................................................... 2, 11, 12, 19
`
`37 C.F.R. § 42.65(a) .......................................................................................... 22, 36
`
`
`
`iv
`
`
`
`
`
`
`
`
`
`
`
`
`
`LIST OF EXHIBITS
`
`Exhibit
`
`Description
`
`Abbreviation
`
`Expert Declaration Of Matthew H. Kulke,
`M.D., M.M.Sc.
`
`Kulke Decl.
`
`Curriculum Vitae of Matthew H. Kulke,
`M.D., M.M.Sc.
`
`Kulke C.V.
`
`2001
`
`2002
`
`2003
`
`Seeley, R. R., Stephens, T.D., & Tate, P.,
`Anatomy & Physiology, 3rd Edition,
`pages 585 – 586 (1995)
`
`2004
`
`Reserved
`
`Seeley
`
`
`
`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
`
`2010
`
`2011
`
`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)
`
`v
`
`
`
`
`
`Motzer
`
`
`
`Pazdur
`
`Kouvaraki
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`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)
`
`Kulke, M.H. et al., “A Phase II Trial Of
`Gemcitabine For Metastatic
`Neuroendocrine Tumors,” Cancer
`101(5): 934-939 (2004)
`
`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)
`
`Delaunoit
`
`Kulke 2003
`
`Kulke 2004
`
`Margolin
`
`Novartis Press
`Release
`
`2017
`
`Ritschel, W.A., Handbook of Basic
`Pharmacokinetics, 4th Edition, pages 6-7,
`264-267 (1992)
`
`Ritschel
`
`vi
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`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
`
`Physicians’ Desk Reference, 59th Edition
`(2005), pages 1844-1849 (Entry for
`Gemzar®(Gemcitabine HCl))
`
`Gemzar®
`Prescribing
`Information 2005
`
`Kulke, M.H. & Mayer, R.J., “Carcinoid
`Tumors,” N. Eng. J. Med. 340(11): 858-
`868 (1999)
`
`Kulke 1999
`
`2018
`
`2019
`
`2020
`
`2021
`
`Gennaro, A.R. (ed.), Remington’s, 18th
`Edition, pages 726-730 (1990)
`
`Remington’s
`
`2022
`
`2023
`
`2024
`
`Yao, J.C. et al., “Everolimus For
`Advanced Pancreatic Neuroendocrine
`Tumors,” N. Eng. J. Med. 364(6): 514-
`523 (2011)
`
`Kola, I. & Landis, J., “Can The
`Pharmaceutical Industry Reduce Attrition
`Rates?,” Nat. Rev. Drug Discov., 3:711-
`715 (2004)
`
`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
`
`Yao
`
`Kola & Landis
`
`Ratain Trial Tr. I
`
`vii
`
`
`
`
`
`
`
`Exhibit
`
`Description
`
`Abbreviation
`
`2025
`
`2026
`
`2027
`
`2028
`
`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
`
`Dancey, J.E., “Inhibitors Of The
`Mammalian Target Of Rapamycin,”
`Expert Opin. Investig. Drugs 14(3): 313-
`328 (2005)
`
`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)
`
`Ratain Trial Tr. II
`
`Ratain Dep. Tr.
`
`Dancey 2005
`
`Duran 2006
`
`viii
`
`
`
`
`
`I.
`
`
`
`Introduction
`
`Novartis AG (“Novartis”) respectfully submits this Preliminary Response to
`
`the Petition of Par Pharmaceutical, Inc. (“Par”) seeking inter partes review of
`
`claims 1-3 of United States Patent No. 9,006,224 (“the ’224 Patent,” Ex. 1001) on
`
`four Grounds (Paper 1, “Petition” or “Pet.”).
`
`Claims 1-3 of the ’224 Patent recite methods of using the compound 40-O-
`
`(2-hydroxyethyl)-rapamycin (commonly known as everolimus) as a monotherapy
`
`to treat pancreatic neuroendocrine tumors (“PNETs”) “wherein the tumors are
`
`advanced tumors after failure of cytotoxic chemotherapy.” Par’s Petition is fatally
`
`flawed for the following three independent reasons.
`
`First, none of the references in Par’s Grounds 3 or 4, alone or in
`
`combination, teaches or suggests the claim element “advanced [PNETs] after
`
`failure of cytotoxic chemotherapy.” Boulay 2004 describes an in vivo study of
`
`everolimus against the CA20948 “rat pancreatic tumor model,” which is not a
`
`model for “advanced [PNETs] after failure of cytotoxic chemotherapy” and does
`
`not teach or suggest using everolimus in such patients. Duran describes an
`
`ongoing Phase II clinical trial with a compound known as temsirolimus—not
`
`everolimus—and none of the patients is stated to have “advanced [PNETs] after
`
`failure of cytotoxic chemotherapy.” Likewise, none of the patients described in
`
`O’Donnell or Tabernero was reported to have advanced PNETs, let alone
`
`1
`
`
`
`
`
`
`
`“advanced [PNETs] after failure of cytotoxic chemotherapy.” Because none of
`
`Boulay 2004, Duran, O’Donnell or Tabernero teaches or suggests the claim
`
`element “advanced [PNETs] after failure of cytotoxic chemotherapy,” Par’s
`
`analysis is deficient under 37 C.F.R. § 42.104(b)(4).
`
`Second, each of Par’s four Grounds is deficient for failing to establish that
`
`one of ordinary skill in the art would have reasonably expected that everolimus
`
`would effectively treat “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy.” Par contends that a person of ordinary skill would have
`
`reasonably expected everolimus to successfully treat advanced PNETs. While
`
`Novartis disagrees that Par’s references support this conclusion, even if it were
`
`true, this conclusion fails to address the relevant question: would a person of
`
`ordinary skill have reasonably expected that everolimus would successfully treat
`
`“advanced [PNETs] after failure of cytotoxic chemotherapy”? The answer is no.
`
`Notably, Par ignores that patients with advanced PNETs who had previously failed
`
`treatment with cytotoxic chemotherapy were known to have a generally more
`
`resistant or aggressive disease than those who had not failed such treatment, and
`
`thus were more difficult to treat. In fact, it was known that after failure of
`
`cytotoxic chemotherapy, the vast majority of advanced PNET patients (over 80%)
`
`failed to respond to drugs with proven clinical efficacy in untreated patients, but as
`
`of November 2005, everolimus had not even demonstrated efficacy in patients with
`
`2
`
`
`
`
`
`
`
`previously untreated advanced PNETs. Thus, one of ordinary skill would not have
`
`had a reasonable expectation that everolimus would successfully treat “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy.”
`
`Third, the results of the methods of claims 1-3 would have been unexpected
`
`to one of ordinary skill in November 2005, and those unexpected results were not
`
`rebutted by Par. The results of the claimed methods are reflected in the results of
`
`the Phase III RADIANT-3 clinical trial that led to the FDA approval of everolimus
`
`and showed that treatment with everolimus produced a statistically significant
`
`improvement in progression free survival (“PFS”) in patients with “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy.” During prosecution, the Patent
`
`Examiner expressly considered the results of the RADIANT-3 clinical trial and
`
`stated they would have been unexpected to a person of ordinary skill in the art.
`
`Indeed, as of November 2005, it was reported that only 5% of oncology drugs
`
`progressed from first-in-human trials to regulatory approval. And no other mTOR
`
`inhibitor, including rapamycin and temsirolimus, has obtained FDA approval for
`
`the treatment of PNETs. Notwithstanding that the Patent Office expressly
`
`considered and relied on these unexpected results in allowing the ’224 Patent, Par’s
`
`Petition fails to address them. These unexpected results constitute unrebutted
`
`evidence of the non-obviousness of the claimed methods.
`
`3
`
`
`
`
`
`
`
`
`
`For each of these independent reasons, Par cannot establish the obviousness
`
`of claims 1-3 of the ’224 Patent. Novartis respectfully requests that the Board
`
`deny institution of inter partes review.
`
`II. The Person Of Ordinary Skill In The Art And Invention Date
`
`For the purposes of this Preliminary Response, Novartis adopts Par’s
`
`proposed definition of a person of ordinary skill in the art (see Pet. 15-16; Ex.
`
`1003, Ratain Decl. ¶ 21) and, like Par, evaluates obviousness of the ’224 Patent as
`
`of its November 21, 2005 priority date (see, e.g., Pet. 5, 15, 29, 37; Ex. 1003,
`
`Ratain Decl. ¶ 17).
`
`III. Background On Neuroendocrine Tumors, Including Advanced PNETs
`
`Neuroendocrine tumors (“NETs”) are tumors that arise from endocrine, i.e.,
`
`hormone-producing cells. Ex. 2001, Kulke Decl. ¶ 24. The term NET describes a
`
`wide range of distinct tumors. Id. at ¶¶ 24-26, 29. These different types of NETs
`
`and their relationships are summarized below (id.):
`
`4
`
`
`
`
`
`
`
`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
`
`
`
`As shown in the figure above, NETs are usually classified as either carcinoid
`
`tumors or pancreatic NETs (i.e., PNETs). Ex. 2001, Kulke Decl. ¶ 24; Ex. 2013,
`
`Kulke 2003 at 1133. Carcinoid tumors may arise from multiple different organs
`
`and are classified according to their site of origin, e.g., foregut (lungs, bronchi, or
`
`stomach), midgut (small intestine, appendix, and proximal large bowel) or hindgut
`
`(distal colon and rectum). Ex. 2001, Kulke Decl. ¶ 24; Ex. 2020, Kulke 1999 at
`
`858. PNETs arise from the endocrine cells of the pancreas. Ex. 2001, Kulke Decl.
`
`¶ 24; Ex. 2018, WHO at 177.
`
`PNETs “include islet cell tumors, APUDomas, insulinomas, glucagonomas,
`
`nonfunctioning pancreatic NETs, pancreatic NETs associated with hypercalcemia,
`
`gastrinomas, VIPomas, somatostatinomas, GRFomas.” Ex. 1001, ’224 Patent, col.
`
`5
`
`
`
`
`
`
`
`2, ll. 54-58, col. 8, ll. 13-17; Ex. 2001, Kulke Decl. ¶ 31; Ex. 2018, WHO at 177;
`
`Ex. 1020, Kaltsas at 472 (Table 2), 475.
`
`While all PNETs are NETs, not all NETs are PNETs and there are
`
`substantial differences between PNETs and carcinoid tumors, i.e., between the
`
`different types of NETs. Ex. 2001, Kulke Decl. ¶ 25. For example, by November
`
`2005, it was known that PNETs and carcinoid tumors produced different clinical
`
`symptoms and responded differently to pharmacotherapies. Id.; Ex. 2013, Kulke
`
`2003 at 1133; Ex. 2010, Pazdur at 311; Ex. 1027, Oberg 2004 at 57.
`
`NETs (carcinoid tumors and PNETs) may pursue a clinical course that is
`
`either benign or malignant, i.e., have the potential to spread to other areas of the
`
`body. Ex. 2001, Kulke Decl. ¶ 26. Malignant NETs, which include both
`
`malignant PNETs and malignant carcinoid tumors, have been referred to as
`
`neuroendocrine carcinomas (NECs). Id.
`
`And, malignant tumors may be either localized or advanced. As discussed
`
`in more detail below, PNETs are referred to as “advanced” PNETs if they have
`
`spread to nearby areas (locally advanced) or more distant areas of the body
`
`(metastatic) and are generally unresectable (i.e., they cannot be cured by surgery).
`
`Id. at ¶ 27.
`
`Challenged claims 1-3 of the ’224 Patent concern the treatment of specific
`
`tumors, namely, advanced pancreatic neuroendocrine tumors (i.e., advanced
`
`6
`
`
`
`
`
`
`
`PNETs), that have failed to respond to cytotoxic chemotherapy. Ex. 1001, ’224
`
`Patent, col. 26, l. 66 – col. 27, l. 8. These tumors are circled in red at the bottom
`
`right of the figure reproduced above on page 5.
`
`IV. Claim Construction
`
` Novartis agrees with Par (Pet. 16-17) that, for the purposes of this inter
`
`partes review, the ’224 Patent claim terms should be given their broadest
`
`reasonable construction in light of the specification of the patent and assigned their
`
`ordinary and customary meaning, as would be understood by one of ordinary skill
`
`in the art at the time of the invention, in the context of the entire patent disclosure.
`
`37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`
`(2016); In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`Par proposes constructions for four claim terms. Pet. 18-21. Novartis does
`
`not believe it is necessary to construe the terms “pancreatic neuroendocrine
`
`tumor,” “unit dose” or “islet cell tumor” at the present stage of the proceedings,
`
`and reserves its right to propose constructions for these and other terms at a later
`
`time, if appropriate. For the reasons discussed below, Novartis respectfully
`
`requests that the Board construe the term “advanced” tumors.
`
`A.
`
`“Advanced” Tumors Are “Metastatic Or Unresectable”
`
`Novartis agrees with Par that “[a] person of ordinary skill in the art at the
`
`time of the alleged inventions would have understood the claim term ‘advanced
`
`7
`
`
`
`
`
`
`
`tumors’ to have its ordinary and customary meaning in the art that is consistent
`
`with the [’224 Patent] specification.” Pet. 19-20. Novartis further agrees with Par,
`
`that “[a]s used by those of skill in the field of oncology, an ‘advanced’ tumor is a
`
`tumor that is unresectable or metastatic.” Pet. 19-20 (emphasis added); Ex.
`
`2001, Kulke Decl. ¶¶ 27-28, 32-34.
`
`This proposed construction is supported by the ’224 Patent specification,
`
`which explains that “advanced” PNETs are those that are “metastatic” (i.e., they
`
`have spread outside of the pancreas), or “unresectable” (i.e., they cannot be cured
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`by surgery, for example, because they have spread to nearby areas (locally
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`advanced)). Ex. 1001, ’224 Patent, col. 26, ll. 57-58; Ex. 2001, Kulke Decl. ¶¶ 33-
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`34.
`
`The ’224 Patent specification’s use of the term “advanced” is consistent with
`
`its ordinary usage in the art as of November 2005. Ex. 2001, Kulke Decl. ¶ 33; see
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`also ¶¶ 27-28; Ex. 1023, Moertel at 520 (describing patients with “advanced”
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`PNETs (referred to as islet-cell carcinomas) as having proof of “unresectable or
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`metastatic” disease). However, the term “advanced” is not specific to PNETs. Ex.
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`2005, Laughlin Cancer Glossary at 4 (defining “advanced cancer” as “[a] general
`
`term describing the stages of cancer in which the disease has spread from the
`
`primary site to other parts of the body. When the cancer has spread only to the
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`surrounding areas, it is called locally advanced. If it has spread further by
`
`8
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`
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`
`
`
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`traveling through the bloodstream or lymph system, it is called metastatic.”); Ex.
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`2001, Kulke Decl. ¶ 28.
`
`B.
`
`The Ordinary And Customary Meaning Of “Advanced”
`Is Not “After Failure Of Cytotoxic Chemotherapy”
`
`To avoid any confusion regarding the scope of the challenged claims and the
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`disclosures of the prior art references that also use the term “advanced,” Novartis
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`respectfully requests that the Board clearly state that its construction of the claim
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`term “advanced” does not mean “after failure of cytotoxic chemotherapy.” Par
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`does not suggest that “advanced” should be construed to encompass a reference to
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`“failure of cytotoxic chemotherapy,” and, as discussed below, such a construction
`
`would be inconsistent with (1) the claim language, (2) the patent specification and
`
`(3) the ordinary and customary meaning of the term “advanced.”
`
`First, claim 1 of the ’224 Patent requires that the PNETs are “advanced
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`tumors after failure of cytotoxic chemotherapy.” If “advanced” PNETs were those
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`that had failed cytotoxic chemotherapy, it would have been unnecessary to
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`separately include the language “after failure of cytotoxic chemotherapy” in the
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`claim. Constructions that render superfluous any claim terms are disfavored.
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`Janssen Pharmaceutica, N.V. v. Eon Labs. Mfg., Inc., 134 Fed. Appx. 425, 428
`
`(Fed. Cir. 2005).
`
`Second, the ’224 Patent specification does not describe “advanced” PNETs
`
`as PNETs that have failed to respond to cytotoxic chemotherapy. To the contrary,
`
`9
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`
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`
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`
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`the specification describes “advanced” PNETs as those that are metastatic or
`
`unresectable. Ex. 1001, ’224 Patent, col. 26, ll. 57-58; Ex. 2001, Kulke Decl. ¶ 33.
`
`The specification also provides that more than half of all patients “present with
`
`liver metastases” at the time their PNET is diagnosed. Ex. 1001, ’224 Patent, col.
`
`3, ll. 2-4; Ex. 2001, Kulke Decl. ¶ 33. Thus, the specification teaches that more
`
`than half of all patients have “advanced” (i.e., metastatic or unresectable) PNETs
`
`when they are first diagnosed. Id. Such patients could not have received any
`
`treatment, including cytotoxic chemotherapy. Id.
`
`In addition, the ’224 Patent specification describes a clinical trial in patients
`
`with “advanced (metastatic or unresectable) [PNETs] after failure of cytotoxic
`
`chemotherapy.” Ex. 1001, ’224 Patent, col. 26, ll. 56-60. If “advanced” meant
`
`that the patients had previously failed to respond to cytotoxic chemotherapy, it
`
`would not have been necessary to specify that the patients were enrolled “after
`
`failure of cytotoxic chemotherapy.” Ex. 2001, Kulke Decl. ¶ 34. The ’224 Patent
`
`specification therefore does not support an interpretation of the term “advanced”
`
`wherein the PNETs have failed to respond to cytotoxic chemotherapy.
`
`Third, a person of ordinary skill would have understood “advanced” tumors
`
`to mean tumors that were metastatic or unresectable (see pages 7-9, above)—not
`
`tumors that failed to respond to cytotoxic chemotherapy. One of ordinary skill also
`
`would have understood, consistent with the ’224 Patent specification, that the
`
`10
`
`
`
`
`
`
`
`majority of PNETs were “advanced” when a patient was first diagnosed with a
`
`PNET and before treatment with any therapy, including cytotoxic chemotherapy.
`
`Ex. 2001, Kulke Decl. ¶¶ 33-34. Therefore, one of ordinary skill would not have
`
`defined “advanced” PNETs as those PNETs that had failed cytotoxic
`
`chemotherapy.
`
`For the above reasons, there is no support in either the ’224 Patent or the art
`
`to equate the terms “advanced” and “after failure of cytotoxic chemotherapy.”
`
`These terms are used to describe two different aspects of the claim element
`
`“advanced [PNETs] after failure of cytotoxic chemotherapy” and should not be
`
`conflated. The plain and ordinary meaning of “advanced” PNETs, as understood
`
`by one of ordinary skill in the art, would be PNETs that were metastatic or
`
`unresectable.
`
`V. The Board Should Deny Grounds 3 And 4 Because No Reference
`Teaches Or Suggests The Claim Element “Advanced [PNETs] After
`Failure Of Cytotoxic Chemotherapy”
`
`To succeed on obviousness, a petitioner must “explain adequately how the
`
`references teach or render obvious the [claim] limitation[s].” NetApp Inc. v.
`
`Crossroads Sys., Inc., IPR2014-01233, 2015 WL 996342, at *5 (Patent Tr. & App.
`
`Bd. Feb. 10, 2015). In particular, a petition “must specify where each element of
`
`the claim is found in the prior art patents or printed publications relied upon.” 37
`
`C.F.R. § 42.104(b)(4). Ignoring a claim element is a basis to deny institution. See
`
`11
`
`
`
`
`
`
`
`IntelGenX Corp. v. ICOS Corp., IPR2016-00678 (Patent Tr. & App. Bd. Sept. 1,
`
`2016), Paper 13 at 6-7 (denying institution where petitioner ignored claim
`
`element); see also Par Pharm., Inc. v. Novartis AG, IPR2016-00078, 2016 WL
`
`2849201, at *6 (Patent Tr. & App. Bd. Apr. 28, 2016) (denying institution where
`
`petitioner failed to indicate why disclosure in prior art reference taught claim
`
`element).
`
`In Ground 3, Par contends that claims 1-3 would have been obvious based
`
`on Boulay 2004 in view of O’Donnell and Duran. Ground 4, which is limited to
`
`claim 2, further relies on Tabernero. But contrary to 37 C.F.R. § 42.104(b)(4),
`
`Par’s Petition fails to specify how the references in Grounds 3 and 4 teach or
`
`suggest the claim element “advanced [PNETs] after failure of cytotoxic
`
`chemotherapy,” and none of those references provides this teaching or suggestion.
`
`A. Boulay 2004
`
`Boulay 2004 does not teach or suggest the claim element “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy,” and Par does not contend that it
`
`does. Boulay 2004 describes in vivo studies with everolimus using cells from the
`
`CA20948 “rat pancreatic tumor model” that had been injected under the skin of
`
`rats. Ex. 1005, Boulay 2004 at 252, 253; Ex. 2001, Kulke Decl. ¶ 36. Boulay
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`2004 does not report results of any testing against “advanced [PNETs] after failure
`
`of cytotoxic chemotherapy” or suggest the use of everolimus in such a setting. Id.
`
`12
`
`
`
`
`
`
`
`Par asserts (albeit incorrectly1) that the CA20948 cell line used in Boulay 2004 is a
`
`model for PNETs, but never suggests that this cell line is a model for “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy.” See Pet. 32-34 (admitting
`
`that Boulay 2004 does not “explicitly identify administration after failure of
`
`cytotoxic chemotherapy”), 49, 50; Ex. 1003, Ratain Decl. ¶¶ 112, 117, 137, 163,
`
`167; Ex. 2001, Kulke Decl. ¶ 36. The CA20948 cell line is not such a model. Ex.
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`2001, Kulke Decl. ¶ 36. As discussed further below (see Section VI.A.), a person
`
`of ordinary skill would have known that “advanced [PNETs] after failure of
`
`cytotoxic chemotherapy” are generally more aggressive and less likely to respond
`
`to subsequent therapies and thus, the alleged disclosure of a model for PNETs in
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`Boulay 2004 is not a disclosure of a model for “advanced [PNETs] after failure
`
`of cytotoxic chemotherapy.” Ex. 2001, Kulke Decl. ¶ 36.
`
`
`
` Novartis does not agree that the CA20948 cell line is a PNET cell line or a model
`
` 1
`
`for PNETs, or that activity in vivo against the CA20948 cell line would have
`
`reasonably predicted efficacy against PNETs in vivo or in humans (see Ex. 2001,
`
`Kulke Decl. ¶ 36 n.2), but does not address these disagreements in this Preliminary
`
`Response. Instead, Novartis focuses on why the CA20948 cell line is not a model
`
`for “advanced [PNETs] after failure of cytotoxic chemotherapy.”
`
`13
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`
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`
`
`
`
`B. O’Donnell
`
`O’Donnell similarly does not teach or suggest the claim element “advanced
`
`[PNETs] after failure of cytotoxic chemotherapy,” and Par does not argue
`
`otherwise. See Pet. 34-35 (admitting that O’Donnell does not “explicitly disclose
`
`the treatment of humans with advanced pancreatic NETs” or “explicitly teach
`
`administration after failure of cytotoxic chemotherapy”), 49, 50; Ex. 1003, Ratain
`
`Decl. ¶¶ 119, 138, 164, 167; Ex. 2001, Kulke Decl. ¶ 37. O’Donnell describes a
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`single Phase I everolimus clinical trial in “solid tumors” of the liver (hepatocellular
`
`carcinoma), soft-tissue (fibrosarcoma), lung (non-small-cell lung cancer
`
`(“NSCLC”)), and other unspecified tissues. Ex. 1029, O’Donnell at 803; Ex. 2001,
`
`Kulke Decl. ¶ 37. None of the patients is stated to have PNETs or advanced
`
`tumors, let alone advanced PNETs. Id. And, none of the patients is stated to have
`
`previously failed cytotoxic chemotherapy. Id.
`
`A person of ordinary skill would not have assumed that the “solid tumors” in
`
`the O’Donnell patients were all advanced tumors that had previously failed to
`
`respond to cytotoxic chemotherapy. Ex. 2001, Kulke Decl. ¶ 38. Cytotoxic
`
`14
`
`
`
`
`
`
`
`chemotherapy was not always used to treat all types of tumors. Id.2 Thus, patients
`
`could have been enrolled in the O’Donnell study without having been previously
`
`treated with cytotoxic chemotherapy. Id.
`
`Thus, there is no basis to conclude that the solid tumors treated with
`
`everolimus in O’Donnell were advanced PNETs, or advanced PNETs that had
`
`previously failed to respond to cytotoxic chemotherapy. Id. at ¶ 39. O’Donnell
`
`does not teach or suggest the claim element “advanced [PNETs] after failure of
`
`cytotoxic chemotherapy.” Id.
`
`C. Duran
`
`Duran also does not teach or suggest the claim element “advanced [PNETs]
`
`after failure of cytotoxic chemotherapy.” Duran is an abstract reporting interim
`
`observations on a single ongoing Phase II clinical trial with the compound
`
`temsirolimus—not everolimus. Ex. 1011, Duran at 3096; Ex. 2001, Kulke Decl.
`
`¶ 40. The trial was conducted in patients with neuroendocrine carcinomas (NECs)
`
`that were metastatic (i.e., advanced tumors that had spread to distant sites in the
`
`
`
` For example, in patients with hepatocellular carcinoma, one of the tumor types
`
` 2
`
`disclosed in O’Donnell, systemically administered chemotherapy “had been
`
`disappointing.” Ex. 2010, Padzur at 330.
`
`15
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`body). Ex. 1011,
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