UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ROXANE LABORATORIES, INC.
`Petitioner
`
`
`
`v.
`
`
`
`NOVARTIS AG
`Patent Owner
`
`
`
`Case No. To Be Assigned
`Patent No. 9,006,224
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 9,006,224
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`
`
`I.
` 
`  MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8 ..................... 4 II.
`
`INTRODUCTION ........................................................................................... 1 
`
`A. 
`Real Party-In-Interest ............................................................................ 4 
`B. 
`Related Matters ...................................................................................... 4 
`C. 
`Lead And Backup Counsel .................................................................... 5 
`D. 
`Service Information ............................................................................... 6 
`PAYMENT OF FEES ..................................................................................... 6 
`III.
` 
`  REQUIREMENTS UNDER 37 C.F.R. § 42.104 ............................................ 6 
`IV.
`A.  Grounds For Standing ........................................................................... 6 
`B. 
`Identification Of Challenge And Precise Relief Requested .................. 7 
`Claims For Which Inter Partes Review Is Requested ................ 7 
`1.
` 
`2.
`The Prosecution History Of The ’224 Patent ............................. 8 
` 
`a. 
`Non-Final Office Action (February 16, 2011) ................. 8 
`b. 
`Response (August 2, 2011) ............................................... 9 
`c. 
`Final Office Action (October 13, 2011) ........................... 9 
`d. 
`Response After Final Office Action (January 13,
`2012) ............................................................................... 10 
`Request For Continued Examination And
`Declaration Filed February 6, 2012 In Support Of
`Non-Obviousness ............................................................ 11 
`Non-Final Office Action (May 9, 2014) ......................... 11 
`f. 
`Response (November 7, 2014) ....................................... 12 
`g. 
`Statutory Grounds On Which The Challenge Is Based ............ 13 
`3.
` 
`Evidence Relied Upon To Support The Challenge ................... 14 
`4.
` 
`How The Challenged Claims Are To Be Construed ................ 14 
`5.
` 
`V.
`  DESCRIPTION OF THE PURPORTED INVENTION ............................... 14 
`  CLAIM CONSTRUCTION .......................................................................... 15 
`VI.
`A.  Applicable Law ................................................................................... 15 
`B. 
`Construction Of Claim Terms ............................................................. 17 
`
`
`e. 
`
`TABLE OF CONTENTS
`
`  PERSON HAVING ORDINARY SKILL IN THE ART ............................. 17 VII.
`
`i
`
`

`
`IX.
`
`X.
`
` 
`
`XI.
`
`  TECHNICAL BACKGROUND AND STATE OF THE ART .................... 18 VIII.
`
`
`A. 
`The Biology Of PNETs ....................................................................... 19 
`B. 
`Everolimus As A Treatment For PNET .............................................. 22 
`C. 
`The Prior Art Taught That Everolimus Has Enhanced Solubility
`And Pharmacokinetics Compared To Rapamycin .............................. 26 
`  THE SCOPE AND CONTENT OF THE PRIOR ART ................................ 27 
`A.  U.S. Patent No. 5,665,772 ................................................................... 27 
`B. 
`U.S. Publication No. 2004/0147541 ................................................... 29 
`C. 
`Tabernero ............................................................................................. 30 
`D.  Dutcher ................................................................................................ 31 
`E. 
`von Wichert ......................................................................................... 32 
`THE PERTINENT LAW REGARDING MOTIVATION TO
`COMBINE THE PRIOR ART REFERENCES ............................................ 33 
`  PRECISE REASONS FOR THE RELIEF REQUESTED ........................... 34 
`A.  Ground 1: Claims 1 And 2 Are Invalid Under 35 U.S.C. § 103
`On The Ground That They Are Rendered Obvious Over The
`’541 Publication In View Of Tabernero .............................................. 35 
`1.
`Claim 1 Of The ’224 Patent Is Obvious Over The ’541
` 
`Publication In View Of Tabernero ............................................ 36 
`a. 
`The Prior Art Taught That Everolimus Decreases
`PNET Growth ................................................................. 36 
`The Prior Art Taught That Everolimus Is Safe And
`Efficacious Against Solid Tumors In Humans ............... 38 
`Claim 2 Of The ’224 Patent Is Obvious Over The ’541
`Publication In View Of Tabernero ............................................ 39 
`Ground 2: Claims 1 And 2 Are Invalid Under 35 U.S.C. § 103
`On The Ground That They Are Rendered Obvious Over von
`Wichert In View Of Dutcher, The ’772 Patent And Tabernero .......... 40 
`1.
`Claim 1 Of The ’224 Patent Is Obvious Over von Wichert
` 
`In View Of Dutcher, The ’772 Patent And Tabernero ............. 40 
`a. 
`The Prior Art Taught That Rapamycin Is
`Efficacious Against PNET Cells .................................... 40 
`The Prior Art Taught That Everolimus And
`Rapamycin Have Similar Antitumor Properties ............. 41 
`
`2.
` 
`
`B. 
`
`b. 
`
`b. 
`
`ii
`
`

`
`c. 
`
`d. 
`
`2.
` 
`
`  SECONDARY CONSIDERATIONS DO NOT RENDER CLAIMS 1 XII.
`
`The Prior Art Taught That Everolimus Has
`Increased Solubility And Improved
`Pharmacokinetic Properties Compared To
`Rapamycin ...................................................................... 42 
`The Prior Art Taught That Everolimus Is Safe And
`Efficacious Against Solid Tumors In Humans ............... 43 
`Claim 2 Of The ’224 Patent Is Obvious Over von Wichert
`In View Of Dutcher, The ’772 Patent And Tabernero ............. 44 
`
`AND 2 NONOBVIOUS ................................................................................ 45 
`A. 
`The Methods Claimed In The ’224 Patent Produced No Relevant
`Unexpected Results ............................................................................. 46 
`The ’224 Patent Did Not Satisfy Any Long Felt But Unmet
`Need, And The Sales Of Afinitor® (Everolimus) Tablets Do Not
`Evidence Commercial Success ............................................................ 48 
`Copying By Generic Drug Makers Is Irrelevant ................................. 49 
`C. 
`
`
`B. 
`
`  CONCLUSION .............................................................................................. 49 XIII.
`
`iii
`
`
`
`
`
`

`
`Exhibit
`No.
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`EXHIBIT LIST
`
`Description
`
`U.S. Patent No. 9,006,224 (“the ’224 Patent”)
`
`Excerpts from File History for the ’224 Patent
`
`Declaration of Dr. Kenneth H. Yu in Support of Petition for Inter Partes
`Review of U.S. Patent No. 9,006,224 (“Yu Declaration”)
`
`Curriculum Vitae of Dr. Kenneth H. Yu
`
`U.S. Patent Application Publication No. 2004/0147541 A1 (“the ’541
`Publication”)
`
`Tabernero et al., A phase I study with tumor molecular
`pharmacodynamics (MPD) evaluation of dose and schedule of the oral
`mTOR-inhibitor Everolimus (RAD001) in patients (pts) with advanced
`solid tumors, DEVELOPMENTAL THERAPEUTICS: MOLECULAR
`THERAPEUTICS, Abstract 3007, 193s (2005) (“Tabernero”)
`
`von Wichert et al., Insulin-like Growth Factor-I is an Autocrine
`Regulator of Chromogranin A Secretion and Growth in Human
`Neuroendocrine Tumor Cells, CANCER RESEARCH, 60: 4573-4581
`(August 15, 2000) (“von Wichert”)
`
`Dutcher, Mammalian Target of Rapamycin (mTOR) Inhibitors, CURRENT
`ONCOLOGY REPORTS, 6: 111-115 (2004) (“Dutcher”)
`
`U.S. Patent No. 5,665,772 (“the ’772 Patent”)
`
`Doran et al., Epidemiology of Pancreatic Neuroendocrine Tumours, in
`PANCREATIC DISEASE: BASIC SCIENCE AND CLINICAL MANAGEMENT, 5
`(Johnson et al. eds., 2004) (“Doran”)
`
`Guo et al., Frequent overexpression of cyclin D1 in sporadic pancreatic
`endocrine tumours, JOURNAL OF ENDOCRINOLOGY, 179: 73-79 (2003)
`(“Guo”)
`
`iv
`
`

`
`Exhibit
`No.
`
`Description
`
`1012 World Health Organization Classification of Tumours, Pathology &
`Genetics | Tumours of Endocrine Organs, (DeLellis et al., Eds.) 175-261
`(April 23-26, 2003)
`
`1013 McStay & Caplin, GI Hormone Producing Tumours: Syndromes and
`Treatment Options, in PANCREATIC DISEASE: BASIC SCIENCE AND
`CLINICAL MANAGEMENT 31 (Johnson et al., eds., 2004) (“McStay”)
`
`1014
`
`Harris, von Hippel-Lindau Syndrome: Target for Anti-Vascular
`Endothelial Growth Factor (VEGF) Receptor Therapy, THE ONCOLOGIST,
`5(suppl. 1): 32-36 (2000) (“Harris”)
`
`1015
`
`Calender, Molecular Genetics of Neuroendocrine Tumors, DIGESTION,
`62(suppl. 1): 3-18 (2000) (“Calender”)
`
`1016 Maxwell et al., The tumour suppressor protein VHL targets hypoxia-
`inducible factors for oxygen-dependent proteolysis, NATURE, 399: 271-
`275 (1999) (“Maxwell”)
`
`1017
`
`1018
`
`1019
`
`1020
`
`Semenza, Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor
`Progression, CRITICAL REVIEWS IN BIOCHEMISTRY & MOLECULAR
`BIOLOGY, 35(2): 71-103 (2000) (“Semenza”)
`
`Kwiatkowski, Rhebbing up mTOR, CANCER BIOLOGY & THERAPY,
`2(5):471-76 (2003) (“Kwiatkowski”)
`
`Brugarolas et al., Regulation of mTOR function in response to hypoxia by
`REDD1 and the TSC1/TSC2 tumor suppressor complex, GENES &
`DEVELOPMENT, 18:2893–2904 (2004) (“Brugarolas”)
`
`Perren et al., Mutation and Expression Analyses Reveal Differential
`Subcellular Compartmentalization of PTEN in Endocrine Pancreatic
`Tumors Compared to Normal Islet Cells, AMERICAN JOURNAL OF
`PATHOLOGY, 157(4): 1097-1103 (October 2000) (“Perren”)
`
`v
`
`

`
`Exhibit
`No.
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`Description
`
`Sekulić et al., A Direct Linkage between the Phosphoinositide 3-Kinase-
`AKT Signaling Pathway and the Mammalian Target of Rapamycin in
`Mitogen-stimulated and Transformed Cells, CANCER RESEARCH, 60:
`3504-3513 (July 1, 2000) (“Sekulić”)
`
`Yee et al., A Phase I/II Study of the Oral mTOR Inhibitor RAD001 in
`Patients with Advanced Hematologic Malignancies, JOURNAL OF
`IMMUNOTHERAPY, 27(6): S35, Abstract (November/December 2004)
`(“Yee”)
`
`Vara et al., PI3K/Akt signalling pathway and cancer, CANCER
`TREATMENT REVIEWS, 30: 193-204 (2004) (“Vara”)
`
`Vignot et al., mTOR-targeted therapy of cancer with rapamycin
`derivatives, ANNALS OF ONCOLOGY, 16: 525-537 (February 22, 2005)
`(“Vignot”)
`
`Boulay 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 RESEARCH, 64: 252-261 (2004)
`(“Boulay”)
`
`Carraway & Hidalgo, New targets for therapy in breast cancer:
`Mammalian target of rapamycin (mTOR) antagonists, BREAST CANCER
`RESEARCH, 6: 219-224 (2004) (“Carraway”)
`
`Podsypanina et al., An Inhibitor of mTOR Reduces Neoplasia and
`Normalizes p70/S6 Kinase Activity in Pten+/- Mice, PNAS, 98(18):
`10320-10325 (2001) (“Podsypanina”)
`
`Hidalgo & Rowinsky, The rapamycin-sensitive signal transduction
`pathway as a target for cancer therapy, ONCOGENE 19: 6680-6686 (2000)
`(“Hidalgo”)
`
`vi
`
`

`
`Exhibit
`No.
`
`1029
`
`Description
`
`Breeman et al., Radioiodinated Somatostatin Analogue RC-160:
`Preparation, Biological Activity, in Vivo Application in Rats and
`Comparison with [123I-Tyr3]Octreotide, EUROPEAN JOURNAL OF
`NUCLEAR MEDICINE, 20: 1089-1094 (1993) (“Breeman”)
`
`1030
`
`Evers et al., Establishment and Characterization of a Human Carcinoid
`in Nude Mice and Effect of Various Agents on Tumor Growth,
`GASTROENTEROLOGY, 101(2): 303-11 (1991) (“Evers”)
`
`1031 Morris, Rapamycins: Antifungal, Antitumor, Antiproliferative, and
`Immunosuppressive Macrolides, TRANSPLANTATION REVIEWS, 6(1): 39-87
`(1992) (“Morris”)
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`Crowe et al., Absorption and Intestinal Metabolism of SDZ-RAD and
`Rapamycin in Rats, DRUG METABOLISM & DISPOSITION, 27(5): 627-32
`(1999) (“Crowe”)
`
`De Jong et al., Therapy of neuroendocrine tumors with radiolabeled
`somatostatin analogues, THE QUARTERLY JOURNAL OF NUCLEAR
`MEDICINE, 43: 356-66 (1999) (“De Jong”)
`
`Houghton & Huang, mTOR as a Target for Cancer Therapy in TOR
`TARGET OF RAPAMYCIN, G. Thomas et al. (eds.) 339-359 (2004)
`(“Houghton”)
`
`Yu et al., mTOR, a Novel Target in Breast Cancer: the Effect of CCI-779,
`an mTOR Inhibitor, in Preclinical Models of Breast Cancer, Endocrine-
`Related Cancer, 8: 249-258 (2001) (“Yu”)
`
`Ahnert-Hilger et al., γ-Aminobutyric Acid Secretion From Pancreatic
`Neuroendocrine Cells, GASTROENTEROLOGY, 110: 1595–1604 (1996)
`(“Ahnert-Hilger”)
`
`Lemmer et al., Expression of dopamine receptors and transporter in
`neuroendocrine gastrointestinal tumor cells, LIFE SCIENCES, 71: 667–678
`(2002) (“Lemmer”)
`
`vii
`
`

`
`Exhibit
`No.
`
`1038
`
`1039
`
`1040
`
`Description
`
`Jonas et al., Somatostatin receptor subtypes in neuroendocrine tumor cell
`lines and tumor tissues, LANGENBECKS ARCHIVES OF SURGERY, 380: 90–
`95 (1995) (“Jonas”)
`
`Detjen, et al., Molecular Mechanism of Interferon Alfa–Mediated Growth
`Inhibition in Human Neuroendocrine Tumor Cells, GASTROENTEROLOGY,
`118: 735–748 (2000) (“Detjen”)
`
`John, et al., Guanylin Stimulates Regulated Secretion From Human
`Neuroendocrine Pancreatic Cells, GASTROENTEROLOGY, 114: 791–797
`(1998) (“John”)
`
`1041 Waiver of the Service of Summons (D.I. 9) as filed on August 21, 2015 in
`C.A. No. 15-474-RGA (D. Del.)
`
`
`
`
`
`viii
`
`

`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 49
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ............................................................................ 33
`
`Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc.,
`752 F3d 967 (Fed. Cir. 2014) ............................................................................. 47
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed Cir. 2014) ............................................................................. 47
`
`Galderma Labs. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 48
`
`In re Geisler,
`116 F.3d 1465 (Fed. Cir. 1997) .......................................................................... 34
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................ 34
`
`Hoffmann-La Roche, Inc. v. Apotex, Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .......................................................................... 47
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 407 (2007) ...................................................................................... 33, 34
`
`Leapfrog Enters. Inc. v. Fisher-Price Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 45
`
`Merck & Co., Inc. v. Biocraft Labs, Inc.,
`874 F.3d 804 (Fed. Cir. 1989) ............................................................................ 34
`
`Merck Co., Inc. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .......................................................................... 49
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) .......................................................................... 16
`
`ix
`
`

`
`Newell Co. v. Kenney Mfg. Co.,
`864 F.2d 757 (Fed. Cir. 1988) ............................................................................ 45
`
`In re PepperBall Techs., Inc.,
`469 F. App’x 878 (Fed. Cir. 2012) ..................................................................... 48
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 45
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 16
`
`Santarus, Inc. v. Par Pharm, Inc.,
`694 F.3d 1357 (Fed. Cir. 2012) ......................................................................... 35
`
`SAP Am., Inc. v. Versata Dev. Grp., Inc.,
`No. CBM2012-00001 (P.T.A.B. Jan. 9, 2013) ................................................... 17
`
`Sibia Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349 (Fed. Cir. 2000) .......................................................................... 49
`
`Versata Dev. Grp., Inc. v. SAP Am., Inc.,
`793 F.3d 1306 (Fed. Cir. 2015) .......................................................................... 16
`
`Statutes
`35 U.S.C. § 102(b) ............................................................................................passim
`
`35 U.S.C. § 103 ............................................................................................ 14, 35, 40
`
`35 U.S.C. § 103(a) ................................................................................................... 13
`
`35 U.S.C. § 301(a) ................................................................................................... 17
`
`35 U.S.C. §§ 311-319 ................................................................................................ 1
`
`35 U.S.C. § 318(a) ..................................................................................................... 7
`
`Other Authorities
`
`37 C.F.R. § 42.8 ......................................................................................................... 4
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 4
`
`x
`
`

`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 4
`37 C.F.R. § 42.8(b)(2) .............................................................................................. ..4
`
`37 C.F.R. § 42.10(b) .................................................................................................. 5
`37 C.F.R. §42.10(b) ................................................................................................ ..5
`
`37 C.F.R. § 42.15(a) ................................................................................................... 6
`37 C.F.R. §42.15(a) ................................................................................................. ..6
`
`37 C.F.R. § 42.100(b) ........................................................................................ 14, 15
`37 C.F.R. §42.100(b) ...................................................................................... ..14, 15
`
`37 C.F.R. § 42.100 et seq. .......................................................................................... 1
`37 C.F.R. § 42.100 et seq ......................................................................................... ..1
`
`37 C.F.R. § 42.104 ..................................................................................................... 6
`37 C.F.R. § 42.104 ................................................................................................... ..6
`
`37 C.F.R. § 42.104(a) ................................................................................................. 6
`37 C.F.R. §42.104(a) ............................................................................................... ..6
`
`37 C.F.R. § 42.104(b) ................................................................................................ 7
`37 C.F.R. §42.104(b) .............................................................................................. ..7
`
`77 Fed. Reg. 48699 .................................................................................................. 16
`77 Fed. Reg. 48699 ................................................................................................ ..16
`
`77 Fed. Reg. 48759-60 ............................................................................................... 4
`77 Fed. Reg. 48759-60 ............................................................................................. ..4
`
`
`
`xi
`
`Xi
`
`

`
`
`I.
`
`INTRODUCTION
`
`Roxane Laboratories, Inc. (“Roxane” or the “Petitioner”) respectfully
`
`requests an inter partes (“IPR”) review for Claims 1 and 2 of U.S. Patent
`
`No. 9,006,224, issued on April 14, 2015 to Marks et al. (“the ’224 Patent”) (Ex.
`
`1001) in accordance with 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42.100 et seq.
`
`The ’224 Patent is directed to a method for treating neuroendocrine tumors
`
`comprising administering a therapeutically effective amount of everolimus, a
`
`derivative of the compound rapamycin, as a monotherapy, wherein the tumors are
`
`advanced tumors after failure of cytotoxic chemotherapy. Claim 1 of the ‘224
`
`Patent reads as follows:
`
`1. A method for treating pancreatic neuroendocrine tumors,
`comprising administering to a human subject in need thereof a
`therapeutically effective amount of 40-0-(2-hydroxyethyl)-
`rapamycin as a monotherapy and wherein the tumors are
`advanced tumors after failure of cytotoxic chemotherapy.
`
`Claim 2 depends from Claim 1 and specifies a unit dose of 10 mg/day. There is a
`
`reasonable likelihood that at least one of Claims 1 and 2 is unpatentable because it
`
`would have been obvious to a person of ordinary skill in the art (“POSA”).
`
`The prior art discloses that CA20948 pancreatic cell line can be used as a
`
`model for pancreatic neuroendocrine tumors (“PNET”). De Jong, Exhibit 1033 at
`
`356; Breeman, Exhibit 1029 at 1089; Boulay, Exhibit 1025 at 252. It was also
`
`1
`
`

`
`known in the prior art that everolimus monotherapy “significantly and consistently
`
`decrease[d] … the rate of CA20948 pancreatic tumor growth.” U.S. Publication
`
`No. 2004/0147541 (“the ’541 Publication”), Exhibit 1005 at [0088]. In addition, a
`
`dose of 10 mg everolimus was known to be safe and effective for treatment of
`
`advanced solid tumors. Tabernero, Exhibit 1006 at 193s. Based on the above
`
`alone, a POSA would have been motivated to use 10 mg of everolimus to treat
`
`advanced PNET and would have had a reasonable expectation of success in doing
`
`so.
`
`The prior art also teaches that rapamycin is an effective inhibitor of
`
`proliferation of BON cells, a cell line established from human pancreatic
`
`neuroendocrine tumor. von Wichert, Exhibit 1007 at 4573; see also Evers, Exhibit
`
`1030 (disclosing that the BON cell line is derived from a metastatic human
`
`carcinoid tumor of the pancreas or PNET); Ahnert-Hilger, Exhibit 1036 at 1601
`
`(describing BON as a PNET cell line); Lemmer, Exhibit 1037 at 667 (describing
`
`BON as a pancreatic neuroendocrine cell line); Jonas, Exhibit 1038 at 91, 92
`
`(describing human neuroendocrine pancreatic cell line BON); Detjen, Exhibit 1039
`
`at 736 (disclosing BON as a neuroendocrine pancreatic cell line); John, Exhibit
`
`1040 at 791, 796 (disclosing BON as a pancreatic cell line derived from a human
`
`neuroendocrine tumor).
`
`2
`
`

`
`Everolimus was known to have antitumor properties and a mechanism of
`
`action similar to rapamycin, was known to be more soluble and bioavailable than
`
`rapamycin, and was known to be suitable for oral administration. Tabernero,
`
`Exhibit 1006 at 193s. Accordingly, a POSA would have reasonably expected that
`
`everolimus would inhibit proliferation of BON cells and would have been
`
`motivated to develop and use everolimus to treat PNET with an expectation of
`
`success in doing so.
`
`In summary, Claims 1 and 2 of the ’224 Patent would have been obvious to a
`
`POSA in view of prior art that teaches at least the following: (1) that everolimus is
`
`effective against CA20948 pancreatic cell line, a rat cell line that has been used as
`
`a model for PNET; (2) that 10 mg everolimus is safe and effective against
`
`advanced solid tumors; (3) that everolimus and rapamycin have similar antitumor
`
`properties and mechanisms of action; (4) that rapamycin inhibits proliferation in
`
`BON cells, a cell line established from human PNET; and (5) that everolimus is
`
`more soluble and bioavailable than rapamycin.
`
`Roxane provides below a detailed comparison of the claimed subject matter
`
`and the prior art. Roxane respectfully submits that Claims 1 and 2 would have
`
`been obvious in view of the prior art presented herein and therefore requests that
`
`the Board institute an inter partes review on this basis.
`
`3
`
`

`
` MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8
`II.
`A. Real Party-In-Interest
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Roxane is a real-
`
`party-in-interest for this proceeding. Out of an abundance of caution, and as a
`
`result of ongoing integration and reorganization activities, Petitioner identifies the
`
`following additional entities as real-parties-in-interest who, going forward, may
`
`have control over this proceeding: Hikma Pharmaceuticals PLC and its U.S.
`
`subsidiary West-Ward Pharmaceuticals Corp. No other parties exercised or could
`
`have exercised control over this petition; no other parties funded or directed this
`
`petition. See Office Patent Trial Practice Guide, 77 Fed. Reg. 48759-60.
`
`B. Related Matters
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is aware of the following
`
`matters: Novartis Pharmaceuticals Corp. v. Breckenridge Pharmaceutical, Inc.,
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`C.A. No. 14-1043-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane
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`Laboratories, Inc., C.A. No. 14-1196-RGA (D. Del.); Novartis Pharmaceuticals
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`Corp. v. Par Pharmaceutical, Inc., C.A. No. 14-1289-RGA (D. Del.); Novartis
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`Pharmaceuticals Corp. v. Par Pharmaceutical, Inc., C.A. No. 14-1494-RGA (D.
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`Del.); Novartis Pharmaceuticals Corp. v. Par Pharmaceutical, Inc., C.A. No. 15-
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`78-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane Laboratories, Inc.,
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`C.A. No. 14-1508-RGA (D. Del.); Novartis Pharmaceuticals Corp. v. Roxane
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`Laboratories, Inc., C.A. No. 15-128-RGA (D. Del.); Novartis Pharmaceuticals
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`Corp. v. Roxane Laboratories, Inc., C.A. No. 15-474-RGA (D. Del.); Par
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`Pharmaceutical, Inc. v. Novartis AG, IPR2016-00084; Breckenridge
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`Pharmaceutical, Inc. v. Novartis AG, IPR2016-01023; Par Pharmaceutical, Inc.
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`v. Novartis AG, IPR2016-01059; Roxane Laboratories, Inc. v. Novartis AG, IPR
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`2016-01102; and Breckenridge Pharmaceutical, Inc. v. Novartis AG, IPR2016-
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`01103.
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`C. Lead And Backup Counsel
`Lead Counsel:
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`Backup Counsel:
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`Keith A. Zullow (Reg. No. 37,975)
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`Marta E. Delsignore (Reg. No. 32,689)
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`(kzullow@goodwinprocter.com)
`
`(mdelsignore@goodwinprocter.com)
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`GOODWIN PROCTER LLP
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`GOODWIN PROCTER LLP
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`The New York Times Building
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`The New York Times Building
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`620 Eighth Avenue
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`620 Eighth Avenue
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`New York, NY 10018-1405
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`New York, NY 10018-1405
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`T: 212-813-8846
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`F: 646-558-4226
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`T: 212-813-8822
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`F: 646-558-4079
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`A Power of Attorney is being filed concurrently herewith in accordance with
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`37 C.F.R. § 42.10(b).
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`Service Information
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`D.
`Papers concerning this matter should be served by EXPRESS MAIL, hand-
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`delivery, or electronic mail at the following address:
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`Mailing Address:
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`Keith A. Zullow, Esq.
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`
`
`
`
`
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`GOODWIN PROCTER LLP
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`The New York Times Building
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`620 Eighth Avenue
`
`
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`New York, NY 10018-1405
`
`Electronic Mail:
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`kzullow@goodwinprocter.com
`
`Telephone:
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`Facsimile:
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`212-813-8846
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`646-558-4226
`
` PAYMENT OF FEES
`III.
`The undersigned authorizes payment of $23,000.00 for the fees set forth in
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`37 C.F.R. § 42.15(a) to be charged to Deposit Account No. 50-6989. The
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`undersigned further authorizes payment for any additional fees that might be due in
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`connection with this Petition to be charged to Deposit Account No. 50-6989.
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`IV.
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` REQUIREMENTS UNDER 37 C.F.R. § 42.104
`A. Grounds For Standing
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ‘224
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`Patent is available for inter partes review and Petitioner is not barred or estopped
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`from requesting inter partes review of the challenged claims of the ‘224 Patent on
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`the grounds identified in this Petition. Neither Petitioner nor any privy of
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`Petitioner has received a final written decision under 35 U.S.C. § 318(a) with
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`respect to any claim of the ’224 Patent on any ground that was raised or could have
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`been raised by Petitioner or its privies in any inter partes review, post grant review,
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`or covered business method patent review.
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`This Petition is timely filed. On June 10, 2015, Novartis Pharmaceuticals
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`Corporation and Novartis AG (“Novartis”) filed a Complaint against Petitioner
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`alleging infringement of, inter alia, the ’224 Patent. C.A. No. 15-474-RGA
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`(D. Del.), D.I. 1. Petitioner executed a waiver of service on July 20, 2015.
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`Pursuant to Rule 4(d)(4) of the Federal Rules of Civil Procedure, Novartis filed the
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`waiver of service on August 21, 2015 (C.A. No. 15-474-RGA, D. Del., D.I. 9;
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`Exhibit 1041), thus starting the one-year time period for Petitioner to file this IPR
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`petition.
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`Identification Of Challenge And Precise Relief Requested
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`B.
`Pursuant to 37 C.F.R. § 42.104(b), Petitioner challenges Claims 1 and 2 of
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`the ’224 Patent and requests that these claims be found unpatentable over the prior
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`art for the reasons given herein.
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`Claims For Which Inter Partes Review Is Requested
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`1.
`Petitioner requests inter partes review of Claims 1 and 2 of the ’224 Patent.
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`Claim 1, the only independent claim in the ’224 patent, is directed to a method for
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`treating PNET comprising administering a therapeutically effective amount of
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`everolimus, wherein the tumors are advanced tumors after failure of cytotoxic
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`chemotherapy. Claim 2 depends directly from Claim 1 and specifies that the unit
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`dose of everolimus is 10 mg/day.
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`The Prosecution History Of The ’224 Patent
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`2.
`U.S. Application No. 12/094,173 (“the ’173 Application”) was filed on
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`August 19, 2008 with twelve claims directed to the use of an mTOR inhibitor for
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`endocrine disorders. In response to a November 30, 2010 Restriction Requirement
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`that required election of a single invention, Applicants elected to proceed with
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`Group I claims directed to a method of treating endocrine tumors and withdrew the
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`remaining claims. Ex. 1002 at 11-14. Claims 1-3, 8-9 and 12 remained pending in
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`the application.
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`a.
`Non-Final Office Action (February 16, 2011)
`The Examiner rejected Claims 1-3 and 12 as anticipated by O’Reilly et al.
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`(Proceedings of the American Association for Cancer Research Annual Meeting,
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`03/2002, Vol. 43, pg. 71) (“O’Reilly”) as evidenced by Merck Manuals (Merck
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`Manuals, Pancreatic endocrine tumors, 2009, pgs. 1-4) (“Merck Manuals”).
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`Exhibit 1002 at 19-20. The Examiner stated that O’Reilly teaches the use of
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`everolimus as a bioavailable rapamycin derivative that has been found to be a
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`potent inhibitor of tumor growth in 10 different cell lines and in vivo against
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`pancreatic tumors. Id. The Examiner stated that Merck Manuals demonstrated that
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`pancreatic cancer is characterized by endocrine tumors and thus pancreatic tumors
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`are classified as endocrine tumors. Id.
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`The Examiner also rejected Claims 1-3, 8-9 and 12 as anticipated by WO
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`97/47317 to Weckbecker (“the ’317 Publication”). Id. at 20-21. The Examiner
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`stated that the ’317 Publication teaches a combination of a somatostatin analogue
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`and a rapamycin derivative, e.g., everolimus, for the prevention and treatment of
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`cell hyperproliferation. Id.
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`b.
`Applicants cancelled Claim 12. In response to the anticipation rejection,
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`Response (August 2, 2011)
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`
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`Applicants amended Claims 1-3 and 8-9 to recite everolimus and argued that the
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`cited art does not disclose or suggest everolimus for the treatment of endocrine
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`tumors or pancreatic neuroendocrine tumors. Id. at 55-58.
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`c.
`The Examiner rejected Claims 1-3 as anticipated by O’Reilly as evidenced
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`Final Office Action (October 13, 2011)
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`
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`by Merck Manuals, reiterating the argument previously made. Id. at 63-64.
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`The Examiner also rejected Claims 1-3 and 8-9 as obvious over the ’317
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`Publication as evidenced by Novartis Data Sheet (Novartis, GEP NE tumors,
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`published online on 4/2005, pgs. 1-2) (“Novartis Data Sheet”). Id. at 65-67. The
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`Examiner stated that the ’317 Publication teaches a combination of a somatostatin
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`analogue and a rapamycin derivative for the prevention and treatment of cell
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`hyperproliferation. Id. The Examiner stated that Novartis Data Sheet demonstrates
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`that gastroenteropancreatic neuroendocrine tumors (“GEP”) are slow growing
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`tumors that occur in the pancreas and gastrointestinal tract an