Petition for Inter Partes Review of USP 9,006,224
`
` 
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`In re Inter Partes Review of:
`U.S. Patent No. 9,006,224
`Issued: Apr. 14, 2015
`Application No.: 12/094,173
`PCT Filing Date: Nov. 20, 2006
`
`
`For: Neuroendocrine Tumor Treatment
`
`FILED VIA E2E
`
`
`
`)
`)
`)
`)
`)
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,006,224
`
`
`
`
`

`

` 
`
`
`Petition for Inter Partes Review of USP 9,006,224
`
`III. 
`
`TABLE OF CONTENTS
`
`TABLE OF AUTHORITIES ...................................................................................... iv 
`I. 
`OVERVIEW ...................................................................................................... 1 
`II. 
`REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW .......... 2 
`A.  Grounds for Standing (37 C.F.R. § 42.104(a)) ....................................... 2 
`B. 
`Notice of Lead and Backup Counsel and Service Information ............... 3 
`C. 
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(l)) ..................... 3 
`D.  Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ................................ 4 
`Fee for Inter Partes Review .................................................................... 5 
`E. 
`F. 
`Proof of Service ....................................................................................... 5 
`IDENTIFICATION OF CLAIMS BEING CHALLENGED (37
`C.F.R. § 42.104(B)) ........................................................................................... 6 
`IV.  SUMMARY OF THE ARGUMENT ................................................................ 6 
`V.  OVERVIEW OF THE ’224 PATENT ............................................................ 15 
`VI.  THE PERSON OF ORDINARY SKILL IN THE ART ................................. 18 
`VII.  CLAIM CONSTRUCTION ............................................................................ 19 
`A.  Applicable Law ..................................................................................... 19 
`B. 
`Construction of Claim Terms ................................................................ 21 
`1. 
`“pancreatic neuroendocrine tumor” ............................................ 22 
`2. 
`“advanced tumors” ...................................................................... 23 
`3. 
`“unit dose” ................................................................................... 24 
`4. 
`“islet cell tumor” ......................................................................... 25 
`VIII.  TECHNICAL BACKGROUND AND STATE OF THE ART AT
`THE TIME OF THE PURPORTED INVENTION ........................................ 26 
`A. 
`Rapamycin was well-known as a potent antitumor agent ..................... 26 
`B. 
`Rapamycin derivatives, like everolimus and temsirolimus, were
`known to have similar biological activity to rapamycin ....................... 26 
`
` 
`
`i
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`
`
`C. 
`
`Petition for Inter Partes Review of USP 9,006,224
`
`D. 
`
`The mechanism of action for the immunosuppressant and
`antitumor activity of rapamycin and its derivatives was well-
`characterized .......................................................................................... 31 
`IX.  THE SCOPE AND CONTENT OF THE ASSERTED PRIOR ART ............ 34 
`A.  Öberg 2004 taught that humans with advanced pancreatic NETs
`should be treated with rapamycin as a monotherapy after
`cytotoxic therapy failed ......................................................................... 34 
`Boulay 2004 taught that everolimus was well-tolerated and
`effective at treating pancreatic NETs in rat models .............................. 37 
`O’Donnell taught that everolimus was well-tolerated and
`showed promise as an antitumor agent in human patients .................... 40 
`Tabernero taught that an appropriate dosage for humans taking
`everolimus for the treatment of advanced solid tumors was
`10 mg/day .............................................................................................. 41 
`Duran taught the use of temsirolimus in the treatment of human
`patients with advanced neuroendocrine carcinomas ............................. 42 
`CLAIMS 1-3 WOULD HAVE BEEN OBVIOUS OVER THE PRIOR
`ART ................................................................................................................. 43 
`A. 
`Legal Background ................................................................................. 43 
`B. 
`Ground 1: Claims 1-3 would have been obvious in view of
`Öberg 2004, Boulay 2004, and O’Donnell ........................................... 46 
`1. 
`Claim 1 ........................................................................................ 46 
`2. 
`Claim 2 ........................................................................................ 53 
`3. 
`Claim 3 ........................................................................................ 55 
`Ground 2: Claim 2 would have been obvious in view of Öberg
`2004, Boulay 2004, O’Donnell, and Tabernero .................................... 55 
`D.  Ground 3: Claims 1-3 would have been obvious in view of
`Boulay 2004, O’Donnell, and Duran .................................................... 56 
`1. 
`Claim 1 ........................................................................................ 56 
`2. 
`Claim 2 ........................................................................................ 58 
`3. 
`Claim 3 ........................................................................................ 60 
`ii
`
`B. 
`
`C. 
`
`E. 
`
`C. 
`
`X. 
`
` 
`
`

`

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`
`
`Petition for Inter Partes Review of USP 9,006,224
`
`E. 
`
`Ground 4: Claim 2 of the ’224 patent is invalid as obvious in
`view of Boulay 2004, O’Donnell, Duran, and Tabernero ..................... 61 
`XI.  SECONDARY CONSIDERATIONS FAIL TO OVERCOME THE
`STRONG EVIDENCE OF OBVIOUSNESS ................................................. 62 
`XII.  CONCLUSION ................................................................................................ 64 
`
`
`
` 
`
`iii
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`

`

` 
`
`
`Cases
`
`Petition for Inter Partes Review of USP 9,006,224
`
`TABLE OF AUTHORITIES 
`
` Page(s)
`
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 63
`
`In re Beattie,
`974 F.2d 1309 (Fed. Cir. 1992) .................................................................... 14, 52
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ............................................................................ 46
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S.Ct. 2131,2142 (2016) ................................................................................ 19
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 63
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 44, 62
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .....................................................................................passim
`
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) .......................................................................... 62
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ........................................................ 53-54, 59, 63
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) .......................................................................... 20
`
`In re PepperBall Techs., Inc.,
`469 F. App’x 878 (Fed. Cir. 2012) ..................................................................... 63
`
` 
`
`iv
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`

`

` 
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 54, 60
`
`Petition for Inter Partes Review of USP 9,006,224
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .................................................... 19-20
`
`Ruiz v. A.B. Chance Co.,
`234 F.3d 654 (Fed. Cir. 2000) ............................................................................ 44
`
`SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349 (Fed. Cir. 2000) .......................................................................... 63
`
`Versata Dev. Grp., Inc. v. SAP Am., Inc.,
`793 F.3d 1306 (Fed. Cir. 2015) .......................................................................... 20
`
`Statutes
`
`35 U.S.C. § 102(a) ............................................................................................. 41, 42
`
`35 U.S.C. § 102(b) ....................................................................................... 34, 37, 40
`
`35 U.S.C. § 103 .................................................................................................... 6, 43
`
`35 U.S.C. § 301(a) ................................................................................................... 21
`
`35 U.S.C. § 318(a) ..................................................................................................... 2
`
`Other Authorities
`
`37 C.F.R. § 42.8(b)(1) ................................................................................................ 3
`
`37 C.F.R. § 42.8(b)(2) ................................................................................................ 4
`
`37 C.F.R. § 42.8(b)(3) ................................................................................................ 3
`
`37 C.F.R. § 42.8(b)(4) ................................................................................................ 3
`
`37 C.F.R. § 42.10(a) ................................................................................................... 3
`
`37 C.F.R. § 42.10(b) .................................................................................................. 3
`
` 
`
`v
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`
`37 C.F.R. § 42.15(a) ................................................................................................... 5
`
`Petition for Inter Partes Review of USP 9,006,224
`
`37 C.F.R. § 42.100(b) .............................................................................................. 19
`
`37 C.F.R. § 42.104(a) ................................................................................................. 2
`
`37 C.F.R. § 42.104(b) ................................................................................................ 6
`
`77 Fed. Reg. 48680, 48699 (Aug. 14, 2012) ........................................................... 20
`
`77 Fed. Reg. 48759-60 ............................................................................................... 4
`
`P.T.A.B. Decision
`
`SAP Am., Inc. v. Versata Dev. Grp., Inc.,
`No. CBM2012-00001 (P.T.A.B. Jan. 9, 2013) ................................................... 21
`
`
`
`
`
` 
`
`vi
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`

`

` 
`
`Exhibit List
`
`
`Petition for Inter Partes Review of USP 9,006,224
`
`1001 U.S. Patent No. 9,006,224 (“the ’224 patent”), titled “Neuroendocrine Tumor
`Treatment”
`
`1002 File History for the ’224 patent
`
`1003 Declaration of Mark J. Ratain, M.D. in Support of Petition for Inter Partes
`Review of U.S. Patent No. 9,006,224 (“Ratain Decl.”)
`
`1004 Curriculum Vitae of Mark J. Ratain, M.D.
`
`1005 A. 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, 64
`CANCER RES. 252 (2004) (“Boulay 2004”)
`
`1006 E. Brown et al., A mammalian protein targeted by G1-arresting rapamycin-
`receptor complex, 369 NATURE 756 (1994) (“Brown”)
`
`1007 P. Buetow et al., Islet cell tumors of the Pancreas: Pathologic-Imaging
`Correlation Among Size, Necrosis and Cysts, Calcification, Malignant
`Behavior, and Functional Status, 165 AM. J. ROENTGENOLOGY 1175 (1995)
`
`1008 Center for Drug Evaluation & Research, Approval Package for NDA 021083
`(Rapamune), Food & Drug Administration (Sept. 15, 1999)
`
`1009 J. Dancey, Clinical development of mammalian target of rapamycin
`inhibitors, 16 HEMATOLOGY/ONCOLOGY CLINICS OF N. AM. 1101
`(2002)(“Dancey”)
`
`1010 M. DeJong et al., Therapy of neuroendocrine tumors with radiolabeled
`somatostatin-analogues, 43 Q. J. NUCLEAR MED. & MOLECULAR IMAGING
`356 (1999) (“DeJong”)
`
`1011 I. Duran et al., A Phase II Trial ofTemsirolimus in Metastatic
`Neuroendocrine Carcinomas (NECs), 23 SUPPL. J. CLIN. ONCOL. 3096
`(2005) (“Duran”)
`
`vii
`
` 
`
`

`

`Petition for Inter Partes Review of USP 9,006,224
`
`1012 J. Dutcher, Mammalian target of rapamycin inhibition, 10 CLIN. CANCER
`RES. 6382s (2004) (“Dutcher”)
`
`1013 C. P. Eng et al., Activity of Rapamycin (AY-22,989) Against Transplanted
`Tumors, 37 J. ANTIBIOTICS 1231 (1984) (“Eng”)
`
`1014 M. Grewe et al., Regulation of Cell Growth and Cyclin Dl Expression by the
`Constitutively Active FRAP-p70s6K Pathway in Human Pancreatic K Cancer
`Cells, 59 CANCER RES. 3581 (1999) (“Grewe”)
`
`1015 M. Guba et al., Rapamycin inhibits primary and metastatic tumor growth by
`antiangiogenesis: involvement of vascular endothelial growth factor, 8
`NATURE MED. 128 (2002) (“Guba”)
`
`1016 M. Hidalgo et al., The rapamycin-sensitive signal transduction pathway as a
`target for cancer therapy, 19 ONCOGENE 6680 (2000) (“Hidalgo”)
`
`1017 S. Huang et al., Inhibitors of mammalian target of rapamycin as novel
`antitumor agents: from bench to clinic, 3 CURRENT OPINION IN
`INVESTIGATIONAL DRUGS 295 (2002) (“Huang 2002”)
`
`1018 S. Huang et al., Rapamycins: Mechanism of Action and Cellular Resistance,
`2 CANCER BIOL. & THER. 222 (2003) (“Huang 2003”)
`
`1019 M. Levy and M. Wiersema, Pancreatic neoplasms, 15 GASTROINTESTINAL
`ENDOSCOPY CLIN. N. AM. 117 (2005) (“Levy”)
`
`1020 G. Kaltsas et al., The Diagnosis and Medical Management of Advanced
`Neuroendocrine Tumors, 25 ENDOCRINE REV. 458 (2004) (“Kaltsas”)
`
`1021 R. Martel et al., Inhibition of the immune response by rapamycin, a new
`antifungal antibiotic, 55 CAN. J. PHYSIOL. PHARMACOL. 48 (1977) (“Martel”)
`
`1022 R. Morris, Rapamycins: Antifungal, Antitumor, Antiproliferative, and
`Immunosuppressive Macro/ides, 6 TRANSPLANTATION REV. 39 (1992)
`(“Morris”)
`
`viii
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`

`Petition for Inter Partes Review of USP 9,006,224
`
`1023 C. Moertel et al., Streptozocin-Doxorubicin, Streptozocin-Fluorouracil, or
`Chlorozotocin in the Treatment of Advanced Islet-Cell Carcinoma, 326 NEW
`ENG. J. MED. 519 (1992) (“Moertel”)
`
`1024 M. Neshat et al., Enhanced sensitivity of PTEN-deficient tumors to inhibition
`of FRAP/mTOR, 98 PNAS 10314 (2001) (“Neshat”)
`
`1025 K. Öberg, Chemotherapy and biotherapy in the treatment of neuroendocrine
`tumours, 12 ANN. ONCOL. S111 (2001) (“Öberg 2001”)
`
`1026 K. Öberg, Management of neuroendocrine tumors, 15 ANN. ONCOLOGY
`iv293 (2004)
`
`1027 K. Öberg, Treatment of neuroendocrine tumors of the gastrointestinal tract,
`27 ONCOLOGIA 57 (2004) (“Öberg 2004”)
`
`1028 K. Öberg and B. Eriksson, Endocrine tumours of the pancreas, 19 BEST
`PRACTICE & RES. CLIN. GASTROENT. 753 (2005) (“Öberg & Eriksson”)
`
`1029 A. O’Donnell et al., A phase I study of the oral mTOR inhibitor RAD001 as a
`monotherapy to identify the optimal biologically effective dose using toxicity,
`pharmacokinetic (PK) and pharmacodynamics (PD) endpoints in patients
`with solid tumors, 22 PROC. AM. SOC’Y OF CLINICAL ONCOLOGY 200(803ab)
`(2003) (“O’Donnell”)
`
`1030 T. O’Reilly et al., In vivo activity of RAD00J, an orally active rapamycin
`derivative, in experimental tumor models, 43 PROC. AM. ASS’N OF CANCER
`RES. 71 (Abstract #359) (2002) (“O’Reilly”)
`
`1031 A. Perren, et al., Mutation and expression analyses reveal differential
`subcellular compartmentalization of PTEN in endocrine pancreatic tumors
`compared to norma/islet cells, 157 AM. J. PATHOLOGY 1097 (2000)
`(“Perren”)
`
`1032 U. Plockinger et al., Guidelines for the Diagnosis and Treatment of
`Neuroendocrine Gastrointestinal Tumours, 80 NEUROENDOCRINOLOGY 394
`(2004) (“NET Guidelines”)
`
`ix
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`

`Petition for Inter Partes Review of USP 9,006,224
`
`1033 R. Rao et al., Mammalian Target of Rapamycin (mTOR) Inhibitors as Anti-
`Cancer Agents, 4 CURR. CANCER DRUG TARGETS 621 (2004) (“Rao”)
`
`1034 C. Sawyers, Will mTOR inhibitors make it as cancer drugs?, 4 CANCER CELL
`343 (2003) (“Sawyers”)
`
`1035 S. Schreiber, Chemistry and biology of the immunophilins and their
`immunosuppressive ligands, 251 SCIENCE 283 (1991) (“Schreiber”)
`
`1036 W. Schuler et al., SDZ RAD, a new rapamycin derivative: pharmacological
`properties in vitro and in vivo, 64 TRANSPLANTATION 36 (1997) (“Schuler”)
`1037 A. Tolcher, Novel therapeutic molecular targets for prostate cancer: the
`mTOR signaling pathway and epidermal growth factor receptor, 171 J.
`UROLOGY S41 (2004) (“Tolcher”)
`
`1038 J. Tabernero et al., A phase I study with tumor molecular pharmacodynamic
`(MPD) evaluation of dose and schedule of the oral mTOR-inhibitor
`Everolimus (RAD00J) inpatients (pts) with advanced solid tumors, 23 J.
`CLINICAL ONCOLOGY 3007 (2005) (“Tabernero”)
`
`1039 S. Vignot et al., mTOR-targeted therapy of cancer with rapamycin
`derivatives, 16 ANN. ONCOL. 525 (2005) (“Vignot”)
`
`1040 U.S. Patent No. 3,929,992 (“the ’992 patent”)
`
`1041 U.S. Patent No. 4,650,803 (“the ’803 patent”)
`
`1042 U.S. Patent No. 4,885,171 (“the ’171 patent”)
`
`1043 U.S. Patent No. 5,100,883 (“the ’883 patent”)
`
`1044 U.S. Patent No. 5,206,018 (“the ’018 patent”)
`
`1045 U.S. Patent No. 5,233,036 (“the ’036 patent”)
`
`1046 U.S. Patent No. 5,362,718 (“the ’718 patent”)
`
`1047 U.S. Patent No. 5,391,730 (“the ’730 patent”)
`
`x
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`

`Petition for Inter Partes Review of USP 9,006,224
`
`1048 U.S. Patent No. 5,665,772 (“the ’772 patent”)
`
`1049 U.S. Patent No. 7,091,213 (“the ’213 patent”)
`
`1050 U.S. Patent No. 8,410,131 (“the ’131 patent”)
`
`1051 L. Wang et al., Differential Expression of the PTEN Tumor Suppressor
`Protein in Fetal and Adult Neuroendocrine Tissues and Tumors: Progression
`Loss of PTEN Expression in Poorly Differentiated Neuroendocrine
`Neoplasms, 10 APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR
`MORPHOLOGY 139 (2002) (“Wang 2002”)
`
`1052 B. Wiedenmann & U. Pape, From Basic to Clinical Research in
`Gastroenteropancreatic Neuroendocrine Tumor Disease-The Clinician-
`Scientist Perspective, 80 NEUROENDOCRINOLOGY 94 (2004) (“Wiedenmann
`2004”)
`
`1053 WO 97/47317 (“Weckbecker”)
`
`1054 WO 02/40000 (“Dukart”)
`
`1055 WO 02/066019 (“Lane”)
`
`1056 Excerpt from the file history of U.S. Application No. 14/608,644,
`Information Disclosure Statement (April, 2015)
`
`1057 Excerpt from the file history of U.S. Application No. 14/608,644, Office
`Action (December 18, 2015)
`
`1058 Dr. Kjell Öberg, Web Bio, Uppsala University, available at
`http://katalog.uu.se/empinfo?languageld=1&id=n96-5147, visited June 26,
`2015 (“Öberg Biography”)
`
`1059 “What is ENETS?,” available at http://www.enets.org/what_is_enets.html,
`visited June 26, 2015 (“ENETS Info”)
`1060 Sandostatin LAR® Prescribing Label (November 1998)
`
`xi
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`Petition for Inter Partes Review of USP 9,006,224
`
`1061 Declaration of Scott Bennett, Ph.D.
`
`1062 D. Clements et al., Regression of Metastatic Vipoma with Somatostatin
`Analogue SMS 201-995, LANCET 874 (1985) (“Clements”)
`
`1063 D. O’Toole et al., Chemotherapy for Gastro-Enteropancreatic Endocrine
`Tumours 80 NEUROENDOCRINOLOGY 79 (2004)
`
`1064 A. Jimeno et al., Pharmacodynamic-guided, modified continuous
`reassessment method (mCRM)-based, dose finding study of rapamycin in
`adult patients with solid tumors, 24 J. CLIN. ONCOL. 3020 (2006)
`
`xii
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`
`
`Petition for Inter Partes Review of USP 9,006,224
`
`West-Ward Pharmaceuticals International Limited (“Petitioner” or “West-
`
`Ward”) requests inter partes review of claims 1-3 of United States Patent No.
`
`9,006,224 (the “’224 patent”), titled “Neuroendocrine Tumor Treatment,” which
`
`according to USPTO records is assigned to Novartis AG (“Patent Owner” or
`
`“Novartis”). In Par Pharmaceutical, Inc. v. Novartis AG, IPR2016-01479 (Paper
`
`No. 8, February 15, 2017), the Board previously instituted an inter partes review
`
`on claims 1-3 of the ’224 patent on the same grounds (Grounds 1-4) upon which
`
`West-Ward relies below.
`
`I.
`
`OVERVIEW
`The Board should grant inter partes review because the ’224 patent claims
`
`nothing more than what was already well-known in the art. The ’224 patent claims
`
`methods of treating advanced pancreatic neuroendocrine tumors with a rapamycin
`
`derivative known as everolimus. The prior art, however, already taught treating
`
`these exact tumors with rapamycin and its derivatives. And everolimus was
`
`identified as having better bioavailability and presenting a “clinical advantage”
`
`over rapamycin. Further, everolimus specifically was taught to be effective in a
`
`recognized rat model of these pancreatic tumors. Additionally, unlike rapamycin,
`
`both everolimus and temsirolimus (another rapamycin derivative) had been shown
`
`
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`1
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`

`

` 
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`to be effective and well-tolerated in human cancer patients, and temsirolimus had
`
`Petition for Inter Partes Review of USP 9,006,224
`
`been shown to be safe and effective in treating humans with advanced
`
`neuroendocrine tumors (“NETs”). Thus, it would have been obvious to use
`
`everolimus to treat advanced pancreatic NETs as recited in the claims.
`
`II. REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ’224
`
`Patent is available for inter partes review. On June 10, 2015, Novartis filed a
`
`complaint in the District of Delaware alleging that Roxane, now West-Ward,
`
`infringed the ’224 Patent. Novartis Pharm. Corp. et al. v. Roxane Labs., Inc., No.
`
`1:15-cv-474-RGA (D. Del.). On February 27, 2017, West-Ward was substituted
`
`as a party for Roxane in the District of Delaware litigation. Although more than
`
`one year has passed since Roxane, now West-Ward, was served with a complaint
`
`alleging infringement of the ’224 Patent, Petitioner is not barred or estopped from
`
`inter partes review of the challenged claims of the ’224 Patent on the grounds
`
`identified in this Petition. Neither Petitioner nor any privy of Petitioner has
`
`received a final written decision under 35 U.S.C. § 318(a) with respect to any
`
`claim of the ’224 Patent on any ground that was raised or could have been raised
`
`
`
`2
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`

`

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`
`by Petitioner or its privies in any inter partes review, post grant review, or
`
`Petition for Inter Partes Review of USP 9,006,224
`
`covered business method patent review. Moreover, the Petition (and an
`
`accompanying motion to join IPR2016-01479) is timely filed, i.e., within one
`
`month of the February 15, 2017 institution of IPR2016-01479.
`
`B. Notice of Lead and Backup Counsel and Service Information
`Pursuant to 37 C.F.R. §§ 42.8(b)(3), 42.8(b)(4), and 42.10(a), West-Ward
`
`provides the following designation of Lead and Back-Up counsel.
`
`LEAD COUNSEL
`Keith A. Zullow (Reg. No. 37,975)
`kzullow@goodwinprocter.com
`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`T: 212-813-8846; F: 646-558-4226
`
`BACKUP COUNSEL
`Marta E. Delsignore (Reg. No. 32,689)
`mdelsignore@goodwinprocter.com
`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`T: 212-813-8822; F: 646-558-4079
`
`
`
` A
`
` Power of Attorney is being filed concurrently herewith in accordance with 37
`
`C.F.R. § 42.10(b). West-Ward consents to electronic service.
`
`C. Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(l))
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that West-Ward 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
`
`
`
`3
`
`

`

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`
`the following additional entity as a real-party-in-interest who, going forward, may
`
`Petition for Inter Partes Review of USP 9,006,224
`
`have control over this proceeding: Hikma Pharmaceuticals PLC and its U.S.
`
`subsidiaries Roxane Laboratories, Inc. and 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.
`
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner is aware of the following
`
`District Court litigations: Novartis Pharm. Corp. v. Breckenridge Pharm., Inc.,
`
`C.A. No. 14-1043-RGA (D. Del.); Novartis Pharm. Corp. v. Roxane Labs., Inc.,
`
`C.A. No. 14-1196-RGA (D. Del.); Novartis Pharm. Corp. v. Par Pharm., Inc.,
`
`C.A. No. 14-1289-RGA (D. Del.); Novartis Pharm. Corp. v. Par Pharm., Inc.,
`
`C.A. No. 14-1494-RGA (D. Del.); Novartis Pharm. Corp. v. Par Pharm., Inc.,
`
`C.A. No. 15-78-RGA (D. Del.); Novartis Pharm. Corp. v. Par Pharm., Inc., C.A.
`
`No. 15-475-RGA (D. Del.); Novartis Pharm. Corp. v. Par Pharm., Inc., C.A. No.
`
`15-1050-RGA (D. Del.); Novartis Pharm. Corp. v. Roxane Labs., Inc., C.A. No.
`
`14-1508-RGA (D. Del.); Novartis Pharm. Corp. v. Roxane Labs., Inc., C.A. No.
`
`15-128-RGA (D. Del.); and Novartis Pharm. Corp. v. Breckenridge Pharm., Inc.,
`
`
`
`4
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` 
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`C.A. No. 16-431-RGA (D. Del.). Petitioner is also aware of the following
`
`Petition for Inter Partes Review of USP 9,006,224
`
`petitions for Inter Partes Review of U.S. Patent No. 9,006,224: Roxane Labs.,
`
`Inc. v. Novartis AG, IPR2016-01461; Argentum Pharm. LLC v. Novartis AG,
`
`IPR2017-01063; and Par Pharm., Inc. v. Novartis AG, IPR2016-01479.
`
`Petitioner is also aware of the following petitions for Inter Partes Review of U.S.
`
`Patent No. 5,665,772: Nos. IPR2016-00084, -01023, -01059, -01102, and -01103.
`
`Petitioner is also aware of the following petitions for Inter Partes Review: Par
`
`Pharm., Inc. v. Novartis AG, IPR2016-00074 (U.S. Patent No. 7,741,338); and
`
`Par Pharm., Inc. v. Novartis AG, IPR2016-00075 (U.S. Patent No. 7,297,703).
`
`Fee for Inter Partes Review
`
`E.
`The undersigned authorizes payment of $23,000.00 for the fees specified by
`
`37 C.F.R. § 42.15(a) for this Petition to be charged to Deposit Account No. 50-
`
`6989. The undersigned further authorizes payment for any additional fees that
`
`might be due in connection with this Petition to be charged to Deposit Account No.
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`50-6989.
`
`Proof of Service
`
`F.
`Proof of service of this petition on the Patent Owner at the correspondence
`
`address of record for the ’224 patent is attached.
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`
`
`5
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`III.
`
`Petition for Inter Partes Review of USP 9,006,224
`
`IDENTIFICATION OF CLAIMS BEING CHALLENGED (37 C.F.R.
`§ 42.104(B))
`
`For the reasons herein, the Board should find claims 1-3 unpatentable on the
`
`following grounds:
`
`Ground 1. Claims 1-3 are unpatentable under 35 U.S.C. § 103 because they
`
`are rendered obvious by Öberg 2004 (Ex. 1027) in combination with Boulay 2004
`
`(Ex. 1005) and O’Donnell (Ex. 1029).
`
`Ground 2. Claim 2 is unpatentable under 35 U.S.C. § 103 because it is
`
`rendered obvious by Öberg 2004 (Ex. 1027) in combination with Boulay 2004
`
`(Ex. 1005) and O’Donnell (Ex. 1029), in further view of Tabernero (Ex. 1038).
`
`Ground 3. Claims 1-3 are unpatentable under 35 U.S.C. § 103 because they
`
`are rendered obvious by Boulay 2004 (Ex. 1005), O’Donnell (Ex. 1029), and
`
`Duran (Ex. 1011).
`
`Ground 4. Claim 2 is unpatentable under 35 U.S.C. § 103 because it is
`
`rendered obvious by Boulay 2004 (Ex. 1005), O’Donnell (Ex. 1029), and Duran
`
`(Ex. 1011), in further view of Tabernero (Ex. 1038).
`
`IV. SUMMARY OF THE ARGUMENT
`The ’224 patent claims methods of treating advanced pancreatic NETs by
`
`administering to a human subject in need thereof a therapeutically effective amount
`
`
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`6
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`of everolimus1 after failure of cytotoxic chemotherapy. Ex. 1001, ’224 patent at
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`Petition for Inter Partes Review of USP 9,006,224
`
`26:65-27:8. Treating advanced pancreatic NETs (such as islet cell tumors) by
`
`administering a therapeutically effective amount (including 10 mg/day) of
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`everolimus after cytotoxic treatment fails would have been obvious at the time of
`
`the purported invention, November 21, 2005.
`
`First (i.e., Grounds 1 and 2), Öberg 2004 disclosed rapamycin as a treatment
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`for advanced pancreatic NETs after cytotoxic treatment failed, and one of skill
`
`would have understood that suggestion to include rapamycin’s other known active
`
`derivatives that had been reported to be administered to human cancer patients,
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`such as everolimus. Ex. 1027, Öberg 2004 at Fig. 1; Ex. 1003, Ratain Decl. ¶¶ 79,
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`83-92, 104. Everolimus was first disclosed in 1992, and subsequent preclinical and
`                                                            
`1
`The claims of the ’224 patent use the term 40-0-(2-hydroxyethyl)-
`
`rapamycin. This compound is also known in the art as everolimus, RAD001, SDZ
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`RAD, and RAD. E.g., Ex. 1001, ’224 patent at 11:50-51; Ex. 1033, Rao at 621;
`
`Ex. 1003, Ratain Decl. ¶ 72. Sometimes Novartis and its predecessor Sandoz refer
`
`to 40-0-(2-hydroxyethyl)-rapamycin as Compound A. ’224 patent at 11:66-67.
`
`For ease of reference, this Petition will primarily use the term “everolimus” in
`
`referencing this compound.
`
`
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`7
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`clinical research touted its activity and identifying it as having a “clinical
`
`Petition for Inter Partes Review of USP 9,006,224
`
`advantage” over rapamycin. Ex. 1003, Ratain Decl. ¶¶ 72, 75-79. Further,
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`everolimus would have been an obvious treatment choice because its efficacy in
`
`treating pancreatic NETs had been demonstrated in laboratory models and the
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`prior art taught that everolimus was safe and effective in treating humans with
`
`solid tumors. Ex. 1005, Boulay 2004 at 254; Ex. 1029, O’Donnell at 803;
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`Ex. 1003, Ratain Decl. ¶¶ 110-123. And although it would have been obvious
`
`to identify an appropriate dose, Tabernero explicitly taught using a unit dose of
`
`10 mg/day of everolimus for treating solid tumors. Ex. 1038, Tabernero at
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`3007; Ex. 1003, Ratain Decl. ¶¶ 126-127, 152.
`
`Second (i.e., Grounds 3 and 4), Boulay 2004 demonstrated that everolimus
`
`was effective in treating pancreatic NETs in rats and would have suggested to one
`
`of ordinary skill to administer everolimus to humans with pancreatic NETs. A
`
`skilled artisan would have had a reasonable expectation that everolimus would be
`
`effective in pancreatic NETs because of the antitumor activity in this preclinical
`
`model. Ex. 1005, Boulay 2004 at 254; Ex. 1003, Ratain Decl. ¶ 112. Further,
`
`O’Donnell taught that everolimus was safe and effective for treating other tumors
`
`in humans. Ex. 1029, O’Donnell at 803; Ex. 1003, Ratain Decl. ¶¶ 119-123. One
`
`
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`8
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`of ordinary skill would have tried, and reasonably expected to succeed, using
`
`Petition for Inter Partes Review of USP 9,006,224
`
`everolimus to treat advanced pancreatic NETs in humans after cytotoxic treatment
`
`failed because Duran had demonstrated that another well-known rapamycin
`
`derivative, temsirolimus,2 was effective in treating advanced NETs. Ex. 1011,
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`Duran at 3096; Ex. 1003, Ratain Decl. ¶¶ 129-131, 167.
`
`To explain further, it was well-known as of November 2005 that rapamycin,
`
`an inhibitor of the protein mTOR, was a potent anti-tumor agent. Ex. 1003, Ratain
`
`Decl. ¶¶ 70-71, 83-92. Researchers had investigated the use of rapamycin in the
`
`treatment of a variety of cancers and tumor models, including two pancreatic
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`cancer cell lines. Id. ¶¶ 70-71.
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`Because of rapamycin’s promising results in that research, researchers
`
`investigated and identified rapamycin derivatives with similar anti-tumor and
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`mTOR-inhibition properties, including everolimus and temsirolimus. Id. ¶¶ 72-82.
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`As of November 2005, everolimus and temsirolimus were the two most studied
`
`rapamycin derivatives. Id. ¶ 75. Differing only at the C40 position (circled in
`
`                                                            
`2
`Temsirolimus is also known as CCI-779 in the literature. Ex. 1033, Rao at
`
`621; Ex. 1003, Ratain Decl. ¶ 73.
`
`
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`9
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`red), these two rapamycin derivatives have identical binding sites for their
`
`Petition for Inter Partes Review of USP 9,006,224
`
`biological targets, mTOR and FKBP123.
`
`
`
`                                                            
`3
`By November 2005, it was known that rapamycin and its derivatives first
`
`bind to the protein FKBP12 and then that rapamcyin-FKBP12 complex interacts
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`with mTOR to inhibit its activity. Ex. 1003, Ratain Decl. ¶ 83.
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`10
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`Petition for Inter Partes Review of USP 9,00