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
`
`
`
`
`
`

`

`
`
`I.
`
`II.
`
`Petition for Inter Partes Review of USP 9,006,224
`
`TABLE OF CONTENTS
`
`Overview .......................................................................................................... 1
`
`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 ............. 2
`C.
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1)) .................. 2
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) .............................. 3
`Fee for Inter Partes Review .................................................................. 3
`E.
`F.
`Proof of Service ..................................................................................... 3
`
`III.
`
`Identification Of Claims Being Challenged (37 C.F.R. § 42.104(B)) ............ 4
`
`IV. Summary of the Argument .............................................................................. 4
`
`V. Overview of the ’224 Patent .......................................................................... 12
`
`VI. The Person Of Ordinary Skill In The Art ...................................................... 15
`
`VII. Claim Construction ........................................................................................ 16
`
`A. Applicable Law ................................................................................... 16
`B.
`Construction of Claim Terms .............................................................. 17
`1.
`“pancreatic neuroendocrine tumor” .......................................... 18
`2.
`“advanced tumors” .................................................................... 19
`3.
`“unit dose” ................................................................................. 20
`4.
`“islet cell tumor” ....................................................................... 21
`
`VIII. Technical Background And State Of The Art At The Time Of The
`Purported Invention ....................................................................................... 21
`
`A.
`B.
`
`C.
`
`Rapamycin was well-known as a potent antitumor agent ................... 21
`Rapamycin derivatives, like everolimus and temsirolimus, were
`known to have similar biological activity to rapamycin ..................... 22
`The mechanism of action for the immunosuppressant and
`antitumor activity of rapamycin and its derivatives was well-
`characterized ........................................................................................ 26
`
`IX. The Scope And Content Of The Asserted Prior Art ...................................... 29
`
`i
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`Petition for Inter Partes Review of USP 9,006,224
`
`B.
`
`C.
`
`A. Oberg 2004 taught that humans with advanced pancreatic NETs
`should be treated with rapamycin as a monotherapy after
`cytotoxic therapy failed ....................................................................... 29
`Boulay 2004 taught that everolimus was well-tolerated and
`effective at treating pancreatic NETs in rat models ............................ 32
`O’Donnell taught that everolimus was well-tolerated and
`showed promise as an antitumor agent in human patients .................. 34
`Tabernero taught that an appropriate dosage for humans taking
`everolimus for the treatment of advanced solid tumors was 10
`mg/day ................................................................................................. 35
`Duran taught the use of temsirolimus in the treatment of human
`patients with advanced neuroendocrine carcinomas ........................... 36
`
`D.
`
`E.
`
`X.
`
`Claims 1-3 Would Have Been Obvious Over the Prior Art .......................... 37
`
`A.
`B.
`
`C.
`
`Legal Background ............................................................................... 37
`Ground 1: Claims 1-3 would have been obvious in view of
`Oberg 2004, Boulay 2004, and O’Donnell ......................................... 40
`1.
`Claim 1 ...................................................................................... 40
`2.
`Claim 2 ...................................................................................... 46
`3.
`Claim 3 ...................................................................................... 47
`Ground 2: Claim 2 would have been obvious in view of Oberg
`2004, Boulay 2004, O’Donnell, and Tabernero .................................. 48
`D. Ground 3: Claims 1-3 would have been obvious in view of
`Boulay 2004, O’Donnell, and Duran .................................................. 49
`1.
`Claim 1 ...................................................................................... 49
`2.
`Claim 2 ...................................................................................... 51
`3.
`Claim 3 ...................................................................................... 52
`Ground 4: Claim 2 of the ’224 patent is invalid as obvious in
`view of Boulay 2004, O’Donnell, Duran, and Tabernero ................... 53
`
`E.
`
`XI. Secondary Considerations Fail To Overcome The Strong Evidence Of
`Obviousness ................................................................................................... 54
`
`XII. The Board Should Not Exercise Its Discretion Under 325(d) in Favor
`of IPR Petition 2016-01461 ........................................................................... 55
`
`XIII. Conclusion ..................................................................................................... 57
`
`
`
`ii
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`Petition for Inter Partes Review of USP 9,006,224
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ............................................................................. 55
`
`Boston Sci. Scimed, Inc. v. Cordis Corp.,
`554 F.3d 982 (Fed. Cir. 2009) ............................................................................... 39
`
`Cuozzo Speed Techs., LLC v. Lee,
`No. 15-446, slip op., 579 U.S. ____ (2016) .......................................................... 16
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................... 55
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ........................................................................................... 38, 54
`
`In re Beattie,
`974 F.2d 1309 (Fed. Cir. 1992) ...................................................................... 11, 45
`
`In re PepperBall Techs., Inc.,
`469 F. App’x 878 (Fed. Cir. 2012) ....................................................................... 54
`
`In re Peterson,
`315 F.3d 1325 (Fed. Cir. 2003) ...................................................................... 47, 52
`
`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) ............................................................................. 54
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ................................................................ 46, 51, 55
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) ...................................................................... 16, 17
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ...................................................................... 47, 52
`
`iii
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`Petition for Inter Partes Review of USP 9,006,224
`
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ............................................................................. 16
`
`Rackspace US, Inc. v. Personal Web Techs., LLC,
`No. IPR2014-00057 (P.T.A.B Apr. 15, 2014), Paper 9 ........................................ 57
`
`Ruiz v. A.B. Chance Co.,
`234 F.3d 654 (Fed. Cir. 2000) ............................................................................... 38
`
`SAP Am., Inc. v. Versata Dev. Grp., Inc.,
`No. CBM2012-00001 (P.T.A.B. Jan. 9, 2013), Paper 36 ..................................... 17
`
`SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349 (Fed. Cir. 2000) ............................................................................. 55
`
`Versata Dev. Grp., Inc. v. SAP Am., Inc.,
`793 F.3d 1306 (Fed. Cir. 2015) ............................................................................. 16
`
`STATUTES
`
`35 U.S.C. § 102 ................................................................................................ passim
`
`35 U.S.C. § 103 ................................................................................................... 4, 37
`
`35 U.S.C. § 325(d) ................................................................................................... 56
`
`OTHER AUTHORITIES
`
`Final Rules, 77 Fed. Reg. 48680, 48699 (Aug. 14, 2012) ....................................... 17
`
`37 C.F.R. § 42.100(b) .............................................................................................. 16
`
`REGULATIONS
`
`
`
`
`
`
`
`iv
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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. De Jong et al., Therapy of neuroendocrine tumors with radiolabeled
`somatostatin-analogues, 43 Q. J. NUCLEAR MED. & MOLECULAR
`IMAGING 356 (1999) (“De Jong”)
`
`1011 I. Duran et al., A Phase II Trial of Temsirolimus in Metastatic
`Neuroendocrine Carcinomas (NECs), 23 SUPPL. J. CLIN. ONCOL. 3096
`(2005) (“Duran”)
`
`1012 J. Dutcher, Mammalian target of rapamycin inhibition, 10 CLIN. CANCER
`RES. 6382s (2004) (“Dutcher”)
`
`v
`
`

`

`Petition for Inter Partes Review of USP 9,006,224
`
`
`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 D1 Expression by
`the Constitutively Active FRAP-p70s6K Pathway in Human Pancreatic
`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 Macrolides, 6 TRANSPLANTATION REV. 39 (1992)
`(“Morris”)
`
`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”)
`
`vi
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`Petition for Inter Partes Review of USP 9,006,224
`
`
`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 RAD001, 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 normal islet cells, 157 AM. J. PATHOLOGY 1097 (2000)
`(“Perren”)
`
`1032 U. Plöckinger et al., Guidelines for the Diagnosis and Treatment of
`Neuroendocrine Gastrointestinal Tumours, 80 NEUROENDOCRINOLOGY 394
`(2004) (“NET Guidelines”)
`
`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)
`
`vii
`
`

`

`
`
`(“Schuler”)
`
`Petition for Inter Partes Review of USP 9,006,224
`
`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 (RAD001) in patients (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”)
`
`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”)
`
`viii
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`Petition for Inter Partes Review of USP 9,006,224
`
`
`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 1, 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?languageId=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)
`
`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)
`
`ix
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`

`

`
`
`Petition for Inter Partes Review of USP 9,006,224
`
`Par Pharmaceutical, Inc. (“Petitioner” or “Par”) 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”).
`
`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
`
`to be effective and well-tolerated in human cancer patients, and temsirolimus had
`
`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.
`
`1
`
`

`

`
`II. REQUIREMENTS FOR PETITION FOR INTER PARTES REVIEW
`
`Petition for Inter Partes Review of USP 9,006,224
`
`A. Grounds for Standing (37 C.F.R. § 42.104(a))
`
`Par certifies that the ’224 patent is available for inter partes review and that
`
`Par is not barred or estopped from requesting inter partes review of the challenged
`
`claims of the ’224 patent.
`
`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), Par provides
`
`the following designation of Lead and Back-Up counsel.
`
`LEAD COUNSEL
`Daniel G. Brown (Reg. No. 54,005)
`(daniel.brown@lw.com)
`Postal & Hand-Delivery Address:
`Latham & Watkins LLP
`885 Third Avenue
`New York, NY 10022-4834
`T: 212-906-1200; F: 212-751-4864
`
`Pursuant to 37 C.F.R. § 42.10(b), a Power of Attorney for Par is attached. Par
`
`BACKUP COUNSEL
`Jonathan M. Strang (Reg. No. 61,724)
`(jonathan.strang@lw.com)
`Postal & Hand Delivery Address:
`Latham & Watkins LLP
`555 Eleventh Street, NW, Ste. 1000
`Washington, DC 20004-1304
`T: 202.637.2200; F. 202.637.2201
`
`consents to electronic service.
`
`C. Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
`
`Par is a real-party-in-interest for this proceeding. Par identifies the following
`
`additional entities as real-parties-in-interest: Endo International PLC; Endo DAC;
`
`Endo Management Limited; Endo Luxembourg Holding Company S.a.r.l.; Endo
`
`2
`
`

`

`
`Luxembourg Finance Company I S.a.r.l.; Endo Luxembourg Finance Company II
`
`Petition for Inter Partes Review of USP 9,006,224
`
`S.a.r.l.; Paladin Labs Canadian Holding Inc.; Paladin Labs Inc.; Luxembourg Endo
`
`Specialty Pharmaceuticals Holding I S.a r l.; Luxembourg Endo Specialty
`
`Pharmaceuticals Holding II S.a r l.; and Par Pharmaceutical Companies, Inc.
`
`D. Notice of Related Matters (37 C.F.R. § 42.8(b)(2))
`
`Novartis Pharm. Corp. et al. v. Par Pharm., Inc., 1:14-cv-1289-RGA (D.
`
`Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., 1:14-cv-1494-RGA (D.
`
`Del.). Novartis Pharm. Corp. et al. v. Par Pharm., Inc., 1:15-cv-78-RGA (D. Del.).
`
`Novartis Pharm. Corp. et al. v. Par Pharm., Inc., 1:15-cv-475-RGA (D. Del.).
`
`Novartis Pharm. Corp. et al. v. Par Pharm., Inc., 1:15-cv-1050-RGA (D. Del.).
`
`Roxane Labs., Inc. v. Novartis AG, IPR2016-1461 (filed July 19, 2016). Petitions
`
`for Inter Partes Review of U.S. Patent No. 5,665,772, Nos. IPR2016-00084, -
`
`01023, -01059, -01102, and -01103. According to USPTO records, U.S. Patent
`
`App. No. 14/608,644 claims priority to the ’224 patent.
`
`E.
`
`Fee for Inter Partes Review
`
`The Director is authorized to charge the fee specified by 37 C.F.R.
`
`§ 42.15(a) to Deposit Account No. 506269.
`
`F.
`
`Proof of Service
`
`Proof of service of this petition on the Patent Owner at the correspondence
`
`address of record for the ’224 patent is attached.
`
`3
`
`

`

`Petition for Inter Partes Review of USP 9,006,224
`
`IDENTIFICATION OF CLAIMS BEING CHALLENGED (37 C.F.R.
`
`
`III.
`
`§ 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 Oberg 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 Oberg 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
`
`4
`
`

`

`
`of everolimus1 after failure of cytotoxic chemotherapy. Ex. 1001, ’224 patent at
`
`Petition for Inter Partes Review of USP 9,006,224
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`26:65-27:8. Treating advanced pancreatic NETs (such as islet cell tumors) by
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`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
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`the purported invention, November 21, 2005.
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`First (i.e., Grounds 1 and 2), Oberg 2004 disclosed rapamycin as a treatment
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`for advanced pancreatic NETs after cytotoxic treatment failed, and one of skill
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`would have understood that suggestion to include rapamycin’s other known active
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`derivatives that had been reported to be administered to human cancer patients,
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`such as everolimus. Ex. 1027, Oberg 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
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`clinical research touted its activity and identifying it as having a “clinical
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`1 The claims of the ’224 patent use the term 40-O-(2-hydroxyethyl)-rapamycin.
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`This compound is also known in the art as everolimus, RAD001, SDZ RAD, and
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`RAD. E.g., Ex. 1001, ’224 patent at 11:50-51; Ex. 1033, Rao at 621; Ex. 1003,
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`Ratain Decl. ¶ 72. Sometimes Novartis and its predecessor Sandoz refer to 40-O-
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`(2-hydroxyethyl)-rapamycin as Compound A. ’224 patent at 11:66-67. For ease of
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`reference, this Petition will primarily use the term “everolimus” in referencing this
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`compound.
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`advantage” over rapamycin. Ex. 1003, Ratain Decl. ¶¶ 72, 75-79. Further,
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`Petition for Inter Partes Review of USP 9,006,224
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`everolimus would have been an obvious treatment choice because its efficacy in
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`treating pancreatic NETs had been demonstrated in laboratory models and the prior
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`art taught that everolimus was safe and effective in treating humans with solid
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`tumors. Ex. 1005, Boulay 2004 at 254; Ex. 1029, O’Donnell at 803; Ex. 1003,
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`Ratain Decl. ¶¶ 110-123. And although it would have been obvious to identify an
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`appropriate dose, Tabernero explicitly taught using a unit dose of 10 mg/day of
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`everolimus for treating solid tumors. Ex. 1038, Tabernero at 3007; Ex. 1003,
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`Ratain Decl. ¶¶ 126-127, 152.
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`Second (i.e., Grounds 3 and 4), Boulay 2004 demonstrated that everolimus
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`was effective in treating pancreatic NETs in rats and would have suggested to one
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`of ordinary skill to administer everolimus to humans with pancreatic NETs. A
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`skilled artisan would have had a reasonable expectation that everolimus would be
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`effective in pancreatic NETs because of the antitumor activity in this preclinical
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`model. Ex. 1005, Boulay 2004 at 254; Ex. 1003, Ratain Decl. ¶ 112. Further,
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`O’Donnell taught that everolimus was safe and effective for treating other tumors
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`in humans. Ex. 1029, O’Donnell at 803; Ex. 1003, Ratain Decl. ¶¶ 119-123. One of
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`ordinary skill would have tried, and reasonably expected to succeed, using
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`everolimus to treat advanced pancreatic NETs in humans after cytotoxic treatment
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`failed because Duran had demonstrated that another well-known rapamycin
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`derivative, temsirolimus,2 was effective in treating advanced NETs. Ex. 1011,
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`Petition for Inter Partes Review of USP 9,006,224
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`Duran at 3096; Ex. 1003, Ratain Decl. ¶¶ 129-131, 167.
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`To explain further, it was well-known as of November 2005 that rapamycin,
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`an inhibitor of the protein mTOR, was a potent anti-tumor agent. Ex. 1003, Ratain
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`Decl. ¶¶ 70-71, 83-92. Researchers had investigated the use of rapamycin in the
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`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
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`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
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`rapamycin derivatives. Id. ¶ 75. Differing only at the C40 position (circled in red),
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`these two rapamycin derivatives have identical binding sites for their biological
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`targets, mTOR and FKBP123:
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`2 Temsirolimus is also known as CCI-779 in the literature. Ex. 1033, Rao at 621;
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`Ex. 1003, Ratain Decl. ¶ 73.
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`3 By November 2005, it was known that rapamycin and its derivatives first bind to
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`the protein FKBP12 and then that rapamcyin-FKBP12 complex interacts with
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`mTOR to inhibit its activity. Ex. 1003, Ratain Decl. ¶ 83.
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`Petition for Inter Partes Review of USP 9,006,224
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`(everolimus)
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`(temsirolimus)
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`Id. ¶¶ 75, 91-92 (citing Ex. 1017, Huang 2002; Ex. 1039, Vignot at 528, Fig. 4).
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`One of ordinary skill in November 2005 would have understood that both
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`everolimus and temsirolimus have similar properties to each other and to
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`rapamycin. Ex. 1003, Ratain Decl. ¶¶ 75-92.
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`Petition for Inter Partes Review of USP 9,006,224
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`Oberg 2004 suggested rapamycin (and therefore its known active
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`derivatives) as a treatment for humans with advanced pancreatic NETs after the
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`failure of chemotherapy. Ex. 1027, Oberg 2004 at 59; Ex. 1003, Ratain Decl. ¶¶
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`100-104. Additionally, Boulay 2004 disclosed that everolimus was well-tolerated
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`and effective in a rat model for pancreatic NETs that had been correlated to clinical
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`efficacy in humans. Ex. 1005, Boulay 2004 at 254; Ex. 1003, Ratain Decl. ¶¶ 110-
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`117. Specifically, Boulay 2004 reported that administering everolimus as a
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`monotherapy to rats injected with pancreatic NET tumor cells showed statistically
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`significant antitumor activity, and was “well tolerated, with no significant body
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`weight loss or mortalities observed.” Ex. 1005, Boulay 2004 at 254; Ex. 1003,
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`Ratain Decl. ¶¶ 115-116. This model was reported to indicate likely clinical
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`activity in pNET. Ex. 1003, Ratain Decl. ¶¶ 112.
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`A person of ordinary skill would have also known that both everolimus and
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`temsirolimus are effective and well-tolerated in human cancer patients. Ex. 1029,
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`O’Donnell at 803; Ex. 1003, Ratain Decl. ¶¶ 79-81; see also Ex. 1009, Dancey at
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`1105-1110; Ex. 1054, Dukart at 5:1-6:26; Ex. 1011, Duran at 3096. In particular,
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`O’Donnell taught that everolimus exhibited anti-tumor effects and “was well
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`tolerated with only mild degrees” of side effects. Ex. 1029, O’Donnell at 803; Ex.
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`1003, Ratain Decl. ¶ 120. And the prior art taught that everolimus was more
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`bioavailable than rapamycin, with a “more favorable” pharmacokinetic profile,
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`proving a “clinical advantage.” Ex. 1009, Dancey, at 1105-06; Ex. 1036, Schuler at
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`Petition for Inter Partes Review of USP 9,006,224
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`36-37, 41; Ex. 1003, Ratain Decl. ¶¶ 76-77. Further, Tabernero recommended that
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`everolimus be administered in 10 mg daily doses as a monotherapy for treating
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`advanced solid tumors. Ex. 1038, Tabernero at 3007.
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`In light of these teachings, a person of ordinary skill in the art seeking to
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`treat patients with advanced pancreatic NETs after the failure of cytotoxic
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`chemotherapy would have been motivated to combine the teachings of Oberg
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`2004, Boulay 2004, and O’Donnell to treat such tumors with everolimus as recited
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`in the claims of the ’224 patent. Ex. 1003, Ratain Decl. ¶¶ 132-138. Although one
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`of ordinary skill would have been able to determine an appropriate dose using
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`routine experimentation, a skilled artisan would have also incorporated the
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`teaching of Tabernero that everolimus should be administered at 10 mg/day for the
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`treatment of solid tumors, as recited in claim 2 of the ’224 patent. Ex. 1038,
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`Tabernero at 3007; Ex. 1003, Ratain Decl. ¶¶ 152-53, 159-160.
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`In addition, the prior art taught that everolimus had preclinical activity in a
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`rat tumor model of pancreatic NETs, Boulay 2004 at 252-54, and clinical activity
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`in treating humans with solid tumors, O’Donnell. A skilled artisan would have also
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`been aware that the rapamycin derivative temsirolimus had been shown to have
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`antitumor activity in humans with advanced neuroendocrine carcinomas, a subset
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`of advanced NETs, who had previously been treated with cytotoxic chemotherapy.
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`Ex. 1011, Duran at 3096; Ex. 1003, Ratain Decl. ¶¶ 94, 130. Therefore, in seeking
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`Petition for Inter Partes Review of USP 9,006,224
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`to treat humans with advanced pancreatic NETs, a skilled artisan would have been
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`motivated to combine the teachings of Boulay 2004, O’Donnell, and Duran, and in
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`doing so, would have reasonably expected that everolimus would be effective in
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`treating humans with advanced pancreatic NETs after failure with cytotoxic
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`chemotherapy. Ex. 1003, Ratain Decl. ¶¶ 139-142, 161-174. And, as stated above,
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`although a person of ordinary skill would have been able to determine an
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`appropriate dose, including 10 mg/day, a skilled artisan would have also
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`incorporated Tabern