UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`BRECKENRIDGE PHARMACEUTICAL, INC.
`Petitioner
`v.
`NOVARTIS PHARMACEUTICALS CORPORATION
`Patent Owner
`________________________
`
`Case IPR2017-_______
`U.S. Patent No. 8,410,131
`________________________
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 8,410,131
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`
`I. 
`
`II. 
`
`OVERVIEW ................................................................................... 1 
`
`REQUIREMENTS FOR PETITION FOR INTER PARTES
`REVIEW ......................................................................................... 2 
`
`A.
`
` 
`
`B.
`
` 
`
`C.
`
` 
`
`Grounds for Standing (37 C.F.R. § 42.104(a)) .................. 2 
`
`Notice of Lead and Backup Counsel and Service
`Information .......................................................................... 3 
`
`Notice of Real-Parties-in-Interest (37 C.F.R. § 42.8(b)(1))
` .............................................................................................. 3 
`
`D.
`
`  Notice of Related Matters (37 C.F.R. § 42.8(b)(2)) ............ 4 
`
`E.
`
` 
`
`F.
`
` 
`
`Fee for Inter Partes Review ................................................ 4 
`
`Proof of Service ................................................................... 4 
`
`III. 
`
`IDENTIFICATION OF CLAIMS BEING CHALLENGED (37
`C.F.R. § 42.104(B)) ........................................................................ 5 
`
`IV.  SUMMARY OF THE ARGUMENT ............................................. 6 
`
`V. 
`
`Summary Of The '131 Patent .......................................................... 9 
`
`VI.  Priority Date for Claims 1-3 and 5-9 of the '131 Patent ............... 11 
`
`VII.  THE PERSON OF ORDINARY SKILL IN THE ART .............. 14 
`
`VIII.  CLAIM CONSTRUCTION .......................................................... 14 
`
`A.
`
` 
`
`B.
`
` 
`
`Applicable Law .................................................................. 14 
`
`Construction of Claim Terms ............................................ 15 
`1. 
`"Inhibiting Growth of Solid Excretory System
`Tumors in a Subject" ................................................ 15 
`"advanced solid excretory system tumor" ................ 16 
`"kidney tumor" ......................................................... 17 
`"unit dosage form" ................................................... 18 
`
`2. 
`3. 
`4. 
`
`IX.  TECHNICAL BACKGROUND AND STATE OF THE ART AT
`
`i
`
`

`

`THE TIME OF THE PURPORTED INVENTION ..................... 18 
`
`A.
`
` 
`
`B.
`
` 
`
`C.
`
` 
`
`D.
`
` 
`
`Schuler teaches that everolimus shares the same
`mechanism of action as rapamycin, and everolimus
`exhibits improved properties compared to rapamycin. .... 21 
`
`Crowe discloses that everolimus shares the same
`mechanism of action as rapamycin, and everolimus
`exhibits an improved oral absorption profile compared to
`rapamycin. .......................................................................... 23 
`
`Neumayer teaches that a therapeutically effective dosage
`amount of everolimus is well-tolerated in human patients.
` ............................................................................................ 23 
`
`Alexandre teaches that temsirolimus, like rapamycin, is an
`mTOR inhibitor, and temsirolimus inhibits growth of
`advanced solid excretory system tumors. .......................... 24 
`
`E.
`
`  Hidalgo teaches that rapamycin and temsirolimus are
`mTOR inhibitors, the antitumor activity associated with
`rapamycin and temsirolimus is due to mTOR inhibition,
`and temsirolimus inhibits growth of advanced solid
`excretory system tumors. ................................................... 25 
`
`F.
`
` 
`
`Luan teaches that sirolimus inhibits growth of advanced
`kidney tumors. .................................................................... 26 
`
`G.
`
`  Wasik teaches that everolimus inhibits growth of
`advanced kidney tumors. ................................................... 27 
`
`H.
`
`  Navarro teaches that pharmaceutical compositions
`containing everolimus in an amount of 10 mg are useful
`to treat tumors. ................................................................... 30 
`
`X. 
`
`CLAIMS 1-3 AND 5-9 ARE ANTICIPATED AND/OR
`OBVIOUS OVER THE PRIOR ART. ......................................... 31 
`
`A.
`
` 
`
`B.
`
` 
`
`C.
`
` 
`
`Legal Background ............................................................. 31 
`
`Ground 1: Claims 1-3 and 5-9 of the '131 patent are
`invalid under 35 U.S.C. § 102(a) or §102(e)(1) as
`anticipated by Wasik. ......................................................... 32 
`
`Ground 2: Claims 1-3 and 5-9 of the '131 patent are
`ii
`
`
`
`

`

`invalid under 35 U.S.C. § 103(a) on the ground that they
`are rendered obvious by Wasik alone or in combination
`with Navarro. ..................................................................... 39 
`
`D.
`
`  Ground 3: Claims 1-3 and 5-9 of the '131 patent are
`invalid under 35 U.S.C. § 103(a) on the ground that they
`are rendered obvious by the combination of Wasik,
`Navarro, Crowe, and Luan. .............................................. 42 
`
`E.
`
` 
`
`F.
`
` 
`
`Ground 4: Claims 1-3 and 5-9 of the '131 patent are
`invalid under 35 U.S.C. § 103(a) on the ground that they
`are rendered obvious by the combination of Hidalgo,
`Alexandre, Crowe, Schuler, Neumayer, and Navarro. .... 45 
`
`Ground 5: Claims 1-3 and 5-9 of the '131 patent are
`invalid under 35 U.S.C. § 103(a) on the ground that they
`are rendered obvious by the combination of Hidalgo,
`Alexandre, Crowe, Schuler, Neumayer, Navarro, and
`Luan. .................................................................................. 54 
`
`XI.  OBJECTIVE INDICIA FAIL TO OVERCOME THE STRONG
`EVIDENCE OF OBVIOUSNESS. ....................................................... 57 
`
`XII.  CONCLUSION ...................................................................................... 60 
`
`iii
`
`
`
`
`
`
`

`

`
`
`Petition for Inter Partes Review of USP 8,410,131
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`In re Aller,
`220 F.2d 454 (CCPA 1955) ................................................................................... 32
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012) ............................................................................. 32
`
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ............................................................................. 59
`
`Concrete Appliances Co. v. Gomery,
`269 U.S. 177 (1925) .............................................................................................. 59
`
`Cuozzo Speed Techs., LLC v. Lee,
`136 S.Ct. 2131 (2016) ........................................................................................... 15
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................... 59
`
`Geo. M. Martin Co. v. Alliance Mach. Sys. Int'l LLC,
`618 F.3d 1294 (Fed. Cir. 2010) ............................................................................. 59
`
`Glaxo Grp., Ltd. v. Apotex, Inc.,
`376 F.3d 1339 (Fed. Cir. 2004) ............................................................................. 31
`
`In re Gosteli,
`872 F.2d 1008 (Fed. Cir. 1989) ............................................................................. 11
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ............................................................................................ 32, 57
`
`KSR Int'l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) .............................................................................................. 32
`
`L.A. Biomedical Research Inst. at Harbor-UCLA Med. Ctr. v.
`Eli Lilly & Co.,
`849 F.3d 1049 (Fed. Cir. 2017) ....................................................................... 12, 13
`
`Leapfrog Enters., Inc. v. Fisher-Price, Inc.,
`485 F.3d 1157 (Fed. Cir. 2007) ............................................................................. 57
`iv
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`
`Merck & Cie v. Gnosis S.p.A.,
`808 F.3d 829 (Fed. Cir. 2015) ......................................................................... 32, 57
`
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................. 32
`
`Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292 (Fed. Cir. 2015) ............................................................................. 15
`
`Purdue Pharma L.P. v. Faulding, Inc.,
`230 F.3d 1320 (Fed. Cir. 2000) ............................................................................. 11
`
`SIBIA Neurosciences, Inc. v. Cadus Pharm. Corp.,
`225 F.3d 1349 (Fed. Cir. 2000) ............................................................................. 59
`
`Versata Dev. Grp., Inc. v. SAP Am., Inc.,
`793 F.3d 1306 (Fed. Cir. 2015) ............................................................................. 15
`
`Verve v. Crane Cams,
`311 F.3d 1116 (Fed. Cir. 2002) ............................................................................. 31
`
`Wasica Fin. GmbH v. Cont'l Auto. Sys.,
`853 F.3d 1272 (Fed. Cir. 2017) ............................................................................. 31
`
`Statutes
`
`35 U.S.C. § 102(a) ............................................................................................... passim
`
`35 U.S.C. § 102(b) ............................................................................................... passim
`
`35 U.S.C. § 102(e)(1) ................................................................................. 5, 27, 31, 32
`
`35 U.S.C. § 103(a) ............................................................................................... passim
`
`35 U.S.C. § 112 ..................................................................................................... 11, 13
`
`Other Authorities
`
`37 C.F.R. § 42.8(b)(1) .................................................................................................. 3
`
`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
`
`
`
`v
`
`

`

`
`37 C.F.R. § 42.10(b) ..................................................................................................... 3
`
`Petition for Inter Partes Review of USP 8,410,131
`
`37 C.F.R. § 42.15(a) ..................................................................................................... 4
`
`37 C.F.R. § 42.100(b) ................................................................................................. 15
`
`37 C.F.R. § 42.104(a) ................................................................................................... 2
`
`37 C.F.R. § 42.104(B) .................................................................................................. 5
`
`37 C.F.R. § 42.104(b)(4) ............................................................................................ 31
`
`Final Rules, 77 Fed. Reg. 48680, 48699 (Aug. 14, 2012) .......................................... 15
`
`
`
`
`
`vi
`
`

`

`Exhibit
`Number
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`Petition for Inter Partes Review of USP 8,410,131
`
`EXHIBIT LIST
`
`Exhibit Description
`
`U.S. Patent No. 8,410,131 ("the '131 patent")
`
`PCT Published Application No. WO 01/51049 A1, O-
`Methylated Rapamycin Derivatives for Alleviation and
`Inhibition of Lymphoproliferative Disorders, to Wasik
`et al. ("Wasik")
`
`PCT Published Application No. WO 00/33878 A2,
`Macrolides, to Navarro et al. ("Navarro")
`
`Crowe et al., Absorption and Intestinal Metabolism of
`SDZ-RAD and Rapamycin in Rats, Drug Metab. Disp.
`(1999), 27(5): 627-632 ("Crowe")
`
`Luan et al., Sirolimus Prevents Tumor Progression:
`mTOR Targeting for the Inhibition of Neoplastic
`Progression, Am. J. Transplant. (2001) 1 Suppl 1, 243
`(Abstr. No. 428) ("Luan")
`
`Hidalgo et al., The Rapamycin-sensitive Signal
`Transduction Pathway as a Target for Cancer
`Therapy, Oncogene (2000) 19(56): 6680-6686
`("Hidalgo")
`
`Alexandre et al., CCI-779, A new Rapamycin Analog,
`Has Antitumor Activity at Doses Including Only Mild
`Cutaneous Effects and Mucositis: Early Results of an
`Ongoing Phase I Study, Clin. Cancer Res. Suppl.
`(1999) 5: 3730s, Abstr. No. 7 (AACR-NCI-EORTC
`International Conference, November 16-19, 1999 held
`in Washington, DC) ("Alexandre")
`
`Schuler et al., SDZ RAD, A New Rapamycin
`Derivative, Transplantation (1997) 64(1): 36-42
`("Schuler")
`
`vii
`
`
`
`
`
`
`
`

`

`Exhibit
`Number
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit Description
`
`Neumayer et al., Entry-into-human Study with the
`Novel Immunosuppressant SDZ RAD in Stable Renal
`Transplant Patients, Br. J. Clin. Pharmacol. (1999)
`48(5): 694-703 ("Neumayer")
`
`Declaration of Allan J. Pantuck, M.D. in Support of
`Petition for Inter Partes Review of U.S. Patent No.
`8,410,131
`
`RAPAMUNE® (sirolimus) Oral Solution
`RAPAMUNE® Approval Letter and approved labeling
`
`Great Britain patent application (GB 0104072.4, "GB
`'072" or "the '072 priority application")
`
`Great Britain patent application (GB0124957.2, "GB
`'957" or "the '957 priority application")
`
`International Patent Application No. PCT/EP02/01714
`("the '714 PCT Application")
`
`IPR Final Rules
`
`Dancey, J. E., Rapamycin-Sensitive Signal-
`Transduction Pathways: Protein Translation Control
`of Cell Proliferation, ASCO Educational Book (2000)
`68-75 ("Dancey")
`
`Sorbera et al, SDZ-RAD, Drugs of the Future (1999)
`24(1): 22-29 ("Sorbera")
`
`U.S. Patent No. 5,362,718, to Skotnicki et al.
`("Skotnichi '718")
`
`U.S. Patent No. 5,665,772 to Cottens et al. ("Cottens
`'772 patent")
`
`Sedrani et al., Chemical Modification of Rapamycin:
`The Discovery of SDZ RAD, Transplantation Proc.
`
`viii
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`Exhibit Description
`
`1021
`
`
`1022
`
`
`1023
`
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`(1998) 30(5): 2192-2194 ("Sedrani")
`
`PCT Published Application No. WO 97/47317 A1,
`Combination of a Somatostatin Analogue and a
`Rapamycin, to G. Weckbecker ("Weckbecker")
`
`U.S. Patent No. 6,331,547, Water Soluble SDZ RAD
`Esters, which issued to Zhu et al. on December 18,
`2001 from U.S. Provisional Patent Application No.
`60/183,035 filed on August 18, 1999 to Zhu ("Zhu '547
`patent")
`
`U.S. Patent Application Publication No. 2002/0183239
`A1, Antineoplastic Combinations, which published on
`December 5, 2002 from an application filed on April 6,
`2001, to Gibbons ("Gibbons US '239")
`
`U.S. Patent Application Publication No. 2003/0008923
`A1, Antineoplastic Combinations, which published on
`January 9, 2003 from an application filed on June 1,
`2001 to Dukart ("Dukart US '923")
`
`Flowcharts for 35 U.S.C. § 102(e) Dates ("102(e) Date
`Flowchart")
`Published Application No. WO 94/09010 A1, O-
`Alkylated Rapamycin Derivatives and their use,
`particularly as immunosuppressants, to Cottens et al.
`("Cottens WO '010")
`Selected portions of Prosecution History Documents
`("May 10, 2010 Amendment re. Cottens WO '010")
`
`Curriculum Vitae of Allan J. Pantuck, M.D.
`2015 Orange Book,"35th Edition (2015) with respect to
`AFINITOR® ("2015 Orange Book ")
`
`Alexandre, Raymond, et al., La rapamycine et le CCI-
`779, Bull. Cancer (1999) 86(10): 808-811
`
`ix
`
`
`
`
`
`

`

`Exhibit
`Number
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit Description
`
`("Alexandre" and Raymond")
`
`Boni et al., Pharmacokinetics of escalating doses of
`CCI-779 in Combination with 5-Fluorouracil and
`Leucovorin in Patients with Advanced Solid Tumors,
`Eur. J. Cancer (2001) 37(Suppl. 6): S68 (Abstr. No.
`242) (The 11th ECCO October 21-25, 2001 meeting
`held in Lisbon, Portugal) ("Boni")
`
`Dinney et al., Biology of Metastasis: Studies in Renal
`Cancer (17-24), in Principles and Practice of
`Genitourinary Oncology (Raghavan et al. eds., 1997)
`("Dinney")
`
`Shi et al., Rapamycin enhances Apoptosis and
`Increases Sensitivity to Cisplatin in Vitro, Cancer
`Research (1995) 55(9): 1982-1988 ("Shi")
`
`Fosså et al., Survival of Patients with Advanced
`Urothelial Cancer treated with Cisplatin-based
`Chemotherapy, Brit. J. Cancer (1996) 74: 1655-1659
`("Fosså")
`
`Motzer et al., Survival and Prognostic Stratification of
`670 Patients with Advanced Renal Cell Carcinoma, J.
`Clin. Oncol. (1999) 17(8): 2530-2540 ("Motzer et al.")
`
`PCT Published Application No. WO 02/40000 A2, Use
`of CCI-779 as an Antineoplastic Agent, to Dukart et al.
`("Dukart WO '000")
`
`PCT Published Application No. WO 02/080975 A1,
`Antineoplastic Combinations such as Rapamycin
`together with Gemcitabine or Fluorouracil, to Gibbons
`et al. ("Gibbons WO '975")
`
`PCT Published Application No. WO 02/098416 A2,
`Antineoplastic Combinations, to Dukart et al. ("Dukart
`
`x
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`WO '416")
`
`Exhibit Description
`
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`U.S. Patent Application Publication No. 2002/0091137
`A1, Use of CCI-779 as an Antineoplastic Agent, which
`published on July 11, 2002, to Dukart ("Dukart '137")
`
`U.S. Patent No. 7,781,446, Use of CCI-779 as an
`Antineoplastic Agent, which issued to Dukart et al. on
`August 24, 2010 ("Dukart '446"), and which claims
`priority to U.S. Provisional Patent Application No.
`60/249,077 ("Dukart")
`
`Perez-Atayde et al., Spectrum of Tumor Angiogenesis
`in the Bone Marrow of Children with Acute
`Lymphoblastic Leukemia, Am. J. Pathol. (1997)
`150(3): 815-821 ("Perez-Atayde")
`
`True et al., Pathology of Renal Cancers (799-811), in
`Principles and Practice of Genitourinary Oncology
`(Raghavan et al. eds., 1997) ("True")
`
`Jennings et al., Renal, Perirenal and Ureteral
`Neoplasms (643-694), In Adult and Pediatric Urology;
`Third Edition. (Gillenwater et al. eds., 3rd ed. 1996,
`Volume 1), Grayhack, Howards, and Duckett Eds.
`Mosby-Year Book, Inc. 1996 ("Jennings")
`
`Robert R. Bahnson, Renal and Urinary Tract
`Neoplasia (371-379), In Primer on Kidney Diseases
`(Greenberg, A. et al. eds., 2nd ed. 1998) ("Bahnson")
`
`Vézina et al., Rapamycin (AY-22,989), A New
`Antifungal Antibiotic I. Taxonomy of the Producing
`Streptomycete and Isolation of the Active Principle, J.
`Antibiot. (1975) 28 (10): 721-726 ("Vézina")
`
`Sehgal et al., Rapamycin (AY-22,989), a New
`Antifungal Antibiotic II. Fermentation, Isolation, and
`Characterization, J. Antibiotics (1975) 28(10): 727-
`
`xi
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`Exhibit Description
`
`732 ("Sehgal")
`
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`Baker et al., Rapamycin (AY-22,989), A New
`Antifungal Antibiotic III. In Vitro and In Vivo
`Evaluation, J. Antibiotics (1978) 31(6): 539-545
`("Baker")
`
`U.S. Patent No. 3,929,992 to Sehgal ("Sehgal '992
`patent")
`
`Martel et al. Inhibition of the Immune Response by
`Rapamycin, a New Antifungal Antibiotic, Can. J.
`Physiol. Pharmacol. (1977) 55(1): 48-51 ("Martel")
`
`Eng et al., Activity of Rapamycin (AY-22,989) against
`Transplanted Tumors, J. Antibiotics (1984) 37(10):
`1231-1237 ("Eng")
`
`U.S. Patent No. 5,066,493 to Sehgal et al. ("Sehgal
`'493 patent")
`
`U.S. Patent No. 5,206,018 to Sehgal et al. ("Sehgal
`'018 patent")
`Calne et al., Rapamycin for Immunosuppression in
`Organ Allografting, Lancet (1989) 2(8656): 227
`("Calne")
`Morris et al., Identification of a New Pharmacological
`Action for an Old Compound, Med. Sci. Res. (1989)
`17(14): 609-610610 ("Morris 1989")
`Morris, R. N., Rapamycins: Antifungal, Antitumor,
`Antiproliferative, and Immunosuppressive Macrolides,
`Transplantation Reviews (1992) 6(1): 39-87 ("Morris
`1992")
`Van Duyne et al., Atomic Structure of the Rapamycin
`Human Immunophilin FKBP-12 Complex, J. Am.
`Chem. Soc. (1991) 113(19): 7433-7434 ("Van Duyne")
`
`xii
`
`
`
`
`
`

`

`Exhibit
`Number
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`
`1062
`
`1063
`
`1064
`
`1065
`
`1066
`
`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit Description
`
`Choi et al., Structure of the FKBP12-Rapamycin
`Complex Interacting with the Binding Domain of
`Human FRAP, Science (1996) 273(5272): 239-242
`("Choi")
`
`Rapamune prescribing information as of August 2000
`
`Garber, K., Rapamycin's Resurrection: A New Way to
`Target the Cancer Cell Cycle, J Natl Cancer Inst.
`(2001) 93(2): 1517-1519 ("Garber")
`
`Breitenbach et al., Rapamycin Inhibits Tumor Growth
`and Metastasis in Mice by Antiangiogenesis, Am. J.
`Transplant. (2001) 1 Suppl 1, 250 (Abstr. No. 459)
`("Breitenbach")
`
`Guba et al, Rapamycin inhibits Tumor Growth and
`Metastasis by Antiangiogenesis, Chirugicshes Forum
`2001 für experimentelle und klinsche Forschung
`(2001) 30: 37-39 ("Guba")
`
`Hosoi et al., Studies on the Mechanism of Resistance to
`Rapamycin in Human Cancer Cells, Mol. Pharmacol.,
`(1998) 54 815-824 ("Hosoi")
`
`Zhang et al., Differences in Phosphorylation of the IL-
`2R Associated JAK/STAT Proteins between HTLV-I
`(+), IL-2-independent and IL-2-dependent Cell Lines
`and Uncultured Leukemic Cells from Patients with
`Adult T-cell Lymphoma/Leukemia, Leukemia Res.
`(1999) 23(4): 373-384 ("Zhang")
`Monograph 8288 of The Merck Index, 12th Ed. (2006)
`("Merck Index")
`
`U.S. Patent No. 5,260,300 to Hu ("Hu '300 patent")
`
`U.S. Patent No. 5,221,670 to Caufield ("Caufield '670
`
`xiii
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`patent")
`
`Exhibit Description
`
`1067
`
`1068
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`U.S. Patent No. 5,434,260 to Skotnicki et al.
`("Skotnicki '260 patent")
`
`Freireich et al., Quantitative Comparison of Toxicity of
`Anticancer Agents in Mouse, Rat, Hamster, Dog,
`Monkey, and Man, Cancer Chemotherapy Reports
`(1966) 50(4): 219-244 ("Freireich")
`
`PRNewswire, August 30, 2000 press release, Novartis
`Announces Positive Trial Results for Two Novel
`Transplantation Drugs ("Press Release")
`AFINITOR® approval letter and prescribing
`information, as of March 30, 2009 ("AFINITOR® Mar
`30, 2009 approval")
`AFINITOR® prescribing information, as of June 14,
`2016 ("AFINITOR® Jun 14, 2016 prescribing
`information")
`ZORTRESS® approval letter and prescribing
`information, as of April 20, 2010 ("ZORTRESS®
`approval")
`
`U.S. Patent No. 7,297,703 to Navarro et al. ("Navarro
`'703 patent")
`
`International Nonproprietary Names of Pharmaceutical
`Substances (INN), WHO Drug Information, (2000)
`14(3): 183-209 ("Everolimus INN")
`
`Majewski et al., The Immunosuppresive Macrolide
`RAD inhibits Growth of Human Epstein-Barr Virus-
`transformed B Lymphocytes in vitro and in vivo: A
`Potential Approach to Prevention and Treatment of
`Postrransplant Lymphoproliferative Disorders, Proc.
`Natl. Acad. Sci. (2000) 97(8): 4285-4290 ("Majewski")
`
`xiv
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`Exhibit Description
`
`1076
`
`1077
`
`1078
`
`1079
`
`1080
`
`1081
`
`1082
`
`1083
`
`Huang et al., Mechanisms of Resistance to Rapamycin,
`Drug Resistance Updates, (2001) 4: 378-392 ("Huang")
`
`Beuvink et al., Antitumor Activity of RAD001, an
`Orally Active Rapamycin Derivative, Proc. Amer.
`Assoc. Cancer Res. (2001) 42, 366, Abstr. No. 1972
`("Beuvink")
`
`International Nonproprietary Names of Pharmaceutical
`Substances (INN), WHO Drug Information, (2005)
`19(3): 243-270 ("Temsirolimus INN")
`
`Wall Street Journal, Drug Progress on Hard-to-Treat
`Cancers is Cited, by Robert Langreth and Michael
`Waldholz in the November 17, 1999 edition
`("Langreth")
`
`Hidalgo et al., A Phase I and Pharmacological Study of
`CCI-779, a Rapamycin Ester Cell Cycle Inhibitor,
`Ann. Oncol. (2000) 11 (Suppl. 4) 133, Abstr. No. 606O
`(25th ESMO Congress, October 13-17, 2000 held in
`Hamburg, DE) ("Hidalgo ESMO Abstract")
`
`December 1, 2000 issue of The Lancet Oncology, CCI-
`779: A New Targeted Anticancer Agent, by Ezzie
`Hutchinson ("Hutchinson")
`
`Hidalgo et al., Phase I and Pharmacological Study of
`CCI-779, a Cell Cycle Inhibitor, Clinical Cancer
`Research (2000), Supplement 6: 4548s-4549s, Abstr.
`No. 413 (11th NCI-EORTC-AACR November 7-10,
`2000 meeting held in Amsterdam, NL) ("Hidalgo NCI
`Abstract")
`
`Raymond et al., CCI-779, an ester analogue of
`rapamycin that interacts with PTEN/PI3 Kinase
`Pathways: A Phase I Study utilizing a Weekly
`Intravenous Schedule, Clinical Cancer Res. (2000)
`
`xv
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`Exhibit Description
`
`1084
`
`1085
`
`1086
`
`1087
`
`1088
`
`1089
`
`1090
`
`Supplement 6: 4549s, Abstr. No. 414 (11th NCI-
`EORTC-AACR November 7-10, 2000 meeting held in
`Amsterdam, The Netherlands) ("Raymond NCI
`Abstract")
`
`DeMario et al., Oral Chemotherapy: Rationale and
`Future Directions, J. Clin. Oncol. (1998) 16(7): 2557-
`2567 ("DeMario")
`
`Gibbons et al., The Effect of CCI-779, a Novel
`Macrolide Anti-Tumor Agent, on the Growth of Human
`Tumor Cells In Vitro and in Nude Mouse Xenographs
`In Vivo, Proc. Amer. Assoc. Cancer Res. (1999) 40:
`301, Abstr. No. 2000 ("Gibbons Abstract")
`
`Geoerger et al., Rapamycin analog CCI 779 inhibits
`growth of Human Medulloblastoma Xenographs, Proc.
`Amer. Assoc. Cancer Res. (1999) 40: 603a, Abstr. No.
`3978 (90th Annual Meeting of the AACR, April 10-14,
`1999 held in Philadelphia, PA) ("Geoerger Abstract")
`
`Geoerger et al., Antitumor Activity of the Rapamycin
`Analog CCI-779 in Human Primitive Neuroectodermal
`Tumor/Medulloblastoma Models as Single Agent and
`in Combination Chemotherapy, Cancer Res. (2001)
`61(4): 1527-1532 ("Geoerger")
`TORISEL® approval letter and prescribing
`information, as of May 30, 2007 ("TORISEL®
`Approval")
`TORISEL® prescribing information, as of July 27,
`2016
`
`Cowan et al., Sirolimus: Mammalian Target of
`Rapamycin Inhibitor to Prevent Kidney Rejection,
`Nephrol. Nursing Journal (2000) 27(6): 623-625
`("Cowan")
`
`xvi
`
`
`
`
`
`

`

`Exhibit
`Number
`
`1091
`
`1092
`
`1093
`
`1094
`
`1095
`
`1096
`
`1097
`
`1098
`
`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit Description
`
`Serkova et al., Tissue Distribution and Clinical
`Monitoring of the Novel Macrolide
`Immunosuppressant SDZ-RAD and its Metabolites in
`Monkey Lung Transplant Recipient: Interaction with
`Cyclosporine, J. Pharmacol. Exper. Therap. (2000)
`294(1): 323-332 ("Serkova")
`
`U.S. Patent No. 6,432,973, to Zhu et al. ("Zhu '973
`patent")
`
`Neshat et al., Enhanced Sensitivity of PTEN-deficient
`Tumors to Inhibition of FRAP/mTOR, Proc. Natl.
`Acad. Sci. USA (2001) 98(18) 10314-10319
`("Neshat")
`
`Podsypanina et al., An Inhibitor of mTOR reduces
`Neoplasia and Normalizes p70/S6 Kinase Activity in
`PTEN+/- Mice, Proc. Natl. Acad. Sci. (2001) 98(18):
`10320-10325 ("Podsypanina")
`
`Yu et al., Deregulated P13k/AKT/TOR Pathway in
`PTEN-Deficient Tumor Cells Correlates with an
`Increased Growth Inhibition Sensitivity to a TOR
`Kinase Inhibitor CCI-779, Proc. Amer. Assoc. Cancer
`Res. (2001) 42: 802 (Abstr. No. 4305) ("Yu")
`
`Wen et al., PTEN controls Tumor-induced
`Angiogenesis, Proc. Natl. Acad. Sci. USA (2001)
`98(8): 4622-4627 (92nd Annual Meeting of the AACR,
`March 24-28, 2001 held in New Orleans, LA) ("Wen")
`
`Cantley et al., New Insights into Tumor Suppression:
`PTEN suppresses Tumor Formation by restraining the
`Phosphoinositide 3-Kinase / AKT Pathway, Proc. Natl.
`Acad. Sci. USA, (1999) 96 (8): 4240-4245 ("Cantley")
`
`Kondo et al., PTEN/MMAC1/TEP1 Mutations in
`Human Primary Renal-Cell Carcinomas and Renal
`
`xvii
`
`
`
`
`
`

`

`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit
`Number
`
`Exhibit Description
`
`1099
`
`1100
`
`1101
`
`1102
`
`1103
`
`1104
`
`1105
`
`1106
`
`Carcinoma Cell Lines, Intl. J. Cancer (2001) 91(2):
`219–224 ("Kondo")
`
`Morita et al., Common Regions of Deletion on
`Chromosomes 5q, 6q, and 10q in Renal Cell
`Carcinoma, Cancer Res. (1991) 51(21): 5817-5820
`("Morita")
`
`Sokoloff et al., Systemic Immunotherapy for
`Genitourinary Neoplasms (869-883), in Principles and
`Practice of Genitourinary Oncology (Raghavan et al.
`eds., 1997) ("Sokoloff")
`
`Motzer et al., Chemotherapy for Renal Cell Carcinoma
`(885-896) in Principles and Practice of Genitourinary
`Oncology (Raghavan et al. eds., 1997) ("Motzer")
`NEXAVAR® approval letter and prescribing
`information as of December 1, 2005 ("NEXAVAR®
`approval letter")
`SUTENT® approval letter and prescribing information
`as of January 26, 2006 ("SUTENT® approval letter")
`
`Quinn et al., Renal-Cell Cancer ― Targeting an
`Immune Checkpoint or Multiple Kinases, New England
`J. Med. (2015) 373(19): 1872-1874 ("Quinn")
`
`Choueiri et al., Cabozantinib versus Everolimus in
`Advanced Renal-Cell Carcinoma, New England
`Journal Med. (2015) 373(19): 1814-1823 ("Choueiri")
`
`R. J. Motzer, B. Escudier et al., Nivolumab versus
`Everolimus in Advanced Renal-Cell Carcinoma, New
`England Journal Med. (2015) 373(19): 1803-1813
`("Escudier")
`
`xviii
`
`
`
`
`
`

`

`Exhibit
`Number
`
`1107
`
`1108
`
`1109
`
`1110
`
`1111
`
`Petition for Inter Partes Review of USP 8,410,131
`
`Exhibit Description
`
`AFINITOR® approval letter and prescribing
`information, as of April 26, 2012 ("AFINITOR® Apr
`26, 2012 approval")
`
`Kenerson et al., Activated Mammalian Target of
`Rapamycin Pathway in the Pathogenesis of Tuberous
`Sclerosis Complex Renal Tumors, Cancer Research
`(2002) 62(2): 5645-5650 ("Kenerson")
`
`Bissler et al., Sirolimus for Angiomyolipoma in
`Tuberous Sclerosis Complex or
`Lymphangioleimyomatosis, New Engl. Journal Med.
`(2008) 358(2): 140-151 ("Bissler")
`
`Henske et al., uberous Sclerosis Complex, mTOR, and
`the Kidney: Report of an NIDDK-sponsored Workshop,
`Am J Physiol Renal Physiol. (2014) 306(3): F279-F283
`("Henske")
`
`Kingswood et al., Review of the Tuberous Sclerosis
`Renal Guidelines from the 2012 Consensus
`Conference: Current Data and Future Study, Nephron.
`Clin. Pract. (2016) 134(2) ("Kingswood")
`
`xix
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`Petition for Inter Partes Review of USP 8,410,131
`
`Breckenridge Pharmaceutical, Inc. ("Petitioner" or "Breckenridge") requests
`
`inter partes review of Claims 1-3 and 5-9 of United States Patent No. 8,410,131
`
`(the "'131 patent" (Ex. 1001)), which according to records of the United States
`
`Patent and Trademark Office ("USPTO") is assigned to Novartis Pharmaceuticals
`
`Corporation ("Novartis").
`
`I.
`
`OVERVIEW
`
`The Board should grant inter partes review because the '131 patent claims
`
`nothing more than the product of ordinary skill based on what was already well-
`
`known in the art. The '131 patent claims a method for inhibiting growth of solid
`
`excretory system tumors, for example, a kidney tumor, with a rapamycin derivative
`
`known as everolimus. However, the prior art specifically discloses using
`
`rapamycin and its derivatives (everolimus and temsirolimus) to inhibit growth of
`
`tumors as claimed by the '131 patent.
`
`The prior art relating to everolimus discloses oral administration of the drug
`
`in therapeutically effective amounts to inhibit growth of solid excretory system
`
`tumors, such as advanced kidney tumors. This provides ample grounds to prove
`
`anticipation or, at the very least, the obviousness of claims 1-3 and 5-9 of the '131
`
`patent.
`
`On top of that, the prior art related to rapamycin and temsirolimus also
`
`shows growth inhibition of advanced kidney tumors, and thus provides additional
`
`
`
`1
`
`

`

`
`grounds of obviousness. Specifically, rapamycin was known to inhibit renal
`
`Petition for Inter Partes Review of USP 8,410,131
`
`cancer tumor growth in a mouse model and temsirolimus was known to inhibit
`
`growth of advanced renal cell carcinoma in humans. Renal cell carcinoma is a
`
`type of kidney tumor. Rapamycin, temsirolimus, and everolimus each were known
`
`to inhibit a kinase (i.e., mTOR) involved in cellular proliferation (e.g., tumor
`
`growth), and thus, rapamycin and its derivatives were known to be mTOR
`
`inhibitors. The reported prior art results confirm that mTOR inhibitors function
`
`similarly as a class. Given that the mTOR inhibitors (i.e., rapamycin,
`
`temsirolimus, and everolimus) share the same function, one of ordinary skill would
`
`have expected that everolimus inhibited growth of advanced kidney tumors when
`
`that activity had been observed for rapamycin and temsirolimus.
`
`Therefore, using everolimus to inhibit growth of solid excretory system