Filed October 17, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICAL S, INC.
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner.
`
`
`Case IPR2016-01316
`
`US. Patent No. 6,774,122
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`TO PETITION FOR INTER PARTES REVIEW
`
`OF US PATENT NO. 6,774,122
`
`InnoPharma Exhibit 1017.0001
`
`

`

`TABLE OF CONTENTS
`
`Case IPR2016-01316
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................ .. 1
`
`THE ’122 PATENT ...................................................................................... ..5
`
`A.
`
`B.
`
`C.
`
`Specification ....................................................................................... ..5
`
`Claims ................................................................................................. ..6
`
`Prosecution history ............................................................................. ..8
`
`III.
`
`PERSON OF ORDINARY SKILL IN THE ART ..................................... ..11
`
`IV.
`
`CLAIM CONSTRUCTION ....................................................................... ..12
`
`A. Malignant diseases of the breast ....................................................... ..12
`
`B.
`
`Sufficient amount of castor oil vehicle ............................................ ..12
`
`C. Whereby a therapeutically significant blood plasma fulvestrant
`concentration of at least 2.5 nng'1 is attained for at least 2
`weeks after injection ......................................................................... ..13
`
`D.
`
`E.
`
`Therapeutically significant ............................................................... ..16
`
`Attained ............................................................................................ ..16
`
`V.
`
`STATE OF THE ART ................................................................................ ..17
`
`A. McLeskey [EX. 1005] and Howell 1996 [EX. 1006] ........................ ..17
`
`B.
`
`Active: A skilled artisan had no reason to start with fulvestrant ..... ..20
`
`1.
`
`Petitioner ignores the many other treatment options
`available to the skilled artisan ................................................ ..21
`
`2.
`
`Fulvestrant had not been established to be an effective
`
`treatment ................................................................................. ..23
`
`C.
`
`Critical questions remained about the amount of fulvestrant to
`deliver and how ................................................................................ ..24
`
`1.
`
`2.
`
`3.
`
`Amount: Therapeutically effective blood plasma levels ....... ..24
`
`Administration: Route, excipients, and result intertwined .... ..25
`
`Claimed combination of excipients was unconventional ...... ..29
`
`VI.
`
`THE ’122 PATENT IS VALID AND NOT OBVIOUS ............................ ..32
`
`A.
`
`Law of Obviousness ......................................................................... ..32
`
`InnoPharma Exhibit 1017.0002
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`Case IPR2016-Ol3 16
`
`Page
`
`B.
`
`Ground One: McLeskey ................................................................... ..34
`
`l.
`
`2.
`
`3.
`
`McLeskey describes the fulvestrant formulations as a
`“treatment failure” .................................................................. ..39
`
`McLeskey utilizes a different route of administration
`(subcutaneous) with vastly different subjects (genetically
`engineered mice) .................................................................... ..42
`
`McLeskey provides no pharmacokinetic data nor any
`suggestion of the specific blood plasma levels and
`durations claimed ................................................................... ..46
`
`4.
`
`McLeskey does not disclose the “exact” formulation ........... ..48
`
`C.
`
`Ground Two: McLeskey In Combination With Howell 1996 ......... ..49
`
`1.
`
`2.
`
`No reason to combine McLeskey with Howell 1996 ............ ..50
`
`No reasonable expectation of success .................................... ..53
`
`VII. OBJECTIVE INDICIA DEMONSTRATE THE NONOBVIOUS
`
`NATURE OF THE CLAIMED METHOD OF TREATMENT ................ ..5 8
`
`VIII. CONCLUSION ........................................................................................... ..60
`
`ii
`
`InnoPharma Exhibit 1017.0003
`
`

`

`TABLE OF AUTHORITIES
`
`Case IPR2016-01316
`
`Page(s)
`
`Cases
`
`Apple, Inc. v. Contentguard Holdings, Inc.,
`IPR2015-00357, 2015 WL 9899009 (P.T.A.B. June 29, 2015) ....................... ..46
`
`Apple, Inc. v. Contentguard Holdings, Inc.,
`IPR2015-00449, 2015 WL 4760572 (P.T.A.B. July 15, 2015) ........................ ..38
`
`BioDelivery Scis. Int’l, Inc. v. RB Pharms. Ltd,
`IPR2014-00325, 2015 WL 4045328 (P.T.A.B. June 30, 2015) ....................... ..15
`
`Boehringer Ingelheim Int’l GmbH v. Biogen Inc.,
`IPR2015-00418, 2015 WL 4467391 (P.T.A.B. July 13, 2015) ................. .. 38, 54
`
`Bumble Bee Foods, LLC v. Kowalski,
`IPR2014-00224, 2014 WL 2584188 (P.T.A.B. June 5, 2014) ......................... ..53
`
`Daiiclzi Sankyo Co. v. Matrix Labs., Ltd,
`619 F.3d 1346 (Fed. Cir. 2010) ........................................................................ ..55
`
`Eisai Co. Ltd. v. Dr. Reddy ’s Labs., Ltd,
`533 F.3d 1353 (Fed. Cir. 2008) ........................................................................ ..55
`
`General Plastic Indus. Co. v. Canon Inc.,
`
`IPR2015-01954, 2016 WL 1084221 (P.T.A.B. Mar. 9, 2016) ......................... ..46
`
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) ........................................................................ ..15
`
`Hofler v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005) ........................................................................ ..13
`
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Cir. 2012) ........................................................... .. 33, 34, 54
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) ........................................................................ ..51
`
`KSR Int ’l Co. v. Teleflex Inc.,
`550 US. 398 (2007) ................................................................................... .. 34, 50
`
`iii
`
`InnoPharma Exhibit 1017.0004
`
`

`

`TABLE OF AUTHORITIES
`
`(continued)
`
`Case IPR2016-01316
`
`Page(s)
`
`Lupin Ltd. v. Pozen Inc.,
`IPR2015—01774, 2016 WL 1081583 (P.T.A.B. Mar. 1, 2016) ........... .. 41, 42, 54
`
`Ortho-McNel'l Pharm, Inc. v. Mylan Labs, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ........................................................................ .34
`
`Pandul't Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) ........................................................................ .33
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ........................................................................ ..57
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ................................................................. .. 33, 38
`
`Universal Remote Control, Inc. v. Uel' Cayman, Inc.,
`1PR2014—01 111, 2014 WL 6737921 (P.T.A.B. NOV. 24, 2014) ....................... ..45
`
`Statutes
`
`35 U.S.C. § 103(a) ................................................................................................. .32
`
`Regulations
`
`37 C.F.R. § 42.104(b)(2) ................................................................................. .. 37, 48
`
`iv
`
`InnoPharma Exhibit 1017.0005
`
`

`

`LIST OF EXHIBITS
`
`
`Case IPR2016-01316
`
`
`Exhibit
`Description
`2001
`Declaration of Lisbeth Illum, Ph.D. In Support Of Patent
`
`Owner’s Preliminary Response
`2002
`Declaration of John F. R. Robertson, MD. In Support Of Patent
`
`Owner’s Preliminary Response
`
`
`
`2011
`
`2012
`
`InnoPharma Exhibit 1017.0006
`
`
`
`2004
`
`2005
`
`2006
`
`2007
`
`2003
`Declaration of Ronald J. Sawchuk, Ph.D. In Support Of Patent
`
`Owner’s Preliminary Response
`Angelo Di Leo et al., Results of the CONFIRM Phase [I] Trial
`Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in
`Postmenopausal Women With Estrogen Receptor-Positive
`Advanced Breast Cancer, 28 J. Clin. Oncol. 4594 (2010) (“Di
`
`Leo 2010”)
`Angelo Di Leo et al., Final Overall Survival: Fulvestrant 500 mg
`vs 250 mg in the Randomized CONFIRM Trial, 106 J. Nat’l
`
`Cancer Inst. 1 (2014) (“Di Leo 2014”)
`S. Ohno et al., Three dose regimens offulvestrant in
`postmenopausal Japanese women with advanced breast cancer:
`resultsfrom a double-blind, phase I] comparative study, 21
`
`Annals Oncol. 2342 (2010) (“FINDER 1”)
`Kathleen I. Pritchard et al., Results ofa phase I] study
`comparing three dosing regimens offulvestrant in
`postmenopausal women with advanced breast cancer
`(FINDER2), 123 Breast Cancer Res. & Treat. 453 (2010)
`
`(“FINDER 2”)
`2008
`Robert T. Greenlee et al., Cancer Statistics, 2000, 50 CA Cancer
`
`J. Clin. 7 (2000) (“Greenlee”)
`2009
`J .F.R. Robertson, Oestrogen receptor: a stable phenotype in
`
`breast cancer, 73 Brit. J. Cancer 5 (1996) (“Robertson 1996”)
`2010
`Monica Fornier et al., Update on the Management ofAdvanced
`
`Breast Cancer, 13 Oncology 647 (1999) (“Fornier”)
`V. Craig Jordan, Alternate Antiestrogens and Approaches to the
`Prevention of Breast Cancer, 22 J. Cell. Biochem. 51 (Supp.
`1995) (“Jordan Supp. 1995”)
`Gabriel N. Hortobagyi et al., Anastrozole (Arimidex®), a New
`Aromatase Inhibitorfor Advanced Breast Cancer: Mechanism of
`Action and Role in Management, 16 Cancer Investigation 385
`
`(1998) (“Hortobagyi Cancer Investigation 1998”)
`
`
`
`

`

`
`
`Case IPR2016-01316
`
`
`
`2017
`
`2020
`
`2024
`
`2025
`
`
`
`Exhibit Description
`
`2013
`S.R.D. Johnston et al., The novel anti-oestrogen idoxifene inhibits
`the growth of human MCF-7 breast cancer xenografts and
`reduces the frequency ofacquired anti-oestrogen resistance, 75
`Brit. J. Cancer 804 (1997) (“Johnston 1997”)
`2014
`Kathleen Pritchard, Ejfects on Breast Cancer.‘ Clinical Aspects,
`in Estrogens and Antiestrogens: Basic and Clinical Aspects 175
`(R. Lindsay et al. eds., 1997) (“Pritchard 1997”)
`2015
`Aman U. Buzdar et al., Tamoxifen and Toremifene in Breast
`Cancer: Comparison of Safety and Ejficacy, 16 J. Clin. Oncol.
`348 (1998) (“Buzdar Clin. Oncol. 1998”)
`2016
`Aman U. Buzdar et al., Update on Endocrine Therapy for Breast
`Cancer, 4 Clin. Cancer Res. 527 (1998) (“Buzdar Clin. Cancer
`
`Res. 1998”)
`V. Craig Jordan, TAMOXIFEN.‘ Toxicities and Drug Resistance
`During the Treatment and Prevention of Breast Cancer, 35 Ann.
`Rev. Pharmacol. Toxicol. 195 (1995) (“Jordan 1995”)
`2018
`Monica Morrow et al., Molecular Mechanisms ofResistance to
`Tamoxifen Therapy in Breast Cancer, 128 Arch. Surg. 1187
`(1993) (“Morrow”)
`2019
`Valerie J. Wiebe et al., Tamoxifen resistance in breast cancer,
`
`14 Crit. Revs. Oncol. Hematol. 173 (1993) (“Wiebe”)
`V. Craig Jordan, The Strategic Use ofAntiestrogens to Control
`the Development and Growth ofBreast Cancer, 70 Cancer 977
`(Supp. 1992) (“Jordan Supp. 1992”)
`2021
`V. Craig Jordan, The Role of Tamoxifen in the Treatment and
`Prevention ofBreast Cancer, Curr. Probl. Cancer 134 (1992)
`(“Jordan 1992”)
`2022
`Susan E. Minton, New Hormonal Therapiesfor Breast Cancer, 6
`
`Cancer Control J. 1 (1999) (“Minton”)
`2023
`TA. Grese et al., Selective Estrogen Receptor Modulators
`
`(SERMs), 4 Current Pharm. Design 71 (1998) (“Grese 1998”)
`Gabriel N. Hortobagyi, Treatment ofBreast Cancer, 339 New
`Eng. J. Med. 974 (1998) (“Hortobagyi New Eng. J. Med. 1998”)
`Shigeru Masamura et al., Aromatase inhibitor developmentfor
`treatment ofbreast cancer, 33 Breast Cancer Res. & Treat. 19
`
`(1994) (“Masamura 1994”)
`
`
`
`Vi
`
`InnoPharma Exhibit 1017.0007
`
`

`

`
`
`Case IPR2016-01316
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`
`
`
`
`
`Exhibit
`Description
`2026
`Gary J. Kelloff et al., Aromatase Inhibitors as Potential Cancer
`Chemopreventives, 7 Cancer Epidemiol, Biomarkers &
`
`Prevention 65 (1998) (“Kelloff 1998”)
`M. Dukes et al., Ejfects ofa non-steroidal pure antioestrogen,
`ZM 189,154, on oestrogen target organs ofthe rat including
`
`bones, J. Endocrinol. 339 (1994) (“Dukes 1994”)
`A. Howell et al., Fulvestrant, Formerly [Cl 182, 780, Is as
`Ejfective as Anastrozole in Postmenopausal Women With
`Advanced Breast Cancer Progressing After Prior Endocrine
`
`Treatment, 20 J. Clin. Oncol. 3396 (2002) (“Howell 2002”)
`OK. Osborne et 211., Double-Blind Randomized Trial Comparing
`the Ejficacy and Tolerability of Fulvestrant Versus Anastrozole
`in Postmenopausal Women with Advanced Breast Cancer
`Progressing on Prior Endocrine Therapy.‘ Results ofa North
`
`American Trial, 20 J. Clin. Oncol. 3386 (2002) (“Osborne 2002”)
`John F. Robertson et al., Comparison of the Short-Term
`Biological Ejfects of7-a-[9- (4,4,55,5-
`pentafluoropentylsulfinyl)-nonyl]estra-l,3, 5, (10)-triene-3, l 7,8-
`diol (Faslodex) versus Tamoxifen in Postmenopausal Women
`with Primary Breast Cancer, 61 Cancer Res. 6739 (2001)
`
`(“Robertson Cancer Res. 2001”)
`John F.R. Robertson et al., Pharmacokinetics ofa Single Dose of
`Fulvestrant Prolonged-Release In tram uscular Injection in
`Postmenopausal Women Awaiting Surgeryfor Primary Breast
`
`Cancer, Clin. Ther. 1440 (2003) (“Robertson Clin. Ther. 2003”)
`Fernand Labrie, Activity and Safety of the Antiestrogen EM—800,
`the Orally Active Precursor ofAcolbifene, in Tamoxifen-Resistant
`
`Breast Cancer, 22 J. Clin. Oncol. 864 (2004) (“Labrie 2004”)
`P. Van de Velde et al., RU58668.‘ Further In Vitro And In Vivo
`Pharmacological Data Related to its Antitumoral Activity, 59 J.
`
`Steroid Biochem. Molec. Biol. 449 (1996) (“Van de Velde”)
`Fernand Labrie, EM-652 (SCH 5 7068), a third generation SERM
`acting as pure antiestrogen in the mammary gland and
`endometrium, 69 J. Steroid Biochem. & Molec. Biol. 51 (1999)
`(“Labrie l999”)
`Gabriel N. Hortobagyi, Progress in Endocrine Therapyfor Breast
`2035
`
`Carcinoma, 83 Cancer 1 (1998) (“Hortobagyi 1998”)
`
`
`
`Vii
`
`InnoPharma Exhibit 1017.0008
`
`

`

`
`
`Case IPR2016-01316
`
`
`Exhibit
`Description
`2036
`J .F.R. Robertson et al., Onapristone, a Progesterone Receptor
`Antagonist, as First—line Therapy in Primary Breast Cancer, 35
`
`Eur. J. Cancer 214 (1999) (“Robertson 1999”)
`Gabriel Hortobagyi, What New Drugs, Biologics, and
`TreatmentApproaches Show Promise in Breast Cancer?, 4
`
`Cancer Control J. l (Supp. 1997) (“Hortobagyi 1997”)
`M. Dowsett, Response to specific anti- oestrogen (1C1l 82 780) in
`tamoxifen-resistant breast cancer, 345 Lancet 525 (1995)
`
`(“Dowsett 1995”)
`E.J. Thomas, The eflects of[Cl 182, 780, a pure anti-oestrogen,
`on the hypothalamic-pituitary-gonadal axis and on endometrial
`proliferation in pre-menopausal women, 9 Hum. Reprod. 1991
`
`(1994) (“Thomas”)
`2040
`Anthony Howell et al., Recent advances in endocrine therapy of
`
`breast cancer, 315 Br. Med. J. 863 (1997) (“Howell 1997”)
`John F.R. Robertson et al., Duration of remission to [C] l 82, 780
`compared to megestrol acetate in tamoxifen resistant breast
`
`cancer, 6 Breast 186 (1997) (“Robertson 1997”)
`
`AACR Journals Online
`2042
`
`2037
`
`2038
`
`2039
`
`2041
`
`
`
`
`
`
`
`2044
`
`2050
`
`2043
`Declaration of Sandra McLeskey, PhD. (Oct. 1, 2014)
`
`(“McLeskey Declaration”)
`Innovative Research of America, Time Release Pellets for
`Biomedical Research, 2014 Product Catalog (“Innovative
`
`Research”)
`Physician’s Desk Reference, 53rd ed., 3425-28 (1999) (“PDR
`2045
`
`1999 NolvadeX®”)
`Physician’s Desk Reference, 53rd ed., 2025-28 (1999) (“PDR
`2046
`
`1999 Femara®”)
`2047
`R.J. Santen, Use of aromatase inhibitors in breast carcinoma, 6
`
`Endocrine-Related Cancer 75 (1999) (“Santen”)
`
`Zoladex® (goserelin acetate implant) (“Zoladex label”)
`2048
`2049
`AstraZeneca Pharmaceuticals LP v. Sagent Pharmaceuticals,
`Inc., No. 14-cv-03547-Rl\/[B-KMW, Trial Transcript (July 14,
`2016) (“July 14 Trial Tr.”)
`D.G. Bratherton, A comparison of two doses of tamoxifen
`(Nolvadex *) in postmenopausal women with advanced breast
`cancer.‘ 10 mg bd versus 20 mg bd, 50 Br. J. Cancer 199 (1984)
`
`(“Bratherton”)
`
`viii
`
`InnoPharma Exhibit 1017.0009
`
`

`

`
`
`Case IPR2016-01316
`
`
`
`2052
`
`2053
`
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`
`
`
`Exhibit
`Description
`2051
`Adam Cohen, What does the investigator need to know about the
`drug?, Ch. 3, A Guide To Clinical Drug Research (1995)
`
`(“Cohen”)
`Stephanie Sweetana, Solubility Principles and Practices for
`Parenteral Drug Dosage Form Development, 50 PDA J. Pharm.
`
`Sci. & Tech. 330 (1996) (“Sweetana”)
`L. Fallowfield et al., Patients ’ preference for administration of
`endocrine treatments by injection or tablets: resultsfrom a study
`ofwomen with breast cancer, 17 Ann. Oncol. 205 (2006)
`
`(“Fallowfield 2006”)
`2054
`Suzanne C. Beyea et al., Administering IM Injections The Right
`
`Way, 96 A. J. Nursing 34 (1996) (“Beyea”)
`John F.R. Robertson et al., Activity ofFulvestrant 500 mg Versus
`Anastrozole I mg as First-Line Treatmentfor Advanced Breast
`Cancer: Resultsfrom the FIRST Study, 27 J. Clin. Oncol. 4530
`
`(2009) (“Robertson 2009”)
`John F.R. Robertson et al., Fulvestrant 500 mg versus
`anastrozole I mgfor the first-line treatment ofadvanced breast
`cancer: follow-up analysisfrom the randomized ‘FIRST’ study,
`
`136 Breast Cancer Res. & Treat. 503 (2012) (“Robertson 2012”)
`John F.R. Robertson et al., Fulvestrant 500 mg versus
`Anastrozole as a First—line Treatment for Advanced Breast
`Cancer: Overall Survival from the Phase II ‘FIRST’ Study, 37th
`Annual San Antonio Breast Cancer Symposium, Publication No.
`
`86-04 (2014) (“Robertson SABCS 2014”)
`Matthew J. Ellis et al., Fulvestrant 500 mg Versus Anastrozole I
`mgfor the First-Line Treatment ofAdvanced Breast Cancer:
`Overall Survival Analysisfrom the Phase II FIRST Study, J. Clin.
`
`Oncol. l (2015) (“Ellis 2015”)
`I. Vergote et al., Postmenopausal women who progress on
`fulvestrant (‘Faslodexj remain sensitive to further endocrine
`therapy, 79 Breast Cancer Res. & Treat. 207 (2003) (“Vergote
`2003”)
`John F.R. Robertson et al., Pharmacokinetic Profile of
`Intramuscular Fulvestrant in Advanced Breast Cancer, 43 Clin.
`
`Pharmacokinet. 529 (2004) (“Robertson 2004”)
`
`
`
`iX
`
`InnoPharma Exhibit 1017.0010
`
`

`

`
`
`Case IPR2016-01316
`
`
`Exhibit
`Description
`2061
`John FR. Robertson et al., Fulvestrant versus Anastrozole for the
`Treatment ofAdvanced Breast Carcinoma in Postmenopausal
`Women: A Prospective Combined Analysis of Two Multicenter
`
`Trials, 98 Cancer 229 (2003) (“Robertson Cancer 2003”)
`Stephen Chia et al., Double-Blind Randomized Placebo
`Controlled Trial ofFulvestrant Compared with Exemestane
`After Prior Nonsteroidal Aromatase Inhibitor Therapy in
`Postmenopausal Women with Hormone Receptor-Positive,
`Advanced Breast Cancer: Resultsfrom EFECT, 26 J. Clin.
`
`Oncol. 1664 (2008) (“Chia 2008”)
`Stephen RD. Johnston et al., Fulvestrant plus anastrozole or
`placebo versus exemestane alone after progression on non-
`steroisal aromatase inhibitors in postmenopausal patients with
`hormone-receptor-positive locally advanced or metastatic breast
`cancer (SoFEA): a composite, multicenter, phase 3 randomised
`
`trial, 14 Lancet Oncol. 989 (2013) (“Johnston 2013”)
`J .FR. Robertson et al., Sensitivity to further endocrine therapy is
`retainedfollowing progression on first-linefulvestrant, 92 Breast
`
`Cancer Res. & Treat. 169 (2005) (“Robertson 2005”)
`S. Johnston, Fulvestrant and the sequential endocrine cascade
`for advanced breast cancer, 90 Brit. J. Cancer S15 (Supp. 2004)
`
`(“Johnston 2004”)
`Pharma Marketletter, AstraZeneca ’s Faslodex Meets Unmet Need
`
`2062
`
`2063
`
`2064
`
`2065
`
`2066
`
`
`
`
`
`
`
`in Breast Cancer, March 29, 2004, available at 2004 WLNR
`
`21943944 (“Pharma Marketletter 2004”)
`Cancer Weekly, European Launch ofFaslodex Reported, Breast
`Cancer, April 13, 2004, available at 2004 WLNR 542429
`
`(“Cancer Weekly April 2004”)
`R. Jeffrey Baumann et al., Clomiphene Analogs with Activity In
`Vitro and In Vivo Against Human Breast Cancer Cells, 55
`
`Biochem. Pharmacol. 841 (1998) (“Baumann 1998”)
`Seppo Pyrhénen et al., High dose toremifene in advanced breast
`cancer resistant to or relapsed during tamoxifen treatment, 29
`Breast Cancer Res. & Treat. 223 (1994) (“Pyrhénen 1994”)
`Lars E. Stenbygaard, Toremifene and tamoxifen in advanced
`breast cancer - a double-blind cross-over trial, 25 Breast
`
`Cancer Res. & Treat. 57 (1993) (“Stenbygaard 1993”)
`
`2067
`
`2068
`
`2069
`
`2070
`
`InnoPharma Exhibit 1017.0011
`
`

`

`Case IPR2016-01316
`
`
`Exhibit Description
`
`2071
`John FR. Robertson et al., A Good Drug Made Better: The
`Fulvestrant Dose-Response Story, 14 Clin. Breast Cancer 381
`(2014) (“Robertson 2014”)
`2072
`C. Barrios et al., The sequential use of endocrine treatmentfor
`advanced breast cancer: where are we?, 23 Ann. Oncol. 1378
`(2012) (“Barrios 2012”)
`2073
`J .FR. Robertson et al., Endocrine treatment options for advanced
`breast cancer 7 the role offulvestrant, 41 Eur. J. Cancer 346
`(2005) (“Robertson Eur. J. Cancer 2005”)
`2074
`“Clinical Practice Guidelines in Oncology: Breast Cancer,”
`National Comprehensive Cancer Network, version 1, MS—16
`(2003) (“Clinical Practice Guidelines 2003”)
`2075
`I. Vergote et al., Fulvestrant, a new treatment option for
`advanced breast cancer: tolerability versus existing agents, 17
`Ann. Oncol. 200 (2006) (“Vergote 2006”)
`2076
`A. Agrawal, Bone turnover markers in postmenopausal breast
`cancer treated with fulvestrant i A pilot study, 18 Breast 204
`(2009) (“Agrawal 2009”)
`2077
`Irene Kuter et al., Dose-dependent change in biomarkers during
`neoaayuvant endocrine therapy with fulvestrant.‘ results from
`NEWEST, a randomized Phase I] study, 133 Breast Cancer Res.
`& Treat. 237 (2012) (“Kuter 2012”)
`2078
`Aman U. Buzdar et al., Fulvestrant.‘ Pharmacologic Profile
`Versus Existing Endocrine Agentsfor the Treatment ofBreast
`Cancer, 40 Ann. Pharmacother. 1572 (2006) (“Buzdar 2006”)
`2079
`AstraZeneca ’s Faslodex met primary endpoint in first-line
`treatment of advanced breast cancer (May 27, 2016) (“FALCON
`Press Release”)
`2080
`Mark A. Longer et al., Sustained-Release Drug Delivery Systems,
`in REMINGTON’S PHARMACEUTICAL SCIENCES, Ch. 91 (Alphonso
`R. Gennaro ed., 18th ed. 1990) (“Remington’s Ch. 91”)
`2081
`Louis G. RaVin et al., Preformulation, in REMINGTON’S
`PHARMACEUTICAL SCIENCES, Ch. 75 (Alfonso Gennaro ed., 18th
`
`ed. 1990) (“Remington’s Ch. 75”)
`
`
`
`2082
`
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`SCIENCE OF DOSAGE FORM DESIGN, Ch. 1 (ME. Aulton ed.,
`
`1988) (“Aulton Ch. 1”)
`
`
`
`X1
`
`InnoPharma Exhibit 1017.0012
`
`

`

`
`
`
`Exhibit
`Description
`2083
`Howard C. Ansel et al., Dosage Form Design: Biopharmaceutic
`& Pharmacokinetic Considerations, in PHARMACEUTICAL
`
`Case IPR2016-01316
`
`
`
`2084
`
`2085
`
`2086
`
`2087
`
`2092
`
`2093
`
`2094
`
`2095
`
`
`
`DOSAGE FORMS & DRUG DELIVERY SYSTEMS, Ch. 4 (7th ed.
`
`1999) (“Ansel Ch. 4”)
`Kenneth E. AViS, Parental Preparations, in Remington’s
`Pharmaceutical Sciences, Ch. 84 (Alphonso R. Gennaro ed., 18th
`
`ed. 1990) (“Remington’s Ch. 84”)
`J .L. Ford, Parenteral Products, in PHARMACEUTICS: THE
`SCIENCE OF DOSAGE FORM DESIGN, Ch. 21 (ME. Aulton ed.,
`
`1988) (“Aulton Ch. 21”)
`Michael J. Groves, Perspectives on the Use and Essential
`Requirements ofParenteral Products, in PARENTERAL
`
`TECHNOLOGY MANUAL, Ch. 2 (2d ed. 1989) (“Groves Ch. 2”)
`Michael J. AkerS, Challenges in the Development oflnjectable
`Products, in INJECTABLE DRUG DEVELOPMENT: TECHNIQUES TO
`REDUCE PAIN & IRRITATION, Ch. 1 (PramOd K. Gupta & Gayle
`
`A. Brazeau edS., 1999) (“Gupta Ch. 1”)
`2088
`Sandeep Nema et al., Exc1pients and Their Use in lnjectable
`
`Products, 51 PDA J. Pharm Sci. Tech. 166 (1997) (“Nema”)
`
`2089
`Vidal® 1999 Le Dictionnaire (75th ed. 1999) (“Vidal 1999”)
`
`2090
`Vidal® 1997 Le Dictionnaire (73d ed. 1997) (“Vidal 1997”)
`2091
`ABPI Compendium Of Data Sheets and Summaries Of Product
`
`Characteristics (1999-2000) (“ABPI 1999-2000”)
`Steven Abbott & Charles M. Hansen, HANSEN SOLUBILITY
`PARAMETERS IN PRACTICE, Introduction (2013), available at
`http://www.pirika.com/ENG/HSP/E-BOOk/IntrOduction.html
`
`(“Abbott & Hansen”)
`Edward Rudnic et al., Oral Solid Dosage Forms, in
`REMINGTON’S PHARMACEUTICAL SCIENCES, Ch. 89 (Alphonso R.
`
`Gennaro ed., 18th ed. 1990) (“Remington’s Ch. 89”)
`J .1. Wells et al., Preformulation, in PHARMACEUTICS: THE
`SCIENCE OF DOSAGE FORM DESIGN, Ch. 13 (ME. Aulton ed.,
`1988) (“Aulton Ch. 13”)
`Howard C. Ansel et al., Capsules and Tablets, in
`PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS,
`
`Ch. 7 (7th ed. 1999) (“Ansel Ch. 7”)
`
`
`
`X11
`
`InnOPharma Exhibit 1017.0013
`
`

`

`
`Exhibit
`Description
`2096
`Howard C. Ansel et al., Solutions, in PHARMACEUTICAL DOSAGE
`FORMS & DRUG DELIVERY SYSTEMS, Ch. 12 (7th ed. 1999)
`
`(“Ansel Ch. 12”)
`Howard C. Ansel et al., Disperse Systems, in PHARMACEUTICAL
`DOSAGE FORMS & DRUG DELIVERY SYSTEMS, Ch. 13 (7th ed.
`
`1999) (“Ansel Ch. 13”)
`MH. Rubinstein, Tablets, in PHARMACEUTICS: THE SCIENCE OF
`DOSAGE FORM DESIGN, Ch. 18 (ME. Aulton ed., 1988) (“Aulton
`
`Ch. 18”)
`BE. Jones et al., Capsules, in PHARMACEUTICS: THE SCIENCE OF
`DOSAGE FORM DESIGN, Ch. 19 (ME. Aulton ed., 1988) (“Aulton
`
`Ch. 19”)
`Shen GaO et al., In Vitro percutaneous absorption enhancement
`of a lipophilic a’rug tamoxifen by terpenes, 51 J. Controlled
`
`Release 193-199 (1998) (“Gao 1998”)
`
`THE MERCK INDEX (12th ed. 1996) (“Merck Index”)
`2101
`2102
`Howard C. Ansel et al., Transa’ermal Drug Delivery Systems, in
`PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS,
`
`Ch. 10 (7th ed. 1999) (“Ansel Ch. 10”)
`Sol Motola et al., Preformulation Research ofParenteral
`Medications, in 1 PHARMACEUTICAL DOSAGE FORMS:
`PARENTERAL MEDICATION, Ch. 4 (Kenneth E. Avis et al. eds, 2d
`
`ed. 1992) (“AVis Ch. 4”)
`J .B. Kayes, Disperse Systems, in PHARMACEUTICS: THE SCIENCE
`OF DOSAGE FORM DESIGN, Ch. 6 (ME. Aulton ed., 1988)
`
`(“Aulton Ch. 6”)
`2105
`Arturo G. Porras et al., Pharmacokinetics ofAlena’ronate, 36
`
`Clin. Pharmacokinet. 315 (1999) (“Porras”)
`Howard C. Ansel et al., Parenterals, in PHARMACEUTICAL
`DOSAGE FORMS & DRUG DELIVERY SYSTEMS, Ch. 14 (7th ed.
`1999) (“Ansel Ch. 14”)
`Richard J. Duma et al., Parenteral Drug Adm inistration.‘ Routes,
`Precautions, Problems, Complications, and Drug Delivery
`Systems, in 1 PHARMACEUTICAL DOSAGE FORMS: PARENTERAL
`MEDICATION , Ch. 2 (Kenneth E. AViS et al. edS., 2d ed. 1992)
`
`(“AViS Ch. 2”)
`
`2103
`
`2104
`
`2106
`
`2107
`
`
`
`
`
`Case IPR2016-01316
`
`2097
`
`2098
`
`2099
`
`2100
`
`
`
`
`
`X111
`
`InnoPharma Exhibit 1017.0014
`
`

`

`
`
`Case IPR2016-01316
`
`
`
`2109
`
`2110
`
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`2117
`
`21 18
`
`
`
`
`Exhibit
`Description
`2108
`Francis L.S. Tse et a1., Bioavailability ofParenteral Drugs I.
`Intravenous and Intramuscular Doses, 34 J. Parenteral Drug
`
`ASS’n 409 (1980) (“Tse I”)
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`estradiol on estrous behavior and energy balance in Syrian
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`Scott G. Lundeen et a1., Characterization of the Ovariectomized
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`
`1997”)
`Patrick P. DeLuca et a1., Formulation ofSmall Volume
`Parenterals, in 1 PHARMACEUTICAL DOSAGE FORMS:
`PARENTERAL MEDICATIONS, Ch. 5 (Kenneth E. Avis et al. eds.,
`
`2d ed. 1992) (“Avis Ch. 5”)
`Robert G. Strickley, Parenteral Formulations ofSmall Molecules
`Therapeutics Marketed in the United States (1999)7Part I, 53
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`PDA J. Pharm. Sci. Tech. 324 (1999) (“Strickley I”)
`S01 Motola, Biopharmaceutics ofInjectable Medication, in 1
`PHARMACEUTICAL DOSAGE FORMS: PARENTERAL MEDICATION,
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`Ch. 3 (Kenneth E. Avis et al. eds., 2d ed. 1992) (“Avis Ch. 3”)
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`(II), 105 Int’l J. of Pharmaceutics 189, 189 (1994) (“Zuidema
`
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`Subcutaneous and Intramuscular Drug Administration, 57 J.
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`Pharm. Sci. 357 (1968) (“Ballard 1968”)
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`DJ. Greenb1att et a1., Absorption of Oral and Intramuscular
`Chlordiazepoxide, 13 Eur. J. C1in. Pharmacol. 267 (1978)
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`John T. Litchfield, Forecasting Drug Eflects in Man from Studies
`in Laboratory Animals, 177 J. Am. Med. ASS’n 34 (1961)
`
`(“Litchfield 1961”)
`
`
`
`XiV
`
`InnOPharma Exhibit 1017.0015
`
`

`

`
`
`Case IPR2016-01316
`
`
`Exhibit
`Description
`2119
`Francis L.S. Tse et al., Bioavailability ofParenteral Drugs II.‘
`Parenteral Doses Other Than Intravenous and Intramuscular
`
`Routes, 34 J. Parenteral Drug Ass’n 484 (1980) (“Tse II”)
`A. Lifschitz et al., Ivermectin disposition kinetics after
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`formulation to cattle, 86 Veterinary Parasitology 203 (1999)
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`E. Lavy et al., Pharmacokinetics of clindamycin HCl
`administered intravenously, intramuscularly, and subcutaneously
`
`to dogs, 22 J. Vet. Pharmacol. Ther. 261 (1999) (“Lavy 1999”)
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`(“Chu 1960”)
`Larry A. Gatlin et al., Formulation and Administration
`Techniques to Minimize Injection Pain and Tissue Damage
`Associated with Parenteral Products, in INJECTABLE DRUG
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`2120
`
`2121
`
`2122
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`2123
`
`
`
`
`
`
`
`DEVELOPMENT: TECHNIQUES TO REDUCE PAIN & IRRITATION, Ch.
`17 (Pramod K. Gupta & Gayle A. Brazeau eds., 1999) (“Gupta
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`Ch. 17”)
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`compositions containing at least 75% benzyl benzoate (“’520
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`
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`Physician’s Desk Reference, 53rd ed., 3404-6 (1999) (“PDR 1999
`2126
`
`ArimideX®”)
`Physician’s Desk Reference, 53rd ed., 3404-6 (1999) (“PDR 1999
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`
`Estrace®”)
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`
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`
`2124
`
`2128
`
`2129
`
`XV
`
`InnoPharma Exhibit 1017.0016
`
`

`

`Case IPR2016-01316
`
`
`
`
`
`
`Exhibit Description
`
`2130
`Levine HB et al., Immunologic impairment in mice treated
`intravenously with killed Coccidioides immitis spherules:
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`2131
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`2132
`Dec. 3, 2002 Office Action, File History for US. Patent No.
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`6,774,122 (“‘Dec. 3, 2002 Office Action”)
`2133
`Aug. 21, 2008 Amendment and Response, File History for US.
`
`Patent No. 7,456,160 (“‘Aug. 21, 2008 Amendment”)
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`THEORY & PRACTICE OF INDUSTRIAL PHARMACY, Ch. 14 (Leon
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`2135
`Aug. 21, 2008 Declaration, File History for US. Patent No.
`
`7,456,160 (“Aug. 21, 2008 Declaration”)
`2136
`June 20, 2011 Information Disclosure Statement, File History for
`
`US Patent No. 8,329,680 (“June 20, 2011 IDS”)
`2137
`Sept. 16, 2011 Office Action, File History for US. Patent No.
`
`8,329,680 (“McLeskey Office Action”)
`2138
`Jan. 13, 2012 Declaration, File History for US. Patent No.
`
`8,329,680 (“‘Jan. 13, 2012 Declaration”)
`2139
`Mar. 20, 2012 Office Action, File History for US. Patent No.
`
`8,329,680 (“Mar 20, 2012 Office Action”)
`2140
`June 4, 2012 Notice of Allowance, File History for US. Patent
`
`No. 8,329,680 (“June 4, 2012 Notice of Allowance”)
`Jan. 17, 2012 Amendment, File History for US. Patent No.
`8,329,680 (“‘Jan. 17, 2012 Amendment”)
`June 20, 2011 Amendment, File History for US. Patent No.
`2142
`8,329,680 (“June 20, 2011 Amendment”)
`
`2134
`
`2141
`
`
`
`xvi
`
`InnoPharma Exhibit 1017.0017
`
`

`

`Case IPR2016-01316
`
`I.
`
`INTRODUCTION
`
`The ’ 122 Patent claims are method of treatment claims—methods to treat
`
`hormonal dependent breast cancer with the active ingredient (fulvestrant)
`
`administered intramuscularly with a combination of ingredients that interact with
`
`the muscle, to provide and maintain specific blood levels over extended periods of
`
`time. At the time the patent application was filed, the skilled artisan reviewing the
`
`prior art would never have expected it to be a successful treatment—it combined
`
`an active ingredient with then-unproven efficacy administered through the
`
`unpredictable intramuscular route using ingredients that interact with the muscle in
`
`a still-unknown manner to achieve blood plasma levels that differed from then-
`
`conventional wisdom and were maintained for 2-5 weeks.
`
`The Petition uses the patent claims to filter out unknowns, failures, and
`
`critical differences, and guide an argument of obviousness over two references: (1)
`
`McLeskey (EX. 1005), about a study of basic biology using a