Filed October 6, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS, INC.
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner.
`
`Case IPR2016-01325
`
`U.S. Patent No. 8,329,680
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`TO PETITION FOR INTER PARTES REVIEW
`
`OF U.S. PATENT NO. 8,329,680
`
`|nnoPharma Exhibit 1017.0001
`
`

`

`TABLE OF CONTENTS
`
`Case IPR20l6-01325
`
`Page
`
`INTRODUCTION ........................................................................................ .. 1
`
`THE ’680 PATENT ...................................................................................... ..5
`
`A.
`
`B.
`
`C.
`
`Specification ....................................................................................... ..5
`
`Claims ................................................................................................. ..6
`
`Prosecution history ............................................................................. ..8
`
`PERSON OF ORDINARY SKILL IN THE ART ..................................... ..ll
`
`CLAIM CONSTRUCTION ....................................................................... ..l2
`
`III.
`
`IV.
`
`A. Malignant diseases of the breast ....................................................... ..l2
`
`B.
`
`Sufficient amount of castor oil vehicle ............................................ ..l2
`
`C. Wherein the method achieves a therapeutically significant
`blood plasma fulvestrant concentration of at least 2.5 ngml'1 for
`at least four weeks ............................................................................ ..l2
`
`D.
`
`E.
`
`Therapeutically significant ............................................................... ..l6
`
`Achieves ........................................................................................... . . 16
`
`STATE OF THE ART ................................................................................ ..l7
`
`A. McLeskey [EX. 1005] and Howell 1996 [EX. 1006] ........................ ..l7
`
`B.
`
`Active: A skilled artisan had no reason to start with fulvestrant ..... .. l9
`
`1.
`
`Petitioner ignores the many other treatment options
`available to the skilled artisan ................................................ ..2l
`
`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 ’680 PATENT IS VALID AND NOT OBVIOUS ............................ ..32
`
`A.
`
`Law of Obviousness ......................................................................... ..32
`
`1
`
`|nnoPharma Exhibit 1017.0002
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`Case IPR20l6-01325
`
`Page
`
`B.
`
`Ground One: McLeskey ................................................................... .34
`
`l.
`
`2.
`
`3.
`
`McLeskey describes the fulvestrant formulations as a
`“treatment failure” .................................................................. ..38
`
`McLeskey utilizes a different route of administration
`(subcutaneous) with Vastly different subjects (genetically
`engineered mice) .................................................................... ..4l
`
`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 ........... ..47
`
`C.
`
`Ground Two: McLeskey In Combination With Howell 1996 ......... ..49
`
`1.
`
`2.
`
`No reason to combine McLeskey with Howell 1996 ............ ..49
`
`No reasonable expectation of success .................................... ..53
`
`VII. OBJECTIVE INDICIA DEMONSTRATE THE NONOBVIOUS
`
`NATURE OF THE CLAIMED METHOD OF TREATMENT ................ ..5 8
`
`VIII. CONCLUSION ........................................................................................... ..6O
`
`ii
`
`|nnoPharma Exhibit 10170003
`
`

`

`TABLE OF AUTHORITIES
`
`Case IPR2016-01325
`
`Page(s)
`
`Cases
`
`Apple, Inc. V. Contentguard Holdings, Inc.,
`IPR2015-00357, 2015 WL 9899009 (P.T.A.B. June 29, 2015) ....................... ..45
`
`Apple, Inc. V. Contentguard Holdings, Inc.,
`IPR2015-00449, 2015 WL 4760572 (P.T.A.B. July 15, 2015) ........................ ..38
`
`Bi0DeliVery Scis Int’l, Inc. V. RB Plzarms Ltd,
`IPR2014-00325, 2015 WL 4045328 (P.T.A.B. June 30, 2015) ....................... ..15
`
`Boelzringer Ingellzeim Int’l GmbH V. Biogen Inc.,
`IPR2015-00418, 2015 WL 4467391 (P.T.A.B. July 13, 2015) ................. .. 37, 54
`
`Bumble Bee Foods, LLC V. Kowalski,
`IPR2014-00224, 2014 WL 2584188 (P.T.A.B. June 5, 2014) ......................... ..52
`
`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) ......................... ..45
`
`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, 53
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) ........................................................................ ..51
`
`KSR Int ’l CO. V. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................... .. 34, 49
`
`iii
`
`|nnoPharma Exhibit 1017.0004
`
`

`

`TABLE OF AUTHORITIES
`
`(continued)
`
`Case IPR2016-01325
`
`Page(s)
`
`Lupin Ltd. V. Pozen Inc.,
`IPR2015—01774, 2016 WL 1081583 (P.T.A.B. Mar. 1, 2016) ........... .. 41, 53, 54
`
`Ortho—McNeil Pharm., Inc. V. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ........................................................................ ..33
`
`Panduit Corp. V. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) ........................................................................ ..32
`
`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. Uei Cayman, Inc.,
`1PR2014-01111, 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
`
`|nnoPharma Exhibit 1017.0005
`
`

`

`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`Case IPR20l6-01325
`
`LIST OF EXHIBITS
`
`Description
`Declaration of Lisbeth Illum, Ph.D. In Support Of Patent
`Owner’s Preliminary Response
`Declaration of John F. R. Robertson, MD. In Support Of Patent
`Owner’s Preliminary Response
`
`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 III 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 II comparative study, 21
`Annals Oncol. 2342 (2010) (“FINDER 1”)
`Kathleen I. Pritchard et al., Results ofa phase II study
`comparing three dosing regimens offulvestrant in
`postmenopausal women with advanced breast cancer
`(FINDER2), 123 Breast Cancer Res. & Treat. 453 (2010)
`(“FINDER 2”)
`Robert T. Greenlee et al., Cancer Statistics, 2000, 50 CA Cancer
`J. Clin. 7 (2000) (“Greenlee”)
`J .F.R. Robertson, Oestrogen receptor: a stable phenotype in
`breast cancer, 73 Brit. J. Cancer 5 (1996) (“Robertson 1996”)
`Monica Fornier et al., Update on the Management ofAdvanced
`Breast Cancer, 13 Oncology 647 (1999) (“Former”)
`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”)
`
`|nnoPharma Exhibit 1017.0006
`
`

`

`Exhibit
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`Case IPR2016-01325
`
`Description
`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”)
`Kathleen Pritchard, Ejfects on Breast Cancer.‘ Clinical Aspects,
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`Aman U. Buzdar et a1., Tamoxifen and Toremifene in Breast
`Cancer.‘ Comparison of Safety and Ejficacy, 16 J. Clin. Oncol.
`348 (1998) (“Buzdar Clin. Oncol. 1998”)
`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 ofBreast Cancer, 35
`Ann. Rev. Pharmacol. Toxicol. 195 (1995) (“Jordan 1995”)
`Monica Morrow et al., Molecular Mechanisms of Resistance to
`Tamoxifen Therapy in Breast Cancer, 128 Arch. Surg. 1187
`(1993) (“Morrow”)
`Valerie J. Wiebe et a1., 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”)
`V. Craig Jordan, The Role of Tamoxifen in the Treatment and
`Prevention ofBreast Cancer, Curr. Probl. Cancer 134 (1992)
`(“Jordan 1992”)
`Susan E. Minton, New Hormonal Therapiesfor Breast Cancer, 6
`Cancer Control J. 1 (1999) (“Minton”)
`TA. Grese et a1., Selective Estrogen Receptor Modulators
`(SERMs), 4 Current Pharin. 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 a1., Aromatase inhibitor developmentfor
`treatment ofbreast cancer, 33 Breast Cancer Res. & Treat. 19
`(1994) (“Masamura 1994”)
`
`Vi
`
`|nnoPharma Exhibit 1017.000?
`
`

`

`Exhibit
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`Case IPR20l6-01325
`
`Description
`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 [CI 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”)
`C.K. Osborne et al., 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— (4,4,5,5,5—
`pentafluoropentylsulfinyl)—nonyl]estra—I,3, 5, (I 0)—triene—3, 1 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 Intramuscular 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.
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`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 1999”)
`Gabriel N. Hortobagyi, Progress in Endocrine Therapyfor Breast
`Carcinoma, 83 Cancer 1 (1998) (“Hortobagyi 1998”)
`
`Vii
`
`|nnoPharma Exhibit 1017.0008
`
`

`

`Exhibit
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`2049
`
`2050
`
`Case IPR2016-01325
`
`Description
`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. 1 (Supp. 1997) (“Hortobagyi 1997”)
`M. Dowsett, Response to specific anti— oestrogen (ICU 82 780) in
`tamoxifen—resistant breast cancer, 345 Lancet 525 (1995)
`(“Dowsett 1995”)
`E.J. Thomas, The ejfects of[CI 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”)
`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 [CI 182,780
`compared to megestrol acetate in tamoxifen resistant breast
`cancer, 6 Breast 186 (1997) (“Robertson 1997”)
`AACR Journals Online
`
`Declaration of Sandra McLeskey, Ph.D. (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
`1999 Nolvadex®”)
`Physician’s Desk Reference, 53rd ed., 2025-28 (1999) (“PDR
`1999 Femara®”)
`R.J. Santen, Use of aromatase inhibitors in breast carcinoma, 6
`Endocrine-Related Cancer 75 (1999) (“Santen”)
`Zoladex® (goserelin acetate implant) (“Zoladex label”)
`AstraZeneca Pharmaceuticals LP V. Sagent Pharmaceuticals,
`Inc., No. 14-cv-03547-R1\/[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
`
`|nnoPharma Exhibit 1017.0009
`
`

`

`Exhibit
`2051
`
`2052
`
`2053
`
`2054
`
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`2060
`
`Case IPR2016-01325
`
`Description
`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”)
`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.
`S6-04 (2014) (“Robertson SABCS 2014”)
`Matthew J. Ellis et al., Fulvestrant 500 mg Versus Anastrozole I
`mgfor the First—Line Treatment ofAdvanced Breast Cancer:
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`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
`
`|nnoPharma Exhibit 1017.001O
`
`

`

`Exhibit
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`2068
`
`2069
`
`2070
`
`Case IPR2016-01325
`
`Description
`John F.R. 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
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`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 .F.R. 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”)
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`
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`breast cancer — a double—blind cross—over trial, 25 Breast
`Cancer Res. & Treat. 57 (1993) (“Stenbygaard 1993”)
`
`|nnoPharma Exhibit 1017.0011
`
`

`

`Exhibit
`2071
`
`2072
`
`2073
`
`2074
`
`2075
`
`2076
`
`2077
`
`2078
`
`2079
`
`2080
`
`2081
`
`2082
`
`Case IPR2016-01325
`
`Description
`John F.R. Robertson et al., A Good Drug Made Better: The
`Fulvestrant Dose—Response Story, 14 Clin. Breast Cancer 381
`(2014) (“Robertson 2014”)
`C. Barrios et al., The sequential use of endocrine treatmentfor
`advanced breast cancer: where are we?, 23 Ann. Oncol. 1378
`(2012) (“Barrios 2012”)
`J .F.R. Robertson et al., Endocrine treatment options for advanced
`breast cancer — the role offulvestrant, 41 Eur. J. Cancer 346
`(2005) (“Robertson Eur. J. Cancer 2005”)
`“Clinical Practice Guidelines in Oncology: Breast Cancer,”
`National Comprehensive Cancer Network, Version 1, MS-16
`(2003) (“Clinical Practice Guidelines 2003”)
`I. Vergote et al., Fulvestrant, a new treatment option for
`advanced breast cancer: tolerability versus existing agents, 17
`Ann. Oncol. 200 (2006) (“Vergote 2006”)
`A. Agrawal, Bone turnover markers in postmenopausal breast
`cancer treated with fulvestrant — A pilot study, 18 Breast 204
`(2009) (“Agrawal 2009”)
`Irene Kuter et al., Dose—dependent change in biomarkers during
`neoaajuvant endocrine therapy with fulvestrant: results from
`NEWEST, a randomized Phase II study, 133 Breast Cancer Res.
`& Treat. 237 (2012) (“Kuter 2012”)
`Aman U. Buzdar et al., Fulvestrant: Pharmacologic Profile
`Versus Existing Endocrine Agentsfor the Treatment ofBreast
`Cancer, 40 Ann. Pharmacother. 1572 (2006) (“Buzdar 2006”)
`AstraZeneca ’s Faslodex met primary endpoint in first—line
`treatment of advanced breast cancer (May 27, 2016) (“FALCON
`Press Release”)
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`SCIENCE OF DOSAGE FORM DESIGN, Ch. 1 (ME. Aulton ed.,
`1988) (“Aulton Ch. 1”)
`
`X1
`
`|nnoPharma Exhibit 1017.0012
`
`

`

`Case IPR20l6-01325
`
`Exhibit
`2083
`
`Description
`Howard C. Ansel et al., Dosage Form Design: Biopharmaceutic
`& Pharmacokinetic Considerations, in PHARMACEUTICAL
`
`2084
`
`2085
`
`2086
`
`2087
`
`2088
`
`2089
`2090
`2091
`
`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 ofInjectable
`Products, in INJECTABLE DRUG DEVELOPMENT: TECHNIQUES TO
`REDUCE PAIN & IRRITATION, Ch. 1 (Pramod K. Gupta & Gayle
`A. Brazeau eds., 1999) (“Gupta Ch. 1”)
`Sandeep Nema et al., Excipients and Their Use in Injectable
`Products, 51 PDA J. Pharm Sci. Tech. 166 (1997) (“Nema”)
`Vidal® 1999 Le Dictionnaire (75th ed. 1999) (“Vidal 1999”)
`Vidal® 1997 Le Dictionnaire (73d ed. 1997) (“Vidal 1997”)
`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”)
`
`xii
`
`|nnoPharma Exhibit 10170013
`
`

`

`Exhibit
`2096
`
`2097
`
`2098
`
`2099
`
`2100
`
`2101
`2102
`
`2103
`
`2104
`
`2105
`
`2106
`
`2107
`
`Case IPR20l6-01325
`
`Description
`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”)
`M.H. Rubinstein, Tablets, in PHARMACEUTICS: THE SCIENCE OF
`DOSAGE FORM DESIGN, Ch. 18 (M.E. Aulton ed., 1988) (“Aulton
`Ch. 18”)
`B.E. Jones et al., Capsules, in PHARMACEUTICS: THE SCIENCE OF
`DOSAGE FORM DESIGN, Ch. 19 (M.E. Aulton ed., 1988) (“Aulton
`Ch. 19”)
`Shen Gao et al., In vitro percutaneous absorption enhancement
`of a lipophilic drug tamoxifen by terpenes, 51 J. Controlled
`Release 193-199 (1998) (“Gao 1998”)
`THE MERCK INDEX (12th ed. 1996) (“Merck Index”)
`in
`Howard C. Ansel et al., Transdermal Drug Delivery Systems,
`PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS,
`Ch. 10 (7th ed. 1999) (“Ansel Ch. 10”)
`S01 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 (M.E. Aulton ed., 1988)
`(“Aulton Ch. 6”)
`Arturo G. Porras et al., Pharmacokinetics ofAlendronate, 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 Administration: 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”)
`
`xiii
`
`|nnoPharma Exhibit 1017.0014
`
`

`

`Exhibit
`2108
`
`2109
`
`2110
`
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`2117
`
`21 18
`
`Case IPR2016-01325
`
`Description
`Francis L.S. Tse et a1., Bioavailability ofParenteral Drugs I.
`Intravenous and Intramuscular Doses, 34 J. Parenteral Drug
`Ass’n 409 (1980) (“Tse I”)
`George N. Wade et a1., ICI I82, 780 antagonizes the eflects of
`estradiol on estrous behavior and energy balance in Syrian
`hamsters, 265 Am. J. Physiol. R1399 (1993) (“Wade 1993”)
`Scott G. Lundeen et a1., Characterization of the Ovariectomized
`Rat Modelfor the Evaluation ofEstrogen Eflects on Plasma
`Cholesterol Levels, 138 Endocrinology 1552 (1997) (“Lundeen
`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 (I999)—Part I, 53
`PDA J. Pharm. Sci. Tech. 324 (1999) (“Strickley I”)
`S01 Motola, Biopharmaceutics ofInjectable Medication, in 1
`PHARMACEUTICAL DOSAGE FORMS: PARENTERAL MEDICATION,
`Ch. 3 (Kenneth E. Avis et al. eds., 2d ed. 1992) (“Avis Ch. 3”)
`J. Zuidema et a1., Release and absorption rates of
`intramuscularly and subcutaneously injected pharmaceuticals
`(II), 105 Int’1 J. of Pharmaceutics 189, 189 (1994) (“Zuidema
`1994”)
`Berton E. Ballard, Biopharmaceutical Considerations in
`Subcutaneous and Intramuscular Drug Administration, 57 J.
`Pharm. Sci. 357 (1968) (“Ballard 1968”)
`Koichiro Hirano, Studies on the Absorption ofpractically Water-
`insoluble Drugs following Injection. I. Intramuscular Absorption
`from Water—immiscible Oil Solutions in Rats, 29 Chem. Pharrn.
`Bull. 519 (1981) (“Hirano 1980”)
`D.J. Greenblatt et a1., Absorption of Oral and Intramuscular
`Chlordiazepoxide, 13 Eur. J. Clin. Pharmacol. 267 (1978)
`(“Greenblatt 1978”)
`John T. Litchfield, Forecasting Drug Eflects in Man from Studies
`in Laboratory Animals, 177 J. Am. Med. Ass’n 34 (1961)
`(“Litchfield 1961”)
`
`xiv
`
`|nnoPharma Exhibit 1017.0015
`
`

`

`Exhibit
`2119
`
`Description
`Francis L.S. Tse et al., Bioavailability ofParenteral Drugs II3
`Parenteral Doses Other Than Intravenous and Intramuscular
`
`Case IPR2016-01325
`
`2120
`
`2121
`
`2122
`
`2123
`
`2124
`
`2125
`
`2126
`
`2127
`
`2128
`
`2129
`
`Routes, 34 J. Parenteral Drug Ass’n 484 (1980) (“Tse II”)
`A. Lifschitz et al., Ivermectin disposition kinetics after
`subcutaneous and intramuscular administration of an oil—based
`formulation to cattle, 86 Veterinary Parasitology 203 (1999)
`(“Lifschitz 1999”)
`E. Lavy et al., Pharmacokinetics of clindamycin HCl
`administered intravenously, intramuscularly, and subcutaneously
`to dogs, 22 J. Vet. Pharrnacol. Ther. 261 (1999) (“Lavy 1999”)
`C. H. U. Chu, A Study of the Subcutaneous Connective Tissue of
`the Mouse, with Special Reference to Nuclear Type, Nuclear
`Division and Mitotic Rhythm, 11 Anatomical Record 11 (1960)
`(“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
`
`DEVELOPMENT: TECHNIQUES To REDUCE PAIN & IRRITATION, Ch.
`17 (Pramod K. Gupta & Gayle A. Brazeau eds., 1999) (“Gupta
`Ch. 17 ”)
`U.S. Patent No. 3,164,520, Raymond Huber, Injectable steroid
`compositions containing at least 75% benzyl benzoate (“’520
`Patent”)
`Affidavit of Internet Archive (Oct. 2016) (“Affidavit of Internet
`Archive”)
`Physician’s Desk Reference, 53rd ed., 3404-6 (1999) (“PDR 1999
`Arimidex®”)
`Physician’s Desk Reference, 53rd ed., 3404-6 (1999) (“PDR 1999
`Estrace®”)
`Skougaard MR et al., Comparative effectiveness of
`intraperitoneal and intramuscular 3H-TDR injection routes in
`mice, 45 Exp. Cell Res. 158 (1967) (“Skougaard”)
`Eagle H et al., The serum concentration of penicillin G in mice,
`rabbits, and men after its intramuscular injection in aqueous
`solution, 57 J. Bacteriol. 119 (1949) (“Eagle”)
`
`XV
`
`|nnoPharma Exhibit 1017.0016
`
`

`

`Case IPR2016-01325
`
`Exhibit
`2130
`
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`Description
`Levine HB et al., Immunologic impairment in mice treated
`intravenously with killed Coccidioides immitis spherules:
`suppressed response to intramuscular doses, 97 J. Immunol. 297
`(1966) (“Levine”)
`Yarinsky A et al., The uptake of tritiated hycanthone by male and
`female Schistosoma mansoni worms and distribution of the drug
`in plasma and whole blood of mice following a single
`intramuscular injection, 42 Bull. World Health Organ. 445
`(1970) (“Yarinsky”)
`Dec. 3, 2002 Office Action, File History for U.S. Patent No.
`6,774,122 (“Dec 3, 2002 Office Action”)
`Aug. 21, 2008 Amendment and Response, File History for U.S.
`Patent No. 7,456,160 (“Aug 21, 2008 Amendment”)
`Nicholas G. Lordi, Sustained Release Dosage Forms, in THE
`THEORY & PRACTICE or INDUSTRIAL PHARMACY, Ch. 14 (Leon
`Lachman et al. eds., 1986) (“Lachman’s”)
`Aug. 21, 2008 Declaration, File History for U.S. Patent No.
`7,456,160 (“Aug. 21, 2008 Declaration”)
`
`XV1
`
`|nnoPharma Exhibit 1017.001?
`
`

`

`Case IPR20l6-01325
`
`I.
`
`INTRODUCTION
`
`The ’680 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 2-4 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 mouse model and
`
`various actives, which identifies fulvestrant formulations as “treatment failures,”
`
`and (2) Howell 1996 (Ex. 1006), about an early stage clinical trial,-
`
`Both were thoughtfully considered during patent prosecution. Three requirements
`
`of the claims highlight the faults in the Petition’s arguments.
`
`First, the claims are to a method of treatment. The lynchpin of Petitioner’s
`
`|nnoPharma Exhibit 1017.0018
`
`

`

`Case IPR20l6-01325
`
`obviousness arguments is that McLeskey discloses the “complete formulation
`
`details” claimed and that they were a successful treatment. Petition at 34
`
`(“McLeskey—disclosed a successful castor oil formulation, including the
`
`complete formulation details.” (emphasis added)). But, the explicit language of
`
`McLeskey repeatedly states the opposite, i.e., that the fulvestrant formulations used
`
`in that study were a “treatmentfailure.” What’s more, McLeskey includes
`
`nothing to recommend its fulvestrant formulation, no physical characteristics
`
`(solubility), no blood plasma levels (if any fulvestrant even reached the blood), and
`
`no in viva activity (failure)—
`
`Second, the claims