Filed June 12, 2017
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________________________________
`
`INNOPHARMA LICENSING, LLC
`Petitioner
`
`v.
`
`ASTRAZENECA AB
`Patent Owner
`______________________________________________
`
`Case IPR2017-00904
`U.S. Patent No. 6,774,122
`______________________________________________
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
` TO PETITION FOR INTER PARTES REVIEW
` OF U.S. PATENT NO. 6,774,122
`
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`
`Case IPR2017-00904
`
`
`Page
`
`
`I.
`II.
`
`INTRODUCTION .......................................................................................... 1
`THE ’122 PATENT ........................................................................................ 5
`A.
`Specification ......................................................................................... 5
`B.
`Claims ................................................................................................... 6
`C.
`Prosecution History .............................................................................. 7
`III. THE DECISION OF THE BOARD IN THE MYLAN IPR ........................ 12
`IV. PERSON OF ORDINARY SKILL IN THE ART ....................................... 18
`V.
`CLAIM CONSTRUCTION ......................................................................... 18
`VI. STATE OF THE ART .................................................................................. 19
`A. Active: Fulvestrant Was Far From Established As An
`Efficacious Treatment ........................................................................ 19
`B. Amount: The Claimed Blood Plasma Levels Are
`Unconventional .................................................................................. 23
`C. Administration: Route, Excipients, And Result Are Intertwined
`And Not “Successfully Answered” By The Prior Art ........................ 26
`Conclusion On State Of The Art ........................................................ 34
`D.
`VII. THE ’122 PATENT IS VALID AND NOT OBVIOUS .............................. 34
`A.
`Law Of Obviousness .......................................................................... 34
`B. Ground One: Howell .......................................................................... 36
`1.
`The Gellert Declaration Does Not Provide A Motivation
`To Make The Formulation Of The Invention .......................... 37
`No Expectation Of Success ...................................................... 40
`2.
`C. Ground Two: Howell In Combination With McLeskey .................... 43
`1.
`Petitioner Cannot Cure The Lack Of Efficacy Or
`Pharmacokinetic Data In McLeskey ........................................ 45
`Petitioner Cannot Cure The Unpredictability Of
`Compositional Differences On Intramuscular
`Administration .......................................................................... 49
`
`2.
`
`i
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`

`

`Case IPR2017-00904
`
`
`Page
`
`
`3.
`
`Petitioner Cannot Change The Fact McLeskey Involves
`Subcutaneous Injection While Howell Involves
`Intramuscular Injection ............................................................ 52
`D. Ground Three: Howell In Combination With McLeskey And
`O’Regan .............................................................................................. 55
`VIII. OBJECTIVE INDICIA DEMONSTRATE THE NONOBVIOUS
`NATURE OF THE CLAIMED METHOD OF TREATMENT .................. 56
`IX. CONCLUSION ............................................................................................. 57
`
`
`TABLE OF CONTENTS
`(Continued)
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`(Continued)
`
`Case IPR2017-00904
`
`Page(s)
`
`
`Cases
`
`Apple, Inc. v. Contentguard Holdings, Inc.,
`IPR2015-00357, 2015 WL 9899009 (P.T.A.B. June 29, 2015) ......................... 54
`
`Bumble Bee Foods, LLC v. Kowalski,
`IPR2014-00224, 2014 WL 2584188 (P.T.A.B. June 5, 2014) ........................... 40
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .......................................................................... 54
`
`Eisai Co. v. Dr. Reddy’s Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 54
`
`Exacq Techs., Inc. v. JDS Techs., Inc.,
`IPR2016-00568, 2016 WL 4987613 (P.T.A.B. June 14, 2016) ......................... 16
`
`Innogenetics, N.V. v. Abbott Labs.,
`512 F.3d 1363 (Fed. Cir. 2008) ......................................................................... 46
`
`In re Cyclobenzaprine HCl Extended-Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) ................................................................... 35, 40
`
`In re Klein,
`647 F.3d 1343 (Fed. Cir. 2011) .......................................................................... 48
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 51
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ..................................................................................... 35, 44
`
`Medtronic, Inc. v. Nuvasive, Inc.,
`IPR2014-00076, 2014 WL 1410363 (P.T.A.B. Apr. 8, 2014) ........................... 39
`
`Merck Sharp & Dohme Corp v. Sandoz Inc.,
`No. 3:12–cv–03289–PGS–LHG,
`2015 WL 5089543 (D.N.J. Aug. 27, 2015) ........................................................ 39
`
`i
`
`

`

`TABLE OF AUTHORITIES
`(Continued)
`
`Case IPR2017-00904
`
`Page(s)
`
`
`Nautilus Hyosung Inc. v. Diebold, Inc.,
`IPR2016-00633, 2016 WL 5219979 (P.T.A.B. Aug. 22, 2016) ........................ 16
`
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ............................................................. 36, 38, 39
`
`Synaptics Inc. v. Amkor Tech., Inc.,
`IPR2017-00085, 2017 WL 1403668 (P.T.A.B. Apr. 18, 2017) ................... 5, 57
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) ................................................................... 34, 36
`
`Universal Remote Control, Inc. v. Uei Cayman, Inc.,
`IPR2014-01111, 2014 WL 6737921 (P.T.A.B. Nov. 24, 2014) ......................... 54
`
`Valeo N. Am., Inc. v. Magna Elecs., Inc.,
`IPR2014-01206, 2014 WL 7336080 (P.T.A.B. Dec. 23, 2014) ......................... 16
`
`Regulations
`
`21 C.F.R. §314.94(a)(9)(iii) .................................................................................... 31
`
`21 C.F.R. §314.127(a)(8)(ii)(B) .............................................................................. 31
`
`35 U.S.C. §325(d) .............................................................................................. 5, 57
`
`37 C.F.R. §42.104(b)(4) ........................................................................................... 16
`
`37 C.F.R. §42.104(b)(5) ........................................................................................... 16
`
`37 C.F.R. §42.22(a)(2) ............................................................................................. 16
`
`37 C.F.R. §42.24(a)(1)(i) ......................................................................................... 16
`
`37 C.F.R. §42.6(a)(3) ............................................................................................... 16
`
`37 C.F.R. §42.65(a) .................................................................................................. 16
`
`MPEP §2141.02 ................................................................................................ 23, 35
`
`
`
`ii
`
`

`

`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`Case IPR2017-00904
`
`LIST OF EXHIBITS
`
`
`Description
`Declaration of Lisbeth Illum, Ph.D. In Support Of Patent
`Owner’s Preliminary Response
`Declaration of John F. R. Robertson, M.D. 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 of fulvestrant in
`postmenopausal Japanese women with advanced breast cancer:
`results from a double-blind, phase II comparative study, 21
`ANNALS ONCOL. 2342 (2010) (“FINDER 1”)
`Kathleen I. Pritchard et al., Results of a phase II study
`comparing three dosing regimens of fulvestrant 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 of Advanced
`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 Inhibitor for Advanced Breast Cancer: Mechanism of
`Action and Role in Management, 16 CANCER INVESTIGATION 385
`(1998) (“Hortobagyi Cancer Investigation 1998”)
`
`i
`
`

`

`Exhibit
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`Case IPR2017-00904
`
`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 of acquired anti-oestrogen resistance, 75
`BRIT. J. CANCER 804 (1997) (“Johnston 1997”)
`Kathleen Pritchard, Effects on Breast Cancer: Clinical Aspects,
`in ESTROGENS AND ANTIESTROGENS: BASIC AND CLINICAL
`ASPECTS, Ch. 13 (Robert Lindsay et al. eds., 1997) (“Pritchard
`1997”)
`Aman U. Buzdar et al., Tamoxifen and Toremifene in Breast
`Cancer: Comparison of Safety and Efficacy, 16 J. CLIN.
`ONCOL. 348 (1998) (“Buzdar Clin. Oncol. 1998”)
`A. Howell et al., Response after withdrawal of tamoxifen and
`progestogens in advanced breast cancer, 3 ANNALS ONCOL. 611
`(1992) (“Howell 1992”)
`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”)
`Monica Morrow et al., Molecular Mechanisms of Resistance to
`Tamoxifen Therapy in Breast Cancer, 128 ARCH. SURG. 1187
`(1993) (“Morrow”)
`Valerie J. Wiebe et al., Tamoxifen resistance in breast cancer,
`14 CRIT. REVS. ONCOL. HEMATOL. 173 (1993) (“Wiebe”)
`V. Craig Jordan, The Strategic Use of Antiestrogens to Control
`the Development and Growth of Breast Cancer, 70 CANCER 977
`(Supp. 1992) (“Jordan Supp. 1992”)
`V. Craig Jordan, The Role of Tamoxifen in the Treatment and
`Prevention of Breast Cancer, CURR. PROBL. CANCER 134 (1992)
`(“Jordan 1992”)
`Susan E. Minton, New Hormonal Therapies for Breast Cancer, 6
`CANCER CONTROL J. 1 (1999) (“Minton”)
`T.A. Grese et al., Selective Estrogen Receptor Modulators
`(SERMs), 4 CURRENT PHARM. DESIGN 71 (1998) (“Grese 1998”)
`Gabriel N. Hortobagyi, Treatment of Breast Cancer, 339 NEW
`ENG. J. MED. 974 (1998) (“Hortobagyi New Eng. J. Med. 1998”)
`Shigeru Masamura et al., Aromatase inhibitor development for
`treatment of breast cancer, 33 BREAST CANCER RES. & TREAT. 19
`(1994) (“Masamura 1994”)
`
`ii
`
`

`

`Exhibit
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`Case IPR2017-00904
`
`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., Effects of a non-steroidal pure antioestrogen,
`ZM 189,154, on oestrogen target organs of the rat including
`bones, 141 J. ENDOCRINOL. 335 (1994) (“Dukes 1994”)
`A. Howell et al., Fulvestrant, Formerly ICI 182,780, Is as
`Effective 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 Efficacy and Tolerability of Fulvestrant Versus Anastrozole
`in Postmenopausal Women with Advanced Breast Cancer
`Progressing on Prior Endocrine Therapy: Results of a North
`American Trial, 20 J. CLIN. ONCOL. 3386 (2002) (“Osborne
`2002”)
`John F. Robertson et al., Comparison of the Short-Term
`Biological Effects of 7-α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-
`nonyl]estra-1,3,5, (10)-triene-3,17β-diol (Faslodex) versus
`Tamoxifen in Postmenopausal Women with Primary Breast
`Cancer, 61 CANCER RES. 6739 (2001) (“Robertson 2001”)
`John F.R. Robertson et al., Pharmacokinetics of a Single Dose of
`Fulvestrant Prolonged-Release Intramuscular Injection in
`Postmenopausal Women Awaiting Surgery for Primary Breast
`Cancer, CLIN. THER. 1440 (2003) (“Robertson Clin. Ther. 2003”)
`Fernand Labrie et al., Activity and Safety of the Antiestrogen EM-
`800, the Orally Active Precursor of Acolbifene, in Tamoxifen-
`Resistant Breast Cancer, 22 J. CLIN. ONCOL. 864 (2004) (“Labrie
`2004”)
`P. Van de Velde et al., RU 58668: 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 et al., EM-652 (SCH 57068), 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 Therapy for Breast
`Carcinoma, 83 CANCER 1 (1998) (“Hortobagyi 1998”)
`
`iii
`
`

`

`Exhibit
`2036
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`2048
`
`2049
`
`Case IPR2017-00904
`
`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
`Treatment Approaches Show Promise in Breast Cancer?, 4
`CANCER CONTROL J. 1 (Supp. 1997) (“Hortobagyi 1997”)
`M. Dowsett et al., Response to specific anti-oestrogen
`(ICI182780) in tamoxifen-resistant breast cancer, 345 LANCET
`525 (1995) (“Dowsett 1995”)
`Daniel F. Hayes et al., Randomized Comparison of Tamoxifen
`and Two Separate Doses of Toremifene in Postmenopausal
`Patients With Metastatic Breast Cancer, 13 J. CLIN. ONCOL.
`2556 (1995) (“Hayes 1995”)
`Anthony Howell et al., Recent advances in endocrine therapy of
`breast cancer, 315 BRIT. MED. J. 863 (1997) (“Howell 1997”)
`Helge Haarstad et al., Droloxifene—A New Anti-estrogen, 31
`ACTA ONCOL. 425 (1992) (“Haarstad 1992”)
`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®”)
`Winrich Rauschning et al., Droloxifene, a new antiestrogen: Its
`role in metastatic breast cancer, 31 BREAST CANCER RES. &
`TREAT. 83 (1994) (“Rauschning 1994”)
`E. J. Thomas et al., The effects of ICI 182780, a pure
`antioestrogen on reproductive endocrinology in normal pre-
`menopausal women, 137S J. ENDOCRINOL. 183 (1993) (“Thomas
`1993”)
`AstraZeneca Pharmaceuticals LP v. Sagent Pharmaceuticals,
`Inc., C.A. No. 1:14-cv-03547 (RMB-KMW) (July 14, 2016
`D.N.J.), Trial Transcript (“July 14 Trial Tr.”)
`
`iv
`
`

`

`Exhibit
`2050
`
`2051
`
`2052
`
`2053
`
`2054
`
`2055
`
`2056
`
`2057
`
`2058
`
`2059
`
`Case IPR2017-00904
`
`Description
`D.G. Bratherton et al., A comparison of two doses of tamoxifen
`(Nolvadex*) in postmenopausal women with advanced breast
`cancer: 10 mg bd versus 20 mg bd, 50 BRIT. J. CANCER 199
`(1984) (“Bratherton”)
`Adam Cohen et al., What does the investigator need to know
`about the drug?, in A GUIDE TO CLINICAL DRUG RESEARCH, Ch.
`3 (1995) (“Cohen”)
`Stephanie Sweetana et al., 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: results from a study
`of women with breast cancer, 17 ANNALS 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 of Fulvestrant 500 mg Versus
`Anastrozole 1 mg as First-Line Treatment for Advanced Breast
`Cancer: Results from the FIRST Study, 27 J. CLIN. ONCOL. 4530
`(2009) (“Robertson 2009”)
`John F.R. Robertson et al., Fulvestrant 500 mg versus
`anastrozole 1 mg for the first-line treatment of advanced breast
`cancer: follow-up analysis from 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 1
`mg for the First-Line Treatment of Advanced Breast Cancer:
`Overall Survival Analysis from the Phase II FIRST Study, J. CLIN.
`ONCOL. 1 (2015) (“Ellis 2015”)
`I. Vergote et al., Postmenopausal women who progress on
`fulvestrant (‘Faslodex’) remain sensitive to further endocrine
`therapy, 79 BREAST CANCER RES. & TREAT. 207 (2003)
`(“Vergote 2003”)
`
`v
`
`

`

`Exhibit
`2060
`
`2061
`
`2062
`
`2063
`
`2064
`
`2065
`
`2066
`
`2067
`
`2068
`
`2069
`
`Case IPR2017-00904
`
`Description
`John F.R. Robertson et al., Pharmacokinetic Profile of
`Intramuscular Fulvestrant in Advanced Breast Cancer, 43 CLIN.
`PHARMACOKINET. 529 (2004) (“Robertson 2004”)
`J. Bellmunt et al., European Early Phase II Dose-Finding Study
`of Droloxifene in Advanced Breast Cancer, 14 AM. J. CLIN.
`ONCOL. S36 (1991) (“Bellmunt 1991”)
`Stephen Chia et al., Double-Blind Randomized Placebo
`Controlled Trial of Fulvestrant Compared with Exemestane
`After Prior Nonsteroidal Aromatase Inhibitor Therapy in
`Postmenopausal Women with Hormone Receptor-Positive,
`Advanced Breast Cancer: Results from EFECT, 26 J. CLIN.
`ONCOL. 1664 (2008) (“Chia 2008”)
`Stephen R.D. Johnston et al., Fulvestrant plus anastrozole or
`placebo versus exemestane alone after progression on non-
`steroidal 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
`retained following progression on first-line fulvestrant, 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
`in Breast Cancer, March 29, 2004, available at 2004 WLNR
`21943944 (“Pharma Marketletter 2004”)
`Cancer Weekly, European Launch of Faslodex 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 Pyrhönen et al., High dose toremifene in advanced breast
`cancer resistant to or relapsed during tamoxifen treatment, 29
`BREAST CANCER RES. & TREAT. 223 (1994) (“Pyrhönen 1994”)
`
`vi
`
`

`

`Exhibit
`2070
`
`2071
`
`2072
`
`2073
`
`2074
`
`2075
`
`2076
`
`2077
`
`2078
`
`2079
`
`2080
`
`Case IPR2017-00904
`
`Description
`Lars E. Stenbygaard et al., Toremifene and tamoxifen in
`advanced breast cancer - a double-blind cross-over trial, 25
`BREAST CANCER RES. & TREAT. 57 (1993) (“Stenbygaard
`1993”)
`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 treatment for
`advanced breast cancer: where are we?, 23 ANNALS ONCOL.
`1378 (2012) (“Barrios 2012”)
`J.F.R. Robertson et al., Endocrine treatment options for advanced
`breast cancer ‒ the role of fulvestrant, 41 EUR. J. CANCER 346
`(2005) (“Robertson Eur. J. Cancer 2005”)
`“Clinical Practice Guidelines in Oncology: Breast Cancer,”
`National Comprehensive Cancer Network, version 1 (2003)
`(“Clinical Practice Guidelines 2003”)
`I. Vergote et al., Fulvestrant, a new treatment option for
`advanced breast cancer: tolerability versus existing agents, 17
`ANNALS ONCOL. 200 (2006) (“Vergote 2006”)
`A. Agrawal et al., 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
`neoadjuvant 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 Agents for the Treatment of Breast
`Cancer, 40 ANN. PHARMACOTHER. 1572 (2006) (“Buzdar 2006”)
`Wolfgang Klement, Pain, Irritation, and Tissue Damage with
`Injections, in INJECTABLE DRUG DEVELOPMENT: TECHNIQUES TO
`REDUCE PAIN & IRRITATION, Ch. 2 (Pramod K. Gupta et al. eds.,
`1999) (“Gupta Ch. 2”)
`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”)
`
`vii
`
`

`

`Exhibit
`2081
`
`2082
`
`2083
`
`2084
`
`2085
`
`2086
`
`2087
`
`2088
`
`2089
`2090
`2091
`
`2092
`
`2093
`
`Case IPR2017-00904
`
`Description
`Louis J. Ravin et al., Preformulation, in REMINGTON’S
`PHARMACEUTICAL SCIENCES, Ch. 75 (Alfonso Gennaro ed., 18th
`ed. 1990) (“Remington’s Ch. 75”)
`P. York, The design of dosage forms, in PHARMACEUTICS: THE
`SCIENCE OF DOSAGE FORM DESIGN, Ch. 1 (M.E. Aulton ed.,
`1988) (“Aulton Ch. 1”)
`A. Buzdar et al., Phase III randomized trial of droloxifene and
`tamoxifen as first-line endocrine treatment of ER/PgR-positive
`advanced breast cancer, 73 BREAST CANCER RES. & TREAT. 161
`(2002) (“Buzdar 2002”)
`Kenneth E. Avis, Parental Preparations, in REMINGTON’S
`PHARMACEUTICAL SCIENCES, Ch. 84 (Alphonso R. Gennaro ed.,
`18th ed. 1990) (“Remington’s Ch. 84”)
`Aman U. Buzdar et al., Phase I trial of droloxifene in patients
`with metastatic breast cancer, 33 CANCER CHEMOTHER.
`PHARMACOL. 313 (1994) (“Buzdar 1994”)
`Michael J. Groves, Perspectives on the Use and Essential
`Requirements of Parenteral Products, in PARENTERAL
`TECHNOLOGY MANUAL, Ch. 2 (2d ed. 1989) (“Groves Ch. 2”)
`Michael J. Akers, Challenges in the Development of Injectable
`Products, in INJECTABLE DRUG DEVELOPMENT: TECHNIQUES TO
`REDUCE PAIN & IRRITATION, Ch. 1 (Pramod K. Gupta et al. eds.,
`1999) (“Gupta Ch. 1”)
`J. Baselga et al., Randomized, double-blind, multicenter trial
`comparing two doses of arzoxifene (LY353381) in hormone-
`sensitive advanced or metastatic breast cancer patients, 14
`ANNALS ONCOL. 1383 (2003) (“Baselga 2003”)
`VIDAL® 1999 LE DICTIONNAIRE (75th ed. 1999) (“Vidal 1999”)
`VIDAL® 1997 LE DICTIONNAIRE (73rd ed. 1997) (“Vidal 1997”)
`ABPI Compendium of Data Sheets and Summaries of Product
`Characteristics (1999-2000) (“ABPI 1999-2000”)
`Declaration of Laird Forrest, Ph.D. in Support of Petition for
`Inter Partes Review, Mylan Pharmaceuticals Inc. v. AstraZeneca
`AB, IPR2016-01325, Ex. 1003 (P.T.A.B. June 29, 2016)
`(“Forrest Mylan Decl.”)
`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”)
`
`viii
`
`

`

`Exhibit
`2094
`
`2095
`
`2096
`
`2097
`
`2098
`
`2099
`
`2100
`
`2101
`2102
`
`2103
`
`2104
`
`2105
`
`2106
`
`Case IPR2017-00904
`
`Description
`J.I. Wells et al., Preformulation, in PHARMACEUTICS: THE
`SCIENCE OF DOSAGE FORM DESIGN, Ch. 13 (M.E. 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”)
`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 (1998) (“Gao 1998”)
`THE MERCK INDEX (12th ed. 1996) (“Merck Index”)
`Howard C. Ansel et al., Transdermal Drug Delivery Systems, in
`PHARMACEUTICAL DOSAGE FORMS & DRUG DELIVERY SYSTEMS,
`Ch. 10 (7th ed. 1999) (“Ansel Ch. 10”)
`Sol Motola et al., Preformulation Research of Parenteral
`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 of Alendronate, 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”)
`
`ix
`
`

`

`Exhibit
`2107
`
`2108
`
`2109
`
`2110
`
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`Case IPR2017-00904
`
`Description
`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”)
`A. U. Buzdar et al., Preliminary Results of a Randomized
`Double-Blind Phase II Study of the Selective Estrogen Receptor
`Modulator (SERM) Arozoxifene (AZ) in Patients (Pts) with
`Locally Advanced or Metastatic Breast Cancer (MBC), 20
`PROCEEDINGS OF ASCO 45a (2001) (“Buzdar ASCO 2001”)
`George N. Wade et al., ICI 182,780 antagonizes the effects of
`estradiol on estrous behavior and energy balance in Syrian
`hamsters, 265 AM. J. PHYSIOL. R1399 (1993) (“Wade 1993”)
`Scott G. Lundeen et al., Characterization of the Ovariectomized
`Rat Model for the Evaluation of Estrogen Effects on Plasma
`Cholesterol Levels, 138 ENDOCRINOLOGY 1552 (1997)
`(“Lundeen 1997”)
`Aman Buzdar et al., Phase II, Randomized, Double-Blind Study
`of Two Dose Levels of Arzoxifene in Patients With Locally
`Advanced or Metastatic Breast Cancer, 21 J. CLIN. ONCOL. 1007
`(2003) (“Buzdar 2003”)
`Robert G. Strickley, Parenteral Formulations of Small Molecules
`Therapeutics Marketed in the United States (1999)—Part I, 53
`PDA J. PHARM. SCI. & TECH. 324 (1999) (“Strickley I”)
`Sol Motola, Biopharmaceutics of Injectable 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 al., Release and absorption rates of
`intramuscularly and subcutaneously injected pharmaceuticals
`(II), 105 INT’L J. PHARMACEUTICS 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 et al., Studies on the Absorption of practically
`Water-insoluble Drugs following Injection. I. Intramuscular
`Absorption from Water-immiscible Oil Solutions in Rats, 29
`CHEM. PHARM. BULL. 519 (1981) (“Hirano 1981”)
`
`x
`
`

`

`Exhibit
`2117
`
`2118
`
`2119
`
`2120
`
`2121
`
`2122
`
`2123
`
`2124
`
`2125
`
`2126
`
`2127
`
`Case IPR2017-00904
`
`Description
`D.J. Greenblatt et al., Absorption of Oral and Intramuscular
`Chlordiazepoxide, 13 EUR. J. CLIN. PHARMACOL. 267 (1978)
`(“Greenblatt 1978”)
`John T. Litchfield, Forecasting Drug Effects in Man from Studies
`in Laboratory Animals, 177 J. AM. MED. ASS’N 34 (1961)
`(“Litchfield 1961”)
`Aman Buzdar et al., Anastrozole, a Potent and Selective
`Aromatase Inhibitor, Versus Megestrol Acetate in
`Postmenopausal Women With Advanced Breast Cancer: Results
`of Overview Analysis of Two Phase III Trials, 14 J. CLIN. ONCOL.
`2000 (1996) (“Buzdar 1996”)
`A. Lifschitz et al., Ivermectin disposition kinetics after
`subcutaneous and intramuscular administration of an oil-based
`formulation to cattle, 86 VET. PARASITOLOGY 203 (1999)
`(“Lifschitz 1999”)
`E. Lavy et al., Pharmacokinetics of clindamycin HCl
`administered intravenously, intramuscularly, and subcutaneously
`to dogs, 22 J. VET. PHARMACOL. 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, 138 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 et al. eds., 1999) (“Gupta Ch. 17”)
`U.S. Patent No. 3,164,520, Raymond Huber, Injectable steroid
`compositions containing at least 75% benzyl benzoate (“Huber”)
`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., 830-33 (1999) (“PDR
`1999 Estrace®”)
`
`xi
`
`

`

`Exhibit
`2128
`
`2129
`
`2130
`
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`2136
`
`2137
`
`Case IPR2017-00904
`
`Description
`M.R. Skougaard et al., Comparative effectiveness of
`intraperitoneal and intramuscular 3H-TDR injection routes in
`mice, 45 EXP. CELL RES. 158 (1966) (“Skougaard”)
`Harry Eagle 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”)
`H.B. Levine et al., Immunologic impairment in mice treated
`intravenously with killed Coccidioides immitis spherules:
`suppressed response to intramuscular doses, 97 J. IMMUNOL. 297
`(1966) (“Levine”)
`A. Yarinsky 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”)
`Werner Lowenthal, Metrology and Calculation, in REMINGTON’S
`PHARMACEUTICAL SCIENCES, Ch. 9 (Alphonso R. Gennaro ed.,
`18th ed. 1990) (“Remington’s Ch. 9”)
`Declaration of Ronald J. Sawchuk, Ph.D. in Support of Patent
`Owner’s Preliminary Response in Mylan Pharmaceuticals Inc. v.
`AstraZeneca AB, IPR2016-01325, Ex. 2003 (P.T.A.B. Oct. 5,
`2016) (“Sawchuk Mylan Decl.”)
`Nicholas G. Lordi, Sustained Release Dosage Forms, in THE
`THEORY & PRACTICE OF INDUSTRIAL PHARMACY, Ch. 14 (Leon
`Lachman et al. eds., 1986) (“Lachman’s”)
`Declaration of Lisbeth Illum, Ph.D. in Support of Patent Owner’s
`Preliminary Response in Mylan Pharmaceuticals Inc. v.
`AstraZeneca AB, IPR2016-01325, Ex. 2001 (P.T.A.B. Oct. 6,
`2016) (“Illum Mylan Decl.”)
`Declaration of John F.R. Robertson, M.D. in Support of Patent
`Owner’s Preliminary Response in Mylan Pharmaceuticals Inc. v.
`AstraZeneca AB, IPR2016-01325, Ex. 2002 (P.T.A.B. Oct. 6,
`2016) (“Robertson Mylan Decl.”)
`Aman U. Buzdar et al., A Phase III Trial Comparing Anastrozole
`(1 and 10 Milligrams), a Potent and Selective Aromatase
`Inhibitor, with Megestrol Acetate in Postmenopausal Women
`with Advanced Breast Carcinoma, 79 CANCER 730 (1997)
`(“Buzdar 1997”)
`
`xii
`
`

`

`Exhibit
`2138
`
`2139
`
`2140
`
`2141
`
`2142
`
`2143
`
`2144
`
`2145
`
`2146
`
`2147
`
`Case IPR2017-00904
`
`Description
`W. Jonat et al., A Randomised Trial Comparing Two Doses of the
`New Selective Aromatase Inhibitor Anastrozole (Arimidex) With
`Megestrol Acetate in Postmenopausal Patients With Advanced
`Breast Cancer, 3