Case IPR2017-00905
`Declaration of Adrian L. Harris Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`INNOPHARMA LICENSING, LLC,
`Petitioner
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`v.
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`ASTRAZENECA AB,
`Patent Owner
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`Case IPR2017-00905
`Patent No. 8,466,139
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`DECLARATION OF ADRIAN L. HARRIS UNDER 37 C.F.R. § 1.68 IN
`SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,466,139
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`
`
`
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`InnoPharma Exhibit 1015.0001
`
`
`Declaration of Adrian L. Harris Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`INNOPHARMA LICENSING, LLC,
`Petitioner
`
`v.
`
`
`
`ASTRAZENECA AB,
`Patent Owner
`
`
`
`
`
`
`
`
`Case IPR2017-00905
`Patent No. 8,466,139
`
`
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`
`
`DECLARATION OF ADRIAN L. HARRIS UNDER 37 C.F.R. § 1.68 IN
`SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U.S.
`PATENT NO. 8,466,139
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`InnoPharma Exhibit 1015.0001
`
`
`
`Case IPR2017-00905
`Declaration of Adrian L. Harris Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION ............................................................................................ 1
`
`II. BACKGROUND AND QUALIFICATIONS ................................................ 3
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ..................... 7
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`IV. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 7
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`V. BROADEST REASONABLE CONSTRUCTION ....................................... 8
`
`VI. UNDERSTANDING OF THE RELEVANT LAW ...................................... 8
`
`VII. OVERVIEW OF THE PATENT AT ISSUE ............................................... 13
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`A. Overview of the ‘139 Patent ................................................................ 13
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`B. Overview of the Prosecution History of the ‘139 Patent .................. 18
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`C. Relevant Related Prosecution Histories ............................................. 18
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`1. The ‘122 Patent Prosecution History ....................................... 19
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`2. The ‘680 Patent Prosecution History ....................................... 21
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`VIII. AVAILABLE THERAPIES AT THE TIME OF THE INVENTION .... 27
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`A. Tamoxifen and Other SERMs ............................................................ 28
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`B. Aromatase Inhibitors (AIs) ................................................................. 31
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`C. Fulvestrant ............................................................................................ 32
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`IX. SCOPE AND CONTENT OF THE PRIOR ART ...................................... 40
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`A. Howell .................................................................................................... 40
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`B. McLeskey .............................................................................................. 42
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`C. O’Regan ................................................................................................ 43
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`
`
`ii
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`InnoPharma Exhibit 1015.0002
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`
`
`Case IPR2017-00905
`Declaration of Adrian L. Harris Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
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`X. DETAILED ANALYSIS ................................................................................ 44
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`A. Summary of Opinion ........................................................................... 44
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`B. Motivation for Combining The Prior Art ......................................... 45
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`1. Motivation to Turn to Howell ................................................... 46
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`2. Motivation to Turn To McLeskey ............................................ 55
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`3. Motivation to Turn To O’Regan .............................................. 61
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`C. A Person of Ordinary Skill Would Have Had a Reasonable
`Expectation of Success in Combining the Prior Art ......................... 62
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`D. There Are No Secondary Considerations Warranting a Finding of
`Nonobviousness .................................................................................... 71
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`1. There Is No Nexus ...................................................................... 72
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`2. There Was No Long-Felt Need ................................................. 74
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`3. There Were No Unexpected Results ........................................ 75
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`XI. SUPPLEMENTATION ................................................................................. 77
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`XII. CONCLUSION ............................................................................................... 77
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`iii
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`InnoPharma Exhibit 1015.0003
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`
`Case IPR2017-00905
`Declaration of Adrian L. Harris Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
`
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`I, Adrian L. Harris, BSc Hons, MB ChB, MA, DPhil FRCP, FMedSci,
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`hereby declare as follows:
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`I.
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`INTRODUCTION
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`1.
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`I have been retained as an expert witness on behalf of InnoPharma
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`Licensing, LLC (“InnoPharma”) for the above-captioned Petition for Inter Partes
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`Review (“IPR”) of U.S. Patent No. 8,466,139 (“the ‘139 patent”). I am being
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`compensated for my time in connection with this IPR at my standard consulting
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`rate of $615.00 per hour. My compensation is in no way dependent on the
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`outcome of this matter.
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`2.
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`I have been asked to provide opinions regarding whether claims 1, 3,
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`10, 11, 13, and 20 of the ‘139 patent are invalid, as anticipated by the prior art, or
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`would have been obvious to a person having ordinary skill in the art at the time of
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`the alleged invention.
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`3.
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`In preparing this Declaration, I have reviewed the ‘139 patent, the file
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`history of the ‘139 patent, and numerous prior art references from the time of the
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`alleged invention.
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`4.
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`I have been advised and it is my understanding that patent claims in
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`an IPR are given their broadest reasonable construction in view of the patent
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`
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`InnoPharma Exhibit 1015.0004
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`specification, file history, and the understanding of one having ordinary skill in the
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`relevant art at the time of the purported invention.
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`5.
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`In forming the opinions expressed in this Declaration, I relied upon
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`my education and experience in the relevant field of the art, and have considered
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`the viewpoint of a person having ordinary skill in the relevant art, as of 2000. My
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`opinions directed to the invalidity of claims 1, 3, 10, 11, 13, and 20 of the ‘139
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`patent are based, at least in part, on the following prior art publications:
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`Reference
`
`
`Howell, Pharmacokinetics,
`Pharmacological and Anti-
`tumor Effects of the Specific
`Anti-Oestrogen ICI 182780 in
`Women with Advanced Breast
`Cancer, BRITISH J. OF CANCER,
`74, p. 300-308 (1996)
`
`McLeskey, Tamoxifen-
`resistant fibroblast growth
`factor-transfected MCF-7 cells
`are cross-resistant in vivo to
`the antiestrogen ICI 182,780
`and two aromatase inhibitors,
`4 CLIN. CANCER RESEARCH
`697–711 (1998)
`
`O’Regan, Effects of the
`Antiestrogens Tamoxifen,
`Toremifene, and ICI 182,780
`on Endometrial Cancer
`Growth, 90 J. NAT’L
`CANCER INST. 1552–1558
`
`Date of Public Availability
`
`Howell was published in 1996 and is
`attached as Exhibit 1007 to the IPR.
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`McLeskey was published in March
`1998 and is attached as Exhibit 1008
`to the IPR.
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`O’Regan was published in March
`1998 and is attached as Exhibit 1009
`to the IPR.
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`
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`2
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`InnoPharma Exhibit 1015.0005
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`(1998)
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`II. BACKGROUND AND QUALIFICATIONS
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`6.
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`A more detailed description of my background and qualifications is
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`provided in my curriculum vitae (attached hereto as Exhibit A). In brief, I am the
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`Professor of Medical Oncology at Oxford University, specializing in breast cancer
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`therapy and research. I have had specialist accreditation in Medical Oncology and
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`General Medicine since 1981. I have trained and worked as a Medical Oncologist
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`(Professor) since 1982, focusing primarily on breast cancer.
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`7.
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`Prior to that, in 1978, I had a clinical research fellowship at the Royal
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`Marsden Hospital. During that time, I developed my research interest in breast
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`cancer and endocrine therapy by developing estrogen assays and developing the
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`first generation of aromatase inhibitor aminoglutethimide.
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`8.
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`In 1982 I was appointed as Professor of Medical Oncology at the
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`University of Newcastle upon Tyne where I established a new department and was
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`the first person to discover the role of epidermal growth factor receptors in breast
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`cancer and their relationship to resistance to hormone therapy.
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`9.
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`In 1989 I was appointed Professor of Medical Oncology at the
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`University of Oxford to set up a new department there, which included developing
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`the breast cancer program and my laboratory research program, which then
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`3
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`InnoPharma Exhibit 1015.0006
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`focused on the microenvironment, angiogenesis and hypoxia and the relationship
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`to breast cancer, including hormone resistance.
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`10.
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`I attend a multi-disciplinary team meeting every week of four medical
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`oncologists, four radiation oncologists and four surgeons and 4 radiologists plus
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`supportive staff to discuss all new patients diagnosed in Oxford, 600 per year, and
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`also am a member of a multi-disciplinary metastatic team.
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`11.
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`I have a Bachelor of Medicine with Honors and a Bachelor of Surgery
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`with Honors, and have a Biochemistry Degree 1st class honors in Liverpool
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`University. I undertook my Membership of Royal College of Physician (UK
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`equivalent of the Board Ccertification) while I was a research fellow at the Medical
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`Research Counsel Department of Clinical Pharmacology in Oxford in 1975.
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`During my PhD, which was in Clinical Pharmacology and Anticancer drugs, I
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`learnt
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`extensively
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`about
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`pharmacokinetics,
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`pharmacodynamics,
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`drug
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`pharmacology and did my research on resistance mechanisms related to
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`pharmacological differences in metabolism.
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`12. My knowledge of treatment of breast cancer includes hormone
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`dependent breast cancer, hormone resistant breast cancer, HER2 positive breast
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`cancer, triple receptor negative breast cancer and extensive experience with
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`chemotherapy and coordination with radiation oncology. I have significant clinical
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`experience in breast cancer care and have been engaged in phase I, II and III trials
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`4
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`InnoPharma Exhibit 1015.0007
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`for breast cancer treatment and have been PI on phase I and II clinical studies.
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`Over my career, I have treated many thousands of women with hormone-
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`dependent and hormone-resistant breast cancer. I see 150 new patients a year in
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`Oxford currently, for which over half have estrogen receptor positive tumors.
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`Over my total experience from 1978 until now I have seen between 50 to 100 new
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`patients a year either on relapse or for primary therapy. I have prescribed
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`fulvestrant to a few dozen patients as a second or third line treatment. I have also
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`used fulvestrant in clinical trials and have used it extensively in vitro. I am
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`familiar with its mechanisms.
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`13. My major laboratory and clinical interests have developed over the
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`years, initially from aromatase inhibitors and hormone resistance mechanisms for
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`growth factor receptors to the microenvironment and the role of angiogenesis and
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`hypoxia in promoting hormone resistant breast cancers. Indeed, very recently in a
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`high impact journal PNAS, we showed that the transcription factor HIF interacts
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`directly with the estrogen receptor and is another mechanism of hormone
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`resistance. I have extensive knowledge of the area and review extensively for the
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`top journals including Nature, Nature Medicine, Cancer Cell, Cell Metabolism,
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`Cancer Research and Clinical Cancer Research in this area. I am the Editor-in-
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`Chief for the British Journal of Cancer, which has many papers per year on breast
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`cancer covering all aspects of preclinical and clinical research
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`5
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`InnoPharma Exhibit 1015.0008
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`14.
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`I have published extensively in the field of cancer, mainly breast
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`cancer, but also on basic and fundamental aspects of biology totaling over 1000
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`papers that are peer reviewed. I am a Highly Cited Researcher 2014, as classified
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`by Thompson Reuters and am included in their 2014 World’s most Influential
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`Scientific Minds. I am on the list of Highly Cited Researchers, which features
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`authors whose published work in their specialty areas has consistently been judged
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`by peers to be of particular significance and utility. There are only 30 UK
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`clinicians with this designation. I have received the Platinum Merit Award,
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`renewed every 5 years since 2001. Only the top 200 clinicians in the UK in all
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`specialties receive this award.
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`15.
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`I regularly give around 10 lectures a year at multidisciplinary
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`meetings including basic science, breast cancer and tumor biology. I am a member
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`of several societies including the British Association of Cancer Research, British
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`Association of Cancer Physicians, American Association of Cancer Research and
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`the American Association of Clinical Oncology. I am also a member of a
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`committee for Cancer Research UK involved in drug development and new drug
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`discovery.
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`16.
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`In 2012, I testified in deposition and at trial in Regeneron
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`Pharmaceuticals Inc. v. Genentech Inc. (Case No. HC 11 C00127) and Bayer
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`Pharma AG v. Genentech Inc. (Case No. HC 11 C00131). The cases were
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`6
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`InnoPharma Exhibit 1015.0009
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`consolidated and were pending at the high Court of Justice, Chancery Division,
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`Patents Court.
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`III. MATERIALS CONSIDERED FOR THIS DECLARATION
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`17. My opinions are based on my years of education, research and
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`experience, as well as my investigation and study of relevant materials. In forming
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`my opinions, I have considered the materials I identify in this report and those
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`listed in Exhibit C.
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`IV. LEVEL OF ORDINARY SKILL IN THE ART
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`18.
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`I have been advised that there are multiple factors relevant to
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`determining the level of ordinary skill in the pertinent art, including the educational
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`level of active workers in the field at the time of the invention, the sophistication of
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`the technology, the type of problems encountered in the art, and the prior art
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`solutions to those problems.
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`19.
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`It is my opinion that a person having ordinary skill in the relevant art
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`at the time of invention would have an advanced degree in pharmaceutics,
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`pharmacy, chemistry, medicine, or a related field, with at least three years of
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`practical experience in analyzing the pharmacokinetics of drug formulations,
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`developing and formulating dosage forms, and/or clinically treating or researching
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`hormone dependent diseases of the breast.
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`
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`7
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`InnoPharma Exhibit 1015.0010
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`V. BROADEST REASONABLE CONSTRUCTION
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`20.
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`I have been advised that InnoPharma has proposed the following
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`constructions under the broadest reasonable interpretation. I understand that these
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`constructions are consistent with the Board’s constructions in IPR2016-01325.
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`Term
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`Broadest Reasonable Construction
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`“the concentration of fulvestrant in a
`patient’s blood plasma is at or above the
`specified minimum concentration for the
`specified time period”
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`No express construction required
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`Limits the invention
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`“achieves” / “attained”
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`“therapeutically significant”
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`“Whereby a therapeutically significant
`blood plasma fulvestrant concentration
`of at least 2.5 ngml-1 is attained for at
`least 2 weeks after injection” / “Wherein
`. . . the blood plasma fulvestrant
`concentration is attained for at least 4
`weeks”
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`
`
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`VI. UNDERSTANDING OF THE RELEVANT LAW
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`21.
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`In expressing my opinions and considering the subject matter of the
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`claims of the ‘139 patent, I am relying upon certain basic legal principles that have
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`been explained to me.
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`22.
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`I understand that prior art to the ‘139 patent includes patents and
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`printed publications that predate the January 10, 2000 priority date.
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`
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`8
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`InnoPharma Exhibit 1015.0011
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`23.
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`I understand that a claim is invalid if it is obvious. Obviousness
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`requires that the claim be obvious from the perspective of a person having ordinary
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`skill in the relevant art at the time the alleged invention was made, without the use
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`of post-filing knowledge. I further understand that an obviousness analysis
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`requires an understanding of the scope and content of the prior art, any differences
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`between the alleged invention and the prior art, and the level of ordinary skill in
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`evaluating the pertinent art.
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`24.
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`I understand that a claim may be obvious in light of one or more prior
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`art references, and that this may be shown by demonstrating that it would have
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`been obvious to a person having ordinary skill in the art to combine the teachings
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`of more than one prior art reference.
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`25.
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`I further understand that examples of where it would have been
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`obvious to a person of ordinary skill in the art to combine a piece of prior art with
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`another piece of prior art, or with other information within the knowledge of one of
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`ordinary skill in the art, include:
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` Using a known technique, or a technique described in another prior
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`art reference, to improve similar methods or products in the same
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`way;
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`
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`9
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`InnoPharma Exhibit 1015.0012
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` Using a predictable variation of a known technique, or a technique
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`described in another prior art reference, to the same or a different
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`field based on design incentives or other market forces;
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` Combining prior art elements according to known methods, or
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`substituting one known element for another, to yield predictable
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`results;
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` Applying a known technique to a known method or product to
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`yield predictable results, or applying a technique or approach that
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`would have been “obvious to try” (choosing from a finite number
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`of identified, predictable solutions, with a reasonable expectation
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`of success); or
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` Inferring that some teaching, suggestion, or motivation in the prior
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`art would have led one of ordinary skill to modify the prior art
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`reference or combine it with another prior art reference.
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`26.
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`I understand that for a motivation to modify the prior art to exist, a
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`person of ordinary skill in the art must only have only a “reasonable expectation of
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`success,” and not “absolute predictability.”
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`27. When obviousness is based on a combination of references, the party
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`seeking to invalidate a patent must show: (i) a motivation to combine the
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`10
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`InnoPharma Exhibit 1015.0013
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`
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`references to achieve the claimed invention; and (ii) a reasonable expectation of
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`success in doing so. I discuss each of these elements below.
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`28. First, with respect to motivation to combine, the motivation may come
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`from the teachings of the prior art, though the precise teachings need not be
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`explicit. Moreover, motivation to combine may be found in the nature of the
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`problem to be solved. For example, when there is market pressure to solve a
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`problem and there are a finite number of identified, predictable solutions, a person
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`of ordinary skill has good reason to pursue the known options within his or her
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`technical grasp. In particular, the normal desire of artisans to improve upon what
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`is already generally known can provide the requisite motivation.
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`29. Generally, a skilled artisan would have been motivated to only
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`combine analogous art. However, analogous art need not be from the same field of
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`endeavor to be considered analogous. Instead, a reference is analogous if it is one
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`which, because of the matter with which it deals, logically would have commended
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`itself to an inventor’s attention in considering his problem.
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`30. Second, with
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`respect
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`to
`
`reasonable expectation of success,
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`obviousness does not require absolute predictability of success. Rather, all that is
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`required is a reasonable expectation of success. A claimed invention is obvious if
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`“one skilled in the art would have had a reasonable expectation of success at the
`
`time the invention was made, and merely had to verify that expectation. Thus,
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`
`
`11
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`InnoPharma Exhibit 1015.0014
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`
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`obviousness cannot be avoided simply by a showing of some degree of
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`unpredictability in the art so long as there was a reasonable probability of success.
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`31.
`
`In that regard, I have been advised that inventions arising from
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`ordinary innovation, ordinary skill, or common sense are not patentable. A patent
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`claim may be obvious if the claimed combination of limitations simply arranges
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`old elements with each performing the same function it had been known to perform
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`and yields no more than what one would expect from such an arrangement. If a
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`person of ordinary skill can implement a predictable variation of limitations, the
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`claimed invention is likely obvious.
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`32.
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`I have been informed that an invention that might be considered an
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`obvious variation or modification of the prior art may be considered nonobvious if
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`one or more prior art references discourages or “teaches away” from the line of
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`inquiry disclosed in the reference(s). However, a reference does not “teach away”
`
`from an invention simply because the reference suggests that another embodiment
`
`of the invention is better or preferred. My understanding of the doctrine of
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`teaching away requires a clear indication that the combination should not be
`
`attempted (e.g., because it would not work or explicit statements saying the
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`combination should not be made).
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`33. Additionally, in determining whether the prior art “teaches away,” I
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`have been advised that the prior art must be viewed as a whole. Even if some
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`
`
`12
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`InnoPharma Exhibit 1015.0015
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`
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`references in the prior art arguably teach away from the alleged invention, the prior
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`art as a whole does not necessarily teach away.
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`34. Finally, I understand that secondary factors may be considered in an
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`obviousness inquiry. I understand that these are also referred to as secondary
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`considerations and may include evidence of long felt need, failure of others,
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`skepticism of those of skill in the art, licensing, commercial success, recognition in
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`the industry, acquiescence, evidence of copying, and unexpected results. While
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`these secondary considerations must be taken into account, they do not necessarily
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`control the obviousness determination.
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`35. Moreover, for objective evidence of non-obviousness to be accorded
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`substantial weight, I understand that the proponent of such evidence must establish
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`a “nexus” between the evidence and the merits of the patent at issue. Specifically,
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`I understand that the secondary consideration must be tied to the merits of the
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`claimed invention of the patent at issue. Where the alleged secondary
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`consideration results from something other than what is both claimed and novel, I
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`understand that there is no nexus to the merits of the claimed invention and the
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`secondary considerations are thus not indicative of non-obviousness. I also
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`understand that it is the patentee’s burden to show that a nexus exists.
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`VII. OVERVIEW OF THE PATENT AT ISSUE
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`A. Overview of the ‘139 Patent
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`
`
`13
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`InnoPharma Exhibit 1015.0016
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`36.
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`I have been asked to consider certain claims of U.S. Patent No.
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`8,466,139, filed September 4, 2012 and issued on June 18, 2013. The ‘139 patent
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`is a continuation of U.S. Patent No. 8,329,680 (“the ‘680 patent”), which is a
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`continuation of U.S. Patent No. 7,456,160 (“the ‘160 patent”), which is in turn a
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`continuation of U.S. Patent No. 6,774,122 (“the ‘122 patent”). The ‘139 patent
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`also asserts priority to two British applications filed on January 10, 2000 and April
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`12, 2000.
`
`37. The ‘139 patent describes its invention as a sustained release
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`pharmaceutical formulation for administration by injection containing the steroidal
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`antiestrogen fulvestrant. ‘139 patent at Abstract. As the patent discloses,
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`antiestrogens are very effective in the fight against breast and reproductive disease,
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`and this effectiveness has been known for the better part of three decades. Id. at
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`1:25-52.
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`38. The patent also explains that the benefits of fulvestrant in particular
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`have been known since as early as 1989. Id. at 1:53-66. The patent discusses the
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`“extreme” clinical importance of fulvestrant:
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`In intact adult rats, fulvestrant achieves maximum regression of the
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`uterus at a dose which does not adversely affect bone density or lead
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`to increased gonadotrophin secretion. If also true in humans, these
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`findings could be of extreme importance clinically. Reduced bone
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`
`
`14
`
`InnoPharma Exhibit 1015.0017
`
`
`
`
`
`density limits the duration of oestrogen-ablative treatment for
`
`endometriosis. Fulvestrant does not block hypothalamic ER.
`
`Oestrogen ablation also causes or exacerbates hot flushes and other
`
`menopausal symptoms; fulvestrant will not cause such effects because
`
`it does not cross the blood-brain barrier.
`
`Id. at 2:22-32.
`
`39. The ‘139 patent discloses that the prior art contains sustained release
`
`injectable steroidal formulations, and that these prior art formulations have
`
`achieved extended release up to eight weeks. Id. at 2:55-66.
`
`40. The ‘139 patent also discloses that a number of the excipients it
`
`claims, such as benzyl benzoate, benzyl alcohol, ethanol, and castor oil, were
`
`included in prior art formulations, , particularly extended release formulations. Id.
`
`at 2:61-65; id. at 5:29-35. Oil-based formulations of fulvestrant in particular were
`
`known since at least 1989, as disclosed in the Dukes patent discussed in the ‘139
`
`patent specification. Id. at 3:55-62.
`
`41. The ‘139 patent describes its purported new discovery as the fact that
`
`“the introduction of a non-aqueous ester solvent which is miscible in the castor oil
`
`and an alcohol surprisingly eases the solubilisation of fluvestrant.” Id. at 5:57-67.
`
`42. The ‘139 patent includes 20 claims. I have been asked to opine on
`
`claims 1, 3, 10, 11, 13, 20 quoted below.
`
`
`
`15
`
`InnoPharma Exhibit 1015.0018
`
`
`
`
`
`
`
`1. A method for treating a hormonal dependent benign or malignant
`
`disease of the breast or reproductive tract comprising administering
`
`intramuscularly to a human in need of such treatment a formulation
`
`comprising:
`
`
`
`
`
`
`
`
`
`
`
`about 50 mgml-1 of fulvestrant;
`
`a mixture of from 17-23% w/v of ethanol and benzyl alcohol;
`
`12-18% w/v of benzyl benzoate; and
`
`a sufficient amount of castor oil vehicle;
`
`wherein the method achieves a blood plasma fulvestrant
`
`concentration of at least 2.5 ngml-1 for at least two weeks.
`
`3. The method of claim 1, wherein formulation comprises:
`
`
`
`
`
`
`
`about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol; and
`
`about 15% w/v of benzyl benzoate.
`
`10. The method of claim 3, wherein the hormonal dependent benign
`
`or malignant disease of the breast or reproductive tract is breast cancer
`
`and the blood plasma fulvestrant concentration is attained for at least
`
`4 weeks.
`
`11. A method for treating a hormonal dependent benign or malignant
`
`disease of the breast or reproductive tract comprising administering
`
`16
`
`InnoPharma Exhibit 1015.0019
`
`
`
`
`
`
`
`intramuscularly to a human in need of such treatment a formulation
`
`consisting essentially of:
`
`
`
`
`
`
`
`
`
`
`
`about 50 mgml-1 of fulvestrant;
`
`a mixture of from 17-23% w/v of ethanol and benzyl alcohol;
`
`12-18% w/v of benzyl benzoate; and
`
`a sufficient amount of castor oil vehicle;
`
`wherein the method achieves a blood plasma fulvestrant
`
`concentration of at least 2.5 ngml-1 for at least two weeks.
`
`13. The method of claim 11, wherein formulation consists essentially
`
`of:
`
`
`
`
`
`
`
`about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol; and
`
`about 15% w/v of benzyl benzoate.
`
`20. The method of claim 13, wherein the hormonal dependent benign
`
`or malignant disease of the breast or reproductive tract is breast cancer
`
`and the blood plasma fulvestrant concentration is attained for at least
`
`4 weeks.
`
`17
`
`InnoPharma Exhibit 1015.0020
`
`
`
`
`
`B. Overview of the Prosecution History of the ‘139 Patent
`
`43.
`
`I reviewed the prosecution history of the ‘139 patent itself in forming
`
`my opinions, though the substantive discussion in that prosecution history is far
`
`more limited and of less use than that of the parent applications.
`
`44. The application claims were rejected once, on January 3, 2013, for
`
`double patenting over claims of the ‘680, ‘122 and ‘160 patents. ‘139 Prosecution
`
`History at 0068-69. The Patent Office found that the claims were not patentably
`
`distinct from the ‘680, ‘122, and ‘160 patents, including because “[t]he ratio of the
`
`solvents and excipients are within the range taught in the ‘122.” Id. at 0069-70.
`
`The Patent Office also rejected two claims under 35 U.S.C. § 101, as claiming the
`
`same invention as the ‘680 patent. Id. at 0071. With the exception of the § 101
`
`rejection, which AstraZeneca simply argued was incorrect based on a comparison
`
`of the claims of the ‘680 and ‘139 patents, id. at 0095-96, AstraZeneca did not
`
`dispute the Patent Office’s conclusions and instead filed a terminal disclaimer to
`
`overcome the double patenting issues. Id. at 0085-87. Following the terminal
`
`disclaimer and remarks on the § 101 rejection, the claims were allowed. Id. at 103.
`
`C. Relevant Related Prosecution Histories
`
`45.
`
`I have also reviewed the prosecution histories of the ‘122 and ‘680
`
`patents, of which the ‘139 patent is a continuation, in forming my opinions
`
`expressed in this declaration. As part of the same family, the prosecution histories
`
`
`
`18
`
`InnoPharma Exhibit 1015.0021
`
`
`
`
`
`of these patents are relevant to the patentability of the ‘139 patent’s claims. The
`
`patents’ applications are also incorporated by reference, in their entirety, into the
`
`‘139 patent. ‘139 Patent at 1:6-15.
`
`1.
`
`The ‘122 Patent Prosecution History
`
`46. The ‘122 patent was filed on January 9, 2001. On August 27, 2003,
`
`the Patent Office issued a Final Rejection, rejecting all but one of the application
`
`claims in light of prior art. In reaching this conclusion, the Patent Office cited to
`
`European Patent 0 346 014, a 1989 patent invented by Michael Dukes and owned
`
`by Zeneca Limited. The Patent Office recognized that “Dukes teaches antiestrogen
`
`agents, including fulvestrant, are useful in treating postmenopausal symptoms such
`
`as urogenital atrophy affecting the vagina . . . . Dukes teaches that antiestrogen
`
`agent, including fulvestrant, may be used in a dosage of 50mg to 5g in vehicle
`
`comprising castor oil and benzyl alcohol . . . .” Exhibit 1006 at 0537.
`
`47. After noting a number of other references that speak specifically to
`
`formulation, the Patent Office found that “[i]t would have been obvious to one of
`
`ordinary skill in the art at the time the invention was made to employ benzyl
`
`benzoate, ethanol, castor oil, and benzyl alcohol, in the herein claimed weight
`
`percent, with fulvestrant in the dosage herein, in a method of treating
`
`postmenopausal symptoms such as urogenital atrophy in the vagina.” Id. at 0538.
`
`
`
`19
`
`InnoPharma Exhibit 1015.0022
`
`
`
`
`
`48. The Patent Office also found that “[o]ne of ordinary skill in the art
`
`would have been motivated to employ benzyl benzoate, ethanol, castor oil, and
`
`benzyl alcohol, in the herein claimed weight percent, with fulvestrant, in the
`
`dosage herein . . . .” Id.
`
`49. As to the specific plasma levels claimed, the Patent Office found that
`
`“[o]ne of ordinary skill in the art would have been motivated to maintain the
`
`plasma concentration of fulvestrant herein because maintaining the therapeutic
`
`plasma level of the active compounds would be considered obvious as being within
`
`the purview of the skilled artisan.” Id. at 0539.
`
`50. The only allowable subject matter was a single claim, on the sole
`
`basis of an alleged “[u]nexpected increase of solubility of fulvestrant by adding
`
`15% of benzyl benzoate into the composition.” Id. at 0541. I understand that other
`
`experts will explain why this result was not at all unexpected, and should not have
`
`rendered the claim patentable.
`
`51.
`
`In its response, AstraZeneca amended their claims to put the only
`
`allowable subject matter into independent form, and asserted certain other
`
`limitations as dependent claims thereto. Id. at 0547. The remainder of the claims
`
`were cancelled, without any argument against the Patent Office’s findings that
`
`fulvestrant’s usefulness was well known, and that a person of ordinary skill in the
`
`art would be motivated to modify fulvestrant as described in the ‘122 patent.
`
`
`
`20
`
`InnoPharma Exhibit 1015.0023
`
`
`
`
`
`2.
`
`The ‘680 Patent Prosecution History
`
`52. The ‘680 Patent was filed on October 15, 2008. In a December 21,
`
`2010 Offi
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