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
`
`US. Patent 8,329,680 B2
`
`DECLARATION OF JOHN F. R. ROBERTSON, M.D. IN SUPPORT OF
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca EX. 2002 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01325
`
`AstraZeneca Exhibit 2136 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00905
`
`

`

`TABLE OF CONTENTS
`
`I)
`
`11)
`
`111)
`
`IV)
`
`V)
`
`VI)
`
`VII)
`
`VIII)
`
`IX)
`
`X)
`
`INTRODUCTION ...................................................................................... .. 1
`
`QUALIFICATIONS AND EXPERIENCE ............................................... ..1
`
`MY UNDERSTANDING OF THE PROCEEDING ................................. .. 5
`
`MY OPINIONS AND THEIR BASES ...................................................... ..6
`
`DOCUMENTS CONSIDERED ................................................................ ..7
`
`THE ’680 PATENT CLAIMS ................................................................... ..7
`
`PERSON OF ORDINARY SKILL IN THE ART ..................................... ..9
`
`LEGAL PRINCIPLES ............................................................................. .. 10
`
`CLAIM CONSTRUCTION ..................................................................... .. 11
`
`STATE OF THE RELEVANT ART ....................................................... ..15
`
`A)
`
`B)
`
`C)
`
`D)
`
`Problem To Be Solved ................................................................... ..15
`
`The Prior Art Taught and Provided a Promising Scientific
`Rationale and Experimental Candidates for Many Different
`Systemic Therapy Approaches to Treating Breast Cancer ............ ..19
`
`l)
`
`2)
`
`3)
`
`4)
`
`Selective Estrogen Receptor Modulators (SERMs) ............ ..19
`
`Aromatase Inhibitors (AIs) .................................................. ..21
`
`Pure Antiestrogens .............................................................. ..23
`
`Other Endocrine Therapies .................................................. ..27
`
`Fulvestrant Was Less Promising Than The Other Available
`Endocrine Agents in 2000 ............................................................. ..28
`
`Fulvestrant Formulations, Schedule And Route Of
`Administration, Optimal Dose, Concentration, and Blood
`Plasma Levels Were Not Well-Known And Were Certainly
`Not “Established” In The Prior Art ............................................... ..33
`
`XI)
`
`REFERENCES CITED IN THE PETITION ........................................... ..40
`
`A) McLeskey (EX. 1005) .................................................................... ..40
`
`B)
`
`C)
`
`D)
`
`Howell 1995 (EX. 1012) ................................................................ ..43
`
`Howell 1996 (Ex. 1006) ................................................................ ..45
`
`Dukes 1989 (EX. 1007) .................................................................. ..49
`
`E) Wakeling 1991 (EX. 1008) ............................................................. ..51
`
`AstraZeneca EX. 2002 p. 2
`
`AstraZeneca Exhibit 2136 p. 2
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`F) Wakeling 1992 (Ex. 1009) ............................................................. ..53
`
`G)
`
`Dukes 1992 (Ex. 1025) .................................................................. ..55
`
`H) Wakeling 1993
`
`1028) ............................................................. ..57
`
`I)
`
`J)
`
`K)
`
`L)
`
`Dukes 1993 (Ex. 1026) .................................................................. ..59
`
`DeFriend 1994 (Ex. 1027) ............................................................. ..61
`
`Osborne 1995 (Ex. 1018) ............................................................... ..64
`
`O’Regan 1998 (Ex. 1013) .............................................................. ..66
`
`XII)
`
`THE CLAIMS OF THE ’680 PATENT ARE NOT OBVIOUS ............. ..67
`
`A)
`
`Ground One: McLeskey ................................................................ ..67
`
`l)
`
`2)
`
`3)
`
`4)
`
`5)
`
`McLeskey Alone Fails To Disclose Nearly All Of The
`Limitations Of The ’680 Patent Claims .............................. ..67
`
`A Skilled Artisan Would Not Look to McLeskey .............. ..69
`
`McLeskey Is A Study Of Basic Biology Unrelated to
`Treatment ............................................................................. ..71
`
`McLeskey Does Not Teach A Successful Fulvestrant
`Formulation ......................................................................... ..75
`
`The Skilled Artisan Would Not Expect the
`Administration Method of McLeskey to Succeed .............. ..78
`
`B)
`
`Ground Two: McLeskey in Combination with Howell 1996 ........ ..80
`
`1)
`
`2)
`
`3)
`
`Howell 1996 Left Many Questions Unanswered And
`Was Questioned By Researchers At The Time ................... ..80
`
`No Reason To Combine McLeskey With Howell 1996 ..... ..89
`
`No Expectation That This Combination Would
`Successfully Treat Hormone Dependent Breast Cancer
`In Humans ........................................................................... ..93
`
`XIII)
`
`SECONDARY CONSIDERATIONS DEMONSTRATE THAT
`THE CLAIMED INVENTION IS NONOBVIOUS ............................... ..97
`
`A)
`
`B)
`
`Long-Felt Unmet Need .................................................................. ..97
`
`Unexpected Results ....................................................................... ..99
`
`1)
`
`Improved Clinical Outcomes ............................................ .. 101
`
`AstraZeneca Ex. 2002 p. 3
`
`AstraZeneca Exhibit 2136 p. 3
`
`

`

`TABLE OF CONTENTS
`
`(continued)
`
`2)
`
`Improved Side Effect Profile ............................................. .. 103
`
`C)
`
`The Invention Method Is The Reason For These Surprising
`Results .......................................................................................... .. 107
`
`XIV) CONCLUSION ...................................................................................... ..114
`
`AstraZeneca EX. 2002 p. 4
`
`AstraZeneca Exhibit 2136 p. 4
`
`

`

`I, John F. R. Robertson, M.D., do hereby make the following declaration:
`
`I)
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am over the age of eighteen and competent to make this declaration.
`
`I have been retained as an expert witness on behalf of AstraZeneca
`
`AB for the above-captioned inter partes review (IPR).
`
`I am being compensated at
`
`my customary rate of £600 per hour for my consultation in connection with this
`
`matter. My compensation is in no way dependent on the outcome of my analysis
`
`or opinions rendered in this matter. A copy of my curriculum vitae, which
`
`includes my academic background, work experience, and select publications and
`
`presentations, is attached to this declaration as Exhibit A.
`
`II)
`
`QUALIFICATIONS AND EXPERIENCE
`
`3.
`
`My name is John Robertson, MD. I am a physician specializing in
`
`breast cancer and surgery, and I have Specialist Accreditation in General
`
`Surgery.
`
`I trained and have worked as a general surgeon, focusing primarily on
`
`breast cancer, for thirty-five years, through which I have acquired extensive
`
`clinical experience in breast disease. Since August 1998, I have been Professor
`
`of Surgery at the University of Nottingham, initially based at the City Hospital,
`
`Nottingham (1988 - 2011) and then based at the Royal Derby Hospital, Derby
`
`(2011 - present). Prior to that, since 1992, my appointments included Senior
`
`Lecturer and Reader in Surgery, both based at the City Hospital, Nottingham.
`
`I
`
`AstraZeneca Ex. 2002 p. 5
`
`AstraZeneca Exhibit 2136 p. 5
`
`

`

`have clinical experience across the continuum of breast care, from preventive
`
`care for high risk patients and routine screening, to diagnosis and treatment
`
`of primary breast cancer, to diagnosis and treatment of locally advanced and
`
`metastatic disease, to palliative care.
`
`4.
`
`I received my MB. ChB. (Bachelor of Medicine, Bachelor of
`
`Surgery), B.Sc. (Bachelor of Science) and MD. (in the UK, a postgraduate
`
`research degree in medicine) all from the University of Glasgow.
`
`1 also was
`
`awarded F.R.C.S. (Fellowship of the Royal College of Surgeons) by the Royal
`
`College of Physicians and Surgeons of Glasgow.
`
`5.
`
`My knowledge concerning the treatment of breast cancer, more
`
`specifically hormonal dependent breast cancer, and the use of hormone (116.,
`
`endocrine) therapies has been gained through my training and personal and
`
`professional experiences. More specifically, these experiences include my own
`
`medical practice over thirty-five years, research that l have conducted (both
`
`laboratory research and clinical trial research), consultancy positions I have held,
`
`and advisory boards and committees that I have served on or been a member of.
`
`In my medical practice, I have gained extensive experience over the last thirty-five
`
`years with every class of approved endocrine agent used to treat hormonal
`
`dependent breast cancer. Over my career, I have treated thousands of women with
`
`hormone dependent breast cancer.
`
`AstraZeneca Ex. 2002 p. 6
`
`AstraZeneca Exhibit 2136 p. 6
`
`

`

`6.
`
`In terms of research, I have been involved in both laboratory research
`
`and clinical trials of all major classes of new endocrine therapies in hormonal
`
`dependent breast cancer over thirty years.
`
`I have consulted for and served on or
`
`chaired advisory boards to major pharmaceutical companies researching and
`
`developing drugs for hormonal dependent breast cancer.
`
`7.
`
`One of my major clinical and laboratory research interests is breast
`
`cancer, particularly hormonal dependent, or hormone receptor positive, breast
`
`cancer and the role of endocrine therapy.
`
`I have also had a focus on advanced
`
`disease—both locally advanced and metastatic breast cancer. As a surgical
`
`oncologist with both a major clinical and laboratory interest in endocrine and
`
`growth factor therapies, I find myself in a central position providing a link
`
`between surgical and non-surgical (clinical and medical) oncologists, which
`
`ensures seamless continuity of care for patients and a rich base from which
`
`clinical and laboratory research can proceed. At the University of Nottingham,
`
`my group’s interest in systemic therapies has placed it at the vanguard of
`
`surgical units performing pre-surgical (‘window of opportunity’) studies which
`
`allows us to combine our skill sets in surgery and systemic therapies into a
`
`translational research program investigating biological changes in breast cancers,
`
`which matches our therapeutic clinical trials in advanced disease. I am currently
`
`one of the three Chief Investigators on the largest trial of peri-operative endocrine
`
`AstraZeneca EX. 2002 p. 7
`
`AstraZeneca Exhibit 2136 p. 7
`
`

`

`therapy in the world (the POETIC trial).
`
`I have been Chief Investigator, or
`
`local Principal Investigator, in a large number of multicenter trials for new
`
`drugs produced by a variety of pharmaceutical companies including AstraZeneca,
`
`Novartis, Amgen, GlaxoSmithKline, Schering, and Bayer.
`
`8.
`
`I have published extensively in the field of cancer, principally,
`
`although not exclusively, on topics related to cancer of the breast with a
`
`particular focus on hormonal dependent breast cancer and endocrine therapies.
`
`I currently have over 300 peer-reviewed publications. Ihave also published
`
`book chapters on the treatment of breast cancer and a book titled, Endocrine
`
`Therapy of Breast Cancer.
`
`9.
`
`I have attended, over the last thirty years, a large number of
`
`professional oncology conferences, with a primary focus on breast cancer.
`
`I
`
`have presented at a number of professional conferences regarding my research
`
`related to breast cancer.
`
`In addition to presenting laboratory and clinical trial
`
`research, I have given invited lectures at both national and international
`
`conferences.
`
`I am frequently invited to lecture at international cancer meetings.
`
`Between 2009 and September 2016, I gave invited lectures at fifty-five
`
`international cancer meetings, often giving multiple lectures at a single meeting.
`
`One of the major topics of invited lectures has been the treatment of breast cancer
`
`and the use of hormone therapies, otherwise known as endocrine therapies.
`
`AstraZeneca EX. 2002 p. 8
`
`AstraZeneca Exhibit 2136 p. 8
`
`

`

`10.
`
`I am a member of several learned societies, including:
`
`the Society
`
`of Academic and Research Surgery, the British Association of Surgical Oncology,
`
`the Association of Breast Surgery, and the British Association of Cancer Research.
`
`I am also a member, or have been a member, of several scientific committees as
`
`well as committees affiliated with universities and health care centers.
`
`I am
`
`the Editor-in-Chief of the journal, Breast Cancer Online.
`
`11.
`
`I have extensive teaching experience, including in the subject of
`
`breast cancer.
`
`In addition, I have supervised a number of under- and post-
`
`graduate medical trainees and non-clinical scientists, including nearly twenty such
`
`physicians and students during the past five years.
`
`12.
`
`I have significant experience in the areas of breast cancer diagnosis
`
`and treatment, breast cancer clinical
`
`trial research, hormonal dependent, or
`
`hormone receptor positive, breast cancer, and hormonal therapies. Therefore, I
`
`believe that I am qualified to render the opinions set forth in this report.
`
`13.
`
`In the past four years, I have testified in the following litigation:
`
`AstraZeneca Pharmaceuticals LP v. Sagent Pharmaceuticals, Inc, No. 14-cv-
`
`O3547-RMB-KMW (D.N.J.).
`
`III) MY UNDERSTANDING OF THE PROCEEDING
`
`14.
`
`I have been informed that this proceeding is an inter partes review
`
`(“IPR”) before the Patent Trial and Appeal Board of the United States Patent and
`
`AstraZeneca Ex. 2002 p. 9
`
`AstraZeneca Exhibit 2136 p. 9
`
`

`

`Trademark Office (“the Board”). I have been informed that an IPR is a proceeding
`
`to review the patentability of one or more issued claims in a United States patent
`
`on the grounds that the patent is the same as or rendered obvious in view of the
`
`prior art.
`
`15.
`
`I have been informed that Mylan Pharmaceuticals Inc. filed a Petition
`
`requesting IPR (“Petition”) of US. Patent No. 8,329,680 (the ’680 Patent”), which
`
`issued to John R. Evans and Rosalind U. Grundy on December 11, 2012 and is
`
`assigned to AstraZeneca AB. I have reviewed the Petition, and understand that it
`
`alleges that claims 1-20 of the ’680 Patent are unpatentable over McLeskey (EX.
`
`1005) and, alternatively, over the combination of Howell 1996 (Ex. 1006) with
`
`McLeskey (EX. 1005).
`
`IV) MY OPINIONS AND THEIR BASES
`
`16.
`
`I have been asked to give my opinion on whether or not a person of
`
`ordinary skill in the art (“POSA”) would understand claims 1-20 of the ’680 Patent
`
`to be rendered obvious by: (l) McLeskey (EX. 1005); or (2) the combination of
`
`Howell 1996 (EX. 1006) with McLeskey (EX. 1005).
`
`17. As part of this opinion, I considered the level of ordinary skill in the
`
`art around January 2000, which represents the filing date of GB 0000313, to which
`
`the ’680 Patent claims priority.
`
`AstraZeneca EX. 2002 p. 10
`
`AstraZeneca Exhibit 2136 p. 10
`
`

`

`V)
`
`DOCUMENTS CONSIDERED
`
`18.
`
`The materials that I have considered, in addition to the exhibits to the
`
`Petition, are those cited herein (which are also listed in Exhibit B). My opinions as
`
`stated in this Declaration are based on the understanding of a POSA in the art as
`
`defined below.
`
`VI) THE ’680 PATENT CLAIMS
`
`19.
`
`I have been informed that the priority date of the ’680 Patent was
`
`January 10; 2000.
`
`20.
`
`Independent claim 1 of the ’680 Patent is provided below.
`
`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 mng'1 of fulvestrant;
`
`about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol;
`
`about 15% w/v of benzyl benzoate; and
`
`a sufficient amount of castor oil vehicle;
`
`wherein the method achieves a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5 nng'1 for
`
`AstraZeneca Ex. 2002 p. 11
`
`AstraZeneca Exhibit 2136 p. 11
`
`

`

`at least four weeks.
`
`21. Dependent claims limit claim 1 to a method: wherein the
`
`therapeutically significant blood plasma fulvestrant concentration is at least 8.5
`
`nng'1 (claim 2); wherein the hormonal dependent benign or malignant disease of
`
`the breast or reproductive tract is breast cancer (claims 3 and 6); wherein the
`
`method comprises administering intramuscularly to a human in need of such
`
`treatment 5 mL of the formulation (claims 4 and 7); wherein the method further
`
`comprises once monthly administration of the formulation (claims 5 and 8);
`
`wherein the formulation is administered in a divided dose (claims 17 and 18).
`
`22.
`
`Independent claim 9 is provided below.
`
`9.
`
`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 consisting essentially of:
`
`about 50 mgml'1 of fulvestrant;
`
`about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol;
`
`about 15% w/v of benzyl benzoate; and
`
`wherein the method achieves a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5 ngml'1 for
`
`AstraZeneca EX. 2002 p. 12
`
`AstraZeneca Exhibit 2136 p. 12
`
`

`

`at least four weeks.
`
`23. Dependent claims limit claim 9 to a method: wherein the
`
`therapeutically significant blood plasma fulvestrant concentration is at least 8.5
`
`nng'1 (claim 10); wherein the hormonal dependent benign or malignant disease of
`
`the breast or reproductive tract is breast cancer (claims 11 and 14); wherein the
`
`method comprises administering intramuscularly to a human in need of such
`
`treatment 5 mL of the formulation (claims 12 and 15); wherein the method further
`
`comprises once monthly administration of the formulation (claims 13 and 16);
`
`wherein the formulation is administered in a divided dose (claims 19 and 20).
`
`VII) PERSON OF ORDINARY SKILL IN THE ART
`
`24.
`
`I have been asked to provide my opinion on the novelty and
`
`obviousness of the asserted claims, from the perspective of a person of ordinary
`
`skill in the relevant art. The skilled person with respect to the ’680 Patent is a
`
`person having a bachelor’s or advanced degree in a discipline such as pharmacy,
`
`pharmaceutical sciences, endocrinology, medicine or related disciplines, and
`
`having at least two years of practical experience in drug development and/or drug
`
`delivery, or the clinical treatment of hormone dependent diseases of the breast and
`
`reproductive tract. Because the drug discovery and development process is
`
`complicated and multidisciplinary, it would require a team of individuals
`
`including, at least, medical doctors, pharmacokineticists, and forrnulators.
`
`AstraZeneca EX. 2002 p. 13
`
`AstraZeneca Exhibit 2136 p. 13
`
`

`

`25. As considered from the perspective of the medical doctor member of
`
`that team, the invention of the ’680 Patent is novel, and not obvious, for the
`
`following reasons.
`
`VIII) LEGAL PRINCIPLES
`
`26.
`
`I am not a lawyer, and I have relied on the explanations of counsel for
`
`an understanding of certain principles of US. patent law that govern the
`
`determination of patentability. The discussion set forth below regarding the law of
`
`obviousness is intended to be illustrative of the legal principles I considered while
`
`preparing my report, and not an exhaustive list.
`
`27.
`
`I am informed by counsel that there is no presumption of validity.
`
`Rather, Mylan must show unpatentability by a preponderance of the evidence, and
`
`preponderance of the evidence means “more probable than not.” I understand that
`
`to institute an inter partes review Mylan must show that there is a reasonable
`
`likelihood that it would prevail in an inter partes review.
`
`28.
`
`I am informed by counsel that for a patent claim to be invalid as
`
`anticipated by a prior art reference, that reference must disclose every limitation of
`
`the claim. Thus, if the inventions of a patent claim were already disclosed, in their
`
`entirety, by a prior art reference, that claim is anticipated and not novel.
`
`29.
`
`I am informed by counsel that for an invention to be obvious, the
`
`patent statute requires that the differences between the invention and the prior art
`
`AstraZeneca Ex. 2002 p. 14
`
`AstraZeneca Exhibit 2136 p. 14
`
`

`

`be such that the “subject matter as a whole would have been obvious at the time
`
`the invention was made to a person of ordinary skill in the art to which such
`
`subject matter pertains.”
`
`30.
`
`I understand that the obviousness evaluation must be from the
`
`perspective of the time the invention was made. The obviousness inquiry must
`
`guard against slipping into use of hindsight.
`
`31.
`
`I understand that even in circumstances where each component of an
`
`invention can be found in the prior art, there must have been an apparent reason to
`
`combine the known elements in the fashion claimed by the patent at issue. For an
`
`invention to be found obvious, to protect against the distortion caused by hindsight
`
`bias, there must be a reason that would have prompted a person of ordinary skill in
`
`the relevant field to combine the elements in the way the claimed new invention
`
`does.
`
`32.
`
`For the method of treatment to be obvious, it must have been among a
`
`finite number of identified, predictable solutions to the problems at hand.
`
`33.
`
`For the reasons explained below, in my opinion, Mylan has not shown
`
`that there is a reasonable likelihood that it would prevail in an inter partes review
`
`of claims 1-20 of the ’680 patent.
`
`IX) CLAIM CONSTRUCTION
`
`34. All of the claims of the ’680 Patent are expressly directed to methods
`
`AstraZeneca Ex. 2002 p. 15
`
`AstraZeneca Exhibit 2136 p. 15
`
`

`

`of treatment. The methods of treatment include choice of an active ingredient, a
`
`method of administration (i.e., a combination of excipients and active injected
`
`intramuscularly), and the amount of the active to be delivered to the blood in a
`
`sustained release fashion to treat hormonal dependent disease of the breast and
`
`reproductive tract.
`
`35. A medical doctor would understand the term “hormonal dependent
`
`benign or malignant disease of the breast or reproductive tract .
`
`.
`
`. [in] a human” in
`
`independent claims 1 and 9 of the ’680 Patent to have its plain and ordinary
`
`meaning. The plain meaning of this term indicates to a medical doctor that the
`
`method of treatment may be used to treat hormonal dependent cancerous and non-
`
`cancerous diseases of the breast or reproductive system, such as breast cancer or
`
`endometriosis, in pre- and post-menopausal women and breast cancer or
`
`gynaecomastia in men.
`
`36. A medical doctor would understand that the blood plasma level
`
`limitations of the ’680 Patent claims are indeed limitations of the claims and
`
`should be given their plain and ordinary meaning. These limitations are in claims
`
`1 and 9: “wherein the method achieves a therapeutically significant blood plasma
`
`fulvestrant concentration of at least 2.5 nng'1 for at least four weeks” and in the
`
`claims which depend on them: “wherein the therapeutically significant blood
`
`plasma fulvestrant concentration is at least 8.5 ngml'l.” A clinician would
`
`AstraZeneca EX. 2002 p. 16
`
`AstraZeneca Exhibit 2136 p. 16
`
`

`

`understand these limitations to mean that the specified blood plasma fulvestrant
`
`concentrations of at least 2.5 nng'1 or 8.5 nng'1 are achieved and maintained for
`
`the specified amount of time. The plain meaning of the words “achieves” and “at
`
`least” indicate to the clinician that the patient’s blood plasma level must remain at
`
`or above the specified concentrations for the entire specified time period.
`
`37.
`
`Dr. Oleksowicz argues that the blood plasma levels “simply express[]
`
`the intended result of a process step positively recited” and inform that “if the as-
`
`claimed method of treatment is followed, the specified therapeutic plasma levels
`
`will be achieved.” Ex. 1004 at 1111 190-191, 223-224. In my opinion, this cannot be
`
`so because, from a clinician’s perspective, these limitations give meaning to and
`
`provide defining characteristics of the method of treatment.
`
`38.
`
`The blood plasma levels achieved and maintained are different for
`
`different claims. These limitations go to the dose and the dosing frequency of the
`
`method of treatment if it is to achieve a therapeutic outcome. Dose and dosing
`
`frequency are pivotal aspects of a method of treatment: they themselves are not
`
`included within the claims since what is even more critical in attaining a
`
`therapeutic outcome, and ultimately decides dose and dose schedule, is that the
`
`drug fulvestrant is delivered in the blood to the tumor at the specified blood plasma
`
`concentration for the specified duration. See, e.g., Ex. 2014 (Pritchard 1997) at 13
`
`(“The endocrine effects of tamoxifen are complex and seem dependent on species,
`
`AstraZeneca Ex. 2002 p. 17
`
`AstraZeneca Exhibit 2136 p. 17
`
`

`

`age, duration, and dose of tamoxifen given, menopausal status, and target organ”).
`
`Furthermore, as will be detailed below the different blood plasma concentrations
`
`lead to different therapeutic outcomes which highlight that the blood plasma
`
`limitations give meaning to and provide defining characteristics of the method of
`
`treatment.
`
`39.
`
`Indeed, clinical studies demonstrated the therapeutic importance of
`
`the different blood plasma level limitations of the claims.
`
`I was a member of the
`
`team that conducted a translational clinical study investigating the 50 mg, 125 mg,
`
`and 250 mg doses of Faslodex® (fulvestrant) intramuscular injection as well as
`
`therapeutic clinical studies investigating 125 mg and 250 mg doses of Faslodex®
`
`(fulvestrant) intramuscular injection. Exs. 2028 (Howell 2002), 2029 (Osborne
`
`2002), 2030 (Robertson Cancer Res. 2001), 2031 (Robertson Clin. Ther. 2003).
`
`The results of the clinical studies, published in 2002, demonstrated that the 125 mg
`
`dose did not achieve the desired therapeutic result and was therefore deemed not
`
`effective to treat hormonal dependent breast cancer. Id. The translational study,
`
`published in 2001, indicated that compared to the 250 mg dose the 50 mg and 125
`
`mg doses appeared not as effective in decreasing estrogen receptor, progesterone
`
`receptor or Ki67 expression in tumors and at the same time achieved lower blood
`
`concentrations throughout the 4 week period. And, in fact, later studies showed
`
`that the 500 mg dose had improved efficacy even over the 250 mg dose (Ex. 2004
`
`AstraZeneca Ex. 2002 p. 18
`
`AstraZeneca Exhibit 2136 p. 18
`
`

`

`(Di Leo 2010); Ex. 2005 (Di Leo 2014)) and this was explicitly linked to the blood
`
`levels achieved by the 500 mg dose (Ex. 2006 (FINDER 1); Ex. 2007 (FINDER 2)).
`
`This demonstrates the criticality of the blood plasma level limitations of the claims.
`
`X)
`
`STATE OF THE RELEVANT ART
`
`A)
`
`Problem To Be Solved
`
`40.
`
`Breast cancer was a problem at the time of the invention.
`
`Approximately 184,200 people in the United States were expected to be diagnosed
`
`with breast cancer in 2000, with over 41,000 deaths expected from the disease. Ex.
`
`2008 (Greenlee) at 6-7. At the time of the invention, a variety of treatments
`
`existed for patients with breast cancer, one of which was endocrine therapies. Such
`
`therapies seek to alter hormone levels in a patient and/or the hormone receptor
`
`levels in the tumor to influence the progression of hormonal dependent breast
`
`cancer. Breast cancer is divided into hormone dependent and hormone
`
`independent subtypes. Approximately 46-77 percent of cases of breast cancer were
`
`considered hormone dependent. Ex. 2009 (Robertson 1996) at 1. The remaining
`
`one-third of breast cancer cases are hormone independent. This classification of
`
`breast cancer as hormone independent and hormone dependent is important
`
`because it guides the clinicians as to which type of treatment may be appropriate
`
`for a particular patient.
`
`41.
`
`Dr. Oleksowicz states that “[h]ormona1-dependent breast cancer in
`
`AstraZeneca Ex. 2002 p. 19
`
`AstraZeneca Exhibit 2136 p. 19
`
`

`

`women was known to correlate with three hormone receptors: estrogen,
`
`progesterone, and human epidermal growth factor receptor 2 (HER2).” Ex. 1004
`
`at 11 37. Estrogen and progesterone receptors are hormone receptors.
`
`Dr. Oleksowicz misclassifies HER2 as a hormone receptor, for as its full name
`
`implies, it is in fact a growth factor receptor. As such, hormone receptors (ER and
`
`PGR) are used to define whether tumors are hormone dependent or independent.
`
`HER2 would be used to select patients for anti-growth factor therapy targeted at
`
`HER2 (e.g., Herceptin®).
`
`42. Of the endocrine therapies available prior to the invention of the ’680
`
`Patent, tamoxifen (“Nolvadex®”) was “the most important hormonal antitumor
`
`agent for breast cancer.” Ex. 2010 (Fornier) at 4; Ex. 2011 (Jordan Supp. 1995) at
`
`1 (“Tamoxifen [] is the endocrine therapy of choice for selected patients with all
`
`stages of breast cancer”).
`
`Indeed, tamoxifen was “the most widely used first-line
`
`hormonal agent in patients with metastatic breast cancer.” Ex. 2012 (Hortobagyi
`
`Cancer Investigation 1998) at 5. “Tamoxifen is a synthetic antiestrogen that blocks
`
`estrogen binding to the estrogen receptor (ER).” Ex. 2010 (Fornier) at 4.
`
`43.
`
`Tamoxifen was known to be a partial agonist/antagonist. It blocked
`
`estrogen from fueling breast cancer tumors in breast tissue. But in other tissues
`
`like bone and the heart it acted like estrogen, providing beneficial protection. Ex.
`
`1018 (Osborne 1995) at 5 . Other references similarly described the importance
`
`AstraZeneca Ex. 2002 p. 20
`
`AstraZeneca Exhibit 2136 p. 20
`
`

`

`and benefits of tamoxifen’s partial agonist/antagonist properties. Ex. 2022
`
`(Minton) at 1; Ex. 2023 (Grese 1998) at 1-2. Tamoxifen was available as a once a
`
`day oral pill.
`
`44.
`
`The success of tamoxifen led to attempts to improve the less desirable
`
`aspects of the drug. A significant clinical problem was that tamoxifen treatment
`
`eventually resulted in tumor resistance. Ex. 2010 (Fornier) at 4 (“‘Unfortunately;
`
`breast cancer in most patients will eventually become resistant to tamoxifen”). In
`
`other words; “most tumours that respond [to tamoxifen] eventually develop
`
`acquired resistance and start to regrow.” Ex. 2013 (Johnston 1997) at 1.
`
`45.
`
`Thus; prior to 2000, there was a need for (1) improved treatments for
`
`hormone dependent breast cancer; and (2) improved treatment options for patients
`
`following tamoxifen failure. Ex. 2014 (Pritchard 1997); Ex. 2015 (Buzdar Clin.
`
`Oncol. 1998); Ex. 2016 (Buzdar Clin. Cancer Res. 1998); Ex. 2013 (Johnston
`
`1997); Ex. 2017 (Jordan 1995); Ex. 2018 (Morrow); Ex. 2019 (Wiebe); Ex. 2020
`
`(Jordan Supp. 1992); Ex. 2021 (Jordan 1992). Metastatic breast cancer is an
`
`incurable condition so an endocrine therapy that could extend a woman’s life
`
`and/or give her a better quality of life was desired.
`
`46. Any treatment would have to be either more effective or at least as
`
`effective but safer than tamoxifen. In addition; it should be as convenient; 118., a
`
`once a day pill. Indeed; physicians thought that patients would not accept any
`
`AstraZeneca Ex. 2002 p. 21
`
`AstraZeneca Exhibit 2136 p. 21
`
`

`

`treatment but a once a day pill. Ex. 2020 (Jordan Supp. 1992) at 4 (“An orally
`
`active agent should be an essential component of any strategy to introduce a new
`
`antiestrogen. Oral tamoxifen is so well tolerated that patients would be reluctant to
`
`consider injections or sustained-release implants as an alternative”).
`
`47. Within the endocrine therapies category, the prior art taught several
`
`different approaches, such as “improved” tamoxifens (other selective estrogen
`
`receptor modulators (SERMs)), aromatase inhibitors (AIS), and oral pure
`
`antiestrogens. Other approaches being used were antiprogestins and high dose
`
`estrogens, the latter which included approved and marketed products at the time.
`
`48.
`
`In my view, Dr. Oleksowicz’s analysis of endocrine therapy is
`
`incomplete (Ex. 1004 at W 41-45), as she ignores whole classes of promising
`
`endocrine therapies, e. g, antiprogestins, progestins and high dose estrogens.
`
`Furthermore, she fails to describe the important advantages of the SERMs currently
`
`used at the time (e.g., bone and cardiovascular effects) but focuses solely on one
`
`uncommon negative effect of tamoxifen (uterine cancer). She also fails to discuss
`
`the extensive research that was ongoing to assess new “designer” SERMs, which
`
`were being developed to optimize the beneficial agonistic properties of SERMs
`
`while minimizing potential harmful agonistic properties. Additionally, Dr.
`
`Oleksowicz fails to recognize that, even beyond the designer SERMs, the aromatase
`
`inhibitors had become the new and preferred focus for pharmaceutical companies
`
`AstraZeneca Ex. 2002 p.