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
`
`U.S. Patent 8,466,139 B2
`
`
`DECLARATIONOF JOHN F. R. ROBERTSON, M.D. INSUPPORT OF
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Exhibit 2002 p. 1
`InnoPharmaLicensing LLC v. AstraZeneca AB IPR2017-00905
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01912
`
`

`

`TABLE OF CONTENTS
`
`1
`
`ID)
`
`II)
`
`IV)
`
`V)
`
`VI)
`
`INTRODUCTION... ccccec cece csseesceeeceseseessecsseessensecssesssensesseenseeseensnsey 1
`
`QUALIFICATIONS AND EXPERIENCE...0....cccccccecceeseeteesetseeteenenes 1
`
`MY UNDERSTANDING OF THE PROCEEDING..........0..0cccccccecceeseeeees 5
`
`MY OPINIONS AND THEIR BASES ......cccccccccccceetcceeeeceteeeeenseessenenees 6
`
`DOCUMENTS CONSIDERED 0......ccccccccceceeteceeesceteteseesesseenseeeenseeseaes 7
`
`THE ?139 PATENT CLAIMS0000. .occcccccccccceccceecnseeseeneensecseeseeteetieesieness 8
`
`VII)
`
`PERSON OF ORDINARYSKILL IN THE ART... cece tees 9
`
`VITD) LEGAL PRINCIPLES 0.0... ccccccccccccce cece cnecseeseenecsseesecssetseessesseesees 10
`
`IX)
`
`X)
`
`CLAIM CONSTRUCTION..0...ccccccccccccccccececeteceeeseeseeteeneesseeeetseeeenins 11
`
`STATE OF THE RELEVANTART 00....occccccccccceecectecsseeseetetneenseeseensess 13
`
`A)—Problem To Be Solved io... cccccccccccccseccseceesseceteeecsseeeseeessaeenses 13
`
`B)
`
`The Prior Art Taught and Provided a Promising Scientific
`Rationale and Experimental Candidates for Many Different
`Systemic Therapy Approachesto Treating Breast Cancer.............. 18
`
`1)
`
`2)
`
`Selective Estrogen Receptor Modulators (SERMs).............. 18
`
`Aromatase Inhibitors (AIS)... ccc ccccecceccteceeseeeeteeeerseenees 20
`
`3) —Pure Antiestrogens........c cc cccccccccccccccecsecesseeeseeessseeeseeneeens 23
`
`C)
`
`D)
`
`4)
`
`Other Endocrine Theraptes.......00...ccccccccccceceeseeeeseeeesseeeses 27
`
` Fulvestrant Was Less Promising Than The Other Available
`Endocrine Agents 1n 2000 0.0... ccccccccceeecsseteseesseeeeeseeeenies 28
`
` Fulvestrant Formulations, Schedule And Route Of
`Administration, Optimal Dose and Pharmacokinetics Were
`Not “Established” In The Prior Art ......0...ccccccccccccccecsseeeseeeeseeeees 36
`
`XT)©REFERENCES CITED IN THE PETITION........0.0ccccccccccccceeeeeteees 39
`
`A)
`
`B)
`
`C)
`
`Howell 1996 (Ex. 1007) .o.ccccccccccc cece ccecsecnseceseseeeceesseeeneeeees 40
`
` McLeskey (Ex. 1008) oo... ccccccccseceesseeetecessseeessesesseesssaeees 48
`
` O’Regan (Ex. 1009) o.oo cccccccececcccteeeesseceseeessseensseeeseeenees 51
`
`XI)
`
`THE CLAIMSOF THE 7139 PATENT ARE NOT OBVIOU................ 52
`
`A)
`
`Ground One: Howell 1996.00.00. cccccctececcecnseeeesessseesesaeees 52
`
`AstraZeneca Exhibit 2002 p. 2
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`1)
`
`Howell 1996 Would Not Have Been A Logical Starting
`Point: It Left Many Questions Unanswered And Was
`Questioned By Researchers At The Time...........0000.0000. 52
`
`B)
`
`Ground Two: Howell 1996 In Combination With McLeskey........ 76
`
`1)
`
`No Reason To Select McLeskey.........0..ccccccccescctceeteeeees 78
`
`(1)
`
`(ii)
`
`|McLeskey Fails To Disclose Nearly All Of The
`Limitations Of The 7139 Patent Claims.........0..00...000.. 78
`
`A Skilled Artisan Would Not Have Considered
`McLeskey Relevant ........00..00ccccccccccccccccssceeessseeeesseeeees 81
`
`(iii) McLeskey Is A Study Of Basic Biology Unrelated
`To Treatment 0.0.00... cccccccccccececeessececesseeeentseeeeseeeeenies 85
`
`(iv) McLeskey Does Not Teach A Successful
`Fulvestrant Formulation ..0..00...000.cccccccccccccsseeesseeeeeeees 90
`
`(v)
`
`The Skilled Artisan Would Not Expect The
`Administration Method Of McLeskey To Succeed......95
`
`2)
`
`3)
`
`No Reason To Combine McLeskey With Howell 1996....... 99
`
`No Expectation That This Combination Would
`Successfully Treat Hormone Dependent Breast Cancer
`Tn Humans 000.00... cc ccc ccceeeeeeceeeeeeeeenseeecessseeesaeesenseees 103
`
`C)
`
`Ground Three: Howell 1996 In Combination With McLeskey
`And OPREGaAN 0 ooo e eee cccce cc ccee ce cecsseessesecesseecesseeesessaeeeeetesenteaeens 110
`
`1)
`
`O’Regan Adds Nothing And Further Supports That One
`Would Not Use The Formulation In McLeskey................. 110
`
`XID)
`
`OBJECTIVE INDICIA DEMONSTRATE THAT THE CLAIMED
`INVENTION IS NONOBVIOUS.......0cccccccccccccse cesses eeseeseeeteeeteeeneees 117
`
`A)
`
`B)
`
`C)
`
`Long-Felt Unmet Need oo... cece ccccccstececeeeneeseeeeseeeesaes 117
`
`Unexpected Results 0... icccccccccccccccsececsseeessesenseeseeeesseeeesaes 120
`
`1)
`
`2)
`
`Improved Clinical Outcomes 0.0.0.0... cccccccceeteeeteeeteee 122
`
`Improved Side Effect Profile... cc ccceeeeeeteee 124
`
`The Invention Method Is The Reason For These Surprising
`ReSUItS 00. cece ccc ccccsececseeenseeeessecessesseeesseeessseesssesesseeeesaeeseeeesaes 128
`
`AstraZeneca Exhibit 2002 p. 3
`
`

`

`TABLE OF CONTENTS
`(continued)
`
`XIV) CONCLUSION 0.00. ec ee ceeeeeeeeeeeeeeseeenaetneeseeeeeeeeneeeneeseeeneeneeens 139
`
`AstraZeneca Exhibit 2002 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 beenretained as an expert witness on behalf of AstraZeneca
`
`AB for the above-captioned inter partes review (IPR).
`
`I am being compensatedat
`
`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.
`
`IT}
`
`QUALIFICATIONS AND EXPERIENCE
`
`3.
`
`My nameis John Robertson, M.D.
`
`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 Exhibit 2002 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 M.B. Ch.B. (Bachelor of Medicine, Bachelor of
`
`Surgery), B.Sc. (Bachelor of Science) and M.D. (in the UK, a postgraduate
`
`research degree in medicine) all from the University of Glasgow.
`
`I 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 dependentbreast cancer, and the use of hormone(i.e.,
`
`endocrine) therapies has been gained through mytraining and personal and
`
`professional experiences. More specifically, these experiences include my own
`
`medical practice for over thirty-five years, research that I have conducted (both
`
`laboratory research and clinical trial research), consultancy positions I haveheld,
`
`and advisory boards and committees that I have served on or been a memberof.
`
`In my medical practice, I have gained extensive experience overthelast thirty-five
`
`years with every class of approved endocrine agent used to treat hormonal
`
`dependent breast cancer. Over mycareer, I have treated thousands of women with
`
`hormone dependentbreast cancer.
`
`AstraZeneca Exhibit 2002 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 changesin breast cancers,
`
`which matchesour therapeutic clinical trials in advanced disease. I am currently
`
`one of the three Chief Investigators on the largest trial of peri-operative endocrine
`
`AstraZeneca Exhibit 2002 p. 7
`
`

`

`therapy in the world (the POETICtrial).
`
`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.
`
`I have 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 andclinical 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 lecturesat 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 knownas endocrine therapies.
`
`AstraZeneca Exhibit 2002 p. 8
`
`

`

`10.
`
`J 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 have
`
`reviewed manuscripts for a number ofjournals and was the founding Editor-in-
`
`Chief of the journal, Breast Cancer Online.
`
`11.
`
`J have extensive teaching experience, including in the subject of
`
`breast cancer.
`
`In addition, I have supervised a number of under- and post-
`
`eraduate medical trainees and non-clinical scientists, including nearly twenty such
`
`physicians and students during the past five years.
`
`12.
`
`J have significant experience in the areas of breast cancer diagnosis
`
`and treatment, breast cancer clinical trial research, hormonal dependent, or
`
`hormonereceptor positive, breast cancer, and hormonal therapies. Therefore,I
`
`believe that I am qualified to render the opinionsset forth in this declaration.
`
`13.
`
`Inthe past four years, I have testified in the following litigation:
`
`AstraZeneca Pharmaceuticals LP v. Sagent Pharmaceuticals, Inc., No. 14-cv-
`
`03547-RMB-KMW(D.N.J.).
`
`Il) MY UNDERSTANDING OF THE PROCEEDING
`
`14.
`
`[have been informed that this proceeding is an inter partes review
`
`AstraZeneca Exhibit 2002 p. 9
`
`

`

`(“IPR”) before the Patent Trial and Appeal Board of the United States Patent and
`
`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 groundsthat the patent is the same as or rendered obvious in view ofthe
`
`priorart.
`
`15.
`
` Jhave been informed that InnoPharma Licensing, LLC
`
`(“InnoPharma’’)filed a Petition requesting IPR (“Petition’’) of U.S. Patent No.
`
`8,466,139 (the ’139 Patent”), which issued to John R. Evans and Rosalind U.
`
`Grundy on June 18, 2013 andis assigned to AstraZeneca AB.
`
`I have reviewed the
`
`Petition, and understand that it alleges that claims 1,3, 10-11, 13 and 20 of the
`
`139 Patent are unpatentable over Howell 1996 (Ex. 1007) and, alternatively, over
`
`the combination of Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008), and the
`
`combination of Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008) and O’Regan
`
`(Ex. 1009).
`
`IV) MY OPINIONS AND THEIR BASES
`
`16.
`
`[have been asked to give my opinion on whetheror not a person of
`
`ordinary skill in the art (“POSA”) would understand claims 1, 3, 10-11, 13 and 20
`
`of the °139 Patent to be rendered obviousby: (1) Howell 1996 (Ex. 1007); (2) the
`
`combination of Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008); or (3) the
`
`combination of Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008) and O’Regan
`
`AstraZeneca Exhibit 2002 p. 10
`
`

`

`(Ex. 1009). Most of my opinionsherein are a direct repeat of the opinions in my
`
`declaration submitted in support of AstraZeneca’s Preliminary Patent Owner
`
`Response in Mylan Pharmaceuticals Inc. v. AstraZeneca AB, Case IPR2016-01325
`
`(P.T.A.B. Oct. 6, 2016) attached hereto for the Board’s convenience as Ex. 2136
`
`(Robertson Mylan Decl.). Critically, and as described in more detail throughout
`
`this declaration, InnoPharmahasessentially presented the same evidence as
`
`Mylan. Furthermore, InnoPharma’s experts did not address many of the arguments
`
`in my previous declaration. At the same time, I think it 1s important to note that
`
`the majority of the opinions in InnoPharma’s expert declarations are conclusory
`
`and/or wholly unsupported by any evidence(e.g., in many instances, full pages of
`
`opinions do not contain a single citation to literature or merely cite to other expert
`
`declarations (similarly unsupported)).
`
`I have tried to note in my declaration (1) the
`
`repetition by InnoPharmaof evidence previously considered in the Mylan IPR and
`
`also (2) the lack of support throughout InnoPharma’s declarations, but both are so
`
`pervasive throughout the declarations that I feel it is necessary to highlight upfront.
`
`17.
`
`As part of this opinion, I considered the level of ordinary skill in the
`
`art around January 2000, which representsthe filing date of GB 0000313, to which
`
`the °139 Patent claimspriority.
`
`V)
`
`DOCUMENTS CONSIDERED
`
`18.|The materials that I have considered, in addition to the exhibits to the
`
`AstraZeneca Exhibit 2002 p. 11
`
`

`

`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 POSAin theart as
`
`defined below.
`
`VI) THE ’139 PATENT CLAIMS
`
`19.
`
`J have been informed that the priority date of the 7139 Patent was
`
`January 10, 2000.
`
`20.
`
`Independent claims | and 11 of the ’139 Patent are provided below.
`
`1[11]. 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 [consisting
`
`essentially of]:
`
`about 50 mgml"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 ofat least 2.5 ngml'for at least two weeks.
`
`21. Dependent claims 3, 10, 13 and 20 limit claims 1 and 11 to a method:
`
`AstraZeneca Exhibit 2002 p. 12
`
`

`

`wherein formulation comprises [consists essentially of]: about 10% w/v of ethanol;
`
`about 10% w/v of benzyl alcohol; and about 15% w/v of benzyl benzoate (claims 3
`
`and 13); and wherein the hormonal dependent benign or malignant disease of the
`
`breast or reproductivetract is breast cancer and the blood plasma fulvestrant
`
`concentration is attained for at least 4 weeks (claims 10 and 20).
`
`VID) PERSON OF ORDINARYSKILL IN THE ART
`
`22.
`
`Jhave been asked to provide my opinion on the novelty and
`
`obviousnessof the asserted claims, from the perspective of a person of ordinary
`
`skill in the relevant art. The skilled person with respect to the ?139 Patent is a
`
`person having a bachelor’s or advanced degree in a discipline such as pharmacy,
`
`pharmaceutical sciences, endocrinology, medicineor 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 process1s
`
`complicated and multidisciplinary, it would require a team of individuals
`
`including, at least, medical doctors, pharmacokineticists, and formulators.
`
`23. Asconsidered from the perspective of the medical doctor memberof
`
`that team, the invention of the ’139 Patent is novel, and not obvious, for the
`
`following reasons.
`
`AstraZeneca Exhibit 2002 p. 13
`
`

`

`VIII) LEGAL PRINCIPLES
`
`24.
`
`Iam nota lawyer, and I have relied on the explanations of counsel for
`
`an understanding of certain principles of U.S. patent law that govern the
`
`determination of patentability. The discussion set forth below regarding the law of
`
`obviousness1s intended to be illustrative of the legal principles I considered while
`
`preparing my declaration, and not an exhaustivelist.
`
`25.
`
`Jam informed by counsel that InnoPharma must show unpatentability
`
`by a preponderance of the evidence, and preponderanceof the evidence means
`
`“more probable than not.” I understand that to institute an inter partes review
`
`InnoPharma must show that there 1s a reasonable likelihood that it would prevail in
`
`an inter partes review.
`
`26.
`
`Iam informed by counselthat for a patent claim to be invalid as
`
`anticipated by a priorart 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.
`
`27.
`
`Iam informed by counselthat for an invention to be obvious, the
`
`patent statute requires that the differences between the invention and the priorart
`
`be such that the “subject matter as a whole would have been obviousat the time
`
`the invention was madeto a person of ordinary skill in the art to which such
`
`subject matter pertains.”
`
`AstraZeneca Exhibit 2002 p. 14
`
`

`

`28.
`
`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.
`
`29.
`
` Junderstand that even in circumstances where each componentof an
`
`invention can be foundin the priorart, 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.
`
`30.
`
`For the method of treatment to be obvious, it must have been among a
`
`finite numberof identified, predictable solutions to the problemsat hand.
`
`31.
`
`For the reasons explained below, in my opinion, InnoPharma has not
`
`shown that there is a reasonable likelihood that it would prevail in an inter partes
`
`review of claims 1, 3, 10-11, 13 and 20 of the 7139 patent.
`
`IX) CLAIM CONSTRUCTION
`
`32.
`
`All of the claims of the ’139 Patent are expressly directed to methods
`
`of treatment. The methods of treatment include choice of an active ingredient, a
`
`method of administration (1.e., a combination of excipients and active injected
`
`intramuscularly), and the amountofthe active to be delivered to the blood in a
`
`AstraZeneca Exhibit 2002 p. 15
`
`

`

`sustained release fashion to treat hormonal dependent disease of the breast and
`
`reproductivetract.
`
`33. A medical doctor would understand that the blood plasmalevel
`
`limitations of the °139 Patent claims are indeed limitations of the claims and
`
`should be given their plain and ordinary meaning. These limitations are in claims
`
`1,3, 10-11, 13 and 20: “wherein the method achieves a blood plasma fulvestrant
`
`concentration of at least 2.5 ngml'' for at least two weeks”; and “wherein the blood
`
`plasma fulvestrant concentration is attained for at least four weeks.” A clinician
`
`would understand these limitations to mean that the specified blood plasma
`
`fulvestrant concentration of at least 2.5 ngml”is achieved and maintained for the
`
`specified amountof time. This is consistent with the Board’s finding in Mylan
`
`Pharmaceuticals Inc. v. AstraZeneca AB, Case IPR2016-01325, Paper No. 11
`
`(P.T.A.B. Dec. 14, 2016) (Ex. 1011) which InnoPharma doesnot dispute. Ex.
`
`1011 (PTAB Decision) at 18 (“[W]e interpret ‘achieves’ in the wherein clauses as
`
`meaning that the concentration of fulvestrant in a patient’s blood plasmaisat or
`
`above the specified minimum concentration for the specified time period.”’);
`
`Petition at 18. Further, these limitations give meaning to and provide defining
`
`characteristics of the method of treatment. Indeed, as the Board previously held,
`
`“rather than merely stating the result of intramuscularly administering the recited
`
`formulation, [] the wherein clause dictates both the administration duration and
`
`AstraZeneca Exhibit 2002 p. 16
`
`

`

`dose of the formulation,i.e., an amount sufficient to provide a therapeutically
`
`significant blood plasmafulvestrant concentration ofat least 2.5 ngml”’”for the
`
`specified amount of time. Ex. 1011 at 17.
`
`InnoPharmadoes notdispute this
`
`finding. Petition at 18-19.
`
`X)
`
`STATE OF THE RELEVANT ART
`
`A)
`
`Problem To Be Solved
`
`34.
`
`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 hormonelevels in a patient and/or the hormone receptor
`
`levels in the tumorto influence the progression of hormonal dependentbreast
`
`cancer. Breast cancer1s 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 dependentis important
`
`because it guides the clinicians as to which type of treatment may be appropriate
`
`for a particular patient.
`
`AstraZeneca Exhibit 2002 p. 17
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`

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`35. Of the endocrine therapies available prior to the invention of the ’139
`
`Patent, tamoxifen (“Nolvadex®”) was“the most important hormonalantitumor
`
`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 withall
`
`stages of breast cancer.”).
`
`Indeed, tamoxifen was “the most widely usedfirst-line
`
`hormonal agent in patients with metastatic breast cancer.” Ex. 2012 (Hortobagyi
`
`CancerInvestigation 1998) at 5. “Tamoxifen is a synthetic antiestrogen that blocks
`
`estrogen bindingto the estrogen receptor (ER).” Ex. 2010 (Fornier)at 4.
`
`36.
`
`Tamoxifen was knownto 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.
`
`1039 (Osborne 1995) at 5. Other references similarly described the importance
`
`and benefits of tamoxifen’s partial agonist/antagonist properties. Ex. 2022
`
`(Minton) at 1; Ex. 2023 (Grese 1998) at 1-2. Tamoxifen wasavailable as a once a
`
`day oralpill.
`
`37.
`
`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 becomeresistant to tamoxifen.”’). In
`
`other words, “most tumours that respond [to tamoxifen] eventually develop
`
`AstraZeneca Exhibit 2002 p. 18
`
`

`

`acquired resistance andstart to regrow.” Ex. 2013 (Johnston 1997)at 1.
`
`38.
`
`Thus, prior to 2000, there was a need for (1) improved treatments for
`
`hormone dependentbreast cancer, and (2) improved treatment options for patients
`
`following tamoxifen failure. Ex. 2014 (Pritchard 1997); Ex. 2015 (Buzdar Clin.
`
`Oncol. 1998); Ex. 1050 (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 canceris 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.
`
`39. Animproved treatment would have to be either more effective orat
`
`least as effective but safer than tamoxifen. In addition, it should be as convenient,
`
`1.e., a once a day pill. Dr. Harris disagrees, instead arguing (without anyliterature
`
`support) that “IM injections are [] favored because they ensure compliance” and
`
`“patients will tolerate pain for lifesaving drugslike cancer treatments.” Ex. 1015
`
`at 99 77, 157-158. This is contrary to the literature at the time which, indeed,
`
`indicates that physicians thought that patients would not accept any treatment but a
`
`once a day pill. Ex. 2020 (Jordan Supp. 1992) at 4 (“An orally active agent should
`
`be an essential componentof 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.”). Dr. Harris describes
`
`AstraZeneca Exhibit 2002 p. 19
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`

`

`this in emotive language “[w]hen given the choice is between an IM injection that
`
`may cause pain but can cure cancer whereother treatments have failed, patients
`
`will accept this tradeoff.” Ex. 1015 at § 158. Advanced breast cancer in 2000 and
`
`even up to the present day is an incurable condition and so this “choice”that Dr.
`
`Harris describesis nota realistic clinical choice which either the patient or doctor
`
`have been or are currently faced with and, as noted above, it was reported at the
`
`time that oral medication was “well tolerated” and an “essential componentof any
`
`strategy to introduce a new antiestrogen.” Ex. 2020at 4.
`
`40. 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.
`
`41.
`
`In my view, InnoPharma’s experts, Drs. Harris and El-Ashry provide
`
`an incomplete analysis of endocrine therapy (Ex. 1015 at 4 69-103; Ex. 1014 at 7
`
`24-31), for at least the following reasons:
`
`e They ignore whole classes of promising endocrine therapies, e.g.,
`
`antiprogestins, progestins and high doseestrogens.
`
`e They fail to describe the important advantages of the SERMscurrently
`
`used at the time (e.g., cardiovascular effects).
`
`AstraZeneca Exhibit 2002 p. 20
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`

`

`e They focus solely on an uncommon negative effect of tamoxifen
`
`(uterine cancer). This is somewhat surprising since O’Regan whom
`
`InnoPharmahasreferencedstated “[i]ndeed, the International Agency
`
`for Research on Cancer IARC), an agency of the World Health
`
`Organization, recently stated that no patient should stop taking
`
`tamoxifen because of concerns aboutthe risk of endometrial cancer
`
`and that the benefits of tamoxifen use far outweigh any risks.” Ex.
`
`1009 at 1. In other words, while endometrial cancer was an
`
`acknowledged risk of tamoxifen treatment it was not deemed sufficient
`
`risk to stop any patient from taking tamoxifen.
`
`e They fail 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.
`
`e They fail to recognize that, even beyond the designer SERMs,the
`
`aromatase inhibitors had become the new and preferred focus for
`
`pharmaceutical companies andclinical researchers seeking new and
`
`more effective endocrine agents, including the second andthird
`
`generation aromatase inhibitors that were being developed for various
`
`clinical indications in breast cancer.
`
`AstraZeneca Exhibit 2002 p. 21
`
`

`

`e
`
`In terms of pure antiestrogens, they do not acknowledgethe other pure
`
`antiestrogens being developed immediately prior to 2000, of which
`
`one in particular, EM-800, was more potent, orally active, had phase II
`
`clinical data, and had started phaseII clinical trials.
`
`42.
`
`For the reasons described above and below,a skilled artisan would not
`
`have begun with fulvestrant as the active ingredient, nor would a skilled artisan
`
`have expected such an approachto succeed.
`
`B)=‘The Prior Art Taught and Provided a Promising Scientific
`Rationale and Experimental Candidates for Many Different
`Systemic Therapy Approaches to Treating Breast Cancer
`
`1)
`
`Selective Estrogen Receptor Modulators (SERMs)
`
`43.
`
`Given the success of tamoxifen and the benefits of its mixed
`
`agonist/antagonist activity, one of the promising areas wasthe search for a new
`
`tamoxifen with a better balance of activities. As of the date of the invention,
`
`several SERMshad already received FDA approval, opportunities existed to
`
`improve the most widely used SERM, tamoxifen, and many promising SERMs
`
`were in development.
`
`44.
`
`Contrary to Dr. Harris’s assertion that some of tamoxifen’s agonist
`
`activity that was not beneficial (the rare instances of endometrial cancer) pointed to
`
`pure estrogen antagonists, Ex. 1015 at 4 87, in reality, at the time of the invention,
`
`many scientists and pharmaceutical companies were attempting to develop better
`
`AstraZeneca Exhibit 2002 p. 22
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`

`

`SERMsbyseeking a superior balance between antiestrogen activity and estrogen
`
`agonist activity, instead of entirely eliminating agonist activity. The prior art
`
`explained exactly that: “[t]he finding of endometrial cancer resulting from
`
`tamoxifen treatment has led researchers to investigate new agents that retain
`
`favorable estrogenic properties in specific tissues and display antiestrogen activity
`
`on the endometrium. Such research has generated the concept of selective estrogen
`
`receptor modulators (SERMs) that mediate either estrogen agonist or estrogen
`
`antagonist effects in different tissues.” Ex. 2022 (Minton) at 1.
`
`45.
`
`In fact, the focus on improving the agonist-antagonist balance of
`
`tamoxifen led to an “explosion of research to understand the molecular basis for
`
`this specificity and a race to develop these ‘designer estrogens’ or Selective
`
`Estrogen Receptor Modulators (SERMs)as pharmaceutical products.” Ex. 2023
`
`(Grese 1998)at 2.
`
`46.
`
` Asof the date of the invention, other SERMsthat had received FDA
`
`approval included toremifene, which was found to be as efficacious as tamoxifen in
`
`the first-line setting (Ex. 2022 (Minton) at 2), and raloxifene for osteoporosis (Ex.
`
`2024 (Hortobagyi New Eng. J. Med. 1998) at 9). Many promising SERMswere
`
`also knownto be in clinical developmentat the time including idoxifene (in a phase
`
`I clinical trial “was well tolerated with only mild toxicities, and the patients had a
`
`partial response rate and stable response rate of 14% and 29%, respectively,
`
`AstraZeneca Exhibit 2002 p. 23
`
`

`

`ranging from 1.4 to 14 months”), droloxifene (multiple phase II trials had been