`
`
`
`EFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner,
`
`V.
`
`ASTRAZENECA AB
`
`Patent Ownerk
`
`
`
`US. Patent Nor 8,329,680
`
`DECLARATION OF LESLIE OLEKSOWICZ, M.D.
`
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`
`US. PATENT NO. 8,329,680
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 1
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`"I.
`Astrafleneca Exhibit 2166 p.
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`
`
`TABLE OF CONTENTS
`
`I‘
`
`QUALIFICATIONS AND BACKGROUND .................................................................. S
`
`A.
`
`B,
`
`C1
`
`Education andExpenence 5
`
`Materials Considered ....................................... . ..................................................... 9
`
`Scope of Work ...................................................................................................... 9
`
`SUMIWARY 0F OPINIDNS ........................................................................................... 10
`
`LEGAL STANDARDS ................................................................................................... 1 1
`
`PERSDN OF ORDINARY SKILL IN THE ART ........................................................... 13
`
`US. PATENT N0. 8,329,680(“1‘P[E ’680 PATENT”) [Exl 100]] ................................ 14
`
`CLAIM CONSTRUCTION ............................................................................................. 17
`
`II.
`
`III,
`
`IV,
`
`V.
`
`V1.
`
`VII,
`
`BACKGROUND OF BREAST CANCER AND TREATMENTS ................................. 18
`
`Al
`
`13.
`
`Hormone Receptor Pesitive (HR+) Breast Cancer in Human Females ............... 18
`
`Treatment Options for HR+ Breast Cancer in Warner] Prior t0 2000 .................. 19
`
`VIII,
`
`SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ................................. 22
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`I.
`
`J;
`
`K.
`
`L.
`
`McLeskey 1998[Ex1 1005] .................................................................................. 22
`
`Hewell 1996 [EL 1006] ................................................................................... 23
`
`Dukes 1%"? [Ex 100?] ........................................................................................ 26
`
`Wakeling 1991 [Ex 1008]27
`
`Wekeling 1992 [Ex 1009] ................................................................................... 28
`
`Dukes 1992 [Ex 1025] ........................................................................................ 30
`
`Wekeling 1993 [Ex 1028] ................................................................................... 31
`
`Dukes 1993 [EL 1026]
`
`33
`
`DeFriend 1994 [Ex 102T] .................................................................................. 35
`
`Osbeme 1995 [Ex 1018] ..................................................................................... 36
`
`Howell 1995 [Ex 1012] ....................................................................................... 38
`
`O’Regan 1998 [Ex 1013] .................................................................................... 39
`
`1X1
`
`FULVESTRANT WAS A WE'LL UNDERSTOOD COMPOUND BY
`
`JANUARY 10,, 2000 ........................................................................................................ 40
`
`A,
`
`13.
`
`Cl
`
`Fulvestrant Was Well Known in the Prim Art. ................................................... 4D
`
`Fulvestrant's Pharmacological Usefulness Was Well Known in the Prior
`Art, ................................................................................................................. . ..... 41
`
`Fulvestrant’s Pre~Clinieel Anti~Tumor and Antianerotrophie Effects
`Were Well Known in the Prior Art. ..................................................................... 42
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 2
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`Astraleneca Exhibit 2166 p. 2
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`
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`D,
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`El
`
`F:
`
`Fulvestrant’s Clinical Efficacy in Human Females With Breast Cancer
`Was Well Known in the Prior Art.................... u................................................... 47
`
`Fulvestrant‘s Efficacy in Human Females with ER—I- Breast Cancer was
`Well Known in the Prior Art................................................................................ 48
`
`Fulvestrant Formulations and Its Intramuscular Route of Administration
`
`Were Established in the Prior Art ........................................................................ 50
`
`‘l
`
`.
`
`2.
`
`3w
`
`£1.
`
`S.
`
`6,
`
`7.
`
`Indication ............................................. . ................................................... SO
`
`Excipients and Percent wfv Concentrations"..,,..,.m..."......_l......m......,4., 51
`
`Route and Schedule of Administration .................................................... 52
`
`Dose of Fulvestrant As-Fonnulated ........................................................ 54
`
`Divided Dose
`
`55
`
`Fulvestrant Concentration of About 50 mgml‘] ....................................... Se
`
`Fulvestrant Total Dose of‘ZSO mg
`
`56
`
`X.
`
`UNPATENTABILITY OF THE ’680 PATENT ............................................................. S7
`
`A,
`
`Claims ‘1»20 of the ”680 patent were obvious over McLeskey. .......................... 58
`
`].
`
`ill
`
`3w
`
`4‘
`
`S.
`
`6,
`
`7.
`
`8.
`
`McLeskey disclosed the claimed fulvestrant formulation. ...................... 58
`
`The prior art disclosed the use of fulvestrant to treat human
`females having HR+ breast cancer: ......................................................... 59
`
`The prior art disclosed delivering fulvestrant intramuscularly to
`humans. ................................................................................................... 60
`
`The prior art disclosed administering a formulation having a
`concentration of about 50 mglml of f‘ulvestrant to human females
`having breast cancer................................................................................. 61
`
`A POSA knew from the prior art to administer to humans a 5 ml
`volume of formulated fulvestrant............................................................. 62.
`
`A POSA would have understood that the 5 ml of formulated
`fulvestrant could have been administered to a human female in a
`
`divided dose. ............................................................................................ 6'3
`
`A PDSA would have understood that the fulvestrant fonnul ation
`
`could have been administered monthly .................................................... 6d
`
`A POSA would have understood that the claimed blood plasma
`fulvestrant concentrations were not limitations of the patent ..
`
`65
`
`Bl
`
`All claims of the “680 patent were obvious over Howell 1996 in View of
`McLeskey ......................................................... , ................................................... 67
`
`l-
`
`Howell 1996 disclosed using fulvestrant to treat breast cancer in a
`human female ........................................................................................... 68
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 3
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`Astraleneca Exhibit 2166 p, 3
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`
`
`2.
`
`3»
`
`44
`
`5.
`
`61
`
`7,
`
`8.
`
`Howell 1996 in View of MoLeskey disclosed administering
`McLeskey‘s complete fulvostmnt fomtulation to a human,
`particularly a human female.................................................................... (39
`
`Howell 1996 in View of MoLe-skey disclosed administering 5 ml of
`fulvestrant intramuscularly to a human female with breast cancer.......... 70
`
`A POSA would have known to administer the 5 ml of formulated
`
`fulvestrant in a divided dose. .................................................................. 72
`
`A POSA would havo known to administer the fulvestrant
`
`formulation to a human monthly ............................................................. 73
`
`Howell 1.996 in View of MoLeskey disclosed administering a
`fhlvestrant fonnulation of 50 mgfml concentration to a human
`female with breast cancer......................................................................... 74
`
`A POSA would have understood that the claimed blood plasma
`fiilvestrant concentrations were not limitations of the patent. ................. 75
`
`Even to the extont the claimed blood plasma fulveatrant
`concentrations are limitations? they were disclosed by Howell
`@963, alone or in View of McLeskay: ...................................................... 76
`
`XL
`
`CONCLUSION ............................................................ i ................................................... 78
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 4
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`Astraleneca Exhibit 2166 p 4
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`
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`l_
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`Education and Experience
`
`My name is Leslie Oleksowicz.
`
`I am a physician and oncologist with
`
`over thirty years of experience, spending over 25 years in clinical practice.
`
`Throughout my career I have conducted clinical research in the field of Medical
`
`Oncology, participated in over 100 clinical trials, and written over 75 publications
`
`in my area of expertise” I have treated hundreds of patients with all stages and
`
`subtypes of breast cancer, and I directed a basic science laboratory research effort
`
`from 1992—2000 which focused on breast cancer adhesive receptors and their role
`
`in tumor metastases In my role as CEO of Leslie Oleksowicz, MD... LLC, I have
`
`also acted as a consultant to provide strategic intelligence to the financial and
`
`pharmaceutical
`
`industries1 advising expertise to biotech and EMR (electronic
`
`health medical record) start-up companies and expert skills in legal cases involving
`
`intellectual property in the context of oncologic phannaccuticals. My full
`
`curriculum vitae (CV) is attached hereto as Exhibit A and is incorporated herein.
`
`2.
`
`I received my BA. in Biological Sciences from Amherst College in
`
`1978, graduating mogno cum {nude and Phi Beta Kappa.
`
`I received my hill from
`
`Tufts University School of Medicine in 1982.
`
`.1.
`
`After finishing medical. school,
`
`[ completed postgraduate training
`
`Internship and Residency Programs in Internal Medicine in 1985 at the Albert
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 5
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`Astraleneca Exhibit 2166 1:). 5
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`
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`Einstein College of Medicine (Montefiore University Hospital, Bronx, Nfi‘ifi) and
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`was certified by the American Board of Internal Medicine (ABIM) in 1988.
`
`Additionally, I received research and clinical training (Fellowship) in the medical
`
`specialties of Hematology, completed in 1987 at Mount Sinai Medical Center
`
`(New York, NY.) and Medical Oncology completed in 1989 at Mount Sinai
`
`Medical Center (New York, NY),
`
`I was certified by the AIIM in Medical
`
`Oncology in 1989. From 198942015,
`
`I held faculty positions as an academic
`
`oncologist at Mount Sinai Medical Center,
`
`(New York, NLY.), Montefiore
`
`University Hospital, (Bronx, NY), Roswell Park Cancer Institute (Buffalo, NY),
`
`University of Cincinnati Cancer Institute (Cincinnati, OH), Saint Louis University
`
`Cancer Center (Saint Louis, MO) and the Dana Farber Cancer Institute (Boston,
`
`MA).
`
`4_
`
`I currently serve as Chief Executive Officer of Leslie Oleksowicz,
`
`MD, LLC, which
`
`provides
`
`strategic
`
`intelligence
`
`to the
`
`financial
`
`and
`
`phannaceutical
`
`industries, advising expertise to biotech and EMR (electronic
`
`health medical record) start-up companies and expert skills in legal cases involving
`
`intellectual property in the context of oncologic pharmaceuticals.
`
`5.
`
`I have been a member of a number of profssiona] societies, including
`
`the American Society of Clinical Oncology (cun‘ent member),
`
`the American
`
`Society of Hematology, SWOG (a worldwide network of researchers that designs
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 6
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`Astraleneca Exhibit 2166 pt 6
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`
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`and conducts cancer clinical trials), the American College of Physicians, and the
`
`National Kidney Cancer Asseciation (current member, editorial advisory board).
`
`6,
`
`I have served as an editer for the following journals: Cancer,
`
`American Journal of Medical Sciences, Seuthem Journal of Medicine, Journal of
`
`Urclegy, Kidney Cancer, and Transfusion.
`
`7.
`
`l have extensive experience treating patients with breast cancer;
`
`including honnnne receptar—pcsitive breast cancers. During my 25 years in
`
`academic practice} I have directed beth basic science and clinical investigatiens in
`
`the area of hormone positive breast cancer. From vl992w—2ODDs lied a basic science
`
`research effert studying adhesive glycepretein receptors expressed by hermene—
`
`positive breast tumor cells that participated in the metastatic precess. As a
`
`principal member of an institutien-wide breast malignancy affinity group,
`
`I
`
`facilitated collaboratiens amongst clinicians and basic science investigators. My
`
`laboratory research was funded by several competitive grant~awarding grcups,
`
`including the American Cancer Society, the Elsa U. Pardee Foundation, Sande:
`
`Phannaceuticals, and the Roswell Park Alliance Foundatiom with the resultant
`
`research
`
`generating
`
`ll
`
`publications
`
`in
`
`top-tier peer-reviewed journals.
`
`Additionally, as an invited guest speaker, I presented my work at multiple NCI—
`
`designated cancer centers including the Albert Einstein Cancer Centerfi the Mcunt
`
`Sinai Medical Center, the Grace Cancer Drug Center and the Roswell Park Cancer
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 7
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`Astraleneca Exhibit 2166 p, 7
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`
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`Institute.
`
`In 2003, when I was recruited to the University of Cincinnati Cancer
`
`Institute, I directed a clinical trials program, focusing in large part on hormone
`
`receptor-positive breast cancer. Over a nine-year interval from 2003~2012, l was
`
`principal investigator of 12 breast cancer clinical trials. From 8/2008 - 5/2012: I
`
`was principal investigator of the SWOG 1222 trial entitled, Phase 1]] Randomized
`
`mm QfAnastmzoZe vs. Aaostrazoie (Md Fttives'tram as First Line Therapy in Post-
`
`Menopnusal Women with Metastatic Breast Comer. and from 10/2011 .. 5/2012, 1
`
`was pfincipal investigator in the SWOG 8100'? trial, which investigated tamoxifen,
`
`letrozole, anastrozole and exemestane with or without chemotherapy in patients
`
`with invasive breast cancer. Additionally. I directed many other clinical trials
`
`evaluating a variety of investigational agents in the setting of early and advanced
`
`hormone receptor—positive breast cancer.
`
`8.
`
`l have also participated in over 100 clinical trials. in over $0 of which
`
`I served as the Principal Investigator. The majority of these involved evaluating
`
`different pharmaceutical interVentions for cancer treatment.
`
`I have served as
`
`Principal Investigator on studies evaluating fulvestrant and tamoxifen as treatments
`
`for breast cancer in women.
`
`9.
`
`I have received a number of awards for my work.
`
`I was awarded the
`
`l-lampden Scholarship during medical school on the basis of my GPA. While
`
`directing a basic science laboratory research effort at the Albert Einstein Cancer
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 8
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`Astraleneca Exhibit 2166 p. 8
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`
`
`Center,
`
`I was the recipient of multiple research grants including an American
`
`Cancer Society and a National Leukemia Fountain Research Award, grants from
`
`multiple pharmaceutical companies including Schering, Chiron, Bristol, Roche,
`
`Novartis, and Sandoz, and multiple research grants from national foundations
`
`including The Irvin A. Hansen Memorial Foundation, the Caro] Solov Abbani
`
`Foundation, the Pardee Foundatiorn and the Bruce Cuvelier Endowed Research
`
`Fund. Finally, I was the recipient of a third-prize award at the annual basic science
`
`investigator’s symposium at Montefiore University Hospital in 1997, and earned a
`
`certificate of recognition for outstanding clinical care at Roswell Park Cancer
`
`Institute in 2002.
`
`10.
`
`I have published my work, and have been named as author or co-
`
`author on over 75 articles and abstracts, predominantly concerning cancer
`
`pathways and treatments.
`
`B. Materials Considered
`
`11.
`
`In connection with forming my opinions and drafting this declaration,
`
`I considered my experience, education, and training, as well as the materials
`
`identified in this declaration and listed in Exhibit B, attached hereto.
`
`C.
`
`Scope of Work
`
`12.
`
`I have been retained by counsel.
`
`for Mylan Phannaceuticals Incl
`
`(“‘Mylanfl in connection with this matter.
`
`I am being compensated at my usual
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 9
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`Astraleneca Exhibit 2166 p. 9
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`
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`rate of $650 per hour for my work on this matter. My compensation does not in
`
`any way depend on the outcome of this proceeding.
`
`[1.
`
`SUMMARY OF OPINIONS
`
`13.
`
`It is my opinion that, for the reasons stated below, claims 1-20 of the
`
`US. Patent No. 8,329,680 (“the ’680 patent") were obvious over McLeskey [Ex
`
`1005].
`
`Independent claims 1 and 20 of the ’630 patent focus on a dosing regimen
`
`of a certain fulvestrant fonnulation, administered as an intramuscular (“im”)
`
`injection,
`
`to treat humans with benign or malignant diseases of the breast or
`
`reproductive tract, such as breast cancer. The fulvestrant compound was already
`
`known to treat at least hormonal dependent breast cancer in women, and the
`
`claimed formulation was specifically disclosed in McLeskey. The remaining
`
`elements of the claims,
`
`including the route and dose of administration, were
`
`already known, and the cited blood plasma fulvestrant concentrations are not
`
`limitations to the method of treatment.
`
`14.
`
`It is also my opinion that claims lm—20 of the ”680 patent were obvious
`
`
`over Howell 1996 [Ex 1006] in View of McLeskey [Ex 1005]. Howell 1996
`
`disclosed a long—acting fulvestrant fonnulation in a castor oil vehicle, administered
`
`to human females with breast cancer via a 5 ml monthly intramuscular injection of
`
`250 mg. Howell 1996 disclosed that the fulvestrant treatment was efficacious,
`
`well-tolerated, and achieved predicted therapeutic concentrations of fulvestrant for
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 10
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`AstraZeneca Exhibit 2166 p. 10
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`
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`1 month following a single intramuscular injection. A POSA investigating prior
`
`art longvtenn and/or castor oil-based fonnulations of fulvestrant would be aware of
`
`or find McLeskey, which disclosed the exact formulation claimed in the ’680
`
`patent. Therefore, the disclosure of Howell 1996 combined with the specific
`
`formulation of McLeskey renders obvious claims 1w20 of the ’680 patent.
`
`1]]. LEGAL STANDARDS
`
`15.
`
`I have been infonned regarding the relevant legal principles.
`
`I have
`
`used my understanding of those principles in preparing and forming my opinions
`
`set forth in this declaration. My understanding of those legal principles is
`
`summarized below.
`
`16.
`
`I have been told that Mylan bears
`
`the burden of proving
`
`unpatentability by a. preponderance of the evidence.
`
`1 am infonned that this
`
`preponderance of the evidence standard means that Mylan must Show that
`
`unpatentability is more probable than not.
`
`I have taken this principle into account
`
`when forming my opinions here.
`
`17.
`
`I have also been told that claims should be construed given their
`
`broadest reasonable interpretation in light of the specification, from the perspective
`
`of a person of ordinary skill in the art at the time of the invention.
`
`’18.
`
`I have been infomed that the claim scope of a method claim is not
`
`limited by a ‘thereby” or “wherein” clause that simply expresses the intended
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 11
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`AstraZeneca Exhibit 2166 p. 1 l
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`
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`result of a process step positively recited.
`
`If the whereby clause does not inform
`
`how the method is carried out, the whereby clause is generally not given patentable
`
`weight.
`
`19.
`
`I have been told that the concept of patent obviousness involves four
`
`factual
`
`inquiries: (l) the scope and content of the prior art; (2) the differences
`
`between the claimed invention and the prior art; (3) the level of ordinary skill in
`
`the art; and (£1) secondary considerations of non—obviousness.
`
`20.
`
`I have been informed that where claimed ranges overlap, lie inside of,
`
`or are close to ranges already disclosed in the prior art, the claims are prima facie
`
`obvious.
`
`‘21.
`
`I have also been informed that when there is some recognized reason
`
`to solve a problemwand there are a finite number of identified, predictable, known
`
`solutionsw—a person of ordinary skill in the art is motivated and has good reason to
`
`pursue the known options within her technical grasp.
`
`If this approach leads to the
`
`expected success, it is likely the product of ordinary skill and common sense rather
`
`than the product of innovation Where a patent simply arranges old elements, with
`
`each element performing its known function and the whole yielding no more than
`
`would be expected, the combination is obvious,
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 12
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`AstraZeneca Exhibit 2166 p. 12
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`
`
`IV.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`22.
`
`As above,
`
`I have been informed by counsel
`
`that the obviousness
`
`analysis is to be conducted from the perspective of a person of ordinary skill in the
`
`art (a “person of ordinary skill,“ or “POSA“) at the time of the invention.
`
`1 have
`
`adopted the understanding of a POSA when discussing the teachings of the prior
`
`eat.
`
`23.
`
`I have also been informed by counsel that in defining a POSA the
`
`following factors may he considered: (l)the educational level of the inventor;
`
`(‘2)the type of problems encountered in the art; (3) prior art solutions to those
`
`problems; (4) speed with which innovations are made; and (5) sophistication of the
`
`technology and educational level of active workers in the field.
`
`24.
`
`The POSA would have had, as of the earliest priority date, a graduate
`
`degree in pharmacy= pharmaceutics, chemistry, or a related discipline, or
`
`equivalent experience in drug development and formulation? and would also have
`
`familiarity with and knowledge of designing and formulating dosage forms. The
`
`POSA would also have access to individuals with expertise in medicine,
`
`biochemistry; and phannacology as part of their drug development and fonnulation
`
`team and would consult with them as appropriate. The POSA’S level of experience
`
`may come from the POSA’S own experience, or may come through the guidance of
`
`other individual(s) with experience in the industry, egt, as members of a research
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 13
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`AstraZeneca Exhibit 2166 p. 13
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`
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`team or group.
`
`The POSA would also be well-versed in the worldwide
`
`publications and literature on steroidal hormone formulations and treatments,
`
`particularly fulvestrant, that were available as of the priority date.
`
`V.
`
`[1.8. PATENT N0. 8,329,680 (“THE ’680 PATENT") |Ex. 1001]
`
`25.
`
`l have read the “680 patent, entitled “Formulation," and its issued
`
`claims. The 2680 patent was filed on October 15, 2008, and claimed priority to
`
`US. Patent Application No.
`
`lO/872,784 (now the ”160 patent) and two foreign
`
`applications, [Great Britain 0000313], dated January 10, 2000, and [Great Britain
`
`0008837], dated Aptil 12, 2000. See “680 Patth File History [Ex 1002]. The
`
`’680 patent issued December 1 l, 2012, and named John R. Evans and Rosalind U.
`
`Grundy as the sole inventors. AstraZeneca AB was listed as the assignee of the
`
`”680 patent.
`
`26.
`
`The following table organizes each element by claim:
`
`Table #1. Correlatitm of I’lllx-‘estrant Claim Elements
`
`Fu|\-'esti'ant Component
`Indications for Fulvestrant
`
`Route of Administration
`
`As Claimed in ’680 Patent
`Claims #1, #9: hormonal dependent
`benign or malignant diseases of the human
`breast or reproductive tract
`Claims #3, #6, #11, #14: breast cancer
`
`Claims #1, #4, #7, #9, #12, #15: int.
`in'ection
`
`
`
`Fre I uenc of Administration
`
`Claims #5, #8, #13, #16: once month]
`
`Volume Formulated Fulvestrant
`
`Claims #4, #7, #12, #15: 5 ml
`
`Administered
`
`Fulvestrant Dose
`
`Claims #17—#20: divided dose
`
`Claims #1, #9: about 50 m/ml
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 14
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`AstraZeneca Exhibit 2166 p. '14
`
`
`
`
`
`Final Formulation of Fulvestrant Claims #1:
`
`
`
`“comprising”
`about 50 mgml'] of fulvestrant
`about 10% w/v ethanol
`
`about 10% w/v benzyl alcohol
`about 15% benzyl benzoate
`
`sufficient mount of a castor oil vehicle
`
`Claim #9:
`
`“consisting essentially of”
`about 50 mng1 of fulvestrnnt
`about 10% we: ethanol
`
`
`
`about 10% WW benzyl alcohol
`
`about 13% benzyl benzoate
`Claims #1, #9: at least 2.5 nghnl for at
`
`least 4 weeks
`
`Blond Plasma Fulvestrant
`Concentration Levels and Their
`
`Claim #2, #10: at least 8.5 ng/‘ml for at
`Duretions
`
`least 4 weeks
`
`27.
`
`I understand that Mylen is challenging all claims of the "”680 patent,
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`namely claims 1w20. The ’680 patent includes 2 independent claims; claims 1 and
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`9.
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`I also understand that the claim terms in the ”680 patent are presumed to take on
`
`their ordinary and customary meaning based on the broadest
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`reasonable
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`construction in light of the specification of the patent in which they appear.
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`28,
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`Independent claim '1
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`recites: “A method for treating a hormonal
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`dependent benign or malignant disease of the breast or
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`reproductive tract
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`comprising administering intramuscularly to a human in need of such treatment a
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`formulation comprising: about 50 mgml“I of fulvestrnnt; about 10% w/v of ethanol;
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`about 10% w/v of benzyl alcohol; about 15% wfv of benzyl benzoate; and a
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`sufficient amount of caster oil vehicle; wherein the method achieves a
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 15
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`AstraZeneca Exhibit 2166 p. 15
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`
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`therapeutically significant blood plasma fulvestrant concentration of at least 2.5
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`tlgmfl for at least four weeks.”
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`29.
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`Independent claim 9 recites: “A method for treating a hormonal
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`dependent benign or malignant disease of the breast or
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`reproductive tract
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`comprising administeiing intramuscularly to a human in need of such treatment a
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`fonnulation consisting essentially of: about 50 mgml‘”I of fulvestrant; about 10%
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`w/v of ethanol; about 10% wz'v of benzyl alcohol; about 15% w/v of benzyl
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`benzoate; and wherein the method achieves a therapeutically significant blood
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`plasma fulvestrant concentration of at least 2.5 agrnl'I for at least four weeks.“
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`30.
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`Independent claims 1 and 9 recite the term “a honnonal dependent
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`benign or malignant disease of the breast or reproductive tract.” As of January 10,
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`2000, a POSA would have interpreted the term to include, at minimum, estrogen
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`receptor—positive (ER+ or ER»positive) female breast cancer.
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`31.
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`Comparing independent claims 1 and 9, the only differences are claim
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`9’s inclusion of “consisting essentially of” and claim 9’s omission of “a sufficient
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`amount of castor oil vehicle.”
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`32.
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`Dependent claims 2~8 and 18—19, which directly or indirectly depend
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`from independent claim 1, and dependent claims 1?.«20; which depend directly or
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`indirectly from independent claim 9, recite a specific type of disease; level and
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 16
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`AstraZeneca Exhibit 2166 p. 16
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`
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`duration of blood plasma fulxrestrant concentration over time; and route, volume,
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`method or frequency of administration.
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`VI. CLAIM CONSTRUCTION
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`33.
`
`Independent claims 1 and 9 of the ’680 patent recite the term
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`“honnonal dependent benign or malignant disease of the breast or reproductive
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`tract; .
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`. [in] a human” in their preamble, and dependent claims 3, 6: ll, and 14
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`specify that “the benign or malignant disease is breast cancer.“ Under the broadest
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`reasonable construction to a POSA as of the priority date, this term includes at
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`least honnonalvdependent malignant breast cancer in women,
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`34.
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`Independent claims 1 and 9 of the ’680 patent recite: ‘Wliereiii the
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`method
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`achieves
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`a
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`therapeutically
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`significant
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`blood plasma
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`fulvestrant
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`concentration of at least 2.5 ngml'1 for at least four weeks.” Dependent claims 2
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`and 10 recite that the method achieves a concentration of at least 8.5 ngml’1 for at
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`least 4 weeks.
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`35.
`
`As stated previously in paragraph 18,
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`I have been informed that
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`“wherein” clauses that simply express the intended result of a process step, without
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`informing how the method is carried out, are generally not given. patentable
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`weight, However, to the extent that such phrases are given patentable weight:
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`(a) Under the broadest reasonable construction to a POSA as of the
`
`priority date, “therapeutically significant” is any blood plasma
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 17
`
`AstraZeneca Exhibit 2166 p. 17
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`
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`fulvestrant concentration greater than or equal to the value specified in
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`the patent (erg, 2.5 ngnil‘l)
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`(lo) Under the broadest reasonable construction to a POSA as of the
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`priority datea “achieved” means “achieved an average concentration in
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`a patient over the specified time period."
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`VII. BACKGROUND OF BREAST CANCER AND TREATMENTS
`
`A.
`
`Hormone Receptor Positive (HRH Breast Cancer in Human
`Females
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`36.
`
`In women, many breast cancer cells are honnonedependent
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`(or
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`hormone—sensitive), meaning that they can use certain hormones to grow. The
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`breast cancer cells contain proteins known as hormone receptors that can become
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`activated when bound to certain hormones. ane activated, they can lead to the
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`stimulation of cell growthmixew cancer.
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`37.
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`Hormonal—dependent breast cancer in women was known to correlate
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`with three hormone receptors: estrogen, progesterone: and human epidermal
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`growth factor receptor 2 (HERZ).
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`Identification of the type of hormone receptors
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`involved in the breast cancer allowed for improved knowledge about how the
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`tumor might act and what treatments were likely to be most effective.
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`38.
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`Each of these hormone receptors could be “positive” or “negative.”
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`Meaning, the breast cancer could be identified as estrogen receptor-positive (1311+)
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`or estrogen receptoranegative’
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`(ER-i); progesterone receptor-positive (PRH or
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 18
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`AstraZeneca Exhibit 2166 p. 18
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`
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`progesterone receptormegative (PRw); and/0r human epidermal growth factor
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`receptor 2-positive (HER2+) or human epidermal growth factor receptor 2-
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`negative (HEM—1 ER+ breast cancer is thus a type of hormone receptor—positive
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`or “HRH” breast cancer. HR+ breast cancer is hormonal dependent breast cancer:
`
`39.
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`HR+ breast cancer is the most common subtype of invasive breast
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`cancers, and is especially prevalent among postqnenopausal women. HR+ breast
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`cancers in women are typically treated with hormone (or endocrine) therapy, which
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`is intended to block the patient’s body from producing hormones or otherwise
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`interfering with hormone action, thereby blocking or minimizing hormone receptor
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`cell activation and slowing or stopping tumor growth
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`40.
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`Hormone therapies for female HR+ breast cancers may be prescribed
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`as either an adjuvant therapy or in patients with early metastatic disease.
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`In the
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`adjuvant setting,
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`the hormone treatment
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`is given after the main treatment
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`(generally surgery) to reduce the risk of relapse. Adjuvant therapy is a long»term
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`therapy,
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`typically spanning multiple years,
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`In patients with early metastatic
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`disease, the hormone treatment is given to minimize and hopefiilly prevent further
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`spreading of the disease in the body.
`
`B.
`
`Treatment Options for HR+ Breast Cancer in Women Prior to
`2000
`
`41.
`
`Prior to 2000, several hormone therapies were approved to treat HR+
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`breast cancer in women. These therapies included selective estrogen receptor
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 19
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`AstraZeneca Exhibit 2166 p. 19
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`
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`modulators
`
`(SERMs),
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`ovarian
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`suppression
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`utilizing gonadotropimreleasing
`
`hormone (GnRH) agonists, and eromatase inhibitors (Als).
`
`42.
`
`SERMS bind to estrogen receptors in breast cells, preventing their
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`ability to bind to estrogen and correspondingly proliferate. Notably, however, cells
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`in other body ti ssueswpatricularly the bones and utemswheve estrogen receptors
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`with slightly different structures. As the name implies, SERMS were known to
`
`have “selective” (or “partial agonist”) estrogen activity:
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`they block estrogen
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`binding in breast cells but can activate estrogen receptors in other cells, such as the
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`uterus, and hence increase the risk of uterine cancers. Tamoxifen was the oldest,
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`most well—known, and most—prescribed SERM. See, 8.5:, Ex. 1018 (Osborne 19:95)
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`at 1; Ex. 1033 (BREASTCANCERflRG, “Selective Estrogen Receptor Modulators
`
`(SERMS),” http://W.breastcancer.orgftreatmentfhorinonol/serms).
`
`43. GnRH-agonists downregulate pituitary GnRH receptors, which
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`suppress hormones that stimulate estrogen-production in the ovaries. GnRH
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`sgonists can therefore act as a phennacologicel altemative to surgical removal of
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`the ovaries (oophorectomy), and are often used in treating pres-menopausal women
`
`with breast cancer.
`
`44. Als block the peripheral production of estrogen via blocking the
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`enzyme aromntase, which converts the hormone androgen into the hormone
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 20
`
`AstraZeneca Exhibit 2166 p. 20
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`
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`estrogen. Als cannot stop the ovaries from producing estrogen, however, and so
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`are rarely used to treat pro—menopausal women.
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`45.
`
`Prior to 2000, ore—menopausal women with HR+ breast cancer who
`
`had in