UNITED STATES PATENT AND TRADEMARK OFFICE
`
`————————————————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`————————————————
`
`MYLAN PHARMACEUTICALS INC.
`Petitioner,
`
`v.
`
`ASTRAZENECA AB
`Patent Owner.
`
`————————————————
`U.S. Patent No. 8,329,680
`————————————————
`
`DECLARATION OF LESLIE OLEKSOWICZ, M.D.
`
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`
`U.S. PATENT NO. 8,329,680
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 1
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`

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`I.
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS AND BACKGROUND ................................................................... 5
`A.
`Education and Experience...................................................................................... 5
`B.
`Materials Considered ............................................................................................. 9
`C.
`Scope of Work ....................................................................................................... 9
`SUMMARY OF OPINIONS ........................................................................................... 10
`II.
`LEGAL STANDARDS ................................................................................................... 11
`III.
`PERSON OF ORDINARY SKILL IN THE ART ........................................................... 13
`IV.
`U.S. PATENT NO. 8,329,680 (“THE ’680 PATENT”) [Ex. 1001]................................ 14
`V.
`CLAIM CONSTRUCTION ............................................................................................. 17
`VI.
`VII. BACKGROUND OF BREAST CANCER AND TREATMENTS................................. 18
`A.
`Hormone Receptor Positive (HR+) Breast Cancer in Human Females ............... 18
`B.
`Treatment Options for HR+ Breast Cancer in Women Prior to 2000.................. 19
`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ................................. 22
`A.
`McLeskey 1998 [Ex. 1005].................................................................................. 22
`B.
`Howell 1996 [Ex. 1006] ....................................................................................... 23
`C.
`Dukes 1989 [Ex. 1007] ........................................................................................ 26
`D. Wakeling 1991 [Ex. 1008] ................................................................................... 27
`E.
`Wakeling 1992 [Ex. 1009] ................................................................................... 28
`F.
`Dukes 1992 [Ex. 1025] ........................................................................................ 30
`G. Wakeling 1993 [Ex. 1028] ................................................................................... 31
`H.
`Dukes 1993 [Ex. 1026] ........................................................................................ 33
`I.
`DeFriend 1994 [Ex. 1027] ................................................................................... 35
`J.
`Osborne 1995 [Ex. 1018] ..................................................................................... 36
`K.
`Howell 1995 [Ex. 1012] ....................................................................................... 38
`L.
`O’Regan 1998 [Ex. 1013] .................................................................................... 39
`FULVESTRANT WAS A WELL UNDERSTOOD COMPOUND BY
`JANUARY 10, 2000 ........................................................................................................ 40
`A.
`Fulvestrant Was Well Known in the Prior Art. .................................................... 40
`B.
`Fulvestrant’s Pharmacological Usefulness Was Well Known in the Prior
`Art. ....................................................................................................................... 41
`Fulvestrant’s Pre-Clinical Anti-Tumor and Anti-Uterotrophic Effects
`Were Well Known in the Prior Art. ..................................................................... 42
`
`IX.
`
`C.
`
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`

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`X.
`
`E.
`
`F.
`
`B.
`
`D.
`
`Fulvestrant’s Clinical Efficacy in Human Females With Breast Cancer
`Was Well Known in the Prior Art. ....................................................................... 47
`Fulvestrant’s Efficacy in Human Females with ER+ 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
`1.
`Indication ................................................................................................. 50
`2.
`Excipients and Percent w/v Concentrations ............................................. 51
`3.
`Route and Schedule of Administration .................................................... 52
`4.
`Dose of Fulvestrant As-Formulated ......................................................... 54
`5.
`Divided Dose ........................................................................................... 55
`Fulvestrant Concentration of About 50 mgml-1 ....................................... 56
`6.
`7.
`Fulvestrant Total Dose of 250 mg ........................................................... 56
`UNPATENTABILITY OF THE ’680 PATENT ............................................................. 57
`A.
`Claims 1–20 of the ’680 patent were obvious over McLeskey. .......................... 58
`1.
`McLeskey disclosed the claimed fulvestrant formulation. ...................... 58
`2.
`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 mg/ml of fulvestrant 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. ............................................................................................ 63
`A POSA would have understood that the fulvestrant formulation
`could have been administered monthly. ................................................... 64
`A POSA would have understood that the claimed blood plasma
`fulvestrant concentrations were not limitations of the patent. ................. 65
`All claims of the ’680 patent were obvious over Howell 1996 in view of
`McLeskey. ............................................................................................................ 67
`Howell 1996 disclosed using fulvestrant to treat breast cancer in a
`1.
`human female. .......................................................................................... 68
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
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`

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`2.
`
`Howell 1996 in view of McLeskey disclosed administering
`McLeskey’s complete fulvestrant formulation to a human,
`particularly a human female. .................................................................... 69
`Howell 1996 in view of McLeskey 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 have known to administer the fulvestrant
`formulation to a human monthly.............................................................. 73
`Howell 1996 in view of McLeskey disclosed administering a
`fulvestrant formulation of 50 mg/ml concentration to a human
`female with breast cancer......................................................................... 74
`A POSA would have understood that the claimed blood plasma
`fulvestrant concentrations were not limitations of the patent. ................. 75
`Even to the extent the claimed blood plasma fulvestrant
`concentrations are limitations, they were disclosed by Howell
`1996, alone or in view of McLeskey. ...................................................... 76
`CONCLUSION ................................................................................................................ 78
`
`5.
`
`6.
`
`7.
`
`8.
`
`3.
`
`4.
`
`XI.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 4
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`

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`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A.
`
`1.
`
`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, M.D., LLC, I have
`
`also acted as a consultant to provide strategic intelligence to the financial and
`
`pharmaceutical 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. My full
`
`curriculum vitae (CV) is attached hereto as Exhibit A and is incorporated herein.
`
`2.
`
`I received my B.A. in Biological Sciences from Amherst College in
`
`1978, graduating magna cum laude and Phi Beta Kappa. I received my M.D. from
`
`Tufts University School of Medicine in 1982.
`
`3.
`
`After finishing medical school, I 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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`Einstein College of Medicine (Montefiore University Hospital, Bronx, N.Y.) 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, N.Y.) and Medical Oncology completed in 1989 at Mount Sinai
`
`Medical Center (New York, N.Y). I was certified by the ABIM in Medical
`
`Oncology in 1989. From 1989–2015, I held faculty positions as an academic
`
`oncologist at Mount Sinai Medical Center, (New York, N.Y.), Montefiore
`
`University Hospital, (Bronx, N.Y), Roswell Park Cancer Institute (Buffalo, N.Y.),
`
`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,
`
`M.D., LLC, which provides strategic
`
`intelligence
`
`to
`
`the financial and
`
`pharmaceutical 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 professional societies, including
`
`the American Society of Clinical Oncology (current 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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`and conducts cancer clinical trials), the American College of Physicians, and the
`
`National Kidney Cancer Association (current member, editorial advisory board).
`
`6.
`
`I have served as an editor for the following journals: Cancer,
`
`American Journal of Medical Sciences, Southern Journal of Medicine, Journal of
`
`Urology, Kidney Cancer, and Transfusion.
`
`7.
`
`I have extensive experience treating patients with breast cancer,
`
`including hormone receptor-positive breast cancers. During my 25 years in
`
`academic practice, I have directed both basic science and clinical investigations in
`
`the area of hormone positive breast cancer. From 1992–2000, I led a basic science
`
`research effort studying adhesive glycoprotein receptors expressed by hormone-
`
`positive breast tumor cells that participated in the metastatic process. As a
`
`principal member of an institution-wide breast malignancy affinity group, I
`
`facilitated collaborations amongst clinicians and basic science investigators. My
`
`laboratory research was funded by several competitive grant-awarding groups,
`
`including the American Cancer Society, the Elsa U. Pardee Foundation, Sandoz
`
`Pharmaceuticals, and the Roswell Park Alliance Foundation, with the resultant
`
`research generating 11 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 Center, the Mount
`
`Sinai Medical Center, the Grace Cancer Drug Center and the Roswell Park Cancer
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 7
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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, I 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 III Randomized
`
`Trial of Anastrozole vs. Anastrozole and Fulvestrant as First Line Therapy in Post-
`
`Menopausal Women with Metastatic Breast Cancer, and from 10/2011 – 5/2012, I
`
`was principal investigator in the SWOG S1007 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.
`
`I have also participated in over 100 clinical trials, in over 80 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
`
`Hampden Scholarship during medical school on the basis of my GPA. While
`
`directing a basic science laboratory research effort at the Albert Einstein Cancer
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`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 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 Carol Solov Abbani
`
`Foundation, the Pardee Foundation, 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.
`
`12.
`
`Scope of Work
`
`I have been retained by counsel for Mylan Pharmaceuticals Inc.
`
`(“Mylan”) in connection with this matter. I am being compensated at my usual
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 9
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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.
`
`II.
`
`SUMMARY OF OPINIONS
`
`13.
`
`It is my opinion that, for the reasons stated below, claims 1–20 of the
`
`U.S. Patent No. 8,329,680 (“the ’680 patent”) were obvious over McLeskey [Ex.
`
`1005]. Independent claims 1 and 20 of the ’680 patent focus on a dosing regimen
`
`of a certain fulvestrant formulation, administered as an intramuscular (“i.m”)
`
`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 1–20 of the ’680 patent were obvious
`
`over Howell 1996 [Ex. 1006] in view of McLeskey [Ex. 1005]. Howell 1996
`
`disclosed a long-acting fulvestrant formulation 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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`1 month following a single intramuscular injection. A POSA investigating prior
`
`art long-term and/or castor oil-based formulations 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 1–20 of the ’680 patent.
`
`III. LEGAL STANDARDS
`
`15.
`
`I have been informed 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.
`
`I am informed 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 informed that the claim scope of a method claim is not
`
`limited by a “whereby” or “wherein” clause that simply expresses the intended
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 11
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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: (1) 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 (4) 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 problem—and there are a finite number of identified, predictable, known
`
`solutions—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.
`
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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. I have
`
`adopted the understanding of a POSA when discussing the teachings of the prior
`
`art.
`
`23.
`
`I have also been informed by counsel that in defining a POSA the
`
`following factors may be considered: (1) 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 pharmacology as part of their drug development and formulation
`
`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, e.g., as members of a research
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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.
`
`U.S. PATENT NO. 8,329,680 (“THE ’680 PATENT”) [Ex. 1001]
`
`25.
`
`I have read the ’680 patent, entitled “Formulation,” and its issued
`
`claims. The ’680 patent was filed on October 15, 2008, and claimed priority to
`
`U.S. Patent Application No. 10/872,784 (now the ’160 patent) and two foreign
`
`applications, [Great Britain 0000313], dated January 10, 2000, and [Great Britain
`
`0008837], dated April 12, 2000. See ’680 Patent File History [Ex. 1002]. The
`
`’680 patent issued December 11, 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. Correlation of Fulvestrant Claim Elements
`Fulvestrant Component
`As Claimed in ’680 Patent
`Claims #1, #9: hormonal dependent
`Indications for Fulvestrant
`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: i.m.
`injection
`Claims #5, #8, #13, #16: once monthly
`Claims #4, #7, #12, #15: 5 ml
`
`Route of Administration
`
`Frequency of Administration
`Volume Formulated Fulvestrant
`Administered
`Fulvestrant Dose
`Fulvestrant Concentration
`
`Claims #17–#20: divided dose
`Claims #1, #9: about 50 mg/ml
`
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`Final Formulation of Fulvestrant Claims #1:
`“comprising”
`about 50 mgml-1 of fulvestrant
`about 10% w/v ethanol
`about 10% w/v benzyl alcohol
`about 15% benzyl benzoate
`sufficient amount of a castor oil vehicle
`Claim #9:
`“consisting essentially of”
`about 50 mgml-1 of fulvestrant
`about 10% w/v ethanol
`about 10% w/v benzyl alcohol
`about 15% benzyl benzoate
`Claims #1, #9: at least 2.5 ng/ml for at
`least 4 weeks
`Claim #2, #10: at least 8.5 ng/ml for at
`least 4 weeks
`
`Blood Plasma Fulvestrant
`Concentration Levels and Their
`Durations
`
`27.
`
`I understand that Mylan is challenging all claims of the ’680 patent,
`
`namely claims 1–20. The ’680 patent includes 2 independent claims: claims 1 and
`
`9. 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 reasonable
`
`construction in light of the specification of the patent in which they appear.
`
`28.
`
`Independent claim 1 recites: “A method for treating a hormonal
`
`dependent benign or malignant disease of the breast or reproductive tract
`
`comprising administering intramuscularly to a human in need of such treatment a
`
`formulation comprising: about 50 mgml-1 of fulvestrant; 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
`
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`therapeutically significant blood plasma fulvestrant concentration of at least 2.5
`
`ngml-1 for at least four weeks.”
`
`29.
`
`Independent claim 9 recites: “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 ngm1-1 for at least four weeks.”
`
`30.
`
`Independent claims 1 and 9 recite the term “a hormonal dependent
`
`benign or malignant disease of the breast or reproductive tract.” As of January 10,
`
`2000, a POSA would have interpreted the term to include, at minimum, estrogen
`
`receptor-positive (ER+ or ER-positive) female breast cancer.
`
`31. Comparing independent claims 1 and 9, the only differences are claim
`
`9’s inclusion of “consisting essentially of” and claim 9’s omission of “a sufficient
`
`amount of castor oil vehicle.”
`
`32. Dependent claims 2–8 and 18–19, which directly or indirectly depend
`
`from independent claim 1, and dependent claims 12–20, which depend directly or
`
`indirectly from independent claim 9, recite a specific type of disease; level and
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 16
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`duration of blood plasma fulvestrant concentration over time; and route, volume,
`
`method or frequency of administration.
`
`VI. CLAIM CONSTRUCTION
`
`33.
`
`Independent claims 1 and 9 of the ’680 patent recite the term
`
`“hormonal dependent benign or malignant disease of the breast or reproductive
`
`tract . . . [in] a human” in their preamble, and dependent claims 3, 6, 11, and 14
`
`specify that “the benign or malignant disease is breast cancer.” Under the broadest
`
`reasonable construction to a POSA as of the priority date, this term includes at
`
`least hormonal-dependent malignant breast cancer in women.
`
`34.
`
`Independent claims 1 and 9 of the ’680 patent recite: “wherein the
`
`method achieves
`
`a
`
`therapeutically significant blood plasma
`
`fulvestrant
`
`concentration of at least 2.5 ngml-1 for at least four weeks.” Dependent claims 2
`
`and 10 recite that the method achieves a concentration of at least 8.5 ngml-1 for at
`
`least 4 weeks.
`
`35. As stated previously in paragraph 18, I have been informed that
`
`“wherein” clauses that simply express the intended result of a process step, without
`
`informing how the method is carried out, are generally not given patentable
`
`weight. However, to the extent that such phrases are given patentable weight:
`
`(a) Under the broadest reasonable construction to a POSA as of the
`
`priority date, “therapeutically significant” is any blood plasma
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`fulvestrant concentration greater than or equal to the value specified in
`
`the patent (e.g., 2.5 ngml-1).
`
`(b)Under the broadest reasonable construction to a POSA as of the
`
`priority date, “achieved” means “achieved an average concentration in
`
`a patient over the specified time period.”
`
`VII. BACKGROUND OF BREAST CANCER AND TREATMENTS
`
`A.
`
`Hormone Receptor Positive (HR+) Breast Cancer in Human
`Females
`
`36.
`
`In women, many breast cancer cells are hormone-dependent (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. Once activated, they can lead to the
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`stimulation of cell growth—i.e., cancer.
`
`37. Hormonal-dependent breast cancer in women was known to correlate
`
`with three hormone receptors: estrogen, progesterone, and human epidermal
`
`growth factor receptor 2 (HER2). Identification of the type of hormone receptors
`
`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.
`
`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 (ER+)
`
`or estrogen receptor-negative (ER-); progesterone receptor-positive (PR+) or
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`progesterone receptor-negative (PR-); and/or human epidermal growth factor
`
`receptor 2-positive (HER2+) or human epidermal growth factor receptor 2-
`
`negative (HER2-). ER+ breast cancer is thus a type of hormone receptor-positive
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`or “HR+” breast cancer. HR+ breast cancer is hormonal dependent breast cancer.
`
`39. HR+ breast cancer is the most common subtype of invasive breast
`
`cancers, and is especially prevalent among post-menopausal women. HR+ breast
`
`cancers in women are typically treated with hormone (or endocrine) therapy, which
`
`is intended to block the patient’s body from producing hormones or otherwise
`
`interfering with hormone action, thereby blocking or minimizing hormone receptor
`
`cell activation and slowing or stopping tumor growth.
`
`40. Hormone therapies for female HR+ breast cancers may be prescribed
`
`as either an adjuvant therapy or in patients with early metastatic disease. In the
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`adjuvant setting, the hormone treatment is given after the main treatment
`
`(generally surgery) to reduce the risk of relapse. Adjuvant therapy is a long-term
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`therapy, typically spanning multiple years. In patients with early metastatic
`
`disease, the hormone treatment is given to minimize and hopefully prevent further
`
`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+
`
`breast cancer in women. These therapies included selective estrogen receptor
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`modulators (SERMs), ovarian suppression utilizing gonadotropin-releasing
`
`hormone (GnRH) agonists, and aromatase inhibitors (AIs).
`
`42.
`
`SERMs bind to estrogen receptors in breast cells, preventing their
`
`ability to bind to estrogen and correspondingly proliferate. Notably, however, cells
`
`in other body tissues—particularly the bones and uterus—have estrogen receptors
`
`with slightly different structures. As the name implies, SERMs were known to
`
`have “selective” (or “partial agonist”) estrogen activity: they block estrogen
`
`binding in breast cells but can activate estrogen receptors in other cells, such as the
`
`uterus, and hence increase the risk of uterine cancers. Tamoxifen was the oldest,
`
`most well-known, and most-prescribed SERM. See, e.g., Ex. 1018 (Osborne 1995)
`
`at 1; Ex. 1033 (BREASTCANCER.ORG, “Selective Estrogen Receptor Modulators
`
`(SERMs),” http://www.breastcancer.org/treatment/hormonal/serms).
`
`43. GnRH-agonists downregulate pituitary GnRH receptors, which
`
`suppress hormones that stimulate estrogen-production in the ovaries. GnRH
`
`agonists can therefore act as a pharmacological alternative to surgical removal of
`
`the ovaries (oophorectomy), and are often used in treating pre-menopausal women
`
`with breast cancer.
`
`44. AIs block the peripheral production of estrogen via blocking the
`
`enzyme aromatase, which converts the hormone androgen into the hormone
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`estrogen. AIs cannot stop the ovaries from producing estrogen, however, and so
`
`are rarely used to treat pre-menopausal women.
`
`45.
`
`Prior to 2000, pre-menopausal women with HR+ breast cancer who
`
`had intact estro