UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner
`
`Case IPR2016—01324
`
`U.S. Patent No. 7,456,160
`
`DECLARATION OF RONALD J. SAWCHUK, Ph.D. IN SUPPORT OF
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Ex. 2003 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01324
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.
`
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner
`
`Case IPR2016—01324
`
`U.S. Patent No. 7,456,160
`
`DECLARATION OF RONALD J. SAWCHUK, Ph.D. IN SUPPORT OF
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Ex. 2003 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01324
`
`
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained by AstraZeneca AB (“Astraleneca”) in
`
`connection with this mterpartes review proceeding (IPR20l6-0l324) before the
`
`United States Patent and Trademark Office Patent Trial and Appeal Board
`
`(“Board”).
`
`2.
`
`I understand that Mylan Pharmaceuticals Inc. (“Mylan”) has
`
`challenged AstraZeneca-owned U.S. Patent No. 7,456,160, which relates to a
`
`method of treating hormonal dependent disease of the breast or reproductive tract,
`
`and, more specifically, hormonal dependent breast cancer.
`
`3.
`
`I further understand that Mylan has petitioned institution of this inter
`
`partes review proceeding on the basis of several references identified in its Petition
`
`(IPR20l6-01324, Paper 1) (“Petition”).
`
`4.
`
`I am being compensated $750 per hour for my time consulting in this
`
`matter.
`
`I have no financial interest in the outcome of this proceeding and my
`
`compensation is in no way contingent upon my opinions or the outcome of this
`
`proceeding.
`
`II.
`
`QUALIFICATIONS
`
`5 .
`
`I am a Professor of Pharmaceutics, Emeritus, and Morse Alumni
`
`Distinguished Teaching Professor at the University of Minnesota.
`
`I also served as
`
`the Director of the Bioanalytic and Pharmacokinetic Services Laboratory at the
`
`AstraZeneca Ex. 2003 p. 2
`
`
`
`University of Minnesota until August of 2014.
`
`I have studied and carried out
`
`clinical and pre-clinical research in the field of pharmacokinetics and
`
`biopharmaceutics for over forty years.
`
`6.
`
`I joined the University of Minnesota in 1971 as an Instructor in
`
`Pharmaceutics after having obtained a Bachelor and Masters of Science Degree
`
`from the University of Toronto in 1963 and 1996, respectively, and completing my
`
`Doctoral Degree (Ph.D.) in Pharmaceutical Chemistry (pharmacokinetics
`
`emphasis) at the University of California, San Francisco, which was granted in
`
`1972.
`
`7.
`
`At the University of Minnesotal served as an Assistant Professor of
`
`Pharmaceutics from 1972 to 1977, an Associate Professor of Pharmaceutics from
`
`1977 to 1983, and a full Professor of Pharmaceutics from 1983 until my retirement
`
`in July of 2010. During this period, I was course director for instruction in
`
`pharmacokinetics, clinical pharmacokinetics, advanced pharmacokinetics, and
`
`pharmacokinetic modeling and simulation.
`
`1 was also a participating instructor in
`
`biopharmaceutics, and advanced pharmacokinetics, 1 continue to provide lectures
`
`relating to preclinical and clinical pharmacokinetics to scientists in the
`
`pharmaceutical industry.
`
`8.
`
`I also served as a member of the graduate programs in Pharmaceutics,
`
`Neurosciences, and Experimental and Clinical Pharmacology. From 1983 to 1989
`
`AstraZeneca Ex. 2003 p. 3
`
`
`
`and 1991 to 1994, I was the Director of Graduate Studies in Pharmaceutics at the
`
`University. From 1982 to 1995, I also served as Director of the Clinical
`
`Pharmacokinetics Laboratory at the College of Pharmacy at the University of
`
`Minnesota. From 1998 to 1999 I served as the Head of the Department of
`
`Pharmaceutics at the University of Minnesota.
`
`9.
`
`Although I have formally retired from the University, my Graduate
`
`Faculty appointment in the Department of Pharmaceutics is still in effect, allowing
`
`me to teach graduate students in the program.
`
`I have advised on the order of forty
`
`graduate students, postdoctoral fellows, and visiting scholars, on projects relating
`
`to preclinical and clinical pharmacokinetics, biopharrnaceutics, and bioanalytical
`
`chemistry.
`
`10. A major focus of my research was preclinical and clinical
`
`pharmacokinetics. I have been involved with many different preclinical and
`
`clinical human trials, and in particular with the analysis of the pharrnacokinetic and
`
`other data generated during those trials.
`
`1 also focused my research on drug
`
`bioavailability and bioequivalence. I have taught, and continue to teach,
`
`pharmacokinetics, and pharmacokinetic modeling and simulation in professional,
`
`graduate, and elective courses at the University of Minnesota and to the
`
`pharmaceutical industry. This instruction includes lectures on the assessment of
`
`bioavailability and bioequivalence.
`
`AstraZeneca Ex. 2003 p. 4
`
`
`
`11.
`
`I have expertise in the determination of pharmacokinetic parameters
`
`and metrics for orally administered drugs, bioanalytical chemistry,
`
`biopharmaceutics, and pharmacodynamics. I have devoted a large part of my
`
`career to the study of the pharmacokinetics of drugs. And, in addition to authoring
`
`numerous publications in this area, I have received funding from various sources in
`
`the public and private sector to support my research in pharmacokinetics, including
`
`support from the National Institutes of Health (“NIH”) and the U.S. Food and Drug
`
`Administration (“FDA”).
`
`12. During my career, I received several honors, scholarships and awards,
`
`including the Weaver Medal of Honor in 2001, the Meritorious Manuscript Award
`
`from the American Association of Pharmaceutical Scientists in 1999 and the Hallie
`
`Bruce Memorial Lecture Award in 1996. In 2007, I received the American
`
`Pharmacists Association (APhA) Research Achievement Award in the Basic
`
`Pharmaceutical Sciences.
`
`13.
`
`I have been a member of numerous scientific and clinical societies.
`
`I
`
`am a Fellow of the American Association of Pharmaceutical Scientists and of the
`
`American Association for the Advancement of Science.
`
`I have been a member of
`
`the International Society of Anti-infective Pharmacology and the International
`
`Society for the Study of Xenobiotics (IS SX).
`
`I served a three-year term as a
`
`AstraZeneca Ex. 2003 p. 5
`
`
`
`member-at-large on the American Association of Pharmaceutical Scientists
`
`(AAPS) Executive Council.
`
`14.
`
`I have served on the editorial boards of scientific journals such as the
`
`Journal of Pharmaceutical Sciences.
`
`I am currently on the Editorial Board of the
`
`AAPS Journal, and on the IS SX Journal, Xenobiotica.
`
`I have also served on
`
`numerous advisory committees and review panels.
`
`15.
`
`I am a named author on over 100 refereed scientific publications,
`
`several book chapters and over 170 abstracts, which have been presented at
`
`scientific meetings. I have also co-edited a book on drug bioavailability and given
`
`hundreds of invited lectures.
`
`16.
`
`I have significant experience in the areas of pharmaceutical research,
`
`pharmacokinetics, and drug development. Therefore, I believe that I am qualified
`
`to render the opinions set forth in this declaration.
`
`17. My academic background and work experience are summarized in my
`
`curriculum vitae, attached to this declaration as Exhibit A.
`
`III.
`
`ISSUES CONSIDERED
`
`18.
`
`In this declaration, I was asked to provide opinions concerning:
`
`i.
`
`The qualifications of a person of ordinary skill in the art as of
`
`January 10, 2000;
`
`ii.
`
`The state of the art as of January 10, 2000;
`
`AstraZeneca Ex. 2003 p. 6
`
`
`
`iii.
`
`The construction of the claim terms “whereby a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 2.5
`
`ngml“ is attained for at least 2 weeks after injection”
`
`(independent Claim 1) and “wherein the blood plasma
`
`fulvestrant concentration is attained for at least 3 weeks after
`
`injection” (dependent Claim 5), “wherein the blood plasma
`
`fulvestrant concentration is attained for at least 4 weeks after
`
`injection” (dependent Claim 6), “wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 3
`
`ngml'1 is attained for at least 2 weeks after injection” (dependent
`
`Claim 7), “wherein a therapeutically significant blood plasma
`
`fulvestrant concentration of at least 8.5 ngml” is attained for at
`
`least 2 weeks after injection” (dependent Claim 8), and “wherein
`
`a therapeutically significant blood plasma fulvestrant
`
`concentration of at least 8.5 ngml” is attained for at least 4
`
`weeks after injection” (dependent Claim 9); and
`
`iv.
`
`The declaration of Dr. Laird Forrest, Ph.D. (Ex. 1003) (“Forrest
`
`Decl.”).
`
`AstraZeneca Ex. 2003 p. 7
`
`
`
`IV. MATERIALS CONSIDERED
`
`19.
`
`In preparing this declaration, I reviewed the IPR Petition submitted by
`
`Mylan; Howell 1996 and McLeskey (Ex. 1005 and Ex. 1006, respectively); the
`
`‘I60 Patent (Ex. 1001); the declaration of Dr. Forrest (Ex. 1003); and the other
`
`exhibits listed in Exhibit B.
`
`V.
`
`SUMMARY OF APPLICABLE LEGAL CONSIDERATIONS
`
`20.
`
`Counsel for AstraZeneca requested that I express my opinions with
`
`certain guidelines in mind, which are set forth below.
`
`21.
`
`For this declaration I have been asked to use January 10, 2000 as the
`
`relevant date for my analysis.
`
`22. AstraZeneca’s counsel informed me that my analysis must be done
`
`through the eyes of the “person of ordinary skill in the art” as of January 10, 2000.
`
`I understand from AstraZeneca’s counsel that a person of ordinary skill in the art is
`
`a hypothetical person, who has the characteristics of an ordinary artisan including
`
`ordinary creativity.
`
`23.
`
`Factually, in my opinion, a person of ordinary skill in the art in 2000
`
`would have been a person having a bachelor’s or advanced degree in a discipline
`
`such as pharmacy, pharmaceutical sciences, endocrinology, medicine or related
`
`disciplines, and having at least two years of practical experience in drug
`
`development and/or drug delivery, or the clinical treatment of hormonal dependent
`
`AstraZeneca Ex. 2003 p. 8
`
`
`
`diseases of the breast and/or reproductive tract. Because drug formulation and
`
`development is complicated and multidisciplinary, it would require a team of
`
`individuals including, at least, medical doctors, formulators and
`
`pharmacokineticists.
`
`24. Unless I expressly state otherwise, all of the opinions provided in this
`
`declaration are made from the perspective of a person of ordinary skill in the art as
`
`of January 10, 2000.
`
`VI.
`
`THE STATE OF THE ART AS OF JANUARY 10, 2000
`
`A.
`
`Drug Delivery And Pharmacokinetics
`
`25. Drug targeting and duration of delivery are two important aspects of
`
`drug delivery. Drug targeting concerns identifying a specific organ or tissue to
`
`which the drug is to be delivered, while duration of delivery refers to how long the
`
`drug is present in the target organ or tissue.
`
`26. Here, the point of the formulations set forth in the challenged patent
`
`claims is to deliver specified blood plasma levels of the drug fulvestrant for
`
`specified times.
`
`27.
`
`In terms of duration, one conventional distinction involves the
`
`difference between immediate and sustained released formulations.
`
`28.
`
`“Immediate release” means the active pharmaceutical ingredient is
`
`released without a delay from its dosage form after it is administered. Most
`
`AstraZeneca Ex. 2003 p. 9
`
`
`
`conventional oral formulations, such as tablets or capsules, are designed for
`
`immediate release of active pharmaceutical ingredients upon administration in
`
`order to rapidly obtain complete absorption.
`
`29.
`
`Characteristic of immediate release formulations is a relatively rapid
`
`rise in the blood plasma drug levels—to an early and high peak—followed by a
`
`relatively rapid decrease in those levels.
`
`30.
`
`In contrast, sustained-release formulations are characterized by a
`
`relatively slow rise in blood plasma drug levels which peak later, and are followed
`
`by a relatively prolonged decrease in those levels. These formulations are also
`
`often referred to as extended-release formulations.
`
`31. With “sustained release” “blood level oscillation characteristic of
`
`multiple dosing of conventional dosage forms is reduced, because a more even
`
`blood level is maintained.” Ex. 2134 (Lachman’s) at 5. “Sustamed—release
`
`systems include any drug delivery system that achieves slow release of drug over
`
`an extended period of time. . .The objective in designing a sustained-release system
`
`is to deliver drug at a rate necessary to achieve and maintain a constant drug blood
`
`level.” Ex. 2080 (Remington’s) at 6.
`
`32. Without question, a person of ordinary skill would have understood
`
`that a “sustained-release” formulation is “designed to achieve a prolonged
`
`therapeutic effect by continuously releasing medication over an extended period of
`
`AstraZeneca EX. 2003 p. 10
`
`
`
`time after administration of a single dose. In the case of inj ectable dosage forms,
`
`this period may vary from days to months.” Ex. 2134 (Lachman’s) at 5. In other
`
`words, sustained release formulations are “designed to achieve a prolonged
`
`therapeutic effect by continuously releasing medication over an extended period of
`
`time after administration of a single dose.” Id.
`
`33. Many sustained—re1ease formulations are described in terms of a
`
`specific minimum drug concentration (“at least concentration X”) that is achieved
`
`and maintained over a particular period of time (e. g., hours, a day, a week, two
`
`weeks, a month).
`
`34.
`
`The study of the time-course of blood plasma levels of a drug
`
`following administration of a particular formulation/active pharmaceutical
`
`ingredient is called pharmacokinetics. Amongst other things, pharmacokinetics
`
`offers a means by which to compare the rate and extent of drug exposure provided
`
`by different formulations and/or dosing of the same active pharmaceutical
`
`ingredient.
`
`35.
`
`This rate and extent of drug exposure requires in vivo pharmacokinetic
`
`studies. In a clinical study setting, pharmacokinetists determine the concentration
`
`of drug in a subject’s plasma over time (by periodically drawing blood) in order to
`
`understand how the body processes the drug as it is being absorbed from a given
`
`formulation after it has been administered. Typically a graph of plasma drug
`
`AstraZeneca Ex. 2003 p. 11
`
`
`
`concentrations as a function of time is generated. This graph is referred to as a
`
`“concentration-time course” or “concentration-time curve.” And, a variety of
`
`analytical methods can then be used to study the results.
`
`36.
`
`The figure below illustrates the difference between the time-course of
`
`a sustained-(solid curve) and immediate-release (dotted curve) formulation for a
`
`single dose. In contrast to an immediate-release formulation, the sustained—release
`
`formulation exhibits a prolonged period during which plasma concentrations are
`
`maintained in a specified range (e. g., above some minimum effective level).
`
`immediate-release
`
`concentrationinplasma
`drug
`
`sustained‘-release
`
`Z
`
`time after dosing
`
`B.
`
`Pharmacokinetics, Pharmacodynamics, And The Development 01'
`Drugs Through Clinical Trials
`
`37.
`
`Clinical trials are conducted in a series of steps, referred to as Phases.
`
`If a drug is found to be “successful” in a given Phase, it is permitted to continue to
`
`the next. Typically there are three such Phases, referred to as Phase I, II and III,
`
`respectively.
`
`AstraZeneca Ex. 2003 p. 12
`
`
`
`38.
`
`The disciplines of pharmacokinetics and pharmacodynamics are
`
`important areas of activity throughout clinical development.
`
`39.
`
`Pharmacokinetics involves studying the relationship between the dose
`
`and/or dosing regimen used and the resulting plasma or serum concentrations of
`
`the drug. The plasma concentration-time profile or levels observed depend upon
`
`the rate and extent of absorption of the drug from its dosage form into the
`
`bloodstream, in addition to how it is distributed within the body, and how rapidly
`
`and efficiently it is clear from the body by the organs of elimination (e.g., kidney
`
`and/or liver).
`
`40.
`
`Related to pharrnacokinetics are bioavailability and bioanalytical
`
`chemistry. Bioavailability is a measure of the rate and extent of absorption of a
`
`drug into systemic blood, in animals or humans. The extent of absorption is
`
`typically characterized by the area under the curve (“AUC”) in the blood plasma
`
`following either a single dose or upon multiple dosing over a specified duration.
`
`The rate of absorption is usually characterized by the maximum concentration of
`
`the drug observed in plasma, and the time at which this maximum is observed.
`
`These parameters or metrics are referred to as “Cmax” and “Tmax,” respectively.
`
`Bioanalytical chemistry involves the quantitative analysis of biological fluids (e. g.,
`
`plasma, whole blood, urine, and cerebrospinal fluid) for endogenous, e. g.,
`
`hormones, and exogenous compounds, e.g., drugs and metabolites. This field
`
`AstraZeneca Ex. 2003 p. 13
`
`
`
`includes the measurement and analysis of drug levels in plasma, which provides
`
`data used to calculate many pharmacokinetic parameters or metrics, such as AUC,
`
`Cmax, and Tmax.
`
`41. Of note, systemic exposure to a drug may be described in terms of the
`
`blood serum or plasma concentrations of the drug during continuous therapy (e.g.,
`
`the steady—state plasma concentration, CSS), or the area under the blood plasma
`
`concentration-time curve (the “area under the curve”, or AUC).
`
`42.
`
`Pharmacodynamics involves the study of the potential relationship
`
`between plasma levels of a drug and the biological effects produced. These
`
`include both the desired therapeutic responses (efficacy) and side effects or adverse
`
`events. Although efficacy (the desired therapeutic response) may be linked to
`
`plasma levels, this relationship is often very difficult to identify for a variety of
`
`reasons including the complex and usually unknown mechanisms of action for
`
`many drugs. Other complicating factors include both the potential disequilibrium
`
`in the concentrations of a drug at the measurement site (i.e. the blood plasma or
`
`serum) with those in what is referred to as the “effect compartment” and the
`
`cascade of events that may need to occur over time before a response to the drug is
`
`observed.
`
`43.
`
`Significant data (usually including data from Phase III clinical trials)
`
`and a careful analysis of the relationship between plasma drug levels and the
`
`AstraZeneca EX. 2003 p. 14
`
`
`
`effects that a drug produces is required to establish any “pharmacokinetic-
`
`pharmacodynamic” link.
`
`C.
`
`Targeted Blood Plasma Drug Concentrations During Therapy
`
`44.
`
`If a relationship between plasma concentrations and response—
`
`efficacy and/or adverse effects—can be established for a drug, that may allow for
`
`the development of a strategy involving achieving and maintaining a target
`
`concentration or a target range of concentrations for individual patients.
`
`45.
`
`This target(s) corresponds with the greatest likelihood of therapeutic
`
`success. Stated differently, ranges of serum or plasma concentrations of a drug
`
`which are known to be therapeutically significant can be used prospectively to
`
`establish a dosing regimen for patients.
`
`46.
`
`It may be important to monitor plasma concentrations in individual
`
`patients during therapy if one wishes to ensure that those levels are within the
`
`therapeutic range, in particular if for some reason the patient’s medical condition
`
`or genomic class warrants it. However, this is not always necessary, for example,
`
`if the field’s experience with the drug product and dosing regimen has established
`
`the typical blood plasma drug concentrations obtained.
`
`AstraZeneca EX. 2003 p. 15
`
`
`
`VII. CLAIM CONSTRUCTION
`
`47.
`
`I have been asked to consider Claims 1 and 5-9 of the ’ 160 Patent, and
`
`specifically the limitations directed to therapeutically significant blood plasma
`
`fulvestrant concentrations and durations.
`
`Claim 1
`
`Claim 5
`
`Claim 6
`
`Claim 7
`
`Claim 8
`
`Claim 9
`
`A method of treating a hormonal dependent benign or malignant disease
`of the breast or reproductive tract by administration to a human in need
`of such treatment an intra-muscular injection of a pharmaceutical
`formulation comprising fulvestrant, a mixture of from 10 to 30% weight
`of ethanol and benzyl alcohol per Volume of formulation and 10 to 25%
`weight of benzyl benzoate per Volume of formulation and a sufficient
`amount of castor oil Vehicle, whereby a therapeutically significant blood
`plasma fulvestrant concentration of at least 2.5 ngml’] is attained for at
`least 2 weeks after injection.
`
`The method as claimed in claim 1, wherein the blood plasma fulvestrant
`concentration is attained for at least 3 weeks after injection.
`
`The method as claimed in claim 1, wherein the blood plasma fulvestrant
`concentration is attained for at least 4 weeks after injection.
`
`The method as claimed in claim 1, wherein a therapeutically significant
`blood plasma fulvestrant concentration of at least 3 ngml'1 is attained for
`at least 2 weeks after injection.
`
`The method as claimed in claim 1, wherein a therapeutically significant
`blood plasma fulvestrant concentration of at least 8.5 ngml_1 is attained
`for at least 2 weeks after injection.
`
`The method as claimed in claim 1, wherein a therapeutically significant
`blood plasma fulvestrant concentration of at least 8.5 ngml_1 is attained
`for at least 4 weeks after injection.
`
`48.
`
`In my opinion, the “whereby” and “wherein” clauses of these claims
`
`are essential in order to practice the claims.
`
`AstraZeneca EX. 2003 p. 16
`
`
`
`49.
`
`The claimed methods do not specifically set forth the dose of
`
`fulvestrant that is to be administered nor the frequency of administration. Rather,
`
`these claims allow for both to be varied so long as the resultant blood plasma
`
`fulvestrant concentration and duration limitations are satisfied—that is more than a
`
`desired result, it is the result that must be obtained in order to practice the claims.
`
`50. Moreover, these therapeutically significant blood plasma fulvestrant
`
`concentration and duration limitations characterize and distinguish the claimed
`
`methods as involving the use of a “sustained release pharmaceutical formulation.”
`
`Ex. 1001, at abstract.
`
`51.
`
`As explained above, a Sustained release formulation slowly releases
`
`drug over an extended period of time to achieve and maintain a prolonged
`
`therapeutic effect (also often described as an extended release formulation). Supra
`
`at W 30-33, 36.
`
`52.
`
`This stands in contrast to conventional or immediate release
`
`formulations, which result in a rapid rise in blood plasma drug levels—to an early,
`
`high peak—followed by a relatively rapid decrease in those levels. Supra at M 28-
`
`29, 36.
`
`53.
`
`The objective of a sustained release fonnulation is completely
`
`different than that for an immediate release formulation: “[t]he objective in
`
`designing a sustained-release system is to deliver drug at a rate necessary to
`
`AstraZeneca Ex. 2003 p. 17
`
`
`
`achieve and maintain a constant drug blood level” for an extended period of time.
`
`Supra at 1] 31. Moreover, again, as can be seen from the image below, a sustained
`
`release formulation exhibits a completely different concentration—time course than
`
`an immediate release formulation.
`
`immediate-release
`
`IHA2"...4/
`
`mini mumeffectiue level
`
`
`
`drugconcentrationinplasma
`
`sustained-1-eleasae
`
`time after dosing
`
`54.
`
`It is clear that the invention here involves use of “sustained release”
`
`forrnulations—a characteristic now firmly set forth in the wherein clauses that
`
`would be removed from the claims if those clauses were to be ignored. As such,
`
`from the perspective of a pharmacokinetist, it makes no sense to ignore those
`
`clauses.
`
`55.
`
`The inventors repeatedly identify “the invention” as concerning a
`
`“sustained release” formulation. For example, in the Abstract the invention is
`
`described as a “novel sustained release pharmaceuticalformulation adapted for
`
`administration by injection containing the compound 7ot-[9-(4,4,5 ,5 ,5 -
`
`pentafluoropentylsulphinyl)nonyl]oestra-l ,3 ,5 (1 0)-triene-3 , l 7 B-diol, more
`
`AstraZeneca Ex. 2003 p. 18
`
`
`
`particularly to a formulation adapted for administration by injection containing the
`
`compound 7(1- [9-(4 ,4,5 ,5 ,5 -pentafluoropentylsulphinyl)nonyl]oestra- l ,3 ,5 (l 0)-
`
`triene—3,l7B—diol in solution in a ricinoleate vehicle which additionally comprises
`
`at least one alcohol and a non-aqueous ester solvent which is miscible in the
`
`ricinoleate vehicle.” Ex. 1001, at abstract (emphasis added). The description of
`
`the invention states: “[t]he invention relates to a novel sustained release
`
`pharmaceutical formulation adapted for administration by injection containing the
`
`compound 70t- [9-(4 ,4,5 ,5 ,5 -pentafluoropentylsulphinyl)nonyl]oestra- l ,3 ,5 (l 0)-
`
`triene-3,l7B-diol.” Ex. 1001, at col.l, ll. 6-9.
`
`56.
`
`The sustained release properties and characteristics of the formulation
`
`are, in fact, discussed throughout the specification. For example, the specification
`
`explains that the inventors “surprisingly found that the .
`
`.
`
`. formulations of the
`
`invention provide, after intra—muscular injection, satisfactory release of
`
`fulvestrant over an extended period of time.” Ex. 1001, at col.8, ll.49-5l.
`
`(emphasis added). Additionally, the inventors explain “[w]e have found that
`
`despite the rapid elimination of the additional solubilizing excipients .
`
`.
`
`. from the
`
`formulation vehicle and the site of injection after injection of the formulation,
`
`AstraZeneca Ex. 2003 p. 19
`
`
`
`extended release at therapeutically significant levels1 of fulvestrant over an
`
`extended period can still be achieved by the formulation of the invention.” Ex.
`
`1001, at col.9, 11.10—16 (emphasis added). Further, the formulation is taught to
`
`achieve a “particularly even release profile,” (Ex. 1001, at col.l0, ll.55-56
`
`(emphasis added)), which as explained above is decidedly not what is achieved
`
`using an immediate release formulation. Supra 1111 28-33, 36.
`
`57.
`
`The patent specification even defines “extended release”: “[b]y use of
`
`the term ‘extended release’ we mean at least two weeks, at least three weeks,
`
`and, preferably at least four weeks of continuous release offulvestrant is
`
`achieved.
`
`In a preferred feature extended release is achieved for 36 days.
`
`Preferably extended release offulvestrant is for at least 2-5 weeks and more
`
`preferablyfor tliefollowingperiods (weeks) 2.5-5, 2.5-4, 3-4, 3.5-4 and most
`
`preferably for at least about 4 weeks.” Ex. 1001, at col.9, ll.24-31 (emphasis
`
`added).
`
`1 Of note, the inventors also state, “[b]y use of the tenn ‘therapeutically significant
`
`levels’ we mean that blood plasma concentrations of at least 2.5 ngml_1, ideally at
`
`least 3 ngml_1, at least 8.5 ngml_1, and up to 12 ngml_1 of fulvestrant are achieved
`
`in the patient.” Ex. 1001, at col.9, ll.l8-21.
`
`AstraZeneca Ex. 2003 p. 20
`
`
`
`58.
`
`Consistent with the specification, the formulation set forth in the
`
`method of use claims is likewise described as a sustained release formulation
`
`throughout the prosecution history. For example:
`
`i.
`
`Ex. 2132 (Dec. 3, 2002 Office Action), at 6-7 (noting the claim
`
`limitations missing from the prior art, including the limitations
`
`found in the wherein clause: “Dukes does not expressly teach
`
`the plasma concentration offulvestrant herein”) (emphasis
`
`added);
`
`Ex. 1002 (Aug. 21, 2008 Amendment), at 157-158 (“The
`
`invention therefore addresses the objective of defining (a) a
`
`pharmaceutically acceptable solvent or mixture of solvents (b)
`
`that will dissolve a sufficient quantity of fulvestrant [at least 250
`
`mg] (c) to form a small enough volume of formulation that is
`
`acceptable for injection [6 ml or less] and will provide ((1) a
`
`fulvestrant concentration of at least 45 mgml’1 [claim 36] and/or
`
`(e) the sustained release of fulvestrant whereby a therapeutically
`
`significant bloodplasmafulvestrant concentration ofat least 2.5
`
`ngml'1 is attainedfor at least 2 weeks [claim 35]”) (emphasis
`
`added);
`
`AstraZeneca Ex. 2003 p. 21
`
`
`
`iii.
`
`EX. 1002 (Aug. 21, 2008 Amendment) at 160-161 (“Support for
`
`the recitation in new dependent claim 39 of ‘wherein the blood
`
`plasma fulvestrant concentration is attained for at least 3 weeks
`
`after injection’ is found in the published specification, inter alia,
`
`at lines 1-2 of paragraph [0048] .”; “Support for the recitation in
`
`new dependent claim 40 of ‘wherein the blood plasma
`
`fulvestrant concentration is attained for at least 4 weeks after
`
`injection’ is found in the published specification, inter alia, at
`
`lines 2-3 of paragraph [0048].”; “Support for the recitation in
`
`new dependent claim 41 of ‘wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 3
`
`ngml'1 is attained’ is found in the published specification, inter
`
`aim, at line 3 of paragraph [O047].”; Support for the recitation in
`
`new dependent claim 42 of ‘wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 8.5
`
`ngm1'1 is attained’ is found in the published specification, inter
`
`aim, at line 3 of paragraph [0048].”; Support for the recitation in
`
`new dependent claim 43 of ‘wherein a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 8.5
`
`ngm1'1 is attained for at least 4 weeks after injection’ is found in
`
`AstraZeneca EX. 2003 p. 22
`
`
`
`the published specification, inter alia, at line 3 of paragraph
`
`[0048] and at lines 2-3 of paragraph [0048].”);
`
`iv.
`
`Ex. 1002 (Aug. 21, 2008 Amendment), at 163 (“The invention is
`
`focused in particular on the discovery of a novel and unobvious
`
`formulation for this extremely difficult to formulate molecule,
`
`which formulation is suitable for intramuscular injection to a
`
`human patient and is capable of dissolving the therapeutic target
`
`amount of fulvestrant in a small enough volume for IM
`
`administration, and which formulation provides for the
`
`satisfactory sustained release of fulvestrant over an extended
`
`period of time as specified in the present claims”) (emphasis
`
`added);
`
`Ex. 1002 (Aug. 21, 2008 Amendment), at 164 (“However,
`
`developing an IM injectable formulation for fulvestrant that
`
`would achieve the satisfactory sustained release of the drug
`
`over an extendedperiod ofweeks presented a particularly
`
`difficult challenge to the experienced formulator”) (emphasis
`
`added);
`
`vi.
`
`Ex. 1002 (Aug. 21, 2008 Declaration), at 185 (explaining the
`
`goal of the research was “to formulate an intramuscular (IM)
`
`AstraZeneca Ex. 2003 p. 23
`
`
`
`injection that would provide for the satisfactory sustained
`
`release of fulvestrant over a period of at least two weeks and
`
`preferably over a period of at least four weeks to reduce the
`
`frequency of administration”) (emphasis added);
`
`Vii.
`
`Ex. 2141 (Jan. 17, 2012 Amendment), at 5 (“The Office
`
`acknowledges that McLeskey does not expressly teach ‘the use
`
`of fulvestrant in treating hormonal dependent diseases of
`
`breast’, ‘the dosing regimen to be once a month, intramuscular
`
`administration’, ‘the Volume administered’, or ‘the herein
`
`claimed serum concentration offulvestranf”) (emphasis added);
`
`Viii.
`
`Ex. 2141 (Jan. 17, 2012 Amendment), at 15, 19 (“The POSITA
`
`would not have had a reasonable expectation that the McLeskey
`
`castor oil composition would have been eflective to administer
`
`fulvestrant intramuscularly to achieve a therapeutic eflectfor at
`
`leastfour weeks, as instantly recited. Two independent reasons
`
`are set forth below supporting a lack of expectation of success
`
`for the combination of the references cited by the Office. .
`
`. [a]
`
`POSITA would not have had an expectation that the results
`
`from subcutaneous injection in McLeskey would have been
`
`applicable to the intramuscular administration of fulvestrant .
`
`.
`
`.
`
`AstraZeneca Ex. 2003 p. 24
`
`
`
`[and n]umerous variables affect the efficacy of an intramuscular
`
`formulation (e.g.,. [sic] identity and proportion of cosolvents)
`
`and a POSITA would have understood that the resulting
`
`variability precludes a POSITA from having an expectation a
`
`priori that a given formulation would be successful in a given
`
`method of treatment until actual suitable in vivo experiments are
`
`performed”) (emphasis added);
`
`ix.
`
`Ex. 2138 (Jan. 17, 2012 Declaration), at 20-21 (“Moreover, the
`
`examples above underscore the fact that efficacy of a given drug
`
`administered by a given route of dosing (e. g., intramuscular)
`
`cannot be known until appropriate comparative studies are
`
`performed in a suitable animal model. For some drugs, the
`
`desired effect might be achieved following a particular route of
`
`dosing, but for other drugs it might not. The rate and extent of
`
`drug absorption, and the associated pharmacodynamics (e. g., the
`
`achievement of a desired drug effect) may differ greatly
`
`depending on the properties of the drug, the choice of an animal
`
`model, and the site of drug administration. Consequently, one
`
`of ordinary skill in the art having the very limited experimental
`
`subcutaneous data from McLeskey would not have had an
`
`AstraZeneca Ex. 2003 p. 25
`
`
`
`expectation that the intramuscular administration of fulvestrant
`
`using the McLesk
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