UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`INNOPHARMA LICENSING, LLC
`
`Petitioner
`
`V.
`
`ASTRAZENECA AB
`
`Patent Owner
`
`
`
`Case IPR2017-00904
`
`U.S. Patent 6,774,122
`
`
`DECLARATION OF RONALD J. SAWCHUK, PH.D. IN SUPPORT OF
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`AstraZeneca Exhibit 2003 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`I)
`
`1)
`
`11)
`
`IV)
`
`V)
`
`VI)
`
`VII)
`
`VII)
`
`INTRODUCTION... cecetec cence eeteeseeeesseesessessecseenseeseeaeeseeseeaeeeens 1
`
`QUALIFICATIONS AND EXPERIENCE....0..00cccccccccecceeceeeeeseeteeteeeees 1
`
`MY UNDERSTANDING OF THE PROCEEDING..........0.:cccccceccesseeeees 5
`
`MATERIALS CONSIDERED 0000... ccececeeccceeeeeeeeeeeeeeecaeeneeaeenaeeseeneeaeeeens 6
`
`MY OPINIONS AND THEIR BASES. .00...ccccccecceeeeetececeeeenseeeteeeeeseesens 6
`
`SUMMARY OF APPLICABLE LEGAL CONSIDERATIONG................ 7
`
`CLAIM CONSTRUCTION...0..0cccceccceeeeeceeeceeceneeeeeeeceeeseneessenseeseeeeatees 8
`
`THE STATE OF THE ART AS OF JANUARY10, 2000.00... 10
`
`A)
`
`Drug Delivery And Pharmacokinetics........0..000.ccecceceecseetteeeteeeee 10
`
`B)—Pharmacokinetics, Pharmacodynamics, And The
`Development Of Drugs Through Clinical Trials......0..0.0... ee 13
`
`C)
`
`Targeted Blood Plasma Drug Concentrations During Therapy......16
`
`[X)
`
`OVERVIEW OF THE PROSECUTIONHISTORY.......0cccceeeeeeseeees 18
`
`A)—The Sawchuk Declaration Describes Numerous Differences
`That Exist Between McLeskeyand the Patent Claims................... 18
`
`B)
`
`The Gellert Declaration and the Sawchuk Declaration Are
`Consistent and Both Support the Patentability of the
`Challenged Claims 0.0.00... cccccccccccececcseceeeseeceseseessesesseseneeeseeensens 20
`
`REFERENCES CITED BY DR. BERGSTROM............ccccceceseteteee 30
`
`A)
`
`B)
`
`C)
`
`Howell (Ex. 1007) oo. cee cecceteeesecnseeteesseessesseeteetseesseeaes 31
`
` McLeskey (Ex. 1008) oo... cece cece sete ceneeenseetseeteesseeetseesaes 37
`
`O’Regan (EX. 1009)... ieee ccc eccrteeecseeeneeeeeesenteeeneeensens AO
`
`THE CLAIM LIMITATIONS TO BLOOD PLASMA
`FULVESTRANT CONCENTRATIONS ARE NOVEL AND NOT
`OBVIOUS00... cccccccccccccccccees eects eecsseeseesseeseceseseeseessecssesseeesesseesseessesseeneeaens 4]
`
`X)
`
`XI)
`
`A)—Therapeutically Significant Blood Plasma Fulvestrant
`Concentrations Are Not Taught or Suggested in the Prior Art....... Al
`
`B)
`
`There Was No Motivation to Combine the Prior Art Cited and
`in Any Event, There Would Have Been No Reasonable
`Expectation of Success in Doing S0........cce ce eceeceeeeeeseenteetteeteeees 47
`
`AstraZeneca Exhibit 2003 p. 2
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`

`

`C)
`
`The Skilled Artisan Would Not Have Expected the Castor
`Oil-Based Formulation in McLeskey to Achieve the Claimed
`Therapeutically Significant Fulvestrant Concentration
`LimmitatiOns.2.... cece eee ec eecceeecees cee eecaseseceeceseeenseesseeeseeesseesseesseeeneens 50
`
`XII)
`
`THE GAPS IN DR. BERGSTROM’S ANALYSIS ARE NOT
`FILLED BY INNOPHARMA’S OTHER EXPERTS’ OPINIONS.......... 54
`
`XIIT) CONCLUSION 0.0. ccceecceteenceceeeeeeeeneeseeneeseeseeeneeneeseesneeneeneeeaes 76
`
`AstraZeneca Exhibit 2003 p. 3
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`

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`I, Ronald J. Sawchuk, Ph.D., do hereby make the following declaration:
`
`IT)
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am overthe age of eighteen and competent to make this declaration.
`
`I have been retained as an expert witness on behalf of AstraZeneca
`
`AB for the above-captioned inter partes review (IPR).
`
`I am being compensatedat
`
`my customary rate of $875 per hour for my consultation in connection with this
`
`matter. My compensation is in no way dependent on the outcome of my analysis
`
`or opinions rendered in this matter.
`
`I) QUALIFICATIONS AND EXPERIENCE
`
`3.
`
`My nameis Ronald J. Sawchuk, Ph.D.
`
`I ama Professor of
`
`Pharmaceutics, Emeritus, and Morse Alumni Distinguished Teaching Professor.
`
`I
`
`also served as the Director of the Bioanalytic and Pharmacokinetic Services
`
`Laboratory at the University of Minnesota until August of 2014 when I completed
`
`a drug developmentcontract at the University.
`
`I have studied and carried out
`
`clinical and pre-clinical research in the field of pharmacokinetics and
`
`biopharmaceutics for over forty years.
`
`4,
`
`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
`
`AstraZeneca Exhibit 2003 p. 4
`
`

`

`emphasis) at the University of California, San Francisco, which wasgranted in
`
`1972.
`
`5.
`
`At the University of Minnesota I 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.
`
`I wasalso a participating instructor in
`
`biopharmaceutics, and advanced pharmacokinetics.
`
`I continue to provide lectures
`
`relating to preclinical and clinical pharmacokineticsto scientists in the
`
`pharmaceutical industry.
`
`6.
`
`I also served as a memberof the graduate programs in Pharmaceutics,
`
`Neurosciences, and Experimental and Clinical Pharmacology. From 1983 to 1989
`
`and 1991 to 1994, I was the Director of Graduate Studies in Pharmaceuticsat the
`
`University. From 1982 to 1995, I also served as Director of the Clinical
`
`Pharmacokinetics Laboratory at the College of Pharmacyat the University of
`
`Minnesota. From 1998 to 1999 I served as the Head of the Department of
`
`Pharmaceutics at the University of Minnesota.
`
`7.
`
`Although I have formally retired from the University, my Graduate
`
`Faculty appointment in the Department of Pharmaceuticsisstill in effect, allowing
`
`AstraZeneca Exhibit 2003 p. 5
`
`

`

`me to teach graduate students in the program.
`
`I have advised on the orderof forty
`
`graduate students, postdoctoral fellows, and visiting scholars, on projects relating
`
`to preclinical and clinical pharmacokinetics, biopharmaceutics, and bioanalytical
`
`chemistry.
`
`8.
`
`A major focus of my research was preclinical and clinical
`
`pharmacokinetics.
`
`I have been involved with manydifferent preclinical and
`
`clinical humantrials, and in particular with the analysis of the pharmacokinetic and
`
`other data generated during those trials.
`
`I 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.
`
`9,
`
`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
`
`numerouspublicationsin 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
`
`AstraZeneca Exhibit 2003 p. 6
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`

`

`Administration (“FDA”).
`
`10. During mycareer, 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.
`
`11.
`
`Ihave been amemberof numerousscientific and clinical societies.
`
`I
`
`am a Fellow of the American Association of Pharmaceutical Scientists and ofthe
`
`American Association for the Advancement of Science.
`
`I have been a memberof
`
`the International Society of Anti-infective Pharmacology and the International
`
`Society for the Study of Xenobiotics (SSX).
`
`I served a three-year term as a
`
`member-at-large on the American Association of Pharmaceutical Scientists
`
`(AAPS) Executive Council.
`
`12.
`
`Ihaveserved on the editorial boards of scientific journals such as the
`
`Journal of Pharmaceutical Sciences.
`
`I am currently on the Editorial Board ofthe
`
`AAPS Journal, and on the ISSX Journal, Xenobiotica.
`
`I have also served on
`
`numerous advisory committees and review panels.
`
`13.
`
`J amanamed author on over 100 refereed scientific publications,
`
`several book chapters and over 170 abstracts, which have been presented at
`
`AstraZeneca Exhibit 2003 p. 7
`
`

`

`scientific meetings.
`
`I have also co-edited a book on drug bioavailability and given
`
`hundredsof invited lectures.
`
`14.
`
`| have significant experience in the areas of pharmaceutical research,
`
`pharmacokinetics, and drug development. Therefore, I believe that I am qualified
`
`to render the opinionsset forth in this declaration.
`
`15. My academic background and work experience are summarized in my
`
`curriculum vitae, attached to this declaration as Exhibit A.
`
`16.
`
`Inthe past four years, I havetestified in the followinglitigation:
`
`Ferring v. Watson (July 17, 2013); Ferring v. Watson and Apotex (Jan 21-30,
`
`2014); Shire v. Actavis et al. (Feb 13, 2014); Astra-Zeneca v. Sandozet al. (June 5,
`
`2015); BMS v. Teva (August 25, 2015); Astra-Zeneca v. Sandozet al. (March 23,
`
`2016); and Astra-Zeneca v. Sagent and Glenmark (July 11-14, 2016).
`
`I) MY UNDERSTANDING OF THE PROCEEDING
`
`17.
`
`I have been informed that this proceeding is an inter partes review
`
`(“IPR”) before the Patent Trial and Appeal Board ofthe United States Patent and
`
`Trademark Office (“the Board”).
`
`I have been informed that an IPR is a proceeding
`
`to review the patentability of one or more issued claims in a United States patent
`
`on the groundsthat the patent is the same as or rendered obviousin view ofthe
`
`prior art.
`
`18.
`
`J understand that InnoPharma Licensing, LLC (“InnoPharma”) has
`
`AstraZeneca Exhibit 2003 p. 8
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`

`

`challenged AstraZeneca-owned U.S. Patent No. 6,774,122, whichrelates to a
`
`method of treating hormonal dependent disease of the breast or reproductive tract,
`
`and, more specifically hormonal dependent breast cancer.
`
`19.
`
`[have been informed that InnoPharmafiled a PetitionUPR2017-
`
`00904, Paper 1) (“Petition”) requesting IPR of U.S. Patent No. 6,774,122 (the
`
`“° 122 Patent’), which issued to John R. Evans and Rosalind U. Grundy on August
`
`10, 2004 andis assigned to AstraZeneca AB.
`
`I have reviewed the Petition, and
`
`understandthatit alleges that claims 1, 2, 5 and 9 of the ’122 Patent are
`
`unpatentable over Howell 1996 (Ex. 1007) and, alternatively, over the combination
`
`of Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008), and the combination of
`
`Howell 1996 (Ex. 1007) with McLeskey (Ex. 1008) and O’Regan (Ex. 1009).
`
`IV) MATERIALS CONSIDERED
`
`20.
`
`In preparing this declaration, I reviewed the Howell 1996 (Ex. 1007),
`
`McLeskey (Ex. 1008) and O’Regan (Ex. 1009); the ’122 Patent (Ex. 1001); the
`
`declaration of Dr. Bergstrom (Ex. 1013); and the other exhibits listed in Exhibit B.
`
`V) MY OPINIONS AND THEIR BASES
`
`21.
`
`In this declaration, I was asked to provide opinions concerning:
`
`A.—The qualifications of a person of ordinary skill in the art as of
`
`January 10, 2000;
`
`B._Thestate of the art as of January 10, 2000;
`
`AstraZeneca Exhibit 2003 p. 9
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`

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`C.
`
`The claim limitations “whereby a therapeutically significant
`
`blood plasmafulvestrant concentration ofat least 2.5 ngml'' is
`
`attained for at least 2 weeks after injection” (Claims 1 and 2);
`
`and
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`D.—The declaration of Dr. Richard Bergstrom, Ph.D. (Ex. 1013)
`
`(“Bergstrom Decl.”) and exhibits cited therein.
`
`22.
`
`As part of this opinion, I considered the level of ordinary skill in the
`
`art around January 2000, which represents the filing date of GB 0000313, to which
`
`the °122 Patent claimspriority.
`
`23.
`
`Based on myreview ofthe materials identified above in Section IV)
`
`as well as the materials listed in Exhibit B, and my knowledge and experience, my
`
`opinionsare as follows:
`
`VI)
`
`SUMMARYOF APPLICABLE LEGAL CONSIDERATIONS
`
`24.
`
`Counsel for AstraZeneca requested that I express my opinions with
`
`certain guidelines in mind, whichare set forth below.
`
`25.
`
`Forthis declaration I have been asked to use January 10, 2000 as the
`
`relevant date for my analysis.
`
`26. 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 theart is
`
`AstraZeneca Exhibit 2003 p. 10
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`

`

`a hypothetical person, who has the characteristics of an ordinary artisan including
`
`ordinary creativity.
`
`27.
`
`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, medicineor 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
`
`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.
`
`28. Unless expressly stated 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.
`
`VID CLAIM CONSTRUCTION
`
`29.
`
`All of the claims of the ’122 Patent are expressly directed to methods
`
`of treatment. The methods of treatment include choice of an active ingredient, a
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`method of administration (1.e., a combination of excipients and active injected
`
`intramuscularly), and the amountof the active to be delivered to the blood ina
`
`sustained release fashion to treat hormonal dependentdisease of the breast and
`
`AstraZeneca Exhibit 2003 p. 11
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`

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`reproductive tract.
`
`30.
`
`J agree with Dr. Bergstrom that the therapeutically significant blood
`
`plasma fulvestrant concentration terms in the ?122 Patent claims are limitations of
`
`the claims. Bergstrom Decl. § 60. These limitations are in claims 1 and 2:
`
`“whereby a therapeutically significant blood plasma fulvestrant concentration ofat
`
`least 2.5 ngml'is attained for at least 2 weeksafter injection.”
`
`31. A person ofskill in the art would understand this limitation to mean
`
`that the specified blood plasma fulvestrant concentrationsofat least 2.5 ngml”is
`
`achieved and maintained for the specified amountof time,1.e., at least 2 weeks.
`
`This is consistent with the Board’s finding in Mylan Pharmaceuticals Inc. v.
`
`AstraZeneca AB, Case IPR2016-01325, Paper No. 11 (P.T.A.B. Dec. 14, 2016).
`
`Ex. 1011 (PTAB Decision) at 18 (“[W]e interpret ‘achieves’ in the wherein clauses
`
`as meaning that the concentration of fulvestrant in a patient’s blood plasmaisat or
`
`above the specified minimum concentration for the specified time period.”’).
`
`32.
`
`Further, these limitations give meaning to and provide defining
`
`characteristics of the method of treatment. Indeed, as the Board previously held,
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`“rather than merely stating the result of intramuscularly administering the recited
`
`formulation, [] the wherein clause dictates both the administration duration and
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`dose of the formulation, i1.e., an amount sufficient to provide a therapeutically
`
`significant blood plasma fulvestrant concentration ofat least 2.5 ngml”forat least
`
`AstraZeneca Exhibit 2003 p. 12
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`

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`four weeks.” Ex. 1011 at 17. And, “[t]hat these parameters are further limited in
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`claim[] 2, [] (‘the therapeutically significant blood plasma fulvestrant
`
`concentrationis at least 8.5 ngml’'’) further indicates that the wherein clauses
`
`provide defining characteristics.” Jd.
`
`VIII) THE STATE OF THE ARTAS OF JANUARY10, 2000
`
`A)
`
`Drug Delivery And Pharmacokinetics
`
`33. 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 ortissue.
`
`34. Here, the point of the formulations set forth in the challenged patent
`
`claims is to deliver specified blood plasmalevels of the drug fulvestrant for
`
`specified times.
`
`35.
`
` Interms of duration, one conventional distinction involves the
`
`difference between immediate and sustained released formulations.
`
`36.
`
`“Immediate release” means the active pharmaceutical ingredientis
`
`released without a delay from its dosage form after it is administered. Most
`
`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.
`
`10
`
`AstraZeneca Exhibit 2003 p. 13
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`

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`37.
`
`Characteristic of immediate release formulationsis a relatively rapid
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`rise in the blood plasma drug levels—to an early and high peak—followedby a
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`relatively rapid decrease in those levels.
`
`38.
`
`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 formulationsare also
`
`often referred to as extended-release formulations.
`
`39. With “sustained release” “blood level oscillation characteristic of
`
`multiple dosing of conventional dosage formsis reduced, because a more even
`
`blood level is maintained.” Ex. 2134 (Lachman’s) at 5. “Sustained-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
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`level.” Ex. 2080 (Remington’s) at 6.
`
`40. 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
`
`time after administration of a single dose. In the case of injectable 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
`
`11
`
`AstraZeneca Exhibit 2003 p. 14
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`

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`therapeutic effect by continuously releasing medication over an extended period of
`
`time after administration of a single dose.” /d.
`
`41. Many sustained-release 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).
`
`42.
`
`The study of the time-course of blood plasmalevels 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.
`
`43.
`
`This rate and extent of drug exposure requires in vivo pharmacokinetic
`
`studies. In a clinical study setting, pharmacokineticists determine the
`
`concentration of drug in a subject’s plasma overtime (by periodically drawing
`
`blood) in order to understand how the body processesthe drugasit is being
`
`absorbed from a given formulation after it has been administered. Typically a
`
`graph of plasma drug 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.
`
`12
`
`AstraZeneca Exhibit 2003 p. 15
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`

`

`44.
`
`The figure below illustrates the difference between the time-course of
`
`a sustained-(solid curve) and immediate-release (dotted curve) formulationfor 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
`
`ee
`
`time after dosing
`
`B)
`
`Pharmacokinetics, Pharmacodynamics, And The Development Of
`Drugs Through Clinical Trials
`
`45.
`
`Clinical trials are conducted in a series of steps, referred to as Phases.
`
`Ifa 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 PhaseI, IJ and UI,
`
`respectively.
`
`46.
`
`The disciplines of pharmacokinetics and pharmacodynamicsare
`
`important areas of activity throughout clinical development.
`
`47.
`
`Pharmacokinetics is essentially the study of the relationship between
`
`La
`
`AstraZeneca Exhibit 2003 p. 16
`
`

`

`the dose, or dosing regimenthat is used in animals or humans, and the plasma or
`
`serum concentrations of the drug that are produced. The profile of plasma
`
`concentrations or levels observed depends uponthe rate and extent of absorption of
`
`the drug from its dosage form into the subject’s bloodstream, in addition to howit
`
`is distributed within the body, and how rapidly andefficiently it is clear from the
`
`body by the organsof elimination.
`
`48.
`
`Related to pharmacokinetics 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 absorption1s
`
`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 “Cyax” and “Tax,” 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
`
`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.
`
`14
`
`AstraZeneca Exhibit 2003 p. 17
`
`

`

`49. 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 underthe blood plasma
`
`concentration-time curve (the AUC).
`
`50.
`
`Pharmacodynamics involvesthe study of the potential relationship
`
`between plasmalevels 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
`
`plasmalevels, this relationship is often very difficult to identify for a variety of
`
`reasons including the complex and usually unknown mechanismsof action for
`
`many drugs. For example, a disequilibrium in the concentrations of the drugat the
`
`measurementsite (1.e. the blood plasma or serum) and those in whatis referred to
`
`as an “effect compartment” often complicates the relationship between drug levels
`
`and therapeutic response. In this case, there may be a significant delay in the
`
`response, such that effects occur much later than expected based upon the pattern
`
`of plasma levels of the drug. Other examples include a situation where there is a
`
`complicated cascade of events that must occur over time (e.g., changes in the level
`
`and activity of clotting factors resulting from the administration of an anticoagulant
`
`that interferes with the “clotting cascade”) before a response to the drug is
`
`observed.
`
`15
`
`AstraZeneca Exhibit 2003 p. 18
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`

`

`51.
`
` Acareful analysis of the relationship between plasma drug levels and
`
`the effects that the drug produces is required to establish any “pharmacokinetic-
`
`pharmacodynamic”link and typically requires careful and detailed observations of
`
`the results of numerousclinical studies. Significant data (usually including data
`
`from PhaseIII clinical trials) and a careful analysis of the relationship between
`
`plasma drug levels and the effects that a drug producesis required to establish any
`
`“pharmacokinetic-pharmacodynamic”link. Indeed, as Dr. Bergstrom correctly
`
`notes (Ex. 1013 § 33), large numbers of patients are needed to establish a
`
`pharmacokinetic-pharmacodynamiclink. I agree.
`
`C)
`
`52.
`
`Targeted Blood Plasma Drug Concentrations During Therapy
`
`Ifarelationship between plasma concentrations and response—
`
`efficacy and/or adverse effects—canbe established for a drug, that may allow for
`
`the developmentofa strategy involving achieving and maintaining a target
`
`concentration or a target range of concentrations for individual patients.
`
`53.
`
`This target(s) corresponds with the greatest likelihood of therapeutic
`
`success. Stated differently, ranges of serum or plasma concentrations of a drug
`
`which are knownto be therapeutically significant can be used prospectively to
`
`establish a dosing regimenforpatients.
`
`54.
`
`It may be important to monitor plasma concentrationsin individual
`
`patients during therapy if one wishes to ensure that those levels are within the
`
`16
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`AstraZeneca Exhibit 2003 p. 19
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`

`

`therapeutic range, in particular if for some reason the patient’s medical condition
`
`or genomicclass warrants it. However, this is not always necessary, for example,
`
`if the field’s experience with the drug product and dosing regimen hasestablished
`
`the typical blood plasma drug concentrations obtained. In any event, clinicians
`
`who havethe responsibility for the care of patients in oncologyare typically well
`
`informed about monitoring patient response, including assessing therapeutic
`
`efficacy, and the incidence of troublesomedrug related side effects, and making a
`
`changein his or her drug therapy as the situation requiresit.
`
`55.
`
`The minimumeffective plasma concentration of a drug (MEC), may
`
`also be considered to be a minimum target concentration for a patient receiving
`
`medication on a multiple dosing regimen. A minimum toxic concentration of a
`
`drug (MTC), if established, would represent the upper end ofthis target range. The
`
`range of plasma concentrations between the MEC and MTCisreferred to as the
`
`“therapeutic window.” Patient factors, such as differences in receptor density,
`
`protein binding, and disease state, may contribute to variability in this range in
`
`somepatients. Nevertheless, therapeutic windowsare considered for many drugs
`
`to represent a range of concentrations within which the likelihood of a desired
`
`clinical effect 1s relatively high, and that of unacceptable toxicity is relatively low.
`
`56.
`
`It should be noted that response to some drugs changes with plasma
`
`drug concentrations closely in time. For other drugs the response may change
`
`17
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`AstraZeneca Exhibit 2003 p. 20
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`

`

`more slowly than the plasma concentrations; this may result from an equilibrium
`
`delay between drug levels in the bloodstream and thoseat the site of action in the
`
`body, as alluded to above. Such a delay mayresult in a slow onsetof effect, and
`
`may allow the desired response to continue with the same intensity even though the
`
`plasma drug concentrations are decreasing. Whether drug effects are closely
`
`associated in time with plasma drug levels, or exhibit a delay in onset or an
`
`extended duration ofaction that is unexpected in view of declining plasmalevels,
`
`depends on the mechanism of action of the drug. Detailed pharmacokinetic—
`
`pharmacodynamic modeling studies are often necessary to understand any linkage
`
`between plasma drug concentrations and the response(e.g., the desired therapeutic
`
`effects) observed for a particular drug.
`
`IX) OVERVIEW OF THE PROSECUTION HISTORY
`
`57.
`
`There are a numberof inaccuracies in Dr. Bergstrom’s description of
`
`the prosecution history. However, because I do not understand Dr. Bergstrom’s
`
`paragraphs 34-48 and 53-59 to be relevant to his opinions regarding the validity of
`
`the challenged claims, I comment here only with regard to the Declaration Under
`
`37 C.F.R. § 1.132 of Ronald J. Sawchuk, dated January 13, 2012 andfiled during
`
`the prosecution of the ’680 patent (Ex. 1019) (the “Sawchuk Declaration’), which I
`
`authored. The Sawchuk Declaration is discussed below.
`
`A)
`
`The Sawchuk Declaration Describes Numerous Differences That
`Exist Between McLeskey and the Patent Claims
`
`18
`
`AstraZeneca Exhibit 2003 p. 21
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`

`

`58. With respect to the information in McLeskey regarding the castoroil
`
`fulvestrant composition, the Sawchuk Declaration explains that “[iJn a liquid
`
`composition, when a solute or cosolvent is a liquid,it is often convenient to
`
`express its concentration as a volumepercent, 1.e., % v/v.” Ex. 1019 at § 17.
`
`Citing numerousprior art examples where that is the case, 1.¢., prior art references
`
`that express the concentration of liquid solutes or cosolvents in liquid compositions
`
`as volume percent (% v/v), the Sawchuk Declaration states my belief that “one of
`
`ordinary skill in the art would have concluded the McLeskeycastoroil
`
`composition wasdescribed in volume/volumeunits (% v/v).” Ex. 1019 at 917. In
`
`reaching that opinion in the Sawchuk Declaration, I did not consider the patents
`
`because they are not part of the state of the art “prior to January 10, 2000.” Ex.
`
`1019 at 7 15.
`
`I do, however, note that Dr. McLeskeyherself testified she believed
`
`the McLeskey castor oil composition described to be in volume/volumeunits (%
`
`v/v). Ex. 2043 at ¥ 8.
`
`59. With respect to Dr. Bergstrom’s paragraphs 49-52, I understand these
`
`paragraphsto be related to Dr. Bergstrom’s opinions regarding validity of the
`
`challenged claims. Accordingly I address these points below in myanalysis of
`
`why, in my opinion, the claimed therapeutically significant blood plasma
`
`fulvestrant concentrations are novel and why oneof ordinary skill in the art would
`
`neither combine Howell and McLeskey, nor be motivated to find or reasonably
`
`19
`
`AstraZeneca Exhibit 2003 p. 22
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`

`

`expect any formulation described in McLeskey to exhibit the sameor similar
`
`pharmacokinetics described in Howell.
`
`B)
`
`The Gellert Declaration and the Sawchuk Declaration Are
`Consistent and Both Support the Patentability of the Challenged
`Claims
`
`60.
`
`In paragraphs 53-57, Dr. Bergstrom attempts to re-write certain facts
`
`of the prosecution history of the ’680 patent prosecution to suggest that the
`
`Sawchuk Declaration was inconsistent with the Declaration Under 37 C.F.R. §
`
`1.132 of Paul Richard Gellert, dated August 8, 2008 andfiled during the
`
`prosecution ofthe ’160 patent (Ex. 1020) (the “Gellert Declaration”).' Contrary to
`
`Dr. Bergstrom’s assertions, the facts of the prosecution history clearly establish the
`
`Gellert and Sawchuk declarations are consistent, and both support the patentability
`
`of the challenged claims. Based on the clear facts in the prosecution history, Dr.
`
`Bergstrom is incorrect.
`
`61.
`
`First, the Gellert and Sawchuk declarations are written from different
`
`perspectives. Unlike the Gellert Declaration, the Sawchuk Declaration is written
`
`from the perspective of one of ordinary skill in the art without the benefit of the
`
`inventors’ confidential research. The purpose of the Sawchuk Declaration wasto
`
`“explain how a person ofordinary skill in that art at that time [1.¢., prior to January
`
`
`
`' The Gellert Declaration was attached as an exhibit to the Sawchuk Declaration.
`See Ex. 1019 at page 27.
`
`20
`
`AstraZeneca Exhibit 2003 p. 23
`
`

`

`10, 2000] would have understood the references cited in the Office Action and how
`
`such a person would haveinterpreted certain experimental results related to various
`
`fulvestrant formulations.” Ex. 1019 at ¥ 15.
`
`62.
`
`On the other hand, the Gellert Declaration, which is not prior art, 1s
`
`written by an internal AstraZeneca scientist familiar with the work of the inventors
`
`and clearly begins with the invention in mind. Ex. 1020 at 7 11. (‘In aboutearly
`
`2000, a person responsiblefor developing a sustained release injectable
`
`formulation suitablefor administration to humansfor a new steroidal compound
`
`such asfulvestrant, would have had specialized training and experience in
`
`developing pharmaceut