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
`
`US 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)
`
`11)
`
`III)
`
`IV)
`
`V)
`
`VI)
`
`VII)
`
`VIII)
`
`INTRODUCTION........................................................................................ 1
`
`QUALIFICATIONS AND EXPERIENCE ................................................. 1
`
`MY UNDERSTANDING OF THE PROCEEDING ................................... 5
`
`MATERIALS CONSIDERED .................................................................... 6
`
`MY OPINIONS AND THEIR BASES ........................................................ 6
`
`SUMMARY OF APPLICABLE LEGAL CONSIDERATIONS ................ 7
`
`CLAIM CONSTRUCTION ......................................................................... 8
`
`THE STATE OF THE ART AS OF JANUARY 10, 2000 ....................... 10
`
`A)
`
`B)
`
`Drug Delivery And Pharmacokinetics ............................................. 10
`
`Pharmacokinetics, Pharmacodynamics, And The
`Development Of Drugs Through Clinical Trials ............................. 13
`
`C)
`
`Targeted Blood Plasma Drug Concentrations During Therapy ...... 16
`
`IX)
`
`OVERVIEW OF THE PROSECUTION HISTORY ................................ 18
`
`A)
`
`B)
`
`The Sawchuk Declaration Describes Numerous Differences
`That EXist Between McLeskey and the Patent Claims .................... 18
`
`The Gellert Declaration and the Sawchuk Declaration Are
`Consistent and Both Support the Patentability of the
`Challenged Claims ........................................................................... 20
`
`X)
`
`REFERENCES CITED BY DR. BERGSTROM ...................................... 30
`
`A)
`
`Howell (EX. 1007) ........................................................................... 31
`
`B) McLeskey (EX. 1008) ...................................................................... 37
`
`C)
`
`O’Regan (EX. 1009) ......................................................................... 40
`
`XI)
`
`THE CLAIM LIMITATIONS TO BLOOD PLASMA
`
`FULVESTRANT CONCENTRATIONS ARE NOVEL AND NOT
`
`OBVIOUS .................................................................................................. 41
`
`A)
`
`B)
`
`Therapeutically Significant Blood Plasma Fulvestrant
`Concentrations Are Not Taught or Suggested in the Prior Art ....... 41
`
`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 So ................................................ 47
`
`AstraZeneca Exhibit 2003 p. 2
`
`

`

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

`

`I, Ronald J. Sawchuk, Ph.D., do hereby make the following declaration:
`
`I)
`
`INTRODUCTION
`
`1.
`
`2.
`
`I am over the age of eighteen and competent to make this declaration.
`
`I have been retained as an expert witness on behalf of AstraZeneca
`
`AB for the above-captioned inter partes review (IPR).
`
`I am being compensated at
`
`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.
`
`II) QUALIFICATIONS AND EXPERIENCE
`
`3.
`
`My name is Ronald J. Sawchuk, PhD.
`
`I am a 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 20 14 when I completed
`
`a drug development contract at the University.
`
`I have studied and carried out
`
`clinical and pre-clinical research in the field of pharmacokinetics and
`
`biopharrnaceutics 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 (PhD) in Pharmaceutical Chemistry (pharmacokinetics
`
`AstraZeneca Exhibit 2003 p. 4
`
`

`

`emphasis) at the University of California, San Francisco, which was granted 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.
`
`1 was also a participating instructor in
`
`biopharrnaceutics, and advanced pharmacokinetics.
`
`I continue to provide lectures
`
`relating to preclinical and clinical pharmacokinetics to scientists in the
`
`pharmaceutical industry.
`
`6.
`
`I also served as a member of 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 Pharmaceutics at the
`
`University. From 1982 to 1995, I also served as Director of the Clinical
`
`Pharrnacokinetics 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.
`
`7.
`
`Although I have formally retired from the University, my Graduate
`
`Faculty appointment in the Department of Pharmaceutics is still in effect, allowing
`
`AstraZeneca Exhibit 2003 p. 5
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`

`

`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, biopharmaceutics, and bioanalytical
`
`chemistry.
`
`8.
`
`A major focus of my research was preclinical and clinical
`
`pharmacokinetics.
`
`l have been involved with many different preclinical and
`
`clinical human trials, and in particular with the analysis of the pharmacokinetic and
`
`other data generated during those trials.
`
`1 also focused my research on drug
`
`bioavailability and bioequivalence.
`
`l 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.
`
`l have expertise in the determination of pharmacokinetic parameters
`
`and metrics for orally administered drugs, bioanalytical chemistry,
`
`biopharrnaceutics, and pharrnacodynamics.
`
`l 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
`
`AstraZeneca Exhibit 2003 p. 6
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`

`

`Administration (“FDA”).
`
`10. 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.
`
`11.
`
`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 (ISSX).
`
`I served a three-year term as a
`
`member-at-large on the American Association of Pharmaceutical Scientists
`
`(AAPS) Executive Council.
`
`12.
`
`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 ISSX Journal, Xenobiotica.
`
`I have also served on
`
`numerous advisory committees and review panels.
`
`13.
`
`I am a named author on over 100 refereed scientific publications,
`
`several book chapters and over 170 abstracts, which have been presented at
`
`AstraZeneca Exhibit 2003 p. 7
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`

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`scientific meetings.
`
`I have also co-edited a book on drug bioavailability and given
`
`hundreds of invited lectures.
`
`14.
`
`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.
`
`15. My academic background and work experience are summarized in my
`
`curriculum vitae, attached to this declaration as Exhibit A.
`
`16.
`
`In the past four years, I have testified in the following litigation:
`
`Ferrmg v. Watson (July 17, 2013); Ferrmg v. Watson and Apotex (Jan 21-30,
`
`2014), Shire v. Actavis et al. (Feb 13, 2014); Astra-Zeneca v. Sandoz et al. (June 5,
`
`2015), EMS v. Teva (August 25, 2015); Astra-Zeneca v. Sandoz et al. (March 23,
`
`2016), and Astra-Zeneca v. Sagent and Glenmark (July 11-14, 2016).
`
`III) 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 of the United States Patent and
`
`Trademark Office (“the Board”).
`
`I have been informed that an IPR is a proceeding
`
`to review the patentability of one or more issued claims in a United States patent
`
`on the grounds that the patent is the same as or rendered obvious in view of the
`
`prior art.
`
`18.
`
`I understand that InnoPharma Licensing, LLC (“InnoPharma”) has
`
`AstraZeneca Exhibit 2003 p. 8
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`

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`challenged AstraZeneca-owned U. S. Patent No. 6,774,122, which relates to a
`
`method of treating hormonal dependent disease of the breast or reproductive tract,
`
`and, more specifically hormonal dependent breast cancer.
`
`19.
`
`l have been informed that InnoPharma filed a Petition (IPR2017-
`
`00904, Paper 1) (“Petition”) requesting IPR of US. Patent No. 6,774,122 (the
`
`122 Patent”), which issued to John R. Evans and Rosalind U. Grundy on August
`
`10, 2004 and is assigned to AstraZeneca AB.
`
`1 have reviewed the Petition, and
`
`understand that it 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 ’12 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, l was asked to provide opinions concerning:
`
`A.
`
`The qualifications of a person of ordinary skill in the art as of
`
`January 10, 2000;
`
`B.
`
`The state of the art as of January 10, 2000;
`
`AstraZeneca Exhibit 2003 p. 9
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`

`

`C.
`
`The claim limitations “whereby a therapeutically significant
`
`blood plasma fulvestrant concentration of at least 2.5 ngml‘1 is
`
`attained for at least 2 weeks after injection” (Claims 1 and 2),
`
`and
`
`D.
`
`The declaration of Dr. Richard Bergstrom, PhD. (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 ’ l22 Patent claims priority.
`
`23.
`
`Based on my review of the materials identified above in Section IV)
`
`as well as the materials listed in Exhibit B, and my knowledge and experience, my
`
`opinions are as follows:
`
`VI)
`
`SUMMARY OF APPLICABLE LEGAL CONSIDERATIONS
`
`24.
`
`Counsel for AstraZeneca requested that I express my opinions with
`
`certain guidelines in mind, which are set forth below.
`
`25.
`
`For this 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 the art 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, 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
`
`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.
`
`VII) 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
`
`method of administration (i.e., a combination of excipients and active injected
`
`intramuscularly), and the amount of the active to be delivered to the blood in a
`
`sustained release fashion to treat hormonal dependent disease of the breast and
`
`AstraZeneca Exhibit 2003 p. 11
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`

`

`reproductive tract.
`
`30.
`
`I 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. 11 60. These limitations are in claims 1 and 2:
`
`“whereby a therapeutically significant blood plasma fulvestrant concentration of at
`
`least 2.5 ngml‘1 is attained for at least 2 weeks after injection.”
`
`31. A person of skill in the art would understand this limitation to mean
`
`that the specified blood plasma fulvestrant concentrations of at least 2.5 nng'1 is
`
`achieved and maintained for the specified amount of time, i.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 plasma is at 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,
`
`“rather than merely stating the result of intramuscularly administering the recited
`
`formulation, [] the wherein clause dictates both the administration duration and
`
`dose of the formulation, i.e., an amount sufficient to provide a therapeutically
`
`significant blood plasma fulvestrant concentration of at least 2.5 ngml'1 for at 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
`
`claim[] 2, [] (‘the therapeutically significant blood plasma fulvestrant
`
`concentration is at least 8.5 nng'1 ’) further indicates that the wherein clauses
`
`provide defining characteristics.” Id.
`
`VIII) THE STATE OF THE ART AS OF JANUARY 10, 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 or tissue.
`
`34. 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.
`
`35.
`
`In terms of duration, one conventional distinction involves the
`
`difference between immediate and sustained released formulations.
`
`36.
`
`“Immediate release” means the active pharmaceutical ingredient is
`
`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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`

`

`37.
`
`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.
`
`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 formulations are also
`
`often referred to as extended-release formulations.
`
`39. 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. “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
`
`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
`
`ll
`
`AstraZeneca Exhibit 2003 p. 14
`
`

`

`therapeutic effect by continuously releasing medication over an extended period of
`
`time after administration of a single dose.” Id.
`
`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 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.
`
`43.
`
`This rate and extent of drug exposure requires in vivo pharrnacokinetic
`
`studies. In a clinical study setting, pharmacokineticists 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 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
`
`

`

`44.
`
`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
`
`/
`
`time after dosing
`
`B)
`
`Pharmacokinetics, Pharmacodynamics, And The Development Of
`Drugs Through Clinical Trials
`
`45.
`
`Climcal trials are conducted in a series of steps, referred to as Phases.
`
`If a drug is found to be “successfu ” in a given Phase, it is pemiitted to continue to
`
`the next. Typically there are three such Phases, referred to as Phase I, II and 111,
`
`respectively.
`
`46.
`
`The disciplines of pharmacokinetics and pharrnacodynamics are
`
`important areas of activity throughout clinical development.
`
`47.
`
`Pharmacokinetics is essentially the study of the relationship between
`
`13
`
`AstraZeneca Exhibit 2003 p. 16
`
`

`

`the dose, or dosing regimen that 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 upon the rate and extent of absorption of
`
`the drug from its dosage form into the subject’s 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.
`
`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 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
`
`includes the measurement and analysis of drug levels in plasma, which provides
`
`data used to calculate many pharmacokinetic parameters or metrics, such as AUC,
`
`CM. and Tmax.
`
`l4
`
`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 under the blood plasma
`
`concentration-time curve (the AUC).
`
`50.
`
`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. For example, a disequilibrium in the concentrations of the drug at the
`
`measurement site (i.e. the blood plasma or serum) and those in what is 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
`
`

`

`51. A careful 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 numerous clinical studies. Significant data (usually including data
`
`from Phase III clinical trials) and a careful analysis of the relationship between
`
`plasma drug levels and the effects that a drug produces is required to establish any
`
`"pharmacokinetic-pharmacodynamic" link. Indeed, as Dr. Bergstrom correctly
`
`notes (EX. 1013 11 33), large numbers of patients are needed to establish a
`
`pharmacokinetic-pharmacodynamic link.
`
`I agree.
`
`C)
`
`Targeted Blood Plasma Drug Concentrations During Therapy
`
`52.
`
`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.
`
`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 known to be therapeutically significant can be used prospectively to
`
`establish a dosing regimen for patients.
`
`54.
`
`It may be important to monitor plasma concentrations in 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 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. In any event, clinicians
`
`who have the responsibility for the care of patients in oncology are typically well
`
`informed about monitoring patient response, including assessing therapeutic
`
`efficacy, and the incidence of troublesome drug related side effects, and making a
`
`change in his or her drug therapy as the situation requires it.
`
`55.
`
`The minimum effective 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 of this target range. The
`
`range of plasma concentrations between the MEC and MTC is referred 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
`
`some patients. Nevertheless, therapeutic windows are considered for many drugs
`
`to represent a range of concentrations within which the likelihood of a desired
`
`clinical effect is 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 those at the site of action in the
`
`body, as alluded to above. Such a delay may result in a slow onset of 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 of action that is unexpected in view of declining plasma levels,
`
`depends on the mechanism of action of the drug. Detailed pharrnacokinetic—
`
`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 number of 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 CPR. § 1.132 of Ronald J. Sawchuk, dated January 13, 2012 and filed 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
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`AstraZeneca Exhibit 2003 p. 21
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`

`

`58. With respect to the information in McLeskey regarding the castor oil
`
`fulvestrant composition, the Sawchuk Declaration explains that “[i]n a liquid
`
`composition, when a solute or cosolvent is a liquid, it is often convenient to
`
`express its concentration as a volume percent, i.e., % v/v.” Ex. 1019 at 11 17.
`
`Citing numerous prior art examples where that is the case, i.e., 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 McLeskey castor oil
`
`composition was described in volume/volume units (% v/v).” Ex. 1019 at 11 17. 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 11 15.
`
`I do, however, note that Dr. McLeskey herself testified she believed
`
`the McLeskey castor oil composition described to be in volume/volume units (%
`
`v/v). Ex. 2043 at 11 8.
`
`59. With respect to Dr. Bergstrom’s paragraphs 49-52, I understand these
`
`paragraphs to be related to Dr. Bergstrom’s opinions regarding validity of the
`
`challenged claims. Accordingly I address these points below in my analysis of
`
`why, in my opinion, the claimed therapeutically significant blood plasma
`
`fulvestrant concentrations are novel and why one of ordinary skill in the art would
`
`neither combine Howell and McLeskey, nor be motivated to find or reasonably
`
`l9
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`AstraZeneca Exhibit 2003 p. 22
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`

`

`expect any formulation described in McLeskey to exhibit the same or similar
`
`pharmacokinetics described in Howell.
`
`B)
`
`The Gellert Declaration and the Sawchuk Declaration Are
`Consistent and Both Support the Patentability 0f 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 CPR. §
`
`1.132 of Paul Richard Gellert, dated August 8, 2008 and filed during the
`
`prosecution of the ’ 160 patent (Ex. 1020) (the “Gellert Declaration”).1 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 was to
`
`“explain how a person of ordinary skill in that art at that time [i.e., prior to January
`
`
`
`1 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 have interpreted certain experimental results related to various
`
`fulvestrant formulations.” Ex. 1019 at 11 15.
`
`62.
`
`On the other hand, the Gellert Declaration, which i