Case IPR20 1 7-00 905
`
`Declaration of Richard Bergstrom, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U. S. Patent No. 8,466,139
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`INNOPHARMA LICENSING, LLC,
`Petitioner
`
`V.
`
`ASTRAZENECA AB,
`Patent Owner
`
`Case IPR2017-00905
`
`Patent No. 8,466,139
`
`
`DECLARATION OF RICHARD BERGSTROM Ph.D. UNDER 37 C.F.R.
`
`§ 1.68 IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF U. S.
`PATENT N0. 8,466,139
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`|nnoPharma Exhibit 10130001
`
`

`

`Case IPR20 l 7-00905
`
`Declaration of Richard Bergstrorn, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................ .. 1
`
`II. BACKGROUND AND QUALIFICATIONS ............................................... .. 3
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ...................... .. 6
`
`IV. SUMMARY OF OPINIONS ........................................................................ .. 6
`
`V. TECHNICAL OVERVIEW OF PHARMACOKINETICS AND
`
`PHARMACODYNAMICS .......................................................................... ..
`
`'7
`
`A. Pharrnacokinetics ............................................................................... .. 7
`
`B.
`
`Pharniacodynaniics ............................................................................ .
`
`. 14
`
`VI. OVERVIEW OF THE ‘ 139 PATENT AND ITS PROSECUTION HISTORY
`
`.................................................................................................................... .
`
`. 16
`
`A. Overview of the ‘ 139 Patent .............................................................. .
`
`. 16
`
`B. Overview of the Prosecution History of the ‘ 139 Patent and Related
`Applications ...................................................................................... ..21
`
`(1) Prosecution History of the ‘ 122 Patent ....................................... ..2l
`
`(2) Prosecution History of the ‘680 Patent ....................................... ..23
`
`(3) Prosecution History of the ‘ 139 Patent ....................................... ..29
`
`VII. LEVEL OF ORDINARY SKILL IN THE PERTINENT ART .................... ..29
`
`VIII.BROADEST REASONABLE CONSTRUCTION ...................................... ..30
`
`IX. UNDERSTANDING OF THE LAW .......................................................... ..3l
`
`X.
`
`SCOPE AND CONTENT OF THE PRIOR ART ........................................ ..36
`
`A. Howell ............................................................................................... ..36
`
`B. McLeskey .......................................................................................... . .39
`
`|nnoPharma Exhibit 10130002
`
`

`

`Case IPR20 1 7-00905
`
`Declaration of Richard Bergstrom, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.S. Patent No. 8,466,139
`
`C. O’Regan ............................................................................................ ..40
`
`XI. DETAILED INVALIDITY ANALYSIS ..................................................... ..4l
`
`A. The Claimed Blood Plasma Fulvestrant Concentrations Are Obvious .42
`
`(1) Howell Expressly Discloses the Claimed Blood Plasma Fulvestrant
`Concentrations ........................................................................... . .42
`
`(2) A Person of Ordinary Skill in the Art Would Be Motivated to
`Achieve the Claimed Blood Plasma Fulvestrant Concentrations ..44
`
`(3) A Person of Skill in the Art Would Have a Reasonable Expectation
`of Success in Achieving the Claimed Blood Plasma Fulvestrant
`Concentrations ........................................................................... . .47
`
`B. A Person of Skill in the Art Would Reasonably Expect that the
`Formulation Disclosed in l\/lcLeskey Would Exhibit the Same or Very
`Similar Pharmacokinetics as Howell ................................................. . .50
`
`XII. CONCLUSION ........................................................................................... . .56
`
`iii
`
`|nnoPharma Exhibit 10130003
`
`

`

`Case IPR20 1 7-00 905
`
`Declaration of Richard Bergstrom, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U. S. Patent No. 8,466,139
`
`I, Richard Bergstrom, Ph.D. hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained as an expert witness on behalf of InnoPha1ma
`
`Licensing, LLC (“InnoPha1ma”) for the above-captioned Petition for Inter Partes
`
`Review (“IPR”) of U.S. Patent No. 8,466,139 (“the ‘139 patent”).
`
`I am being
`
`compensated for my time in connection with this IPR at my standard consulting
`
`rate of $375 per hour. My compensation is in no way dependent on the outcome of
`
`this matter.
`
`2.
`
`I have been asked to provide my opinions regarding whether the blood
`
`plasma fulvestrant concentrations recited in claims 1, 3, 10, ll, 13, and 20 of the
`
`‘139 patent would have been obvious to a person having ordinary skill in the art at
`
`the time of the alleged invention.
`
`3.
`
`In preparing this Declaration, I have reviewed the ‘ 139 patent, the file
`
`history of the ‘139 patent,
`
`the prosecution histories of related patents, and
`
`numerous prior art references from the time of the alleged invention.
`
`4.
`
`I have been advised and it is my understanding that patent claims in
`
`an IPR are given their broadest reasonable construction in view of the patent
`
`specification, file history, and the understanding of one having ordinary skill in the
`
`relevant art at the time of the purported invention.
`
`|nnoPharma Exhibit 1013.0004
`
`

`

`In forming the opinions expressed in this Declaration, I relied upon
`
`~ 3
`
`.
`
`my education and experience in the relevant field of the art, and have considered
`
`the viewpoint of a person having ordinary skill in the relevant art, as of 2000. My
`
`opinions directed to the invalidity of claims 1, 3, 10, 11, 13, and 20 of the ‘139
`
`patent are based, at least in part, on the following prior art publications:
`
`Howell, Pharmacokinefics,
`Pharmacological and Ann'-
`tumor Eflects ofrhe Specific
`Anti"-Oeslrogen ICI 182780 in
`Women with Advanced Breast
`
`Cancer, BRITISH J. OF CANCER,
`
`74, p. 300-308 (1996)
`
`McLeskey, Tam0xzfen-
`resistantfibroblasz,‘ growth
`factor-rrarzsfected MCF—7 cells
`are cr()ss-resistant in vivo to
`
`the anfiestrogen ICI 182,780
`and two aromatase inhibitors,
`4 CLIN. CANCER RESEARCH
`
`697-711 (1998)
`
`0’Reg3Il, Ejfecls Ofihe
`A4ntiestr0gens Tamoxifin,
`Toremtfene, and [CI 182, 780
`on Endomemal Cancer
`
`Growth, 90 J. NATL CANCER
`
`INST. 1552—l 558 (1998)
`
`Howell was published in 1996 and is
`attached as Exhibit 1007 to the IPR.
`
`McLesl<ey was published in March
`1998 and is attached as Exhibit 1008
`to the IPR.
`
`O°Regan was published in March
`1998 and is attached as Exhibit 1009
`to the 1pR_
`
`|nnoPharma Exhibit 1013.0005
`
`

`

`II.
`
`BACKGROUND AND QUALIFICATIONS
`
`6.
`
`I am an expert in pharmacokinetics, which is frequently abbreviated
`
`as “PK.” Pharmacokinetics is the branch of pharmacology that deals with the
`
`movement of a drug Within the body of a living patient through the mechanisms of
`
`absorption, distribution, metabolism, and excretion.
`
`I am also an expert
`
`in
`
`pharmacodynamics, which is the study of a drug’s pharmacological effect on the
`
`body. My background and qualifications are set forth in my curriculum Vitae,
`
`which is attached to this declaration as Exhibit A and includes a complete list of
`
`my publications over the past ten years.
`
`7.
`
`In brief, I received a Bachelor of Science degree in Pharmacy from
`
`the University of Pittsburgh in 1973, and a Master of Science degree from Butler
`
`University in l977.
`
`I also received a Doctor of Philosophy degree in
`
`Pharmaceutical Chemistry at The University of Michigan in 1980.
`
`8.
`
`At the University of Michigan, I studied under the mentorship of
`
`Professor John G. Wagner, who is considered to be one of the pioneers in the
`
`discipline of pharmacokinetics. Professor Wagner is the author of many seminal
`
`manuscripts and two of the first published pharmacokinetics textbooks. Professor
`
`Wagner’s textbooks discuss foundational pharmacokinetic concepts and are still in
`
`broad usage.
`
`I am familiar with these textbooks and the concepts they discuss, and
`
`also
`
`follow and
`
`am generally
`
`familiar with the pharmacokinetic
`
`and
`
`|nnoPharma Exhibit 1013.0006
`
`

`

`pharmacodynamic literature.
`
`9.
`
`I am a Fellow of the American Association of Pharmaceutical
`
`Scientists and I have served in a variety of voluntary and elected leadership
`
`positions in that association including President (2000).
`
`I am also a member of the
`
`Editorial Board for the American Associations of Pharmaceutical Scientists
`
`Journal.
`
`I have also served on other editorial boards, serve as a reviewer for a
`
`variety of pharmaceutical
`
`journals, and participate in a number of other
`
`professional associations.
`
`10.
`
`I currently hold academic appointments as an Adjunct Professor of
`
`Medicine at The Indiana University School of Medicine, Department of Medicine,
`
`Division of Clinical Pharmacology, in Indianapolis, Indiana.
`
`I am also an Adjunct
`
`Professor of Pharmaceutical Sciences, at Butler University College of Pharmacy
`
`and Health Sciences in Indianapolis,
`
`Indiana.
`
`In addition,
`
`I
`
`serve as an
`
`independent expert and consultant in pharmacokinetics, pharmacodynamics, and
`
`toxicokinetics for a variety of clients in the pharmaceutical industry.
`
`I have held
`
`these positions since 2009, and they build upon my 30 plus year career as a
`
`Research Scientist and Pharmacokineticist at Eli Lilly and Company (“Lilly”) in
`
`Indianapolis, Indiana.
`
`11.
`
`I became a Senior Research Scientist at Lilly upon the completion of
`
`my Ph.D. in 1980.
`
`I worked at the Lilly Laboratory for Clinical Research for more
`
`|nnoPharma Exhibit 1013.000?
`
`

`

`than 20 years and worked at the Lilly Corporate Center for more than six years.
`
`Throughout my career at Lilly, I continually used and expanded my expertise in
`
`clinical research and pharmacokinetics.
`
`I also contributed to the development of
`
`many of Lilly’s most medically and commercially successful drugs including,
`
`among others, Oraflex®, Axidm, Humulin®, Strattera®, Prozac®, Prozac Weeklym,
`
`Zyprexa®, Zyprexa® lntraMuscular, Zyprexa Zydis®, Zyprexa Relprevvm,
`
`Symbyax®, and Cymbalta®.
`
`12. Many of the projects that I was responsible for at Lilly included the
`
`design and evaluation of pharmaceutical dosage forms and formulations, including
`
`intramuscular dosage forms. My role in these projects was to use my
`
`pharmacokirietic expertise to assist
`
`in the design of the dosage forms and
`
`formulations, and to use my clinical skills to design, execute, and analyze animal
`
`and human PK studies to assess the in viva performance of dosage forms and
`
`formulations.
`
`13.
`
`The design of a human PK study requires expertise in the impact of
`
`Various factors on the disposition of a drug in the body, including, but not limited
`
`to, gender, race, age, and genetics. These factors are known to influence how a
`
`drug is processed in the body through absorption, distribution, metabolism, and
`
`excretion. In addition, the design of a PK study requires a detailed understanding
`
`of the physiochemical properties of the drug being evaluated and the potential
`
`|nnoPharma Exhibit 1013.0008
`
`

`

`impact of these properties on the in viva disposition of the drug.
`
`I am qualified by
`
`my training and research experience to assess all of these properties and to design,
`
`implement and analyze a PK study of a drug.
`
`I am also qualified to assess the
`
`pharmacokinetic properties of drugs and dosage forms.
`
`14. Within the past four years, I have testified by deposition in the matters
`
`of Galderma Labs. Inc. v. Amneal Pharmst, LLC, No.
`
`lill-cv-01106-LPS
`
`Del.), Forest Labs, Inc. v. Teva Pharms. USA, Inc, No.
`
`l:l-4-cv-l2l-LPS (D.
`
`Del), and Shire LLC, et al. v. Abhai, LLC, No. 1:15-cv-13909 (D. Mass).
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION
`
`15.
`
`In addition to my general knowledge, education, and experience, I
`
`considered the materials listed in Exhibit B in forming my opinions.
`
`IV.
`
`SUMMARY OF OPINIONS
`
`16.
`
`Based on my review of the ‘ l 39 patent, its prosecution history, related
`
`patents’ prosecution histories (including the Sawchuk and Gellert Declarations),
`
`the PTAB’s decision in the Mylan ‘68O IPR, the other materials I have considered,
`
`and my knowledge and experience, my opinions are as follows:
`
`0 The “blood plasma fulvestrant concentration of at least 2.5 ngml'1 for at least
`
`2 weeks” as required by claims 1, 3, 11, and 13, and “at least four weeks” as
`
`required by claims 10 and 20 would have been obvious to a person of skill in
`
`the art.
`
`In particular, Howell discloses
`
`that exact claimed blood
`
`|nnoPharma Exhibit 1013.0009
`
`

`

`concentration and discloses that
`
`those concentrations are achieved and
`
`maintained for approximately 28 days after intramuscular injection. As I
`
`describe below, a person of skill in the art would have been motivated to
`
`achieve these plasma concentrations given the high response rate (69%) and
`
`lack of adverse effects described in Howell, and would have had a
`
`reasonable expectation of success in doing so.
`
`A person of skill
`
`in the art would reasonably expect that intramuscular
`
`administration of the formulation described in McLeskey would produce the
`
`same or highly similar pharmacokinetic profile as Howell on day 28. As I
`
`explain below, a person of skill in the art would readily appreciate that the
`
`co—solvents described in McLeskey would more readily dissipate from the
`
`injection site,
`
`leaving castor oil as
`
`the rate-limiting component
`
`for
`
`fulvestrant release. Given that Howell expressly discloses a “castor oil-
`
`based vehicle” and the same 50 mg/ml concentration of fulvestrant, a person
`
`of skill
`
`in the art would reasonably expect the same or highly similar
`
`pharmacokinetic profiles if the McLeskey formulation was administered
`
`intramuscularly.
`
`TECHNICAL OVERVIEW OF PHARMACOKINETICS AND
`
`PHARMACODYNAMICS
`
`A.
`
`Pharmacokinetics
`
`17.
`
`Pharmacokinetics is
`
`the area of pharmaceutical
`
`science that
`
`is
`
`7
`
`|nnoPharma Exhibit 1013.0010
`
`

`

`concerned with the study of how drugs are processed by an animal or human being
`
`following the administration of a dosage form,
`
`including the processes of
`
`absorption into the bloodstream, distribution Within the body, metabolism by
`
`organs or tissues in the body, and excretion from the body. Exhibit 1022 at 0004.
`
`Scientists who are knowledgeable about pharmacokinetics often work closely with
`
`drug formulators.
`
`18. When a drug is administered to a subj ect, there are various factors that
`
`affect the manner in which the drug moves through and is processed by the body.
`
`For example, the process of absorption may be affected by the physicochemical
`
`properties of the drug or dosage form, the dosage form’s solubility and rate of
`
`release of active ingredient,
`
`the subject’s overall health and condition,
`
`the
`
`anatomical or physiological environment in which the drug is placed, and the
`
`distribution of the drug into the peripheral tissues of the subject. The composite
`
`effect of these various factors is typically characterized in a bioavailability or PK
`
`study.
`
`In the course of my career, I have designed, analyzed, and reported on
`
`many such studies.
`
`19.
`
`Bioavailability studies may be designed in a variety of different ways.
`
`In one type of study design (a single dose PK study), a single dose of the drug
`
`product is given to a group of subjects after which the systemic concentration of
`
`the active ingredient is assessed over a period of time.
`
`|nnoPharma Exhibit 10130011
`
`

`

`20.
`
`In another
`
`type of PK study, multiple doses of the drug are
`
`administered on a standardized schedule (e.g., twice daily) until the subjects have
`
`achieved “steady—state” pharmacokinetics. “Steady state” means that the rate and
`
`extent of absorption of the drug (input) equals the rate and extent of elimination of
`
`the drug (output) from the bloodstream. In both types of PK study, blood is drawn
`
`from the subjects at predetermined time intervals so that scientists can measure the
`
`concentration of the drug in systemic circulation and use that data to assess other
`
`pharmacokinetic parameters.
`
`21.
`
`Pharmacokineticists frequently design single-dose human PK studies
`
`to determine the maximum plasma concentration, or “Cmax,
`
`that an active
`
`)3
`
`ingredient reaches in the bloodstream of a subject following a dose of the drug.
`
`Exhibit 1023 at 0006. Given the single dose data, pharmacokineticists can model
`
`the minimum plasma concentration of the drug in the bloodstream, which is
`
`referred to as “Cmm.” Cmin results from administering the drug at some frequency
`
`or dosage schedule.
`
`22.
`
`Pharmacokineticists also frequently measure and record another
`
`parameter called “Tmax,” which is the time required for the systemic concentrations
`
`of the drug to reach Cmax. Together, Cmax and Tmax are an indication of how slowly
`
`or rapidly the active ingredient of a drug product reaches the systemic circulation,
`
`i.e., the rate of drug absorption.
`
`|nnoPharma Exhibit 1013.0012
`
`

`

`23.
`
`Scientists also sometimes determine another parameter called “AUC,”
`
`or area under
`
`the curve. AUC is calculated by serially measuring drug
`
`concentrations in samples of blood, plasma or serum obtained over a period of time
`
`and integrating the measured concentrations over time. These concentration Values
`
`are typically plotted on a Cartesian coordinate graph to illustrate the plasma
`
`concentration curve where the y axis represents the systemic concentration of the
`
`drug (for example in ng/ml) and the X axis represents time (for example in hours or
`
`minutes). The AUC is calculated by integrating the concentration and time Values
`
`to provide the total area under the curve. The AUC reflects the total amount of a
`
`drug product that has been absorbed by the subject and the rate of the drug
`
`elimination from the body during the period of measurement. Exhibit 1023 at
`
`0004. A graph depicting these concepts is shown below:
`
`.Cmax (maximum concentration)
`
`in
`‘
`Cmin
`(minimum or
`ahea under Curviému=:i&T"“"‘“*’° =——‘»—)_%,.___ x_§m____tWrquggh concentr_ation)
`
`Tmax
`
`(Iin1vofCnm.r)
`
`l0
`
`|nnoPharma Exhibit 1013.0013
`
`s:
`O
`'5
`(U
`.3‘:
`s:
`Q)
`
`U s
`
`:O U(
`
`'5
`EU)
`
`2m
`
`

`

`24. Drugs may be formulated in various ways, depending on the desired
`
`pharmacokinetic profile. A drug “formulation” generally refers to the specific
`
`recipe or listing of ingredients used to make a final drug product or “dosage form.”
`
`A “dosage form,” in contrast, is the physical form in which a drug is produced or
`
`dispensed, such as a tablet or capsule. See Drugs@FDA, Glossary of Terms,
`
`http ://wwwfda. gov/Drugs/InformationOnDrugs/ucm079436.htm at l .
`
`25.
`
`“Immediate release” dosage forms provide rapid dissolution that
`
`facilitates an immediate or rapid entry of the active ingredient into the bloodstream
`
`of the subject. Exhibit 1024 at 0005.
`
`In such dosage forms, no excipients are
`
`added to intentionally retard the rate of release of the active ingredient or its entry
`
`into the bloodstream.
`
`26. Drugs can also be formulated in “modified release” dosage forms that
`
`are specifically engineered to alter the timing and/or rate of release of the active
`
`drug substance.
`
`Id.
`
`In modified release dosage forms, excipients are added for the
`
`express purpose of retarding or otherwise altering the timing or rate of release of
`
`the active ingredient. This delayed or altered release results in a longer period of
`
`time to reach Cmx after a single dose, Le. , greater Tmx. Prolonged release typically
`
`also decreases the magnitude of Cmx.
`
`Ideally, however, prolonged release has no
`
`impact on AUC. Modified release dosage forms are also sometimes referred to as
`
`“extended release” or “sustained release” drugs.
`
`I have included a graph below
`
`ll
`
`|nnoPharma Exhibit 1013.0014
`
`

`

`comparing and contrasting the PK profiles for an immediate release Versus a
`
`modified release dosage form (with immediate release labelled as “conventional
`
`profile”):
`
`r~_.
`
`U S(
`
`D
`
`L.“
`
`27.
`
`The concentrations of a drug in the bloodstream over time reflect the
`
`aggregate impact of the processes of absorption, distribution, metabolism, and
`
`excretion. Absorption refers to the processes that lead to the entry of a drug from
`
`its site of administration into the bloodstream. Exhibit 1025 at 0001. The most
`
`common site of absorption is the gastrointestinal tract, where the drug must cross
`
`cell membranes to enter the bloodstream, resulting in Varying rates of absorption
`
`and bioavailability. After the drug enters the bloodstream, it is distributed into
`
`Various tissues of the body. Id. at 0002.
`
`28. Different amounts of the drug are partitioned to different organs and
`
`tissues and remain there for Varying amounts of time. Factors that determine how
`
`12
`
`|nnoPharma Exhibit 1013.0015
`
`Therapeutic
`- Controlled
`
`Range
`
`5
`.2-0-3
`GS
`33
`8U
`
`cO U(
`
`

`

`drugs are distributed include the diffusion rate across lipid membranes, regional
`
`blood flow, and the ability of the drug to bind to proteins in tissues and blood. The
`
`drug then undergoes metabolism, or biotransformation, during which enzymes in
`
`the body, particularly those in the liver, break down the parent drug into new
`
`compounds called metabolites.
`
`Id. at 0003.
`
`In the typical case, the processes
`
`involving metabolism generate inactive metabolites that can be more readily
`
`excreted from the body because they are more polar. The drug and its metabolites
`
`are removed from the body through excretion. The rate of excretion determines
`
`the degree of accumulation of the drug and its metabolites. The frequency and
`
`amount of drug administered over
`
`time may lead to drug or metabolite
`
`accumulation when this rate exceeds the rate of drug excretion. The accumulation
`
`of these substances can be used to achieve the desired drug exposure and
`
`pharmacological effects or if excessive can adversely affect the well-being of the
`
`patient resulting from undesired pharmacological effects. Excretion occurs when
`
`the drug and/or its metabolites leave the body through urine or feces. Id. at 0009.
`
`29.
`
`In order
`
`to
`
`predict
`
`a drug’s
`
`behavior
`
`through the
`
`body,
`
`pharmacokineticists use the concept of compartmentalization to mathematically
`
`model the complex processes described above. Exhibit 1022 at 0009.
`
`The
`
`compartment model is based on the assumption that each compartment represents a
`
`group of similar tissues or fluids. To construct such a model, simplifications of
`
`13
`
`|nnoPharma Exhibit 1013.0016
`
`

`

`body structures and systems are made because organs and tissues that have similar
`
`characteristics in the context of drug distribution are grouped as a single
`
`compartment. For example, blood, heart, kidneys, liver, and lungs are considered
`
`highly perfused organs and they may exhibit similar patterns of drug distribution.
`
`As a result, they are often grouped as a single compartment.
`
`Similarly, other
`
`organs and tissues are less highly perfused, such as bone or
`
`fat, and drug
`
`distribution into and out of these tissues may be represented by other
`
`compartments, also called peripheral compartments. Under either single or
`
`muticompartmental assumptions, a plasma drug concentration-time curve can be
`
`developed, and the plasma concentration of a drug at any time can be predicted.
`
`Id. at 0013.
`
`B.
`
`Pharmacodynamics
`
`30. Whereas pharmacokinetics measures the animal or human body’s
`
`effect on how a drug moves through the body and is processed, pharmacodynamics
`
`measures the body’s biochemical and physiological response to the presence of a
`
`drug.
`
`Exhibit 1026 at 0006.
`
`Pharmacodynamics
`
`is
`
`the
`
`study of the
`
`pharmacological response to a drug, which usually involves measuring receptor
`
`binding and other interactions between the drug and the body.
`
`It is Worth noting
`
`that there are many factors that cause a degree of inter-subject variability in the
`
`pharmacological response to a drug, such as the physiological health and age of the
`
`14
`
`|nnoPharma Exhibit 1013.001?
`
`

`

`patient and interactions with other drugs in the body.
`
`Id. at 0008. As a result, for
`
`most drugs, pharmacodynamics, along with pharmacokinetics, is used to develop
`
`the optimal dose of a drug that is effective in the majority of patients representing a
`
`population. However, pharmacokinetics and pharmacokinetics are also used to
`
`understand how individual patients differ from one another and how the optimal
`
`dose can be modified to individualize patient therapy. Id. at 0018.
`
`31.
`
`Pharmacodynamics is primarily concerned with the dose-response
`
`relationship, or the relationship between the concentration of a drug and its effect
`
`on the body. Dose-response data is often presented, like in the graph below, with
`
`the dose or concentration on the X-axis and the measured drug effect, for example,
`
`the fraction of bound receptors, on the y-axis.
`
`In this figure, the curve on the right
`
`(purple line compared to the blue line) represents the drug with less potency.
`
`Dose-Response Curves
`
`"U
`
`C3o
`
`CG
`CI
`.9-I-3
`s3-!
`LL:
`
`Ua
`
`1
`
`10
`
`Ligand Concentration
`
`15
`
`|nnoPharma Exhibit 1013.0018
`
`

`

`32.
`
`The relationship between pharmacokmetics and pharmacodynamics
`
`effect is known as the PK/PD relationship or link. There are several ways to
`
`characterize the PK/PD relationship. One of these ways is to use animal models,
`
`which “are useful for determining the appropriate PK/PD parameters.” Exhibit
`
`1027 at 0023; Exhibit 1028 at 0009 (“Animal studies can provide preliminary data
`
`for the development of mechamsm-based PK/PD models”). As discussed earlier,
`
`inter—subject variability in a pharmacological response to any particular drug is
`
`often very high.
`
`33. Due to this variability,
`
`in order to determine the precise PK/PD
`
`relationship, large sample sizes of patients are used. Exhibit 1029 at 0006 (“[T]his
`
`approach is relatively imprecise due to its sensitivity to inter—subject variability in
`
`pharmacokinetic as well as pharmacological factors. It is the imprecision and non-
`
`specificity of this method which requires the study of large numbers of patients to
`
`determine a therapeutic dose range”); Exhibit 1030 at 0011 (“This
`
`large
`
`interindividual variance in parasite clearance responses will probably necessitate
`
`relatively large sample sizes for adequate precision”).
`
`VI. OVERVIEW OF THE ‘139 PATENT AND ITS PROSECUTION
`
`HISTORY
`
`A.
`
`Overview of the ‘139 Patent
`
`34.
`
`The ‘ 139 patent was filed on September 4, 2012, and asserts priority
`
`16
`
`|nnoPharma Exhibit 1013.0019
`
`

`

`to British applications filed on January 10, 2000 and April 12, 2000. The ‘139
`
`patent is generally directed to a “sustained release pharmaceutical formulation” of
`
`fulvestrant “adapted for administration by injection.” ‘ 139 patent at Abstract.
`
`35.
`
`Fulvestrant
`
`is a steroidal antiestrogen that was first patented and
`
`described more than a decade before the earliest priority date of the ‘ 139 patent.
`
`Id. at 1:51-60. The ‘139 patent acknowledges that antiestrogens have been long
`
`known to be efficacious against “many benign and malignant diseases of the breast
`
`and reproductive tract,” and that “the rationale for [their] design and testing” was
`
`described in the literature well before the ‘680 patent. Id. at 1:25-30', 1:49-52.
`
`36.
`
`The ‘l39 patent similarly acknowledges that
`
`the formulation of
`
`sustained release steroidal dosage forms was well—known in the art.
`
`Indeed, the
`
`‘139 patent recognizes that “there are a number of sustained release steroidal
`
`formulations which have been commercialized,” including formulations that could
`
`achieve an extended release for as long as 8 weeks.
`
`Id. at 2:54-66. The ‘l39
`
`patent concedes that a number of these steroidal formulations included “additional
`
`excipients such as benzyl benzoate, benzyl alcohol, and ethanol”—the same
`
`excipients AstraZeneca now seeks to claim.
`
`Id. at 2:61-64. A number of the
`
`formulations also contained castor oil, which was known to have “a greater
`
`solvating ability” for steroidal compounds since at least 1964—nearly forty years
`
`before the earliest priority date of the ‘139 patent.
`
`Id. at 5:30-35.
`
`17
`
`|nnoPharma Exhibit 1013.0020
`
`

`

`37.
`
`Because these formulation techniques and the fulvestrant compound
`
`itself were well-known, oil-based formulations of fulvestrant were developed long
`
`before the ‘ l39 patent. For example, the ‘l39 patent acknowledges that another
`
`AstraZeneca inventor, Dukes,
`
`first disclosed a
`
`fulvestrant pharmaceutical
`
`formulation in l989—approximately 11 years before the ‘l39 patent’s earliest
`
`priority date. Id. at 3:55-62. Like the claimed formulation, the Dukes formulation
`
`included 50 mg/ml fulvestrant, castor oil, and benzyl alcohol. Id.
`
`38.
`
`The ‘l39 patent asserted that its improvement over this established
`
`prior art was the “surprising” discovery that benzyl benzoate—a non-aqueous ester
`
`solvent—increased the solubility of fulvestrant. Id. at 5:57-65. The ‘ l39 inventors
`
`made this assertion despite the fact that benzyl benzoate was known in the art to
`
`“enhance steroid solubility in oils,” (Exhibit 1018 at 0022) and that each of the
`
`commercially available castor oil-based formulations in Table 1 contained benzyl
`
`benzoate. Exhibit l00l at Table l.
`
`39.
`
`The ‘l39 patent does not contain a meaningful disclosure of the
`
`pharmacokinetic or pharmacodynamic properties of the claimed fulvestrant
`
`formulation.
`
`Indeed,
`
`the entirety of the disclosure relating to fulvestrant
`
`pharmacokinetics spans 13 lines.
`
`Id. at l0:20—32. Those 13 lines relate to the
`
`blood plasma concentration of fulvestrant in rabbits over 5 days.
`
`Id. There is no
`
`data in the ‘l39 patent related to the use of fulvestrant in humans, nor is there any
`
`l8
`
`|nnoPharma Exhibit 10130021
`
`

`

`data spanmng more than 5 days. There is also no data concerning a purported
`
`pharmacokinetic/pharmacodynamic (“PK/PD”) link between specific blood levels
`
`and therapeutic effects.
`
`40.
`
`As issued, the ‘l39 patent includes 20 claims.
`
`I have been asked to
`
`opine on claims 1, 3, 10, ll, 13, and 20 in my analysis, which I have included
`
`below:
`
`1. A method for treating a hormonal dependent benign or
`
`malignant disease of the breast or reproductive tract
`
`comprising administering mtramuscularly to a human in
`
`need of such treatment a formulation comprising: about
`
`50 mgmll of fulvestrant; a mixture of from l7—23% W/v
`
`of ethanol and benzyl alcohol; 12-18% w/v of benzyl
`
`benzoate; and a sufficient amount of castor oil vehicle;
`
`wherein the method achieves a blood plasma fulvestrant
`
`concentration of at
`
`least 2.5 ngml-l
`
`for at
`
`least
`
`two
`
`weeks.
`
`3. The method of claim l, wherein formulation
`
`comprises: about 10% w/v of ethanol; about l0% W/v of
`
`benzyl alcohol; and about 15% w/v of benzyl benzoate.
`
`10. The method of claim 3, wherein the hormonal
`
`l9
`
`|nnoPharma Exhibit 10130022
`
`

`

`dependent benign or malignant disease of the breast or
`
`reproductive tract is breast cancer and the blood plasma
`
`fulvestrant concentration is attained for at least 4 weeks.
`
`11. A method for treating a hormonal dependent benign
`
`or malignant disease of the breast or reproductive tract
`
`comprising administering mtramuscularly to a human in
`
`need of
`
`such treatment
`
`a
`
`formulation consisting
`
`essentially of: about 50 mgml'1 of fulvestrant; a mixture
`
`of from 17-23% w/v of ethanol and benzyl alcohol; 12-
`
`l8% w/v of benzyl benzoate; and a sufficient amount of
`
`castor oil vehicle", wherein the method achieves a blood
`
`plasma fulvestrant concentration of at least 2.5 ngml-1
`
`for at least two weeks.
`
`13. The method of claim ll, wherein formulation
`
`consists essentially of: about 10% w/v of ethanol; about
`
`10% w/v of benzyl alcohol; and about 15% w/v of benzyl
`
`benzoate.
`
`20. The method of claim 13, wherein the hormonal
`
`dependent benign or malignant disease of the breast or
`
`reproductive tract is breast cancer and the blood plasma
`
`20
`
`|nnoPharma Exhibit 10130023
`
`

`

`fulvestrant concentration is attained for at least 4 weeks.
`
`B.
`
`Overview of the Prosecution History of the ‘139 Patent and
`Related Applications
`
`41.
`
`I have reviewed the prosecution history of the ‘ 139 patent in forming
`
`my opinions for the purposes of this declaration.
`
`I have also reviewed and
`
`considered the prosecution histories of the ‘122 and ‘680 patents in forming my
`
`opinions, as they are related patents and their prosecution histories are incorporated
`
`into the ‘ 139 patent.
`
`(1)
`
`Prosecution History of the ‘ 122 Patent
`
`42.
`
`I discuss three aspects of the ‘122 patent prosecution history that are
`
`relevant to my o