Case IPR20 1 7-00 904
`
`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. 6,774,122
`
`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
`
`Patent No. 6,774,122
`
`
`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. 6,774,122
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`InnoPharma Exhibit 1013.0001
`
`

`

`Case IPR2017—00904
`
`Declaration of Richard Bergstrorn, Ph.D. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.3. Patent No. 6,774,122
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................ .. 1
`
`II. BACKGROUND AND QUALIFICATIONS ............................................... .. 3
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION ...................... .. 6
`
`IV. SUIVIMARY OF OPINIONS ........................................................................ .. 6
`
`V. TECHNICAL OVERVIEW OF PHARMACOKINETICS AND
`
`PHARMACODYNAMICS .......................................................................... ..
`
`’7
`
`A. Pharmacokinetics ............................................................................... .. 7
`
`B.
`
`Pharmacodynaniics ............................................................................ .
`
`. 14
`
`VI. OVERVIEW OF THE ‘ 122 PATENT AND ITS PROSECUTION HISTORY
`
`.................................................................................................................... ..16
`
`A. Overview of the ‘ 122 Patent .............................................................. .
`
`. 16
`
`B. Overview of the Prosecution History of the “ 122 Patent and Related
`Applications ...................................................................................... .
`
`. 1 9
`
`(1) Prosecution History of the ‘ 122 Patent ....................................... ..19
`
`(2) Prosecution History of Related Applications .............................. ..22
`
`(a) The Sawchuk Declaration ................................................... .22
`
`(b) The Gellert Declaration ...................................................... .25
`
`VII. LEVEL OF ORDINARY SKILL IN THE PERTINENT ART .................... .26
`
`VIIIBROADEST REASONABLE CONSTRUCTION ...................................... ..27
`
`IX. UNDERSTANDING OF THE LAW .......................................................... .28
`
`X.
`
`SCOPE AND CONTENT OF THE PRIOR ART ........................................ ..33
`
`A. Howell ............................................................................................... . .33
`
`ii
`
`InnoPharma Exhibit 1013.0002
`
`

`

`Case IPR2017-00904
`
`Declaration of Richard Bergstrom, PhD. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U.3. Patent No. 6,774,122
`
`B. McLeskey .......................................................................................... . .36
`
`C. O’Regan ............................................................................................ .37
`
`XI. DETAILED INVALIDITY ANALYSIS ..................................................... .38
`
`A. The Claimed Therapeutically Significant Blood Plasma Fulvestrant
`Concentrations Are Obvious .............................................................. .38
`
`(1) Howell Expressly Discloses the Claimed Therapeutically
`Significant Blood Plasma Fulvestrant Concentrations ................ . .38
`
`(2) A Person of Skill in the Art Would Be Motivated to Achieve
`Therapeutically Significant Blood Plasma Fulvestrant
`Concentrations ........................................................................... . .41
`
`(3) A Person of Skill in the Art Would Have a Reasonable Expectation
`of Success in Achieving Therapeutically Significant Blood Plasma
`Fulvestrant Concentrations ......................................................... ..45
`
`B. A Person of Skill in the Art Would Reasonably Expect that the
`Formulation Disclosed in McLeskey Would Exhibit the Same or Very
`Similar Pharmacokinetics as Howell ................................................. . .47
`
`XII. CONCLUSION ........................................................................................... . .53
`
`iii
`
`InnoPharma Exhibit 1013.0003
`
`

`

`Case IPR20 1 7-00 904
`
`Declaration of Richard Bergstrom, PhD. Under 37 C.F.R. § 1.68 in Support of
`Petition for Inter Partes Review of U. S. Patent No. 6,774,122
`
`1, Richard Bergstrom, PhD. hereby declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been retained as an expert witness on behalf of InnoPharma
`
`Licensing, LLC (“lnnoPharma”) for the above-captioned Petition for Inter Partes
`
`Review (“IPR”) of US. Patent No. 6,774,122 (“the ‘122 patent”).
`
`1 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
`
`therapeutically significant blood plasma fulvestrant concentrations recited in
`
`claims 1 and 2 of the ‘122 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 ‘ 122 patent, the file
`
`history of the ‘ 122 patent, 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.
`
`InnoPharma Exhibit 1013.0004
`
`

`

`,—
`
`3.
`
`In forming the opinions expressed in this Declaration, I relied upon
`
`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 and 2 of the ‘122 patent are based, at
`
`least in part, on the following prior art publications:
`
`
`Howell was published in 1996 and is
`attached as Exhibit 1007 to the lPR.
`
`McLeskey was published in March
`1998 and is attached as Exhibit 1008
`to the IPR.
`
`Howell, Pharmacokz‘nettcs,
`Pharmacological and Anti-
`tumor Eflects of the Specific
`Anti-Oesfiogen ICI 182780 in
`Women with Advanced Breast
`
`Cancer, BRITISH J. OF CANCER,
`
`74, p. 300-308 (1996)
`
`McLeskey, Tamoxzfen-
`resistantfibroblast growth
`factor-Wansfected MCF—7 cells
`are cross-resistant in vivo to
`
`the antz'estrogerz ICI 182, 780
`and two aromatase inhibitors,
`4 CLIN. CANCER RESEARCH
`
`697—711 (1998)
`
`INST. 1552—1558 (1998)
`
`O’Regan, Effects 0fthe
`Antiem’Ogem Tamoxflén,
`Toremtflene, and [CI 182, 780
`on Endomem'al Cancer
`
`Growth, 90 J. NAT’L CANCER
`
`O’Regan was published in March
`1998 and is attached as Exhibit 1009
`to the IPR.
`
`InnoPharma 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, 1 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 1977.
`
`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 pharrnacokinetics. Professor Wagner is the author of many seminal
`
`manuscripts and two of the first published pharmacokinetics textbooks. Professor
`
`Wagner’s textbooks discuss foundational pharmacokmetic 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 pharmacokmetic
`
`and
`
`InnoPharma 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 PhD. in 1980.
`
`I worked at the Lilly Laboratory for Clinical Research for more
`
`InnoPharma Exhibit 1013.0007
`
`

`

`than 20 years and worked at the Lilly Corporate Center for more than six years.
`
`Throughout my career at Lilly, 1 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 l 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
`
`pharmacokinetic 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
`
`InnoPharma 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 Pharms., LLC, No.
`
`lill-cv-01106-LPS
`
`Del.), Forest Labs, Inc. v. Teva Pharms. USA, Inc, No.
`
`l:l4-cv—lZl-LPS (D.
`
`Del), and Shire LLC, et a]. v. Abhai, LLC, No. 1:15-cv-l3909 (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 “122 patent, its prosecution history, the
`
`Sawchuk Declaration, the Gellert Declaration, the PTAB’s decision in the Mylan
`
`‘680 IPR,
`
`the other materials I have considered, and my knowledge and
`
`experience, my opinions are as follows:
`
`a The “therapeutically significant blood plasma fulvestrant concentration of at
`
`least 2.5 ngml'1 is attained for at least 2 weeks after injection” recited in
`
`claims 1 and 2 of the ‘122 would have been obvious to a person of skill in
`
`the art.
`
`In particular, Howell discloses
`
`that exact claimed blood
`
`InnoPharma 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
`
`l7.
`
`Pharmacokinetics is
`
`the area of pharmaceutical
`
`science that
`
`is
`
`7
`
`InnoPharma 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 pharmacokmetics often work closely with
`
`drug formulators.
`
`18. When a drug is administered to a subject, 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.
`
`InnoPharma Exhibit 1013.0011
`
`

`

`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 “Cmin.” 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, Cmle 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.
`
`InnoPharma 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:
`
`S:
`o
`153
`cc:
`3‘3
`s:
`Q)
`
`(Iinm oanmx)
`
`.Cmax (maximum concentration)
`
`'
`
`x
`
`Cmin
`(minimum or
`al'ea under Curvémn=:7¢¥T‘"‘“‘1" ;;mw_w_ Mmtwrgugth concentlfition)
`
`Tmax
`
`10
`
`InnoPharma Exhibit 1013.0013
`
`U s
`
`:o U(
`
`U EU
`
`)
`
`.2
`Qt
`
`

`

`24. Drugs may be formulated in various ways, depending on the desired
`
`pharmacokmetic 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 ://www.fda. 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 me after a single dose, tie. , greater me. Prolonged release typically
`
`also decreases the magnitude of QM.
`
`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
`
`InnoPharma 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”):
`
`—t
`
`G 8(
`
`I)
`
`SP
`
`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
`
`InnoPharma Exhibit 1013.0015
`
`Therapeutic
`- Controlled
`
`Range
`
`{:2
`.94.»
`GS
`.23
`8U
`C?
`
`O 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
`
`InnoPharma 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
`
`InnoPharma Exhibit 1013.0017
`
`

`

`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
`
`
`
`"c
`
`C:
`
`.01
`
`1
`
`10
`
`100
`
`Ligand Concentration
`
`15
`
`InnoPharma Exhibit 1013.0018
`
`1om C
`
`"
`.9a
`:3-!
`Ln
`
`Ua
`
`

`

`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 mechanism-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 ‘122 PATENT AND ITS PROSECUTION
`
`HISTORY
`
`A.
`
`Overview of the ‘122 Patent
`
`34.
`
`The ‘ 122 patent was filed on January 9, 2001, and asserts priority to
`
`16
`
`InnoPharma Exhibit 1013.0019
`
`

`

`British applications filed on January 10, 2000 and April 12, 2000. The ‘122 patent
`
`is generally directed to a “sustained release pharmaceutical
`
`formulation” of
`
`fulvestrant “adapted for administration by injection.” Exhibit 1001 at Abstract.
`
`35.
`
`Fulvestrant is a steroidal antiestrogen. The efficacy of antiestrogens
`
`against “many benign and malignant diseases of the breast and reproductive tract”
`
`has been known in the art for decades.
`
`Id. at 1:16-22. As the ‘122 patent
`
`acknowledges, “the rationale for design and testing” of antiestrogens was described
`
`in literature numerous times well before the earliest priority date of the ‘ 122 patent.
`
`Id. at 1:43-46. Fulvestrant itself predates the ‘122 patent by more than a decade,
`
`having been described at least as early as 1989. Id. at 1:45-55.
`
`36.
`
`The “122 patent similarly acknowledges that
`
`the formulation of
`
`sustained release steroidal dosage forms was well-known in the art. The ‘122
`
`patent
`
`recognizes that “there are a number of sustained release steroidal
`
`formulations which have been commercialized,” achieving extended release
`
`periods ranging from one to eight weeks.
`
`Id. at 2:55-67. The ‘122 patent
`
`concedes that many of these steroidal formulations included the same excipients
`
`now claimed by AstraZeneca: benzyl benzoate, benzyl alcohol, ethanol, and castor
`
`oil.
`
`Id. at 2:61-65; 5:20-25.
`
`Indeed, the “122 patent acknowledges that castor oil
`
`was known to have “a greater solvating ability” for steroidal compounds since at
`
`least 1964. Id. at 5:20-25.
`
`17
`
`InnoPharma Exhibit 1013.0020
`
`

`

`37.
`
`In light of these well-known elements, it is unsurprising that oil-based
`
`formulations of fulvestrant had been developed long before the ‘122 patent—for
`
`example, the Dukes patent,
`
`invented by an AstraZeneca employee, disclosed a
`
`formulation of 50 mg/ml fulvestrant, castor oil, and benzyl alcohol approximately
`
`11 years before the ‘122 patent. Id. at 3:60-67.
`
`38.
`
`The ‘122 patent asserted that its improvement over this established
`
`prior art was the discovery that benzyl benzoate—a non-aqueous ester solvent—
`
`increased the solubility of fulvestrant. Id. at 5:48-55. Contrary to the ‘ 122 patent’s
`
`characterization, this discovery was not surprising in light of the knowledge in the
`
`art that benzyl benzoate enhances the solubility of steroids in oil. Exhibit 1018 at
`
`0022.
`
`Indeed, each of the commercially available castor oil-based formulations
`
`referenced in the ‘122 patent contained benzyl benzoate. Exhibit 1001 at Table 1.
`
`39.
`
`The ‘122 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 14 lines.
`
`Id. at 10:24-55. Those 14 lines relate to the
`
`blood plasma concentration of fulvestrant in rabbits over 5 days.
`
`Id. There is no
`
`data in the ‘ 122 patent related to the use of fulvestrant in humans, nor is there any
`
`data spanning more than 5 days. There is also no data concerning a purported
`
`pharmacokmetic/pharmacodynamic (“PK/PD”) link between specific blood levels
`
`18
`
`InnoPharma Exhibit 1013.0021
`
`

`

`and therapeutic effects.
`
`40.
`
`As issued, the ‘122 patent includes 9 claims.
`
`I have been asked to
`
`opine on claims 1 and 2 in my analysis, whichl have included below:
`
`1. A method of treating a hormonal dependent benign or
`
`malignant disease of the breast or reproductive tract by
`
`administration to a human in need of such treatment an
`
`intra-muscular injection of a pharmaceutical formulation
`
`comprising fulvestrant, a mixture of 10% weight of
`
`ethanol per volume of formulation, 10% weight of benzyl
`
`alcohol per volume of formulation and 15% weight of
`
`benzyl benzoate per volume of formulation and a
`
`sufficient amount of a castor oil vehicle, whereby a
`
`therapeutically significant blood plasma
`
`fulvestrant
`
`concentration of at least 2.5 ngml_1 is attained for at least
`
`2 weeks after injection.
`
`2. The method as claimed in claim 1 wherein the benign
`
`or malignant disease is breast cancer.
`
`B.
`
`Overview of the Prosecution History of the ‘122 Patent and
`Related Applications
`
`(1)
`
`Prosecution History of the ‘ 122 Patent
`
`41.
`
`I have reviewed the prosecution history of the ‘ 122 patent in forming
`
`l9
`
`InnoPharma Exhibit 1013.0022
`
`

`

`my opinions for purposes of this declaration.
`
`I discuss three aspects of the
`
`prosecution history that are relevant to my opinion below.
`
`42.
`
`First,
`
`the Patent Office recognized that numerous aspects of the
`
`claims were well-known in the art and obvious to a person of skill in the art.
`
`0
`
`“One of ordinary skill in the art would have been motivated to employ
`
`benzyl benzoate, ethanol, castor oil, and benzyl alcohol,
`
`in the herein
`
`claimed weight percent, with fulvestrant,
`
`in the dosage herein] .
`
`.
`
`.
`
`.
`
`3?
`
`Exhibit 1006 at 0538',
`
`o
`
`“Castor oil and benzyl alcohol are known to be eflective as vehicle for
`
`0
`
`0
`
`fulvestrant.” Id',
`
`“Ethanol is a commonly used pharmaceutical solvent.” Id',
`
`“Benzyl benzoate is known to be effective as
`
`solvent
`
`for steroidal
`
`compounds.” Id.
`
`0
`
`“[C]ombining one or more agents, which are known to be useful as
`
`commonly used solvents, such as benzyl benzoate, ethanol, castor oil, and
`
`benzyl alcohol, together and incorporated such combination with an estrogen
`
`derivatives,
`
`fulvestrant, would be reasonably expected to be useful in
`
`formulating a pharmaceutical composition.” Id.
`
`43.
`
`Recognizing the substantial overlap between the prior art and the
`
`1 Unless otherwise noted, all emphases are added.
`
`20
`
`InnoPharma Exhibit 1013.0023
`
`

`

`claimed invention, the sole basis on which the Patent Office found the claims
`
`patentable was an alleged “[u]nexpected increase of solubility of fulvestrant by
`
`adding 15% of benzyl benzoate into the composition.” Id. at 0540', see also id. at
`
`0572. Significantly, neither the