`INNOPHARMA LICENSING, LLC,
`Petitioner
`
`v.
`
`
`ASTRAZENECA AB,
`Patent Owner
`
`
`
`
`
`
`
`
`Case IPR2017-00900
`Patent No. 8,329,680
`
`
`
`
`
`Case IPR2017-00900
`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. 8,329,680
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
`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. 8,329,680
`
`
`Mail Stop: Patent Board
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`
`
`InnoPharma Exhibit 1013.0001
`
`

`

`Case IPR2017-00900
`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. 8,329,680
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION .............................................................................................. 1
`
`I.
`
`II. BACKGROUND AND QUALIFICATIONS ................................................... 3
`
`III. MATERIALS CONSIDERED FOR THIS DECLARATION .......................... 6
`
`IV. SUMMARY OF OPINIONS ............................................................................. 6
`
`V. TECHNICAL OVERVIEW OF PHARMACOKINETICS AND
`PHARMACODYNAMICS ................................................................................ 9
`
`A. Pharmacokinetics ..................................................................................... 9
`
`B. Pharmacodynamics ................................................................................ 18
`
`VI. OVERVIEW OF THE ‘680 PATENT AND ITS PROSECUTION HISTORY
` .......................................................................................................................... 20
`
`A. Overview of the ‘680 Patent .................................................................. 20
`
`B. Overview of the Prosecution History of the ‘680 Patent ....................... 23
`
`VII. LEVEL OF ORDINARY SKILL IN THE PERTINENT ART....................... 29
`
`VIII.BROADEST REASONABLE CONSTRUCTION ......................................... 30
`
`IX. UNDERSTANDING OF THE LAW ............................................................... 31
`
`X. SCOPE AND CONTENT OF THE PRIOR ART ........................................... 36
`
`A. Howell .................................................................................................... 36
`
`B. McLeskey ............................................................................................... 39
`
`C. O’Regan ................................................................................................. 40
`
`D. DeFriend ................................................................................................. 41
`
`XI. DETAILED INVALIDITY ANALYSIS ......................................................... 42
`
`A. The Claimed Therapeutically Significant Blood Plasma Fulvestrant
`
`ii
`
`InnoPharma Exhibit 1013.0002
`
`

`

`Case IPR2017-00900
`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. 8,329,680
`
`
`Concentrations Are Obvious .................................................................. 43
`
`(1) The Prior Art Expressly Discloses the Claimed Therapeutically
`Significant Blood Plasma Fulvestrant Concentrations .................. 43
`
`(a) Howell Discloses Fulvestrant Concentrations of At Least 2.5
`ngml-1 After Four Weeks ........................................................ 43
`
`(b) The Prior Art Discloses Fulvestrant Concentrations of At
`Least 8.5 ngml-1 After Four Weeks ........................................ 45
`
`(i) Howell Teaches Fulvestrant Concentrations of At Least
`8.5 ngml-1 After Four Weeks .......................................... 45
`
`(ii) Howell and DeFriend Teach Fulvestrant Concentrations
`of At Least 8.5 ngml-1 After Four Weeks ....................... 51
`
`(2) A Person of Ordinary Skill in the Art Would Be Motivated to
`Achieve Therapeutically Significant Blood Plasma Fulvestrant
`Concentrations ................................................................................ 56
`
`(a) A Person of Skill in the Art Would Be Motivated to Achieve
`the Positive Results Reported in Howell ................................ 56
`
`(b) A Person of Skill in the Art Would Be Further Motivated to
`Increase Dose and Blood Concentration to Achieve Complete
`Downregulation of Estrogen Receptors ................................. 56
`
`(i) DeFriend Would Motivate a Person of Skill in the Art to
`Double the Dose in Howell ............................................ 58
`
`(ii) DeFriend Would Motivate a Person of Skill in the Art to
`Use a Loading Dose ........................................................ 60
`
`(c) Rebuttal to AstraZeneca’s Arguments ................................... 63
`
`(3) A Person of Skill in the Art Would Have a Reasonable Expectation
`of Success in Achieving Therapeutically Significant Blood Plasma
`Fulvestrant Concentrations............................................................. 66
`
`(a) A Person of Skill in the Art Would Have a Reasonable
`
`iii
`
`InnoPharma Exhibit 1013.0003
`
`

`

`Case IPR2017-00900
`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. 8,329,680
`
`
`Expectation of Success in Achieving Fulvestrant
`Concentrations of At Least 2.5 ngml-1 For Four Weeks ........ 66
`
`(b) A Person of Skill in the Art Would Have a Reasonable
`Expectation of Success in Achieving Fulvestrant
`Concentrations of At Least 8.5 ngml-1 For Four Weeks ........ 67
`
`(c) Rebuttal to AstraZeneca’s Arguments ................................... 69
`
`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 ..................................................... 70
`
`XII. CONCLUSION ................................................................................................ 76 
`
` 
`
`iv
`
`InnoPharma Exhibit 1013.0004
`
`

`

`Case IPR2017-00900
`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. 8,329,680
`
`
`I, Richard Bergstrom, Ph.D. hereby declare as follows:
`
`I.
`
`INTRODUCTION
`1.
`
`I have been retained as an expert witness on behalf of InnoPharma
`
`Licensing, LLC (“InnoPharma”) for the above-captioned Petition for Inter Partes
`
`Review (“IPR”) of U.S. Patent No. 8,329,680 (“the ‘680 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
`
`therapeutically significant blood plasma fulvestrant concentrations recited in
`
`claims 1-3 and 6 of the ‘680 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 ‘680 patent, the file
`
`histories of the ‘680 patent and 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.
`
`5.
`
`In forming the opinions expressed in this Declaration, I relied upon
`
`
`InnoPharma Exhibit 1013.0005
`
`

`

`
`
`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, 2, 3, and 6 of the ‘680 patent are
`
`based, at least in part, on the following prior art publications:
`
`Reference
`
`Howell, Pharmacokinetics,
`Pharmacological and Anti-
`tumor Effects of the Specific
`Anti-Oestrogen ICI 182780 in
`Women with Advanced Breast
`Cancer, BRITISH J. OF CANCER,
`74, p. 300-308 (1996)
`
`McLeskey, Tamoxifen-
`resistant fibroblast growth
`factor-transfected MCF-7 cells
`are cross-resistant in vivo to
`the antiestrogen ICI 182,780
`and two aromatase inhibitors,
`4 CLIN. CANCER RESEARCH
`697–711 (1998)
`
`O’Regan, Effects of the
`Antiestrogens Tamoxifen,
`Toremifene, and ICI 182,780
`on Endometrial Cancer
`Growth, 90 J. NAT’L CANCER
`INST. 1552–1558 (1998)
`
`DeFriend, Investigation of a
`New Pure Antiestrogen (ICI
`182780) in Women with
`Primary Breast Cancer, 54
`CANCER RESEARCH 408–414
`(1994)
`
`Date of Public Availability
`
`Howell was published in 1996 and is
`attached as Exhibit 1007 to the IPR.
`
`McLeskey 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 IPR.
`
`DeFriend was published in January
`1994 and is attached as Exhibit 1038
`to the IPR.
`
`
`
`2
`
`InnoPharma Exhibit 1013.0006
`
`

`

`
`
`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 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 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
`
`
`
`3
`
`InnoPharma Exhibit 1013.0007
`
`

`

`
`
`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
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`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
`
`
`
`4
`
`InnoPharma Exhibit 1013.0008
`
`

`

`
`
`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®, Axid™, Humulin®, Strattera®, Prozac®, Prozac Weekly™,
`
`Zyprexa®, Zyprexa® IntraMuscular, Zyprexa Zydis®, Zyprexa Relprevv™,
`
`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
`
`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 vivo 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
`
`
`
`5
`
`InnoPharma Exhibit 1013.0009
`
`

`

`
`
`impact of these properties on the in vivo 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. 1:11-cv-01106-LPS (D.
`
`Del.), Forest Labs, Inc. v. Teva Pharms. USA, Inc., No. 1:14-cv-121-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 ‘680 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:
`
` The “therapeutically significant blood plasma fulvestrant concentration of at
`
`least 2.5 ngml-1 for at least four weeks” recited in claims 1 and 3 of the ‘680
`
`patent would have been obvious to a person of skill in the art. In particular,
`
`Howell discloses that exact claimed blood concentration and discloses that
`
`
`
`6
`
`InnoPharma Exhibit 1013.0010
`
`

`

`
`
`
`
`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.
`
` The “therapeutically significant blood plasma fulvestrant concentration of at
`
`least 8.5 ngml-1 for at least four weeks” recited in claims 2 and 6 of the ‘680
`
`patent would have been obvious to a person of skill in the art for at least
`
`three reasons:
`
` Figure 2 of Howell confirms that at least some patients will have day 28
`
`minimum fulvestrant concentrations above 8.5 ngml-1, especially if those
`
`results are applied to a broader patient population. As with the 2.5 ngml-1
`
`blood concentrations, a person of skill in the art would be motivated to
`
`achieve those levels given the high response rate (69%) and lack of
`
`adverse effects reported in Howell, and would have a reasonable
`
`expectation in doing so.
`
` A person of skill in the art would have been motivated to achieve steady
`
`state faster based on the results disclosed in Howell. In particular,
`
`Howell does not show that steady state was reached by month 6.
`
`Moreover, of
`
`the patients
`
`in Howell who experienced disease
`
`7
`
`InnoPharma Exhibit 1013.0011
`
`

`

`
`
`
`
`progression, they experienced that progression within 8 weeks. Thus, a
`
`person of skill in the art would have been motivated to administer a 500
`
`mg loading dose (two 250 mg injections) to more quickly achieve steady
`
`state and prevent disease progression. By administering a 500 mg
`
`loading dose, a person of ordinary skill in the art would reasonably
`
`expect to achieve concentrations of fulvestrant higher than those reported
`
`in Figure 2 of Howell.
`
` A person of skill in the art would be motivated to increase the dose
`
`disclosed in Howell to the 500 mg/month equivalent dose reported in
`
`DeFriend. DeFriend specifically discloses that the pharmacokinetics of
`
`fulvestrant are dose dependent—meaning that increasing the dose would
`
`result in increased fulvestrant concentrations. Based on the disclosure in
`
`DeFriend, a person of skill in the art would reasonably expect that
`
`increasing
`
`the dose would
`
`result
`
`in greater estrogen
`
`receptor
`
`downregulation and greater efficacy. Additionally, a 500 mg/month dose
`
`would result in plasma fulvestrant concentrations of at least 8.5 ngml-1
`
`for at least four weeks, as I explain below.
`
` 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
`
`8
`
`InnoPharma Exhibit 1013.0012
`
`

`

`
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`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 profile if the McLeskey formulation was administered
`
`intramuscularly.
`
`V. TECHNICAL OVERVIEW OF PHARMACOKINETICS AND
`PHARMACODYNAMICS
`A.
`Pharmacokinetics
`17. Pharmacokinetics is the area of pharmaceutical science that is
`
`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 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
`
`
`
`9
`
`InnoPharma Exhibit 1013.0013
`
`

`

`
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`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.
`
`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
`
`
`
`10
`
`InnoPharma Exhibit 1013.0014
`
`

`

`
`
`to determine the maximum plasma concentration, or “Cmax,” that an active
`
`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, 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.
`
`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
`
`
`
`11
`
`InnoPharma Exhibit 1013.0015
`
`

`

`
`
`
`
`drug prroduct thaat has beenn absorbedd by the
`
`
`
`
`
`
`
`
`
`subject annd the ratte of the
`
`
`
`drug
`
`
`
`eliminattion from
`
`the body
`
`
`
`
`
`
`
`ement. Eof measureduring the period o
`
`
`
`xhibit 10223 at
`
`
`
`
`
`
`
`
`
`0004. AA graph deepicting theese conceppts is shownn below:
`
`
`
`
`
`224. Whenn establishhing targeet serum
`
`
`
`
`
`
`
`
`
`concentraation, and
`
`
`
`by extennsion
`
`
`
`dosing rregimens,
`
`
`
`a person oof skill in
`
`
`
`the art willl considerr the therappeutic winndow
`
`
`
`
`
`
`
`for the
`
`
`drug at is
`
`sue. For aany drug,
`
`there is a
`
`
`
`minimumm effective
`
`
`
`concentraation,
`
`
`
`necessary
`
`which
`
`
`
`is the minnimum seerum conc
`entration
`
`
`
`sired to achievve the des
`
`
`
`
`
`therapeuutic effect.. Similarlyy, each druug will havve a minimmum toxic
`
`
`
`
`
`
`
`
`
`
`
`
`
`which iis the miniimum seruum concenntration whhich causess toxicity.
`
`
`
`
`
`
`
`
`
`
`
`
`
`concentraation,
`
`
`
` The rangge of
`
`serum
`
`
`
`concentrattions betwween the
`
`
`
`minimum
`
`effective
`
`concentr
`
`ation and
`
`the
`
`
`
`minimuum toxic cooncentratioon is definned as the
`
`
`
`
`
`
`
`
`
`
`
`
`
`therapeuticc window.. The goaal for
`
`
`
`the therappeutic winddow.
`
`
`
`
`
`any treaatment regiimen is to kkeep patiennts within
`
`
`
`
`
`
`
`
`
`12
`
`InnoPharma Exhibit 1013.0016
`
`

`

`
`
`25. The mean, standard deviation, and standard error of a dataset are also
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`useful statistics for understanding pharmacokinetic results. Standard deviation
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`describes the variability between subjects in the population studied. Exhibit 1093
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`at 0001. A large standard deviation describes a dataset with points that are a larger
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`distance from the mean, while a small standard deviation describes data points that
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`are clustered more closely to the mean. These statistical metrics are used
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`commonly to describe various pharmacokinetic data and their application assumes
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`that the pharmacokinetic data are reasonably represented by a bell-shaped or so-
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`called normal distribution.
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`26.
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`In a normal distribution, 68% of the data is within one standard
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`deviation of the mean, 95% of the data is within two standard deviations, and
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`99.7% is within 3 standard deviations. Exhibit 1092 at 0002; Figure 1. Standard
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`error of the mean is a statistical metric that describes the uncertainty concerning
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`how well the sample mean represents the true mean of the population. While
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`standard deviation is used to describe the variability of the data within a single
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`sample or set of data, the standard error of the mean is used to describe the
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`variability in the estimation of the mean between different samples from the same
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`population. The standard error of the mean is estimated by dividing the standard
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`deviation of the sample by the square root of the sample size. Thus, standard error
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`(SE) is estimated using the following formula, where SD is the standard deviation
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`13
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`InnoPharma Exhibit 1013.0017
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`of the sample and N is the sample size.
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`27. Thus, a larger sample size results in a smaller standard error and a
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`larger standard deviation results in a larger standard error. Thus, standard error for
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`any given data set is always smaller than the standard deviation.
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`28. Drugs may be formulated in various ways, depending on the desired
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`pharmacokinetic profile. A drug “formulation” generally refers to the specific
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`recipe or listing of ingredients used to make a final drug product or “dosage form.”
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`A “dosage form,” in contrast, is the physical form in which a drug is produced or
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`dispensed, such as a tablet or capsule. See Drugs@FDA, Glossary of Terms,
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`http://www.fda.gov/Drugs/InformationOnDrugs/ucm079436.htm at 1.
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`29.
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`“Immediate release” dosage forms provide rapid dissolution that
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`facilitates an immediate or rapid entry of the active ingredient into the bloodstream
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`of the subject. Exhibit 1024 at 0005. In such dosage forms, no excipients are
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`added to intentionally retard the rate of release of the active ingredient or its entry
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`into the bloodstream.
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`30. Drugs can also be formulated in “modified release” dosage forms that
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`are specifically engineered to alter the timing and/or rate of release of the active
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`14
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`InnoPharma Exhibit 1013.0018
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`drug subbstance. IId. In moddified releaase dosage
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`forms, exccipients aree added fo
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`r the
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`express
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`purpose oof retardingg or otherwwise alteriing the timming or ratte of releasse of
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`the activve ingredient. This
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`delayed orr altered reelease resuults in a loonger periood of
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`time to
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`ngle dose, reach Cmaxx after a sin
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`i.e., greate
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`cally elease typicer Tmax. Prrolonged re
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`also deccreases thee magnitud
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`prolonged however, pde of Cmax. Ideally, h
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`release haas no
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`impact
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`on AUC.
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`Modified
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`ms are also release doosage form
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`to as sometimess referred t
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`included
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`a graph beelow
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`s. I have tained relee” or “sust“extendded release ase” drugs
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`comparing and ccontrasting
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`us a the PK pprofiles foor an immmediate rellease versu
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`rm (with iimmediatee release laabelled as
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`“conventiional
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`modifieed release
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`dosage fo
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`profile””):
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`1. The c
`3
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`concentrations of a ddrug in thee bloodstreeam over ttime reflec
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`t the
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`and
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`aggregaate impact
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`etabolism, bution, meion, distribof absorptiof the prrocesses o
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`excretioon. Absorpption referrs to the prrocesses thhat lead to
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`the entry oof a drug ffrom
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`15
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`InnoPharma Exhibit 1013.0019
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`its site of administration into the bloodstream. Exhibit 1025 at 0001. The most
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`common site of absorption is the gastrointestinal tract, where the drug must cross
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`cell membranes to enter the bloodstream, resulting in varying rates of absorption
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`and bioavailability. After the drug enters the bloodstream, it is distributed into
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`various tissues of the body. Id. at 0002.
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`32. Different amounts of the drug are partitioned to different organs and
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`tissues and remain there for varying amounts of time. Factors that determine how
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`drugs are distributed include the diffusion rate across lipid membranes, regional
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`blood flow, and the ability of the drug to bind to proteins in tissues and blood. The
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`drug then undergoes metabolism, or biotransformation, during which enzymes in
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`the body, particularly those in the liver, break down the parent drug into new
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`compounds called metabolites. Id. at 0003. In the typical case, the processes
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`involving metabolism generate inactive metabolites that can be more readily
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`excreted from the body because they are more polar. The drug and its metabolites
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`are removed from the body through excretion. The rate of excretion determines
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`the degree of accumulation of the drug and its metabolites. The frequency and
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`amount of drug administered over time may lead to drug or metabolite
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`accumulation when this rate exceeds the rate of drug excretion. The accumulation
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`of these substances can be used to achieve the desired drug exposure and
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`pharmacological effects or if excessive can adversely affect the well-being of the
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`16
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`InnoPharma Exhibit 1013.0020
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`patient resulting from undesired pharmacological effects. Excretion occurs when
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`the drug and/or its metabolites leave the body through urine or feces. Id. at 0009.
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`33.
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`In order
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`to predict a drug’s behavior
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`through
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`the body,
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`pharmacokineticists use the concept of compartmentalization to mathematically
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`model the complex processes described above. Exhibit 1022 at 0009. The
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`compartment model is based on the assumption that each compartment represents a
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`group of similar tissues or fluids. To construct such a model, simplifications of
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`body structures and systems are made because organs and tissues that have similar
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`characteristics in the context of drug distribution are grouped as a single
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`compartment.
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`34. For example, blood, heart, kidneys, liver, and lungs are considered
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`highly perfused organs and they may exhibit similar patterns of drug distribution.
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`As a result, they are often grouped as a single compartment. Similarly, other
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`organs and tissues are less highly perfused, such as bone or fat, and drug
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`distribution into and out of these tissues may be represented by other
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`compartments, also called peripheral compartments. Under either single or
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`muticompartmental assumptions, a plasma drug concentration-time curve can be
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`developed, and the plasma concentration of a drug at any time can be predicted.
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`Id. at 0013.
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`17
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`InnoPharma Exhibit 1013.0021
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`B.
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`Pharmacodynamics
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`35. Whereas pharmacokinetics measures the animal or human body’s
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`effect on how a drug moves through the body and is processed, pharmacodynamics
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`measures the body’s biochemical and physiological response to the presence of a
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`drug.
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` Exhibit 1026 at 0006.
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` Pharmacodynamics is the study of the
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`pharmacological response to a drug, which usually involves measuring receptor
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`binding and other interactions between the drug and the body. It is worth noting
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`that there are many factors that cause a degree of inter-subject variability in the
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`pharmacological response to a drug, such as the physiological health and age of the
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`patient and interactions with other drugs in the body. Id. at 0008. As a result, for
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`most drugs, pharmacodynamics, along with pharmacokinetics, is used to develop
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`the optimal dose of a drug that is effective in the majority of patients representing a
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`population. However, pharmacokinetics and pharmacokinetics are also used to
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`understand how individual patients differ from one another and how the optimal
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`dose can be modified to individualize patient therapy. Id. at 0018.
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`36. Pharmacodynamics is primarily concerned with the dose-response
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`relationship, or the relationship between the concentration of a drug and its effect
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`on the body. Dose-response data is often presented, like in the graph below, with
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`the dose or concentration on the x-axis and the measur