Filed on behalf of: Corcept Therapeutics, Inc.
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`
` Entered: May 20, 2019
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
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`NEPTUNE GENERICS, LLC,
`Petitioner,
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`v.
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`CORCEPT THERAPEUTICS, INC.,
`Patent Owner.
`_______________________
`Case IPR2018-01494
`U.S. Patent No. 8,921,348
`_______________________
`
`DECLARATION OF HARTMUT DERENDORF, PH.D., IN SUPPORT OF
`PATENT OWNER’S RESPONSE
`
`Ex. 2014-0001
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`IPR2018-01494 (USP 8,921,348)
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`TABLE OF CONTENTS
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`Dr. Derendorf’s Declaration
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`I.
`II.
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`Page
`INTRODUCTION AND QUALIFICATIONS ............................................... 1
`LEGAL STANDARDS ................................................................................... 4
`A. Obviousness ........................................................................................... 4
`B.
`Relevant Time Period for the Obviousness Analysis ............................ 6
`III. Materials Relied on in Forming My Opinion .................................................. 7
`IV. CLAIM CONSTRUCTION ............................................................................ 7
`V.
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 9
`VI. TECHNICAL BACKGROUND ................................................................... 11
`A.
`Pharmacokinetics Overview ................................................................ 11
`1.
`PK Parameters And Steady State .............................................. 12
`2.
`Single-Dose Versus Multiple-Dose Studies ............................. 14
`The Difference Between Linear And Non-Linear
`Pharmacokinetics Profiles ................................................................... 15
`1.
`Linear Pharmacokinetics Profiles ............................................. 16
`2.
`Non-Linear Pharmacokinetics Profiles ..................................... 16
`The Relationship Between Pharmacokinetics and
`Pharmacodynamics .............................................................................. 19
`1. Measuring Blood Serum Levels................................................ 20
`The Pharmacokinetics of Mifepristone ............................................... 21
`1. Mifepristone Has A Non-Linear PK Profile ............................. 21
`2. Mifepristone Has A Complicated Metabolic Profile ................ 25
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`B.
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`C.
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`D.
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`Ex. 2014-0002
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`VII. PETITIONER’S PRIOR ART REFERENCES ............................................ 28
`A.
`Belanoff ’953 ....................................................................................... 28
`B.
`Belanoff ’848 ....................................................................................... 32
`C.
`Belanoff 2002 ...................................................................................... 34
`D.
`Chu & Belanoff ................................................................................... 36
`E. Murphy ................................................................................................ 38
`F.
`Sitruk-Ware ......................................................................................... 40
`VIII. THE ’348 PATENT ....................................................................................... 45
`A.
`The ’348 Invention .............................................................................. 45
`B.
`The ’348 Claims .................................................................................. 48
`C.
`The ’348 File History .......................................................................... 49
`IX. THE ’348 PATENT CLAIMS ARE NOT OBVIOUS BASED ON
`THE PRIOR ART .......................................................................................... 51
`A. Opinions on Ground 1 ......................................................................... 55
`1.
`Belanoff ’848 Does Not Disclose, Teach, or Motivate the
`POSA to Arrive at the Critical 1300 ng/mL Threshold or
`Use It to Adjust the Patient’s Dose ........................................... 56
`Belanoff ’848 Teaches that Dosing Should be Adjusted
`Based on Psychiatric Testing, Not Drug Serum Levels ........... 60
`Belanoff ’848 Does Not Disclose, Teach, or Motivate the
`Optimization Protocol Described in the ’348 Patent of
`Monitoring of Mifepristone Serum Levels and Adjusting
`Dose Based on Drug Levels for Efficacy ................................. 62
`Belanoff ’848 Does Not Render Obvious the Dependent
`Claims ....................................................................................... 66
`Opinions on Ground 2 ......................................................................... 67
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`B.
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`2.
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`3.
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`4.
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`Dr. Derendorf’s Declaration
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`ii
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`Ex. 2014-0003
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`IPR2018-01494 (USP 8,921,348)
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`1.
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`Dr. Derendorf’s Declaration
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`Neither Belanoff 2002 nor Chu & Belanoff Teach that
`the Need for Dose Adjustment Should Be Determined
`Based on Drug Serum Levels ................................................... 67
`Sitruk-Ware Does Not Teach or Motivate a POSA to
`Target the 1300 ng/mL Level for Efficacy, Or Develop
`an Optimization Protocol Based on Blood Level ..................... 69
`Petitioner’s Arguments Assuming the Target Therapeutic
`Level of 1300 ng/mL are Premised on Hindsight ..................... 81
`None of Petitioner’s Prior Art References Disclose
`Mifepristone’s PK/PD Relationship, or the Drug Serum
`Level Required for Efficacy ...................................................... 83
`Petitioner’s Proposed Combinations Do Not Teach or
`Motivate the ’348 Patent’s Optimization Protocol ................... 86
`A POSA Would Have Had No Reasonable Expectation
`of Success in Arriving at the 1300 ng/mL Level Due to
`Mifepristone’s Non-Linear PK and Complex Metabolism
`Complicating Serum Level Determination ............................... 89
`A POSA Would Have Had No Motivation to Combine
`the Contraceptive Reference Sitruk-Ware With The
`Mental Disorder References Belanoff 2002 And Chu &
`Belanoff ..................................................................................... 94
`Belanoff 2002 in View of Chu & Belanoff and Sitruk-
`Ware Does Not Render Obvious the Dependent Claims .......... 96
`Opinions on Ground 3 ......................................................................... 97
`C.
`D. Opinions on Ground 4 ......................................................................... 99
`E.
`Opinions on Ground 5 ....................................................................... 100
`F.
`Opinions on Ground 6 ....................................................................... 101
`CONCLUSION ............................................................................................ 103
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`X.
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`iii
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`Ex. 2014-0004
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`IPR2018-01494 (USP 8,921,348)
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`I.
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`INTRODUCTION AND QUALIFICATIONS
`1.
`I have been retained by Corcept Therapeutics, Inc. (“Patent Owner” or
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`Dr. Derendorf’s Declaration
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`“Corcept”) to provide my opinion on, and explain, factual issues related to the
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`validity of U.S. Patent No. 8,921,348 (“the ’348 Patent”) in support of Patent
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`Owner’s Response in IPR2018-01494.
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`2.
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`I am being compensated at my standard hourly rate of $600 per hour,
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`with reimbursement for reasonable expenses, for my work related to the IPR
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`proceeding cited above. My compensation is not dependent on, and in no way
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`affects, the substance of my statements in this Declaration.
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`3.
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`I am a Distinguished Emeritus Professor in the Department of
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`Pharmaceutics at the University of Florida College of Pharmacy. I also serve as the
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`Principal Scientific Advisor for PK-P’Dyne, Inc., a consulting company.
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`4.
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`I received my B.S. in Pharmacy in 1976 and Ph.D., summa cum laude,
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`in Pharmacy in 1979, both from the University of Münster in Germany. After
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`working as an Assistant Scientist at the University of Münster from 1979-1980, I
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`joined the Department of Pharmaceutics at the University of Florida, first as a
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`Postdoctoral Fellow in 1981 and later as an Assistant Professor in 1983. I became
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`an Associate Professor in 1987, Professor in 1993, and Distinguished Professor in
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`2003, a title I retained until I retired in 2018. I was named V. Ravi Chandran
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`1
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`Ex. 2014-0005
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`Professor of Pharmaceutical Sciences in 2013. For 28 years, I served as Chairman
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`of the department from 1987-1995 and 1998-2018.
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`5.
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`I teach and consult in the areas of biopharmaceutics, pharmacokinetics,
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`pharmacodynamics, and clinical pharmacokinetics. For over 30 years, I have taught
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`classes in pharmacokinetics, pharmacodynamics, and drug level monitoring. I have
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`received numerous awards at my academic institution, including an early University
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`of Florida Teaching Improvement Award, Howard Hughes Medical Institute
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`Distinguished Mentorship Award, University of Florida Research Foundation
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`Professorship, CVS Pharmacy Endowed Professorship, International Educator of the
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`Year Award, and University of Florida Doctoral Advisor/Mentoring Award. I have
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`supervised over 50 Ph.D. students.
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`6.
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`I have published over 490 scientific publications and over twenty
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`textbooks in English and German. The vast majority of these publications are related
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`to pharmacokinetics and pharmacodynamics. I have given over 900 presentations at
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`national or international meetings. I am either an Editor or Associate Editor of the
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`Journal of Clinical Pharmacology, International Journal of Clinical Pharmacology
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`and Therapeutics, International Journal of Antimicrobial Agents, and Die
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`Pharmazie, and serve on the editorial board of several other journals. My research
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`interests include the pharmacokinetics and pharmacodynamics of corticosteroids,
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`analgesics, antibiotics, as well as drug interactions.
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`Ex. 2014-0006
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`7.
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`I have served as President of the American College of Clinical
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`Pharmacology (ACCP) and President of the International Society of Anti-Infective
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`Pharmacology (ISAP). I won the McKeen-Cattel Award for the best publication in
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`the Journal of Clinical Pharmacology in 1995 and the Faculty Award of Utrecht
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`University, Netherlands in 2005. In 2003, I was awarded the Nathaniel T. Kwit
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`Distinguished Service Award of ACCP and the Research Achievement Award in
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`Clinical Science of the American Association of Pharmaceutical Sciences (AAPS).
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`I am a Fellow of the AAPS and ACCP, as well as a former review panel member of
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`the NASA Human Research Program. In 2010, I was awarded the Volwiler Award
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`of the American Association of Colleges of Pharmacy and the ACCP Distinguished
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`Investigator Award, the highest research awards of both organizations. In 2013, I
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`was awarded the Leadership Award of the International Society of Pharmacometrics
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`(ISOP). In 2015, I received the Merit Medal of the Westphalian Chamber of
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`Pharmacy, as well as the ACCP Mentorship Award. I served as the 18th University
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`of Florida Distinguished Alumni Professor from 2015-2017. In 2018, I was awarded
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`the Mentor Award of the American Society for Clinical Pharmacology and
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`Therapeutics.
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`8.
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`A copy of my curriculum vitae is attached as Ex. 2015.
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`Ex. 2014-0007
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`II. LEGAL STANDARDS
`9.
`I am not an attorney and, consequently, will offer no opinion on the law
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`itself. My understanding of the pertinent law is outlined in sections II.A and II.B to
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`follow and is the result of explanations provided by counsel. I have applied this
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`understanding in my analysis.
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`A. Obviousness
`10.
`I understand that a patent claim is unpatentable if it is obvious in view
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`of the prior art. I further understand that the frame of reference for determining
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`whether a patent is obvious is from the perspective of a person of ordinary skill in
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`the relevant art (“POSA”) at the time the invention was made (in this case, the
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`priority date of August 30, 2007).
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`11.
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`In analyzing obviousness in light of the prior art, I understand that it is
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`important to understand the scope of the claims, the level of skill in the relevant art,
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`the scope and content of the prior art, the differences between the prior art and the
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`claimed invention, and any objective indicia of non-obviousness (also called
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`secondary considerations).
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`12.
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`It is my understanding that a claimed invention is unpatentable as
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`obvious if the differences between the invention and the prior art are such that the
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`subject matter as a whole would have been obvious at the time the invention was
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`made to a person having ordinary skill in the art to which the subject matter pertains.
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`4
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`Ex. 2014-0008
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`13.
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`I have been informed that the Supreme Court has recognized several
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`rationales for combining references or modifying a reference to show obviousness
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`of the claimed subject matter. I understand that several of these rationales are: 1)
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`combining prior art elements according to known methods to yield predictable
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`results; 2) simple substitution of one known element for another to obtain
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`predictable results; 3) use of a known technique to improve a similar device
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`(method or product) in the same way; 4) applying a known technique to a known
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`device (method or product) ready for improvement to yield predictable results;
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`5 ) choosing from a finite number of identified, predictable solutions, with a
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`reasonable expectation of success, 6 ) and some teaching, suggestion, or
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`motivation in the prior art that would have led one of ordinary skill to modify the
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`prior art reference or to combine prior art reference teachings to arrive at the
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`claimed invention.
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`14.
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`I understand that a patent claim is obvious over multiple, combined
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`references only if the prior art as a whole taught or suggested the invention, if there
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`was a motivation or reason to combine the teachings of the prior art references to
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`achieve the claimed invention, and if a POSA would have had a reasonable
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`expectation of success in doing so. I also understand that references that “teach
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`away” from the invention—in other words, references that would lead the POSA in
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`a different direction from that taken by the patentee—must be considered.
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`5
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`Ex. 2014-0009
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`15.
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`I also understand that the use of hindsight must be avoided in
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`determining whether an invention would have been obvious because the obviousness
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`of an invention is evaluated from the perspective of a POSA at the time the invention
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`was conceived. In addition, I understand that the passage of time between the prior
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`art and the date of the patented invention also supports the non-obviousness of the
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`invention.
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`16. As stated above, I understand that the obviousness inquiry also takes
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`into account objective indicia of non-obviousness, or secondary considerations of
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`non-obviousness. I understand that commonly recognized objective indicia of non-
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`obviousness include: the failure of others to solve the problem addressed by the
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`invention, the unexpected or surprising results of the invention, the existence of a
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`long-felt but unmet need for the invention, the commercial success of the invention,
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`and the copying of the invention by others. I understand that the Federal Circuit has
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`recognized that such evidence may often be the most probative and cogent evidence
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`in the record.
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`B. Relevant Time Period for the Obviousness Analysis
`17.
`I understand that the earliest patent application leading to issuance of
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`the ’348 Patent was filed on August 30, 2007. I understand that the Petitioner is not
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`contesting that the relevant date for the analysis is August 30, 2007. My opinions in
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`Ex. 2014-0010
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`this Declaration are based on the knowledge and perspective of a POSA as of this
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`date.
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`III. Materials Relied on in Forming My Opinion
`18.
`In forming my opinions in this Declaration, I have reviewed the
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`materials cited in and listed in the Appendix to this Declaration.
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`19.
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`I have further drawn on my experience in pharmacokinetics and
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`pharmacodynamics as well as the knowledge of a POSA in the relevant timeframe.
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`Each of the statements below reflects my opinion.
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`IV. CLAIM CONSTRUCTION
`20.
`I understand from the legal standards shared with me by counsel that
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`claim terms are given their broadest reasonable construction in light of the
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`specification in which they appear. I understand, however, that the preamble of the
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`claim can be limiting when it provides meaning to the claim. In my opinion the
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`preamble of Claim 1, “[a] method for optimizing levels of mifepristone in a patient
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`suffering from a disorder amenable to treatment by mifepristone” provides context
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`and meaning to the claim, including based on the specification of the ’348 Patent.
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`21. First, I understand the term disorder “amenable to treatment by
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`mifepristone,” as it appears in the preamble of independent claim 1 of the ’348
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`Patent, is expressly defined in the ’348 Patent specification and limits the scope of
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`the claims to “a condition that is known to be treated by glucocorticoid antagonists
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`Ex. 2014-0011
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`such as mifepristone.” See Ex. 1001 (’348 Patent) at 3:7-9. Therefore, in my
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`opinion, the proper construction for disorder “amenable to treatment by
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`mifepristone” is “a condition that is known to be treated by glucocorticoid
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`antagonists such as mifepristone.”
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`22.
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`I understand the term “optimizing” in the claim term “method for
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`optimizing levels of mifepristone” as it appears in the preamble of independent claim
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`1 of the ’348 Patent, is defined in the ’348 Patent specification as “the process of
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`testing mifepristone blood levels and adjusting the dosage of mifepristone
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`administered to the patient in need in order to achieve mifepristone blood levels
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`above 1300 ng/mL.” Ex. 1001 (’348 Patent) at 5:53-65. As further explained in the
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`specification, the invention “provides a method for optimizing the blood serum
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`levels of mifepristone so that the blood serum levels remain in an efficacious range
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`and the patient receives the necessary treatment.” Ex. 1001 (’348 Patent) at 2:57-
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`61; 6:11-14. Therefore, in my opinion, the proper construction for “method for
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`optimizing levels of mifepristone” is “the process of testing mifepristone blood
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`levels and adjusting the dosage of mifepristone administered to the patient in need
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`in order to achieve mifepristone blood levels above 1300 ng/mL.”
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`Ex. 2014-0012
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`V.
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`PERSON OF ORDINARY SKILL IN THE ART
`23.
`I understand from the legal principles shared with me by counsel that
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`Dr. Derendorf’s Declaration
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`obviousness must be analyzed from the perspective of a person of ordinary skill in
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`the art (“POSA”).
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`24. A POSA is a hypothetical person who is presumed to be familiar with
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`the relevant scientific field and its literature at the time of the inventions. This
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`hypothetical person is also a person of ordinary creativity capable of understanding
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`the scientific principles applicable to the pertinent field. I was advised that the time
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`of invention for the ’348 Patent is August 30, 2007.
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`25.
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`I understand that Neptune Generics, LLC (“Petitioner” or “Neptune”)
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`has defined the person of ordinary skill in the art (“POSA”) as an individual with
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`“either a Pharm. D. or a Ph.D. in organic chemistry, pharmacy, pharmacology, or a
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`related discipline; or a Bachelor’s or Master’s degree in organic chemistry or a
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`related field with at least four years of experience relating to the study of
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`pharmacokinetics or dosing of drugs, their detection and quantification, or their
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`metabolism.” Petition at 12. Petitioner has further stated that a “POSA may have
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`collaborated with others having expertise in, for example, methods of treating
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`diseases and administering medicines.” Id.
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`26.
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`In my opinion, a POSA is an individual with either a Pharm. D. or Ph.D.
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`in pharmacy, pharmacology, or a related discipline; or a Bachelor’s or Master’s
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`Ex. 2014-0013
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`degree in pharmacy or a related field with at least four years of experience relating
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`to the study of pharmacokinetics and pharmacodynamics, including the relationship
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`between the two, as well as experience with measuring, monitoring, and adjusting
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`drug levels. In addition, a POSA may have collaborated with physicians and/or
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`clinicians with experience in the treatment of psychiatric disease.
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`27.
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`I qualify as a POSA under either standard above at the time the patent
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`application for the ’348 Patent was filed. I have a sufficient level of knowledge,
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`experience and education to provide an expert opinion in the fields encompassed by
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`the ’348 Patent. My own skill level is commensurate with and/or exceeds that of
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`one of ordinary level of skill in the art, as I received a Ph.D. in Pharmacy in 1979
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`from the University of Münster in Germany and have more than 30 years of
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`experience in pharmacokinetics and pharmacodynamics. For over 30 years, I have
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`taught classes in pharmacokinetics, pharmacodynamics and drug level monitoring.
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`28. While my opinions in this Declaration are based on the perspective of
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`a POSA as I defined above, my opinions would remain the same if Petitioner’s
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`definition of a POSA is adopted.
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`29.
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`I understand that Petitioner’s expert, Dr. Heikinheimo testified that he
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`analyzed the obviousness of the Challenged Claims of the ’348 Patent through the
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`lens of his 35 years of experience with the compound mifepristone, not that of a
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`Ex. 2014-0014
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`POSA under Neptune’s proposed definition. Ex. 2009 (Heikinheimo Deposition) at
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`44.
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`VI. TECHNICAL BACKGROUND
`A.
`Pharmacokinetics Overview
`30. Pharmacokinetics is the study of what a person’s body does to a drug
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`after administration, including a drug’s absorption, distribution, and elimination in
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`the human body. These characteristics describe a drug’s pharmacokinetic profile.
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`31. Absorption describes the transit of the drug from time of administration
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`(e.g., orally or through injection) to the systemic circulation (e.g., the blood stream).
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`For example, after a patient swallows an orally-administered drug, the drug must
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`pass through different parts of the gastrointestinal tract before it can reach the
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`circulating blood and be considered “absorbed.”
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`32. Distribution reflects the phase when the drug reaches various organs
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`and tissues through the systemic circulation, including the drug’s site of action.
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`33. Elimination refers to the processes by which the drug is removed from
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`the body: metabolism and excretion. Metabolism is the chemical alteration of a
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`drug by the body or the process by which the drug molecule breaks down in the
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`body. In general, the body metabolizes drugs to change them into compounds that
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`can be readily excreted, which are also referred to as the drug’s metabolites.
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`Metabolites may be inactive or active. Active metabolites exhibit an effect on
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`therapeutic activity and/or toxicity. These effects may be similar to the drug itself,
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`or they can be different.
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`34. Excretion represents the process by which the drug is removed from the
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`body. Drugs are primarily excreted though the urine, but drugs may also be excreted
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`through feces, the skin, or the lungs. I understand that the primary elimination route
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`for mifepristone is in urine, mainly as metabolites, and in feces via biliary excretion.
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`35. The absorption, distribution, and elimination profile of a drug can be
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`measured by determining the concentration of the drug in the body (e.g., in the blood
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`serum) at different points in time, plotting those time points on a graph, and fitting
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`a curve to the data points. This curve, called the PK profile, reflects the
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`pharmacokinetic properties of a drug.
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`1.
`PK Parameters And Steady State
`36. From this curve, certain PK parameters can be identified, including
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`Cmax, Tmax, Cmin, and AUC.
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`37. Cmax is the maximum or “peak” plasma concentration of a drug in a
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`person’s blood plasma after the administration of a dose. Tmax is the point in time
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`after administration when Cmax occurs. Cmin is the minimum or “trough”
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`concentration of a drug in a person’s blood after its administration, just prior to
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`administration of a subsequent dose.
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`12
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`Ex. 2014-0016
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`38. AUC (or the “area under the blood plasma concentration curve”) is a
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`measurement of the body’s total exposure of the drug. AUC can be mathematically
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`calculated by plotting the concentration of the drug in the body (e.g., in plasma)
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`versus time and applying the trapezoidal rule.
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`39. Drugs often need to be maintained at a certain serum level in the blood
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`to be effective, this is referred to as the minimum effective concentration. In
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`addition, drugs also have a toxicity threshold, or a minimum concentration in the
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`blood where a patient starts to experience toxicity or adverse side effects. This
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`defines the upper limit of the drug concentration in the blood plasma before a patient
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`starts to experience unacceptable side effects. These two parameters define the
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`therapeutic window.
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`40. Steady state is a distinct concept that refers to the circumstance where
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`the rate of drug input is equal to the rate of drug elimination, or in other words, where
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`the drug concentration in the blood is “steady” or relatively constant. At steady state
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`during each dosing interval the same concentration profile repeats.
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`41. Before a patient reaches steady state, each additional dose (for drugs
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`with a linear PK profile) results in a higher Cmax, Cmin, and AUC. At steady-state,
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`each dose would give the same Cmax, Cmin, and AUC.
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`42. Cmax refers to the concentration in the blood at a single point in time
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`(the peak or highest drug concentration). Steady state refers to a specific
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`pharmacokinetic phenomenon where certain PK parameters—including Cmax—
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`remain the same upon administration of additional doses of the drug to a patient.
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`While Cmax can be ascertained for any given dose, steady state requires the
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`administration of several doses before this blood concentration phenomenon is
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`achieved. The Cmax resulting from a single dose does not inform the blood
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`concentration profile at steady state.
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`2.
`Single-Dose Versus Multiple-Dose Studies
`43. PK parameters vary based on a number of factors, including dose,
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`dosing frequency, and the number of doses given. The PK profile after a single dose
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`is usually different from the PK profile after multiple or continuous doses of the
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`same drug. After administration of a single dose, the peak plasma level is reached
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`(Cmax) and then the plasma level in the blood continues to decline to its Cmin. If the
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`concentration is below the minimum effective concentration, this results in an
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`absence of therapeutic effect.
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`44. As discussed, the PK profiles after a single dose and after multiple
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`doses are usually different. When multiple doses are administered, drug
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`concentration in the blood can accumulate. For drugs with a linear PK profile,
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`multiple-dose administration shows a higher and predictable mean concentration in
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`the blood (as well as a higher Cmax and Cmin), because of the continued addition of
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`drug. For drugs with a non-linear PK profile, multiple doses could result in a higher
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`than predicted concentration in the blood, or could result in the same or lower than
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`predicted blood concentrations. This is because dose does not proportionally
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`correlate with concentration. Furthermore, pharmacokinetic parameters may not be
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`constant with time. For example, enzymatic auto-induction leads to increased
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`clearance with time and to lower blood levels at later time points. Some of the
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`mifepristone literature reported that the blood concentration after four daily doses
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`was lower than that reported after three daily doses. Ex. 1013 (Heikinheimo 1989)
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`at 2; see also Ex. 2009 (Heikinheimo Deposition) at 102-106.
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`45. For these reasons, drug development studies frequently conduct PK
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`studies based on single-dose and multiple-dose administration. Both of these are
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`separately done because they provide separate and distinct information that guides
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`the understanding of the drug’s PK profile and influences the determination of
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`pharmacodynamics, as discussed in further detail below.
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`B.
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`The Difference Between Linear And Non-Linear Pharmacokinetics
`Profiles
`46. Pharmacokinetic profiles can be described as linear or non-linear. In
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`general, linear profiles show a linear correlation between dose and drug
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`concentration; whereas, nonlinear profiles do not demonstrate a proportional dose-
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`drug concentration relationship.
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`1.
`Linear Pharmacokinetics Profiles
`47. Drugs with a linear pharmacokinetic profile (also described as showing
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`“first order” kinetics) show a direct relationship or correlation between dose and
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`drug exposure or serum concentration. In other words, an increase in dose
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`corresponds with an increase in drug concentration in the blood serum. For example,
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`for a drug with a linear PK, a two-fold increase in dose would result in a two-fold
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`increase in serum concentration. This necessarily assumes that the clearance and
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`bioavailability are constant, and sometimes “linear PK” is substituted with the term
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`“constant clearance.” If the clearance and bioavailability do not change, then
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`exposure increases linearly with dose.
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`48. Where the PK profile is linear, PK parameters can be predicted based
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`on a given dose. In these circumstances, the determination of a dosing regimen can
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`proceed on the predicted PK profile in response to a given dose.
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`49. This
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`is because
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`the plasma concentration
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`increases directly
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`proportionally to the dose. In contrast, for non-linear drugs, as dose increases, there
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`can be little to no corresponding increase in drug concentration. As discussed below,
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`this is the case for mifepristone.
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`2.
`Non-Linear Pharmacokinetics Profiles
`50. Drugs with a non-linear pharmacokinetic profile do not show a
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`proportional relationship or correlation between dose and serum concentration. In
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`other words, an increase in dose does not necessarily correspond with an increase in
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`serum level. Using the same example above, a two-fold increase in dose would not
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`predictably result in a two-fold increase in serum concentration. As of 2007, a POSA
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`understood that various causes of nonlinear pharmacokinetic behavior are
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`theoretically possible, including saturation of plasma protein-binding or carrier-
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`mediated systems (processes defining absorption, distribution, and elimination), and
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`pathologic alteration in drug absorption, distribution, and elimination.
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`51. The varying mechanisms result in different permutations of non-
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`linearity. For example, saturable absorption and saturable protein binding leads to
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`less than proportional increases in drug exposure. In contrast, enzyme saturation
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`leads to increases in drug exposure that are more than proportional.
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`52. One reason for non-linearity is related to the clearance of the drug from
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`the body. The following question helps explain how the clearance could result in
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`different serum concentrations for the same dose:
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`53. Where the clearance is not constant (i.e., “1/CL” changes),