UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`V.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
`______________________
`
`SECOND DECLARATION OF WILLIAM J. JUSKO, PH.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2024
`
`

`

`
`
`I.
`
`TABLE OF CONTENTS
`
`Page
`Introduction ...................................................................................................... 1
`
`II.
`
`A Person of Ordinary Skill in the Art .............................................................. 9
`
`III. The Subjects of Pharmacokinetics and Pharmacodynamics ......................... 12
`
`IV. The Many “Perplexities” of Fingolimod ....................................................... 18
`
`V.
`
`Pharmacologist’s View of the State of the Art .............................................. 21
`
`A. No Difference Between 5.0 and 1.25 mg in Human
`Multiple Sclerosis Phase II Results – Kappos 2005 .......................................... 22
`
`B. Art Taught 80% Lymphocyte Suppression Needed To
`See Efficacy in Human Transplant Clinical Studies ......................................... 24
`
`C. Art Taught 70% Lymphocyte Suppression Needed To
`See Efficacy in EAE Model of RRMS .............................................................. 32
`
`D. Pharmacokinetic and Pharmacodynamic Modeling ................................... 42
`
`VI. The ’405 Patent .............................................................................................. 46
`
`VII. The Novartis Report ...................................................................................... 49
`
`VIII. Dr. Giesser Uses Terms Differently Than a Person Of Ordinary Skill ......... 54
`
`A. Lymphopenia Is Not a “Clinical End-Point” for MS ................................. 54
`
`B. A Pharmacologic Effect May or May Not Be Therapeutic ....................... 58
`
`
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`i
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`
`
`C “Daily” Dose Does Not Mean a One-Time
`Administration ................................................................................................... 59
`
`D. FTY, FTY720, Fingolimod and the HCl Salt Used
`Interchangeably .................................................................................................. 60
`
`IX. Dr. Giesser’s Disagreement with Novartis’ Statements in the ’405 Patent
`File History Are Based on Misreading Kovarik and an Incorrect
`Equation in an Off-Point Textbook ............................................................... 63
`
`A. Dr. Giesser Misreads Kovarik .................................................................... 63
`
`B. Dr. Giesser Relies on a Mistake In an Off-Topic
`Textbook ............................................................................................................ 64
`
`
`X.
`
`Claims Were Not Obvious to A Person of Ordinary Skill in the Art ............ 67
`
`XI. Ground 1 – Kovarik and Thomson ................................................................ 69
`
`A. Kovarik Would Not Be Considered Relevant to a Person
`of Skill ................................................................................................................ 70
`
`B. The Board Misunderstood the Loading Dose Notation in
`Kovarik .............................................................................................................. 71
`
`C. Dr. Giesser Misconstrues the Word “Daily” .............................................. 73
`
` D
`
` “Standard Daily Dose” in Kovarik Presumes
`Effectiveness Was Already Established ............................................................ 74
`
`E. No Motivation to Combine Kovarik with Thomson. ................................. 77
`
`F. Thomson Does Not Fix the Deficiencies of Kovarik................................. 78
`
`XII. Ground 2 – Chiba and Budde and Kappos 2005 ........................................... 80
`
`XIII. Ground 3 – Kappos 2010 ............................................................................... 86
`
`
`
`ii
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`
`
`XIV. Conclusion ..................................................................................................... 89
`
`XIV. Conclusion ..................................................................................................... 89
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`I, William J. Jusko, Ph.D., declare as follows:
`
`I.
`
`Introduction
`1.
`I previously submitted a May 2, 2017 declaration in this IPR, Exhibit
`
`2005. I am a Professor of Pharmaceutical Sciences with over 50 years of experience
`
`and over 600 research articles in the area of pharmaceutical sciences. I have
`
`extensive experience in the design of pre-clinical and human clinical trials. My work
`
`has focused on the pharmacology of immunosuppressants and changes in cell
`
`trafficking that result. I have studied and published on the pharmacokinetics and
`
`pharmacodynamics of fingolimod in several animal species. My full qualifications
`
`and expertise are set out in my first declaration along with my curriculum vitae and
`
`publication list.
`
`2.
`
`I understand that Apotex and now other companies have filed Petitions
`
`challenging the validity of U.S. Patent No. 9,187,405 (“’405 Patent”), owned by
`
`Novartis. The ’405 Patent claims methods for ameliorating relapsing-remitting
`
`multiple sclerosis (RRMS) by administering 0.5 mg daily of fingolimod without a
`
`preceding loading dose. Since the submission of my first declaration, I understand
`
`the Board has instituted this IPR.
`
`3.
`
`Counsel for Patent Owner Novartis asked me to review the Petitions in
`
`view of the Board’s Institution Decision, focusing on the declaration from Dr.
`
`Barbara Giesser, Exhibit 1002. I understand Novartis filed an application for the
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`’405 Patent on June 27, 2006 and that a person of ordinary skill would use that date
`
`to define what is included in the prior art.
`
`4.
`
`I was first retained in this matter in April 2017. In preparing my
`
`testimony in both declarations, I have worked approximately 35 hours, including
`
`time spent conducting my own research into the prior art. I have spoken with counsel
`
`and reviewed and commented upon drafts they prepared based on our discussions. I
`
`have reviewed the contents of my final declaration and believe this document
`
`accurately sets forth my views. I reserve the right to amend any part of my testimony
`
`in the event of new information brought to my attention.
`
`5.
`
`As I explain in more detail below, Dr. Giesser is mistaken that the
`
`claimed methods for treating RRMS with 0.5 mg of fingolimod daily would have
`
`been obvious to a person of skill in June 2006, for several reasons.
`
`6.
`
`First, the art taught away from a dose of 0.5 mg daily. A skilled
`
`pharmacologist faced with identifying a therapeutic fingolimod dose for RRMS in
`
`June 2006 would have surveyed the available fingolimod data in the literature.
`
`7.
`
`At that time, only one human trial had tested fingolimod in RRMS
`
`patients, the Phase II trial described in the Kappos 2005 report. (Kappos 2005, Ex.
`
`1007). That trial tested doses of 1.25 mg and 5.0 mg per day. (Id. at II/41.) A
`
`pharmacologist would also consult the other human fingolimod data from stable,
`
`renal transplant patients (e.g., Kahan 2003 (Ex. 1031), Park 2003 (Ex. 2048), and
`
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`Park 2005 (Ex. 1019)) and healthy subjects (e.g., Kovarik 2004 (Ex. 2045)) to take
`
`into account fingolimod’s pharmacology in those settings in humans, as well as data
`
`from rodent EAE models of multiple sclerosis using fingolimod (e.g., Webb 2004
`
`(Ex. 2014)).
`
`8.
`
`Taken together, these data taught that a human fingolimod dose should
`
`be at least 1.0 mg to achieve a therapeutic effect, thus teaching away from the
`
`claimed 0.5 mg daily dose. At the time, although the full extent of its mechanism of
`
`action was (and remains) unknown, fingolimod was thought to work mainly by
`
`sequestering lymphocytes in lymphatic tissue outside the blood stream, thereby
`
`suppressing the number of lymphocytes in the blood that could cause harm. Human
`
`data showed that only high levels of suppression correlated with a clinical effect. It
`
`took about 80% suppression to show a clinical benefit in transplant patients as shown
`
`in Park 2005 (Ex. 1019 at 683), Park 2003 (Ex. 2048 at 333), and Dumont (Ex. 1018
`
`at 241). Similarly, an EAE study by Webb showed it took at least 70% suppression
`
`to have “any efficacy” in an RRMS model. (Ex. 2014 at 118.)
`
`9.
`
`The human data showed that only doses of 1.0 mg daily or higher could
`
`achieve these levels of suppression. (Ex. 1019 at 683; Ex. 2048 at 333; Ex. 1018 at
`
`241.) For instance, data from organ transplant patients showed 2.5 mg daily of
`
`fingolimod achieved good efficacy for the prevention of acute rejection after kidney
`
`transplantation, but 1.0 mg daily did not. (Budde 2006, Ex. 2030 at 21.) Moreover,
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`lower doses suppressed lymphocytes in patients to highly variable extents. (Park
`
`2005, Ex. 1019 at 692.)
`
`10.
`
`In other words, the literature taught that the correlation between
`
`lymphocyte suppression and clinical efficacy existed only when the lymphocyte
`
`suppression was at high levels, such as 80% or 70%. In contrast, there was no
`
`correlation shown between lymphocyte suppression and clinical efficacy at lower
`
`levels of lymphocyte suppression, such as at 40% or 50%.
`
`11. Dr. Giesser is of the view that any level of lymphocyte suppression
`
`indicates there will be clinical efficacy. (Ex. 1002 ¶¶ 139-140.) This is not correct.
`
`It conflicts with teachings from many scientific papers published by different
`
`research groups at the time, which show that only high levels of lymphocyte
`
`suppression correlate with clinical efficacy. I understand from Dr. Giesser’s
`
`deposition testimony that she did not consider the Webb reference when forming her
`
`opinion, and had trouble interpreting the data when she did look at it. (Giesser Dep.,
`
`Ex. 2039 at 67:1-67:22, 71:2-86:8.)
`
`12. Relatedly, Dr. Giesser mistakenly equates lymphocyte suppression—
`
`which she and others sometimes call “lymphopenia”—with a clinical effect or
`
`“clinical end-point.” (Ex. 1002 ¶ 60.) The lymphopenic effect of fingolimod is a
`
`biomarker and not a clinical effect, since lymphopenia is not a measure of RRMS.
`
`(McAlpine’s MS, Ex. 2047 at 9-50.) Dr. Giesser’s opinion that lymphocyte
`
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`suppression was “often used as a clinical end-point” is not correct. (Ex. 1002 ¶ 60.)
`
`Lymphocyte suppression is not among the various clinical measures of RRMS as set
`
`out by physicians treating MS patients.
`
`13. Second, persons in the field had no reasonable expectation that 0.5 mg
`
`daily would be therapeutically effective. In addition to the literature teaching away
`
`from 0.5 mg, papers described the Phase III clinical trial as seeking to “confirm” the
`
`Phase II results, i.e., to prove the efficacy and safety seen in the Phase II trial of a
`
`1.25 mg dose. (Budde 2006, Ex. 2030 at 22.) Papers described the 0.5 mg dose
`
`being tested in much more circumspect terms, as “a lower dose” to be “evaluated.”
`
`(Doggrell 2007, Ex. 2036 at 385.) There was no data to suggest that the lower dose
`
`would work for MS patients. At that time, the 0.5 mg dose had not yet been given
`
`to human MS patients. There was a lack of any experience with that dose in the MS
`
`patient population. Therefore, there would have been no reasonable expectation of
`
`success of the 0.5 mg dose for MS patients.
`
`14. Third, Petitioners offer no real opinion on pharmacology. The
`
`testimony from Dr. Giesser is incomplete in that I did not see any opinion from her
`
`on a number of the key references in the prior art regarding fingolimod and its effects
`
`on EAE models, human transplant patients, or its pharmacology. And, the opinion
`
`Dr. Giesser does offer is based on an apparent misunderstanding of pharmacology
`
`and of the mathematics underlying parameters such as half-life and clearance. Dr.
`
`
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`U.S. Patent No. 9,187,405
`Giesser also apparently confused the data presented in certain figures of the Webb
`
`paper during her deposition. Finally, Dr. Giesser apparently was unfamiliar with the
`
`common statistical methods and notations used in the Webb paper.
`
`15. Ground 1 is based on a published patent application, Kovarik (Ex.
`
`1004), teaching loading dose regimens for use with immunomodulatory drugs.
`
`There is no dose recited in Kovarik that is not associated with a loading dose. At the
`
`outset, a person of skill wanting to treat MS patients with fingolimod would not have
`
`been interested in the Kovarik reference at all because no loading dose was needed.
`
`Human Phase II trial results were already published with no loading dose used, and
`
`those would have been the most relevant data to the person of skill. A person of skill
`
`thus would not have thought to introduce a loading dose after that study. Dr. Giesser
`
`and I agree that no one working on dosing regimens for multiple sclerosis as of June
`
`2006 used loading doses. (Ex. 1002 ¶¶ 67-72.) “Loading” or giving a large dose of
`
`a drug to a naïve patient could cause problems, and it is preferable to avoid this if
`
`possible. It follows then that such a person of skill in the art would not have
`
`considered a loading dose patent publication like Kovarik as relevant to the problem
`
`of how to dose a human multiple sclerosis patient with fingolimod.
`
`16. Thomson (Ex. 1005) is the other reference Dr. Giesser cites in her first
`
`obviousness Ground. (Ex. 1002 ¶¶ 81-88, 109-116.) It summarizes clinical trial
`
`reports and other literature about research into using fingolimod to treat MS, none
`
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`of which points to a dose of 0.5 mg. Thomson does no more than summarize earlier
`
`papers and trials, reinforcing the teaching of higher doses in prior human transplant
`
`trials.
`
`17. Next, in Ground 2 Dr. Giesser combines Chiba (Ex. 1006), Budde (Ex.
`
`1008), and Kappos 2005 (Ex. 1007). These references would not have led a person
`
`of skill to believe the invention was obvious in June 2006. Budde reports results of
`
`a Phase I study in which stable renal transplant patients each received a single dose
`
`of fingolimod, such that different patients received different amounts. (Ex. 1008 at
`
`1073.) Dr. Giesser over-reads the single-dose data in Budde and ignores the warning
`
`from the Budde authors in a subsequent paper not to extrapolate the single-dose
`
`study to the multi-dose situation. (Ex. 1002 ¶ 139.)
`
`18. Simply put, a pharmacologist would not go backward to combine a
`
`2005 Phase II clinical MS study dosing daily over six months (Kappos 2005), with
`
`a 2002 Phase I single-dose clinical study in stable, renal transplant patients (Budde).
`
`A pharmacologist likewise would also not think to use a 1999 patent publication
`
`(Chiba, Ex. 1006) in solving this problem. Chiba merely offers a wide range of
`
`fingolimod doses with no specific indication or dosing regimen mentioned. Neither
`
`Budde nor Chiba show any clinical effect on MS patients. Thus, a person of skill
`
`given these three references, and knowing the state of the art, would be pointed to
`
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`using 1.25 mg daily for human use to treat MS. This teaching is away from the 0.5
`
`mg daily dosage regimen claimed here.
`
`19.
`
`I understand that in Ground 3 Petitioners say that the patent application
`
`does not support the phrase “absent an immediately preceding loading dose
`
`regimen.” I have read the ’405 Patent and a person of ordinary skill reading of the
`
`’405 Patent would understand that it teaches a daily dose of fingolimod absent any
`
`preceding loading dose. Such a person would know to take the dosage regimen
`
`disclosures as they are written and not add in a loading dose. The dosing regimens
`
`recited in the ’405 Patent are complete as written and a person of skill would
`
`understand this to be true. The specification describes a 0.5 mg daily dose. That
`
`necessarily excludes a loading dose, which involves adminsitering a higher dose at
`
`the outset of therapy. There would be no need to explicitly instruct a person of
`
`ordinary skill in the art not to use a loading dose. At least one embodiment of the
`
`invention excludes a loading dose. Therefore, the claims as written in the ’405
`
`Patent are fully supported in the patent specification.
`
`20. Finally, Dr. Giesser reads the specification and Kovarik in opposite
`
`ways and this is not what a skilled pharmacologist would do. On one hand, Dr.
`
`Giesser says that a person of skill reading Kovarik would not pay any attention to
`
`the Kovarik loading dose disclosure. (Ex. 1002 ¶ 119.) She and I agree that a person
`
`of skill looking to solve the problem of a dosing regimen for fingolimod to treat
`
`
`
`8
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`RRMS patients would not think about using a loading dose. (Id. at ¶¶ 67-72.) On
`
`the other hand, Dr. Giesser concludes (with no analysis) that the ’405 Patent
`
`specification does not support the phrase “absent an immediately preceding loading
`
`dose regimen.” (Id. at ¶ 144.) But, this does not fit with her statements about a
`
`person of skill.
`
`21. Dr. Giesser is incorrect that a person of skill would not take the Kovarik
`
`disclosure for all that it teaches, including its main idea of using a loading dose. In
`
`fact, a person of skill reading the ‘405 would know that it teaches not to use a loading
`
`dose. and that the invention disclosed is administering a daily dose absent an
`
`immediately preceding loading dose regimen. To a skilled pharmacologist, the
`
`regimen of a daily 0.5 mg dose as taught in the ’405 specification negates the idea
`
`of a loading dose. There would be no need to explicitly instruct a person of ordinary
`
`skill in the art not to use a loading dose. Therefore, the claims as written in the ’405
`
`Patent are fully supported in the patent specification.
`
`II. A Person of Ordinary Skill in the Art
`22.
`In the Institution Decision, the Board set out a definition of a person of
`
`ordinary skill: “On the record before us, we find that one of ordinary skill in the art
`
`may be part of a multi-disciplinary research team including 1) a Ph.D. with expertise
`
`in the area of neurology and/or an M.D. having several years of clinical experience
`
`treating multiple sclerosis patients, and who would be knowledgeable about the
`
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`U.S. Patent No. 9,187,405
`multiple sclerosis medical literature, and 2) a pharmacologist with experience in
`
`drug development.” (Institution Decision, Paper 11 at 9.)
`
`23.
`
`I agree with the Board’s definition. As a pharmacologist, I often work
`
`within a multi-disciplinary research team including physicians and/or other
`
`researchers in carrying out my pharmacology work. I often co-author publications
`
`with clinicians and other research scientists.
`
`24. Examples are at reference numbers 246, 327, 343, 354, and 592 in my
`
`curriculum vitae under “Publications.” (Ex. 2006.) Ref. 354 is an example of my
`
`work with an immunosuppressant in the clinical context in which we reported on the
`
`pharmacokinetics of prednisolone during administration of sirolimus in patients with
`
`renal transplants. I was a co-author with Dr. Kahan, who also authored Exhibit 1031.
`
`Ref. 343 studies another immunosuppressant; we reported on tacrolimus (FK506) in
`
`combination with other compounds for prevention of acute graft-versus-host disease
`
`in marrow transplant patients. Ref. 327 is a report of work on the pharmacokinetics
`
`of tacrolimus in liver transplant patients. Ref. 592 reports pharmacokinetics and
`
`bioequivalence of hydroxyurea in children with sickle cell anemia. These are just a
`
`few examples, and there were many others as shown in the titles and underlying
`
`substance of the references on my CV.
`
`25.
`
`I have reviewed Dr. Giesser’s declaration and CV. (Ex. 1002; Ex.
`
`1003.) Dr. Giesser lacks a degree in pharmacology and apparently lacks experience
`
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`in drug development as required in the Board’s definition of a person of skill. I
`
`understand Dr. Giesser has admitted that she is not a pharmacologist (Giesser Dep.,
`
`Ex. 2039 at 11:12-13.) Thus, Dr. Giesser can at most reflect the view of only the
`
`first team member under the Board’s definition, the M.D. with experience treating
`
`multiple sclerosis patients. Dr. Giesser does not have the expertise to offer a
`
`pharmacologist’s point of view, even if she took courses on the topic when she was
`
`in school. The few pharmacology courses medical students take do not teach the
`
`mathematics and other skills needed to be a pharmacologist, nor the interpretive
`
`skills needed for the relatively complex PK/PD profiles of fingolimod that made up
`
`the state of the art at the time. This deficiency in Dr. Giesser’s experience was
`
`apparent during her deposition, when she was questioned about the Webb paper and
`
`made mistakes in interpreting data and figures. (Ex. 2039 at 71:2-86:8.)
`
`26. Further, as I discuss below in Section X, Dr. Giesser made an error
`
`related to pharmacology that also shows she is not a person of skill in the area of
`
`pharmacology. Briefly, Dr. Giesser relies on an equation in a textbook entitled
`
`“Critical Care Pediatrics” (Ex. 1021). It is not clear to me why Dr. Giesser would
`
`choose a book in the area of critical care pediatrics for this case. The textbook has
`
`an error in an equation showing a relationship between half-life and clearance. Dr.
`
`Giesser relies on that equation, and reiterates the error in her declaration, apparently
`
`ignorant of the error. (Ex. 1002 ¶¶ 28, 68.)
`
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`IPR2017-00854
`U.S. Patent No. 9,187,405
`27. Although Dr. Giesser may fulfill the first part of the Board’s definition
`
`of a person of ordinary skill, in my opinion she is not a pharmacologist with
`
`experience in drug development. Thus, Dr. Giesser does not fulfill the second part
`
`of the Board’s definition of a person of ordinary skill.
`
`III. The Subjects of Pharmacokinetics and Pharmacodynamics
`28. Drug development encompasses moving from pre-clinical in vitro and
`
`in vivo animal model studies of a drug into human clinical trials. The pre-clinical
`
`and human clinical trial phases are shown below in the Fig. 1-4 reproduced from
`
`Rowland and Tozer. (Ex. 2050 at 5.) The pharmacokinetics and pharmacodynamics
`
`of the candidate drug are studied beginning in in vitro and animal studies. That data
`
`is not disease specific and can be crucial in designing human clinical trials. Phase I
`
`is the first-in-human clinical trial that assesses initial safety of the drug using a single
`
`dose with different patients receiving different escalating doses. (Id.) Phase II
`
`usually tests a few different doses to collect dose-response data in humans, and to
`
`assesses efficacy in treating a particular disease. (Id.) Phase III trials look at certain
`
`doses in a large number of patients to confirm safety and efficacy for a particular
`
`disease state with statistical significance. (Id.)
`
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`U.S. Patent No. 9,187,405
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`
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`29. Pharmacokinetics is the study of what a body does to a compound once
`
`administered. (Id. at 3.) Pharmacokinetics analyzes the time-course of drug
`
`absorption, distribution, metabolism and excretion. These parameters are important
`
`for understanding the extent and duration of time the body is exposed to a drug, and
`
`determining the relative risk of reaching toxic concentrations or falling below
`
`minimum effective concentrations during treatment. The type and intensity of a
`
`drug’s effect in the body results from an interaction between parameters such as the
`
`time-course of the concentration of the drug at the target site, affinity and specificity
`
`of the drug to its target, and the ability to change relevant biological processes.
`
`30. A pharmacokinetic analysis must be made in the context of, be
`
`consistent with, and explain the array of basic data regarding the properties and
`
`disposition characteristics of the drug in question. In my book chapter entitled
`
`
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`U.S. Patent No. 9,187,405
`“Guidelines for Collection and Analysis of Pharmacokinetic Data” at Exhibit 2041,
`
`I point out that the interpretation of pharmacokinetic data can be complicated. These
`
`guidelines state that “[i]n general, the pharmacokinetic model and analysis should
`
`either conform to, or account for, the known properties and accumulated data related
`
`to the drug. One set of disposition data may misrepresent the characterization of the
`
`drug because of any one or combination of reasons. Experienced judgment is usually
`
`required in the final interpretation of any experimental findings and analysis.” (Ex.
`
`2041 at 10.)
`
`31. Pharmacodynamics is the study of what a compound does to a body
`
`after administration. (Rowland and Tozer, Ex. 2050 at 3.) The pharmacodynamic
`
`effects that a single drug can have on a body can be numerous. The pharmacological
`
`effects of a compound can include both desired and undesired effects, as well as side
`
`effects unrelated to the medical condition being treated. (Id. at 3-4.) Pharmacologic
`
`effects can serve as feedback control in refinement of a dosage regimen. This
`
`process works best when the pharmacologic effects are a direct result of the
`
`administered drug, and if the pharmacologic effects are easily and accurately
`
`measurable, and importantly, if the pharmacologic effects are correlated to the
`
`drug’s ability to treat the disease or condition.
`
`32. These two areas can be theoretical or applied in nature and are crucial
`
`in designing animal and/or human studies. The events following drug administration
`
`
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`can be divided into two stages. The first is the pharmacokinetic stage “in which the
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`adjustable elements of dose, dosage form, frequency, and route of administration are
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`related to drug level-time relationships in the body….” (Id. at 3.) The second is the
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`pharmacodynamic stage “in which the concentration of drug at the site(s) of action
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`is related to the magnitude of the effect(s) produced.” (Id. at 3.) See also Figure 1-
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`2 from Rowland and Tozer (Ex. 2050) below illustrating a general approach to
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`designing a dosage regimen using pharmacokinetics and pharmacodynamics. (Id. at
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`3.)
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`33. The data gathered regarding pharmacokinetics and pharmacodynamics
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`are not necessarily disease-specific. The information gathered during this work can
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`be useful to the person of skill in the art working to find a proper dosing regimen for
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`one indication or another. The “effects” produced in Fig. 1-2 are referred to as
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`“feedback” to help understand how to modify a dose. The effects may or may not
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`be therapeutic in nature. Mechanism-based modeling of drug responses in animals
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`and humans based on
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`the
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`integration of fundamental pharmacokinetic,
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`pharmacological and physiological processes
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`is possible, and a skilled
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`pharmacologist would understand that pharmacological terms are fixed across
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`species. (Mager and Jusko, Ex. 2058 at 911-12.)
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`34.
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`In designing a dosing regimen, a clinical research team has to balance
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`the therapeutic effects and the possible adverse effects at any given dose. (DeVane
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`1982, Ex. 2060 at 143.) Often a clinical research team will seek to define the
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`minimum effective concentration for a drug. The usual procedures for doing this are
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`explained in my paper entitled “Dosage Regimen Design.” (Id. at 143-163). Figure
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`1 from this paper is shown below with a common dose-response curve and dotted
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`lines showing the common therapeutic range of a drug based on the effects seen a
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`population of patients. (Id. at 144.)
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`35. A biomarker is a measurable effect in a subject whose presence is
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`indicative of the drug being in the body and functioning. A biomarker is one type
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`of pharmacologic effect. The biomarker may or may not be therapeutic in nature,
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`depending on the context of the drug administered, the disease of interest, and the
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`understanding of the mechanism of action of the drug on the disease state. A
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`biomarker can serve as a measure of dose-response when the value of the biomarker
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`itself shows a direct relationship to the dose of drug given. If the relationship is not
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`direct, or if the biomarker is not easily and accurately measurable, it may not serve
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`as a proper biomarker in the end.
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`36. A number of parameters can be measured for a new candidate drug.
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`One is the drug’s half-life. (DeVane 1982, Ex. 2060 at 147-49.) Another is a drug’s
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`EC50 which is the concentration of a drug that gives half-maximal response. In
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`other words, the EC50 is the concentration of a drug that will achieve half of the
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`largest effect of the drug. There are many other parameters that can be measured for
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`any particular drug, such as clearance rate, etc. These parameters are useful in the
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`pharmacology work done to design dosing regimens for a new candidate drug.
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`IV. The Many “Perplexities” of Fingolimod
`37. Fingolimod is a novel immunomodulator with a mode of action
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`completely different
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`than
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`the prior known
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`immunosuppressants, such as
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`cyclosporine A or tacrolimus. Unlike some other immunosuppressants, fingolimod
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`does not impair T-cell and B-cell activation, proliferation, or effector function.
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`(Pinschewer 2000, Ex. 2049 at 5761.) Because of this different mechanism of action,
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`fingolimod
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`originally was
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`proposed
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`in
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`combination with
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`classical
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`immunosuppressants as a new option for transplant patients.
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`38. Fingolimod is the active ingredient in Gilenya®, a medicine sold by
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`Novartis. Fingolimod is a sphingosine 1-phosphate receptor modulator indicated for
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`the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) to
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`reduce the frequency of clinical exacerbations and to delay the accumulation of
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`physical disability. (Gilenya Label, Ex. 2040 at 1.) The Gilenya label says the
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`following about the mechanism of action of fingolimod: “The mechanism by which
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`fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may
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`involve reduction of lymphocyte migration into the central nervous system.” (Ex.
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`2040 at 12.) So, even today, it is not known how fingolimod exerts its therapeutic
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`effects to treat MS.
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`39. Fingolimod is known to bind to four out of the five known S1P
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`receptors. S1P receptors (or sphingosine-1-phosphate receptors) are cell surface
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`receptor proteins that are involved in complex regulation of a wide variety of
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`fundamental biological processes such as cell proliferation, angiogenesis, cell
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`migration, immune cell trafficking, organization of the cell cytoskeleton, and
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`endothelial cell chemotaxis or movement. The S1P receptors are found in a
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`multitude of tissues throughout the body including the brain, the heart, the gut, and
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`others. Therefore, when designing a dosing regimen, a skilled pharmacologist would
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`worry that fingolimod might cause pharmacologic effects in a variety of tissues in
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`the body.
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`40. A skilled pharmacologist would be cautious in judging the clinical
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`therapeutic benefit of administering fingolimod because one would not want to
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`expose a patient to the risk of side-effects without confidence that the dose provided
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`sufficient benefit.