`
`
`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 INDUSTIRES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`
`v.
`
`NOVARTIS A.G.,
`Patent Owner.
`
`_____________________________
`
`IPR2017-008541
`Patent No. 9,187,405
`
`_____________________________
`
`REPLY DECLARATION OF LESLIE Z. BENET, PH.D.
`_____________________________
`
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`APOTEX ET AL. - EXHIBIT 1047
`Apotex Inc. et al. v. Novartis AG
`IPR2017-00854
`
`

`

`
`
`TABLE OF CONTENTS
`
`EFFICACY OF KOVARIK’S 0.5 MG DAILY DOSAGE MAINTENANCE
`
`QUALIFICATIONS ........................................................................................... 1
`I.
`SCOPE OF WORK ............................................................................................ 8
`II.
`PTAB’S INSTITUTION DECISION ................................................................... 10
`III.
`A.
`Person Of Ordinary Skill In The Art ................................................. 11
`B.
`Claim Construction ........................................................................... 12
`IV. KOVARIK DISCLOSES A 0.5 MG DAILY DOSAGE MAINTENANCE
`THERAPY, NOT A HYPOTHETICAL DOSE ....................................................... 14
`V.
`THERAPY IS NOT DEPENDENT ON A LOADING DOSE REGIMEN....................... 16
`VI. THE PRIOR ART DOES NOT TEACH AWAY FROM THE 0.5 MG DAILY
`DOSE ........................................................................................................... 19
`A. Webb, Kahan 2003 And Park Do Not Teach Away From The
`0.5 mg Daily Dose. ........................................................................... 19
`1.
`Efficacy. ................................................................................. 20
`2.
`mg Dose For Achieving Therapeutic Efficacy. ....................... 25
`3.
`Dose For Achieving Therapeutic Efficacy. ............................. 28
`Teaching Away Argument. ............................................................... 32
`1.
`Against RR-MS. ..................................................................... 33
`2.
`Efficacy In Humans Against RR-MS As The 1.25 mg Dose. .. 36
`3.
`
`A POSA Would Not Read Webb As Establishing That At Least
`70% Lymphopenia Was Necessary For Achieving Therapeutic
`
`A POSA Would Not Read Kahan 2003 As Discrediting The 0.5
`
`A POSA Would Not Read Park As Discrediting The 0.5 mg
`
`Subsequent Prior Art References Undermine The Proposed
`
`B.
`
`A POSA Would Have Understood Kataoka To Suggest The 0.5
`mg Maintenance Dose Would Be Efficacious In Humans
`
`A POSA Would Have Understood Kataoka To Suggest The 0.5
`mg Maintenance Dose Would Have Substantially Similar
`
`A POSA Would Have Understood The Prior Art Phase II
`Clinical Trial Publications To Suggest the 0.5 mg Maintenance
`Dose Would Have Therapeutic Efficacy In Humans Against
`
`-i-
`
`
`
`

`

`
`
`Iterative Clinical Trials Do Not Undermine The Rationale For
`
`RR-MS. .................................................................................. 42
`C.
`Using A 0.5 mg Dose. ....................................................................... 47
`VII. SUBSTANTIALLY EQUIVALENT CLINICAL EFFICACY OF 0.5 MG AS
`COMPARED TO 1.25 MG WAS NOT UNEXPECTED........................................... 49
`A.
`Part Of The ’405 Patent Claims. ....................................................... 51
`B.
`Premised On A False And Arbitrary Analysis. .................................. 53
`VIII. DRS. STEINMAN AND JUSKO DO NOT APPLY THE BROADEST
`REASONABLE CONSTRUCTION OF DAILY DOSAGE......................................... 55
`IX. CONCLUSION ............................................................................................... 59
`CONCLUDING STATEMENTS .......................................................................... 60
`X.
`
`Intermittent Dosing And Angiogenesis Measurement Are Not
`
`Dr. Steinman’s 60% Reduction Of The 1.25 mg Dose Is
`
`
`
`
`-ii-
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`
`I, Leslie Z. Benet, declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am currently a Professor of Bioengineering and Therapeutic
`
`Sciences, Schools of Pharmacy and Medicine, at the University of California, San
`
`Francisco (“UCSF”).
`
`2.
`
`I received my Bachelor of Arts in English in 1959 and my Bachelors
`
`of Science in Pharmacy in 1960 from the University of Michigan. In 1962, I
`
`received a Master’s Degree in Pharmaceutical Chemistry, also from the University
`
`of Michigan. Three years later, in 1965, I was awarded a doctorate degree from
`
`UCSF in Pharmaceutical Chemistry. Since obtaining that degree, I have received
`
`nine honorary doctorate degrees, five from European universities and four from US
`
`institutions, the last in June, 2016 from the University of Lisbon. I held a licentiate
`
`in Pharmacy and am a credentialed Applied Pharmacologists with the American
`
`Board of Clinical Pharmacology.
`
`3.
`
`In 1965, I joined the faculty of the School of Pharmacy at Washington
`
`State University, in Pullman, Washington. In 1969, I joined the Departments of
`
`Pharmacy and Pharmaceutical Chemistry within the School of Pharmacy at UCSF
`
`as an Assistant Professor. From 1969 to 1976, I progressed first from Assistant
`
`Professor to Associate Professor, and then to Professor. I served as chairman of the
`
`department at UCSF from 1978-1998.
`
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`
`4. My areas of specialization over the course of my career include
`
`pharmacokinetics/pharmacodynamics, biopharmaceutics, drug delivery and dosage
`
`forms, drug metabolism, drug transporters, bioequivalence, animal and human drug
`
`pharmacology and other scientific aspects of drug regulatory issues.
`
`5.
`
`In addition to my teaching responsibilities, I have held leadership
`
`positions in a number of organizations in my field of study, including:
`
`a. From 1985 to 1986, I served as President of the Academy of
`
`Pharmaceutical Research and Science (formerly the Academy of
`
`Pharmaceutical Sciences).
`
`b. In 1986, I founded and served as the first President of the American
`
`Association of Pharmaceutical Scientists (AAPS). From 1986 to 1993, I
`
`variously held the positions of Treasurer, Member, and Chair of the
`
`Board of Directors of AAPS.
`
`c. From 1988 to 2004, I served as a Specialist Member, Chairman, Past
`
`Chair and Member of the Executive Committee of the Board of
`
`Pharmaceutical Sciences for the International Pharmaceutical Federation
`
`(FIP). From 2007 through 2012, I served as Chair of the FIP Foundation
`
`for Education and Research.
`
`-2-
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`

`

`
`
`d. From 1992 to 1995 I served as a Member, President, and Chair of the
`
`Board of Directors of the American Association of Colleges of Pharmacy
`
`(AACP).
`
`6.
`
`I have been awarded numerous awards, prizes and honors for work I
`
`have conducted in my field, including:
`
`a. In 1982, I received the American Pharmacists Association (APhA)
`
`Academy of Pharmaceutical Sciences Research Achievement Award in
`
`Pharmaceutics and the University of Michigan, College of Pharmacy
`
`Distinguished Alumnus Award.
`
`b. In 1987, I was elected to membership in the National Academy of
`
`Medicine (NAM) of the U.S. National Academy of Sciences.
`
`c. In 1988, I received the Distinguished Service Award of the American
`
`College of Clinical Pharmacology (ACCP), and in 1989 I was chosen to
`
`receive the first AAPS Distinguished Pharmaceutical Scientist Award.
`
`d. In 1990, I was the recipient of the Rho Chi Lecture Award, and the UCSF
`
`School of Pharmacy Long Teaching Award.
`
`e. In 1991, I received the AACP Volwiler Research Achievement Award.
`
`f. In 1995, I received the Rawls-Palmer Progress in Medicine Award of the
`
`American Society of Clinical Pharmacology and Therapeutics (ASCPT)
`
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`

`
`
`and delivered the American College of Clinical Pharmacy “Therapeutic
`
`Frontiers Lecture.”
`
`g. In 1996, I received the AAPS Distinguished Service Award, and in 2000
`
`the APhA Takeru Higuchi Research Prize and the AAPS Wurster
`
`Research Award in Pharmaceutics.
`
`h. In 2001, I was awarded the FIP Høst-Madsen Medal and the UCSF
`
`Outstanding Faculty Mentorship Award.
`
`i. In 2003, I was listed as one of the most highly cited pharmacologists
`
`worldwide, and continue to maintain that distinction for the years 2001
`
`through 2017, with my published peer reviewed publications having been
`
`cited more than 26,000 times.
`
`j. In 2004, I was awarded the Pharmaceutical Sciences World Congress
`
`Research Achievement Award and the Controlled Release Society’s
`
`Career Achievement in Oral Drug Delivery Award.
`
`k. In 2007, I was selected as the Distinguished Clinical Research Lecturer at
`
`UCSF and made an International Honorary Member of the Japan Society
`
`for the Study of Xenobiotics.
`
`l. In 2008, I was selected for the Nagai Foundation Tokyo Distinguished
`
`Lectureship.
`
`-4-
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`

`

`
`
`m. In 2010, I was selected to receive the ASCPT Oscar B. Hunter Memorial
`
`Award in Therapeutics and in 2011, the ACCP Distinguished Investigator
`
`Award.
`
`n. In 2012, I was made an Honorary Member of FIP.
`
`o. In 2012, the September issue of Pharmaceutical Research was dedicated
`
`in my honor under the title “50 Years of Scientific Excellence and Still
`
`Going Strong” and in 2013, the September issue of the Journal of
`
`Pharmaceutical Sciences was dedicated in my honor under the title
`
`“Perspectives on a Pharmacokinetics Legend.”
`
`p. In 2013 I received the APhA Ebert prize for what was viewed as the most
`
`outstanding publication appearing in the Journal of Pharmaceutical
`
`Sciences during the previous year, and the AAPS Journal Outstanding
`
`Manuscript Award for the same recognition in that journal.
`
`q. In 2015, I was awarded the North American Scientific Achievement
`
`Award of the International Society for the Study of Xenobiotics.
`
`r. In 2016, I received the Remington Honor Medal of the American
`
`Pharmacists Association, the highest award in the profession of pharmacy
`
`in the US and once again was chosen to receive the UCSF Outstanding
`
`Mentorship award.
`
`-5-
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`

`
`
`s. In May 2017, a full day symposium in my honor entitled “The Cutting
`
`Edge in Pharmaceutical Sciences – 50 Years of Progress Celebrating Les
`
`Benet’s 80th Birthday” was held in conjunction with the Pharmaceutical
`
`Sciences World Congress in Stockholm, Sweden.
`
`7.
`
`I have published more than 560 articles, 7 books, and been granted 12
`
`patents in the areas of pharmacokinetics, biopharmaceutics, drug delivery and
`
`pharmacodynamics. My published peer reviewed publications have been cited on
`
`more than 26,000 occasions in the scientific literature. My most recent work
`
`addresses the cooperative effects of metabolic enzymes of Cytochromes P-450 and
`
`transport proteins as related to the oral bioavailability and hepatic elimination of
`
`drugs. My most highly cited recent paper was my 2005 work describing a
`
`Biopharmaceutics Drug Disposition Classification System in which I proposed
`
`methodologies for predicting drug absorption and disposition, as well as drug-drug
`
`interactions, for all therapeutic drug agents.
`
`8.
`
`Based on my expertise in the field of pharmacology,
`
`pharmacokinetics, drug delivery and drug metabolism, I have been invited to serve
`
`(and currently serve) on the editorial boards of several journals, including
`
`Pharmacology (1978 to present), The AAPS Journal (1999 to present), Chemistry
`
`and Pharmaceutical Bulletin (2000 to present), Expert Opinion on Drug
`
`Metabolism and Toxicology (2004 to present) and Archives of Drug Information
`
`-6-
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`
`

`

`
`
`(2007 to present). Selection to the editorial boards of these journals is based upon
`
`recognition by the scientific community that the individual is an established leader
`
`in the field of pharmacology, pharmacokinetics, drug delivery and drug
`
`metabolism. As a member of these editorial boards, I have reviewed, evaluated,
`
`and selected articles for publication based upon scientific merit in the general area
`
`of pharmacology, pharmacokinetics, drug delivery and drug metabolism. In
`
`addition to my roles on the above-mentioned editorial boards, I was a Founder and
`
`Editor of the Journal of Pharmacokinetics and Biopharmaceutics (1973 to 1998)
`
`and served as the Associate Editor for Pharmacology and Therapeutics (1995 to
`
`2000).
`
`9.
`
`I served as Chair of the Pharmacology Study Section and the
`
`Pharmacological Sciences Review Committee for the NIH, the FDA CBER Peer
`
`Review Committee, the FDA Expert Panel on Individual Bioequivalence, the
`
`Board of Pharmaceutical Sciences of the International Pharmaceutical Federation,
`
`the Organizing Committee for the Millennial World Congress of Pharmaceutical
`
`Sciences, and as a member of the FDA Generic Drugs Advisory Committee and
`
`the FDA Science Board. In 2011, I completed a term as a member of the National
`
`Research Council Biodefense Standing Committee for the Department of Defense
`
`and in 2012 I completed a 9-year term as a member of the Institute of Medicine
`
`(now the NAM), Forum on Drug Discovery, Development and Translation. I
`
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`

`
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`presently serve on the Boards of Directors of Impax Laboratories Inc. and Chair of
`
`the Board of Directors of Medicines360.
`
`10.
`
`In addition to my activities related to drug development with the FDA,
`
`NAM and NIH, I am a frequent consultant to the pharmaceutical industry as
`
`indicated in my curriculum vitae. I believe that at one time or another I have
`
`consulted in multiple areas of drug development for almost every major US and
`
`European Pharma company and for the majority of Japanese companies.
`
`Furthermore, I am the co-founder of 4 biopharmaceutical companies.
`
`11. A copy of my curriculum vitae providing a more comprehensive
`
`review of my work is being submitted simultaneously with this declaration as
`
`Exhibit 1048. It includes a list of occasions since 2006 where I have testified as an
`
`expert at trial or by deposition.
`
`II.
`
`SCOPE OF WORK
`
`12.
`
`I have been retained by counsel for Apotex Inc. in connection with the
`
`above-captioned IPR concerning U.S. Patent No. 9,187,405 (“the ’405 patent”).
`
`This declaration addresses certain issues raised by experts retained by Patent
`
`Owner, Novartis A.G. In preparing this declaration, I was provided with each of
`
`the Declarations of Drs. Lublin, Jusko, and Steinman, (EX2003, EX2025; EX2005,
`
`EX2024; EX2022), as well as the exhibits cited therein, U.S. Patent No. 8,741,963
`
`(EX1013), and the transcript of the deposition of Dr. Lublin (EX1042). A list of
`
`-8-
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`

`
`
`these documents is provided in Appendix A to this declaration. I was also provided
`
`with the Patent Trial and Appeal Board (“PTAB”)’s Institution Decision. I have
`
`also relied on a prior art FDA Guidance publication that has been labeled as
`
`Exhibit 1049.
`
`13.
`
`It has been my intention in drafting this declaration to refer to the
`
`document or documents I relied upon in offering a given opinion. In some cases,
`
`there may exist other documents in the record that also support my opinions.
`
`Unless explicitly stated, I am not relying on any representations from counsel as a
`
`basis for my opinions. In addition to documentary evidence, I have also relied on
`
`my own knowledge, education, and training, which is reflected in my
`
`qualifications discussed above and in EX1048.
`
`14. For this declaration, I was asked to evaluate the following issues:
`
`a. Dr. Steinman’s opinions that Kovarik’s 0.5 mg daily dose of fingolimod
`
`is just an “example” or “hypothetical” dose “simply used to illustrate
`
`how Kovarik’s loading dose might be used for ‘an’ unspecified
`
`autoimmune disease,” and that Kovarik does not “embrace any particular
`
`daily dose, or any particular condition.” EX2022 at ¶¶143-47.
`
`b. Whether the PTAB’s conclusions in the Institution Decision (at 13-14,
`
`18) regarding loading doses should be altered by Dr. Jusko’s arguments
`
`(EX2024 at ¶¶118-23) about Equation 14.4.
`
`-9-
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`

`
`
`c. The arguments from Drs. Jusko, Steinman, and Lublin that the prior art
`
`would have discredited Kovarik and discouraged a person of ordinary
`
`skill in the art from employing its 0.5 mg daily maintenance therapy dose
`
`for the treatment of RR-MS.
`
`d. The arguments from Drs. Jusko, Steinman, and Lublin that it was
`
`unexpected that the 0.5 mg dose would have any clinical efficacy in RR-
`
`MS patients or would have substantially equivalent efficacy to the 1.25
`
`mg dose.
`
`e. Whether Drs. Jusko and Steinman’s proposed constructions of the term
`
`“at a daily dosage of 0.5 mg” as used in the claims of the ’405 patent set
`
`forth the term’s broadest reasonable interpretation as it would be
`
`understood by a person of ordinary skill in the art in June 2006 in view of
`
`the specification of the ’405 patent.
`
`III. PTAB’S INSTITUTION DECISION
`
`15.
`
`In evaluating these issues, I have applied the PTAB’s instructions in
`
`the Institution Decision regarding the meaning of the claims of the ’405 patent and
`
`its identification of a person of ordinary skill in the art of the ’405 patent.
`
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`

`
`
`A.
`
`16.
`
`Person Of Ordinary Skill In The Art
`
`In the PTAB’s Institution Decision (at 7-8, citing Pet. 18-19), the
`
`PTAB states that Petitioner contended that a person of ordinary skill in the art
`
`(“POSA”) as of the date of the invention:
`
`would typically include a person with a medical degree (M.D.) and
`
`several years of experience treating multiple sclerosis patients. . . .
`
`would be familiar with administering therapeutic agents for the
`
`treatment of multiple sclerosis, including RR-MS, and dosing
`
`regimens of the various therapeutic agents available for treating RR-
`
`MS. . . . [and] would be knowledgeable about the multiple sclerosis
`
`medical literature available at the relevant time.
`
`17. The PTAB then states that “[t]his is consistent with the definition
`
`offered during prosecution that, ‘[t]he relative skill of those in the art is high,
`
`generally that of an M.D. or Ph.D. with expertise in the area of neurology.’”
`
`Institution Decision at 8. The PTAB then states that the specification of the ’405
`
`patent describes “a prophetic clinical trial of fingolimod (‘Compound A’) in
`
`treating RR-MS,” and “suggests that one of ordinary skill in the art would possess
`
`a medical or related doctoral degree and have experience in the field of MS
`
`treatment and clinical research.” Id.
`
`18. The PTAB then states (at 8-10):
`
`In the context of the ’405 patent and prior art, we agree with Patent
`
`Owner that expertise in pharmacology may be useful in determining
`
`-11-
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`

`
`
`obviousness, particularly in light of the prior art proffered in the
`
`Preliminary Response….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 multiple sclerosis medical literature, and 2) a pharmacologist with
`
`experience in drug development.
`
`19.
`
`I am “a pharmacologist with experience in drug development.” For
`
`the purposes of my opinions, I have assumed that the relevant date for evaluating
`
`the prior art available to a person or skill in the art of the ’405 patent is June 27,
`
`2006, its earliest claimed priority date, as identified in the Institution Decision (at
`
`3). I note that Dr. Lublin, Novartis’s expert, agreed during his deposition that June
`
`2006 is “the critical date” for evaluating prior art to the ’405 patent. EX1042 at
`
`66:22-67:20, 220:8-23 (“critical date”).
`
`B. Claim Construction
`
`20. The Institution Decision (at 10) states: “In an inter partes review,
`
`claim terms in an unexpired patent are interpreted according to their broadest
`
`reasonable construction in light of the specification of the patent in which they
`
`appear.” The PTAB notes (at 10-12, 18-19) that the preamble phrases “reducing or
`
`preventing or alleviating relapses” and “slowing progression” are “subsumed
`
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`

`
`
`within the genus of ‘treating’ RR-MS,” and that these preamble differences limit
`
`the claims by “specifying the needs of the ‘subject’ alluded to later.”
`
`21. Based on the PTAB’s construction, I understand that Claim 3, for
`
`example, requires:
`
`a. Orally administering fingolimod at a daily dosage of 0.5 mg
`
`b. To a subject in need of a method for treating RR-MS
`
`c. Absent an immediately preceding loading dose regimen.
`
`22.
`
`In claims 1 and 5, respectively, the subject is in need of a method for
`
`reducing or preventing or alleviating relapses in RR-MS or in need of a method for
`
`slowing progression of RR-MS.
`
`23.
`
`I have applied the PTAB’s claim constructions throughout this
`
`declaration.
`
`24.
`
` I note that Dr. Lublin confirmed during his deposition that a POSA in
`
`June 2006 would have known that each of the patients involved in the Phase II and
`
`Phase III trials of fingolimod was a subject in need of (1) a method for treating
`
`RR-MS; (2) a method for reducing, or preventing, or alleviating relapses in RR-
`
`MS; and (3) a method for slowing progression of RR-MS. EX1042 at 72:9-74:15
`
`(Kappos 2005), 225:4-227:17 (Chavez, EX2031), 243:13-245:6 (Press Release,
`
`EX2072).
`
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`
`
`IV. KOVARIK DISCLOSES A 0.5 MG DAILY DOSAGE MAINTENANCE THERAPY,
`NOT A HYPOTHETICAL DOSE
`
`25.
`
`I have been asked to evaluate Dr. Steinman’s opinions that Kovarik’s
`
`0.5 mg daily dose maintenance therapy is just an “example” or “hypothetical” dose
`
`of fingolimod. Dr. Steinman argues that the 0.5 mg daily dose was “simply used to
`
`illustrate how Kovarik’s loading dose might be used for ‘an’ unspecified
`
`autoimmune disease,” and that Kovarik does not “embrace any particular daily
`
`dose, or any particular condition.” EX2022 at ¶¶143-47. I disagree with Dr.
`
`Steinman’s assertions.
`
`26. The 0.5 mg daily dosage was not merely a hypothetical or assumed
`
`dose. Kovarik discloses FTY720 as a “particularly preferred S1P receptor agonist”
`
`and discloses the “lower daily dosage” of 0.5 mg as a “maintenance therapy” for its
`
`“particularly preferred dosage.” EX1004 at 13, 15. It also discloses a “method for
`
`treating an autoimmune disease in a subject in need thereof” that includes
`
`administering “a daily dosage of FTY720 of about 0.1 to 0.5mg.” Id. at 17.
`
`27.
`
`I disagree with Dr. Steinman’s assertion that Kovarik “merely
`
`describe[s] hypothetical daily dose ranges for unspecified diseases to illustrate
`
`Kovarik’s loading dose method” because RR-MS allegedly “is just one of dozens
`
`if not over 100 autoimmune diseases.” EX2022 at ¶¶8, 146. Dr. Steinman appears
`
`to ignore Kovarik’s explicit identification of a small list of five autoimmune
`
`diseases as “preferred” disease targets of the medication, with multiple sclerosis at
`
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`
`
`the head of the list. EX1004 at 14, 17. Dr. Steinman also fails to account for
`
`Kovarik’s disclosure that “the standard daily dosage (also called maintenance
`
`dose) refers to the dosage of an S1P receptor modulator or agonist necessary for a
`
`steady-state trough blood level of the medication or its active metabolite(s)
`
`providing effective treatment.” Id. at 14. Kovarik’s disclosure of the 0.5 mg of
`
`fingolimod as a “maintenance therapy dose” is thus a teaching that the 0.5 mg dose
`
`achieves a steady-state trough blood level providing effective treatment.
`
`28. Although Kovarik does not limit this maintenance therapy dose only
`
`to treating multiple sclerosis, a POSA would not have understood Kovarik to imply
`
`that fingolimod was less efficacious at treating RR-MS than at preventing allograft
`
`rejection. As discussed in detail below in Section VI.A of my declaration, a POSA
`
`would have been aware as of June 2006 that the doses of fingolimod proven to be
`
`therapeutically effective against RR-MS were lower than the doses of fingolimod
`
`that had been proven to be therapeutically effective against allograft rejection in
`
`humans. Thus, Kovarik’s disclosure that the 0.5 mg maintenance therapy dose is
`
`efficacious against multiple conditions, including allograft rejection and multiple
`
`sclerosis, does not undermine Kovarik’s claim to efficacy.
`
`29. Dr. Steinman suggests that a POSA would ignore the Kovarik
`
`reference because it “provides no data.” EX2022 at ¶147. However, I note that the
`
`’405 patent also contains no human efficacy data for the 0.5 mg dose and merely
`
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`
`
`outlines a planned “prophetic clinical trial.” Although the ’405 patent asserts that a
`
`once-weekly dose of 0.3 mg/kg fingolimod showed some efficacy in rat
`
`experiments, it provides no data in support of this assertion as well. I note that a
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`Novartis entity is the assignee to each of the ’405 patent and the Kovarik
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`application. Data are, of course, important to a scientist. However, it is also the
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`case that a POSA before June 2006 would have taken note of the disclosure by an
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`important pharmaceutical company like Novartis in the Kovarik reference that the
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`0.5 mg could be used as a maintenance therapy for treatment of multiple sclerosis.
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`30. As discussed below in Section VII, a POSA would not disregard
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`Kovarik’s disclosure of the 0.5 mg maintenance therapy in view of the totality of
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`the prior art.
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`V. EFFICACY OF KOVARIK’S 0.5 MG DAILY DOSAGE MAINTENANCE THERAPY
`IS NOT DEPENDENT ON A LOADING DOSE REGIMEN
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`31. Dr. Jusko argues that Equation 14.4 contains an error and that
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`Equation 14.4 provides only an approximation of fingolimod’s pharmacokinetics.
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`EX2024 at ¶¶26, 118-23. I have been asked to evaluate whether Dr. Jusko’s
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`arguments should alter the PTAB’s conclusions in the Institution Decision that the
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`efficacy against MS of Kovarik’s 0.5 mg maintenance therapy does not depend on
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`the loading dose regimen.
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`32. Dr. Jusko’s exposition in EX2024 ¶¶26, 118-23 related to Equation
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`14.4 appears to be related to his effort to show that Dr. Giesser is not an expert in
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`pharmacokinetics rather than addressing the issue as to whether maintenance
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`therapy is or is not dependent on a loading dose. None of the pharmacokinetic
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`parameters of a drug (clearance, volume, half-lives and bioavailability) are affected
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`by a loading dose for a drug that follows the pharmacokinetics for fingolimod
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`described by Dr. Jusko. Dr. Jusko would have to agree with Petitioner’s argument
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`that maintenance doses are not dependent on loading dose regimens, which as
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`noted below was found “persuasive” in the Institution Decision.
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`33. The Institution Decision (at 13-14) found “persuasive” Petitioner’s
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`argument that “maintenance doses are not dependent on loading dose regimens.
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`Rather maintenance doses are dependent on the desired steady state plasma
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`concentration and the clearance rate of the drug.” The PTAB noted (at 14-15) that
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`the Kovarik reference states (at 14) that a “maintenance dose” refers to the “dosage
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`of an S1P receptor modulator or agonist necessary for a steady-state trough blood
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`level of the medication or its active metabolite(s) providing effective treatment.”
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`The Institution Decision notes (at 15) that Kovarik discloses (at 15) a
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`“maintenance therapy, e.g. a daily dosage of 0[.]5 mg.”
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`34. The Institution Decision also states (at 18):
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`Further, based on the evidence of record, we accept the testimony of
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`Petitioner’s expert that “a person of ordinary skill would recognize
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`that the loading dose regimen taught by Kovarik is not necessary to
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`obtain therapeutic efficacy,” but is merely a means to achieve rapid,
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`steady-state drug concentrations, which may be beneficial in organ
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`transplantation, but was not standard practice in the treatment of MS.
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`See Ex. 1002 ¶¶ 67, 72, 119, 121–22. We further note that Kovarik
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`teaches that, whereas, a standard daily dose (i.e., “maintenance dose”)
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`provides a steady-state trough blood level of the drug or its active
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`metabolites for “effective treatment,” the addition of a loading dose
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`provides “further unexpected benefits.” See Ex. 1004, 1, 14 (italics
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`added). Kovarik, thus, teaches the addition of a loading dose as an
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`improvement to fingolimod dosage regimes known in the art. It,
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`therefore, stands to reason that one of ordinary skill in the art would
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`understand that a standard daily dose (e.g., the 0.5 mg daily dose
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`recited at page 15 of Kovarik) will provide therapeutic benefits absent
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`a loading dose. See Ex. 1002 ¶ 120.
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`35.
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`I agree with the PTAB’s analysis of this issue. A POSA before June
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`2006 would have known that the therapeutic efficacy against MS of the 0.5 mg
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`daily dose maintenance therapy disclosed in the Kovarik reference would not be
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`dependent on the loading dose.
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`36.
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`I note that Drs. Jusko and Steinman have conceded that loading doses
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`are used merely to increase the rate at which steady state is achieved. EX2024 at
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`¶131 (“Loading doses can be used to achieve the effect of the drug faster”);
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`EX2022 at ¶¶157-58 (loading doses used in transplant studies such as Kahan 2003
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`to avoid “4-day delay to reach the nadir lymphocyte count”). This is correct. Dr.
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`Jusko’s analysis regarding Equation 14.4 does not undermine the Board’s
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`conclusions, which are correct.
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`37. Dr. Jusko states that Exhibits 1021 and 1041 contain an “error in an
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`equation showing a relationship between half-life and clearance.” EX2024 at ¶¶26,
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`118-22. Dr. Jusko does not expressly assert that any “error” he discusses would
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`alter the Board’s conclusion that maintenance doses are not dependent on loading
`
`dose regimens. It would have been an error for Dr. Jusko to make such an assertion
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`in this case. Dr. Jusko identifies no “error” that should alter the Board’s conclusion
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`that therapeutic efficacy of a maintenance therapy dose would not be dependent on
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`the loading dose.
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`VI. THE PRIOR ART DOES NOT TEACH AWAY FROM THE 0.5 MG DAILY DOSE
`
`A. Webb, Kahan 2003 And Park Do Not Teach Away From
`The 0.5 mg Daily Dose.
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`38.
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`I have been asked to evaluate the arguments from Drs. Jusko, Lublin,
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`and Steinman that Webb (EX2014), Kahan 2003 (EX1031), and Park (EX1019,
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`EX2048) would have discredited Kovarik and discouraged a person of ordinary
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`skill in the art from employing its 0.5 mg daily dose maintenance therapy for the
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`treatment of RR-MS. Drs. Jusko, Lublin and Steinman each repeat the argument
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`that a POSA would ignore Kovarik’s disclosure of the 0.5 mg daily dose
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`maintenance therapy because, they argue, it would have been expected to fail to
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`meet the “at least 70%” lymphocyte sequestration threshold they say a POSA
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`would have believed was required to achieve any therapeutic efficacy for RR-MS
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`treatment. See, e.g., EX2024 (Jusko) at ¶¶6-10, 45-82, 154-55, 164-66; EX2022
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`(Steinman) at ¶¶4-5, 47-93, 127-42; EX2025 at ¶¶32-38, 62; EX2005 (Jusko) at
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`¶¶36-39; EX2003 (Lublin) at ¶¶28-33, 36-39.
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`39. Drs. Jusko, Steinman, and Lublin primarily rely on a single reference
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`(Webb, EX2014) to establish a 70% lymphocyte sequestration threshold for
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`achieving clinical efficacy in treating RR-MS. EX2022 at ¶¶5, 74-85; EX2024 at
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`¶¶8, 65-82, 92; EX2003 at ¶¶32-33, 39; EX1042 at 209:3-211:2. They then rely on
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`Kahan 2003 and Park to establish that a 0.5 mg daily dose of fingolimod did not
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`achieve “at least 70% suppression” of lymphocytes and would therefore not be
`
`expected to provide clinical efficacy for treating RR-MS. I disagree with their
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`analysis.
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`1. A POSA Would Not Read Webb As Establishing That At Least
`70% Lymphopenia Was Necessary For Achieving Therapeutic
`Efficacy.
`
`40. A person of ordinary skill in the art in June 2006 would not read
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`Webb as establishing that at least 70% lymphocyte sequestration was required to
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`see any efficacy for treating RR-MS and would not be discouraged by Webb from
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`administering the 0.5 mg daily dose.
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`41. Webb administered fingolimod at doses of 0.03 mg/kg, 0.3 mg/kg, 1
`
`mg/kg, and 3 mg/kg to mice to evaluate its prophylactic and therapeutic effects.
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`For therapeutic experiments reported in Figures 5 and 6, each dose was
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`administered to 4 mice for about 10 days. EX2014 at 111 (n=4), 114-15 & Figs. 5-
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`6 (days 14-25). Figure 5B indicates that Webb observed a stat