UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`
`v.
`MERCK SERONO SA,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00480
`Patent 7,713,947
`
`Case IPR2023-00481
`Patent 8,377,903
`____________________________________________________
`
`DECLARATION OF DR. BERND MEIBOHM
`
`MERCK 2052
`HOPEWELL v MERCK
`IPR2023-00481
`
`
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`
`v.
`MERCK SERONO SA,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00480
`Patent 7,713,947
`
`Case IPR2023-00481
`Patent 8,377,903
`____________________________________________________
`
`DECLARATION OF DR. BERND MEIBOHM
`
`MERCK 2052
`HOPEWELL v MERCK
`IPR2023-00481
`
`
`
`
`I.
`
`IPR2023-00480; IPR2023-00481
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`
`I, Dr. rer. nat. Bernd Meibohm, declare as follows:
`INTRODUCTION
`1.
`I have been asked by counsel for Merck Serono S.A. (“Patent
`
`Owner”) to provide my opinion in connection with the following Inter Partes
`
`Review proceedings: IPR2023-00480 (“’480 IPR”) and IPR2023-00481 (“’481
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`IPR”). I understand that the subject of the ’480 IPR is U.S. Patent No. 7,713,947
`
`(“the ’947 patent”) and the subject of ’481 IPR is U.S. Patent No. 8,377,903 (“the
`
`’903 patent”).
`
`2.
`
`I am providing this declaration as an expert in pharmaceutics and
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`clinical pharmacology.
`
`3.
`
`In forming my opinions set forth in this Declaration, I have considered
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`and relied on my education and experience in the field of pharmaceutical science,
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`including pharmacokinetics, pharmacodynamics, clinical trial design, and
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`pharmaceutical drug development. In preparing this Declaration, I have also
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`reviewed and considered the documents identified in Appendix B.
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`4.
`
`This Declaration identifies my opinions to date. I reserve the right to
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`amend or supplement this Declaration, if allowed under the relevant rules, to
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`address any issues raised by Petitioner, Petitioner’s expert(s) or resulting from
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`further discovery relating to any of the opinions stated herein.
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`
`
`1
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`
`
`II. BACKGROUND AND QUALIFICATIONS
`5.
`I am currently a Distinguished Professor, Associate Dean for Research
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`IPR2023-00480; IPR2023-00481
`
`
`and Graduate Programs, and Chair of the Department of Pharmaceutical Sciences
`
`at the College of Pharmacy, The University of Tennessee Health Science Center
`
`located in Memphis, Tennessee.
`
`6.
`
`A detailed recitation of my education, experience, publications,
`
`awards and honors, patents, publications, and presentations is provided in my CV,
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`a copy of which is attached as Appendix A to this Declaration. A brief discussion
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`of my experience and qualifications is included below.
`
`7.
`
`I trained as a pharmacist at the Technical University Carolo-
`
`Wilhelmina in Braunschweig, Germany from 1984 to 1988. From 1988 to 1989, I
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`completed practical training as a pharmacist in Germany. From September 1989 to
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`July 1994, I completed my doctoral degree (Dr. rer. nat., i.e. Doctor of Natural
`
`Sciences) in Pharmaceutics at the Technical University Carolo-Wilhelmina.
`
`8.
`
`After receiving my board certification in clinical pharmacy from the
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`Pharmacist Guild of Lower Saxony in 1992, I undertook a postdoctoral research
`
`fellowship in Clinical Pharmacology at the University of Florida from November
`
`1995 to October 1997.
`
`9.
`
`From November 1997 to December 1998, I was a Visiting Assistant
`
`Professor of Pharmaceutics in the Department of Basic Pharmaceutical Sciences at
`
`
`
`2
`
`
`
`IPR2023-00480; IPR2023-00481
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`the College of Pharmacy, the University of South Carolina, and from January 1999
`
`to July 1999 I was an Assistant Professor of Pharmaceutics at the University of
`
`South Carolina.
`
`10.
`
`In 1999, I joined the University of Tennessee. From August 1999 to
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`June 2002, I was an Assistant Professor of Pharmaceutical Sciences in the
`
`Department of Pharmaceutical Sciences at the College of Pharmacy. From July
`
`2002 to June 2007, I was an Associate Professor and in 2007, I became a tenured
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`member of the faculty. From July 2007 to the present, I have been a Professor of
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`Pharmaceutical Sciences at the University of Tennessee Health Science Center. In
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`2021, I became a UTHSC Distinguished Professor. I also hold the Harriet S. Van
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`Fleet Endowed Professorship in Pharmaceutics, and I serve as Chair of the
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`Department of Pharmaceutical Sciences at the University of Tennessee Health
`
`Science Center.
`
`11.
`
`In addition to my Professorship, I have been the Associate Dean for
`
`Research and Graduate Programs for the College of Pharmacy at the University of
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`Tennessee Health Science Center since 2008.
`
`12.
`
`In the course of my career, my research focus has primarily been on
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`pharmacokinetic and pharmacodynamic principles for pre-clinical and clinical drug
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`development and applied pharmacotherapy. My focus has been on small molecule
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`drugs.
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`
`
`3
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`
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`I have also worked with biologic drugs (also referred to as
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`
`13.
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`‘biologics’), which include therapeutic proteins derived from living cells and
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`organisms.
`
`14. Additionally, I have worked on the development of various anti-
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`infective drugs and anti-viral drugs. Specifically, my research has included
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`profiling pharmacodynamic and pharmacokinetic properties of novel chemical
`
`entities, to identify which compounds have the potential for therapeutic use and
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`how they can best be used to achieve maximum efficacy and minimal toxicity.
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`This includes the exploration of different routes of administration (including oral,
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`intravenous, subcutaneous, and pulmonary drug delivery) as well as different
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`dosing regimens for approved and new drug candidates. Part of my research has
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`included working on developing dosing regimens for drugs in different patient
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`subgroups.
`
`15. Throughout my career, I have been a member of and served the
`
`American Association of Pharmaceutical Scientists, the American College of
`
`Clinical Pharmacology, and the International Society of Pharmacometrics. I have
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`published more than 200 books, book chapters and peer-reviewed scientific journal
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`articles.
`
`16.
`
`In addition to my above qualifications and experiences, I have served
`
`as a consultant to drug manufacturers in pre-clinical and clinical capacities. In the
`
`
`
`4
`
`
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`IPR2023-00480; IPR2023-00481
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`past, I have consulted for and been invited to present my research by Merck KGaA
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`on various pharmacokinetic and pharmacodynamic issues. My last such work with
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`Merck was in 2022. My prior experience with Merck KGaA has no bearing or
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`effect on my opinion as provided in this declaration.
`
`17. Over the course of my career, I have also interacted with various
`
`experts and inventors in pharmaceutics, including Dr. Nicholas Bodor, who I
`
`understand to be a named inventor of the PCT Application WO 2004/087101 (the
`
`“Bodor” reference or “Bodor”). ’480 Ex. 1022; ’481 Ex. 1022. My prior
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`interactions with Dr. Bodor has no bearing or effect on my opinion as provided in
`
`this declaration.
`
`18.
`
`I am being compensated for my time in connection with this IPR at
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`my standard legal consulting rate, which is $600/hour. My compensation is in no
`
`way contingent on the substance of my testimony or the outcome of this or any
`
`other proceeding. I have no interest in this proceeding.
`
`III. SUMMARY OF OPINIONS
`19.
`I understand that the Petitions allege that claims 36, 38, 39, 41-46 of
`
`the ’947 patent, and claims 17, 19, 20, 22-27 of the ’903 patent are obvious in view
`
`of Bodor and Stelmasiak. ’480 Pet. 8-9; ’481 Pet. 8-9. It is my opinion that a
`
`POSA, as advised by a pharmacologist, would not be motivated to combine or
`
`modify Bodor and Stelmasiak.
`
`
`
`5
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`
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`20. First, Bodor and Stelmasiak fail to teach or suggest weight-based
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`dosing of cladribine and a POSA, advised by a pharmacologist, would not have
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`been motivated to modify Bodor and Stelmasiak’s flat, fixed dosing regimens to a
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`weight-based dosing regimen, or have had any reasonable expectation of success in
`
`doing so. As I will discuss further below, weight-based dosing and flat, fixed
`
`dosing are fundamentally different. Neither Bodor nor Stelmasiak teaches or
`
`suggests weight-based dosing; they only teach the use of a flat, fixed dose for their
`
`disclosed formulations, which a POSA, advised by a pharmacologist, would not
`
`have been motivated to convert to a weight-based dosing regimen in view of Bodor
`
`or Stelmasiak’s teachings.
`
`21. Second, a POSA, with the advice of a pharmacologist, would not have
`
`been motivated to combine/modify Bodor and Stelmasiak at least because Bodor
`
`teaches a formulation having lower bioavailability compared to Stelmasiak’s
`
`formulation. And whereas Bodor teaches no multiple sclerosis (“MS”) treatment
`
`efficacy and Stelmasiak reported only limited MS treatment efficacy, a POSA
`
`would not have been motivated to lower the dosage in Stelmasiak’s regimen to the
`
`dosage disclosed in Bodor, or have had any reasonable expectation of success in
`
`doing so. Specifically, because a POSA would have understood the foregoing, a
`
`POSA would not have been motivated to modify Stelmasiak’s initial treatment
`
`
`
`6
`
`
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`phase of 300 mg administered orally over six months with Bodor’s 100-140 mg
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`cladribine doses administered orally over two months.
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`22. Lastly, it is also my opinion that Petitioner’s Declarant, Dr. Miller,
`
`fails to support his argument that a POSA would have been motivated to combine
`
`or modify Bodor and Stelmasiak to arrive at the claimed dosing regimen.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`23. Petitioner asserts that “[a] POSA for the [’903/’947 patents] would
`
`have the knowledge of multiple disciplines, such as immunology, biochemistry,
`
`and human physiology and anatomy, and also typically be a clinician with
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`experience and/or training in neurology.” ’480 Pet. 28; ’481 Pet. 28. Petitioner
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`further asserts that a “POSA typically would be a medical doctor with a specialty
`
`in neurology, specifically in treating autoimmune disorders of the nervous system,
`
`such as multiple sclerosis, and typically at least 2 years of experience with
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`administering treatments to patients and evaluating results of such treatments, as
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`well as experience or knowledge in related research and development.” ’480 Pet.
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`29; ’481 Pet. 29. According to Petitioner, a POSA “would have drawn upon the
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`knowledge and experience of related disciplines of a multi-disciplinary team that
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`might lie outside the POSA’s primary training” such as “the knowledge and
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`experience of a pharmacologist on a multi-disciplinary team to determine the
`
`appropriate dose for a particular patient.” ’480 Pet. at 28; ’481 Pet. at 28.
`
`
`
`7
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`
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`It is my opinion that a pharmacologist on any such multi-disciplinary
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`24.
`
`team would have had specific experience investigating and comparing the
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`pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, developing
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`pharmaceutical drugs and designing clinical trials.
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`25.
`
`In my opinion, a POSA with respect to the inventions described in the
`
`challenged claims is a person having an M.D. with at least two years of experience
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`treating neurological conditions, with a focus on autoimmune disorders, including
`
`but not limited to multiple sclerosis, and prescribing immunotherapies to treat such
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`neurological conditions. A POSA would also be part of a team including
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`individuals with experience in investigation of the pharmacokinetics (PK) and
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`pharmacodynamics (PD) of drugs, pharmaceutical drug development, and clinical
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`trial design.
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`26. Under either definition, a POSA would have access to or rely on the
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`knowledge and expertise of a pharmacologist, including knowledge and expertise
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`in investigating and comparing the pharmacokinetics (PK) and pharmacodynamics
`
`(PD) of drugs, which include studies of drug dosing routes and bioavailability. I
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`have been an expert in pharmacology including pharmacokinetics (PK) and
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`pharmacodynamics (PD) of drugs, pharmaceutical drug development, and clinical
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`trial design since well before 2004. Thus, my background, expertise, and
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`knowledge with respect to pharmacology would be a part of the knowledge and
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`
`
`8
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`expertise a POSA would draw upon or rely on under either definition of a POSA. I
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`am providing my opinion from the perspective of a pharmacologist who would
`
`advise a POSA and what a POSA would understand in consultation with a
`
`pharmacologist. My opinion is the same under either party’s definition of a POSA.
`
`V. TECHNICAL BACKGROUND
`A.
`Pharmacokinetics
`27. Pharmacokinetics (“PK”) is the study of a drug’s absorption,
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`distribution, metabolism, and excretion when administered to a patient’s body, in
`
`other words, the relationship between drug administration and the resulting levels
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`of that drug in the body.
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`28. A drug’s PK properties may depend on many factors including dosage
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`form, route of administration, and individual properties of the drug and the treated
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`patient.
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`29. Bioavailability refers to the percentage of an administered dose of a
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`drug that reaches the systemic circulation in the treated patient. Bioavailability of
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`a drug may vary among patients and patient populations.
`
`30.
`
` A standard method for determining the bioavailability of a drug is to
`
`use the area under the concentration-time curve (“AUC”). AUC is a measurement
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`of the extent of absorption of the drug, i.e., it is a measure of a patient’s cumulative
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`systemic exposure to the drug from administration through complete clearance of
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`the drug. AUC is calculated by plotting the concentrations of the drug in the body
`9
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`(e.g., in plasma) versus different time points to construct a curve and measuring the
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`area under the curve.
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`31.
`
` In general, a drug’s PK properties are affected by the method or route
`
`of administration. For example, an intravenously administered drug is injected
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`directly into a patient’s vein to directly reach systemic circulation. Thus, for
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`intravenous (“IV”) drugs, the bioavailability of a drug is generally 100%.
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`Subcutaneously administered drugs are injected in a site under the skin into tissue.
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`Unlike IV administration, the drug must be absorbed into the systemic circulation
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`from the subcutaneous injection site. Bioavailability of subcutaneous (SC) drugs is
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`typically, but not always, lower than IV. Last, for orally administered drugs, the
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`bioavailability is commonly lower than for IV administration and often also lower
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`than for the SC administered route of the same drug. This is because the orally
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`administered drugs will need to first be absorbed through the gastrointestinal
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`system and then pass through the liver, which typically metabolizes at least a
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`portion of the drug, before the remaining drug can enter the systemic circulation.
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`32.
`
` Bioavailability of orally-administered drugs (e.g., tablets or oral
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`solutions) can be determined by calculating the AUC from a drug concentration-
`
`time point curve. Specifically, blood from treated patients can be taken at periodic
`
`intervals after drug administration to determine the drug concentrations to plot a
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`curve and the AUC can be calculated from such a curve. Bioavailability is
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`
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`10
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`
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`typically calculated by comparing the AUCs of a drug orally-administered vs.
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`intravenously administrated. Ex. 2043, 1515.1
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`33.
`
` PK properties of a drug usually influence the design of an appropriate
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`dosing regimen. PK properties may inform how to select a drug’s optimal dose,
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`dosing method or dosing schedule. When designing a dosing regimen, one
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`important consideration is a drug’s overall bioavailability, because it informs the
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`percentage of the administered drug that actually reaches the systemic circulation
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`in the treated patient. Ex. 2063, 3.
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`34.
`
` Among a patient population, patients will have different weights.
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`Depending on the drug and its formulation, patient weights may affect drug
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`concentrations in the patients’ blood and whether an administered dose of a drug is
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`therapeutically adequate or toxic, even when the same absolute amount of a drug is
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`given. In some instances, the same amount of a drug, e.g., 100 mg, may well be
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`sufficient for a patient with lighter weight to result in acceptable pharmacologic
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`effect, but may fail to result in sufficient therapeutic effects in a heavier patient as
`
`an increase in body size and weight may mean a larger volume of distribution and
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`a higher drug-clearance from the body. For instance, low molecular weight
`
`
`1 All citations to Patent Owner’s exhibits are in reference to Patent Owner’s exhibit
`
`filed contemporaneously in IPR2023-00480 and IPR2023-00481.
`
`
`
`11
`
`
`
`heparins such as tinzaparin need to be dosed based on body weight. See Ex. 2062,
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`817. For some drugs, however, the variability in pharmacologic effect by weight
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`may be minimal. In these cases, a fixed or flat dosing of a drug would be the
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`preferred dosing method for better compliance and easy administration.
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`35.
`
` A drug treatment dosage can be designed using a number of dosing
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`approaches. The most common dosing regimens are flat, fixed dosing. A flat,
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`fixed dosing regimen is a regimen in which a drug is administered without
`
`consideration of a patient’s weight. In contrast, in a weight-based dosing regimen
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`(also known as bodyweight-based), each patient will get a different dose of a drug
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`that is proportional to that patient’s body weight.
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`36.
`
` I understand that by 2004, there were several drugs approved by the
`
`FDA for treating MS. Among these, the interferons Betaseron®, Avonex®, and
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`Rebif® are administered 0.25 mg every other day, 30 μg/week, and 44 μg three
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`times/week, respectively; Tysabri® (natalizumab) is dosed 300 mg once every four
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`weeks; and Copaxone® (glatiramer acetate) is administered 20 mg/day. Ex. 2014
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`(Betaseron_Label), 12; Ex. 2015 (Avonex_Label), 3; Ex. 2016 (Rebif_Label), 17;
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`Ex. 2019 (Tysabri_Label), 10; Ex. 2017 (Copaxone_Label), 19. All of these MS
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`drugs are administered using a flat or fixed dose.
`
`37.
`
` On the other hand, Mavenclad® is dosed by weight. Ex. 2001
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`(Mavenclad® Label), 1. As described in “2.2 Recommended Dosage,” “[t]he
`
`
`
`12
`
`
`
`recommended cumulative dosage of MAVENCLAD is 3.5 mg per kg body weight
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`administered orally and divided into 2 treatment courses (1.75 mg per kg per
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`treatment course). . . .” Ex. 2001, 5. As previously noted, weight-based dosing
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`may be better in achieving the same pharmacological effect across patients with
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`different body weights. See Ex. 2062, 822-23.
`
`B.
`38.
`
`The ’947 and ’903 Patents
`I have reviewed both the ’947 and ’903 patents that are the subject of
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`the above referenced inter partes review proceedings. The ’947 and ’903 patents
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`recite claims directed to methods of treating certain forms of multiple sclerosis
`
`using a four-step weight-based oral administration dosing regimen. The claims
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`recite an induction period wherein cladribine is administered using a weight-based
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`dosage (mg/kg), a cladribine-free period, a maintenance period, and an additional
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`cladribine-free period. ’480 Ex. 1001 (’947 Patent), 19:13-30; ’481 Ex. 1001 (’903
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`Patent), 18:7-26.
`
`C. References
`1.
`Bodor
` Bodor discloses a solid oral (tablet) cladribine formulation
`
`39.
`
`comprising a particular cladribine-cyclodextrin complex. ’480 Ex. 1022; ’481 Ex.
`
`1022. Bodor describes an oral cladribine tablet comprising a complex of inclusion
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`and non-inclusion complexes of cladribine and cyclodextrin, which it refers to as a
`
`
`
`13
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`
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`"complex cladribine-cyclodextrin complex”. ’480 Ex. 1022, 16:25-28; ’481 Ex.
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`1022, 16:25-28.
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`40. Bodor’s claimed cladribine-cyclodextrin formulation purports to
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`provide “novel therapeutic modalities for the treatment of patients in need of
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`treatment with cladribine.” ’480 Ex. 1022, 22:4-6; ’481 Ex. 1022, 22:4-6. Bodor
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`reflects that some pharmacokinetic testing was performed with examples of the
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`claimed formulation, including the results of that testing, but Bodor does not
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`describe any testing for or results related to the efficacy of its claimed cladribine-
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`cyclodextrin formulation. Id. In particular, Bodor discloses in “Example 3” that 3
`
`mg (Batch N0120) and 10 mg (Batch N0126) oral cladribine tablets were
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`manufactured for use in a clinical pharmacokinetic study. ’480 Ex. 1022, 32:5-6;
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`’481 Ex. 1022, 32:5-6. Bodor’s 3 mg and 10 mg oral tablets were dosed in a flat,
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`fixed dosage in a clinical pharmacokinetic study to investigate the bioavailability
`
`of the disclosed cladribine-cyclodextrin formulations. See ’480 Ex. 1022, 33:25-27
`
`at Example 4 (“Patients received randomly three different fixed oral doses (3.0 mg)
`
`and a fixed subcutaneous dose of 3.0 mg); ’480 Ex. 1022, 36:18-20 at Example 5
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`(“Patients received randomly two different fixed oral doses (3.0 mg and 10.0 mg)
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`and a fixed intravenous dose of 3.0 mg[.]”) (emphases added); ’481 Ex. 1022,
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`33:25-27 (Example 4); ’481 Ex. 1022, 36:18-20 (Example 5).
`
`
`
`14
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`
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`41. With respect to “Example 4,” Bodor states “[t]he objective of this
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`study was to assess the relative bioavailability of three oral cladribine
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`formulations” including “a cyclodextrin-based formulation according to the instant
`
`invention (Tablet 1: complex FD05, i.e. Batch No. N0120 tablets described
`
`above),” a mucoadhesive formulation, a hard-gel capsule formulation, in
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`comparison with a fixed subcutaneous cladribine administration. ’480 Ex. 1022,
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`33:12-23; ’481 Ex. 1022, 33:12-23. Bodor’s relative bioavailability study was an
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`open-label, randomized, 4-way crossover single dose study using 12 patients with
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`MS. ’480 Ex. 1022, 33:24-25; ’481 Ex. 1022, 33:24-25. In the study, patients
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`received “three different fixed oral doses (3.0 mg) and a fixed subcutaneous dose of
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`3.0 mg.” ’480 Ex. 1022, 33:26-27; ’481 Ex. 1022, 33:26-27 (emphases added).
`
`42. Bodor explains that the plasma concentrations of cladribine were
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`measured and plotted over various time points to determine the AUC. Bodor
`
`reported the results of its study in the table below.
`
`
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`15
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`43.
`
`Specifically, with respect to the 3 mg oral cladribine-cyclodextrin
`
`complex formulation, Bodor finds a relative bioavailability of 41.9 % and 43.1 %
`
`for its oral tablet relative to a fixed subcutaneous dose, dependent on which AUC
`
`term is used.
`
`44. With respect to “Example 5,” titled “CLINICAL STUDY: DOSE
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`RESPONSE AND ABSOLUTE BIOAVAILABILITY,” Bodor states “[t]he
`
`objective of this study was to assess the systemic availability of cladribine after
`
`oral administration in two different fixed oral doses, in comparison with one fixed
`
`intravenous administration (reference formulation) in patients with MS (multiple
`
`sclerosis), and to evaluate the safety and tolerability of cladribine in this
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`population.” ’480 Ex. 1022, 36:12-16; ’481 Ex. 1022, 36:12-16. Bodor’s absolute
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`bioavailability study was an open-label, randomized, 3-way crossover single dose
`16
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`study consisting of twenty-six patients with MS. In the study, patients purportedly
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`“received two different fixed oral doses (3.0 mg and 10.0 mg) and a fixed
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`intravenous dose of 3.0 mg . . . .” ’480 Ex. 1022, 36:17-20; ’481 Ex. 1022, 36:17-
`
`20.
`
`45.
`
`In the clinical study disclosed in “Example 5,” Bodor determined the
`
`area under curve (“AUC”) by plotting the concentrations of cladribine in patient
`
`plasma over various time points. Bodor reported the results of its study in the table
`
`below.
`
`46.
`
`Specifically, with respect to the 10 mg oral cladribine-cyclodextrin
`
`complex formulation, Bodor found an absolute bioavailability of 39.1 and 39.4%
`
`for its 10 mg oral tablet, in comparing against the AUC obtained by using an
`
`intravenously-administered cladribine dosing route. Indeed, Dr. Miller confirms
`
`17
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`
`
`that “the bioavailability that Bodor reports for its 10 milligram tablets is 39.1 or
`
`IPR2023-00480; IPR2023-00481
`
`
`39.4 percent[.]” Ex. 2009, 61:13-18.
`
`47. With respect to the bioavailability studies conducted using Bodor’s
`
`claimed cladribine-cyclodextrin formulations, a POSA would have understood that
`
`Bodor reported a relative bioavailability of 41.9 % and 43.1% for its 3 mg tablet
`
`compared to subcutaneous administration, and an absolute bioavailability of 39.1
`
`and 39.4% for its 10 mg oral cladribine-cyclodextrin tablets. ’480 Ex. 1022, 36
`
`(Table VI); ’480 Ex. 1022, 38 (Table VIII); ’481 Ex. 1022, 36 (Table VI); ’481 Ex.
`
`1022, 38 (Table VIII). In Bodor’s disclosed clinical bioavailability studies
`
`discussed in “Examples 4 and 5,” all of the doses of oral, subcutaneous, and
`
`intravenous administrations were flat, fixed doses, not weight-based doses.
`
`48. Bodor does not disclose any MS efficacy studies using its cladribine-
`
`cyclodextrin oral tablets. Bodor also does not describe a treatment regimen for any
`
`proposed clinical study. Bodor, does, however, discuss a theoretical treatment
`
`regimen:
`
`At the present time, it is envisioned that, for the treatment of multiple
`sclerosis, 10 mg of cladribine in the instant complex cladribine-
`cyclodextrin complex in the instant solid dosage form would be
`administered once per day for a period of five to seven days in the
`first month, repeated for another period of five to seven days in the
`second month, followed by ten months of no treatment.
`
`’480 Ex. 1022, 23:15-20; ’481 Ex. 1022, 23:15-20.
`
`
`
`18
`
`
`
`49. The above proposed treatment regimen expressly discloses only a flat
`
`IPR2023-00480; IPR2023-00481
`
`
`dose of 10 mg/day for five to seven days for a two-month period, followed by 10
`
`months of no treatment. The disclosure of the theoretical treatment regimen
`
`indicates that patients may receive a cumulative oral dose between 100 mg and 140
`
`mg (inclusive). The disclosure does not reference patient weight at all or provide
`
`any criteria from which to determine whether or how different doses would be
`
`given to different patients. As would be expected with flat, fixed dosing, the above
`
`theoretical regimen is administered without consideration of patient weight. Thus,
`
`Bodor’s disclosed treatment regimen does not disclose any weight-based dose or
`
`associate any dose with any patient (by weight or otherwise).
`
`2.
`Stelmasiak
`50. Stelmasiak is a report of a cladribine study published in 1998 (the
`
`“Stelmasiak study”). ’480 Ex. 1013, 4; ’481 Ex. 1013, 4. The Stelmasiak study
`
`involved 10 patients with remitting-relapsing MS, who were treated with either a
`
`10 mg cladribine saline liquid solution administered orally or a 5 mg cladribine
`
`saline liquid solution administered subcutaneously, once daily for five consecutive
`
`days (50 mg oral dose; 25 mg SC dose). This treatment course was given once a
`
`month for 6 months followed by additional 1- month courses (again using 50 mg
`
`oral dose or 25 mg SC dose) at month 9 and month 12 or 15. ’480 Ex. 1013, 5;
`
`’481 Ex. 1013, 5. As described in the above treatment regimen from Stelmasiak,
`
`
`
`19
`
`
`
`patients received a 300 mg cumulative flat oral cladribine dose over the first 6
`
`IPR2023-00480; IPR2023-00481
`
`
`months of treatment followed by 50 mg at month 9, and 50 mg at either month 12
`
`or month 15. ’480 Ex. 1013, 5; ’481 Ex. 1013, 5.
`
`51. With respect to the 10 mg cladribine oral solution, Stelmasiak utilized
`
`a formulation prepared as a phosphate-buffered solution. As described in
`
`Stelmasiak, the oral formulation was “a sterile solution in isotonic saline” and
`
`“phosphate-buffered at pH 7.4.” ’480 Ex. 1013, 5; ’481 Ex. 1013, 5. Both the oral
`
`solution and the subcutaneous injection were administered as flat, fixed doses. No
`
`placebo or control arm was used in the study.
`
`52. As Stelmasiak reports, six patients received a subcutaneous cladribine
`
`dose while four patients received Stelmasiak’s oral liquid formulation. Although
`
`Stelmasiak dosed every patient using a flat, fixed dose regardless of patient weight,
`
`Stelmasiak did report on the patient weights of the study group. ’480 Ex. 1013, 5;
`
`’481 Ex. 1013, 5. Stelmasiak’s 10-person study group consisted of 8 females and 2
`
`males, aged 21-51 years, and between 52-75 kg (median body weight was 66 kg).
`
`’480 Ex. 1013, 5; ’481 Ex. 1013, 5. Due to the flat, fixed dosing and the different
`
`weights of each patient, Stelmasiak was able to investigate the effect, if any, of
`
`weight on the pharmacokinetic properties of its oral liquid formulation. In that
`
`regard, Stelmasiak reports that “[t]here was no indication that a ‘good response’ is
`
`related to the actual cladribine dose per body weight” and that “there was no
`
`
`
`20
`
`
`
`correlation between the depth of lymphocyte nadir, or the magnitude of
`
`IPR2023-00480; IPR2023-00481
`
`
`lymphocyte count reduction from the initial value, and the drug dose expressed per
`
`kg of body weight.” ’480 Ex. 1013, 7, 6; ’481 Ex. 1013, 7, 6.
`
`53. Stelmasiak reports some limited efficacy results as measured by
`
`EDSS scores during and after treatment, and the reduction in relapse rate. ’480 Ex.
`
`1013, 6 (“Analysis of the data for the whole group revealed that EDSS scores were
`
`significantly reduced during the treatment compared to the initial values … (Table
`
`1).”; ’480 Ex. 1013, 7 (“The relapse rate in some (but not all) patients is
`
`impressively decreased.”); ’481 Ex. 1013, 6; ’481 Ex. 1013, 7. Stelmasiak further
`
`describes the study group as “responders” and “non-responders” based on whether
`
`there were changes in their relapse rate during the treatment period. ’480 Ex.
`
`1013, 6; ’480 Ex. 1013, 7; ’481 Ex. 1013, 6; ’481 Ex. 1013, 7. Stelmasiak does
`
`not disclose which of the “responders” or “non-responders” received Stelmasiak’s
`
`oral solution or subcutaneous injection.
`
`54. Stelmasiak’s study also reports lymphocyte count for the study group
`
`during the treatment period. As stated in Stelmasiak, “[t]he magnitude of
`
`lymphocyte count reduction varied among the patients was different in particular
`
`cases, ranging from virtually no effect in one patient to a transient drop by 80% of
`
`the initial value. … However, there was no correlation between the depth of
`
`lymphocyte nadir, or the magnitude of lymphocyte count reduction from the initial
`
`
`
`21
`
`
`
`value, and the drug dose expressed per kg of body weight … .” ’480 Ex. 1013, 6;
`
`IPR2023-00480; IPR2023-00481
`
`
`’481 Ex. 1013, 6. Although Stelmasiak plots the average lymphocyte count across
`
`the study group during and after treatment (Figure 1), Stelmasiak does not
`
`disaggregate this data by any individual patient data or study parameters.
`
`Stelmasiak does not report lymphocyte count by patients who received an oral
`
`cladribine solution or subcutaneous injection. Stelmasiak does note that of the
`
`three “non-responders” in the study, two “non-responders” “showed the reduction
`
`of approximately the same magnitude as in some of the ‘responders’” with respect
`
`to lymphocyte count. ’480 Ex. 1013, 6; ’481 Ex. 1013, 6.
`
`55. As shown in Figure 1 below, Stelmasiak reported a reduction in
`
`lymphocytes per microliter at 3 months (wherein the cumulative dosage of
`
`cladribine under Stelmasiak’s regimen would have been 150 mg) and 6 months
`
`(wherein the cumulative dosage of cladribine under Stelmasiak’s regimen would
`
`have been 300 mg) and throughout a 2-year period.
`
`
`
`22
`
`
`
`IPR2023-00480; IPR2023-00481
`
`’480 Ex. 1013, 5 (Figure 1); ’481 Ex. 1013, 5 (Figure 1).
`
`56.
`
`In addition to the limited efficacy findings discussed above,
`
`Stelmasiak reports the bioavailability of the oral formulation used in its study, with
`
`reference to an earlier study authored by Liliemark, Albertioni, Hassan, and
`
`Juliusson, “On the bioavailability of oral and subcutaneous 2-chloro-2’-
`
`deoxyadenosine in humans: alternative routes of administration,”2 which I will
`
`discuss in greater detail below. ’480 Ex. 1013, 5; ’481 Ex. 1013, 5.
`
`2 It appears the citation to Liliemark (reference No. 12 in Stelmasiak)
`
`contains a typographical error: the year of the Liliemark study’s date of publication
`
`is 1992 and not 1991. This citation error has no bearing on my opinion.
`
`23
`
`
`
`57. According to Stelmasiak, the 5 mg subcutaneous cladribine dose and
`
`IPR2023-00480; IPR2023-00481
`
`
`the 10 mg oral cladr
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