UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`APOTEX INC.,
`Petitioner,
`
`v.
`
`CELGENE CORPORATION,
`Patent Owner
`
`____________________________________________
`
`Case IPR2023-00512
`Patent 8,846,628
`____________________________________________
`
`EXPERT DECLARATION OF GEORGE M. GRASS IV, PH.D.
`
`CELGENE 2052
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

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`
`
`
`TABLE OF CONTENTS
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`Page
`
`I.
`
`II.
`
`INTRODUCTION AND BACKGROUND .................................................... 1
`A. Qualifications and Experience .............................................................. 1
`B.
`Compensation ........................................................................................ 4
`LEGAL PRINCIPLES ..................................................................................... 4
`A. Anticipation ........................................................................................... 4
`B.
`Obviousness ........................................................................................... 5
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 7
`III.
`IV. BASIS OF OPINIONS .................................................................................... 8
`V.
`BACKGROUND ............................................................................................. 8
`A. Oral Drug Administration ..................................................................... 8
`B.
`Overview of 5-Azacytidine ................................................................. 15
`C.
`The ’628 Patent ................................................................................... 16
`VI. THE PETITION ............................................................................................. 18
`VII. THE ASSERTED REFERENCES ................................................................ 19
`A.
`Ionescu ................................................................................................. 19
`B.
`Atadja .................................................................................................. 20
`C.
`Gibson.................................................................................................. 21
`D.
`PR-Press Release ................................................................................. 21
`VIII. SUMMARY OF OPINIONS ......................................................................... 22
`IX. GROUND 1: Ionescu Does Not Inherently Anticipate the
`Pharmacokinetic Values Recited by Claims 11, 12, 18-22, or 38-43. .......... 23
`A.
`Ionescu Does Not Provide Any Pharmacokinetic Values. .................. 23
`B.
`There Is No Evidence That The Claimed Pharmacokinetic
`Values Are Natural Results of Administering A Formulation
`From Ionescu. ...................................................................................... 24
`Dr. Batchelor’s In Silico Modeling Is Fundamentally Flawed. .......... 26
`1.
`Dr. Batchelor’s Modeling Ignores Metabolic Degradation
`Of 5-Azacytidine. ...................................................................... 28
`
`C.
`
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`2.
`
`3.
`
`B.
`
`C.
`D.
`
`
`
`X.
`
`Dr. Batchelor’s model uses hydrolysis rates at a more
`neutral pH than that encountered by orally administered
`drugs. ......................................................................................... 35
`Dr. Batchelor neglected to use available experimental
`data. ........................................................................................... 38
`Dr. Batchelor did not perform any model validation. ............... 40
`4.
`Conclusion for Ground 1 ..................................................................... 42
`D.
`CLAIMS 11, 12, 18-22, AND 38-43 OF THE ’628 PATENT ARE
`NOT INHERENTLY OBVIOUS IN VIEW OF IONESCU IN
`COMBINATION WITH ATADJA, GIBSON AND THE
`KNOWLEDGE OF A POSA (GROUND 2)................................................. 42
`A. None of Ionescu, Atadja, Or Gibson Provide Any
`Pharmacokinetic Values. ..................................................................... 43
`There Is No Evidence That The Claimed Pharmacokinetic
`Values Are Natural Results of Administering The Alleged
`Obvious Formulation. .......................................................................... 43
`Dr. Batchelor’s In Silico Modeling Is Fundamentally Flawed. .......... 43
`Extrapolation using Vidaza® pharmacokinetics and Pharmion-
`PR’s bioavailability for Claims 11 and 38 Is Fundamentally
`Flawed. ................................................................................................ 45
`Conclusion for Ground 2 ..................................................................... 48
`E.
`XI. CLAIMS 11, 12, 18-22, AND 38-43 OF THE ’628 PATENT ARE
`NOT OBVIOUS IN VIEW OF IONESCU IN COMBINATION
`WITH ATADJA, GIBSON, Pharmion-PR, AND THE
`KNOWLEDGE OF A POSA (GROUND 3)................................................. 49
`XII. OBJECTIVE INDICIA SUPPORT NON-OBVIOUSNESS OF
`CLAIMS 11, 18, 38, AND 40 OF THE '628 PATENT ................................ 49
`A.
`The pharmacokinetic values recited by claims 11, 18, 38, and
`40 were unexpected for a non-enteric coated tablet comprising a
`therapeutically effective amount of 5-azacytidine. ............................. 51
`Nexus ................................................................................................... 53
`B.
`XIII. CONCLUSION .............................................................................................. 53
`XIV. AVAILABILITY FOR CROSS-EXAMINATION ...................................... 53
`XV. RIGHT TO SUPPLEMENT .......................................................................... 54
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`XVI. JURAT ........................................................................................................... 55
`XVI. JURAToe eccesseseeeseeeseeeseecsseessessseeesescseseseessueeeesssassseecsesesesesaeeseasseaegeas 55
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`iii
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`Grass Decl. IPR2023-00512
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`I, George M. Grass IV, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION AND BACKGROUND
`
`1.
`
`I have been retained by counsel for Celgene Corporation (“Patent
`
`Owner”) as an expert in Apotex Inc. v. Celgene Corporation, No. IPR2023-00512,
`
`challenging claims 1, 2, 6-9, 11-28, 32-36, and 38-43 of U.S. Patent No. 8,846,628
`
`(“the ’628 patent”).
`
`2.
`
`I understand that Apotex Inc. (“Apotex”) have filed an Inter Partes
`
`Review (IPR) at the USPTO challenging claims 1, 2, 6-9, 11-28, 32-36, and 38-43
`
`of the ’628 patent.
`
`A.
`
`3.
`
`Qualifications and Experience
`
`I am President of G2 Research, Inc., a company I founded in August
`
`2001 to provide consulting services to pharmaceutical and biotechnology
`
`companies in a variety of areas. Among other things, I have performed
`
`pharmacokinetic modeling to evaluate clinical regimens for antibodies and small
`
`molecules. I have also developed computer simulation software and models to
`
`predict drug pharmacokinetics.
`
`4.
`
`I obtained a Ph.D. in Pharmaceutics at the University of Wisconsin,
`
`Madison in 1985. My Ph.D. thesis was entitled “Mechanisms of Corneal Drug
`
`Penetration.” As a result of this research, I was the co-recipient of the 1989 Ebert
`
`Prize, awarded by the American Pharmacists Association Academy of
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`1
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`Grass Decl. IPR2023-00512
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`Pharmaceutical Research and Sciences, for a series of manuscripts published in the
`
`Journal of Pharmaceutical Sciences entitled “Mechanisms of Corneal Drug
`
`Penetration.” I obtained an M.S. degree in Pharmaceutics at the University of
`
`Wisconsin, Madison in 1983. I obtained a Pharm. D. (clinical pharmacy) degree
`
`from the University of Nebraska in 1980 and was licensed to practice pharmacy in
`
`the state of Nebraska.
`
`5.
`
`I have spent more than thirty years working in the pharmaceutical
`
`industry. From 1985 to 1991, I worked as a Research Scientist at Syntex Research
`
`in Palo Alto, where I was responsible for formulation development and research in
`
`oral drug absorption, including methods to orally deliver peptides. Since 1991, I
`
`have been a pharmaceutical industry consultant. In 1991, I started my own
`
`company, Precision Instrument Design Inc., and, in 1997, I started another
`
`company, NaviCyte, Inc. In 1999, NaviCyte, Inc. was acquired by Trega
`
`Biosciences, and I served as Chief Technology Officer at Trega Biosciences, Inc.
`
`until 2001. In 2001, I founded G2 Research, Inc. where I am currently the
`
`president and consult with clients on matters including pharmaceutical product and
`
`formulation development, pharmacokinetic simulation, pharmacokinetic modeling,
`
`and software development. In 2001, I also founded RaptorGraphics, Inc., a
`
`computer visualization and simulation business. From 2005 to 2007, I was Vice
`
`President of Product Development and Chief Technology Officer for PDxRx, Inc.,
`
`
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`Grass Decl. IPR2023-00512
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`a specialty-focused pediatrics company. From 2007 to 2010, I was Senior Vice
`
`President of Research and Development for Sorbent Therapeutics, Inc., a company
`
`developing novel polymer therapeutics for sodium and fluid removal in End Stage
`
`Renal Disease. From January 2016 until May 2017, I was Senior Vice President of
`
`non-clinical development and founder for NeuroVia, Inc., a company developing a
`
`novel compound for childhood cerebral adrenoleukodystrophy. From 2018 to
`
`2022, I managed and directed the development of an oral drug product for Galera
`
`Therapeutics, Inc.
`
`6.
`
`I developed the iDEA pharmacokinetic simulation software, a tool
`
`used to estimate absorption, distribution, metabolism, and excretion (ADME) in
`
`the pharmaceutical industry. I also maintain the iDEA affiliated databases and web
`
`sites (www.admedata.com; www.admemodel.com). I have presented numerous
`
`papers and abstracts on the iDEA software and general drug delivery at industry
`
`conferences such as the American Association of Pharmaceutical Scientists Annual
`
`Meeting and at many pharmaceutical companies throughout the world. I have also
`
`conducted drug-delivery and pharmacokinetic analyses for clinical development. I
`
`have presented the results of such analyses to FDA.
`
`7.
`
`I am the author or co-author of more than 30 published scientific
`
`articles, primarily in the areas of models to predict drug pharmacokinetics, corneal
`
`permeability and drug transport, and intestinal transport and drug absorption. I
`
`
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`Grass Decl. IPR2023-00512
`
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`have authored book chapters related to drug delivery and basic pharmaceutics and
`
`have been an invited speaker at scientific meetings. I have been a peer reviewer
`
`for a number of journals such as Pharmaceutical Research and Journal of
`
`Pharmaceutical Sciences. I am an inventor or co-inventor on eight U.S. patents
`
`and four additional U.S. patent applications and several foreign patents. My
`
`curriculum vitae is attached as Appendix A.
`
`B. Compensation
`
`8.
`
`I am being compensated at my normal consulting rate for my work,
`
`which is $775 per hour. My compensation is not dependent on, and in no way
`
`affects, the substance of my opinions in this Declaration.
`
`II. LEGAL PRINCIPLES
`
`9.
`
`The opinions I express in this Declaration involve the application of
`
`my technical knowledge and professional experience to the evaluation of certain
`
`art with respect to the ’628 patent. Because I am not an attorney, I have applied
`
`the following legal principles explained to me by Patent Owners’ legal counsel
`
`(“counsel”).
`
`A. Anticipation
`
`10.
`
`I have been informed by counsel that a patent claim is invalid under
`
`35 U.S.C. § 102 as anticipated if each element of that claim is present either
`
`explicitly or inherently in a single prior art reference. I have also been informed
`
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`4
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`Grass Decl. IPR2023-00512
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`that, to be an inherent disclosure, the prior art reference must necessarily disclose
`
`the limitation, and the fact that the reference might possibly practice or possibly
`
`contain a claimed limitation is insufficient to establish that the reference inherently
`
`teaches the limitation. I have also been informed that, to find anticipation, each
`
`and every limitation recited in a claim must be found in one item of prior art
`
`arranged in the same way as it is claimed. I have also been informed that
`
`references that are ambiguous to the presence or description of a particular claim
`
`element cannot anticipate a claim. I have also been informed that, for anticipation,
`
`a prior art reference must clearly direct those skilled in the art to the claimed
`
`invention without any need for picking, choosing, and combining various
`
`disclosures not directly related to each other.
`
`B. Obviousness
`
`11.
`
`I have been informed that a patent claim is unpatentable under 35
`
`U.S.C. § 103 as obvious if the subject matter as a whole would have been obvious
`
`to one of ordinary skill in the art at the time the invention was made. I understand
`
`that the obviousness analysis involves several factual inquiries: (1) the scope and
`
`content of the prior art; (2) the differences between the prior art and the claimed
`
`invention; (3) the level of ordinary skill in the art at the time of the invention; and
`
`(4) the existence of objective indicia of non-obviousness (“objective indicia”), such
`
`as a long-felt but unresolved need, industry praise, the failure of others, unexpected
`
`
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`5
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`Grass Decl. IPR2023-00512
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`results, and commercial success. I understand that for objective indicia to be given
`
`weight, there must be a nexus between the evidence of objective indicia and the
`
`merits of the claimed invention.
`
`12.
`
`I have been informed that a patent claim is unpatentable as obvious if
`
`it is obvious to try. I understand that to establish a claimed invention was obvious
`
`to try, a party must establish, at the time of the invention: (1) that there was a
`
`recognized problem or need in the art, including a design need or market pressure;
`
`(2) that there was a finite number of identified, predictable solutions to the
`
`recognized problem or need; (3) that one of ordinary skill in the art could have
`
`pursued these finite, identified, and predictable solutions with a reasonable
`
`expectation of success; and (4) whatever additional facts may be necessary, in view
`
`of the facts of the case under consideration, to explain a conclusion of obviousness.
`
`13.
`
`I understand that a petitioner in an IPR bears the burden of proving
`
`the obviousness of the claimed invention. My understanding is that obviousness is
`
`not proven by mere conclusory statements or conclusory expert testimony.
`
`Instead, I understand there must be some articulated reasoning with a rational
`
`underpinning to satisfy the legal standard of obviousness. I understand that, for a
`
`claim to have been obvious, there must have been some reason or motivation for a
`
`POSA to modify or combine the teachings of the prior art references to achieve the
`
`claimed invention, and the POSA must have had a reasonable expectation of
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`Grass Decl. IPR2023-00512
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`success in doing so. I have also been informed that it is improper to rely on
`
`hindsight reasoning in the obviousness analysis.
`
`III. PERSON OF ORDINARY SKILL IN THE ART
`
`14. A POSA relating to the subject matter of the ʼ628 patent would have
`
`had (1) a Pharm.D., and/or a Ph.D. in pharmaceutical sciences, biomolecular
`
`engineering, chemical engineering, chemistry, or related discipline or an M.D.; and
`
`(2) at least two years of experience with oncology, medicine, pharmaceutical
`
`design, or formulation of oral dosage forms. As of December 2008, I would have
`
`been a POSA.1
`
`
`1 Petitioner’s experts, Drs. Buckton and Batchelor, each put forth identical
`
`definitions of a POSA. Ex.1002(Buckton Decl.), ¶17; Ex.1003(Batchelor Decl.),
`
`¶16. They both opine that a POSA as of December 5, 2008 “would have had (1) a
`
`Pharm.D., or a Ph.D. in pharmaceutical sciences, chemical engineering, chemistry,
`
`or related discipline; and (2) at least two to four years of experience with
`
`pharmaceutical design, formulation, development, and/or manufacturing of oral
`
`dosage forms.” Ex.1002(Buckton Decl.), ¶17; Ex.1003(Batchelor Decl.), ¶16. I
`
`qualify (and have qualified since before the priority dates of the ’628 patent) as a
`
`POSA under Petitioner’s definition. My opinions would not change under
`
`Petitioner’s definition.
`
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`7
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`Grass Decl. IPR2023-00512
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`IV. BASIS OF OPINIONS
`
`15.
`
`In forming my opinions set forth in this Declaration, I have considered
`
`and relied on my education and experience in the fields of pharmaceutical
`
`development, pharmacokinetics, and pharmacokinetic modeling. I have also relied
`
`on the materials listed in Appendix B and on a conversation with Dr. Cory
`
`Berkland.
`
`V. BACKGROUND
`
`A. Oral Drug Administration
`
`16. Drugs can be administered by a variety of routes, such as intravenous
`
`injection, subcutaneous injection, and oral administration. See, e.g.,
`
`Ex.2067(Aulton), 3-6. In each instance, the drug must be bioavailable.
`
`Bioavailability is “a fundamental property of a pharmaceutical product for a given
`
`route of administration.” Ex.2122(Toutain), 455. “Bioavailability is understood to
`
`be the extent and the rate at which a substance or its active moiety is delivered
`
`from a pharmaceutical form, and becomes available in the general circulation.”
`
`Ex.2122(Toutain), 455 (internal quotations omitted). Intravenous injections are
`
`used to introduce substances directly into systemic circulation in the blood stream.
`
`Ex.2067(Aulton), 360. Subcutaneous injections are provided under the skin into
`
`the subcutaneous tissue where it is then absorbed into the bloodstream.
`
`Ex.2067(Aulton), 360.
`
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`Grass Decl. IPR2023-00512
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`17. Compared to drugs administered via intravenous or subcutaneous
`
`injections, the absorption of an orally administered drug is more complex. An oral
`
`formulation, such as a tablet, must be consumed, disintegrate to release the drug
`
`substance, be absorbed at its absorption location (typically in the upper
`
`gastrointestinal tract), and then pass into the hepatic portal system for presentation
`
`to the liver before it reaches systemic circulation in the bloodstream.
`
`Ex.2067(Aulton), 148.
`
`18. This process can be affected by several variables including, for
`
`example, (1) an inappropriately timed release of the drug from the formulation so
`
`the drug substance is not released from the formulation by the time it reaches its
`
`absorption location or is released early and eliminated before it reaches its
`
`absorption location; (2) decomposition of the drug in the gastrointestinal tract or
`
`formation of a non-absorbable complex of the drug so that the drug substance
`
`cannot be absorbed; (3) failure to transport the drug across the gut wall (e.g., drug
`
`permeability) so that the drug cannot be absorbed; (4) and metabolization and other
`
`elimination of the drug on the way to systemic circulation. Ex.2078(Dressman),
`
`12; see also Ex.1018-0004(Thomson) (“Many factors can influence bioavailability,
`
`including the physicochemical characteristics of the drug and its formulation, the
`
`degree of first-pass metabolism in the liver or intestine, the activity of gut
`
`transporters…, the co-administration of other drugs and gastrointestinal
`
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`9
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`conditions[.]”). Because of this “the amount [of a drug] that reaches the systemic
`
`circulation is usually less than the [orally] administered dose.” Ex.1018-
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`Grass Decl. IPR2023-00512
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`0004(Thomson).
`
`19. More specifically, an oral formulation is subject to metabolism and
`
`other types of elimination mechanisms that prevent it from ever reaching systemic
`
`circulation, which include:
`
` acidic decomposition of the drug substance in the gastrointestinal tract
`
`(e.g., the stomach) (see Ex.2078(Dressman), 12, 14);
`
` enzymatic degradation of the drug substance in the gastrointestinal
`
`tract (see id., 15);
`
` lack of permeability leading to the drug not being absorbed (see id.,
`
`12-13);
`
` metabolism by the gut wall (see id., 12);
`
` metabolism by the liver (see id., 12); and
`
` biliary excretion (see id., 12).
`
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`10
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`20. The schematic below summarizes these potential elimination
`
`pathways for an orally administered drug:
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`Grass Decl. IPR2023-00512
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`
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`Ex.2078(Dressman), 12. As this figure suggests, the gastrointestinal tract is a
`
`dynamic system that includes drug decomposition, drug absorption, and the rate of
`
`drug movement through the gastrointestinal tract. Ex.2078(Dressman), 12.
`
`21. As noted above, bioavailability may be affected by metabolic
`
`digestion in the liver (e.g., first pass metabolism). Ex.2122(Toutain), 455. First
`
`pass metabolism of orally administered drugs that occurs presystemically is “[a]
`
`particularly important characteristic of drugs that show a high hepatic extraction
`
`ratio” that can result in “the amount of drug reaching the systemic circulation
`11
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`Grass Decl. IPR2023-00512
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`[being] considerably less than the dose administered.” Ex.2148(Gibaldi), 332.
`
`“Since the entire blood supply draining the upper gastrointestinal tract passes
`
`through the liver before reaching the general circulation, the fraction F of an oral
`
`dose that reaches the systemic circulation, assuming complete absorption, is given
`
`by F = 1 - ER where ER is the extraction ratio.” Id. Thus, some drugs exhibit
`
`significantly reduced area-under-the-curve (AUC) measurements when
`
`administered orally compared to the same drug administered intravenously. Id. In
`
`addition, presystemic metabolism can also occur in the intestinal mucosa, further
`
`enhancing the first-pass effect. The flow chart reproduced below depicts the
`
`
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`12
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`course of drugs given orally and intravenously showing that orally administered
`
`drugs are subject to first pass metabolism in the gut wall and in the liver:
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`Grass Decl. IPR2023-00512
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`
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`Id., 337.
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`22. These processes, in turn, affect other pharmacokinetic values, such the
`
`maximum plasma concentration (Cmax) and time to the maximum plasma
`
`concentration (Tmax). Ex.2122(Toutain), 462, 463. Both Tmax and Cmax are
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`13
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`Grass Decl. IPR2023-00512
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`influenced by the rates of drug absorption and drug decomposition.
`
`Ex.2122(Toutain), 463.
`
`23. For all of these reasons, the bioavailability of a drug may change
`
`depending on its dosage form and path of administration. As recognized in the
`
`literature, “[a] given drug may… show differences in its bioavailability from one
`
`type of dosage form to another [even] when given by the same route, e.g. a tablet, a
`
`hard gelatin capsule and an aqueous suspension administered by the peroral route.”
`
`Ex.2067(Aulton), 133. Thus, “different formulations of the same type of dosage
`
`form or [among] different types of dosage f[or]ms” of the same drug may produce
`
`different pharmacokinetics. Ex.2067(Aulton), 133. For example, if the
`
`bioavailability of a drug administered via intravenous injection was known, one
`
`would not assume the same bioavailability for an orally administered tablet.
`
`Similarly, if the bioavailability for drug administered as an orally administered
`
`liquid was known, one would not assume the same bioavailability for an orally
`
`administered tablet, even though both are oral formulations. Incorrectly assuming
`
`that two different dosage forms or two different routes of administration will be
`
`equally bioavailable can “cause patients to be under- or overmedicated” leading to
`
`“therapeutic failure or serious adverse effects….” Ex.2067(Aulton), 133.
`
`24. All of this would be taken into account by a POSA attempting to
`
`develop a drug product. See, e.g., Ex.2078(Dressman), 11-12.
`
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`14
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`Grass Decl. IPR2023-00512
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`B. Overview of 5-Azacytidine
`
`25.
`
`5-azacytidine is an analog of the nucleoside cytidine. Ex.1001(’628
`
`patent), 2:37-38. 5-azacytidine possesses a nitrogen atom in place of a carbon
`
`atom at position 5 of cytidine’s ring as highlighted in the structure below
`
`(Ex.1001(’628 patent), 2:41-62):
`
`
`
`26.
`
`I understand from conversations with Dr. Corey Berkland that
`
`although researchers synthesized 5-azacytidine in the 1960s, they struggled with
`
`developing a proper clinical formulation of 5-azacytidine for several decades due
`
`to 5-azacytidine’s chemical and enzymatic instability. This understanding is
`
`further supported by my review of the ’628 patent. See, e.g., Ex.1001(’628 patent),
`
`3:54-56 (disclosing “oral delivery [of 5-azacytidine] prove[d] difficult due to
`
`combinations of chemical instability, enzymatic instability, and/or poor
`
`permeability”). 5-Azacytidine was approved by the FDA for subcutaneous
`
`injection in 2004, and for intravenous injection in 2007 and is marketed as
`
`Vidaza®. Ex.1007(Vidaza® Label 2004); Ex.1008(Vidaza® Label 2007).
`
`
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`15
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`Grass Decl. IPR2023-00512
`
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`C. The ’628 Patent
`
`27. The ’628 patent is directed to “pharmaceutical compositions
`
`comprising cytidine analogs,” specifically 5-azacytidine, “for oral administration,
`
`wherein the compositions release the cytidine analog…substantially in the
`
`stomach” as well as “methods of treating diseases and disorders using the oral
`
`formulations provided.” Ex.1001(’628 patent), Abstract. The patent includes two
`
`independent claims: claim 1 and claim 28. Independent claim 1 of the ’628 patent
`
`is reproduced below:
`
`1. A pharmaceutical composition for oral administration comprising a
`therapeutically effective amount of 5-azacytidine and at least one
`pharmaceutically acceptable excipient, wherein the composition is a
`non-enteric coated tablet.
`
`28. Dependent claims 11, 12, and 18-22 each depend from independent
`
`claim 1 and recite an area-under-the-curve (AUC) value (claims 11 and 12), a
`
`maximum plasma concentration (Cmax) value (claims 18 and 19), or a time to
`
`maximum plasma concentration (Tmax) value (claims 20-22). Ex.1001(’628
`
`patent), claims 11, 12, and 18-22. Each of these claims is reproduced below:
`
`11. The composition of claim 1, which has been shown to achieve an
`area-under-the-curve value of at least about 200 ng-hr/mL following
`oral administration to a test subject.
`
`12. The composition of claim 1, which has been shown to achieve an
`area-under-the-curve value of at least about 400 ng-hr/mL following
`oral administration to a test subject.
`
`
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`16
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`Grass Decl. IPR2023-00512
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`18. The composition of claim 1, which has been shown to achieve a
`maximum plasma concentration of at least about 100 ng/mL following
`oral administration to a test subject.
`
`19. The composition of claim 1, which has been shown to achieve a
`maximum plasma concentration of at least about 200 ng/mL following
`oral administration to a test subject.
`
`20. The composition of claim 1, which has been shown to achieve a
`time to maximum plasma concentration of less than about 180
`minutes following oral administration to a test subject.
`
`21. The composition of claim 1, which has been shown to achieve a
`time to maximum plasma concentration of less than about 90 minutes
`following oral administration to a test subject.
`
`22. The composition of claim 1, which has been shown to achieve a
`time to maximum plasma concentration of less than about 60 minutes
`following oral administration to a test subject.
`
`29.
`
`Independent claim 28 of the ’628 patent is reproduced below:
`
`28. A method for treating one or more symptoms of a disease
`associated with abnormal cell proliferation, comprising orally
`administering to a subject in need thereof a pharmaceutical
`composition comprising a therapeutically effective amount of 5-
`azacytidine and at least one pharmaceutically acceptable excipient,
`wherein the composition is a non-enteric coated tablet, and wherein
`the disease associated with abnormal cell proliferation is
`myelodysplastic syndrome or acute myelogenous leukemia.
`
`30. Dependent claims 38-43 each depend from independent claim 28 and
`
`recite an area-under-the-curve value (claims 38 and 39), a maximum plasma
`
`concentration value (claims 40 and 41), or a time to maximum plasma
`
`concentration value (claims 42 and 43). Ex.1001(’628 patent), claims 38-43. Each
`
`of these claims is reproduced below:
`
`
`
`17
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`Grass Decl. IPR2023-00512
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`38. The method of claim 28, which has been shown to achieve an
`area-under-the-curve value of at least about 200 ng-hr/mL following
`oral administration to a test subject.
`
`39. The method of claim 28, which has been shown to achieve an
`area-under-the-curve value of at least about 400 ng-hr/mL following
`oral administration to a test subject.
`
`40. The method of claim 28, which has been shown to achieve a
`maximum plasma concentration of at least about 100 ng/mL following
`oral administration to a test subject.
`
`41. The method of claim 28, which has been shown to achieve a
`maximum plasma concentration of at least about 200 ng/mL following
`oral administration to a test subject.
`
`42. The method of claim 28, which has been shown to achieve a time
`to maximum plasma concentration of less than about 180 minutes
`following oral administration to a test subject.
`
`43. The method of claim 28, which has been shown to achieve a time
`to maximum plasma concentration of less than about 90 minutes
`following oral administration to a test subject.
`
`VI. THE PETITION
`
`31.
`
`I understand that the Petition requests cancellation of the following
`
`claims of the ’628 patent: 1, 2, 6-9, 11-28, 32-36, and 38-43. See, e.g., Pet., 6. All
`
`of the dependent claims depend directly or indirectly from independent claims 1 or
`
`28. Ex.1001(’628 patent), claims 2, 6-9, 11-27, 32-36, and 38-43; Pet., 18.
`
`32.
`
`It is my understanding that the Petition requests cancellation of the
`
`claims of the ’628 patent for 3 reasons:
`
` Ground 1: alleged anticipation of claims 1, 2, 6-8, 11, 13-18, 20-23, 28,
`
`32-35, 38, 40, 42, and 43 based on Ionescu (Ex.1004);
`
`
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`18
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`Grass Decl. IPR2023-00512
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` Ground 2: alleged obviousness of claims 1, 2, 6-9, 11-28, 32-36, and 38-
`
`43 over Ionescu (Ex.1004) in view of Atadja (Ex.1005), Gibson
`
`(Ex.1006), and the knowledge of a POSA; and
`
` Ground 3: alleged obviousness of claims 1, 2, 6-9, 11-28, 32-36, and 38-
`
`43 over Ionescu (Ex.1004) in view of Pharmion-PR (Ex.1010), Atadja
`
`(Ex.1005), Gibson (Ex.1006), and the knowledge of a POSA. See Pet.,
`
`1-3.
`
`33.
`
`It is also my understanding that the dependent claims recite all of the
`
`limitations in the independent claims from which they depend, and then add
`
`additional limitations. If the Petition fails to establish that the independent claims
`
`are invalid as anticipated and obvious, then the dependent claims also cannot be
`
`anticipated or obvious.
`
`VII. THE ASSERTED REFERENCES
`
`A.
`
`Ionescu
`
`34.
`
`Ionescu is a patent reference that discusses the crystalline structures of
`
`5-azacytidine and “relat[ing] to the isolation of crystalline polymorphic and
`
`pseudopolymorphic forms of 5-azacytidine….” Ex.1004(Ionescu), 1:8-10. “It is
`
`an object of the present invention [disclosed in Ionescu] to characterize the
`
`polymorphic forms of 5-azacytidine.” Ex.1004(Ionescu), 2:7-9.
`
`
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`19
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`Grass Decl. IPR2023-00512
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`35.
`
`Ionescu refers to injectable formulations of 5-azacytidine “slurries”
`
`suspended in a water-based solution. See, e.g., Ex.1004(Ionescu), 9:11-14
`
`(disclosing the “typically prepared” 5-azacytidine is “administered by
`
`subcutaneous injection as an aqueous suspension (‘slurry’).”), 21:24-22:6. Ionescu
`
`provides no working examples of oral 5-azacytidine administration and does not
`
`disclose any pharmacokinetic data for an oral (or any) 5-azacytidine formulation.
`
`See, Ex.1004(Ionescu), 15:5-22:6.
`
`B. Atadja
`
`36. Atadja is a patent reference that “relates to a combination which
`
`comprises (a) one or more chemotherapeutic agents and (b) a histone deacetylase
`
`inhibitor…especially for use in the treatment of proliferative diseases…in a
`
`mammal, particularly a human,” “pharmaceutical compositions comprising such a
`
`combination,” and discloses histone deacetylase inhibitors (HDAIs) and their
`
`structures. Ex.1005(Atadja), Abstract; 9:15-22:5. Atadja includes 5-azacytidine as
`
`a possible chemotherapeutic agent for administration in combination with a HDAI.
`
`See, e.g., Ex.1005(Atadja), 26:28-27:16. Atadja does not provides a working
`
`example of oral 5-azacytidine administration, and does not disclose any
`
`pharmacokinetic data for an oral (or any)