UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________________________________
`
`APOTEX INC.,
`Petitioner,
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`v.
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`CELGENE CORPORATION,
`Patent Owner
`
`____________________________________________
`
`Case IPR2023-00512
`Patent 8,846,628
`____________________________________________
`
`EXPERT DECLARATION OF CORY BERKLAND, PH.D.
`
`CELGENE 2001
`APOTEX v. CELGENE
`IPR2023-00512
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`Berkland Decl. IPR2023-00512
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`TABLE OF CONTENTS
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`I.
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`II.
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`Page
`INTRODUCTION AND BACKGROUND .................................................... 1
`A. Qualifications and Experience .............................................................. 1
`B.
`Compensation ........................................................................................ 5
`C.
`Bases of Opinions .................................................................................. 5
`LEGAL PRINCIPLES ..................................................................................... 6
`A.
`Claim Construction................................................................................ 6
`B.
`Anticipation ........................................................................................... 8
`C.
`Obviousness ........................................................................................... 9
`III. A PERSON OF ORDINARY SKILL IN THE ART .................................... 10
`IV. THE ’628 PATENT ....................................................................................... 12
`V.
`THE PETITION ............................................................................................. 13
`VI. REFERENCES CITED IN THE GROUNDS ............................................... 14
`A.
`Ionescu ................................................................................................. 14
`B.
`Atadja .................................................................................................. 16
`C.
`Gibson.................................................................................................. 18
`D.
`Pharmion-PR ....................................................................................... 19
`VII. SUMMARY OF OPINIONS ......................................................................... 20
`VIII. PETITIONER’S ARGUMENTS DO NOT ESTABLISH A REASONABLE
`LIKELIHOOD OF UNPATENTABILITY .................................................. 21
`A.
`State of The Art: 5-Azacytidine Formulations in 2008...................... 21
`B.
`Petitioner Fails to Establish That The Cited References Disclose “A
`Non-Enteric-Coated Tablet” ............................................................... 22
`1.
`A sugar coating is a common type of multi-layered formulation
`and says nothing about the release profile of the drug ............. 23
`A tablet with a sugar coating may include an enteric coating or
`a non-enteric coating ................................................................. 27
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`2.
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`C.
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`2.
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`b.
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`Berkland Decl. IPR2023-00512
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`3.
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`4.
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`A tablet formulation of 5-azacytidine would have been
`understood by a POSA to include an enteric coating in 2008 .. 32
`Petitioner fails to establish that Ionescu anticipates the claims
`(Ground 1) ................................................................................. 32
`Petitioner Fails to Establish That The References Cited in Grounds 2
`and 3 Teach A Non-Enteric Coated Tablet of 5-Azacytidine and That
`A POSA Would Have Had A Reasonable Expectation of Success in
`Formulating A Non-Enteric Coated Tablet of 5-Azacytidine ............. 33
`1.
`Petitioner fails to show that the additional references disclose a
`non-enteric coated formulation of 5-azacytidine ...................... 33
`Petitioner fails to establish that a POSA would have had a
`reasonable expectation of success in formulating a non-enteric
`coated tablet of 5-azacytidine in view of its known instability 35
`a.
`There was no reasonable expectation of success in
`developing a non-enteric coated 5-azacytidine tablet
`because a POSA would have understood the drug to be
`rapidly hydrolyzed and inactivated in the stomach ........ 38
`There was also no reasonable expectation of success in
`developing a non-enteric coated 5-azacytidine tablet
`because a POSA would have understood the drug to be
`degraded by the enzyme cytidine deaminase .................. 46
`IX. CONCLUSION .............................................................................................. 50
`X. AVAILABILITY FOR CROSS-EXAMINATION ...................................... 50
`XI. RIGHT TO SUPPLEMENT .......................................................................... 51
`XII. JURAT ........................................................................................................... 52
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`Berkland Decl. IPR2023-00512
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`I.
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`INTRODUCTION AND BACKGROUND
`I, Cory Berkland, Ph.D., have been retained by counsel for Celgene
`1.
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`Corporation (“Patent Owner”) as an expert in Apotex Inc. v. Celgene Corporation,
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`No. IPR2022-00512, challenging claims 1, 2, 6-9, 11-28, 32-36, and 38-43 of U.S.
`
`Patent No. 8,846,628 (“the ’628 patent”).
`
`A. Qualifications and Experience
`I am currently a Professor of Pharmaceutical Chemistry and a
`2.
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`Professor of Chemical and Petroleum Engineering at The University of Kansas. I
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`also have an appointment as a courtesy professor in the Chemistry Department at
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`The University of Kansas. I also assisted in designing the BioEngineering
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`graduate program at The University of Kansas, and I am the former director of the
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`Biomolecular Engineering track within the BioEngineering program.
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`3.
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`I teach courses to undergraduate and graduate students at The
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`University of Kansas on, among other things, pharmaceutical formulation
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`(including solid oral dosage forms), drug delivery, dissolution methods, and
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`modeling dissolution profiles.
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`4.
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`I received a Doctor of Philosophy degree from the University of
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`Illinois in 2003 and a Master of Science degree from the University of Illinois in
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`2001, both from the Department of Chemical and Biomolecular Engineering. I
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`Berkland Decl. IPR2023-00512
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`received a Bachelor of Science degree in Chemical Engineering from Iowa State
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`University in 1998.
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`5.
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`I have worked in the area of pharmaceutical formulation for over 20
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`years. A significant portion of my career has been dedicated to the study of
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`formulating therapeutics for delivery to patients. I currently research the design of
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`molecules and materials specialized for a particular disease and targeted drug
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`delivery to maximize their therapeutic effect while limiting side-effects. I have
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`extensive experience in the area of pharmaceutical delivery design including
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`preformulation, formulation, analysis, and related theories.
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`6.
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`I have published over 200 peer-reviewed papers, and I have presented
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`my research at many national and international research conferences and to
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`companies, including more than 75 invited talks. I have also given distinguished
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`lectures such as the Nagai Foundation Distinguished Lectureship in Japan and a
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`lectureship at the Center of Excellence in Nanotechnology at the Massachusetts
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`Institute of Technology. I also serve or have served on the editorial advisory board
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`for a number of peer-reviewed journals: Therapeutic Delivery, The Journal of
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`Pharmaceutical Sciences, and The Journal of Pharmaceutical Innovation. I also
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`serve or have served on advisory boards for the Center for Cancer Engineering at
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`The Ohio State University, the Drug Discovery and Development of Experimental
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`Berkland Decl. IPR2023-00512
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`Therapeutics program, and the National Institutes of Health Pharmaceutical
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`Aspects of Biotechnology training grant program at The University of Kansas.
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`7.
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`I have received funding for my research from the National Institutes
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`of Health including the National Cancer Institute, the National Science Foundation,
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`the Department of Defense, the Defense Threat Reduction Agency, the PhRMA
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`Foundation, the Coulter Foundation, the American Heart Association, the Cystic
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`Fibrosis Foundation, the Juvenile Diabetes Research Foundation, several other
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`philanthropic organizations, and multiple pharmaceutical companies.
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`8.
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`Over the years I have been an active participant in a number of
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`professional societies including the American Institute of Chemical Engineers, the
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`Controlled Release Society, the American Chemical Society, and the American
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`Association of Pharmaceutical Scientists. I have also been elected Fellow of the
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`American Institute for Medical and Biological Engineering and was elected to the
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`National Academy of Inventors.
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`9.
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`I have received numerous awards in recognition of my research,
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`including the Controlled Release Society Young Investigator Award and the
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`Coulter Translational Research Award. At the University of Kansas, I have
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`received major research awards such as the University Scholarly Achievement
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`Award, the Jim Baxendale Commercialization Award, the Leading Light Award,
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`Berkland Decl. IPR2023-00512
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`and the Miller Professional Development Award for Research, and I was named a
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`Bellows Scholar in the School of Engineering at The University of Kansas. I have
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`also received the W.T. Kemper Fellowship for teaching excellence at The
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`University of Kansas.
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`10.
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`I have been granted multiple patents and have co-founded seven
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`companies: Bond Biosciences, Exodus Biosciences, Orbis Biosciences (acquired
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`by Adare Pharmaceuticals), Kinimmune, Orion BioScience, Axioforce, and Savara
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`Pharmaceuticals. I have held executive positions at each of these companies. I am
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`currently the Chief Executive Officer and Chairman of the Board of Directors at
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`Bond Biosciences. I am also currently the Chief Executive Officer and Chairman
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`of the Board of Directors at Kinimmune.
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`11.
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`I have worked as a consultant in the pharmaceutical industry
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`providing formulation advice to multiple major pharmaceutical and biotechnology
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`companies. I also worked at a biotechnology investment firm, Sofinnova
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`Ventures, during a six-month sabbatical in 2014.
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`12. Overall, I have about 20 years of experience designing therapeutic
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`formulations and testing their release profiles. In my work described above, I have
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`performed formulation delivery testing many times on oral solid dosage forms, for
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`example, tablets, powders, capsules, and suspensions. I have performed analysis
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`of release profiles for delivery of therapeutics, for example, in my research work at
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`The University of Kansas. This includes analysis of both controlled and immediate
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`release formulations.
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`13.
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`I have conducted many comparative dissolution studies in my work
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`described above. Much of this work has been optimizing formulations for either
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`immediate or extended release, for example, in my work consulting for
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`pharmaceutical companies in connection with FDA filings for pharmaceutical
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`products and in my research.
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`14.
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`I have, on many occasions, designed and optimized solid oral dosage
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`forms, including tablets, powders, capsules, and suspensions, for example, in my
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`work at Orbis Biosciences.
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`15. My curriculum vitae, which lists my professional experience and
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`qualifications in greater detail, is attached hereto as Appendix A.
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`B. Compensation
`I am being compensated at my normal consulting rate for my work,
`16.
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`which is $750 per hour. My compensation is not dependent on, and in no way
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`affects, the substance of my opinions in this Declaration.
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`C. Bases of Opinions
`In forming my opinions set forth in this Declaration, I have considered
`17.
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`and relied on my education and experience in the fields of pharmaceutical design,
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`Berkland Decl. IPR2023-00512
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`formulation, development, and manufacturing of oral dosage forms. I have also
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`relied on the materials listed in Appendix B.
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`II. LEGAL PRINCIPLES
`18. The opinions I express in this Declaration involve the application of
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`my technical knowledge and professional experience to the evaluation of certain
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`art with respect to the ’628 patent. Because I am not an attorney, I have applied
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`the following legal principles explained to me by Patent Owners’ legal counsel
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`(“counsel”).
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`A. Claim Construction
`19. For the purposes of this Declaration, I understand that certain
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`principles of law are relevant to my analysis and opinions. For example, I
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`understand that before a patent validity determination can be made, the claims
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`must be construed by the Board.
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`20.
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`I understand that in an Inter Partes Review (“IPR”), the Board
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`construes claim terms in light of the specification of the patent in which they
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`appear. I further understand that a claim construction analysis begins with the
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`ordinary meaning of the disputed claim term, and there is a presumption that claim
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`terms carry their accustomed meaning to a person of ordinary skill in the art
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`(“POSA”). I have also been informed that the ordinary and customary meaning of
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`a claim term may be determined by reviewing a variety of sources, including the
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`Berkland Decl. IPR2023-00512
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`claims themselves, the specification (or “written description”) of a patent, its
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`prosecution history, and dictionaries and treatises.
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`21.
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`I understand that the patent specification is the single best guide to the
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`meaning of a disputed term. I understand that the intrinsic evidence, namely the
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`patent specification and the prosecution history, may clarify whether the patentee
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`intended a claim term to have a meaning that is different than its ordinary and
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`customary meaning, or clearly disavowed the ordinary meaning in favor of some
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`special meaning. The specification may include a special definition given to a
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`claim term by the patentee that differs from its ordinary meaning. In such cases,
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`the inventor’s lexicography governs.
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`22.
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`I further understand that a patent is a fully integrated written
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`instrument, and a skilled artisan is deemed to read the claim term in the context of
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`both the particular claim where the disputed term appears and the entire patent,
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`including the specification. Accordingly, it is my understanding that the
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`specification is always highly relevant to the claim construction analysis and is the
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`single best guide to the meaning of a disputed term.
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`23.
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`I understand that extrinsic evidence, which includes expert and
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`inventor testimony, dictionaries, and learned treatises, may also be considered
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`during the claim construction process. However, extrinsic evidence is given less
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`Berkland Decl. IPR2023-00512
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`weight than the intrinsic record in determining the meaning of disputed claim
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`terms. I understand that dictionary definitions may reflect or establish the plain
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`and ordinary meaning of claim terms; however, when construing claim terms,
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`reference should also be made to the intrinsic record to determine which dictionary
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`definition(s) are appropriate in light of the use of the claim terms by the inventor.
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`B. Anticipation
`I have been informed by counsel that a patent claim is invalid under
`24.
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`35 U.S.C. § 102 as anticipated if each element of that claim is present either
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`explicitly or inherently in a single prior art reference. I have also been informed
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`that, to be an inherent disclosure, the prior art reference must necessarily disclose
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`the limitation, and the fact that the reference might possibly practice or possibly
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`contain a claimed limitation is insufficient to establish that the reference inherently
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`teaches the limitation. I have also been informed that, to find anticipation, each
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`and every limitation recited in a claim must be found in one item of prior art
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`arranged in the same way as it is claimed. I have also been informed that
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`references that are ambiguous to the presence or description of a particular claim
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`element cannot anticipate a claim. I have also been informed that, for anticipation,
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`a prior art reference must clearly direct those skilled in the art to the claimed
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`Berkland Decl. IPR2023-00512
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`invention without any need for picking, choosing, and combining various
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`disclosures not directly related to each other.
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`C. Obviousness
`I have been informed that a patent claim is unpatentable under 35
`25.
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`U.S.C. § 103 as obvious if the subject matter as a whole would have been obvious
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`to one of ordinary skill in the art at the time the invention was made. I understand
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`that the obviousness analysis involves several factual inquiries: (1) the scope and
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`content of the prior art; (2) the differences between the prior art and the claimed
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`invention; (3) the level of ordinary skill in the art at the time of the invention; and
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`(4) the existence of objective indicia of non-obviousness (“objective indicia”), such
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`as a long-felt but unresolved need, the failure of others, unexpected results, and
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`commercial success. I understand that for objective indicia to be given weight,
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`there must be a nexus between the evidence of objective indicia and the merits of
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`the claimed invention.
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`26.
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`I have been informed that a patent claim is unpatentable as obvious if
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`it is obvious to try. I understand that to establish a claimed invention was obvious
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`to try, a party must establish, at the time of the invention: (1) that there was a
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`recognized problem or need in the art, including a design need or market pressure;
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`(2) that there was a finite number of identified, predictable solutions to the
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`Berkland Decl. IPR2023-00512
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`recognized problem or need; (3) that one of ordinary skill in the art could have
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`pursued these finite, identified, and predictable solutions with a reasonable
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`expectation of success; and (4) whatever additional facts may be necessary, in view
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`of the facts of the case under consideration, to explain a conclusion of obviousness.
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`27.
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`I understand that a petitioner in an IPR bears the burden of proving
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`the obviousness of the claimed invention. My understanding is that obviousness is
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`not proven by mere conclusory statements or conclusory expert testimony.
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`Instead, I understand there must be some articulated reasoning with a rational
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`underpinning to satisfy the legal standard of obviousness. I understand that, for a
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`claim to have been obvious, there must have been some reason or motivation for a
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`POSA to modify or combine the teachings of the prior art references to achieve the
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`claimed invention, and the POSA must have had a reasonable expectation of
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`success in doing so. I have also been informed that it is improper to rely on
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`hindsight reasoning in the obviousness analysis.
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`III. A PERSON OF ORDINARY SKILL IN THE ART
`28. The analysis I provide in this Declaration is from the perspective of a
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`person of ordinary skill in the art of the ’628 patent at the time of the invention. I
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`have been asked to assume a priority date for the claimed invention of the ’628
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`Berkland Decl. IPR2023-00512
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`patent of December 5, 2008.1 No. IPR2023-00512, Petition for Inter Partes
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`Review, Paper No. 1 (“Pet.”), 19.2
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`29. Petitioner’s experts, Drs. Buckton and Batchelor, each put forth
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`identical definitions of a POSA. Ex.1002(Buckton Decl.), ¶17; Ex.1003(Batchelor
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`Decl.), ¶16. They both opine that a POSA as of December 5, 2008 “would have
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`had (1) a Pharm.D., or a Ph.D. in pharmaceutical sciences, chemical engineering,
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`chemistry, or related discipline; and (2) at least two to four years of experience
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`1 I understand that Petitioner contends that the earliest effective filing date of the
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`challenged claims is December 5, 2008, which corresponds to the second of three
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`provisional applications to which the ʼ628 patent claims priority. Pet., 19. For the
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`purposes of this Declaration only, I have applied this date. Adopting a priority
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`date of either of the other two provisional applications or the non-provisional
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`application that issued as the ’628 patent would not affect my opinions.
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`2 For the purpose of this Declaration, I primarily analyze the independent claims of
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`the challenged patent. I understand that where Petitioner fails to demonstrate a
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`reasonable likelihood of prevailing with respect to an independent claim, Petitioner
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`will also fail to demonstrate a reasonable likelihood with respect to the dependent
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`claims that depend from that independent claim.
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`with pharmaceutical design, formulation, development, and/or manufacturing of
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`oral dosage forms.” Ex.1002(Buckton Decl.), ¶17; Ex.1003(Batchelor Decl.), ¶16.
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`I qualify (and have qualified since before the priority dates of the ’628 patent) as a
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`person having at least ordinary skill in the art under this definition. See I.
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`30. For purposes of this Declaration, I do not currently dispute
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`Petitioner’s proposed definition of a POSA. If a trial is instituted, I reserve the
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`right to offer a different POSA definition than proposed by Petitioner and its
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`experts.
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`IV. THE ’628 PATENT
`31. The ’628 patent is directed to “pharmaceutical compositions
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`comprising cytidine analogs,” specifically 5-azacytidine, “for oral administration,
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`wherein the compositions release the cytidine analog…substantially in the
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`stomach” as well as “methods of treating diseases and disorders using the oral
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`formulations provided herein.” Ex.1001(’628 patent), Abstract. The patent
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`includes two independent claims: claim 1 and claim 28. The elements of these
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`claims include a pharmaceutical composition for oral administration comprising a
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`therapeutically effective amount of 5-azacytidine and at least one pharmaceutically
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`acceptable excipient, wherein the composition is a non-enteric coated tablet.
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`Ex.1001(’628 patent), claims 1, 28. The claimed methods are directed toward
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`administering the non-enteric coated 5-azacytidine composition to treat a
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`symptom(s) of myelodysplastic syndrome (MDS) or acute myelogenous leukemia
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`(AML). Ex.1001(’628 patent), claim 28.
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`32.
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`Independent claim 1 of the ’628 patent is reproduced below:
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`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.
`Independent claim 28 of the ’628 patent is reproduced below:
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`33.
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`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.
`V. THE PETITION
`I understand that the Petition attempts to invalidate the following
`34.
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`claims of the ’628 patent: 1, 2, 6-9, 11-28, 32-36, and 38-43. See, e.g., Pet., 6. All
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`of the dependent claims depend directly or indirectly from independent claims 1 or
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`28. Ex.1001(’628 patent), claims 2, 6-9, 11-27, 32-36, and 38-43; Pet., 18.
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`35.
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`It is my understanding that the Petition attempts to invalidate the
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`claims of the ’628 patent for 3 reasons: (1) alleged anticipation based on Ionescu
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`(Ex.1004) (Ground 1); (2) alleged obviousness over Ionescu (Ex.1004) in view of
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`Berkland Decl. IPR2023-00512
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`Atadja (Ex.1005), Gibson (Ex.1006), and the knowledge of a POSA (Ground 2);
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`and (3) alleged obviousness over Ionescu (Ex.1004) in view of Pharmion-PR
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`(Ex.1010), Atadja (Ex.1005), Gibson (Ex.1006), and the knowledge of a POSA
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`(Ground 3). See Pet., 1-3.
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`36.
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`It is also my understanding that the dependent claims recite all of the
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`limitations in the independent claims from which they depend, and then add
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`additional limitations. If the Petition fails to establish that the independent claims
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`are invalid as anticipated and obvious, then the dependent claims also cannot be
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`anticipated or obvious. My analysis in this Declaration therefore focuses on the
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`limitations in the independent claims.
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`VI. REFERENCES CITED IN THE GROUNDS
`Ionescu
`A.
`37.
`Ionescu is a patent reference directed to crystalline structures of 5-
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`azacytidine and “relat[ing] to the isolation of crystalline polymorphic and
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`pseudopolymorphic forms of 5-azacytidine….” Ex.1004-0003(Ionescu), 1:8-10.
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`“It is an object of the present invention [disclosed in Ionescu] to characterize the
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`polymorphic forms of 5-azacytidine.” Ex.1004-0004(Ionescu), 2:7-9.
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`38.
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`Ionescu discloses X-ray powder diffraction patterns for “eight
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`different polymorphic and pseudopolymorphic crystalline forms (Forms I-VIII)” of
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`5-azacytidine. Ex.1004-0004(Ionescu), 2:11-14; -0005-0014, 3:7-12:6; Figs. 1-8.
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`Berkland Decl. IPR2023-00512
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`Ionescu further discloses the existence of an amorphous form of 5-azacytidine and
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`methods for synthesizing several of the disclosed forms. Ex.1004-0004(Ionescu),
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`2:11-14, 2:23-26; -0014, 12:7-12:10; -0017-0024, 15:5-22:26.
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`39. While Ionescu provides a generic, laundry-list disclosure of types of
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`formulations, it does not provide specific details or examples of 5-azacytidine
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`formulations. Ionescu notes that “5-azacytidine may be used in the treatment of
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`disease, including the treatment of myelodysplastic syndromes” (Ex.1004-
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`0003(Ionescu), 1:10-11) and provides a general disclosure of “pharmaceutical
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`compositions comprising the various forms of 5-azacytidine together with one or
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`more pharmaceutically acceptable excipients, diluents, or carriers.” Ex.1004-
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`0002(Ionescu), 2:26-28. Ionescu discloses a generic list of many different types of
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`pharmaceutical formulations without any preference for oral formulations of any
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`kind. Ex.1004-0014-0016(Ionescu), 12:11-14:29; see also Ex.1004-0014(Ionescu),
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`12:17-25 (disclosing pharmaceutical forms “can be in the form of a capsule,
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`sachet, tablet, buccal, lozenge, paper, or other container” or “in the form of tablets,
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`pills, powders, elixirs, suspensions, emulsions, solutions, syrups, capsules…,
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`suppositories, sterile injectable solutions, and sterile packaged powders.”). Ionescu
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`notes that “[i]f coated tablets, capsules, or pulvules are desired, such tablets,
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`capsules, or pulvules may be coated with a concentrated solution of sugar, which
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`may contain gum arabic, gelatin, talc, titanium dioxide, or with a lacquer dissolved
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`in the volatile organic solvent or mixture of solvents” and that “various dyes may
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`be added [to the coating] in order to distinguish among tablets with different active
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`compounds or with different amounts of the active compound present.” Ex.1004-
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`0014-0015(Ionescu) 13:16-21(emphasis added). Separately, without further
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`guidance and without reference to any particular embodiment or formulation,
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`Ionescu discloses that “[t]he compositions of the invention can be formulated so as
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`to provide quick, sustained, controlled, or delayed release of the drug substance
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`after administration to the patient by employing procedures well known in the art.”
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`Ex.1004-0015(Ionescu), 13:7-10.
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`B. Atadja
`40. Atadja “relates to a combination which comprises (a) one or more
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`chemotherapeutic agents and (b) a histone deacetylase inhibitor…especially for use
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`in the treatment of proliferative diseases…in a mammal, particularly a human,”
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`“pharmaceutical compositions comprising such a combination,” “a method of
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`preventing or treating proliferative diseases…with such a combination,” and “a
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`commercial package or product comprising such a combination” and discloses
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`histone deacetylase inhibitors as well as their structures. Ex.1005-0001(Atadja),
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`Abstract; -0010-0023, 9:15-22:5. Atadja states that “[p]referably, the compounds
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`or the pharmaceutically acceptable salts [of the chemotherapeutic agents], are
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`administered as an oral pharmaceutical formulation in the form of a tablet, capsule
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`or syrup; or as parenteral injections if appropriate.” Ex.1005-0028(Atadja), 27:16-
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`18. Atadja also discloses that the phrase “‘chemotherapeutic agent(s)’ is [] broad.”
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`Ex.1005-0003(Atadja), 2:23. Atadja provides a long list of compounds such as
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`aromatase inhibitors, antiestrogens, anti-androgens, gonadorelin agonists,
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`topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents,
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`alkylating agents, antineoplastic antimetabolites, platin compounds, compounds
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`targeting or decreasing a protein or lipid kinase or phosphatase activity, bradykinin
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`1 receptors, angiotensin II antagonists, cyclooxygenase inhibitors, bisphosphonate,
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`rapamycin derivatives, heparanase inhibitors, biological response modifiers,
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`inhibitors which block anti-apoptotic pathways, inhibitors of Ras oncogenic
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`isoforms, farnesyl transferase inhibitors, telomerase inhibitors, protease inhibitors,
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`matrix metalloproteinase inhibitors, methionine aminopeptidase inhibitors, and
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`proteosome inhibitors. Ex.1005-0004(Atadja), 3:1-24; see also Ex.1005-0004-
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`0010(Atadja), 3:25-9:14 (providing examples of chemotherapeutic agents). Atadja
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`refers to 5-azacytidine as only one possible chemotherapeutic option for
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`administration in combination with a histone deacetylase inhibitor. See, e.g.,
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`Ex.1005-0027-0028(Atadja), 26:28-27:16.
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`C. Gibson
`41. Gibson is a general reference textbook. It is “intended to be a
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`practical guide to pharmaceutical preformulation and formulation” that “can be
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`used as a reference source and a guidance tool for those working in the
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`pharmaceutical industry or related industries….” Ex.2042(Gibson Supplemental),
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`1. “Special considerations and issues for the formulation development of each
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`route [of administration] and type of dosage form are discussed” in Gibson.
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`Ex.2042(Gibson Supplemental), 11. According to Gibson, oral solid dosage forms
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`may be sugar-coated through a “multistep process” typically employing “three
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`types of coats: a sealing coat, a subcoat and a smoothing coat.” Ex.1006-
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`0062(Gibson); see also Ex.1006-0063(Gibson) (depicting the “Stages of sugar
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`coating”); VIII.B (reproducing Figure 11.24 of Gibson). Gibson discloses that
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`“[o]ne of the reasons for [sugar] coating tablets is to protect the drug substances
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`from environmental factors such as moisture” and that the sealing coat ensures that
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`coating solutions do not penetrate into the core. Ex.1006-0063(Gibson). Gibson
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`discloses enteric coated tablets as well as non-enteric coated tablets. See, e.g.,
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`Ex.1006-0068(Gibson). Gibson also explicitly notes that sugar-coated tablets may
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`be enterically coated. Ex.1006-0070(Gibson) (“The original enteric coating
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`material [shellac], originally used in sugar-coated tablets.”). In fact, Gibson
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`discloses that “[t]he most common type of modified release coating is the enteric
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`coat that is designed to prevent release of the drug substance in the stomach
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`because the drug is either irritant to the gastric mucosa or it is unstable in the
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`gastric juice.” Ex.1006-0068(Gibson) (emphasis added). Gibson does not
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`mention 5-azacytidine or any treatment of MDS or AML.
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`Pharmion-PR
`D.
`42. Pharmion-PR is a press release. I understand that Pharmion was the
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`predecessor to Patent Owner and original employer of the inventors of the ’628
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`patent. Pharmion-PR discloses an overview of results from a “study…designed to
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`assess the safety, tolerability, and pharmacokinetics of escalating single doses of
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`orally administered Azacitidine in patients with Myelodysplastic Syndromes
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`(MDS), acute myeloid leukemia (AML), or other solid tumors.”3 Ex.1010-
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`0005(Pharmion-PR). The study ended, and a subsequent “multi-dose escalating
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`study of oral azacitidine [was then] underway.” Ex.1010-0005(Pharmion-PR).
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`Pharmion-PR does not disclose the formulation of 5-azacytidine employed in
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`either study.
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`3 “5-azacytidin