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 CORY BERKLAND, PH.D.
`
`CELGENE 2051
`APOTEX v. CELGENE
`IPR2023-00512
`
`

`

`TABLE OF CONTENTS
`
`
`
`I.
`
`II.
`
`INTRODUCTION AND BACKGROUND .................................................... 1
`A. Qualifications and Experience .............................................................. 1
`B.
`Compensation ........................................................................................ 5
`LEGAL PRINCIPLES ..................................................................................... 5
`A.
`Claim Construction................................................................................ 6
`B.
`Anticipation ........................................................................................... 8
`C.
`Obviousness ........................................................................................... 8
`PERSON OF ORDINARY SKILL IN THE ART ........................................10
`III.
`IV. BASIS OF OPINIONS ..................................................................................11
`V.
`BACKGROUND ...........................................................................................11
`A. Acute Myeloid Leukemia (AML) and Myelodysplastic
`Syndrome (MDS) ................................................................................11
`5-Azacytidine ......................................................................................12
`B.
`Development History of 5-Azacytidine ..............................................13
`C.
`Injectable 5-Azacytidine .....................................................................19
`D.
`Oral 5-Azacytidine ..............................................................................20
`E.
`VI. THE ’628 PATENT .......................................................................................22
`A.
`The Invention of Orally-Administered 5-Azacytidine ........................22
`B.
`Non-Enterically Coated Formulations ................................................23
`C.
`Specification ........................................................................................24
`D.
`Prosecution History .............................................................................25
`E.
`Claims ..................................................................................................26
`VII. THE PETITION .............................................................................................29
`VIII. THE ASSERTED REFERENCES ................................................................30
`A.
`Ionescu (Ex.1004) ...............................................................................30
`B.
`Atadja (Ex.1005) .................................................................................31
`C.
`Gibson (Ex.1006) ................................................................................32
`
`
`
`i
`
`

`

`
`
`2.
`
`2.
`
`B.
`
`D.
`Pharmion-PR (Ex.1010) ......................................................................35
`IX. SUMMARY OF OPINIONS .........................................................................36
`X.
`THE ’628 PATENT CLAIMS ARE NOT ANTICIPATED BY
`IONESCU (GROUND 1) ..............................................................................37
`A.
`Petitioner Failed to Show that Ionescu Discloses a Non-Enteric
`Coated Tablet as Required by All of The Claims Challenged in
`Ground 1 ..............................................................................................37
`1.
`Ionescu’s sugar-coated tablets do not disclose a “non-
`enteric coated tablet.” ................................................................37
`A POSA in December 2008 would at most have
`understood that, to the extent any 5-azacytidine tablets
`were coated with sugar, such tablets would be enterically
`coated ........................................................................................44
`Ionescu Fails to Disclose a Film Coated Tablet as Required by
`Claims 14 and 15 Challenged in Ground 1 .........................................45
`Ionescu Is Not Enabling ......................................................................45
`C.
`XI. THE ’628 PATENT CLAIMS ARE NOT OBVIOUS IN VIEW OF
`IONESCU IN COMBINATION WITH ATADJA AND GIBSON
`AND THE KNOWLEDGE OF A POSA (GROUND 2) ..............................48
`A. A POSA Would Not Have Been Motivated to Pursue and Select
`an Oral, Non-Enteric Coated Tablet of 5-Azacytidine .......................48
`1.
`A POSA would not select a non-enteric coated tablet as
`the “default” choice for 5-azacytidine ......................................48
`Disclosures of “liquid formulations” would not have
`assuaged a POSA’s concerns over 5-azacytidine’s
`stability ......................................................................................53
`3. When read as a whole, a POSA would not credit Ionescu
`or Atadja as disclosing or relating to therapeutically
`effective oral formulations of 5-azacytidine .............................54
`Petitioner Has Failed to Establish a Reasonable Expectation of
`Success ................................................................................................57
`1.
`Given the well-established instability of 5-azacytidine, a
`POSA would have had no reasonable expectation that a
`ii
`
`B.
`
`
`
`

`

`
`
`2.
`
`3.
`
`non-enteric coated tablet formulation would have been
`therapeutically effective ............................................................57
`Preliminary bioavailability data for unknown oral
`formulations does not provide a reasonable expectation
`that a non-enteric coated tablet formulation of 5-
`azacytidine would be therapeutically effective .........................59
`The claims are not obvious to try because a non-enteric
`coated tablet formulation would not have been a
`predictable solution for 5-azacytidine .......................................60
`Ionescu, Atadja, Gibson, and Knowledge of a POSA Do Not
`Render Obvious Claims 6, 7, or 32. ....................................................61
`Ionescu, Atadja, Gibson, and Knowledge of a POSA Do Not
`Render Obvious the Dose Values Recited by Claims 9, 24, 25,
`26, 27, and 36 ......................................................................................63
`XII. THE ’628 PATENT CLAIMS ARE NOT OBVIOUS IN VIEW OF
`IONESCU IN VIEW OF PHARMION-PR, ATADJA AND GIBSON
`AND THE KNOWLEDGE OF A POSA (GROUND 3) ..............................66
`XIII. OBJECTIVE INDICIA SUPPORT NON-OBVIOUSNESS OF THE
`CLAIMS ........................................................................................................66
`A.
`The Field Was Skeptical of A Non-Enteric Coated, Oral 5-
`Azacytidine Tablet ..............................................................................67
`Unexpected Results .............................................................................69
`B.
`Long-Felt, Unmet Need .......................................................................71
`C.
`The Medical Industry Praised Onureg® .............................................72
`D.
`Nexus ...................................................................................................72
`E.
`XIV. AVAILABILITY FOR CROSS-EXAMINATION ......................................78
`XV. RIGHT TO SUPPLEMENT ..........................................................................79
`XVI. JURAT ...........................................................................................................80
`
`
`C.
`
`D.
`
`
`
`iii
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`I, Cory Berkland, 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. Qualifications and Experience
`I am currently a Professor of Pharmaceutical Chemistry and a
`3.
`
`Professor of Chemical and Petroleum Engineering at The University of Kansas. I
`
`also have an appointment as a courtesy professor in the Chemistry Department at
`
`The University of Kansas. I also assisted in designing the BioEngineering
`
`graduate program at The University of Kansas, and I am the former director of the
`
`Biomolecular Engineering track within the BioEngineering program.
`
`4.
`
`I teach courses to undergraduate and graduate students at The
`
`University of Kansas on, among other things, pharmaceutical formulation
`
`(including solid oral dosage forms), drug delivery, dissolution methods, and
`
`modeling dissolution profiles.
`
`
`
`1
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`5.
`
`I received a Doctor of Philosophy degree from the University of
`
`Illinois in 2003 and a Master of Science degree from the University of Illinois in
`
`2001, both from the Department of Chemical and Biomolecular Engineering. I
`
`received a Bachelor of Science degree in Chemical Engineering from Iowa State
`
`University in 1998.
`
`6.
`
`I have worked in the area of pharmaceutical formulation for over 20
`
`years. A significant portion of my career has been dedicated to the study of
`
`formulating therapeutics for delivery to patients. I currently research the design of
`
`molecules and materials specialized for a particular disease and targeted drug
`
`delivery to maximize their therapeutic effect while limiting side-effects. I have
`
`extensive experience in the area of pharmaceutical delivery design including
`
`preformulation, formulation, analysis, and related theories.
`
`7.
`
`I have published over 200 peer-reviewed papers, and I have presented
`
`my research at many national and international research conferences and to
`
`companies, including more than 75 invited talks. I have also given distinguished
`
`lectures such as the Nagai Foundation Distinguished Lectureship in Japan and a
`
`lectureship at the Center of Excellence in Nanotechnology at the Massachusetts
`
`Institute of Technology. I also serve or have served on the editorial advisory board
`
`for a number of peer-reviewed journals: Therapeutic Delivery, The Journal of
`
`Pharmaceutical Sciences, and The Journal of Pharmaceutical Innovation. I also
`
`
`
`2
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`serve or have served on advisory boards for the Center for Cancer Engineering at
`
`The Ohio State University, the Drug Discovery and Development of Experimental
`
`Therapeutics program, and the National Institutes of Health Pharmaceutical
`
`Aspects of Biotechnology training grant program at The University of Kansas.
`
`8.
`
`I have received funding for my research from the National Institutes
`
`of Health including the National Cancer Institute, the National Science Foundation,
`
`the Department of Defense, the Defense Threat Reduction Agency, the PhRMA
`
`Foundation, the Coulter Foundation, the American Heart Association, the Cystic
`
`Fibrosis Foundation, the Juvenile Diabetes Research Foundation, several other
`
`philanthropic organizations, and multiple pharmaceutical companies.
`
`9.
`
`Over the years I have been an active participant in a number of
`
`professional societies including the American Institute of Chemical Engineers, the
`
`Controlled Release Society, the American Chemical Society, and the American
`
`Association of Pharmaceutical Scientists. I have also been elected Fellow of the
`
`American Institute for Medical and Biological Engineering and was elected to the
`
`National Academy of Inventors.
`
`10.
`
`I have received numerous awards in recognition of my research,
`
`including the Controlled Release Society Young Investigator Award and the
`
`Coulter Translational Research Award. At the University of Kansas, I have
`
`received major research awards such as the University Scholarly Achievement
`
`
`
`3
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`Award, the Jim Baxendale Commercialization Award, the Leading Light Award,
`
`and the Miller Professional Development Award for Research, and I was named a
`
`Bellows Scholar in the School of Engineering at The University of Kansas. I have
`
`also received the W.T. Kemper Fellowship for teaching excellence at The
`
`University of Kansas.
`
`11.
`
`I have been granted multiple patents and have co-founded seven
`
`companies: Bond Biosciences, Exodus Biosciences, Orbis Biosciences (acquired
`
`by Adare Pharmaceuticals), Kinimmune, Orion BioScience, Axioforce, and Savara
`
`Pharmaceuticals. I have held executive positions at each of these companies. I am
`
`currently the Chief Executive Officer and Chairman of the Board of Directors at
`
`Bond Biosciences. I am also currently the Chief Executive Officer and Chairman
`
`of the Board of Directors at Kinimmune.
`
`12.
`
`I have worked as a consultant in the pharmaceutical industry
`
`providing formulation advice to multiple major pharmaceutical and biotechnology
`
`companies. I also worked at a biotechnology investment firm, Sofinnova
`
`Ventures, during a six-month sabbatical in 2014.
`
`13. Overall, I have about 20 years of experience designing therapeutic
`
`formulations and testing their release profiles. In my work described above, I have
`
`performed formulation delivery testing many times on oral solid dosage forms, for
`
`example, tablets, powders, capsules, and suspensions. I have performed analysis
`
`
`
`4
`
`

`

`Berkland Decl. IPR2023-00512
`
`of release profiles for delivery of therapeutics, for example, in my research work at
`
`The University of Kansas. This includes analysis of both controlled and immediate
`
`release formulations.
`
`14.
`
`I have conducted many comparative dissolution studies in my work
`
`described above. Much of this work has been optimizing formulations for either
`
`immediate or extended release, for example, in my work consulting for
`
`pharmaceutical companies in connection with FDA filings for pharmaceutical
`
`products and in my research.
`
`15.
`
`I have, on many occasions, designed and optimized solid oral dosage
`
`forms, including tablets, powders, capsules, and suspensions, for example, in my
`
`work at Orbis Biosciences.
`
`16. My curriculum vitae, which lists my professional experience and
`
`qualifications in greater detail, is attached hereto as Appendix A.
`
`B. Compensation
`
`17.
`
`I am being compensated at my normal consulting rate for my work,
`
`which is $750 per hour. My compensation is not dependent on the outcome of this
`
`matter, and it in no way affects the substance of my opinions in this Declaration.
`
`II. LEGAL PRINCIPLES
`
`18. The opinions I express in this Declaration involve the application of
`
`my technical knowledge and professional experience to the evaluation of certain
`
`
`
`5
`
`

`

`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
`
`Berkland Decl. IPR2023-00512
`
`
`(“counsel”).
`
`A. Claim Construction
`19. For the purposes of this Declaration, I understand that certain
`
`principles of law are relevant to my analysis and opinions. For example, I
`
`understand that before a patent validity determination can be made, the claims
`
`must be construed by the Board.
`
`20.
`
`I understand that in an Inter Partes Review (“IPR”), the Board
`
`construes claim terms in light of the specification of the patent in which they
`
`appear. I further understand that a claim construction analysis begins with the
`
`ordinary meaning of the disputed claim term, and there is a presumption that claim
`
`terms carry their accustomed meaning to a person of ordinary skill in the art
`
`(“POSA”). I have also been informed that the ordinary and customary meaning of
`
`a claim term may be determined by reviewing a variety of sources, including the
`
`claims themselves, the specification (or “written description”) of a patent, its
`
`prosecution history, and dictionaries and treatises.
`
`21.
`
`I understand that the patent specification is the single best guide to the
`
`meaning of a disputed term. I understand that the intrinsic evidence, namely the
`
`patent specification and the prosecution history, may clarify whether the patentee
`
`
`
`6
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`intended a claim term to have a meaning that is different than its ordinary and
`
`customary meaning, or clearly disavowed the ordinary meaning in favor of some
`
`special meaning. The specification may include a special definition given to a
`
`claim term by the patentee that differs from its ordinary meaning. In such cases,
`
`the inventor’s lexicography governs.
`
`22.
`
`I further understand that a patent is a fully integrated written
`
`instrument, and a skilled artisan is deemed to read the claim term in the context of
`
`both the particular claim where the disputed term appears and the entire patent,
`
`including the specification. Accordingly, it is my understanding that the
`
`specification is always highly relevant to the claim construction analysis and is the
`
`single best guide to the meaning of a disputed term.
`
`23.
`
`I understand that extrinsic evidence, which includes expert and
`
`inventor testimony, dictionaries, and learned treatises, may also be considered
`
`during the claim construction process. However, extrinsic evidence is given less
`
`weight than the intrinsic record in determining the meaning of disputed claim
`
`terms. I understand that dictionary definitions may reflect or establish the plain
`
`and ordinary meaning of claim terms; however, when construing claim terms,
`
`reference should also be made to the intrinsic record to determine which dictionary
`
`definition(s) are appropriate in light of the use of the claim terms by the inventor.
`
`
`
`
`
`7
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`B. Anticipation
`I have been informed by counsel that a patent claim is invalid under
`24.
`
`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
`
`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.
`
`C. Obviousness
`I have been informed that a patent claim is unpatentable under 35
`25.
`
`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
`
`
`
`8
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`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, the failure of others, unexpected 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.
`
`26.
`
`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.
`
`27.
`
`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
`
`
`
`9
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`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
`
`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
`28. 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
`
`
`
`
`
`10
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`IV. BASIS OF OPINIONS
`In forming my opinions set forth in this Declaration, I have considered
`29.
`
`and relied on my education and experience in the fields of pharmaceutical design,
`
`formulation, development, and manufacturing of oral dosage forms. I have also
`
`relied on the materials listed in Appendix B and on a conversation with Dr. Jeffrey
`
`Etter, a conversation with Dr. William Blum, and a conversation with Dr. George
`
`Grass.
`
`V. BACKGROUND
`
`A. Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome
`(MDS)
`I spoke with Dr. Blum, a clinician who treats patients with AML and
`
`30.
`
`MDS, and I have read his declaration (Ex.2053). As described in the ’628 patent, I
`
`understand that acute myeloid leukemia (AML) and myelodysplastic syndrome
`
`(MDS) are disorders that impact blood cells. Ex.1001(’628 patent), 1:39-64. I
`
`understand that AML and MDS are serious conditions that often result in patient
`
`death. Dr. Blum explained that as of December 2008, the FDA had only approved
`
`
`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.
`
`
`
`11
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`

`

`Berkland Decl. IPR2023-00512
`
`
`one oral therapy to treat MDS and no oral or maintenance therapies for AML.
`
`Ex.2053(Blum Decl.), ¶13.
`
`B.
`31.
`
`5-Azacytidine
`I have spoken with one of the inventors of the ’628 patent, Dr. Jeff
`
`Etter, who worked on developing a therapeutically effective oral formulation of 5-
`
`azacytidine and I have read his declaration (Ex.2054). As described in the ’628
`
`patent, I understand 5-azacytidine is a nucleoside similar to the endogenous
`
`nucleoside cytidine, but it possesses a nitrogen atom in place of a carbon atom,
`
`which is highlighted in the structure below. Ex.1001(’628 patent), 2:37-62.
`
`
`
`Ex.1001(’628 patent), 2:48-62. Once 5-azacytidine of is administered, the cancer
`
`cells incorporate the 5-azacytidine into DNA and RNA. Ex.1001(’628 patent),
`
`3:9-27. I understand that upon incorporation, 5-azacytidine “restor[es] normal
`
`functions” by promoting “re-expression of genes involved in normal cell cycle
`
`regulation, differentiation and death” leading to “the death of rapidly dividing
`
`cells, including cancer cells….” Ex.1001(’628 patent), 3:9-27.
`
`
`
`
`
`12
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`

`

`Berkland Decl. IPR2023-00512
`
`
`C. Development History of 5-Azacytidine
`32. The below figure is a timeline spanning the forty-year period between
`
`the synthesis of 5-azacytidine and the development of a therapeutically effective
`
`non-enteric tablet formulation of 5-azacytidine claimed in the ’628 patent. Pink-
`
`colored entries represent publications (e.g., patent applications, peer-reviewed
`
`publications, and the FDA-approved package insert for Vidaza®) that disclose that
`
`5-azacytidine is unstable (e.g., due to hydrolysis and/or enzymatic metabolism).
`
`
`
`
`
`
`
`13
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`Stoltz; Ex.1034
`
`2006
`
`Mund; Ex.2022
`
`2006
`
`Kornblith; Ex.2092
`
`2002
`
`Aparicio; Ex.2003
`
`2002
`
`Pharmion-PR; Ex.1010
`
`2007 
`
`Gibson; Ex.1010
`
`2001
`
`Gaubert; Ex.2017
`
`2000
`
`Surbone; Ex.2121
`
`1990
`
`IARC; Ex.1042
`
`1990
`
`Kissinger; Ex.2019
`
`1986
`
`Convey; Ex.2074
`
`1986
`
`Connors; Ex.2014
`
`1986
`
`Dover; Ex.1031
`
`1985 
`
`Desimone; Ex.2077
`
`1985 
`
`Zielinski; Ex.2131
`
`1984
`
`Cheung; Ex.2011
`
`1984
`
`Disclosures of enteric-coated tablet formula�ons
`Documents characterized by Pe��oner or Board as disclosing an a�empted oral formula�on
`Disclosures of instability (e.g., hydrolysis and/or enzyma�c metabolism)
`
`Chen; Ex.2010
`
`2008
`
`Stresemann; Ex.2029
`
`2008
`
`US2008/0057086; Ex.1026
`WO2008/028193; Ex.2041
`
`2008 
`
`’875 Provisional; Ex.1050
`
`December 2008
`
`2000
`
`1990
`
`Atadja; Ex.1005
`
`2004
`
`Ionescu; Ex.1004
`
`2004
`
`Sands; Ex.1021
`
`2004 
`
`VidazaApproval; Ex.1007
`
`2004
`
`WO2004/082618; Ex.2044
`
`2004
`
`Kaminskas; Ex.2018
`
`2005
`
`Ben-Kasus; Ex.2070
`
`2005
`
`1980
`
`Glover; Ex.2034
`
`1987
`
`1987
`Dunbar; Ex.2079
`
`1989 
`
`Antonsson; Ex.2066
`
`Lin; Ex.2021
`
`1981
`Chan; Ex.1014
`
`1979
`NCI; Ex.2061
`
`1978
`
`Fu�erman; Ex.2083
`
`1978
`
`Beisler; Ex.2004
`
`1977
`
`Von Hoff; Ex.2128
`
`1976
`
`VoglerII; Ex.2127
`
`1976
`
`Vorbruggen; Ex.1016
`
`1974
`Weiss; Ex.2031
`
`1972
`
`1970
`
`1960
`
`McCredie; Ex.2100
`
`1973
`
`Karon; Ex.2090
`
`1973
`
`Chabner; Ex.2009
`
`1973
`
`Neil; Ex.2101
`
`1975 
`
`Notari; Ex.2024
`
`1975
`
`VoglerI; Ex.2126
`
`1975
`
`14
`
`Pískala; Ex.1024
`Synthesis of 5-Aza
`
`1964
`
`
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`33. Researchers were interested in 5-azacytidine as an anti-cancer
`
`pharmaceutical since it was first synthesized in 1964. Ex.1024(Pı´skala).
`
`Researchers immediately recognized 5-azacytidine had the ability to halt the
`
`spread or development of cancer cells and began studying the compound’s
`
`properties. See Ex.2116(Sorm); Ex.2012(Čihák); Ex.2027(Piťhová);
`
`Ex.2085(Goldin). By the 1970s, researchers began administering 5-azacytidine to
`
`patients as injectable formulations in clinical trials. Ex.2128(VonHoff), 237; see
`
`also Ex.2088(Hrodek); Ex.2112(Shnider); Ex.2096(Lomen); Ex.2100(McCredie)
`
`(describing clinical trials of intravenous or subcutaneous formulations throughout
`
`the 1970s).
`
`34.
`
`In 2008 a POSA would have understood that 5-azacytidine is not
`
`stable and rapidly breaks down when exposed to water. Because in vitro studies
`
`showed that 5-azaytidine was rapidly hydrolyzed, in clinical trials the drug had to
`
`be administered shortly after reconstitution:
`
`• Ex.2128(VonHoff), 238, 239-240 (disclosing administering injections
`
`“within 30 min[utes]” of reconstitution because 5-azacytidine in “solution
`
`hydrolyzes at room temperature”), Table 1;
`
`• Ex.2031(Weiss), 413-414 (reporting that 5-azacytidine needs to be “given
`
`immediately” intravenously after being dissolved in solution), 418;
`
`
`
`15
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`• Ex.2090(Karon) (disclosing 5-azacytidine should be injected “within 15
`
`min[utes] of reconstitution since the drug begins to decompose in aqueous
`
`solution within 1 h[ou]r”);
`
`• Ex.2100(McCredie) (disclosing intravenous administration “immediately”
`
`after reconstitution in solution);
`
`• Ex.2127(VoglerII) (disclosing that without using a specially formulated
`
`solution 5-azacytidine “must be given by rapid intravenous infusion because
`
`of its instability”).
`
`35.
`
`In addition to hydrolytic degradation, 5-azacytidine is broken down by
`
`an enzyme called “cytidine deaminase,” which renders the drug ineffective.
`
`Researchers measured the rate of enzymatic deamination of 5-azacytidine and
`
`concluded that it also “may compromise the effectiveness of 5-azacytidine in
`
`treating human leukemia.” Ex.2009(Chabner), 2763, 2765.
`
`36. By the end of the 1970s, researchers understood 5-azacytidine’s
`
`instability to limit its bioavailability and clinical use. See, e.g., Ex.1014(Chan),
`
`807 (5-Azacytidine “has long been known to be unstable in aqueous solution…
`
`attributed to [its] facile hydrolytic cleavage,” and “[c]onsequently, proper
`
`formulation has been a problem in its clinical use.”); Ex.2024(Notari), 1157
`
`(concluding that the “apparent instability of 5-azacytidine suggests that it would be
`
`prudent to prepare solutions shortly before use to avoid significant degradation”).
`
`
`
`16
`
`

`

`37. Early attempts to develop oral formulations were unsuccessful. The
`
`Berkland Decl. IPR2023-00512
`
`
`difficulty in orally administering 5-azacytidine led researchers to suggest
`
`alternative strategies such as “the use of prodrugs to modify chemical and
`
`enzymatic instability, and/or the use of enzymatic inhibitors.”
`
`Ex.2041(WO2008/028193), ¶¶[0007], [0008]-[0011]. These strategies had limited
`
`success. Researchers found that administering 5-azacytidine solutions by oral
`
`intubation to mice resulted in “much lower” blood levels of the drug than when
`
`injected. Ex.2101(Neil), 463, 464. Researchers did not see any increase in
`
`hemoglobin production in baboons receiving oral 5-azacytidine concluding that
`
`“only a fraction of the administered amount [wa]s available” potentially because 5-
`
`azacytidine “is rapidly deaminated… by cytidine deaminase….”
`
`Ex.2077(DeSimone), 285, 283-284. Researchers working on sickle cell anemia
`
`saw no effect when oral 5-azacytidine was given alone, instead only seeing an
`
`increase in F reticulocyte production if given with tetrahydrouridine.
`
`Ex.1031(Dover), Abstract, 528. Additionally, even when administered to β-
`
`thalassemia patients with a cytidine deaminase inhibitor, 5-azacytidine “was
`
`ineffective.” Ex.2079(Dunbar), 467.
`
`38. Researchers in the 1980s continued to perform experiments and
`
`recognize a “major problem encountered in the clinical formulation of 5-
`
`azacytidine is its chemical instability….” Ex.2021(Lin), 1229. By 1986, some
`
`
`
`17
`
`

`

`Berkland Decl. IPR2023-00512
`
`
`considered abandoning 5-azacytidine in favor of searching for alternatives
`
`chemotherapeutics. Ex.2074(Covey). A 1987 review of 5-azacitidine researchers
`
`from the NIH stated that there was no “definitive roll” for 5-azacytidine in treating
`
`leukemias due to its chemical instability in solution and enzymatic degradation.
`
`Ex.2034(Glover), 742.
`
`39. That is, from the 1970s through the 1990s, researchers and clinicians
`
`routinely reported that 5-azacytidine was unstable. In addition to the discussion
`
`above, exemplary disclosures of 5-azacytidine’s instability from this period are
`
`provided below:
`
`“The instability of azacitidine in the aqueous solutions studied
`•
`suggests that the drug should be administered [by injection] immediately
`after preparation….” Ex.2011(Cheung), 1159.
`
`“In aqueous solutions 5-azacytidine decomposes rapidly….”
`•
`Ex.2131(Zielinski), 5029.
`
`5-azacytidine’s “triazine ring is highly susceptible to