UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__
`
`APOTEX INC.,
`Petitioner
`
`v.
`
`CELLGENE CORPORATION,
`Patent Owner
`__
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case IPR2023-00512
`U.S. Patent No. 8,846,628
`Issued: September 30, 2014
`
`Title:
`ORAL FORMULATIONS OF CYTIDINE ANALOGS AND METHODS OF USE THEREOF
`
`DECLARATION OF GRAHAM BUCKTON, Ph.D.
`
`
`
`
`
`
`
`By:
`
`
`
`
`
`February 10, 2023
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0001
`
`

`

`TABLE OF CONTENTS
`
` 
`
`Page
`INTRODUCTION ......................................................................................... 1 
`I. 
`II.  QUALIFICATIONS ...................................................................................... 2 
`III.  APPLICABLE STANDARDS ...................................................................... 5 
`A. 
`Person of Ordinary Skill in the Art ....................................................... 5 
`B. 
`Patent Priority Date / Earliest Effective Filing Date ............................. 7 
`C. 
`Claim Construction ............................................................................... 9 
`D. 
`Invalidity ............................................................................................. 10 
`Anticipation ............................................................................... 10 
`Obviousness .............................................................................. 11 
` 
`IV.  DOCUMENTS ............................................................................................. 13 
`V. 
`SUMMARY OF OPINIONS ....................................................................... 17 
`VI.  BACKGROUND AND STATE OF THE ART ........................................ 17 
`A.  Knowledge in the Prior Art Would Have Led a POSA to the
`Claimed Invention ............................................................................... 17 
`5-Azacytidine Was a Long-Known Therapeutic
`Compound for Treating One or More Symptoms of a
`Disease Associated With Abnormal Cell Proliferation
`Such As Myelodysplastic Syndrome and Acute
`Myelogenous Leukemia ............................................................ 17 
`Oral Administration of 5-Azacytidine Was Known and
`Preferred at the Time of Invention ............................................ 19 
`Non-enteric Coated (Non-EC) Tablets of 5-Azacytidine
`Were Known and Preferred ...................................................... 23 
`It Would Have Been Routine to Use Well-Known and
`Conventional In Silico Modeling to Determine the
`Pharmacokinetics of Oral 5-Azacytidine Dosage Forms .......... 27 
`
` 
`
`- i -
`
` 
`
` 
`
` 
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0002
`
`

`

` 
`
` 
`
` 
`
` 
`
` 
`
`B. 
`
`The ’628 Patent ................................................................................... 30 
`The Specification ...................................................................... 30 
`The Prosecution History ........................................................... 31 
`The Challenged Claims ............................................................. 34 
`Priority Date / Earliest Effective Filing Date of the
`Challenged Claims .................................................................... 35 
`Claim Construction ............................................................................. 37 
`C. 
`VII.  CLAIMS 1, 2, 6-9, 11-28, 32-36, AND 38-43 OF THE ʼ628
`PATENT ARE UNPATENTABLE ............................................................ 39 
`A.  Ground 1: Claims 1, 2, 6-8, 11, 13-18, 20-23, 28, 32-35, 38, 40,
`42, and 43 Are Anticipated by Ionescu ............................................... 39 
`Independent Claims 1 and 28: Ionescu Discloses Non-EC
`Tablets of 5-Azacytidine to Treat One or More
`Symptoms of a Disease Associated With Abnormal Cell
`Proliferation Such as MDS ....................................................... 39 
`a. 
`[1a] “A pharmaceutical composition for oral
`administration comprising” ............................................ 40 
`[1b] “a therapeutically effective amount of 5-
`azacytidine” .................................................................... 40 
`[1c] “at least one pharmaceutically acceptable
`excipient” ........................................................................ 41 
`[1d] “wherein the composition is a non-enteric
`coated tablet” .................................................................. 41 
`Claim 28 .......................................................................... 42 
`e. 
`Dependent Claims 2, 6, 7, 13-15, 32, and 34 Reciting
`Formulation Limitations: Ionescu Discloses a Sugar-
`Coated Tablet of 5-Azacytidine Comprising Mannitol,
`Microcrystalline Cellulose, Crospovidone, and
`Magnesium Stearate .................................................................. 43 
`
`b. 
`
`c. 
`
`d. 
`
` 
`
`- ii -
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0003
`
`

`

`a. 
`
`c. 
`
`b. 
`
`c. 
`
`b. 
`
`Dependent Claims 2 and 34 Reciting
`Pharmaceutically Acceptable Excipients ....................... 43 
`Dependent Claims 6, 7, and 32 Reciting
`“Essentially Free” of Cytidine Deaminase
`Inhibitor, Like THU ........................................................ 44 
`Dependent Claims 13-15 Reciting Film Coatings
`Like HPMC, HPC, or MC .............................................. 45 
`Dependent Claims 8, 16, 17, 23, 33, and 35 Reciting
`Dosage Limitations: Ionescu Discloses Tablets
`Containing “About 5 mg to 200 mg, More Usually About
`100 mg” of 5-Azacytidine ......................................................... 46 
`a. 
`Dependent Claims 8, 16, 17, and 35 Reciting
`Various Dosage Amounts ............................................... 47 
`Dependent Claim 23 Reciting Dosage Amount of
`“120 to 480 mg”.............................................................. 47 
`Dependent Claim 33 Reciting a “Single Unit
`Dosage Form” ................................................................. 49 
`Dependent Claims 11, 18, 20-22, 38, 40, 42, and 43:
`Ionescu Inherently Discloses the Claimed PK Properties
`(AUC, Cmax, and Tmax) ............................................................... 49 
`Ground 2: Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 Would
`Have Been Obvious Over Ionescu in View of Atadja, Gibson,
`and the Knowledge of a POSA ........................................................... 52 
`Independent Claims 1 and 28 Would Have Been Obvious ...... 52 
`a. 
`A POSA Would Have Been Motivated to Pursue
`an Oral, Non-EC Tablet of 5-Azacytidine ...................... 53 
`i. 
`A POSA Would Have Been Motivated to Pursue
`and Select an Oral Dosage Form of 5-Azacytidine
`From the Dosage Forms Ionescu .......................... 53 
`
` 
`
` 
`
` 
`
`B. 
`
`- iii -
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0004
`
`

`

`ii. 
`
`b. 
`
`A POSA Would Have Been Motivated to Pursue
`and Select a Non-EC Tablet of 5-Azacytidine
`From the Oral Dosage Forms of Ionescu ............. 59 
`A POSA Would Have Had a Reasonable
`Expectation of Arriving at the Claimed
`Compositions and Methods of Treatment ...................... 62 
`Dependent Claims 2, 6, 7, 13-15, 32, and 34 Reciting
`Formulation Limitations Would Have Been Obvious .............. 63 
`a. 
`Dependent Claims 2 and 34 Reciting
`Pharmaceutically Acceptable Excipients ....................... 63 
`Dependent Claims 6, 7, and 32 Reciting
`“Essentially Free” of Cytidine Deaminase
`Inhibitor, Like THU ........................................................ 64 
`Dependent Claims 13-15 Reciting Film Coatings
`Like HPMC, HPC, or MC .............................................. 66 
`A POSA Would Have Had a Reasonable
`Expectation of Arriving at Claims 2, 6, 7, 13-15,
`32, and 34 ........................................................................ 69 
`Dependent Claims 8, 9, 16, 17, 23-27, 33, 35, and 36
`Reciting Dosage Limitations Would Have Been Obvious ....... 70 
`a. 
`Dependent Claims 8, 9, 16, 17, 23-27, 33, 35, and
`36 Reciting Various Dosage Amounts ........................... 70 
`Dependent Claim 33 Reciting a “Single Unit
`Dosage Form” ................................................................. 74 
`A POSA Would Have Had a Reasonable
`Expectation of Arriving at Claims 8, 9, 16, 17, 23-
`27, 33, 35, and 36 ........................................................... 76 
`Dependent Claims 11, 12, 18-22, and 38-43 Reciting PK
`Limitations Would Have Been Obvious ................................... 77 
`
`b. 
`
`c. 
`
`d. 
`
`b. 
`
`c. 
`
` 
`
` 
`
` 
`
`- iv -
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0005
`
`

`

` 
`
`C. 
`
`Patent Owner Failed to Show Unexpected Results
`Sufficient to Rebut the Strong Showing of Obviousness
`of Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 ............................ 82 
`Ground 3: Claims 1, 2, 6-9, 11-28, 32-36, and 38-43 Would
`Have Been Obvious Over Ionescu in View of Pharmion-PR,
`Atadja, Gibson, and the Knowledge of a POSA ................................. 89 
`VIII.  CONCLUSION ............................................................................................ 93 
`
`
`
`- v -
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0006
`
`

`

`
`
`I, Graham Buckton, Ph.D., of London, UK, declare as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I have been asked by counsel for Apotex Inc. (“Petitioner”) to
`
`investigate and provide opinions relating to the validity/patentability of certain
`
`claims of U.S. Patent No. 8,846,628 (“ʼ628 patent”) (EX-1001, ʼ628 patent) for the
`
`above-captioned inter partes review (“IPR”). The ʼ628 patent is generally directed
`
`to non-enteric coated (“non-EC”) tablets of 5-azacytidine and methods of treatment
`
`of certain cancers using such tablets. (EX-1001, ʼ628 patent at Abstract, claims.)
`
`2.
`
`I understand that Petitioner petitions for IPR of Claims 1, 2, 6-9, 11-
`
`28, 32-36, and 38-43 of the ʼ628 patent and requests that the United States Patent
`
`and Trademark Office (“USPTO”) cancel Claims 1, 2, 6-9, 11-28, 32-36, and 38-
`
`43 of the ʼ628 patent. I further understand that Celgene Corporation (“Patent
`
`Owner”) purports to own the ʼ628 patent.
`
`3.
`
`In preparing this Declaration, I have reviewed and considered the
`
`documents identified in Section IV in light of the general knowledge in the
`
`relevant art. In forming my opinions, I relied upon my education, knowledge, and
`
`experience in the field of pharmaceutical formulation and development and
`
`considered the level of ordinary skill in the art as discussed below.
`
`4.
`
`I expect to be called to provide expert testimony, if necessary,
`
`regarding the opinions and issues considered in this Declaration. This Declaration
`
`1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0007
`
`

`

`
`
`identifies my opinions to date. I reserve the right to amend or supplement this
`
`Declaration, if allowed under the relevant rules, to address any issues raised by
`
`Patent Owner’s expert(s) or resulting from further discovery relating to any of the
`
`opinions stated herein. I may also testify as to the matters set forth in any
`
`additional reports, declarations, witness statements, and/or testimony submitted by
`
`Patent Owner regarding validity/patentability of the ʼ628 patent.
`
`II. QUALIFICATIONS
`
`5. My name is Graham Buckton. I am an Emeritus Professor of
`
`Pharmaceutics in the UCL School of Pharmacy of the University of London. I was
`
`employed at the School of Pharmacy of the University of London from 1988 to
`
`2015, initially as Lecturer, then Senior Lecturer, Reader and Professor, during
`
`which time I served as the Head of the Department of Pharmaceutics between
`
`January 2001 and April 2007. I served as Chair of the Master of Sciences in
`
`Pharmacy (MPharm) Exam Board between 2002 and 2012, and have been an
`
`MPharm (or Bachelors in Pharmacy, BPharm) Examiner at Queens University of
`
`Belfast, Cardiff University, University of Nottingham, Kings College, University
`
`of Colombo, Sri Lanka, Robert Gordon University and the University of East
`
`Anglia. I received my Ph.D. in Pharmaceutics from Kings College London in
`
`1985.
`
`2
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0008
`
`

`

`
`
`6.
`
`In 2000 I founded a contract services company called Pharmaterials
`
`Ltd. I sold the majority stake to a U.S. company, Pharmaceutics International Inc.
`
`(PII), in 2008 and the remaining stake in 2012, at which time I exited. I was Chief
`
`Executive Officer from 2000-2012. Pharmaterials carries out materials
`
`characterization, salt selection, polymorph screening, pre-formulation, formulation
`
`development, assay development and clinical trial manufacture.
`
`7.
`
`I have served on the Committee on Safety of Medicines (CSM), which
`
`is the body in the UK that grants (and revokes) marketing authorizations (the
`
`equivalent of the FDA in the US), and I chaired its Chemistry, Pharmacy and
`
`Standards (CPS) sub-committee. I retired as a member of CPS of the Commission
`
`on Human Medicines (a renamed version of CSM) in September 2022 after over
`
`20 years’ service. I have been a member of the British Pharmacopoeia
`
`Commission and have been a member of working parties for the European and the
`
`United States Pharmacopoeias.
`
`8. My research has focused on investigating the behavior of
`
`pharmaceutical materials, especially interfacial interactions between two or more
`
`material surfaces, and their use in processing and drug delivery. Applications of
`
`my research include studies of surface interactions, adaptation of physical
`
`properties of powders by crystallization and physical manipulation such as milling,
`
`and the preparation of drug dosage forms including solid oral dosage forms and
`
`3
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0009
`
`

`

`
`
`inhalation dosage forms, including film-coatings. I have published on my work in
`
`this field, presenting data on film coating solutions.
`
`9. My research has been funded by such organizations as the
`
`Engineering and Physical Sciences Research Council (EPSRC), Pfizer,
`
`AstraZeneca, GSK, and Novartis, as well as other foundations and companies in
`
`industry.
`
`10.
`
`I served a 10 year term as Editor of the International Journal of
`
`Pharmaceutics and have been a member of the editorial boards of a number of
`
`journals, including Pharmaceutical Research, the AAPS Journal and AAPS Pharm
`
`SciTec.
`
`11.
`
`I have authored a book on Interfacial Phenomena in Drug Delivery
`
`and Targeting. I have also authored or co-authored over 180 peer-reviewed journal
`
`articles, of which numerous articles present original research related to solid
`
`dosage forms, including film-forming materials and film-coatings. In addition, I
`
`have authored or co-authored more than 100 abstracts and book reviews. I am
`
`listed as an inventor on 6 patents or patent applications. Additionally, I have
`
`lectured at over 130 conferences, seminars, and symposia around the world and
`
`have served as a testifying expert witness on 32 cases.
`
`12.
`
`I have received numerous awards and honors, specifically, the
`
`appointment in 2003 as the Science Chairman for the British Pharmaceutical
`
`4
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0010
`
`

`

`
`
`Conference, the first recipient of the Academy of Pharmaceutical Sciences Medal
`
`in 2000, the 1998 Stig Sunner Award, the 1998 Foss Near Infrared European Users
`
`Group Award, the 1993 British Pharmaceutical Conference Science Medal, and the
`
`1992 Pfizer Award for “excellence in published research.”
`
`13. A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is attached as Exhibit A to this Declaration.
`
`14.
`
`I am being compensated for my time in connection with this IPR at
`
`my standard consulting rate, which is £500 per hour. My compensation is not
`
`dependent in any way upon the outcome of this matter.
`
`III. APPLICABLE STANDARDS
`
`15.
`
`I have been asked to investigate and provide opinions relating to the
`
`ʼ628 patent and as discussed herein from the perspective of a person of ordinary
`
`skill in the art (sometimes referred to as a “person of ordinary skill” or “POSA”) at
`
`the time of the priority date of the challenged claims of the ʼ628 patent, and
`
`according to the applicable legal standards provided to me below and otherwise set
`
`forth in this Declaration.
`
`A.
`
`16.
`
`Person of Ordinary Skill in the Art
`
`I understand that a POSA is a hypothetical person who is presumed to
`
`be aware of pertinent art including knowledge in the art, thinks along conventional
`
`5
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0011
`
`

`

`
`
`wisdom in the art, and is a person of ordinary creativity. I understand that this
`
`hypothetical POSA is considered to have the normal skills and knowledge of a
`
`person in the technical field.
`
`17. A POSA relating to the subject matter of the ʼ628 patent 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. A POSA may also work as part of a multidisciplinary team and
`
`draw upon not only his or her own skills, but also take advantage of certain
`
`specialized skills of others in the team to solve a given problem. To the extent
`
`necessary, this person would have worked in collaboration with others with the
`
`requisite education and experience in candidate drug selection, clinical use, clinical
`
`testing, design, formulation, development, and/or manufacturing of pharmaceutical
`
`oral dosage forms.
`
`18. Based on my experience, I have a good understanding of the
`
`capabilities of a POSA in the time frame leading up to the earliest effective filing
`
`date of the ʼ628 patent, which, as I describe below in Section VI.B.4, is December
`
`5, 2008. Indeed, I had the qualifications of a POSA by 2008, and have personal
`
`and extensive experience working with, and training, POSAs in 2008 and earlier,
`
`6
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0012
`
`

`

`
`
`and I am knowledgeable as to what a POSA would have understood from the prior
`
`art references described below and from the state of the art at the time.
`
`19.
`
`B.
`
`20.
`
`I have applied this definition of a POSA herein.
`
`Patent Priority Date / Earliest Effective Filing Date
`
`I understand that a patent priority date is the earliest date to which a
`
`patent application can claim priority. I understand that a patent application can
`
`claim priority from the filing date of a prior patent application.
`
`21.
`
`I understand that, for a patent to claim priority from the filing date of
`
`its provisional application, the specification of the provisional application must
`
`contain a written description of the invention and the manner and process of
`
`making and using it, in such full, clear, concise, and exact terms, to enable an
`
`ordinarily skilled artisan to practice the invention claimed in the patent. I
`
`understand that this comprises two requirements: a written description requirement
`
`and an enablement requirement.
`
`22. Written description requirement: To satisfy the written description
`
`requirement, I understand that the specification of the provisional application must
`
`clearly allow POSAs to recognize that the inventor invented what is claimed. In
`
`other words, I understand that the test is whether the disclosure of the provisional
`
`application reasonably conveys to a POSA that the inventor had possession of the
`
`claimed subject matter as of the filing date. I understand that the test for written
`
`7
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0013
`
`

`

`
`
`description requires an objective inquiry into the four corners of the specification
`
`from the perspective of a POSA. I understand that actual possession or reduction
`
`to practice outside of the specification is not enough. Rather, I understand that it is
`
`the specification itself that must demonstrate possession of the claimed subject
`
`matter.
`
`23. Enablement requirement: I understand that the enablement
`
`requirement is separate from the written description requirement discussed above.
`
`I understand that the specification of the provisional application must enable a
`
`POSA to practice the full scope of the claimed invention. I understand that the
`
`enabling disclosure of the specification of the provisional application must be
`
`commensurate in scope with the claim under consideration. I understand that the
`
`enablement requirement is satisfied when a POSA, after reading the specification
`
`of the provisional application, could practice the claimed invention without undue
`
`experimentation. I understand that factors to be considered in determining whether
`
`a disclosure would require undue experimentation include (1) the quantity of
`
`experimentation necessary, (2) the amount of direction or guidance presented, (3)
`
`the presence or absence of working examples, (4) the nature of the invention, (5)
`
`the state of the prior art, (6) the relative skill of those in the art, (7) the
`
`predictability or unpredictability of the art, and (8) the breadth of the claims.
`
`8
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0014
`
`

`

`
`
`C. Claim Construction
`
`24.
`
`I understand that “claim construction” is the interpretation of the
`
`meaning of patent claims. I understand that, in an IPR, words of a claim are
`
`generally given their ordinary and customary meaning, which is the meaning the
`
`term or phrase would have to a POSA at the time of the invention. I understand
`
`that both intrinsic and extrinsic evidence can be used to assist in understanding the
`
`meaning of a claim. Intrinsic evidence includes the claim language, language in
`
`other claims of the patent, the specification, and the prosecution history. I further
`
`understand that, unless required by the claim language or specification, claims
`
`should generally not be limited to embodiments in the specification, including
`
`preferred embodiments. I understand that extrinsic evidence, which consists of all
`
`evidence external to the patent and prosecution history including expert and
`
`inventor testimony, dictionaries, and technical publications, including those known
`
`and authoritative in a particular technical field, may also be relevant to claim
`
`construction. I further understand that a patent applicant may act as his or her own
`
`lexicographer and set forth a special definition of a claim term in the specification.
`
`25.
`
`I have been asked to review the claims and ascertain the meaning of
`
`the claims from the perspective of a POSA. Any opinions on claim construction
`
`expressed in this declaration are from the perspective of a POSA as of the priority
`
`date of the challenged claims of the ʼ628 patent and are consistent with my
`
`9
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0015
`
`

`

`
`
`understanding of the applicable claim construction standards stated above. As I
`
`describe below in Section VI.B.4, the earliest effective filing date of the challenged
`
`claims of the ʼ628 patent is December 5, 2008.
`
`D.
`
`Invalidity
`
`
`
`Anticipation
`
`26.
`
`I understand that a patent claim is unpatentable and invalid if the
`
`claim is “anticipated” by the prior art. I understand that a claimed invention is not
`
`novel and is anticipated if:
`
`1)
`
`2)
`
`the invention was known or used by others in this country, or
`was patented or described in a printed publication in this or a
`foreign country, before the invention by the patent applicant;
`the invention was patented or described in a printed publication
`in this or a foreign country or in public use or on sale in this
`country more than one year prior to the date of the application
`for patent in the United States; or
`a patent was granted for the same invention on an application
`for patent by another inventor filed in the United States before
`the invention by the applicant for patent.
`See 35 U.S.C. § 102 (pre‑AIA).
`27.
`I understand that anticipation occurs when a single piece of prior art
`
`3)
`
`describes every element of the claimed invention, either expressly or inherently,
`
`arranged in the same way as in the claim. I understand that, for inherent
`
`anticipation, it is required that the missing descriptive material is necessarily
`
`present in the prior art.
`
`10
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0016
`
`

`

`
`
`28.
`
`“[I]nherent anticipation does not require that a person of ordinary skill
`
`in the art at the time would have recognized the inherent disclosure.” Schering
`
`Corp. v. Geneva Pharms., 339 F.3d 1373, 1377 (Fed. Cir. 2003) Rather, as the
`
`Federal Circuit has explained:
`
`Under the principles of inherency, if the prior art necessarily
`functions in accordance with, or includes, the claimed
`limitations, it anticipates. A discovery of a previously
`unappreciated property of a prior art composition, or of a
`scientific explanation for the prior art’s functioning, does not
`render the old composition patentably new to the discoverer.
`
`Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999)
`(internal citations omitted).
`
`29.
`
`It is “well established” that “reliance on extrinsic evidence is proper in
`
`an inherency analysis” (and such evidence “need not antedate the critical date of
`
`the patent at issue”). See Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`
`878 F.3d 1336, 1345 (Fed. Cir. 2018). “Extrinsic evidence can be used to
`
`demonstrate what is ‘necessarily present’ in a prior art embodiment even if the
`
`extrinsic evidence is not itself prior art.” Hospira, Inc. v. Fresenius Kabi USA,
`
`LLC, 946 F.3d 1322, 1329 (Fed. Cir. 2020).
`
` Obviousness
`
`30.
`
`I further understand that a patent claim is unpatentable and invalid if
`
`the subject matter of the claim as a whole would have been obvious to a person of
`
`ordinary skill of the claimed subject matter as of the time of the invention at issue.
`
`11
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0017
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`

`

`
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`I understand that obviousness may be shown by considering more than one item of
`
`prior art. I understand that the following factors should be evaluated to determine
`
`whether the claimed subject matter is obvious: (1) the scope and content of the
`
`prior art; (2) the difference or differences, if any, between each claim of the patent
`
`and the prior art; and (3) the level of ordinary skill in the art at the time the patent
`
`was filed. See Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
`
`31.
`
`I understand that “objective indicia of non‐obviousness,” also known
`
`as “secondary considerations,” are also to be considered when assessing
`
`obviousness, if present, including commercial success; long‐felt but unresolved
`
`needs; failure of others to solve the problem that the inventor solved; unexpected
`
`results; copying of the invention by others; and industry recognition or expressions
`
`of disbelief by experts in the field of the claimed invention. I also understand that
`
`there must be a nexus between the objective indicia of non‐obviousness and the
`
`patent claims. I understand, in other words, that objective indicia of non‐
`
`obviousness must be commensurate in scope with the claimed subject matter.
`
`32.
`
`I understand that the test for obviousness is whether the claimed
`
`invention, as a whole, would have been obvious to a person of ordinary skill as of
`
`the date of the invention in light of the prior art. I understand that the use of
`
`hindsight must be avoided when considering whether the alleged invention would
`
`have been obvious to the person of ordinary skill.
`
`12
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0018
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`

`

`
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`33.
`
`I understand that in determining obviousness, a person of ordinary
`
`skill is a person of ordinary creativity. I understand that, when there is a design
`
`need or market pressure to solve a problem and there are a finite number of
`
`identified, predictable solutions, a person of ordinary skill has good reason to
`
`pursue the known options within his or her technical grasp.
`
`34.
`
`“When the prior art does not expressly disclose a claim limitation,
`
`‘inherency may supply a missing claim limitation in an obviousness analysis.’”
`
`Hospira, 946 F.3d at 1329 (Fed. Cir. 2020) (affirming district court finding of
`
`obviousness by combining inherent teaching of prior art with knowledge of a
`
`skilled artisan). “An inherent characteristic of a formulation can be part of the
`
`prior art in an obviousness analysis even if the inherent characteristic was
`
`unrecognized or unappreciated by a skilled artisan.” Persion Pharms. LLC v.
`
`Alvogen Malta Operations Ltd., 945 F.3d 1184, 1190 (Fed. Cir. 2019) (quoting
`
`Endo Pharm. Sols., Inc. v. Custopharm Inc., 894 F.3d 1374, 1381 (Fed. Cir.
`
`2018)).
`
`IV. DOCUMENTS
`
`35.
`
`In preparing this Declaration, I reviewed and considered the
`
`documents identified in the below table:
`
`13
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0019
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`

`

`
`
`Exhibit No.
`
`Description
`
`1001
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1015
`
`U.S. Patent No. 8,846,628 (the “’628 patent”)
`
`Declaration of Dr. Hannah K. Batchelor (“Batchelor Decl.”)
`
`WO 2004/082619 (“Ionescu”)
`
`WO 2004/103358 (“Atadja”)
`
`Gibson, M., Ch. 11, Oral Solid Dosage Forms, PHARMA.
`PREFORMULATION AND FORMULATION, CRC Press (2001) (“Gibson”)
`
`Vidaza Label 2004
`
`Vidaza Label 2007
`
`WO 2004/082822 (“Ionescu ʼ822”)
`
`Press Release, Pharmion, “Clinical Data Presented on Pilot
`Pharmacokinetic Study of Oral Azacitidine” (June 2, 2007)
`(“Pharmion-PR”)
`
`Press Release, Pharmion, “Pharmion’s Oral Azacitidine Granted Fast
`Track Status for Myelodysplastic Syndromes” (August 29, 2007)
`(“Pharmion-PR II”)
`
`Pharmion Corporation, Form 10-K (February 29, 2008) (“Pharmion
`10-K”)
`Excerpts from Rowe, R.C., et al., Handbook of Pharma. Excipients,
`Pharma. Press, 5th ed. (2006) (“Handbook”)
`Kelley et al., “Furanose-Pyranose Isomerization of Reduced
`Pyrimidine and Cyclic Urea Ribosides,” 29 J. Med. Chem. 2351
`(1986) (“Kelley”)
`
`1016
`
`U.S. Patent No. 3,817,980 (“Vorbruggen”)
`
`14
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0020
`
`

`

`
`
`Exhibit No.
`
`Description
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1029
`
`1030
`
`Marcucci, G., et al., “Bioavailability of Azacitidine Subcutaneous
`Versus Intravenous in Patients With the Myelodysplastic
`Syndromes,” 45 J. Clin. Pharmacology 597 (2005) (“Marcucci”)
`
`Thomson, A., “Back to basics: pharmacokinetics,” 272 Pharma. J
`769 (2004) (“Thomson”)
`
`U.S. Patent Publication No. 2006/0074046 (“Redkar”)
`
`Dintaman, et al., Pharmaceutical Research, 1999, 16(10), 1550-1556
`(“Dintaman”)
`
`U.S. Patent Publication No. 2004/0162263 (“Sands”)
`
`Application File History for the ʼ628 Patent, U.S. App. No.
`12/466,213 (the “File History”)
`
`U.S. Patent No. 3,350,388
`
`Piskala, A. and Sorm, F., Collect. Czech. Chem. Commun., 29,
`2060-2076 (1964)
`
`Piskala, A. and Sorm, F., GB 1227691 (1971)
`
`U.S. Publication No. 2008/0057086 (“ʼ086 Publication”) (filed as
`U.S. Application No. 11/849,958 (“ʼ958 application”))
`
`GastroPlus version 5.2 Manual (“GP5.2 manual”)
`
`Kotke, M.K. and Rudnic, E.M, Ch. 10, Tablet Dosage Forms,
`MODERN PHARMACEUTICS, 4th ed. (2002) (“Modern Pharmaceutics”)
`
`Ch. 45, Oral Solid Dosage Forms, and Ch. 46, Coating of
`Pharmaceutical Dosage Forms, REMINGTON, THE SCIENCE AND
`PRACTICE OF PHARMACY, 20th ed., Lippincott Williams & Wilkins
`(2000) (“Remington”)
`
`15
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1002-0021
`
`

`

`
`
`Exhibit No.
`
`Description
`
`1032
`
`1033
`
`1034
`
`1036
`
`1037
`
`1038
`
`1042
`
`1045
`
`1046
`
`1047
`
`1049
`
`1050
`
`Hardy et al., Drug Delivery to the Gastrointestinal Tract, 1989 Ch. 7,
`83-96 (“Hardy”)
`
`Ewe et al., Digestive Diseases and Science, 1991, 36(2) 146-152
`(“Ewe”)
`
`Stoltz et al., Development of an Oral Dosage Form of Azacitidine:
`Overcoming Challenges in Chemistry, Formulation, and
`Bioavailability, Blood 108:4850 (2006) (“Stoltz”)
`
`U.S. Provisional Application No. 61/053,609 (“ʼ609 provisional”)
`
`Schwarz et al., Gastrointestinal Transit Times in Mice and Humans
`Measured With 27Al and 19F Nuclear Magnetic Resonance, Magnetic
`Resonance in Medicine 48:255-261, 260 (2002) (“Schwarz”)
`
`Amidon et al., A