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`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
`____________________________________________
`
`PATENT OWNER’S RESPONSE
`
`
`
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`
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`

`

`Patent Owner’s Response
`IPR2023-00512
`
`TABLE OF CONTENTS
`
`D. 
`
`TABLE OF AUTHORITIES ..................................................................................... v
`PATENT OWNER’S EXHIBIT LIST ..................................................................... vi
`I. 
`INTRODUCTION ........................................................................................... 1 
`II. 
`BACKGROUND ............................................................................................. 3 
`A.  MDS and AML ...................................................................................... 3 
`B. 
`5-Azacytidine ........................................................................................ 4 
`C. 
`The Known Challenges to Developing a Therapeutically Effective
`Formulation of 5-Azacytidine ............................................................... 5 
`The Therapeutic Use of 5-Azacytidine ................................................. 8 
`1. 
`Injectable 5-azacytidine .............................................................. 8 
`2. 
`Oral 5-azacytidine ....................................................................... 8 
`III.  THE ’628 PATENT ......................................................................................... 9 
`A. 
`The Invention of Orally Administered 5-Azacytidine .......................... 9 
`1. 
`Enterically-coated formulations .................................................. 9 
`2. 
`Non-enterically coated formulations ........................................ 11 
`Specification ........................................................................................ 12 
`B. 
`Prosecution History ............................................................................. 14 
`C. 
`Challenged Claims .............................................................................. 15 
`D. 
`Onureg® .............................................................................................. 15 
`E. 
`IV.  PERSON OF ORDINARY SKILL IN THE ART ........................................ 16 
`V. 
`CLAIM CONSTRUCTION .......................................................................... 16 
`A. 
`“Non-Enteric Coated” ......................................................................... 16 
`B. 
`“Test Subject” ...................................................................................... 17 
`C. 
`Claims 14 and 15 ................................................................................. 17 
`VI.  THE ASSERTED REFERENCES ................................................................ 18 
`A. 
`Ionescu (Ex.1004) ............................................................................... 18 
`B. 
`Atadja (Ex.1005) ................................................................................. 20 
`C. 
`Gibson (Ex.1006) ................................................................................ 21 
`i
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`

`2. 
`
`B. 
`
`C. 
`
`Patent Owner’s Response
`IPR2023-00512
`Pharmion-PR (Ex.1010) ...................................................................... 23 
`D. 
`VII.  THE ’628 PATENT CLAIMS ARE NOT ANTICIPATED BY IONESCU
`(GROUND 1) ................................................................................................. 24 
`A. 
`Petitioner Has Failed to Show That Ionescu Discloses a Non-Enteric
`Coated Tablet as Required by All Challenged Claims ....................... 24 
`1. 
`Ionescu’s “sugar-coated” tablets do not disclose a “non-enteric
`coated tablet” ............................................................................. 24 
`A POSA in December 2008 would not have understood that
`sugar-coated tablets of 5-azacytidine would have been non-
`enterically coated ...................................................................... 26 
`Ionescu Fails to Disclose a Film Coated Tablet as Required by Claims
`14 and 15 ............................................................................................. 27 
`Ionescu Does Not Inherently Anticipate the Pharmacokinetic Values
`Required by Claims 11, 18, 20-22, 38, 40, 42, and 43. ....................... 27 
`Ionescu Is Not Enabling. ..................................................................... 29 
`D. 
`VIII.  THE ’628 PATENT CLAIMS WOULD NOT HAVE BEEN OBVIOUS IN
`VIEW OF IONESCU IN COMBINATION WITH ATADJA AND GIBSON
`AND THE KNOWLEDGE OF A POSA (GROUND 2) .............................. 32 
`A.  A POSA Would Not Have Been Motivated to Pursue and Select an
`Oral, Non-Enteric Coated Tablet of 5-Azacytidine ............................ 32 
`1. 
`Petitioner’s theory that a POSA would have selected a non-
`enteric coated tablet from Ionescu’s disclosure is flawed for the
`same reasons as its anticipation challenge ................................ 32 
`Petitioner has not shown that a POSA would select a non-
`enteric coated tablet as the “default” choice for 5-azacytidine 33 
`a. 
`Petitioner’s obviousness theory cannot be reconciled with
`the known instability of 5-azacytidine ........................... 34 
`There was no prior art disclosure of the use of non-
`enterically coated 5-azacytidine tablet ........................... 36 
`Disclosures of “liquid formulations” would not have assuaged a
`POSA’s concerns over 5-azacytidine’s stability ....................... 41 
`
`2. 
`
`3. 
`
`b. 
`
`
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`ii
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`

`

`B. 
`
`C. 
`
`D. 
`
`E. 
`
`Patent Owner’s Response
`IPR2023-00512
`4.  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 ................................................... 43 
`Petitioner Has Failed to Establish a Reasonable Expectation of
`Success ................................................................................................ 46 
`1. 
`Given the well-established instability of 5-azacytidine, a POSA
`would not have had a reasonable expectation that a non-enteric
`coated tablet formulation would have been therapeutically
`effective ..................................................................................... 46 
`Preliminary bioavailability data for unknown oral formulations
`does not provide a reasonable expectation that a non-enteric
`coated tablet of 5-azacytidine would be therapeutically effective
` ................................................................................................... 49 
`The claims are not obvious to try because a non-enteric coated
`tablet would not have been a predictable solution for 5-
`azacytidine ................................................................................ 52 
`Ionescu, Atadja, Gibson, and Knowledge of a POSA Do Not Render
`Obvious Claims 6, 7, or 32 .................................................................. 54 
`Ionescu, Atadja, Gibson, and Knowledge of a POSA Do Not Render
`Obvious the Doses Recited in Claims 9, 24-27, and 36 ...................... 56 
`Ionescu, Atadja, Gibson, and Knowledge of a POSA Do Not Render
`Obvious The Pharmacokinetic Values Required by Claims 11, 12, 18-
`22 and 38-43 ........................................................................................ 58 
`1. 
`Petitioner’s inherency argument fails at least because the prior
`art does not disclose a non-enteric coated tablet ...................... 58 
`Dr. Batchelor’s modeling is faulty and does not indicate the
`claimed pharmacokinetic values are inherent to any formulation
` ................................................................................................... 59 
`Extrapolation using Vidaza® pharmacokinetics and Pharmion-
`PR’s bioavailability does not render obvious claims 11 and 38
` ................................................................................................... 62 
`IX.  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) ........................................ 63 
`
`2. 
`
`3. 
`
`2. 
`
`3. 
`
`
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`Patent Owner’s Response
`IPR2023-00512
`X.  OBJECTIVE INDICIA REINFORCE THE NON-OBVIOUSNESS OF THE
`CHALLENGED CLAIMS ............................................................................ 64 
`A. 
`Long-felt But Unmet Need .................................................................. 64 
`B. 
`Skepticism and Failure of Others ........................................................ 66 
`C. 
`Unexpected Results ............................................................................. 68 
`D. 
`Industry Praise ..................................................................................... 71 
`E. 
`Nexus ................................................................................................... 73 
`XI.  CONCLUSION .............................................................................................. 74 
`
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`iv
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`

`TABLE OF AUTHORITIES
`
`Patent Owner’s Response
`IPR2023-00512
`
`Page(s)
`
`
`
`CASES
`Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293 (Fed. Cir. 2015) ................................ 58
`Daiichi Sankyo v. Matrix Lab, 619 F.3d 1346 (Fed. Cir. 2010) .............................. 36
`Dayco Prod., Inc. v. Total Containment, Inc., 329 F.3d 1358 (Fed.
`Cir. 2003) ....................................................................................................... 26
`Elan Pharms., Inc. v. Mayo Found. for Med. Educ. & Research, 346
`F.3d 1051 (Fed. Cir. 2003) ............................................................................ 29
`EmeraChem Holdings, LLC v. Volkswagen Grp. of Am., Inc., 859 F.3d
`1341 (Fed. Cir. 2017)..................................................................................... 25
`Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366 (Fed. Cir. 2019) ......................... 73
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litigation, 676 F.3d 1063 (Fed. Cir. 2012) ........................................ 49
`In re Wands, 858 F.2d 731 (Fed.Cir.1988) .............................................................. 29
`Leo Pharmaceutical Products, Ltd. v. Rea, 2013 WL 4054937 (Fed.
`Cir. 2013) ....................................................................................................... 53
`PAR Pharm., Inc. v. TWI Pharms., Inc., 773 F.3d 1186 (Fed. Cir.
`2014) .............................................................................................................. 58
`Quanergy Sys., Inc. v. Velodyne Lidar USA, Inc., 24 F.4th 1406 (Fed.
`Cir. 2022) ....................................................................................................... 73
`Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2002) ....................... 36
`Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530 (Fed. Cir. 1983) ........................ 64
`Verve, LLC v. Crane Cams, Inc., 311 F.3d 1116 (Fed. Cir. 2002) .......................... 26
`Wasica Fin. GmbH v. Cont’l Auto. Sys., 853 F.3d 1272 (Fed. Cir.
`2017) .............................................................................................................. 26
`v
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`

`Patent Owner’s Response
`IPR2023-00512
`
`PATENT OWNER’S EXHIBIT LIST
`
`No.
`
`Exhibit
`
`2001 Declaration of Dr. Corey Berkland
`
`2002
`
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`
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`
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`https://www.fda.gov/drugs/resources-information-approved-drugs/fda-
`approves-onureg-azacitidine-tablets-acute-myeloid-leukemia (“FDA
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`
`Aparicio, A. & Weber, J., Review of the clinical experience with 5-
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`Beisler, J., et al., Chemistry of Antitumor Triazine Nucleosides. An
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`
`2005
`
`Reserved
`
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`
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`
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`
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`
`vi
`
`
`
`
`
`
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
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`
`
`
`
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
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`
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`
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`
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`
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`
`
`
`
`
`viii
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
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`2034 Glover, A., et al., Azacitidine: 10 Years Later, 71 CANCER TREATMENT
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`
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`
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`
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`
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`
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`
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`
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`
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`
`
`
`
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
`
`Exhibit
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`
`2049 Deposition Transcript of Hannah K. Batchelor (“Batchelor Tr.”)
`
`2050 Deposition Transcript of Graham Buckton, Ph.D. (“Buckton Tr.”)
`
`2051 Declaration of Corey Berkland, Ph.D. (“Berkland Decl.”)
`
`2052 Declaration of George M. Grass, Ph.D. (“Grass Decl.”)
`
`2053 Declaration of William G. Blum, M.D. (“Blum Decl.”)
`
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`
`2055
`
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`
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`
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`
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`
`2059
`
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`
`2060
`
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`
`2061
`
`Reserved
`
`2062 Onureg® Label
`
`2063
`
`Gibson, M., Pharm. PREFORMULATION AND FORMULATION: A
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`
`x
`
`
`
`
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
`Exhibit
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`
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`
`xi
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
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`Exhibit
`
`2074
`
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`
`
`
`xii
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`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
`
`Exhibit
`
`2083
`
`2084
`
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`
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`2089
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`2091
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`IPR2023-00512
`
`No.
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`Exhibit
`Phase III Trial: A Cancer and Leukemia Group B Study, 20 J. OF CLIN.
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`
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`
`
`
`xiv
`
`

`

`Patent Owner’s Response
`IPR2023-00512
`
`No.
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`Exhibit
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`
`xv
`
`

`

`Patent Owner’s Response
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`No.
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`
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`
`
`xvi
`
`

`

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`
`No.
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`
`2125
`
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`xvii
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`

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`
`No.
`
`Exhibit
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`2133
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`Exemestane Label (“Exemestane”)
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`2134 Anastrozole Label (“Anastrozole”)
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`No.
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`
`
`
`
`
`xix
`
`

`

`I.
`
`INTRODUCTION
`This proceeding involves a challenge to U.S. Patent No. 8,846,628 (“the
`
`Patent Owner’s Response
`IPR2023-00512
`
`’628 patent”), which claims pharmaceutical compositions and methods of
`
`treatment using orally administered 5-azacytidine in a non-enteric coated tablet. 5-
`
`azacytidine and its anticancer properties have been known since the 1960s.
`
`However, the drug was known to readily break down in water and be quickly
`
`metabolized in the body by an enzyme called cytidine deaminase. The drug’s
`
`instability made it difficult to develop a usable therapeutic formulation of 5-
`
`azacytidine. Indeed, it took 40 years after 5-azacytidine’s initial discovery before
`
`any use of the drug received FDA approval. And even then, a suitable, orally
`
`administered formulation proved elusive. 5-azacytidine was approved only for
`
`administration as an injectable formulation, which had significant drawbacks in
`
`terms of patient comfort and compliance.
`
`
`
`Before the invention of the ’628 patent, nobody believed it would be
`
`possible to develop a therape