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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 PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
`
`
`
`
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`

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`Patent Owner’s Preliminary Response
`IPR2023-00512
`
`TABLE OF CONTENTS
`
`3.
`
`I.
`II.
`
`INTRODUCTION ........................................................................................... 1
`BACKGROUND ............................................................................................. 3
`A.
`State of The Art ..................................................................................... 3
`1.
`5-Azacytidine .............................................................................. 3
`2.
`Challenges to developing an oral formulation of
`5-azacytidine ............................................................................... 5
`A POSA would have attempted to develop enteric coated
`tablets .......................................................................................... 9
`Onureg® .................................................................................... 10
`4.
`The ’628 Patent ................................................................................... 11
`B.
`III. PROSECUTION HISTORY OF THE ’628 PATENT .................................. 13
`IV. PERSON OF ORDINARY SKILL IN THE ART ........................................ 17
`V.
`CLAIM CONSTRUCTION .......................................................................... 18
`VI. THE ASSERTED REFERENCES ................................................................ 20
`A.
`Ionescu ................................................................................................. 20
`B. Atadja .................................................................................................. 21
`C. Gibson.................................................................................................. 22
`D.
`Pharmion-PR ....................................................................................... 24
`VII. THE BOARD SHOULD DENY INSTITUTION OF GROUND 1
`BECAUSE PETITIONER HAS FAILED TO DEMONSTRATE A
`REASONABLE LIKELIHOOD THAT THE CHALLENGED
`CLAIMS ARE ANTICIPATED UNDER 35 U.S.C. § 102(b) ..................... 25
`A.
`Ionescu Fails to Disclose A Non-Enteric Coated Tablet as
`Required by All of The Claims Challenged in Ground 1 ................... 25
`1.
`Petitioner fails to establish that Ionescu discloses “a non-
`enteric-coated tablet” ................................................................ 26
`a.
`Ionescu’s disclosure that tablets may be coated
`with sugar does not disclose a type of coating that
`determines the release profile of the tablet ..................... 26
`
`
`
`
`
`i
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`

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`Patent Owner’s Preliminary Response
`IPR2023-00512
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`b.
`
`
`Based on the prior art, a POSA in December 2008
`would at most have understood that to the extent any
`5-azacytidine tablets were coated with sugar, as
`disclosed in Ionescu, such tablets would be
`enterically coated tablets ................................................ 32
`VIII. THE BOARD SHOULD DENY INSTITUTION OF GROUNDS
`2 AND 3 BECAUSE PETITIONER HAS FAILED TO DEMONSTRATE
`A REASONABLE LIKELIHOOD THAT THE CHALLENGED CLAIMS
`ARE OBVIOUS UNDER 35 U.S.C. § 103(A) ............................................. 37
`A.
`Petitioner Fails to Establish That The Art Cited in Grounds 2 and 3
`Discloses The Limitation “Wherein The Composition Is A Non-
`Enteric Coated Tablet” of Independent Claims 1 and 28 .................... 39
`Petitioner Fails to Establish A Reasonable Expectation of Success ... 40
`B.
`IX. THIS PETITION WOULD MERIT DISCRETIONARY DENIAL OF
`GROUNDS 1-3 PURSUANT TO 35 U.S.C. § 325(D) ................................. 46
`A.
`Step 1 of Advanced Bionics Favors Denying Institution Under §
`325(d) Because The Same or Substantially The Same Art or
`Arguments Were Previously Presented to The Office ........................ 50
`1.
`The Examiner considered Ionescu and related disclosures ...... 50
`a.
`The Examiner considered Ionescu .................................. 50
`b.
`The Examiner considered Ionescu family members
`with substantially the same disclosure as Ionescu .......... 51
`An ISR considered by the Examiner cited an Ionescu
`family member ................................................................ 52
`Atadja, Gibson, and Pharmion-PR are substantially the
`same as references previously presented and extensively
`discussed during prosecution .................................................... 55
`Step 2 of Advanced Bionics Favors Denying Institution Under §
`325(D) Because Petitioner Has Not Demonstrated That The Office
`Erred in A Manner Material to The Patentability of The Challenged
`Claims .................................................................................................. 59
`
`c.
`
`2.
`
`B.
`
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`ii
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`

`

`1.
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`2.
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`3.
`
`Patent Owner’s Preliminary Response
`IPR2023-00512
`The Examiner did not err in evaluating the prior art because the
`art fails to disclose non-enteric coated tablets of 5-azacytidine
` ................................................................................................... 59
`The Examiner considered Ionescu, making Petitioner’s
`citation to Lyft clearly distinguishable on the facts .................. 61
`The experts’ declarations and modeling do not provide new
`evidence that warrant reconsideration of the prior art or
`arguments .................................................................................. 63
`a.
`Dr. Buckton’s declaration does not present additional
`evidence that warrants reconsideration of the prior art .. 64
`Dr. Batchelor’s declaration does not present additional
`evidence that warrants reconsideration of the prior art
`references ........................................................................ 66
`CONCLUSION .............................................................................................. 69
`
`b.
`
`
`
`iii
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`X.
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`Patent Owner’s Preliminary Response
`IPR2023-00512
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`CASES
`Dayco Prod., Inc. v. Total Containment, Inc., 329 F.3d 1358 (Fed.
`Cir. 2003) ....................................................................................................... 32
`Eli Lilly & Co. v. Teva Pharm. Int'l GmbH, 8 F.4th 1331 (Fed. Cir.
`2021) .............................................................................................................. 40
`Honeywell Int'l Inc. v. Mexichem Amanco Holding S.A. De C.V., 865
`F.3d 1348 (Fed. Cir. 2017) ............................................................................ 41
`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ................................................. 40
`Verve LLC v. Crane Cams Inc., 311 F.3d 1116 (Fed. Cir. 2002) ............................ 32
`Wasica Fin. GmbH v. Cont'l Auto. Sys., 853 F.3d 1272 (Fed. Cir.
`2017) .............................................................................................................. 32
`
`
`
`DOCKETED CASES
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH, No. IPR2019-01469 8 (P.T.A.B. Feb. 13, 2020) ......................passim
`Becton, Dickinson and Co. v. B. Braun Melsungen AG, No. IPR2017-
`01586 (P.T.A.B. Dec. 15, 2017) .............................................................. 47, 48
`Intel Corporation v. ACQIS LLC, No. IPR2021-01105 (P.T.A.B. Dec.
`12, 2022) ........................................................................................................ 60
`
`Ivantis, Inc., Alcon Research, LLC, Alcon Vision, LLC, and Alcon
`Inc., v. Sight Sciences, Inc., No. IPR2022-01530 (P.T.A.B.
`Mar. 27, 2023) .................................................................................. 59, 62, 65
`
`
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`iv
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`Patent Owner’s Preliminary Response
`IPR2023-00512
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`Ivantis, Inc., Alcon Research, LLC., Alcon Vision, LLC, and Alcon
`Inc. v. Sight Sciences, Inc., No. IPR2022-01540 (P.T.A.B. Mar.
`22, 2023) .................................................................................................. 60, 61
`Lyft v. Rideshare Displays, No. IPR2021-01601(P.T.A.B. Apr. 11,
`2022) ........................................................................................................ 47, 63
`Nespresso USA, Inc. v. K-Fee System GMHB, No. IPR2021-01222
`(P.T.A.B. Jan. 6, 2022) .................................................................................. 64
`Risen (Suzhou) Pharma Tech Co., Ltd. V. Alzheon, Inc., No.
`PGR2022-00051 (P.T.A.B. Jan. 13, 2023) .............................................. 61, 62
`Samsung Electronics Co., Ltd. v. Power2B, Inc., No. IPR2021-01190
`(P.T.A.B. Jan. 6, 2022) ................................................................................. 58
`Wabco Holdings Inc., et al., v. Transtex Composite Inc., No.
`IPR2018-00737 (P.T.A.B. Sep. 27, 2018) ..................................................... 68
`Xerox Corp. v. Bytemark, Inc., No. IPR2022-00624
`(P.T.A.B. Aug. 24, 2022) ....................................................................... 64, 65
`
`
`
`STATUTES, RULES, AND REGULATIONS
`37 C.F.R. 1.132 ........................................................................................................ 15
`37 C.F.R. § 42.24(a)(1) ............................................................................................ 70
`37 C.F.R. §42.24(d) ........................................................................................... 70, 71
`37 C.F.R. § 42.100(b) .............................................................................................. 18
`35 U.S.C. § 102(b) ................................................................................................... 25
`35 U.S.C. § 103(A) .................................................................................................. 37
`35 U.S.C. § 282(b) ................................................................................................... 18
`35 U.S.C. § 325(d) ............................................................................................passim
`
`
`
`
`
`v
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`

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`Patent Owner’s Preliminary Response
`IPR2023-00512
`
`PATENT OWNER’S EXHIBIT LIST
`
`Exhibit
`
`Declaration of Dr. Corey Berkland
`
`FDA approves Onureg® (azacitidine tablets) for acute myeloid
`leukemia (“FDA Approves Onureg®”)
`
`Aparicio 2002 (“Aparicio”)
`
`Beisler 1977 (“Beisler”)
`
`Reserved
`
`Canadian Product 200mg Onureg® Product Information
`
`Canadian Product 300mg Onureg® Product Information
`
`Canadian Product Monograph Onureg®
`
`Chabner 1973 (“Chabner”)
`
`Chen 2008 (“Chen”)
`
`Cheung 1984 (“Cheung”)
`
`Čihák 1965 (“Čihák”)
`
`European Commission Decision 17.6.21
`
`Connors 1986 (“Connors”)
`
`Evans 1988 (“Evans”)
`
`FASTtrack 2010 (“FASTtrack”)
`
`Gaubert 2001 (“Gaubert”)
`
`Kaminskas 2005 (“Kaminskas”)
`
`vi
`
`No.
`
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`
`
`
`
`

`

`Patent Owner’s Preliminary Response
`IPR2023-00512
`
`Exhibit
`
`Kissinger 1986 (“Kissinger”)
`
`Lieberman 1990 (“Lieberman”)
`
`Lin 1981 (“Lin”)
`
`Mund 2006 (“Mund”)
`
`National Cancer Institute 1978 (“National Cancer Institute”)
`
`Notari 1975 (“Notari”)
`
`Onureg® Label
`
`International Pat. Appl. Pub. No. WO2009/139888
`(“WO2009/139888”)
`
`Piťhová 1965 (“Piťhová”)
`
`Remington 2005
`
`Stresemann 2008 (“Stresemann”)
`
`U.S. Pat. Pub. No. US20040186065A1 (“Ionescu-065”)
`
`Weiss 1972 (“Weiss”)
`
`Celgene v. Accord 1:21-cv-01795-RGA Doc 40
`
`U.S. Pat. No. 7,189,740 (“Zeldis”)
`
`Glover 1987 (“Glover”)
`
`U.S. Pat. No. 6,887,855 (“Ionescu-855”)
`
`U.S. Pat. No. 7,078,518 (“Ionescu-518”)
`
`U.S. Pat. No. 7,772,199 (“Ionescu-199”)
`
`U.S. Pat. Pub. No. US20060247189 (“Ionescu-189”)
`vii
`
`No.
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`
`2025
`
`2026
`
`2027
`
`2028
`
`2029
`
`2030
`
`2031
`
`2032
`
`2033
`
`2034
`
`2035
`
`2036
`
`2037
`
`2038
`
`
`
`
`
`

`

`Patent Owner’s Preliminary Response
`IPR2023-00512
`
`No.
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`2044
`
`2045
`
`2046
`
`2047
`
`Exhibit
`
`U.S. Pat. Pub. No. US20100298253 (“Ionescu-253”)
`
`Ward 2007 (“Ward”)
`
`International Pat. Appl. Pub. No. WO2008/028193
`(“WO2008/028193”)
`
`Gibson Supplemental
`
`Lieberman Vol. 2
`
`International Pat. Appl. Pub. No. WO2004/082618
`(“WO2004/082618”)
`
`Celgene v. Accord 1:21-cv-01795-RGA Doc 35
`
`Reserved
`
`Savage 1967 (“Savage”)
`
`
`
`
`
`
`
`
`
`viii
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`

`

`IPR2023-00512
`
`I.
`
`INTRODUCTION
`U.S. Patent No. 8,846,628 (the “’628 patent”) claims pharmaceutical
`
`compositions and methods of use for the oral administration of 5-azacytidine,
`
`which is used for the treatment of certain types of leukemia. Scientists had known
`
`about 5-azacytidine and its anticancer properties for decades before the ’628
`
`patent. However, the compound was known to be chemically unstable, particularly
`
`in the harsh acidic environment of the stomach, and to be enzymatically
`
`metabolized. As a result, prior to the invention of the ’628 patent, no one had
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`successfully developed an oral formulation of 5-azacytidine. And to the extent that
`
`anyone tried to develop an oral formulation, those prior efforts focused on the use
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`of “enterically coated” tablets to protect 5-azacytidine against degradation in the
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`stomach.
`
`The inventors of the ’628 patent made the surprising discovery that it is
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`possible to treat cancer patients by orally administering 5-azacytidine tablets
`
`without an enteric coating. Their discovery is described and claimed in the ’628
`
`patent and ultimately resulted in the development of the medicine Onureg®, which
`
`is the first orally administered tablet of 5-azacytidine approved by the FDA.
`
`The Board should deny institution against all challenged claims of the ’628
`
`patent for two independent reasons.
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`
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`1
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`

`

`IPR2023-00512
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`First, the Petition fails to establish that the limitation of a “non-enteric
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`coated tablet” in all challenged claims was disclosed or would have been obvious
`
`in view of the cited art. The Petition relies exclusively on the disclosure in Ionescu
`
`that tablets “may be coated with a concentrated solution of sugar” (Petitioner’s
`
`“sugar-coated tablets”) for this limitation. See Ex.1004-0015(Ionescu) 13:16-18;
`
`Pet., 22. But sugar-coated tablets are not synonymous with non-enteric coated
`
`tablets; indeed, Petitioner’s own cited art discloses sugar coatings on enterically
`
`coated tablets. And Petitioner fails to establish obviousness and a reasonable
`
`expectation of success in view of challenges known in the art (e.g., the known
`
`chemical instability of 5-azacytidine in the acidic environment of the stomach).
`
`Second, this Petition merits discretionary denial under 35 U.S.C. § 325(d).
`
`The Examiner considered the disclosure of Ionescu—Petitioner’s primary
`
`reference—at least five times; indeed, the same portions of the reference relied
`
`upon by the Petition were called out in an International Search Report considered
`
`during prosecution. And Petitioner has not identified error or anything about
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`Ionescu that the Examiner allegedly misunderstood or overlooked. The expert
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`declarations add no material evidence the Examiner missed in his analysis. Thus,
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`denying institution would best serve the integrity of the patent system.
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`
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`
`2
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`

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`IPR2023-00512
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`Petitioner cannot demonstrate that it is reasonably likely to prevail in
`
`establishing the unpatentability of any challenged claim, and the Board should
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`decline to institute inter partes review.
`
`II. BACKGROUND
`A.
`State of The Art
`1.
`5-Azacytidine
`5-azacytidine is a nucleoside similar to the naturally occurring nucleoside,
`
`cytidine. Ex.1001(’628 patent), 2:37-62. 5-azacytidine possesses a nitrogen atom
`
`in place of a carbon atom present in cytidine, which is highlighted in the structure
`
`below:
`
`
`
`Id., 2:48-62. Cancer cells incorporate 5-azacytidine into DNA and RNA. Id., 3:9-
`
`27. 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….” Id., 3:9-22.
`
`
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`
`3
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`

`

`IPR2023-00512
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`Researchers first synthesized 5-azacytidine in the early 1960s.
`
`Ex.2012(Čihák); Ex.2027(Piťhová); Ex.2001(Berkland Decl.) at ¶46. The first
`
`European and United States clinical trials with 5-azacytidine were underway in
`
`1967 and 1970, respectively. Ex.2034(Glover), 737; Ex.2001(Berkland Decl.) at
`
`¶46. Scientists had identified 5-azacytidine’s anti-tumoral effect as early as 1972.
`
`Ex.2031(Weiss); Ex.2001(Berkland Decl.) at ¶46. For forty years, the field
`
`worked to develop pharmaceutically acceptable formulations, including oral
`
`formulations, of 5-azacytidine without success. It was not until May 2004 that the
`
`FDA approved intravenous or subcutaneous injection of 5-azacytidine, which was
`
`marketed as Vidaza®. Ex.1007(Vidaza® Label 2004); Ex.2018(Kaminskas);
`
`Ex.2001(Berkland Decl.) at ¶46.
`
`
`
`
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`4
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`

`IPR2023-00512
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`2.
`
`Challenges to developing an oral formulation of 5-
`azacytidine
`Prior to the December 5, 2008, the alleged priority date of the inventions
`
`described in the ’628 patent,1 a person of ordinary skill in the art (“POSA”) would
`
`have expected that 5-azacytidine would have been degraded by the stomach, which
`
`has a very acidic pH that can reach values of about 1. Pet., 40; Ex.1002(Buckton
`
`Decl.), ¶138; Ex.1003(Batchelor Decl.), ¶41; Ex.2015(Evans), 1035;
`
`Ex.2043(Lieberman Vol. 2), 349-50; Ex.2001(Berkland Decl.) at ¶71; see also id.
`
`at ¶¶68-78. As Petitioner’s experts concede, it was widely understood that 5-
`
`azacytidine was unstable and underwent rapid hydrolysis that would result in its
`
`break down in the stomach before a therapeutically effective amount of the drug
`
`could be absorbed in the gastrointestinal tract. Ex.1002-0065(Buckton Decl.),
`
`¶119; Ex.1003-0020(Batchelor Decl.), ¶¶34-35; Ex.1014(Chan), 807;
`
`Ex.1021(Sands), ¶[0012]; Ex. 1034-0001(Stoltz); Ex.2014(Connors), 239;
`
`
`1 Petitioner contends that the earliest effective filing date of the challenged claims
`
`is December 5, 2008, which corresponds to the second of three provisional
`
`applications to which the ʼ628 patent claims priority. Pet., 19. For the purposes of
`
`this POPR only, and without conceding the priority date, Patent Owner has applied
`
`the date of December 5, 2008 to the challenged claims.
`
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`5
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`IPR2023-00512
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`Ex.2041(WO2008/028193), ¶¶[0024]-[0025]; Ex.2001(Berkland Decl.) at ¶¶64-78.
`
`Thus, a POSA attempting to develop an oral tablet formulation of 5-azacytidine
`
`would have understood that any successful formulation would have to address this
`
`acid instability in the stomach to deliver a therapeutically effective amount of the
`
`drug to a patient. Ex.2001(Berkland Decl.) at ¶66-67. Significantly, in its
`
`challenges to the independent claims of the ’628 patent, the Petition does not
`
`engage or explain how a POSA would have addressed hydrolytic degradation.
`
`Pet., 21-23, 31-38, 58-62.2
`
`Additionally, a POSA attempting to develop an oral tablet formulation in
`
`December 2008 would have been concerned that a second pathway—enzymatic
`
`cytidine deamination—would also rapidly degrade 5-azacytidine.
`
`Ex.2001(Berkland Decl.) at ¶¶66-67, 79-85; Ex.2043(Lieberman Vol. 2), 349
`
`
`2 Petitioner’s expert, Dr. Batchelor, attempts to explain how to account for
`
`hydrolytic degradation only in the context of certain dependent claims. See, e.g.,
`
`Ex.1003(Batchelor Decl.), ¶¶34-36, 46-47; Pet., 30-31, 50-51. Patent Owner
`
`disagrees with Dr. Batchelor’s method to account for this degradation, along with
`
`other issues in her analysis, but does not address these here because her analysis is
`
`limited to certain dependent claims only.
`
`
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`6
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`IPR2023-00512
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`(disclosing that “[d]rugs are metabolized by enzyme systems of the body” and
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`“[t]he net effect may be inactivation or detoxification of the compound….”). The
`
`prior art recognized that 5-azacytidine “suffers [] from several drawbacks”
`
`including “the ubiquitous cellular enzyme cytidine deaminase (CDA) since
`
`deamination of [5-azacytidine] results in total loss of activity.” Ex.2017(Gaubert),
`
`837-838; Ex.2001(Berkland Decl.) at ¶81. This “degradation of [] cytidine
`
`analog[s]” such as 5-azacytidine “by cytidine deaminases” was associated with
`
`“[t]he poor bioavailability of such cytidine analogs….” Ex.1021(Sands), ¶[0012];
`
`Ex.2001(Berkland Decl.) at ¶81.3 Again, a POSA would have understood that
`
`cytidine deaminases would also metabolize 5-azacytidine before a therapeutically
`
`effective amount of the drug could be absorbed in the gastrointestinal tract, thus
`
`complicating any oral formulation development. See, e.g., Ex.1021(Sands),
`
`¶¶[0012], [0029]-[0030]; Ex. 1034-0001(Stoltz); Ex.2001 (Berkland Decl.) at
`
`¶¶65-67.
`
`Further, a POSA would have understood that drug formulation development
`
`is a complicated process. Ex.2001(Berkland Decl.) at ¶64. For instance, “[c]ertain
`
`
`3 Neither of Petitioner’s experts nor the Petition addresses the instability of 5-
`
`azacytidine due to enzymatic degradation.
`
`
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`
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`7
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`

`

`IPR2023-00512
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`pharmaceutical agents, particularly…many chemotherapeutic agents, can only be
`
`given parenterally because they are inactivated in the gastrointestinal tract when
`
`given by mouth.” Ex.2028(Remington 2005) at 802; Ex.2001(Berkland Decl.) at
`
`¶64. Gibson, cited by Petitioner in Grounds 2 and 3, states that formulating any
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`pharmaceutical dosage form involves finding “an equilibrium between the
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`bioavailability of the product, its chemical and physical stability and the technical
`
`feasibility of producing it” because “[a]ny changes made to a formulation in an
`
`attempt to optimise one of these properties” was known to “likely [] have an effect
`
`on the other[s]” which “is especially true of immediate-release solid dosage
`
`forms.”4 Ex.1006-0032(Gibson); Ex.2001(Berkland Decl.) at ¶64. Thus, it would
`
`have been well understood by a POSA in December 2008 that developing
`
`therapeutic, oral tablet 5-azacytidine formulations to overcome the harsh acidic
`
`environment of the stomach and enzymatic metabolism was both necessary and
`
`challenging. Ex.2001(Berkland Decl.) at ¶66-67.
`
`Due to these numerous challenges, it took many years to develop an oral
`
`tablet formulation of 5-azacytidine, even after the FDA approved intravenous or
`
`subcutaneous administered 5-azacytidine (Vidaza®). Ex.1007(Vidaza® Label
`
`
`4 All quoted emphasis is added unless otherwise noted.
`
`
`
`
`
`8
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`

`

`IPR2023-00512
`
`2004); Ex.2018(Kaminskas); Ex.1001(’628 patent), 3:54-56; Ex.2025(Onureg®
`
`Label); Ex.2001(Berkland Decl.) at ¶¶46-47. The combination of chemical
`
`instability and enzymatic instability frustrated development of 5-azacytidine
`
`formulations for oral delivery. Ex.1001(’628 patent), 3:54-56; Ex.2001(Berkland
`
`Decl.) at ¶47. Because “[a] drug administered as a tablet…must be released and
`
`reach its site of action in an active state before it can exert a pharmacological
`
`response,” a POSA would have recognized the above degradation pathways as
`
`impeding non-enteric coated oral formulations of 5-azacytidine.
`
`Ex.2043(Lieberman Vol. 2), 352-53; Ex.2001(Berkland Decl.) at ¶¶64-67.
`
`3.
`
`A POSA would have attempted to develop enteric coated
`tablets
`To overcome these challenges, a POSA would have attempted to protect 5-
`
`azacytidine from degradation by using an enteric coating. Ex.1001(’628 patent),
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`3:58-65 (citing Ex.1021(Sands)); Ex.2001(Berkland Decl.) at ¶67. Enteric coated
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`tablets are delayed release formulations that are not soluble in the highly acidic
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`stomach but readily dissolve in the near neutral pHs of the intestines once the
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`tablet has passed through the stomach. Ex.1006-0068(Gibson), -0070; Ex.1030-
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`0049(Remington); Ex.2015(Evans), 1035; Ex.2043(Lieberman Vol. 2), 349-50;
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`Ex.2001(Berkland Decl.) at ¶49. Enteric coated tablets are used in situations
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`where release of compounds in the stomach results in undesirable effects including
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`compound degradation or inactivation by stomach contents. Ex.1006-
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`0068(Gibson); Ex.1030-0049(Remington); Ex.2001(Berkland Decl.) at ¶49. In
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`contrast to an enteric coated tablet, a non-enteric coated tablet does not contain a
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`coating designed to prevent release of the drug in the acidic environment of the
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`stomach. Ex.1001(’628 patent), 11:42-45; Ex.2001(Berkland Decl.) at ¶49. Thus,
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`it was well understood by a POSA in December 2008 that an enteric coated tablet,
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`rather than a non-enteric coated tablet, should be used for an oral formulation to
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`protect 5-azacytidine from degradation by the harsh, acidic stomach environment
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`to the extent a POSA would have been motivated to make an oral tablet of 5-
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`azacytidine at all. See VIII.B; Ex.2001(Berkland Decl.) at ¶¶57, 77, 83.
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`4. Onureg®
`Contrary to the expectations taught in the art, the inventors developed a non-
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`enteric coated tablet of oral 5-azacytidine as disclosed and claimed in the ’628
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`patent. Ex.1001(’628 patent), claims 1, 28. This non-enteric coated tablet
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`formulation of oral 5-azacytidine was approved by the FDA in September 2020 as
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`Onureg®, almost fifty years after scientists had identified 5-azacytidine’s anti-
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`tumoral effect and more than a decade and a half after FDA-approval of the
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`injectable formulation Vidaza®. Ex.2002(FDA Approves Onureg®);
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`Ex.1007(Vidaza® Label 2004); Ex.2018(Kaminskas); Ex.2025(Onureg® Label).
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`Onureg®, which has been granted orphan drug designation, became the first oral
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`tablet formulation of 5-azacytidine approved for continued treatment of patients
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`with acute myeloid leukemia (“AML”) who achieved remission following
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`intensive induction chemotherapy and are not able to complete intensive curative
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`therapy. Ex.2025(Onureg® Label), 1. Canada and Europe followed suit, approving
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`Onureg® in January and June 2021, respectively. Ex.2006(Canadian Product
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`200mg Onureg® Product Information); Ex.2007(Canadian Product 300mg Onureg®
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`Product Information); Ex.2008(Canadian Product Monograph Onureg®);
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`Ex.2013(European Commission Decision 17.6.21).
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`B.
`The ’628 Patent
`The inventions claimed in the ’628 patent relate to a pharmaceutical
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`composition comprising therapeutically effective amounts of 5-azacytidine for oral
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`administration in a non-enteric coated tablet as well as methods for treating
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`diseases and disorders (e.g., AML or myelodysplastic syndromes (MDS)) using
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`these compositions. Ex.1001(’628 patent), Abstract, 6:56-65, 11:42-48, claims 1,
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`28; Ex.2001(Berkland Decl.) at ¶¶31-33.
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`As discussed above and explained in the ’628 patent, it was known in the art
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`as of December 2008 that “oral delivery of cytidine analogs has proven difficult
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`due to combinations of chemical instability, enzymatic instability, and/or poor
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`permeability.” Ex.1001(’628 patent), 3:54-56. The ’628 patent explains that
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`“[p]revious attempts to develop oral dosage forms of cytidine analogs have
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`required enteric coating of the drug core to protect the active pharmaceutical
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`ingredient (API) from what was understood and accepted to be therapeutically
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`unacceptable hydrolysis in the stomach, such that the drug is preferably absorbed
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`in specific regions of the lower gastrointestinal tract….” Id. 3:58-65. The ’628
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`patent notes that a POSA also would have been concerned with hydrolysis during
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`formulation, and coatings were thus limited to organic solvent-based systems. Id.
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`4:1-7.
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`Unexpectedly, the inventors found that “formulations comprising…5-
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`azacytidine…and, optionally, one or more excipients…effect[ing] an immediate
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`release of the API upon oral administration” were therapeutically effective.
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`Ex.1001(’628 patent), 34:30-36; 4:21-27. The ’628 patent specification further
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`describes non-limiting embodiments of methods of treating disorders, including
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`AML, with non-enteric coated tablets comprising 5-azacytidine. See, e.g., Id.,
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`57:46-63, 68:47-73:8. These novel non-enteric coated formulations “demonstrated
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`bioavailability in patients” with “positive clinical activity [for] patients” and with
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`“[n]o safety issues….” Id., 71:39-44. Additionally, they also “provided a superior
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`percent exposure…[compared to] enteric-coated azacitidine formulations”5 despite
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`being released in the harsh environment of the stomach. Id., 73:1-6.
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`III. PROSECUTION HISTORY OF THE ’628 PATENT
`U.S. Patent Application 12/466,213 (the “’213 application”) underwent
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`extensive and substantive examination at the Patent Office before being properly
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`granted as the ’628 patent.
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`Before examination, Applicant submitted a first IDS including three versions
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`of Ionescu, the primary reference cited in the Petition. See Ex.1022-0185-
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`0187(IDS submitted April 2, 2010, disclosing U.S. Pat. Nos. 6,887,855 (“Ionescu-
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`855”) and 7,078,518 (“Ionescu-518”) and U.S. Pat. Pub. No. US2006/0247189
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`(“Ionescu-189”), which are substantively identical to Ionescu); Pet., 1-4.
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`Applicant’s first IDS also included an International Search Report (“ISR”) relating
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`to an International Patent Application in the same family as the ’213 application.
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`See Ex.1022-0187(IDS submitted April 2, 2010). The ISR submitted by Applicant
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`cites to another reference substantively identical to Ionescu. Ex.1022-0187(IDS
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`submitted April 2, 2010); Ex.1022-0633-0636(ISR citing U.S. Pat. Pub. No.
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`5 “5-azacytidine” and “azacitidine” are interchangeable terms for the same
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`compound. See Ex.1001(’628 patent), 2:33-35.
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`US2004/0186065 (“Ionescu-065”)). The Examiner considered this IDS and the
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`cited references before issuing a first Office Action rejecting the claims as both
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`allegedly anticipated and obvious. Ex.1022-0707-0709(IDS considered July 19,
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`2011); see also Ex.1022-0646(Office Action dated August 1, 2011, disclosing
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`“One Information Disclosure Statement (IDS) filed April 2, 2010, has been
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`received with all cited references, annotated, and made of record”), -0651-0654.
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`Along with a response to the first Office Action, Applicant submitted a
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`second IDS that included two additional references with disclosures that are
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`substantively identical to Ionescu. Ex.1022-0735(IDS submitted December 1,
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`2011, disclosing U.S. Pat. No. 7,772,199 (“Ionescu-199”) and U.S. Pat. Pub. No.
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`US2010/0298253 (“Ionescu-253”)). The Examiner considered both references and
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`“carefully reviewed the prior art of record cited above” before issuing a second
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`Office Action withdrawing the anticipation rejection. Ex.1022-1100(IDS
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`considered February 23, 2012); see also Ex.1022-1074(Office Action dated Feb.
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`28, 2012, disclosing “One additional or supplemental Information Disclosure
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`Statement (1 IDS) filed December 1, 2011, has been received with all cited non-US
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`patent references, annotated, and made of record.”), -1082.
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`Shortly after the second Office Action issued, and before another
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`communication from the Patent Office, Applicant submitted a third IDS disclosing
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`Ionescu (Ex.1022-1129(IDS submitted September 5, 2012 disclosing International
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`Pat. Appl. No. WO2004/082619 (Ex.1004, “Ionescu”))), which the Examiner
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`considered (Ex.1022-2027(IDS considered August 24, 2013); see also (Ex.1022-
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`2017(Office Action dated August 29, 2013 disclosing an “additional or
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`supplemental Information Disclosure Statement[]…filed September 5, 2012…ha[s]
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`been received with all cited non-US patent references, annotated, and made of
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`record.”)).
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`Following a third Office Action, Applicant filed a response, successfully
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`arguing that “[a] novel and unique element of the claimed composition is the
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`absence of an enteric coating, i.e., a coating that is designed to release the active
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`ingredient beyond the acidic environment of the stomach when orally
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`administered.” Ex.1022-2072-2073(Office Action Response dated February 27,
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`2014). Applicant’s response was accompanied by a declaration of Dr. Charles L.
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`Beach under 37 C.F.R. 1.