UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`APOTEX INC.,
`Petitioner
`
`v.
`
`CELGENE 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
`
`
`
`
`
`PETITIONER’S SECOND SET OF OBJECTIONS TO
`PATENT OWNER’S EVIDENCE PURSUANT TO 37 C.F.R. § 42.64
`
`
`
`
`Doc # NY/32417550v3
`
`
`
`
`
`

`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Pursuant to 37 C.F.R. § 42.64(b)(1), Petitioner Apotex Inc. (“Petitioner”)
`
`submits the following objections to evidence served by Celgene Corporation
`
`(“Patent Owner”) with Patent Owner’s Response (“POR”) (Paper No. 15), in the
`
`above-captioned
`
`proceeding.
`
` These
`
`objections
`
`are
`
`timely
`
`under
`
`37 C.F.R. § 42.64(b)(1) because they are being filed within five (5) business days
`
`of service of evidence to which these objections are directed. Petitioner’s
`
`objections provide notice to Patent Owner that Petitioner may move to exclude
`
`these exhibits under 37 C.F.R. § 42.64(c). Petitioner’s objections apply equally to
`
`Patent Owner’s reliance on the exhibit in any documents concurrently-filed with
`
`the exhibit or any subsequently-filed documents.
`
`In this paper, a reference to “FRE” means the Federal Rules of Evidence and
`
`“’628 patent” means U.S. Patent No. 8,846,628. Exhibit descriptions provided in
`
`Table 1 are from Patent Owner’s exhibit list and are used for identification
`
`purposes only. The use of an exhibit description does not indicate that Petitioner
`
`agrees with that description or characterization of the document.
`
`Notwithstanding these objections, Petitioner expressly reserves the right to
`
`rely on any evidence submitted by Patent Owner, including on the ground that such
`
`evidence constitutes a party admission.
`
`Petitioner incorporates by reference and reiterates, as if expressly stated
`
`herein, all objections previously served on Patent Owners on August 3, 2023.
`
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`

`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Petitioner objects to Exhibits 2051-2054 as incomplete, lacking relevance,
`
`and because any probative value is substantially outweighed by the danger of
`
`undue prejudice (due to confusing the issues, misleading the fact finder, undue
`
`delay, wasting time, and/or needlessly presenting cumulative evidence). See FRE
`
`106, 401, 402, and 403.
`
`Petitioner further objects to Exhibit 2051, “Expert Declaration of Cory
`
`Berkland, Ph.D.” Petitioner objects to ¶¶ 30-32, 34-38, 40-41, 43-45, 47, 70-85,
`
`88-98, 100-104, 106-107, 109-115, 118-124, 126-134, 136-144, 149 of Exhibit
`
`2051 and all paragraphs that rely on those paragraphs. These paragraphs lack a
`
`disclosed basis of sufficient facts or data (FRE 705; 37 C.F.R. § 42.65), are not
`
`based on sufficient facts or data (FRE 702), and/or are not the product of reliable
`
`principles and methods (FRE 702). Additionally, Petitioner objects to the above
`
`referenced paragraphs of Exhibit 2051 and all paragraphs that rely on those
`
`paragraphs as misleading, incomplete, and lacking relevance and because any
`
`probative value is substantially outweighed by the danger of unfair prejudice,
`
`confusing the issues, misleading the fact finder, undue delay, wasting time, and
`
`needlessly presenting cumulative evidence (FRE 106, 401, 402, and 403).
`
`Petitioner further objects to ¶¶ 1-29, 42, 45-49, 51-60, 70-74, 94, 120, 122-
`
`126, 135, 145-146, 150-151 of Exhibit 2051 and all paragraphs of any declaration
`
`that rely on those paragraphs. These paragraphs are irrelevant (FRE 401 and 402),
`
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`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`and any probative value is substantially outweighed by the risk of undue prejudice
`
`and/or confusion (FRE 403).
`
`Petitioner further objects to ¶¶ 29-31, 45, 47, 52-53, 98, 119-120, 144 of
`
`Exhibit 2051 and all paragraphs of any declaration that rely on those paragraphs.
`
`These paragraphs rely on out of court statements for their truth, thus constituting
`
`impermissible hearsay. See FRE 801-804.
`
`Petitioner further objects to Exhibit 2052, “Expert Declaration of George M.
`
`Grass IV, Ph.D.” Petitioner objects to ¶¶ 26, 39-46, 48-60, 62-77, 79-87, 92-97 of
`
`Exhibit 2052 and all paragraphs that rely on those paragraphs. These paragraphs
`
`lack a disclosed basis of sufficient facts or data (FRE 705; 37 C.F.R. § 42.65), are
`
`not based on sufficient facts or data (FRE 702), and/or are not the product of
`
`reliable principles and methods (FRE 702). Additionally, Petitioner objects to the
`
`above referenced paragraphs of Exhibit 2052 and all paragraphs that rely on those
`
`paragraphs as misleading, incomplete, and lacking relevance and because any
`
`probative value is substantially outweighed by the danger of unfair prejudice,
`
`confusing the issues, misleading the fact finder, undue delay, wasting time, and
`
`needlessly presenting cumulative evidence (FRE 106, 401, 402, and 403).
`
`Petitioner further objects to ¶¶ 1-15, 25-26, 31-34, 36-38, 91-92, 96, 99-100
`
`of Exhibit 2052 and all paragraphs of any declaration that rely on those paragraphs.
`
`These paragraphs are irrelevant (FRE 401 and 402), and any probative value is
`
`
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`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`substantially outweighed by the risk of undue prejudice and/or confusion (FRE
`
`403).
`
`Petitioner further objects to ¶¶ 15, 26, 92, 96-97 of Exhibit 2052 and all
`
`paragraphs of any declaration that rely on those paragraphs. These paragraphs rely
`
`on out of court statements for their truth, thus constituting impermissible hearsay.
`
`See FRE 801-804.
`
`Petitioner further objects to Exhibit 2053, “Expert Declaration of William G.
`
`Blum, MD.” Petitioner objects to ¶¶ 21, 24-40, 47 of Exhibit 2053 and all
`
`paragraphs that rely on those paragraphs. These paragraphs lack a disclosed basis
`
`of sufficient facts or data (FRE 705; 37 C.F.R. § 42.65), are not based on sufficient
`
`facts or data (FRE 702), and/or are not the product of reliable principles and
`
`methods (FRE 702). Additionally, Petitioner objects to the above referenced
`
`paragraphs of Exhibit 2053 and all paragraphs that rely on those paragraphs as
`
`misleading, incomplete, and lacking relevance and because any probative value is
`
`substantially outweighed by the danger of unfair prejudice, confusing the issues,
`
`misleading the fact finder, undue delay, wasting time, and needlessly presenting
`
`cumulative evidence (FRE 106, 401, 402, and 403).
`
`Petitioner further objects to ¶¶ 1-10, 17-23, 28, 38-40, 48-50 of Exhibit 2053
`
`and all paragraphs of any declaration that rely on those paragraphs. These
`
`paragraphs are irrelevant (FRE 401 and 402), and any probative value is
`
`
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`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`substantially outweighed by the risk of undue prejudice and/or confusion (FRE
`
`403).
`
`Petitioner further objects to ¶¶ 21, 32-47 of Exhibit 2053 and all paragraphs
`
`of any declaration that rely on those paragraphs. These paragraphs rely on out of
`
`court statements for their truth, thus constituting impermissible hearsay. See FRE
`
`801-804.
`
`Petitioner further objects to Exhibit 2054, “Expert Declaration of Jeffrey
`
`Etter, Ph.D.” Petitioner objects to the entirety of Exhibit 2054 (1) as an improper
`
`expert declaration by an interested fact witness and (2) as irrelevant and unduly
`
`prejudicial because it contains opinions and/or factual recitations not based on
`
`patents or printed publications. FRE 401-403; see also 35 U.S.C. § 311(b), Patent
`
`Trial and Appeal Board Consolidated Trial Practice Guide (Nov. 2019) at 36
`
`(“expert testimony may explain ‘patents and printed publications,’ but is not a
`
`substitute for disclosure in a prior art reference itself.”)
`
`Petitioner further objects to ¶¶ 8-35 of Exhibit 2054 and all paragraphs that
`
`rely on those paragraphs. These paragraphs lack a disclosed basis of sufficient
`
`facts or data (FRE 705; 37 C.F.R. § 42.65; FRE 403), are not based on sufficient
`
`facts or data, are not the product of reliable principles and methods (FRE 702; FRE
`
`403), are not based on the kinds of facts or data experts would reasonably rely on
`
`in forming an opinion (FRE 703), and/or are based on facts or data that would
`
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`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`otherwise be inadmissible and the probative value of these paragraphs do not
`
`outweigh their prejudicial effect (FRE 703; FRE 705; 37 C.F.R. § 42.63).
`
`Additionally, Petitioner objects to the above referenced paragraphs of Exhibit 2054
`
`and all paragraphs that rely on those paragraphs as misleading, incomplete, and
`
`lacking relevance and because any probative value is substantially outweighed by
`
`the danger of unfair prejudice, confusing the issues, misleading the fact finder,
`
`undue delay, wasting time, and needlessly presenting cumulative evidence. See
`
`FRE 106, 401, 402, and 403.
`
`Petitioner further objects to ¶¶ 8-35 of Exhibit 2054 for a lack of evidence
`
`sufficient to support a finding that the witness has personal knowledge of the
`
`matter (FRE 602) and/or as improper lay testimony (FRE 701).
`
`Petitioner further objects to ¶¶ 1, 3-7, 36-38 of Exhibit 2054 and all
`
`paragraphs that rely on those paragraphs. These paragraphs are irrelevant (FRE
`
`401 and 402), and any probative value is substantially outweighed by the risk of
`
`undue prejudice and/or confusion (FRE 403).
`
`Petitioner further objects to ¶¶ 12, 35 of Exhibit 2054 and all paragraphs of
`
`any declaration that rely on those paragraphs. These paragraphs rely on out of
`
`court statements for their truth, thus constituting impermissible hearsay. See FRE
`
`801-804.
`
`
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`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Petitioner also objects to Exhibits 2051-2054 for lacking relevance to the
`
`extent they rely on or cite to a document with a purported date that is after the
`
`priority date of the ’628 patent for any purpose other than in connection with a
`
`purported unexpected results, industry praise, skepticism, or satisfaction of a long-
`
`felt need (but not the existence of a long-felt need). See FRE 401, 402, and 403.
`
`Petitioner also objects to Exhibit 2001 to the extent it relies on an exhibit
`
`containing an out of court statements for
`
`their
`
`truth,
`
`thus constituting
`
`impermissible hearsay. See FRE 801-804. Petitioner also objects to Exhibits
`
`2051-2054 to the extent they rely on or cite a document lacking proper
`
`authentication. See FRE 901-902.
`
`Petitioner further objects to any portion of Exhibits 2051-2054 that relies on
`
`or cites to an Exhibit listed below in Table 1 for the same reasons included in
`
`Table 1 for that Exhibit. Petitioner further objects to Patent Owner’s exhibits and
`
`Patent Owner’s reliance on them for the reasons set forth below in Table 1 and the
`
`Objection Key.
`
`No.
`
`1022
`
`Table 1.
`Exhibit
`Prosecution History of the ’628 patent, in particular the
`Declaration of Dr. Charles L. Beach under 37 C.F.R. §
`1.132 (“Beach Decl.”)
`2001 Declaration of Dr. Corey Berkland
`U.S. Food and Drug Admin., FDA approves Onureg®
`(azacytidine tablets) for acute myeloid leukemia (2020),
`https://www.fda.gov/drugs/resources-information-
`
`2002
`
`Objections
`
`F
`
`H
`
`B, C, D, E, H
`
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`

`

`No.
`
`2023
`
`2040
`
`2042
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`approved-drugs/fdaapproves-onureg-azacitidine-tablets-
`acute-myeloid-leukemia (“FDA Approves Onureg®”)
`2006 Canadian Product 200mg Onureg® Product Information B, C, D, E, G, H
`2007 Canadian Product 300mg Onureg® Product Information B, C, D, E, G, H
`2008 Canadian Product Monograph Onureg®
`B, C, D, E, G, H
`2013 European Commission Decision 17.6.21
`B, C, D, E, H
`2016 FASTtrack 2010 (“FASTtrack”)
`B, C, D, E, H
`National Cancer Institute, Bioassay of 5-azacytidine for
`Possible Carcinogenicity, U.S. DEP’T OF HEALTH,
`EDUC., AND WELFARE (1978) (“National Cancer
`Institute”)
`2025 Onureg® Label
`2026 International Pat. Appl. Pub. No. WO2009/139888
`(“WO2009/139888”)
`2028 REMINGTON, THE SCIENCE AND PRACTICE OF PHARMACY
`C, D, E, F, G
`802–938 (21st Ed. 2005) (“Remington 2005”)
`2030 U.S. Pat. Pub. No. US20040186065A1 (“Ionescu-065”) C, D, E, H
`2035 U.S. Pat. No. 6,887,855 (“Ionescu-855”)
`C, D, E, H
`2036 U.S. Pat. No. 7,078,518 (“Ionescu-518”)
`C, D, E, H
`2037 U.S. Pat. No. 7,772,199 (“Ionescu-199”)
`C, D, E, H
`2038 U.S. Pat. Pub. No. US20060247189 (“Ionescu-189”)
`C, D, E, H
`2039 U.S. Pat. Pub. No. US20100298253 (“Ionescu-253”)
`B, C, D, E, H
`Ward, M., et al., An oral dosage formulation of
`azacytidine: A pilot pharmacokinetic study, J. OF
`CLINICAL ONCOLOGY (2007) (“Ward”)
`2041 International Pat. Appl. Pub. No. WO2008/028193
`(“WO2008/028193”)
`Gibson, M., Pharm. PREFORMULATION AND
`FORMULATION: A PRACTICAL GUIDE FROM CANDIDATE
`DRUG SELECTION TO COMMERCIAL DOSAGE FORM 1-11
`(2001) (“Gibson Supplemental”)
`2043 Lieberman, H., et al., PHARMACEUTICAL DOSAGE FORMS
`2 (2nd Ed. 1990) (“Lieberman Vol. 2”)
`2044 International Pat. Appl. Pub. No. WO2004/082618
`(“WO2004/082618”)
`2047 Savage 1967 (“Savage”)
`2048 Pawar, et al., Integration of Biorelevant Pediatric
`Dissolution Methodology into PBPK Modeling to
`
`A, C, D, E, H
`
`B, C, D, E, H
`B, C, D, E, H
`
`C, D, E
`
`B, C, D, E, F
`
`A, C, D, H
`
`C, D, E, H
`
`C, D, E
`C, D, E, H
`B, C, D, F
`
`
`
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`

`

`No.
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Predict In Vivo Performance and Bioequivalence of
`Generic Drugs in Pediatric Populations: A
`Carbamazepine Case Study, 25 AAPS J. 67 (2023)
`(“Pawar”)
`
`2049 Deposition Transcript of Hannah K. Batchelor
`(“Batchelor Tr.”)
`
`2050 Deposition Transcript of Graham Buckton, Ph.D.
`(“Buckton Tr.”)
`
`2055
`
`U.S. Food and Drug Admin., FDA approves Onureg®
`(azacytidine tablets) for acute myeloid leukemia (2020),
`https://www.fda.gov/drugs/resources-information-
`approved-drugs/fdaapproves-onureg-azacitidine-tablets-
`acute-myeloid-leukemia (“FDA Approves Onureg®”)
`2056 Canadian Product 200mg Onureg Product Information
`2057 Canadian Product 300mg Onureg Product Information
`2058 Canadian Product Monograph Onureg
`2059 European Commission Decision 17.6.21
`2060 Perrie, Y. & Rades, T., PHARMACEUTICAL: DRUG
`DELIVERY AND TARGETING (2010) (“FASTtrack”)
`
`Petitioner
`incorporates by
`reference and
`reiterate the
`objections made
`on the record
`during the
`deposition
`Petitioner
`incorporates by
`reference and
`reiterate the
`objections made
`on the record
`during the
`deposition.
`Additionally,
`Exhibit 2050 is
`incomplete
`because it does
`not include the
`errata that was
`timely returned.
`
`B, C, D, E, F, G
`
`B, C, D, E, F
`B, C, D, E, F, G
`B, C, D, E, F, G
`B, C, D, E, F, G
`B, C, D, E, F, G
`
`
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`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`B, C, D, E, F, G
`
`A, C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`No.
`2062 Onureg® Label
`Gibson, M., Pharm. PREFORMULATION AND
`FORMULATION: A PRACTICAL GUIDE FROM CANDIDATE
`DRUG SELECTION TO COMMERCIAL DOSAGE FORM 1-11
`(2001) (“Gibson Supplemental”)
`2064 Altman, R, & Sarg, M., CANCER DICTIONARY: REVISED
`EDITION 16–17, 197 (2000) (“Altman”)
`2065 Allen, L, Et Al., ANSEL’S PHARM. DOSAGE FORMS AND
`DRUG DELIVERY SYS. (8th Ed. 2005) (“Ansel”)
`Antonsson, B., et al., Effect of 5-Azacytidine and
`Congeners on DNA Methylation and Expression of
`Deoxycytidine Kinase in the Human Lymphoid Cell
`Lines CCRF/CEM/0 and CCRF/CEM/dCk-1, 47 CANCER
`RESEARCH 3762–78 (1987) (“Antonsson”)
`2067 Aulton, M., PHARMACEUTICS: THE SCIENCE OF DOSAGE
`FORM DESIGN (1988) (“Aulton”)
`Bankhead, C., Year in Review: Acute Myeloid
`Leukemia, MedPage Today (Nov. 29, 2020),
`https://www.medpagetoday.com/hematologyoncolog
`y/leukemia/89909 (“Bankhead”)
`Ben-Kasus, T., et al., Metabolic activation of
`zebularine, a novel DNA methylation inhibitor, in
`human bladder carcinoma cells, 70 BIOCHEM. PHARM.
`121–33 (2005) (“Ben-Kasus”)
`Carter, J., et al., Targeting multiple signaling pathways:
`the new approach to acute myeloid leukemia therapy, 5
`SIGNAL TRANSDUCTION AND TARGETED THERAPY 288
`(2020) (“Carter”)
`Choi, Y., et al., Oral Maintenance Chemotherapy with
`6-Mercaptopurine and Methotrexate in Patients with
`Acute Myeloid Leukemia Ineligible for Transplantation,
`30 KOREAN ACADEMY OF MED. SCI. 1416–22 (2015)
`(“Choi”)
`Cogle, C., et al., Oral Azacitidine (CC-486) for the
`Treatment of Myelodysplastic Syndromes and Acute
`Myeloid Leukemia, 20 ONCOLOGIST 1404–12 (2015)
`(“Cogle”)
`
`2063
`
`2066
`
`2068
`
`2070
`
`2071
`
`2072
`
`2073
`
`
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`
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`

`

`No.
`
`2074
`
`2076
`
`2077
`
`2078
`
`2080
`
`2081
`
`2082
`
`2083
`
`2084
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Covey, J., et al., Differences in DNA Damage Produced
`by Incorporation of 5-Aza-2’-deoxycytidine or 5,6-
`Dihydro-5-azacytidine into DNA of Mammalian Cells,
`46 CANCER RESEARCH 5511–17 (1986) (“Covey”)
`2075 Craig, C. & Stitzel, R., MODERN PHARMACOLOGY WITH
`CLINICAL APP. (6th Ed. 2004) 48–55 (“Craig”)
`Curtiss, F., Pharmacy Benefit Spending on Oral
`Chemotherapy Drugs, 12 J. OF MANAGED CARE
`PHARMACY 570–77 (2006) (“Curtiss”)
`DeSimone, J., et al., Tetrahydrouridine, Cytidine,
`Analogues, and Hemoglobin F, 18 AM. J. OF
`HEMATOLOGY 283–88 (1985) (“DeSimone”)
`Dressman, J., et al., Dissolution Testing as a Prognostic
`Tool for Oral Drug Absorption: Immediate Release
`Dosage Forms, 15 PHARM. RESEARCH 11–22 (1998)
`(“Dressman”)
`2079 Case Reports, 72 BRITISH J. OF HAEMATOLOGY 467–68
`(1989) (“Dunbar”)
`Ellison, R., et al., Arabinosyl Cytosine: A Useful Agent
`in the Treatment of Acute Leukemia in Adults, 32 J. OF
`HEMATOLOGY 507–23 (1968) (“Ellisson”)
`The ASCO Post Staff, “FDA Approves Oral Azacitidine
`as Maintenance Therapy for Adults With AML in First
`Remission” (Sept. 25, 2020),
`https://ascopost.com/issues/september-25-
`2020/fdaapproves-oral-azacitidine-as-maintenance-
`therapy-for-adults-withaml-in-first-remission/ (“FDA
`Approves Oral Azacitidine”)
`Frisch, A., et al., How we treat older patients with acute
`myeloid leukaemia, 191 BRITISH J. OF HAEMATOLOGY
`682–91 (2020) (“Frisch”)
`Futterman, B., et al., Studies on the Cytostatic Action
`Phosphorylation and Deamination of 5-Azacytidine and
`5,6-Dihydro-5-Azacytidine in Hela Cells, 27 BIOCHEM.
`PHARM. 907–9 (1978) (“Futterman”)
`Garcia-Manero, G., et al., Phase I Study of Oral
`Azacitidine in Myelodysplastic Syndromes, Chronic
`Myelomonocytic Leukemia, and Acute Myeloid
`
`C, D, E, F
`
`B, C, D, E, F
`
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`

`

`No.
`
`2085
`
`2086
`
`2087
`
`2089
`
`2090
`
`2091
`
`2092
`
`2093
`
`A, C, D, E, F, G
`
`B, C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Leukemia, 29 J. OF CLIN. ONCOLOGY 2521–27 (2011)
`(“Garcia-Manero”)
`Goldin, A., et al., Relation of Structure of Purine and
`Pyrimidine Nucleosides to Antitumor Activity, 1
`CANCER CHEMOTHERAPY 1–29, 268 (1968) (“Goldin”)
`Griffiths, E., Oral hypomethylating agents: beyond
`convenience in MDS, 2021 HEMATOLOGY 439–47
`(2021) (“Griffiths”)
`Grønbæk, K., et al., Epigenetic Changes in Cancer as
`Potential Targets for Prophylaxis and Maintenance
`Therapy, 103 BASIC & CLINICAL PHARM. &
`TOXICOLOGY 389–96 (2008) (“Grønbæk”)
`2088 Hrodek, O. & Vesely J., 5-Azacytidine in Childhood
`Leukemia, 18 NEOPLASMA 493–503 (1971) (“Hrodek”) C, D, E, F
`Kantarjian, H., et al., Acute Myeloid Leukemia:
`Historical Perspective and Progress in Research and
`Therapy Over 5 Decades, 21 CLIN. LYMPHOMA,
`MYELOMA AND LEUKEMIA 580–97 (2021)
`(“Kantarjian”)
`Karon, M., et al., 5-Azacytidine: A New Active Agent for
`the Treatment of Acute Leukemia, 42 BLOOD 359–65
`(1973) (“Karon”)
`Kipp, D. & Wei, A., The path to approval for oral
`hypomethylating agents in acute myeloid leukemia and
`myelodysplastic syndromes, 17(20) FUTURE ONCOL.
`2563–71 (2021) (“Kipp”)
`Kornblith, A., et al., Impact of Azacytidine on the
`Quality of Life of Patients With Myelodysplastic
`Syndrome Treated in a Randomized Phase III Trial: A
`Cancer and Leukemia Group B Study, 20 J. OF CLIN.
`ONCOLOGY 2441–52 (2002) (“Kornblith”)
`Lammers, P. & Cashen, A., Azacitidine: A Review of its
`Use in the Management of Myelodysplastic Syndromes,
`1 CLIN. MED. THERAPEUTICS 1189–97 (2009)
`(“Lammers”)
`
`B, C, D, E, F
`
`
`
`- 13 -
`
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`
`

`

`B, C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Lin, R., Allogeneic Transplantation for Older Patients
`with Acute Myeloid Leukemia: The Dawn of a New Era,
`28 TRANSPLANTATION AND CELLULAR THERAPY 793–94
`(2022) (“Lin 2022”)
`2095 Liu, H., Emerging agents and regimens for AML, 14 J.
`HEMATOLOGY & ONCOLOGY 19 (2021) (“Liu”)
`Lomen, V., et al., “Phase I Study of 5-Azacytidine
`Using 24 Hrs Continuous Infusion for 5 Days” 16
`PROCEEDINGS OF THE AM. ASS. FOR CANCER RESEARCH
`& AM. SOC. OF CLIN. ONCOLOGY 52 (Mar. 1975)
`(“Lomen”)
`Lӧwenberg, B., et al., Mitoxantrone Versus
`Daunorubicin in Induction-Consolidation
`Chemotherapy, 16 J. OF CLIN. ONCOLOGY 872–81
`(1998) (“Lӧwenberg”)
`Ma, X., et al., Myelodysplastic Syndromes: Incidence
`and Survival in the United States, 109 AM. CANCER
`SOC. 1536–42 (2007) (“Ma”)
`McCredie, K., Treatment of Acute Leukemia with 5-
`Azacytidine (NSC-102816), 57 CANCER CHEMOTHERAPY
`REP. 319–23 (1973) (“McCredie”)
`Neil, G., et al., Enhancement by Tetrahydrouridine
`(NSC-112907) of the Oral Activity of 5-Azacytidine
`(NSC-102816) in L1210 Leukemic Mice, 59 CANCER
`CHEMOTHERAPY REP. 459–65 (1975) (“Neil”)
`Odenike, O., Incorporating novel approaches in the
`management of MDS beyond conventional
`hypomethylating agents, AM. SOC. OF HEMATOLOGY
`460–69 (2017) (“Odenike”)
`Goodman, A., “Oral CC-486 Maintenance Therapy
`Extends Survival in Older Patients with AML” THE
`ASCO POST (Jan. 25, 2020),
`https://ascopost.com/issues/january-25-2020/oral-cc-
`486-maintenancetherapy-extends-survival-in-older-
`patients-with-aml/ (“Oral CC-486”)
`Perl, A., The role of targeted therapy in the
`management of patients with AML, 1 BLOOD ADVANCES
`AND HEMATOLOGY 2281–94 (2017) (“Perl”)
`
`No.
`
`2094
`
`2096
`
`2097
`
`2098
`
`2100
`
`2101
`
`2102
`
`2103
`
`2104
`
`B, C, D, E, F, G
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`
`
`- 14 -
`
`Doc # NY/32417550v3
`
`

`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`No.
`2107 Porta, M., A DICTIONARY OF EPIDEMIOLOGY 226–27
`A, B, C, D, E, F
`(5th Ed. 2008) (“Porta”)
`Preisler, H., et al., Comparison of Three Remission
`Induction Regimens and Two Postinduction Strategies
`for the Treatment of Acute Nonlymphocytic Leukemia,
`69 BLOOD 1441–49 (1987) (“Preisler”)
`Récher, C., The beginning of a new therapeutic era in
`acute myeloid leukemia, 2 J. HAEMATOLOGY 823–
`33(2021) (“Récher”)
`2111 Reville, P., Maintenance Therapy in AML, 10
`FRONTIERS IN ONCOLOGY (2021) (“Reville”)
`Shnider, B., et al., A Phase I Study of 5-Azacytidine
`(NSC-102816), 16(4) J. OF CLIN. PHARMACOLOGY 205–
`12 (1976) (“Shnider”)
`Slater, H., Phase 3 QUAZAR AML-001 Trial Finds Oral
`Azacitidine Extends Survival in Older Adults with AML,
`Cancer Network (Jan. 12, 2021) (“Slater”)
`Sochacka-Ćwikła, A., et al., FDA-Approved Drugs for
`Hematological Malignancies—The Last Decade Review,
`14 CANCERS 87 (2022) (“Sochacka-Ćwikła”)
`Sorm, F., et al., 5-Azacytidine, a New, Highly Effective
`Cancerostatic, 20 INSTITUTE OF ORGANIC CHEM. AND
`BIOCHEM. 202–3 (1964) (“Sorm”)
`Sorrentino, V., et al., Hypomethylating
`Chemotherapeutic Agents as Therapy for
`Myelodysplastic Syndromes and Prevention of Acute
`Myeloid Leukemia, 14 PHARMACEUTICALS 641 (2021)
`(“Sorrentino”)
`Southall, J., “Oral azacytidine extends survival for
`patients with AML in remission after chemotherapy”
`HemOncToday (Jan. 5, 2021) (“Southall”)
`Steensma, D., ASH 2010 Meeting Report—Top 10
`clinically-oriented abstracts in myelodysplastic
`syndromes (MDS), 86 AM. J. OF HEMATOLOGY 385–91
`(2011) (“Steensma”)
`
`C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`2108
`
`2110
`
`2112
`
`2114
`
`2115
`
`2116
`
`2118
`
`2119
`
`2120
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`
`
`- 15 -
`
`Doc # NY/32417550v3
`
`

`

`No.
`
`2121
`
`2122
`
`2125
`
`2126
`
`2127
`
`2128
`
`2129
`
`2130
`
`C, D, E, F
`
`C, D, E, F
`
`B, C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Surbone, A., et al., Phase I and Pharmacokinetic Study
`of Arabinofuranosyl-5-azacytosine (Fazarabine, NSC
`281272), 50 CANCER RESEARCH 1220–25 (1990)
`(“Surbone”)
`Toutain, P. & Bousquet-Melou, A., Bioavailability and
`its assessment, 27 J. VET. PHARMACOLOGY. THERAP.
`455–66 (2004) (“Toutain”)
`2123 U.S. Provisional 60/824320 File History (“60/824,320”) B, C, D, E, F
`2124 U.S. Patent Application US 2008/0057086
`B, C, D, E, F
`(“US2008/0057086”)
`Vigil, C., et al., Safety and efficacy of azacitidine in
`myelodysplastic syndromes, 4 DRUG DESIGN,
`DEVELOPMENT AND THERAPY 221–29 (2010) (“Vigil”)
`Vogler, W., et al., “Remission Induction in Refractory
`Myeloblastic Leukemia with Continuous Infusion of 5-
`Azacytidine” 16 PROCEEDINGS OF THE AM. ASS. FOR
`CANCER RESEARCH & AM. SOC. OF CLIN. ONCOLOGY
`155 (Mar. 1975) (“VoglerI”)
`Vogler, W., 5-Azacytidine (NSC 102816): A New Drug
`for the Treatment of Myeloblastic Leukemia, 48 BLOOD
`331–37 (1976) (“VoglerII”)
`Von Hoff, D., et al., 5-Azacytidine A New Anticancer
`Drug with Effectiveness in Acute Myelogenous
`Leukemia, 85 ANNALS OF INTERNAL MEDICINE 237–45
`(1976) (“VonHoff”)
`Wei, A., et al., Long-term survival with oral azacitidine
`for patients with acute myeloid leukemia in first
`remission after chemotherapy, 98 AM. J. OF
`HEMATOLOGY E84–87 (2023) (“Wei”)
`Weill Cornell Medicine, “New maintenance treatment
`for acute myeloid leukemia prolongs the lives of
`patients” NEW ENGLAND J. OF MED. (Jan. 22, 2021),
`https://news.weill.cornell.edu/news/2021/01/new-
`maintenancetreatment-for-acute-myeloid-leukemia-
`prolongs-the-lives-of-patients, (“Weill Cornell”)
`
`B, C, D, E, F
`
`B, C, D, E, F
`
`
`
`- 16 -
`
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`
`

`

`No.
`
`2131
`
`2132
`
`2136
`
`2140
`
`2141
`
`2142
`
`2143
`
`2144
`
`C, D, E, F
`
`B, C, D, E, F
`
`B, C, D, E, F, G
`B, C, D, E, F, G
`B, C, D, E, F, G
`
`B, C, D, E, F
`
`B, C, D, E, F, G
`B, C, D, E, F, G
`B, C, D, E, F, G
`
`C, D, E, F
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Zielinski, W. & Sprinzl, M., Chemical synthesis of 5-
`azacytidine nucleotides and preparation of tRNAs
`containing 5-azacytidine in its 3’-terminus, 12 NUCLEIC
`ACIDS RESEARCH 5025–36 (1984) (“Zielinski”)
`Ziemba, A., et al., Development of an Oral Form of
`Azacytidine: 2‘3‘5Triacetyl-5-Azacytidine, 2011
`CHEMOTHERAPY RESEARCH AND PRACTICE 1–9 (2011)
`(“Ziemba”)
`2133 Exemestane Label (“Exemestane”)
`2134 Anastrozole Label (“Anastrozole”)
`2135 Letrozole Label (“Letrozole”)
`Blum W, et al., Maintenance therapy with decitabine in
`younger adults with acute myeloid leukemia in first
`remission: a phase 2 Cancer and Leukemia Group B
`Study (CALGB 10503), 31 LEUKEMIA 34–39 (2017)
`(“Blum”)
`2137 Cytarabine Label (“Cytarabine”)
`2138 Dacogen Label (“Dacogen”)
`2139 Mitoxantrone Label (“Mitoxantrone”)
`Finkel, M., The Orphan Drug Act and the Federal
`Government’s Orphan Products Development Program,
`99 PUBLIC HEALTH REPS. 313–16 (1984) (“Finkel”)
`Martinez, M. & Amidon, G., A Mechanistic Approach
`to Understanding the Factors Affecting Drug
`Absorption, 42 J. OF CLIN. PHARMACOLOGY 620–43
`(2002) (“Martinez”)
`European Medicines Agency, Assessment Report of
`Onureg EMA/308711/2021(“European Medicines
`Report”)
`Hirayama, H., et al., Distribution and Excretion of
`Cyclocytidine in Monkeys, Dogs, and Rats, 65 GANN
`153–61 (1974) (“Hirayama”)
`Lieberman, H., et al., PHARMACEUTICAL DOSAGE
`FORMS: TABLETS 1 (2nd Ed. 1989) (“Lieberman Vol.
`1”)
`2145 Dean, D., et al., PHARMACEUTICAL PACKAGING
`TECHNOLOGY (2000) (“Dean”)
`
`C, D, E, F
`
`B, C, D, E, F, G
`
`C, D, E, F
`
`C, D, E, F
`
`C, D, E, F
`
`
`
`- 17 -
`
`Doc # NY/32417550v3
`
`

`

`No.
`
`2146
`
`2147
`
`2150
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Exhibit
`Objections
`Gennaro, A., REMINGTON’S PHARMACEUTICAL SCIENCES
`257–309, 1519–44, 1615–32 (18th Ed. 1990)
`(“Remington 1990”)
`REMINGTON, THE SCIENCE AND PRACTICE OF PHARMACY
`319–37, 702–19, 745–75, 1025–36 (21st Ed. 2005)
`(“Remington 2005 II”)
`2148 Gibaldi, M. & Perrier, D., PHARMACOKINETICS (2nd Ed.
`2007) 271–353 (“Gilbaldi”)
`Huls, G., et al. Azacitidine maintenance after intensive
`chemotherapy improves DFS in older AML patients,
`133 BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY
`OF HEMATOLOGY 1457–64 (2019) (“Huls”)
`
`
`C, D, E, F,
`
`C, D, E, F, G
`
`C, D, E, F
`
`B, C, D, E, F
`
`
`
`
`
`
`
`- 18 -
`
`Doc # NY/32417550v3
`
`

`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`Objection Key:
`A: FRE 106 (incomplete) the document is an incomplete writing.
`B:
`FRE 401/402/403 (relevance) the document is not relevant to any issue in
`this IPR proceeding beyond purported unexpected results, industry praise,
`skepticism, or satisfaction of a long-felt need (but not the existence of a long-felt
`need) because the purported date of the document is after the priority date of the
`’628 patent.
`C:
`FRE 401/402 (relevance) the document is not relevant to any issue in this
`IPR proceeding.
`D:
`FRE 403 (unduly prejudicial, waste of time, confusing) the document is not
`relevant to any issue in the IPR proceeding because any probative value is
`substantially outweighed by the danger of undue prejudice, confusing the issues,
`undue delay, misleading the factfinder, or wasting time.
`E:
`FRE 403 (cumulative) the document is not relevant to any issue in the IPR
`proceeding because any probative value is substantially outweighed by the danger
`of needlessly presenting cumulative evidence.
`F:
`FRE 801-804 (hearsay) the document contains out of court statements that
`Patent Owner relies on for their truth, thus constituting impermissible hearsay.
`G: FRE 901-902 the document lacks proper authentication and is not self-
`authenticating.
`H: Not relied upon by any expert cited in Patent Owner’s Response or cited in
`Patent Owner’s Response.
`
`
`
`
`
`
`
`- 19 -
`
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`
`

`

`Dated: October 19, 2023
`
`
`
`
`
`
`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`/s/ Vishal C. Gupta
`
`Vishal C. Gupta (Reg. No. 67,284)
`John J. Molenda (Reg. No. 47,804)
`Tyler Doh (Reg. No. 80,274)
`STEPTOE & JOHNSON LLP
`1114 Avenue of the Americas
`New York, NY 10036
`Tel: (212) 506-3900
`
`Robert Kappers (Reg. No. 70,202)
`STEPTOE & JOHNSON LLP
`227 West Monroe Street
`Suite 4700
`Chicago, IL 60606
`Tel: (312)-577-1300
`
`Counsel for Petitioner
`
`
`
`- 20 -
`
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`
`

`

`IPR2023-00512
`Petitioner’s Second Set of Objections to Evidence
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6(e), I certify that I caused to be served a true and
`
`correct copy of the foregoing: PETITIONER’S SECOND SET OF OBJECTIONS
`
`TO PATENT OWNER’S EVIDENCE by email to the electronic service addresses
`
`for Patent Owner:
`
`Lead Counsel
`Heather M. Petruzzi,
`Reg. No. 71,270
`Wilmer Cutler Pickering Hale and Dorr
`LLP
`2100 Pennsylvania Avenue N.W.
`Washington, DC 20037
`Tel: 202-663-6028
`Email:
`Heather.Petruzzi@wilmerhale.com
`
`Back-up Counsel
`Laura Macro, Ph.D.,
`Reg. No. 80,908
`Wilmer Cutler Pickering Hale and Dorr
`LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`Tel: 212-295-6446
`Email: Laura.Macro@wilmerhale.com
`
`Gabriel J. Rosanio, Ph.D.,
`Reg. No. 81,426
`Wilmer Cutler Pickering Hale and Dorr
`LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`Tel: 212-295-6363
`