Sheet 1 of 2
`
`Application Number
`12/466,213
`
`Filing Date
`May 14, 2009
`
`First Named Inventor
`Jeffrey B. ETTER
`
`Art Unit
`1623
`
`Examiner Name
`CRANE, Lawrence L!.
`Attorney Docket No.
`95 116-847-999
`CAM No.
`501872-999847
`
`LIST OF REFERENCES CITED BY APPLICANT
`(Use severalsheets if necessary)
`
`U.S. PATENT and PUBLICATION DOCUMENTS
`
`
`
`*Examiner
`Initials
`
`
`
`
`
`Document Number
`
`Nameof Patentee or Applicant
`of Cited Document
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`
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`
`
`
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`
`
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`A48|US 2012/0196823 2012-08-02 Tutino et al.
`
`
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`A49|US 2013/0109644 2013-05-02 MacBeth etal.
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`Foreign Patent Document
`Nameof Patentce or Applicant
`Date
`Country Code, Number,
`*Examiner
`Initials
`Kind Code(if known)
`yyyy-mum-dd
`of Cited Document
`
`
`B13|WO 2004/082822 2004-09-30|Pharmion Corporation
`
`B14_| WO 2006/089290 2006-08-24|American Bioscience Inc.
`
`
`
`B15|WO 2009/139888 2009-11-19|Celgene Corporation
`
`BI6_| WO 2010/059969 2010-05-27|Genentech Inc.
`
`
`T
`
`
`
`
`
`B17|WO 2012/135405 2012-10-04|Pharmion LLC
`
`B18|WO 2013/022872 2013-02-14|Celgene Corporation
`
`
`
`NON PATENT LITERATURE DOCUMENTS
`
`Include nameof the author (in CAPITAL LETTERS), (when appropriate),title of the item (book, magazine, journal,
`*Examiner
`
`Initials
`serial, symposium, catalog, etc.), date, page(s), volume-issue number(s), publisher, city and/or country where published.
`T
`C72.|ANONYMOUS, “A Phase 1|/II Clinical Trial of Vidaza with Abraxane in the Treatment of Patients with
`Advanced or Metastatic Solid Tumors and Breast Cancer,” ClinicalTrials.gov archive, pages 1-3,
`retrieved from the Internet: http://clinicaltrials.gov/archive/NCT00748553/201 1_08_05, on January 31,
`2013
`C73.|ANONYMOUS, “Oral Azacitidine as a Single Agent and in Combination with Carboplatin or Abraxane in
`Subjects with Relapsed or Refractory Solid Tumors,” ClinicalTrials.gov archive, pages 1-4, retrieved
`
`from the Internet: http://clinicaltrials.gov/archive/NCT01478685/2011_11_22, on January 31, 2013
`C74|BASTetal., “A Phase lla Study of a Sequential Regimen Using Azacitidine to Reverse Platinum
`Resistance to Carboplatin in Patients with Platinum Resistant or Refractory Epithelial Ovarian Cancer,”
`Journal of Clinical Oncology, 26, Abstract 3500,
`(2008
`C75|COWANetal., “Will DNA Methylation Inhibitors Work in Solid Tumors? A Review of the Clinical
`Experience with Azacitidine and Decitabine in Solid Tumors,” Epigenomics, Future Medicine Ltd,
`United Kingdom, 2(1}:71-86 (2010)
`C76|GLASER, “HDACInhibitors: Clinical Update and Mechanism-Based Potential,” Biochem. Pharm.,
`74:659-71 (2007
`
`SDI-162357v1
`
`EXAMINER
`
`DATE CONSIDERED
`
`
`
`
`*EXAMINER:Initial if reference considered, whether or not citation is in conformance with MPEP 609; Drawline throughcitationif not in
`conformance and not considered. Include copyof this form with next communication to applicant.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1335
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1335
`
`

`

`Sheet 2 of 2
`
`
`Application Number
`12/466,213
`Filing Date May 14, 2009
`
`
`First Named Inventor
`Jeffrey B. ETTER
`
`Art Unit
`1623
`
`Examiner Name
`CRANE, Lawrence L!.
`Attorney Docket No.
`95 116-847-999
`CAM No.
`501872-999847
`
`
`
`
`
`
`
`
`LIST OF REFERENCES CITED BY APPLICANT
`(Use severalsheets if necessary)
`
`NON PATENT LITERATURE DOCUMENTS
`
`Include nameofthe author (in CAPITAL LETTERS), (when appropriate), title of the item (book, magazine, journal,
`*Examiner
`T
`serial, symposium, catalog, etc.), date, page(s), volume-issue number(s), publisher, city and/or country where published.
`Initials
`C77|HOWELLetal., “Demethylating Agents in the Treatment of Cancer,” Pharmaceuticals, 3(7):2022-44
`2010
`C78|JUERGENS etal., “Interim Analysis of a Phase || Trial of 5-Azacitidine (6AC) and Entinostat (SNDX-
`275) in Relapsed Advanced Lung Cancer (NSCLC},” Journal of Clinical Oncology, 27(15S}:8055 (2009)
`C79|MOMPARLER, “Epigenetic Therapy of Cancer with 5-Aza-2’-Deoxycitidine (Decitabine),” Seminarsin
`Oncology, 32(5):443-51 (2005
`C80|STATHIS et al., “Phase | Study of Decitabine in Combination with Vorinostat in Patients with Advanced
`Solid Tumors and Non-Hodgkin’s Lymphomas,”Clinical Cancer Research, 17(6):1582—90 (2011
`i Vidaza™ Label
`(azacitidine for injectable suspension), Version: 5-18-04.
`C82 Vidaza™ (azacitidine for injection) Prescribing Information, dated January 2012.
`
`SDI-162357v1
`
`
`EXAMINER
`
`DATE CONSIDERED
`
` *EXAMINER:Initial if reference considered, whether or not citation is in conformance with MPEP 609; Drawline throughcitationif not in
`
`conformance and not considered. Include copyof this form with next communication to applicant.
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1336
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1336
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`30 September 2004 (30.09.2004)
`
` (10) International Publication Number
`
`WO 2004/082822 A2
`
`(51) International Patent Classification’:
`
`BO1J
`
`(21) International Application Number:
`PCT/US2004/007896
`
`(22) International Filing Date:
`
`16 March 2004 (16.03.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`10/390,530
`
`17 March 2003 (17.03.2003)
`
`US
`
`except US):
`(for all designated States
`(71) Applicants
`PHARMION CORPORATION [US/US], 2525 28th
`Street, Boulder, CO 80301 (US). ASH STEVENS INC
`[US/US]; 5861 John C Lodge Freeway, Detroit, MI 48202
`(US).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): LONESCU, Du-
`mitru [RO/US]; 2828 Grant Drive, Ann Arbor, MT 48108
`(US). BLUMBERGS, Peter [US/US]: 4105 Springer,
`Royal Oak, MT 48073 (US). SILVEY, Gary, L. [US/US];
`10139 Switzer Circle, Overland Park, KS 66212 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AL, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, IT,
`GB, GD, GE, GH, GM, HR, HU,ID,IL, IN, IS, JP, KE,
`KG,KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH,PL, PT, RO, RU, SC, SD, ST, SG, SK, SL, SY, TJ, TM,
`‘TN, TR, TL, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, 2M,
`ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, 1.S, MW, MZ, SD, SL, SZ, TZ, UG, 7M, ZW),
`Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Euro-
`pean (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR,
`GB, GR, HU,IE, IT, LU, MC, NL, PL, PT, RO, SE, SI, SK,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`uponreceipt of that report
`
`(74) Agents: SWANSON & BRATSCHUNLLE€ etal.; 1745
`Shea Center Drive, Suite 330, Highlands Ranch, CO 80129
`(US).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations” appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`
`
`(54) Title: METHODS FOR TSOLATING CRYSTALLINE FORM I OF 5-AZACYTIDINE
`
`cytidine substantially free of other forms, wherein 5-azacytidine is represented by the
`formula: The invention also includes pharmaceutical compositions comprising FormI of
`
`5-azacytidine. (57) Abstract: The invention includes methods for isolating crystalline FormI of 5-aza-
`
`AN
`
`< Na
`
`A
`oe
`aA
`oO
`—)—
`
`>——
`
`)N S
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1337
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1337
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`METHODS FOR ISOLATING CRYSTALLINE FORM | OF
`
`5-AZACYTIDINE
`
`
`
`FieldoftheInvention
`
`The invention relates to the isolation of crystalline polymorphic FormI of 5-azacytidine
`(also known as azacitidine and 4-amino-1-B-D-ribofuranosyl-S-triazin-2(1H)-one). 5-
`azacytidine may be used in the treatment of disease, including the treatment of
`myelodysplastic syndromes (MDS).
`
`Backeround of the Invention
`
`Polymorphsexist as two or more crystalline phases that have different arrangements
`and/or different conformations of the molecule in a crystal lattice. When a solvent molecule(s)
`is contained within the crystal lattice the resulting crystal is called a pseudopolymorph, or
`solvate. If the solvent molecule(s) within the crystal structure is a water molecule, then the
`pseudopolymorph/solvate is called a hydrate. The polymorphic and pseudopolymorphicsolids
`display different physical properties, including those due to packing, and various
`thermodynamic, spectroscopic, interfacial and mechanical properties (See H. Brittain,
`Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, NY, 1999, pp. 1-2).
`Polymorphic and pseudopolymorphic formsof the drug substance (also known as the "active
`pharmaceutical ingredient" (API)), as administered by itself or formulated as a drug product
`(also known asthe final or finished dosage form, or as the pharmaceutical composition) are
`well known and mayaffect, for example, the solubility, stability, flowability, fractability, and
`compressibility of drug substances and the safety and efficacy of drug products,(see, e.g.,
`Knapman, Kk Modern Drug Discoveries, March 2000: 53).
`
`5-Azacytidine (also known as azacitidine and 4-amino-1-8-D-ribofuranosyl-S-triazin-
`2(1)-one; Nation Service Center designation NSC-102816; CAS Registry Number 320-67-2)
`has undergone NCI-sponsoredtrials for the treatment of myelodysplastic syndromes (MDS).
`See Kornblith e¢ al., J. Clin. Oncol. 20(10): 2441-2452 (2002) and Silvermanefal., J. Clin.
`Oncol. 20(10): 2429-2440 (2002). 5-azacytidine may be defined as having a formula of
`CgHi2NaQs, a molecular weight of 244.20 and a structure of:
`
`10
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`35
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1338
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1338
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`
`
`In the United States Patent Application Serial No. 10/390,578 entitled "Formsof 5-
`
`azacytidine," filed March 17, 2003 and incorporated herein by referencein its entirety, eight
`different polymorphic and pseudopolymorphic forms of 5-azacytidine (FormsI-VIID,in
`addition to an amorphous form, are described. Forms I-VIII each have characteristic X-Ray
`Powder Diffraction (XRPD) patterns and are easily distinguished from one another using
`XRPD.
`
`10
`
`15
`
`5-azacytidine drug substance used in the previousclinical trials has typically been
`
`20
`
`synthesized from 5-azacytosine and 1,2,3,5,-tetra-O-acetyl-f-D-ribofuranose by the method
`
`presented in Example 1. The last step of this methodis a recrystallization of the crude
`
`synthesis product from a methanol/DMSO co-solvent system. Specifically, the crude
`
`synthesis product is dissolved in DMSO (preheated to about 90°C), and then methanolis
`
`added to the DMSO solution. The product is collected by vacuum filtration and allowedto air
`
`25
`
`dry.
`
`In In the United States Patent Application Serial No. 10/390,578 entitled "Formsof 5-
`
`azacytidine,"filed March 17, 2003 and incorporated herein by referencein its entirety,it is
`demonstrated that this prior art method forthe recrystallization of the crude synthesis product
`does not control for the polymorphic forms of 5-azacytidine. Specifically, the priorart
`recrystallization procedure produces either Form I substantially free of other forms, or a Form
`I/II mixed phasei.e. a solid material in which 5-azacytidine is present in a mixed phase of both
`polymorphic Form I and polymorphic Form II. Thus, the prior art procedures do not allow
`oneto reliably target Form I as the single polymorphic formin the drug substance. The present
`invention provides methodsthat allow oneto recrystallize 5-azacytidine as polymorphic Form
`T robustly and reproducibly.
`
`30
`
`35
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1339
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1339
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`Summary of the Invention
`
`The present invention provides methods for robustly and reproducibly isolating 5-
`
`azacytidine as polymorphic Form I substantially free of other forms. The methods involve
`
`recrystallizing dissolved 5-azacytidine from a primary solvent/co-solvent mixture and then
`
`collecting the resultant crystals. The invention also provides pharmaceutical compositions
`
`comprising Form I of 5-azacytidine together with a pharmaceutically acceptable excipient,
`
`diluent, or carrier.
`
`Detailed Description of the Preferred Embodiments
`
`10
`
`15
`
`Polymorphic Form I of 5-azacytidine
`
`Form I of 5-azacytidine is described in United States Patent Application Serial No.
`
`10/390,578 entitled "Forms of 5-azacytidine," filed March 17, 2003 and incorporated herein
`
`by reference in its entirety. Table 1 provides the most prominent 29 angles, d-spacing and
`
`20
`
`relative intensities for Form I observed using X-Ray Powder Diffraction (XRPD) performed
`
`according the method of Example 4:
`
`d-spacing (A)
`
`Relative Intensity
`
`25
`
`Table 1: 5-azacytidine Form I - the most prominent 20 angles, d-spacing andrelative
`intensities (Cu Ko radiation)
`
`-3-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1340
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1340
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`Isolation of Polymorphic FormI of 5-azacytidine by Recrystallization
`
`FormI of 5-azacytidine may be reproducibly isolated substantially free of other forms by
`recrystallizing dissolved 5-azacytidine and collecting the resultant crystals. Specifically, 5-
`azacytidine is first dissolved completely in at least one suitable primary solvent, preferably a
`polar solvent, more preferably a polar aprotic solvent. Suitable polar aprotic solvents include,
`but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA),
`dimethylsulfoxide (DMSO), and N-methylpyrrolidinone (NMP), The mostpreferred polar
`aprotic solvent is DMSO. Mixtures of two or more primary solvents are also contemplated for
`dissolving the 5-azacytidine, for example a mixture of DMSO and DMF.
`
`The 5-azacytidine used to form the solution may be synthesized by any procedure known
`in the art; an exemplary priorart synthesis schemeis provided in Example 1. Any
`polymorphic or pseudopolymorphic form(s) of 5-azacytidine, including mixed phases, may be
`used to form the solution. Amorphous 5-azacytidine may also be used to form the solution. It
`is preferred, but not required, that the primary solvent is preheated to an elevated temperature
`in order to ensure that the 5-azacytidine is dissolved completely. An especially preferred
`primary solvent is dimethyl sulfoxide, (DMSO), most preferably preheated to a temperature in
`the range of about 40°C to about 90°C.
`
`Following solvation of the 5-azacytidine in the primary solvent, at least one co-solvent is
`added to the solution of 5-azacytidine. Suitable co-solvents include C2-Cs alcohols (which
`term hereinafter refers to C2-Cs alcohols that are independently: branched or unbranched,
`substituted or unsubstituted), aliphatic ketones (which term hereinafter refers to aliphatic
`ketones that are indepedently: branched or unbranched, substituted or unsubstituted), and alkyl
`cyanides (which term hereinafter refers to alkyl cyanidesthat are independently: branched or
`unbranched, substituted or unsubstituted). Preferred C2-Cs alcohols, aliphatic ketones, and
`alkyl cyanides, along with other suitable solvents, are listed below as Class 2 (solvents to be
`limited) and Class 3 (solvents of low toxic potential) per the International Conference on
`Harmonization's (ICH) Guideline for Residual Solvents, July 1997). The use of mixtures of
`two or more of any of the aforementioned co-solvents is also included within the scope of the
`invention.
`
`10
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`20
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`25
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`30
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`35
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1341
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1341
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`Class2
`
`Acetonitrile
`
`Chlorobenzene
`
`Cyclohexane
`
`1,2-Dichloroethene
`
`Dichloromethane
`
`1,2-Dimethoxyethane
`
`N,N-Dimethylformamide
`
`N,N-Dimethylacetamide
`
`1,4-Dioxane
`
`2-Ethoxyethanol
`
`Ethyleneglycol
`
`Formamide
`
`2-Methoxyethanol
`
`Methylbutyl] ketone
`
`Methylcyclohexane
`
`Nitromethane
`
`Pyridine
`
`Sulfolane
`
`Tetralin
`
`1,1,2-Trichloroethene
`
`10
`
`15
`
`20
`
`25
`
`Class3
`
`30
`
`35
`
`1-Butanol
`
`1-Pentanol
`
`1-Propanol
`
`2-Butanol
`
`2-Methy]-1-propanol
`
`2-Propanol (isopropyl alcohol)
`
`3-Methyl-1-butanol
`
`Acetone
`
`Anisole
`
`Butyl acetate
`
`Cumene
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1342
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1342
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`Ethanol
`
`Ethyl! acetate
`
`Ethyl] ether
`
`Ethyl formate
`
`Isobutyl acetate
`
`Isopropyl acetate
`
`Methyl acetate
`
`Methylethyl ketone
`
`Methylisobutyl ketone
`
`Propyl acetate
`
`tert-Butylmethyl ether
`
`Tetrahydrofuran
`
`10
`
`15
`
`It is preferred, but not required, that the co-solvents are preheated before mixing with the
`
`20
`
`primary solvent, preferably to a temperature below the temperature at which a substantial
`
`portion of the co-solvent would boil, most preferably to about 50°C. It is also preferred, but
`
`not required, that the co-solvent(s) is added gradually to the primary solvent(s).
`
`Following mixing, the primary solvent(s)/co-solvent(s) mixture is then equilibrated at
`
`25
`
`different temperatures in order to promote either a slow recrystallization or a fast
`
`recrystallization of Form I of 5-azacytidine, as described below.
`
`By slow recrystallization is meant that the co-solvent/DMSO solution is allowed to
`
`equilibrate at a temperature in the range from about 0°C to about 40°C, preferably in the range
`of about 15°C to about 30°C, and most preferably at about ambient temperature. Slow
`
`30
`
`recrystallization of Form I of 5-azacytidine is preferably performed using C2-Cs alcohols,
`
`aliphatic ketones, or alkyl cyanides as the co-solvent. More preferably, slow recrystallization
`
`is performed with Class 3 C2-Cs alcohols, Class 3 aliphatic ketones, or acetonitrile (Class 2).
`
`The most preferred Class 3 C2-Cs alchohols are ethanol, isopropyl alcohol, and 1-propanol,
`
`35
`
`and the most preferred Class 3 aliphatic ketone is methylethyl ketone.
`
`By fast recrystallization is meant that the co-solvent solution is allowed to equilibrate at a
`temperature of below 0°C, preferably below about -10°C, and most preferably at about -20°C.
`-6-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1343
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1343
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`Fast recrystallization of Form I of 5-azacytidine is preferably performed with a C3 - Cs alcohol
`(which term hereinafter refers to C3-Cs alcohols which are independently: branched or
`unbranched, substituted or unsubstituted) or an alkyl cyanide as the co-solvent. More
`preferably the C3 - Cs alcohol is a Class 3 solvent, and the alkyl cyanide is acetonitrile. The
`most preferred Class 3 C3-Cs alcohols are isopropyl alcohol (2-propanol) and 1-propanol.
`
`Non-limiting examples of protocols for the recrystallization of Form I accordingto the
`methods described hercin are provided in Examples 2 (slow recrystallization with DMSO as
`
`the primary solvent and ethanol, isopropyl alcohol, acetonitrile, or methylethyl ketone as the
`co-solvent) and 3 (fast recrystallization with DMSOasthe primary solvent, and isopropyl
`alcohol or acetonitrile as the co-solvent) below,
`
`Following recrystallization, the Form I of 5-azacytidine crystals may be isolated from the
`co-solvent mixture by any suitable method known in the art. Preferably, the Form I crystals
`are isolated using vacuum filtration through a suitable filter medium or by centrifugation.
`
`Using the novel methods providedherein,it is possible for the first time to target Form I of
`5-azacytidine as the drug substance reproducibly and robustly. In particular, isopropyl alcohol
`and acetonitrile reliably produce Form I independent of cooling rate (either slow
`recrystallization or fast recrystallization) and are preferred as the recrystallization co-solvents
`
`to recover Form I. Most preferably, Form I is isolated using isopropyl alcoholas the co-
`solvent since isopropyl alcohol carries a Class 3 risk classification (solvent of low toxic
`potential), whereas acetonitrile carries a Class 2 risk classification (solvent to be limited). The
`use of the DMSO/isopropylalcohol system allows Form I of 5-azacytidineto be reliably
`recoveredfor the first time from solvents of low toxic potential without requiring control over
`the rate of recrystallation. In the most preferred embodiment, Form I of 5-azacytidine may be
`recovered simply by dissolving 5-azacytidine in DMSO (preferably heated to a temperature in
`the range of about 40°C to about 90°C prior to the addition of 5-azacytidine), adding isopropyl
`alcohol, and allowing the resulting solvent mixture to equilibrate at about ambient
`
`temperature.
`
`In some embodimentsof the invention, Form I of 5-azacytidine may be recovered from a
`primary solvent(s)/co-solvent(s) mixture by "seeding" with a small amount of Form I of 5-
`azacytidine either prior to, or during, the addition of the co-solvent(s). By seeding with Form
`-7-
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`30
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`35
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1344
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1344
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`L, it is possible to expandthe list of suitable co-solvents and co-solvent classes beyond those
`listed above. For example, it is known that recrystallization from the DMSO/methanol system
`produces either Form I, or a Form I/II mixed phase (see Example 1). Ifa small amount of
`Form I is addedto the solution of 5-azacytidine in DMSO priorto addition of the methanol co-
`
`solvent, or is added during the addition of the methanol co-solvent, then Form I of 5-
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`azacytidine may bereliably isolated.
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`By allowing the isolation of a single polymorphic form, one skilled in the art will
`
`appreciate that the present invention allowsfor thefirst time the production of 5-azacytidine
`drug substance with uniform and consistent properties from batch to batch, which properties
`include but are not limited to solubility and dissolution rate. In turn, this allows one to provide
`5-azacytidine drug product (see below) which also has uniform and consistent properties from
`batch to batch.
`
`Pharmaceutical Formulations
`
`For the most effective administration of drug substance of the present invention,it is
`preferred to prepare a pharmaceutical formulation (also known as the "drug product" or
`"pharmaceutical composition") preferably in unit dose form, comprising one or moreofthe 5-
`azacytidine polymorphsof the present invention and one or more pharmaceutically acceptable
`carrier, diluent, or excipient. Most preferably, Form I 5-azacytidine prepared accordingto the
`methods provided herein is used to prepare the pharmaceutical formulation.
`
`Such pharmaceutical formulation may, without being limited by the teachingsset forth
`herein, include a solid form of the present invention which is blended with at least one
`
`pharmaceutically acceptable excipient, diluted by an excipient or enclosed within such a
`carrier that can be in the form of a capsule, sachet, tablet, buccal, lozenge, paper, or other
`container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid
`material which acts as a vehicle, carrier, or medium for the 5-azacytidine polymorph(s). Thus,
`the formulations can be in the form oftablets, pills, powders,elixirs, suspensions, emulsions,
`solutions, syrups, capsules (such as, for example, soft and hard gelatin capsules),
`suppositories, sterile injectable solutions, and sterile packaged powders.
`
`Examplesof suitable excipients include, but are not limited to, starches, gum arabic,
`calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and
`3.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1345
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1345
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`methyl] cellulose. The formulations can additionally include lubricating agents such as, for
`example, talc, magnesium stearate and mineraloil; wetting agents; emulsifying and
`suspending agents; preserving agents such as methyl- and propyl- hydroxybenzoates;
`sweetening agents; or flavoring agents. Polyols, buffers, and inert fillers may also be used.
`Examples of polyols include, but are not limited to: mannitol, sorbitol, xylitol, sucrose,
`maltose, glucose, lactose, dextrose, and the like. Suitable buffers encompass, but are not
`limited to, phosphate, citrate, tartrate, succinate, and the like. Otherinert fillers which may be
`used encompass those which are known in the art and are useful in the manufacture of various
`
`dosage forms. If desired, the solid pharmaceutical compositions may include other
`components such as bulling agents and/or granulating agents, and the like. The compositions
`of the invention can be formulated so as to provide quick, sustained, controlled, or delayed
`release of the drug substance after administration to the patient by employing procedures well
`known in theart.
`
`In certain embodiments of the invention, the 5-azacytidine polymorph(s) may made into
`the form of dosage units for oral administration. The 5-azacytidine polymorph(s) may be
`mixed with a solid, pulverant carrier such as, for example, lactose, saccharose, sorbitol,
`mannitol, starch, amylopectin, cellulose derivatives or gelatin, as well as with an antifriction
`agent such as for example, magnesium stearate, calcium stearate, and polyethylene glycol
`waxes. The mixture is then pressed into tabletsor filled into capsules. If coated tablets,
`capsules,or pulvules are desired, such tablets, capsules, or pulvules may be coated with a
`concentrated solution of sugar, which may contain gum arabic, gelatin, talc, titanium dioxide,
`or with a lacquer dissolved in the volatile organic solvent or mixture of solvents. To this
`coating, various dyes may be addedin order to distinguish amongtablets with different active
`compoundsor with different amounts of the active compound present.
`
`Soft gelatin capsules may be prepared in which capsules contain a mixture of the 5-
`azacytidine polymorph(s) and vegetable oil or non-aqueous, water miscible materials such as,
`for example, polyethylene glycol andthe like. Hard gelatin capsules may contain granules or
`powderofthe 5-azacytidine polymorphin combination with a solid, pulverulent carrier, such
`as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch,
`amylopectin, cellulose derivatives, or gelatin.
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1346
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1346
`
`

`

`WO 2004/082822
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`PCT/US2004/007896
`
`Tablets for oral use are typically prepared in the following manner, although other
`
`techniques may be employed. Thesolid substances are gently ground or sieved to a desired
`
`particle size, and a binding agent is homogenized and suspendedin a suitable solvent. The 5-
`
`azacytidine polymorph(s) and auxiliary agents are mixed with the binding agent solution. The
`
`resulting mixture is moistened to form a uniform suspension. The moistening typically causes
`
`the particles to aggregate slightly, and the resulting mass is gently pressed through a stainless
`steel sieve having a desired size. The layers of the mixture are then dried in controlled drying
`units for a pre-determined length of time to achieve a desired particle size and consistency.
`
`The granules of the dried mixture are gently sieved to remove any powder. Tothis mixture,
`
`disintegrating, anti-friction, and anti-adhesive agents are added. Finally, the mixture is pressed
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`into tablets using a machine with the appropriate punches and dies to obtain the desired tablet
`
`size.
`
`In the event that the above formulations are to be used for parenteral administration,
`such a formulation typically comprisessterile, aqueous and non-aqueousinjection solutions
`comprising one or more 5-azacytidine polymorphs for which preparations are preferably
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`isotonic with the blood of the intended recipient. These preparations may contain anti-
`
`oxidants, buffers, bacteriostats, and solute; which renderthe formulation isotonic with the
`
`blood of the intended recipient. Aqueous and non-aqueous suspensions may include
`
`suspending agents and thickening agents. The formulations may be present in unit-dose or
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`multi-dose containers, for example, sealed ampules and vials. Extemporaneousinjection
`
`solutions and suspensions may be prepared from sterile powders, granules, and tablets of the
`
`kind previously described.
`
`Liquid preparations for oral administration are prepared in the form of solutions, syrups, or
`suspensions with the latter two forms containing, for example, 5-azacytidine polymorph(s),
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`sugar, and a mixture of ethanol, water, glycerol, and propylene glycol. If desired, such liquid
`
`preparations contain coloring agents, flavoring agents, and saccharin. Thickening agents such
`
`as carboxymethylcellulose may also be used.
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`35
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`Assuch, the pharmaceutical formulations of the present invention are preferably
`
`prepared in a unit dosage form, cach dosage unit containing from about 5 mg to about 200 mg,
`
`more usually about 100 mg of the 5-azacytidine polymorph(s). In liquid form, dosage unit
`
`contains from about 5 to about 200 mg, more usually about 100 mgofthe 5-azacytidine
`-10-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1347
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1347
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`polymorph(s). The term "unit dosage form"refers to physically discrete units suitable as
`unitary dosages for humansubjects/patients or other mammals, each unit containing a
`predetermined quantity of the S-azacytidine polymorph calculated to produce the desired
`therapeutic effect, in association with preferably, at least one pharmaceutically acceptable
`carrier, diluent, or excipient.
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`10
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`The following examples are providedforillustrative purposes only, and are not to be
`construedas limiting the scope of the claims in any way.
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`-1ll-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1348
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1348
`
`

`

`WO 2004/082822
`
`Examples
`
`Example |
`
`PCT/US2004/007896
`
`Prior Art Procedure for Synthesis and Recrystallization of 5-azacytidine Drug Substance
`
`5-azacytidine may be synthesized using commercially available 5-azacytosine and 1,2,3,5-
`tetra-O-acetyl-B-D-ribofuranose (RTA) according to the following pathway:
`
`NHSi(CH3)3
`
`as
`
`ra
`
`Ho
`
`NHp
`
`LL A
`N
`0
`
`
`.
`
`H
`
`OH
`
`OH
`
`GB)
`
`(H3C)3Si0
`
`N
`
`(1) SnCly, CH3CN
`(2) NaOCH3, CH30H
`a
`
`Be
`
`3
`
`NHp
`
`N @
`
`a HIN(Si(CH3)3)9
`
`
`(NH2)2S0,q, Heat
`
`
`
`HO
`
`AcO.
`
`:
`
`NHSi(CH3)3
`HA
`Na sy
`pe |
`
`SN
`N
`
`*
`
`(H3C)3810
`
`OAc
`
`Y
`
`H
`OAc
`
`a
`
`OAc
`
`H
`
`0
`
`@)
`
`The crude synthesis productis dissolved in DMSO (preheated to about 90°C), and then
`methanol is added to the DMSO solution. The co-solvent mixture is equilibrated at
`approximately -20°C to allow 5-azacytidine crystal formation. The productis collected by
`
`vacuum filtration and allowedto air dry.
`
`Example 2
`
`Form J of 5-azacytidine: Slow Recrystallization of 5-azacytidine from Co-Solvent Systems
`Approximately 250 mg of 5-azacytidine was dissolved with approximately 5 ml of
`dimethyl sulfoxide (DMSO), preheated to approximately 90 °C, in separate 100-mL beakers.
`The solids were allowed to dissolve to a clear solution. Approximately 45 mL of ethanol,
`isopropyl alcohol, acetonitrile, or methyl ethyl ketone co-solvent, preheated to approximately
`50 °C, was added to the solution and the resultant solution was mixed. The solution was
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`covered and allowed to equilibrate at ambient conditions. The product was collected by
`
`vacuum filtration using a Buchner funnel.
`
`-12-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1349
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-1349
`
`

`

`WO 2004/082822
`
`PCT/US2004/007896
`
`Example 3
`
`
`Form I of 5-azacytidine: Fast Recrystallization of 5-azacytidine from Co-Solvent Systems
`Approximately 250 mg of 5-azacytidine was dissolved with approximately 5 mL of
`DMSO,preheated to approximately 90 °C, in separate 100-ml beakers. The solids were
`allowed to dissolve to a clear solution. Approximately 45 mL