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`
`APPLICATION NUMBER: 12/466,213
`FILING DATE: May 14, 2009
`PATENT NUMBER: 8846628
`ISSUE DATE: September 30, 2014
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0001
`
`

`

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`ORAL FORMULATIONS OF CYTIDINE ANALOGS AND
`
`METHODS OF USE THEREOF
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`NYI-4183306v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0002
`
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0002
`
`

`

`
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`Sir:
`
`Date: May 14, 2009
`
`The following utility patent application is enclosed for filing:
`
`Applicant(s):
`
`Jeffrey B. Etter
`Mei Lai
`Jay Thomas Backstrom
`
`Executed on:
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`unexecuted
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`ORAL FORMULATIONS OF CYTIDINE ANALOGS AND METHODSOF USE
`THEREOF
`
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`NYT-4 1 83304vI
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0003
`
`

`

`Atty Docket No.
`501872-999847/95 16-847-999
`
`ORAL FORMULATIONS OF CYTIDINE ANALOGS
`AND METHODSOF USE THEREOF
`
`I.
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`This application claimspriority to U.S. Provisional Patent Application Nos.
`{0001}
`61/053,609, filed May 15, 2008; 61/201,145, filed December 5, 2008; and 61/157,875, filed
`
`March 5, 2009, the contents of each of which are incorporated by reference herein in their
`entireties.
`
`Il.
`
`FIELD
`
`Provided herein are pharmaceutical formulations comprising cytidine analogs, or
`[0002]
`their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral administration in
`
`subjects. Also provided are methods for making the formulations and methodsfor using the
`formulations to treat diseases and disorders including cancer, disorders related to abnormal
`cell proliferation, hematologic disorders, and immune disorders, amongothers.
`
`i.
`
`BACKGROUND
`
`Cancer is a major worldwide public health problem; in the United States alone,
`[0003]
`approximately 570,000 cancer-related deaths were expected in 2005. See, e.g., Jemalet al,
`CA Cancer J. Clin, 55(1):10-30 (2005). Many types of cancer have been described in the
`medical literature. Examples include cancer of the blood, bone, lung (¢.g., non-small-cell
`lung cancer and small-cell lung cancer), colon, breast, prostate, ovary, brain, and intestine.
`The incidence of cancer continues to climb as the general population ages and as new forms
`of cancer develop. A continuing need exists for effective therapies to treat subjects with
`cancer,
`
`Myelodysplastic syndromes (MDS)refers to a diverse group of hematopoietic
`[0004]
`stem cell disorders. MDS affects approximately 40,000-50,000 people in the U.S. and
`75,000-85,000 subjects in Europe. MDS may be characterized by a cellular marrow with
`impaired morphology and maturation (dysmyelopoiesis), peripheral blood cytopenias, and a
`
`NYI-4182720vI
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0004
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0004
`
`

`

`variable risk of progression to acute leukemia, resulting from ineffective blood cell
`production. See, e.g., The Merck Manual 953 (17th ed. 1999); List et al., J. Clin. Oncol.
`
`8:1424 (1990).
`[0005]
`MDSare grouped together because of the presence of dysplastic changes in one or
`more of the hematopoietic lineages including dysplastic changes in the myeloid, erythroid,
`and megakaryocytic series. These changes result in cytopenias in one or moreofthe three
`lineages. Patients afflicted with MDS may develop complicationsrelated to anemia,
`neutropenia (infections), and/or thrombocytopenia (bleeding). From about 10% to about 70%
`of patients with MDS may develop acute leukemia. In the early stages of MDS, the main
`cause of cytopenias is increased programmedcell death (apoptosis). As the disease
`progresses and converts into leukemia, a proliferation of leukemic cells overwhelmsthe
`healthy marrow. The disease course differs, with some cases behaving as an indolent disease
`and others behaving aggressively with a veryshort clinical course that converts into an acute
`form of leukemia. The majority of people with higher risk MDS eventually experience bone
`marrow failure. Up to 50% of MDS patients succumb to complications, such as infection or
`
`bleeding, before progressing to AML.
`[0006]
`Primary and secondary MDS are defined by taking into accountpatients’ prior
`history: previous treatments with chemotherapy, radiotherapy or professional exposure to
`toxic substances are factors delineating secondary MDS (sMDS)from primary MDS.
`Cytogenetically, one difference between the two groupsis the complexity of abnormal
`karyotypes; single chromosomeaberrations are typical for primary MDS, while multiple
`changes are more frequently seen in secondary disorders. Some drugs may have specific
`targets such as hydroxurea for 17p and topoisomerases inhibitors for 11q23 and 21q22. The
`genetic changesin the malignant cells of MDSresult mainly in the loss ofgenetic material,
`
`including probable tumor suppressor genes.
`[0007]
`An international group of hematologists, the French-American-British (FAB)
`Cooperative Group,classified MDSinto five subgroups, differentiating them from acute
`myeloid leukemia.See, e.g., The Merck Manual 954 (17th ed. 1999); Bennett J. M., et al.,
`Ann. Intern. Med., 103(4): 620-5 (1985); and Besa E. C., Med. Clin. North Am. 76(3): 599-
`617 (1992). An underlyingtrilineage dysplastic change in the bone marrowcells of the
`patients is found in all subtypes. Information is available regarding the pathobiology of
`MDS, certain MDSclassification systems, and particular methodsoftreating and managing
`
`
`
`NYI-4182720vI
`
`-2-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0005
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0005
`
`

`

`MDS. See, e.g., U.S. Patent No. 7,189,740 (issued March 13, 2007), which is incorporated by
`reference herein in its entirety.
`
`Nucleoside analogs have been usedclinically for the treatment ofviral infections
`[0008]
`and cancer. Most nucleoside analogsare classified as anti-metabolites. After they enter the
`cell, nucleoside analogs are successively phosphorylated to nucleoside 5'-mono-phosphates,
`di-phosphates, and tri-phosphates.
`
`5-Azacytidine (National Service Center designation NSC-102816; CAS Registry
`[0009]
`Number 320-67-2), also known as azacitidine, AZA, or 4-amino-|-$-D-ribofuranosyl-1,3,5-
`triazin-2(LH)-one,is currently marketed as the drug product VIDAZA”. 5-Azacytidineis a
`nucleoside analog, more specifically a cytidine analog. 5-Azacytidine is an antagonistofits
`related natural nucleoside, cytidine. 5-Azacytidine and 5-aza-2'-deoxycytidine (also known
`as decitabine, an analog of deoxycytidine) are also antagonists of deoxycytidine. A structural
`difference between these cytidine analogs and their related natural nucleoside is the presence
`of a nitrogen at position 5 ofthe cytosine ring in place of a carbon. 5-Azacytidine may be
`defined as having the molecular formula CgH)2N4Os, a molecular weight of 244.21 grams per
`mole, and the following structure:
`
`NH»
`
`wan
`LAs
`
`HO
`
`H
`
`OH
`
`H
`OH
`
`5-Azacytidine.
`
`Other membersof the class of cytidine analogs include, for example: 1-B-D-
`[0010]
`arabinofuranosylcytosine (Cytarabine or ara-C); 5-aza-2'-deoxycytidine (Decitabine or 5-aza-
`CdR); pseudoisocytidine (psi ICR); 5-fluoro-2'-deoxycytidine (FCdR); 2'-deoxy-2',2'-
`difluorocytidine (Gemcitabine); 5-aza-2'-deoxy-2',2'-difluorocytidine; 5-aza-2'-deoxy-2'-
`fluorocytidine; |-B-D-riboturanosyl-2(1 H)-pyrimidinone (Zebularine); 2',3'-dideoxy-5-fluoro-
`3'-thiacytidine (Emtriva); 2'-cyclocytidine (Ancitabine); 1-B-D-arabinofuranosyl-5-
`azacytosine (Fazarabineor ara-AC); 6-azacytidine (6-aza-CR); 5,6-dihydro-5-azacytidine
`
`NYI-4182720v1
`
`-3-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0006
`
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0006
`
`

`

`(dH-aza-CR); N*-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecitabine); N‘-octadecyl-
`cytarabine; and elaidic acid cytarabine.
`[0011]
`After its incorporation into replicating DNA, 5-azacytidine or 5-aza-2'-
`deoxycytidine forms a covalent complex with DNA methyltransferases. DNA
`methyltransferases are responsible for de novo DNA methylation and for reproducing
`established methylation patterns in daughter DNAstrandsofreplicating DNA. Inhibition of
`DNA methyltransferases by 5-azacytidine or 5-aza-2'-deoxycytidine leads to DNA
`hypomethylation, thereby restoring normal functions to morphologically dysplastic, immature
`hematopoietic cells and cancer cells by re-expression of genes involved in normalcell cycle
`regulation, differentiation and death. The cytotoxic effects of these cytidine analogs cause
`the death of rapidly dividingcells, including cancer cells, that are no longer responsive to
`normalcell growth control mechanisms. 5-azacytidine, unlike 5-aza-2'-deoxycytidine, also
`incorporates into RNA. The cytotoxic effects of azacitidine may result from multiple
`mechanisms,including inhibition of DNA, RNAandprotein synthesis, incorporation into
`
`RNAand DNA,and activation of DNA damage pathways.
`[0012]
`5-Azacytidine and 5-aza-2'-deoxycytidine have beentested in clinical trials and
`showedsignificant anti-tumoractivity, such as, for example, in the treatment of
`myelodysplastic syndromes (MDS), acute myelogenous leukemia (AML), chronic
`myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), and non Hodgkin’s
`lymphoma (NHL).See, e.g., Aparicio et al., Curr. Opin. Invest. Drugs 3(4): 627-33 (2002).
`5-Azacytidine has undergone NCI-sponsoredtrials for the treatment of MDSand has been
`approvedfor treating all FAB subtypes of MDS. See,e.g., Kornblith et al., J. Clin. Oncol.
`20(10): 2441-2452 (2002); Silvermanet al., J. Clin. Oncol. 20(10): 2429-2440 (2002). 5-
`Azacytidine mayalter the natural course of MDS by diminishing the transformation to AML
`through its cytotoxic activity and its inhibition of DNA methyltransferase.
`In a PhaseII]
`study, 5-azacytidine administered subcutaneously significantly prolonged survival and time
`to AMLtransformation or death in subjects with higher-risk MDS. See, e.g., P. Fenaux ef al,
`Lancet Oncol., 2009, 10(3):223-32; Silverman et al., Blood 106(11): Abstract 2526 (2005).
`[0013}
`5-Azacytidine and other cytidine analogs are approved for subcutaneous (SC) or
`intravenous (IV) administration to treat various proliferative disorders. Oral dosing of
`cytidine analogs would be more desirable and convenientfor patients and doctors, e.g., by
`eliminating injection-site reactions that may occur with SC administration and/or by
`permitting improved patient compliance. However, oral delivery of cytidine analogs has
`
`NYI-4182720v1
`
`-~-4-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0007
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0007
`
`

`

`proven difficult due to combinations of chemicalinstability, enzymatic instability, and/or
`poor permeability. For example, cytidine analogs have been considered acid labile and
`
`unstable in the acidic gastric environment. Previous attempts to develop oral dosage forms of
`cytidine analogs have required enteric coating of the drug core to protect the active
`
`pharmaceutical ingredient (API) from what was understood and accepted to be
`
`therapeutically unacceptable hydrolysis in the stomach, such that the drug is preferably
`
`absorbedin specific regions of the lower gastrointestinal tract, such as the jejunum in the
`
`small intestine. See, e.g., Sands, ef al., U.S. Patent Publication No. 2004/0162263 (App. No.
`
`10/698,983). In addition, a generally accepted belief in the art has been that water leads to
`
`detrimental hydrolytic degradation of cytidine analogs during formulation, subsequently
`affecting the stability of the API in the dosage form. Asa result, coatings applied to the drug
`core for prospective oral delivery of cytidine analogs have previously been limited to organic
`solvent-based systems to minimize exposure of the API to water.
`
`A great need remains for oral formulations and dosage formsof cytidine analogs,
`[0014]
`suchas, e.g., 5-azacytidine, to potentially permit, inter alia, more advantageous dosing
`amounts or dosing periods; improved pharmacokinetic profiles, pharmacodynamicprofiles,
`
`or safety profiles; evaluation of the benefits of long-term or maintenancetherapies;
`
`development of improved treatment regimens that maximize biologic activity; use of cytidine
`analogsfor treating new diseases or disorders; and/or other potential advantageous benefits.
`
`IV.
`
`SUMMARY
`
`[0015]
`
`Provided herein are pharmaceutical compositions comprising cytidine analogs,
`
`wherein the compositions release the API substantially in the stomach upon oral
`
`administration. Also provided are methods for making the compositions, and methods for
`
`using the compositions to treat diseases and disorders including cancer, disorders related to
`
`abnormalcell proliferation, and hematologic disorders, among others.
`
`[0016]
`
`In certain embodiments, the cytidine analog is 5-azacytidine.
`
`In other
`
`In yet
`embodiments, the cytidine analog is 5-aza-2'-deoxycytidine (decitabine or 5-aza-CdR).
`other embodiments, the cytidine analog is, for example: 1-f-D-arabinofuranosylcytosine
`
`(Cytarabine or ara-C); pseudoisocytidine (psi ICR); 5-fluoro-2'-deoxycytidine (FCdR); 2'-
`deoxy-2',2'-difluorocytidine (Gemcitabine); 5-aza-2'-deoxy-2',2'-difluorocytidine; 5-aza-2'-
`deoxy-2'-fluorocytidine; 1-B-D-ribofuranosyl-2(1H)-pyrimidinone (Zebularine); 2',3'-dideoxy-
`5-fluoro-3'-thiacytidine (Emtriva); 2'-cyclocytidine (Ancitabine); |-8-D-arabinofuranosy]-5-
`
`NYT-4182720v1
`
`~5-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0008
`
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0008
`
`

`

`azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza~CR); 5,6-dihydro-5-azacytidine
`(dH-aza-CR); N*-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecitabine), N*-octadecyl-
`cytarabine; elaidic acid cytarabine; or their derivatives or related analogs.
`[0017]
`Certain embodiments herein provide compositions that are single unit dosage
`forms comprising a cytidine analog. Certain embodiments herein provide compositions that
`are non-enteric-coated. Certain embodiments herein provide compositions that are tablets
`
`comprising a cytidine analog. Certain embodiments herein provide compositionsthat are
`capsules comprising a cytidine analog. The capsules maybe, e.g., a hard gelatin capsule or a
`soft gelatin capsule; particular embodiments provide hydroxypropy! methylcellulose (HPMC)
`capsules. In certain embodiments, the single unit dosage forms optionally further contain one
`or more excipients. In certain embodiments, the tablets optionally further contain one or
`more excipients. In other embodiments, the capsules optionally further contain one or more
`excipients. In certain embodiments, the compositionis a tablet that effects an immediate
`release of the API upon oral administration. In other embodiments, the compositionis a
`
`tablet that effects a controlled release of the API substantially in the stomach. In certain
`
`embodiments, the composition is a capsule that effects an immediate release of the API upon
`
`oral administration.
`
`In other embodiments, the composition is a capsule that effects a
`
`controlled release of the API substantially in the stomach. In particular embodiments, the
`
`tablet contains a drug core that comprises a cytidine analog, and optionally further contains a
`coating of the drug core, wherein the coating is applied to the drug core using an aqueous
`solvent, such as, for example, water, or non-aqueoussolvent, such as, for example ethanol.
`[0018]
`Certain embodiments herein provide methods of making formulations of cytidine
`analogs intended for oral delivery. Further provided are articles of manufacture containing
`packaging material, an oral formulation of a cytidine analog, and a label that indicatesthat
`the formulation is for the treatment of certain diseases or disorders including,e.g., a cancer, a
`
`disorder related to abnormalcell proliferation, a hematologic disorder, or an immune
`
`disorder.
`
`Certain embodiments herein provide methods of using the formulations provided
`[0019]
`herein to treat diseases or disorders including, ¢.g., cancer, disorders related to abnormalcell
`
`In certain
`proliferation, hematologic disorders, or immunedisorders, among others.
`embodiments, the formulations ofcytidine analogsare orally administered to subjects in need
`
`thereof to treat a cancer or a hematological disorder, such as, for example, MDS, AML, ALL,
`
`CML, NHL,leukemia, or lymphoma; or a solid tumor, such as, for example, sarcoma,
`
`NY1-4182720v1
`
`-6-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0009
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0009
`
`

`

`melanoma,carcinoma,or cancerof the colon, breast, ovary, gastrointestinal system, kidney,
`
`lung (e.g., non-small-cell lung cancer and small-cell lung cancer), testicle, prostate, pancreas
`
`or bone. In certain embodiments, the formulations of cytidine analogsare orally
`
`administered to subjects in need thereof to treat an immunedisorder. In certain
`
`embodiments, the oral formulations provided herein are co-administered with one or more
`
`therapeutic agents to provide a synergistic therapeutic effect in subjects in need thereof.
`
`In
`
`certain embodiments, the oral formulations provided herein are co-administered with one or
`
`more therapeutic agents to provide a resensitization effect in subjects in need thereof. The
`
`co-administered agents may be a cancer therapeutic agent, as described herein.
`
`In certain
`
`embodiments, the co-administered agent(s) may be dosed, e.g., orally or by injection.
`
`[0020]
`
`In particular embodiments, provided herein are tablets containing 5-azacytidine
`
`and methods for making and using the tablets to treat cancer, disorders related to abnormal
`
`cell proliferation, or hematologic disorders. In certain embodiments, the tablets optionally
`further contain one or more excipients such as, for example, glidants, diluents, lubricants,
`
`colorants, disintegrants, granulating agents, binding agents, polymers, and/or coating agents.
`
`Examples of ingredients useful in preparing certain formulations provided herein are
`
`describedin, e.g., Etter et al., U.S. Patent Application Publication No. 2008/0057086 (App.
`No. 11/849,958), which is incorporated herein by reference in its entirety.
`
`[0021]
`
`Specific embodiments herein provide, inter alia, pharmaceutical compositions
`
`comprising a therapeutically effective amount of 5-azacytidine, wherein the composition
`
`releases the 5-azacytidine substantially in the stomach following oral administration to a
`
`subject. Further embodiments provide the aforementioned compositions, which: are
`
`immediate release compositions; do not have an enteric coating (i.e., are non-enteric-coated);
`
`are tablets; are capsules; further comprise an excipient selected from any excipient disclosed
`
`herein; further comprise a permeation enhancer; further comprise d-alpha-tocopheryl
`
`polyethylene glycol 1000 succinate; further comprise a permeation enhancerin the
`
`formulation at about 2% by weight relative to the total weight of the formulation; are
`
`essentially free of a cytidine deaminase inhibitor; are essentially free of tetrahydrouridine;
`
`have an amountof5-azacytidine of at least about 40 mg; have an amountof 5-azacytidine of
`
`at least about 400 mg; have an amountof 5-azacytidine of at least about 1000 mg; achieve an
`
`area-under-the-curve value of at least about 200 ng-hr/mL following oral administration to a
`
`subject; achieve an area-under-the-curve value ofat least about 400 ng-hr/mL following oral
`
`administration to a subject; achieve a maximum plasma concentration ofat least about 100
`
`NYI-4182720v1
`
`-7-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0010
`
`
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0010
`
`

`

`ng/mL following oral administration to a subject; achieve a maximum plasmaconcentration
`of at least about 200 ng/mL following oral administration to a subject; achieve a time to
`maximum plasma concentration of less than about 90 minutes following oral administration
`to a subject; and/or achieve a time to maximum plasma concentration of less than about 60
`
`minutes following oral administration to a subject.
`[0022]
`Specific embodiments herein provide a pharmaceutical composition for oral
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`the 5-azacytidine substantially in the stomach and achieves an area-under-the-curve value of
`
`at least about 200 ng-hr/mL following oral administration.
`[0023]
`Specific embodiments herein provide a pharmaceutical composition for oral
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`the 5-azacytidine substantially in the stomach and achieves an area-under-the-curve value of
`at least about 400 ng-hr/mL following oral administration.
`[0024]
`Specific embodiments herein provide a pharmaceutical composition for oral
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`the 5-azacytidine substantially in the stomach and achieves a maximum plasma concentration
`
`of at least about 100 ng/mL following oral administration.
`
`Specific embodiments herein provide a pharmaceutical composition for oral
`[0025]
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a maximum plasmaconcentration
`
`of at least about 200 ng/mL following oral administration.
`[0026]
`Specific embodiments herein provide a pharmaceutical composition for oral
`administration comprising a therapeutically effective amount of S-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a time to maximum plasma
`
`concentration of, e.g., less than about 6 hr, less than about 5 hr, less than about 4 hr, less than
`
`about 3 hr, less than about 2.5 hr, less than about 2 hr, less than about 1.5 hr, less than about 1
`
`hr, less than about 45 min, or less than about 30 min following oral administration.
`
`In
`
`specific embodiments, the presence of food may affect (e.g., extend) the total exposure and/or
`
`time to maximum plasma concentration.
`[0027]
`Specific embodiments herein provide a pharmaceutical composition for oral
`administration comprising a therapeutically effective amount of 5-azacytidine, which releases
`
`the 5-azacytidine substantially in the stomach and achieves a time to maximum plasma
`
`concentration of less than about 60 minutes following oral administration.
`
`NY1-4182720v 1
`
`-§-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0011
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0011
`
`

`

`[0028]
`
`Specific embodiments herein provide any of the aforementioned compositions, as
`
`single unit dosage forms, tablets, or capsules.
`
`[0029]
`
`Specific embodiments herein provide, inter alia, methodsfortreating a subject
`
`having a disease associated with abnormalcell proliferation, comprising orally administering
`
`to the subject a pharmaceutical composition comprising a therapeutically effective amount of
`
`5-azacytidine, wherein the composition releases the 5-azacytidine substantially in the
`
`stomachfollowing oral administration to the subject. Further embodiments herein provide
`
`the aforementioned methods, in which:
`
`the disease is myelodysplastic syndrome; the disease
`
`is acute myelogenous leukemia; the method further comprises co-administering to the subject
`
`in need thereofan additional therapeutic agent selected from any additional therapeutic agent
`disclosed herein; the composition is an immediate release composition; the composition does
`
`not have an enteric coating; the composition further comprises a permeation enhancer; the
`
`composition further comprises the permeation enhancer d-alpha-tocopheryl polyethylene
`
`glycol 1000 succinate; the composition further comprises d-alpha-tocopheryl polyethylene
`glycol 1000 succinate in the formulation at about 2% by weight relative to the total weight of
`the formulation; the method further comprises not co-administering a cytidine deaminase
`
`inhibitor with the cytidine analog; the composition is a single unit dosage form; the
`
`composition is a tablet; the composition is a capsule; the composition further comprises an
`
`excipient selected from any excipient disclosed herein; the amount of5-azacytidineis at least
`
`about 40 mg; the amount of5-azacytidine is at least about 400 mg; the amountof 5-
`
`azacytidine is at least about 1000 mg; the method achieves an area-under-the-curve value of
`
`at least about 200 ng-hr/mL following oral administration to the subject; the method achieves
`
`an area-under-the-curve value ofat least about 400 ng-hr/mL following oral administration to
`
`the subject; the method achieves a maximum plasma concentration ofat least about 100
`
`ng/mL following oral administration to the subject; the method achieves a maximum plasma
`concentration ofat least about 200 ng/mL following oral administration to the subject; the
`
`method achieves a time to maximum plasma concentration ofless than about 90 minutes
`
`following oral administration to the subject; and/or the method achieves a time to maximum
`
`plasma concentration ofless than about 60 minutes following oral administration to the
`
`subject
`
`[0030]
`
`Specific embodiments herein provide, inter alia, pharmaceutical compositions
`
`comprising a therapeutically effective amount of5-azacytidine, wherein the compositions are
`
`for treating a disease or disorder associated with abnormalcell proliferation, wherein the
`
`NYT-4182720v1
`
`-9.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0012
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1022-0012
`
`

`

`compositions are prepared for oral administration, and wherein the compositions are prepared
`for release of the 5-azacytidine substantially in the stomach. Further embodiments herein
`provide the aforementioned compositions, which: have an amount of 5-azacytidine of about
`40 mg, about 400 mg, or about 1000 mg; are prepared to achieve an area-under-the-curve
`value ofat least about 200 ng-hr/mL or 400 ng-hr/mL following oral administration; are
`
`prepared to achieve a maximum plasma concentration ofat least about 100 ng/mL or 200
`ng/mL following oral administration; are prepared to achieve a time to maximum plasma
`concentration of less than about 60 minutes or 90 minutes after being administered; are
`
`prepared in the form of an immediate release composition; are prepared for oral
`
`administration in combination with an additional therapeutic agent selected from any
`
`additional therapeutic agent disclosed herein; are for treating myelodysplastic syndrome or
`
`acute myelogenous leukemia; further comprise a permeation enhancer; which further
`comprise the permeation enhancer d-alpha-tocopheryl polyethylene glycol 1000 succinate;
`are single unit dosage forms; are tablets or capsules; and/or further comprise an excipient
`
`selected from any excipient disclosed herein.
`
`Specific embodiments herein provide, inter alia, uses of 5-azacytidine for the
`[0031)
`preparation of a pharmac