COVER SHEET FOR PROVISIONAL APPLICATION FOR PATENT
`
`Commissioner for Patents
`P.O. Box [450
`Alexandria, VA 22313-1450
`Sir:
`
`Docket Number
`
`INVENTOR(s) APPLICANT(s)
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`LAST NAME MIDDLE INITIAL|RESIDENCE (CITY AND EITHER STATE OR FOREIGN COUNTRY)FIRST NAME
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`This is a request for filing a PROVISIONAL APPLICATIONunder 37 CFR 1.53(c).
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`95 16-825-888
`inside this box 6
`Type a plus sign (+)
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`
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`
`
`
`
`
`Backstrom
`Etter
`Lai
`
`Jay
`Jeff
`Mei
`
`T
`B
`
`Boulder, CO
`Boulder, CO
`Longmont, CO
`
`
`TITLE OF THE INVENTION (280 characters max)
`
`ORAL DOSAGE FORMS OF CYTIDINE ANALOGS AND METHODSOF USE THEREOF
`
`JONES DAY
`CORRESPONDENCE ADDRESS
`
`ENCLOSED APPLICATION PARTS(check all that apply)
`
` EX Specification
`(J Applicant claims small entity status, see 37 CFR §1.27
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`EXTRA
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`NOQ. FILED
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`Total Numberof
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`96 * 0.75 = 72
`Pages w/ drawings
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` Total Filing Fee
`220,00
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`[J] A check or moneyorderis enclosed to cover the Provisionalfiling fees.
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`$270.00 for each 50 pages
`over 100
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`$
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`Applicant qualifies for the 50% Reduction for Independent inventor, Nonprofit Organization or Small Business
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`0.00
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`220.00
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`&] The abovecalculation is an estimate ofthe fees due. The fees will be paid via EFS-Web. Please charge any
`additional fees to Jones Day Deposit Account No. 50-3013, if required.
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`BI No.
`[] Yes, the name ofthe U.S. Government agency and the Government contract numberare:
`
`Respecifully submitted,
`
`Signature
`
`
`
`/
`
`Robert’ Chang
`3.753) REGISTRATION NO.
`for Anthony M.Insog
`(ifappropriate}
`
`JONES DAY
`
`ao
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`5
`35,203
`
`Dat
`ate
`
`March 5, 2009
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`
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`[J Additional inventors are being named on separately numbered sheets attached hereto.
`
`Total number of cover sheet pages.
`PROVISIONAL APPLICATION FILING ONLY
`
`LAI-3007509v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0001
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0001
`
`

`

`ORAL DOSAGE FORMSOF CYTIDINE ANALOGS
`AND METHODS OF USE THEREOF
`
`I. FIELD
`
`[0001]
`
`Provided herein are pharmaceutical dosage forms comprising cytidine
`
`analogs, or their salts, solvates, hydrates, precursors, and/or derivatives thereof, for oral
`
`administration in subjects. Also provided are methods for making the dosage forms and
`
`for using the dosage formsto treat cancer and disorders related to abnormalcell
`
`proliferation.
`
`il. BACKGROUND
`
`[8002]
`
`Cancer is a major worldwide public health problem; in the United States
`
`alone, approximately 570,000 cancer-related deaths were expected in 2005. See, e.g.,
`
`Jemal et 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
`
`(e.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.
`
`{0003}
`
`Myelodysplastic syndromes (MDS)refers to a diverse group of
`
`hematopoietic 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 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).
`
`[0004]
`
`MDSare grouped together because of the presence of dysplastic changes in
`
`one or more ofthe hematopoietic lineages including dysplastic changes in the myeloid,
`
`erythroid, and megakaryocytic series. These changes result in cytopenias in one or more
`
`of the three lineages. Subjects afflicted with MDS may develop complications related 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
`
`NY1-4164551v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0002
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0002
`
`

`

`overwhelms the healthy marrow. The disease course differs, with some cases behaving
`as an indolent disease and others behaving aggressively with a very short clinical course
`
`that converts into an acute form of leukemia. The majority of people with higher risk
`
`MDSeventually experience bone marrow failure. Up to 50% of MDSpatients succumb
`
`to complications, such as infection or bleeding, before progressing to AML.
`[0005]
`Aninternational group of hematologists, the French-American-British (FAB)
`Cooperative Group, classified MDS into five subgroups, differentiating them from acute
`
`myeloid leukemia. See, e.g., The Merck Manual 954 (17th ed. 1999); Bennett J. M., e¢
`
`al., Ann. Intern. Med., 103(4): 620-5 (1985); and Besa E. C., Med. Clin. North Am.
`
`76(3): 599-617 (1992). An underlying trilineage dysplastic change in the bone marrow
`
`cells of the patients is foundin all subtypes. Information is available regarding the
`pathobiology of MDS,certain MDSclassification systems, and particular methods of
`treating and managing MDS. See, e.g., U.S. Patent No. 7,189,740 (issued March13,
`
`2007), which is incorporated by reference herein in its entirety.
`
`[0006]
`
`Nucleoside analogs have been used clinically for the treatmentofviral
`
`infections 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. In most cases, nucleosidetri-
`phosphatesare the chemical entities that inhibit DNA or RNA synthesis, either through
`competitive inhibition of polymerases or through incorporation of the modified
`
`nucleotides into DNA or RNA sequences. Nucleosides mayalso act as di-phosphates.
`[0007]
`5-Azacytidine (National Service Center designation NSC-102816; CAS
`
`Registry Number 320-67-2), also known as azacitidine, AZA, or 4-amino-I-B-D-
`ribofuranosyl-1,3,5-triazin-2(1H)-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
`analogsandtheir related natural nucleoside is the presence ofa nitrogen at position 5 of
`the cytosine ring in place of a carbon. 5-Azacytidine may be defined as having the
`molecular formula CgHi2N4Qs, a molecular weight of 244.21 grams per mole, and the
`following structure:
`
`NYI-4164551v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0003
`
`

`

`HO
`
`OH
`
`OH
`
`5-Azacytidine.
`
`[0008]
`
`Other membersofthe class of cytidine analogs include, for example: 1-B-D-
`
`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; 1-B-D-ribofuranosyl-2(1 H)-pyrimidinone (Zebularine); 2',3'-
`
`dideoxy-5-fluoro-3'-thiacytidine (Emtriva); 2'-cyclocytidine (Ancitabine); 1-B-D-
`
`arabinofuranosyl-5-azacytosine (Fazarabine or ara-AC); 6-azacytidine (6-aza-CR); 5,6-
`dihydro-5-azacytidine (dH-aza-CR); N‘-pentyloxycarbony]-5'-deoxy-5-fluorocytidine
`(Capecitabine); N*-octadecyl-cytarabine; and elaidic acid cytarabine.
`[0009]
`After its incorporation into replicating DNA, 5-azacytidine or 5-aza-2'-
`
`deoxycytidine forms a covalent complex with DNA methyltransferase. DNA
`
`methyltransferase is responsible for reproducing the methylation patterns in the daughter
`
`strands. Inhibition of DNA methyltransferase by a cytidine analog leads to DNA
`
`hypomethylation, thereby reestablishing the anti-proliferative signals extinguished by
`
`DNAhypermethylation in malignant cells, such as morphologically dysplastic and
`
`immature hematopoietic cells. The cytotoxic effects of these cytidine analogs cause the
`
`death of rapidly dividing cells, including cancercells, that are no longer responsive to
`
`normal cell growth control mechanisms.
`
`[0610]
`
`5-Azacytidine and 5-aza-2'-deoxycytidine have been tested in clinicaltrials
`
`and showedsignificant anti-tumor activity, such as, for example, in the treatment
`
`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 ef al., Curr. Opin. Invest. Drugs 3(4): 627-33
`
`(2002). 5-Azacytidine has undergone NCI-sponsoredtrials for the treatment of MDS
`
`and has been approved fortreating all FAB subtypes of MDS. See, ¢.g., Kornblith e¢ a/.,
`
`J Clin. Oncol. 20(10): 2441-2452 (2002); Silverman ef al., J. Clin. Oncol. 20(10): 2429-
`
`NYL-4164551v1
`
`-3-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0004
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0004
`
`

`

`2440 (2002). 5-Azacytidine may alter the natural course of MDS bydiminishing the
`
`transformation to AMLthrough its cytotoxic activity and its inhibition of DNA
`
`methyltransferase.
`
`In a Phase III study, 5-azacytidine significantly prolonged survival
`
`and time to AMLtransformation or death in elderly subjects. See, e.g., Silverman et al,
`
`Blood 106(11): Abstract 2526 (2005).
`
`[OOL1]
`
`5-Azacytidine and other cytidine analogs are approved for subcutaneous (SC)
`
`or intravenous (1V) administration to treat various proliferative disorders. Oral dosing of
`
`cytidine analogs would be more desirable and convenient for patients and doctors, e.g..
`
`byeliminating injection-site reactions that may occur with SC administration and/or by
`
`permitting improved patient compliance. However, oral delivery of cytidine analogs has
`
`proven difficult due to combinations of chemical instability, 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 absorbed in specific regions of the lower gastrointestinal tract, such as the
`
`jejunum in the small intestine. See, e.g., Sands, et al., U.S. Patent Publication No.
`
`2004/0162263 (App. No. 10/698,983). In addition, a generally accepted beliefin 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.
`
`As a 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.
`
`[0012]
`
`A great need remainsfor oral formulations and dosage forms of cytidine
`
`analogs, such as, ¢.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
`
`maintenance therapies; development of improved treatment regimens that maximize
`
`demethylation or gene re-expression; use of cytidine analogs for treating new diseases or
`
`disorders; and/or other potential advantageous benefits.
`
`NY1-4164551vI
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0005
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0005
`
`

`

`LL SUMMARY
`
`{0013}
`
`Provided herein are pharmaceutical formulations comprising cytidine
`
`analogs, wherein the formulations release the API substantially in the stomach uponoral
`
`administration. Also provided are methods for making the formulations, and methods
`
`for using the formulations to treat cancer and disorders related to abnormalcell
`
`proliferation.
`
`[0014]
`
`In certain embodiments, the cytidine analog is 5-azacytidine.
`
`In other
`
`embodiments, the cytidine analog is 5-aza-2'-deoxycytidine (decitabine or 5-aza-CdR).
`
`In yet other embodiments, the cytidine analog is, for example: 1-B-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; |-B-D-ribofuranosyl-2(1 H)-
`
`pyrimidinone (Zebularine); 2',3'-dideoxy-5-fluoro-3'-thiacytidine (Emtriva); 2'-
`
`cyclocytidine (Ancitabine); 1-B-D-arabinofuranosyl-5-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.
`
`(0015)
`
`Certain embodiments herein provide formulations that are single unit dosage
`
`forms comprising a cytidine analog. Certain embodiments herein provide formulations
`
`that are tablets comprising a cytidine analog. Certain embodiments herein provide
`
`formulations that are capsules comprising a cytidine analog. The capsules may be,e.v.,
`
`a hard gelatin capsule or a soft gelatin capsule. In certain embodiments, the single unit
`
`dosage formsoptionally 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 formulation is a tablet that effects an immediate release of the API
`
`upon oral administration.
`
`In other embodiments, the formulation is a tablet that effects a
`
`controlled release of the API substantially in the stomach. In certain embodiments, the
`
`formulation is a capsule that effects an immediate release of the API upon oral
`
`administration. In other embodiments, the formulation 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.
`
`NYI-4164551v1
`
`-5-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0006
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0006
`
`

`

`[0016]
`
`Certain embodiments herein provide methods of making the formulations of
`
`cytidine analogs intended for oral delivery. Further provided are articles of manufacture
`
`containing packaging material, an oral formulation ofa cytidine analog, and a label that
`
`indicates that the formulation is for the treatment of certain disorders related to abnormal
`
`cell proliferation, such as, for example, a cancer.
`
`[0017]
`
`Certain embodiments herein provide methods of using the formulations
`
`provided herein to treat cancers or other disorders related to abnormal cell proliferation.
`
`In certain embodiments, the formulations of cytidine analogs are orally administered to
`
`subjects in need thereof to treat a cancer, including, but not limited to, a hematological
`
`disorder, such as, for example, MDS, AML, ALL, CML, NHL, leukemia, or lymphoma;
`
`or a solid tumor, such as, for example, sarcoma, melanoma, carcinoma, or cancer of 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 oral formulations provided herein are co-administered with one or
`
`more therapeutic agents to provide a synergistic therapeutic 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.
`
`[0018]
`
`In particular embodiments, provided herein are tablets containing 5-
`
`azacytidine and methods for making and using the tablets to treat cancer and disorders
`
`related to abnormal cell proliferation. 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 described in, 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.
`
`[0019]
`
`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; are tablets; are capsules; further comprise an excipient selected from any
`
`excipient disclosed herein; further comprise a permeation enhancer; further comprise d-
`
`NYI-416455l1v1
`
`-6-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0007
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0007
`
`

`

`
`
`alpha-tocophery! polyethylene glycol 1000 succinate; further comprise a permeation
`
`enhancer in 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 amount of 5-azacytidine ofat least about 40 mg; have an
`
`amount of 5-azacytidine ofat least about 400 mg; have an amount of 5-azacytidine ofat
`
`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
`
`of at least about 400 ng-hr/mL following oral administration to a subject; achieve a
`
`maximumplasma concentration ofat least about 100 ng/mL following oral
`
`administration to a subject; achieve a maximum plasma concentration 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.
`
`[0020]
`
`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.
`
`[0021]
`
`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.
`
`[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 a maximum plasma
`
`concentration of at least about 100 ng/mL following oral administration.
`
`[0023]
`
`Specitic 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 200 ng/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 time to maximum
`
`plasmaconcentration of less than about 90 minutes following oral administration.
`
`NYI-4164551v1
`
`-7-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0008
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0008
`
`

`

`
`
`[0025]
`
`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.
`
`[0026]
`
`Specific embodiments herein provide any ofthe aforementioned
`
`compositions, as single unit dosage forms, tablets, or capsules.
`
`[0027]
`
`Specific embodiments herein provide, inter alia, methodsfor treating 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 stomach following 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 thereof an 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 weightrelative 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 compositionis a tablet; the composition is a capsule; the composition
`
`further comprises an excipient selected from any excipient disclosed herein; the amount
`
`of 5-azacytidineis at least about 40 mg; the amountof5-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 of at 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
`
`NY1-4164551v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0009
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0009
`
`

`

`
`
`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
`
`[0028]
`
`Specific embodiments herein provide, inter alia, pharmaccutical
`
`compositions comprising a therapeutically effective amount of 5-azacytidine, wherein
`
`the compositions are for treating a disease or disorder associated with abnormalcell
`
`proliferation, wherein the 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 of5-azacytidine of about 40 mg, about 400 mg, or about 1000
`
`mg; are prepared to achieve an area-under-the-curve value of at 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 syndromeor 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.
`
`[0029]
`Specific embodiments herein provide, inter alia, uses of 5-azacytidine and,
`optionally, a permeation enhancer, for the preparation of a pharmaceutical composition
`for treating a disease associated with abnormalcell proliferation, wherein the
`
`composition is prepared for oral administration, and wherein the composition is prepared
`for release of the 5-azacytidine substantially in the stomach. Further embodiments
`
`herein provide the aforementioned uses, in which:
`
`the disease is myelodysplastic
`
`syndrome or acute myelogenous leukemia; the amount of 5-azacytidine is selected from
`
`any amountdisclosed herein; and/or the composition is prepared for immediate release.
`
`NY1I-4164551 v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0010
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0010
`
`

`

`IV. BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0030]
`
`Figure 1 represents processes and steps that may be used to make particular
`
`tablets comprising azacitidine for oral dosing.
`[0031]
`Figure 2 represents human PK profiles following 75 mg/m* SC dosing of
`azacitidine on Days 1 and 7 in a multiple dose escalation study (n = 18). The X-axis
`
`represents time; the Y-axis represents azacitidine plasma concentrations (mean + SD).
`|0032|
`Figure 3 represents human PK profiles following SC (75 mg/m’) and PO
`(240 mg, 300 mg, and 360 mg) dosing ofazacitidine in a multiple dose escalation study.
`
`The azacitidine plasma PK profiles are compared among various doses. The X-axis
`
`represents time; the Y-axis represents azacitidine plasma concentrations (mean + SD).
`
`[0033]
`
`Figure 4 represents PD data from anindividual patient (Subject 02008, 80
`
`year old male, RAEB-1) collected during a multiple dose escalation study. The patient
`
`was dosed with azacitidine Formulation #3, 240 mg. Platelets (K/uL), Hgb (g/dL), ANC
`
`(K/uL), and Relative BM Blast (%) are plotted versus sampling dates over the course of
`
`the study.
`
`[0034]
`
`Figure 5 represents PD data from an individual patient (Subject 02007, 76
`
`year old male, CMML)collected during a multiple dose escalation study. The patient
`
`was dosed with azacitidine Formulation #3, 240 mg. Platelets (K/uL), Hgb (g/dL), ANC
`
`(K/L), and Relative BM Blast (°%) are plotted versus sampling dates over the course of
`
`the study.
`
`[0035]
`
`Figure 6 represents PD data froman individual patient (Subject 02004, 61
`
`year old male, MDS, MDACC)collected during a multiple dose escalation study. The
`
`patient was dosed with azacitidine Formulation 1, 120 mg. Platelets (K/uL), Hgb
`
`(g/dL), ANC (K/pL), and Relative BM Blast (%) are plotted versus sampling dates over
`
`the course of the study.
`
`[0036]
`
`Figure 7 represents a study design of a Rapid Aza Clinical Evaluation
`
`(RACE) study. Doses given on various days within a treatment cycle are depicted.
`
`Dose may be administered + 1 day, as long as there is at least 48 hours between doses.
`
`Figure 8 represents azacitidine human PKprofiles from an individual patient
`[0037]
`(Subject 106003, N = 1) following SC (124 mg, 75 mg/m’) and PO (180 mg, 360 mg,
`1,200 mg, Formulation 4) dosing of azacitidine from a RACEclinical study. AUC(0-t)
`
`values for the SC and PO doses are depicted.
`
`Figure 9 represents azacitidine human PK profiles from an individual patient
`[0038]
`(Subject 106004, N = 1) following SC (120 mg, 75 mg/m’) and PO (180 mg, 360 mg,&
`
`NYI-4164551v1
`
`-10-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0011
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0011
`
`

`

`1,200 mg, Formulation 6) dosing of azacitidine from a RACEclinical study. AUC(0-0)
`
`values for the SC and PO doses are depicted.
`
`[0039]
`
`Figure 10 represents human PK profiles (linear scale) following SC and oral
`
`administration of azacitidine in clinical studies.
`
`[0040]
`
`Figure 11 represents human PK profiles (semi-log scale) following SC and
`
`oral administration of azacitidine in clinical studies.
`
`[0041]
`
`Figure 12 represents human AUC values following SC dosing of azacitidine
`
`and oral dosing ofazacitidine with Formulations #3, #4, and #6 at various dosage levels
`
`in clinical studies.
`
`[0042]
`
`Figure 13 represents human Cmax valuesin patients following SC dosing of
`
`azacitidine and oral dosing of azacitidine with Formulations #3, #4, and #6 at various
`
`dosage levels in clinical studies.
`
`[0043]
`
`Figure 14 represents relative oral bioavailability in humans following oral
`
`dosing of azacitidine with Formulations #3, #4, and #6 at various dosage levels.
`
`[0044]
`
`Figure 15 represents percent exposure in humansrelative to SC
`
`administration following oral dosing of azacitidine with Formulations #3, #4, and #6 at
`
`various dosage levels.
`
`[0045]
`
`Figure 16 represents a plot of percent methylated CpG loci in the blood DNA
`
`from an individual patient dosed with azacitidine in a MTD study.
`
`[0046]
`
`Figure 17 represents a plot of percent highly methylated CpG loci in the
`
`blood DNA from an individual patient dosed with azacitidine in a MTD study.
`
`Vv. DETAILED DESCRIPTION
`
`[0047]
`
`Unless defined otherwise, all technical and scientific terms used herein have
`
`the same meaning as commonly understood byone ofordinary skill in the art. All
`
`publications and patents referred to herein are incorporated by reference herein in their
`
`entireties.
`
`5.1 Definitions
`
`[0048]
`
`As used in the specification and the accompanying claims, the indefinite
`
`articles “‘a” and “an” and the definite article “the” include plural as well as singular
`
`referents, unless the context clearly dictates otherwise.
`
`[0049]
`
`The term “about” or “approximately” means an acceptable error for a
`
`particular value as determined byone of ordinary skill in the art, which depends in part
`
`on how the value is measured or determined. In certain embodiments, the term “about”
`
`NY1-4164551v1
`
`Apotexv.Cellgene -IPR2023-00512
`Petitioner Apotex Exhibit 1050-0012
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1050-0012
`
`

`

`or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain
`
`embodiments, the term “about” or “approximately” means within 30%, 25%, 20%, 15%,
`
`10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or
`
`range.
`
`As used herein, and unless otherwise specified, the terms “treat,” “treating”
`[0050]
`and “treatment” refer to the eradication or amelioration of a disease or disorder, or of
`
`one or more symptomsassociated with the disease or disorder. In certain embodiments,
`
`the terms refer to minimizing the spread or worsening ofthe disease or disorder resulting
`from the administration of one or more prophylactic or therapeutic agents to a subject
`with such a disease or disorder. In some embodiments, the terms refer to the
`
`administration of a compound or dosage form provided herein, with or without one or
`
`more additional active agent(s), a