a,
`Sb
`s
`e
`. = 2
`|
`Ree S
`oe PROVISIONAL APPLICATION FOR PATENT COVER SHEET at;Sntae
`
`Express Mail No. EM198023845US
`
`12/05/2008
`
`,
`
`oS on.
`=
`=—=sinnussionerfor Patents
`P.O.
`Bax 1450
`Alexandria, VA 22313-1450
`3
`Sir:
`
`ofthis sheet is enclosed, payment to Jones Day Deposit Account
`
`This is a request for filing a PROVISIONAL APPLICATIONunder 37 CFR 1.53(c).
`
`Given Name {first and middle (if any)}
`
`Family Name or Surname
`
`Residence (City And Either State Or Foreign Country)
`
`INVENTOR(s) APPLICANT(s)
`
`Summit, New Jerse
`Summit, New Jerse
`
`{J Additional inventors are being named on separately numberedsheets attached hereto.
`
`Total number of cover sheet pages. 1.
`
`TITLE OF THE INVENTION(500 characters max)
`
`ORAL DOSAGE FORMS AND COMPOSITIONS FOR IMMEDIATE RELEASE OF CYTIDINE ANALOGS
`
`JONES DAY
`CORRESPONDENCE ADDRESS:
`
`20583
`
`ENCLOSED APPLICATION PARTS(check all that apply)
`
`IX] Specification
`
`Number ofPages
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`CO Applicantclaims small entity status, see 37 CFR §1.27
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`EJ Drawing(s)
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`C2 Application Data Sheet. See 37 CFR 1.76
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`(CO Other(specify)
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`FEES DUE: Filing Fee of $220 ($110 for smali entity). If the specification and drawings exceed 100 sheets of paper, an application size fee is also due,
`which is $270 ($135 for small entity) for each additional 50 sheets or fraction thereof. See 35 U.S.C. 41(a)(1)(G) and 37 CFR 1.16(s).
`EXTRA RATE
`TYPE
`NO. FILED
`LESS
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`Total Number of
`Pages w/ drawings
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`$270.00 for each 50 pages
`over 100
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`30
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`Applicant qualifies for the 50% Reduction for Independent Inventor, Nonprofit Organization or Small Business
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`A check or moneyorderis enclosed to cover the filing fee and application size fee (if applicable).
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`Total Filing Fee
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`The Director is hereby authorized to charge thefiling fee and application size fee (if applicable) or credit any
`i
`No. 50-3013. A copy
`
`The invention was made by an agency of the United States Governmentor undera contract with an agency of the United States Government.
`K No.
`(7 Yes, the name of the U.S. Government agency and the Government contract numberare:
`Respectfully submitted,
`
`Signature
`
`
`for4Anthony M. Insogna (Reg. No. 35,203)
`JONES DAY
`
`REGISTRATION NO.
`(ifappropriate)
`
`59,239
`
`Date
`
`12/5/08
`
`USE ONLY FOR FILING A PROVISIONAL APPLICATION FOR PATENT
`
`NY1-4143897v1
`
`4
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0001
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0001
`
`

`

`
`QRAL DOSAGE FORMS AND COMPOSITIONS FOR
`
`
`IMMEDIATE RELEASE OF CYTIDINE ANALOGS
`
`
`I. FIELD
`
`Provided herein are oral dosage forms and compositions comprising one or more
`[0001]
`cytidine analogs, including but not limited to 5-azacytidine (azacitidine), which effect an
`
`immediate release of the active pharmaceutical ingredient (API) upon administration.
`
`ll. BACKGROUND
`
`[0002]
`
`5-Azacytidine (also known as azacitidine; AZA; 4-amino-l-B-D-ribofuranosyl-
`
`1 ,3,5-triazin-2(1)-one; Nation Service Center designation NSC-102816; CAS Registry
`Number 320-67-2; and marketed as the drug product VIDAZA®) has undergone NCI-
`sponsored trials for the treatment of myelodysplastic syndromes (“MDS”). See, e.g.,
`
`Kornblith et al., J. Clin. Oncol. 20(10): 2441-2452 (2002); Silverman etal., J. Clin. Oncol.
`
`20(10): 2429-2440 (2002). Azacitidine may be defined as having a molecular formula of
`
`CsgHi2NaOs, a molecular weight of 244.20 grams per mole, andastructure of:
`
`NH2
`
`ASN
`a
`
`H
`
`OH
`
`H
`OH
`
`5-Azacytidine (azacitidine).
`
`Azacitidine is a nucleoside analog, more specifically, a cytidine analog.
`[0003]
`Azacitidine is an antagonist ofits related natural nucleoside, cytidine. Azacitidine, as well as
`
`decitabine, i.¢., 5-aza-2'-deoxycytidine, are antagonists of decitabine's related natural
`
`nucleoside, deoxycytidine. The only structural difference between the analogs and their
`
`related natural nucleosides is the presence ofnitrogen at position 5 ofthe cytosine ring in
`place of oxygen.
`(0004
`Other membersof the class of deoxycytidine and cytidine analogs include,e.g.,
`arabinosylcytosine (Cytarabine), 2'-deoxy-2',2'-difluorocytidine (Gemcitabine), 5-aza-2'-
`
`deoxycytidine (Decitabine), 2(1H)-pyrimidine riboside (Zebularine), 2',3'-dideoxy-5-fluoro-
`
`NY1-$143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0002
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0002
`
`

`

`3'-thiacytidine (Emtriva), N‘-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecitabine), 2'-
`cyclocytidine, arabinofuanosy1-5-azacytidine, dihydro-5-azacytidine, N*-octadecyl-
`cytarabine,elaidic acid cytarabine, and cytosine I-8-D-arabinofuranoside (ara-C).
`[9005]
`5-Azacytidine has been approved forintermittent subcutaneous (SC) and
`intravenous(IV) administration. For example, efficacy has been demonstrated in patients
`with MDSand acute myelogenous leukemia (“AML”). An oral formulation, however, would
`provide a more desirable route of administration and eliminate injection-site reactions that
`can occur with subcutaneous administration of azacitidine.
`[0006}
`Previous attempts to develop oral dosage formsof citidine analogs have employed
`enteric-coated cores to protect these APIs from what was understood and accepted to be
`therapeutically unacceptable hydrolysis in the stomach. Due to concerns for detrimental
`hydrolytic degradation of cytidine analogs, prior film-coating of dosage cores for prospective
`oral delivery of cytidine analogs has been limited to organic solvents specifically to prevent
`exposure of the cytidine-analog-containing cores to water during production. Water has not
`previously been employedin the film coating of cytidine-analog-containingtablets due to the
`art-accepted beliefofits prospective level of inherent hydrolytic degradation of cytidine
`analogsin the tablets and unacceptable effect subsequently on the stability of the compound.
`See, e.g., Sands, ef al., US Application No. 10/698,983, Publication No. 20040162263,
`entitled “Pharmaceutical Formulations Targeting Specific Regions of the Gastrointestinal
`Tract.”
`,
`[0007]
`Therefore, there is a great need for alternative formulations and delivery routes for
`cytidine analogs, e.g., azacitidine, such as, for example, immediate release formulations
`comprising cytidine analogs.
`
`
`
`Ill. SUMMARY
`[0008]
`Provided herein are tablets which effect an immediate release ofa cytidine analog,
`for example, azacitidine, upon oral administration.
`[9009]=In one embodiment, provided herein is a tablet which releases a cytidine analog,
`for example, azacitidine, substantially in the stomach uponoral administration.
`{0010}
`In another embodiment, providedherein is a tablet which effects an immediate
`release of a cytidine analog, for example, azacitidine, upon oral administration, wherein the
`tablet comprisesa film coating and the film coating is produced and applied to a core using
`an aqueous-based solvent.
`
`NYI-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0003
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0003
`
`

`

`[0011]=In another embodiment, provided herein is a tablet which effects an immediate
`
`release of a cytidine analog, for example azacitidine, upon oral administration, wherein the
`
`tablet comprises a specific amountofthe cytidine analog, for example azacitidine.
`
`In
`
`particular embodiments, the contemplated specific amount of azacitidinein the tabletis, e.g.,
`
`at least 20 mg,at least 40 mg,at least 60 mg, at least 80 mg,at least 100 mg,at least 120 mg,
`
`at least 140 mg,at least 160 mg, at least 180 mg, at least 200 mg, at least 220 mg,at least
`
`240, at least 260 mg, at least 280 mg,at least 300 mg,at least 400 mg,at least 500 mg,at
`
`least 600 mg,at least 700 mg,at least 800 mg,at least 900 mg,at least 1000 mg,at least 1100
`
`mg, at least 1200 mg, at least 1300 mg,at least 1400 mg,at least 1500 mg,at least 1600 mg,
`
`at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg,at least 2100 mg,at
`
`least 2200 mg,at least 2300 mg,at least 2400 mg,or at least 2500 mg.
`
`[0012]
`
`In another embodiment, provided herein is a methed for treating a patho-
`
`physiological condition manifested by abnormal cell proliferation, including but not limited
`
`to, lymphoma, leukemia, MDS, AML, hematological disorders, and solid tumors,by orally
`
`administering a tablet which effects an immediate release of a citidine analog, including but
`
`not limited to, azacitidine.
`
`IV. BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0013]
`
`Figure 1 represents an example of a manufacturing process for preparing tablets
`
`comprising azacitidine.
`
`{0014]
`
`Figures 2a and 2b represent plasma pharmacokinetics (PK) parameters of
`
`azacitidine from patients dosed with azacitidine subcutaneously ororally.
`
`[0015]
`
`Figure 3 represents Area Under Curve (AUC) data of azacitidine on Day | and 7
`
`at particular doses.
`
`[0016]
`
`Figure 4 represents plasma concentration versus time PK profiles of azacitidine on
`
`Day | and 7 after oral dosing at particular doses.
`
`[0017}
`
`Figure 5 represents plasma concentration versus time PK profiles of azacitidine on
`
`Day | and 7 after oral or subcutaneous dosing.
`
`{0018}
`
`Figure 6 represents plasma concentration versus time PK profiles of azacitidine in
`
`individual patients on Day 1 and 7.
`
`[0019]
`
`Figure 7 represents plasma PK parameters of azacitidine in patients on Day | and
`
`7 of Cycle | and 2.
`
`NY1-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0004
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0004
`
`

`

`
`V. DETAILED DESCRIPTION
`{0020]
`Unless defined otherwise,all technical and scientific terms used herein have the
`same meaning as commonly understood by one ofordinary skill in the art. All publications
`andpatents referred to herein are incorporated by reference herein in their entireties.
`[0021]
`In one embodiment, provided herein are pharmaceutical formulations of cytidine
`analogs andderivatives, for example, azacitidine, 5-aza-2'-deoxy-2',2'-difluorocytidine, 5-
`aza-2'-deoxy-2'-fluorocytidine, 2'-deoxy-2',2'-difluorocytidine, and cytosine | -B-D-
`arabinofuranoside, as well as methods of administering cytidine analogs or derivatives to
`treat conditions or diseases, such as MDS, AML,leukemia, lymphoma, hematological
`
`disorders, and solid tumors. See, e.g., Etter, U.S. Application No. 11/849,958.
`[0022]
`Provided herein are embodimentsbased on the surprising discovery that 5-
`azacytidine and related compoundsare best absorbed and mostefficaciously delivered if
`instantly released, upon oral administration,in the uppergastrointestinal tract, e.g., the
`stomach. Accordingly, in one embodiment, provided herein is the preparation ofa solid oral
`dosage form of a cytidine analog, for example, 5-azacytidine, using common pharmaceutical
`excipients designed for releasing pharmaceutical compositions immediately in the stomach.
`[0023)
`In one embodiment, provided herein is a controlled release pharmaceutical
`composition for oral administration of a cytidine analog that releases the drug in the stomach,
`comprising: (a) a therapeutically effective amount of a cytidine analog; and (b) a drug release.
`controlling component for providing the release of the cytidine analog primarily in the upper
`
`gastrointestinal tract, e.g. the stomach.
`[0024]
`In one embodiment, the cytidine analog provided herein includes any compound
`whichis structurally related to cytidine or deoxycytidine and functionally mimics and/or
`antagonizestheaction of cytidine or deoxycytidine. These cytidine analogs mayalso be
`termed cytidine derivatives.
`In one embodiment, a cytidine analog provided herein include5-
`aza-2'-deoxycytidine (decitabine), 5-azacytidine, 5-aza-2'-deoxy-2',2'-difluorocytidine, 5-aza-
`2'-deoxy-2'-fluorocytidine, 2'-deoxy-2',2'-difluorocytidine (also called gemcitabine), cytosine
`1-B-D-arabinofuranoside (also called ara-C), 2-(1)-pyrimidine riboside (also called
`zebularine), 2'-cyclocytidine, arabinofuanosyl-S-azacytidine, dihydro-5-azacytidine, N‘-
`octadecyl-cytarabine, andelaidic acid cytarabine.
`In particular embodiments, the cytidine
`analog is 5-azacytidine or 5-aza-2'-deoxycytidine. The definition of a cytidine analog
`provided herein also includes mixtures of cytidine analogs.
`
`NV1-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0005
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0005
`
`

`

`[0025]
`
`In one embodiment, provided herein are methodsto treat patho-physiological
`
`conditions manifested by abnormalcell proliferation including, but not limited to, MDS,
`
`AML, lymphoma, leukemia, hematological disorders, and solid tumors, wherein azacitidine
`
`and at least one histone deacetylase (HDAC)inhibitor(e.g., V-(2-aminopheny])-4-((4-
`
`(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide, also known as MGCD0103),are co-
`
`formulated to effect oral co-administration and yield a synergistic therapeutic effect.
`
`[0026]
`
`In one embodiment, the controlled release pharmaceutical composition includes a
`
`drug release controlling component and releases the API primarily and immediately in the
`
`upper gastrointestinaltract. In particular embodiments,the drug release controlling
`
`componentis adjusted suchthat the release of the cytidine analog is immediate and occurs
`
`primarily in the stomach. In one embodiment,at least about 95% of the cytidine analogis
`
`released in the stomach, or at least about 90% of the cytidine analog is released in the
`
`stomach. In other embodiments, at least about 80% of the cytidine analog is released in the
`
`stomach,at least about 70% ofthe cytidine analog is released in the stomach,at least about
`
`60% of the cytidine analogis released in the stomach,orat least about 50% of the cytidine
`
`analogis released in the stomach. In other embodiments, the amountreleased in the stomach
`
`is at least about 40%,at least about 30%, or at least about 20% ofthe cytidine analog. The
`
`term “release”refers to the process whereby the cytidine analog is made available for uptake
`
`by or transport across the epithelial cells that line the stomach and then made available to the
`
`body.
`
`[0027]
`Inone embodiment, the pharmaceutical composition provided herein is intended
`for oral delivery. Oral delivery includes formats suchas, e.g., tablets, capsules, caplets,
`solutions, suspensions, and/or syrups, and may also comprise a plurality of granules, beads,
`
`powdersor pellets that may or may not be encapsulated. Such formats mayalso bereferred
`
`to as the “drug core” which contains the cytidine analog. Such dosage forms are prepared
`using conventional methods known to those skilled in the field of pharmaceutical formulation
`
`and are describedin pertinenttexts. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF
`PHARMACY, 20th Edition, Lippincott Williams & Wilkins, (2000).
`
`Tablets and capsules represent the most convenient oral dosage forms in cases
`[0028]
`where solid pharmaceutical carriers are employed. In one embodiment,tablets are used.
`particular embodiments, tablets may be manufactured using standard tablet processing
`procedures and equipment. In one embodiment, the method for forming thetablets is by
`direct compression of a powdered, crystalline or granular composition containing the cytidine
`
`In
`
`NYE-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0006
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0006
`
`

`

`analog,alone or in combination with one or more carriers, additives, or the like. In another
`embodiment,as an alternative to direct compression,the tablets may be prepared using wet
`granulation or dry-granulation processes.
`In another embodiment, the tablets may also be
`moldedrather than compressed,starting with a moist or otherwise tractable material.
`In
`particular embodiments, compression and granulation techniques are used.
`[0029]
`In another embodiment, capsules are used.
`In particular embodiments, soft gelatin
`capsules may be prepared in which the capsules contain a mixture of the active ingredient and
`vegetable oil or non-aqueous, water miscible materials such as, for example, polyethylene
`glycol andthe like.
`In another embodiment, hard gelatin capsules may be prepared
`containing granules ofthe active ingredient in combination with a solid, pulverulentcarrier,
`suchas, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corm starch,
`amylopectin, cellulose derivatives, or gelatin. In one embodiment, a hard gelatin capsule
`shell may be prepared from a capsule composition comprising gelatin and a small amount of
`plasticizer such as glycerol. In another embodiment,as an alternative to gelatin, the capsule
`shell may be madeof a carbohydrate material. In one embodiment, the capsule composition
`mayadditionally include colorings, flavorings and opacifiers as required.
`{0030]
`In one embodiment, the oral dosage form of a cytidine analogis prepared as a
`controlled release tablet or capsule whichincludes a drug core comprising the pharmaceutical
`composition and optional excipients. Optionally, a seal coat is applied.
`[0031]
`In one embodiment, the oral dosage form of the cytidine analogis a tablet
`containinga film coat applied to the drug core using aqueous solvents.
`In one embodiment,
`exemplary tablets are aqueousfilm-coated. In particular embodiments, water is employed as
`the solvent for film-coating. In particular embodiments, the tablet containing the cytidine
`analogis film-coated using aqueous-basedsolvents without effecting degradation ofthe
`pharmaceutical composition.
`In particular embodiments, water is used as the film coating
`solvent without effecting degradation of the pharmaceutical composition. In one
`embodiment,the oral dosage form of azacitidine with the aqueousfilm coat effects
`immediate drug release uponoral delivery.
`In another embodiment, the oral dosage form of
`azacitidine with aqueousfilm coat effects controlled drug release to the upper gastrointestinal
`tract, e.g. the stomach, uponoral delivery. In particular embodiments, the tablet with
`aqueous-based solventfilm coating contains azacitidine as the API. In another embodiment,
`the tablet with water-basedfilm coating contains azacitidine as the API.
`
`
`
`NYI-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0007
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0007
`
`

`

`| ||
`
`|
`
`ii|| |||
`
`[0032]
`
`Certain embodiments herein provide oral dosage formsof a cytidine analog in
`
`whichless than all of the cytidine analogueis enteric coated, allowingfor partial release in
`
`the upper gastrointestinal tract and partial release in the lower gastrointestinal tract. For
`
`example,in particular embodiments, the oral dosage form ofthe cytidine analogis a tablet
`
`that containsan enteric-coated core containing a cytidine analog with one or more non-
`
`enteric-coated outer layers containing a cytidine analog. In certain embodiments, such oral
`
`dosage forms control the release of the API in both the upper and lowergastrointestinal tract.
`In particular embodiments, the oral dosage form contains azacitidine as the API.
`In particular
`
`embodiments, the oral dosage form releases azacitidine primarily in the stomach,i.e., makes
`
`azacitidine available for uptake by or transport across the epithelial cells that line the stomach
`
`and subsequently available to the body, with the remaining azacitidine available for release in
`
`the lower gastrointestinal tract. In particular embodiments,at least about 95% of azacitidine
`
`is released in the stomach,at least about 90% of azacitidine is released in the stomach,at
`
`least about 80% ofazacitidine is released in the stomach,at least about 70% of azacitidine is
`
`released in the stomach,at least about 60% ofazacitidine is released in the stomach,at least
`
`about 50% ofazacitidine is released in the stomach,at least about 40% ofazacitidine is
`
`released in the stomach, at least about 30% of azacitidine is released in the stomach,at least
`
`about 20% of azacidine is released in the stomach,or at least about 10% of azacidine is
`
`released in the stomach. In particular embodiments, the contemplated specific amount of
`
`azacitidine in a tabletis, e.g, at least 20 mg, at least 25 mg, at least 50 mg,at least 75 mg, at
`
`least 100 mg,at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg,at least 350
`
`mg,at least 400 mg, at least 450 mg,at least 500 mg, at least 750 mg, at least 1000 mg,at
`
`least about 1250 mg, at least about 1500 mg, at least about 1750 mg,at least about 2000 mg,
`
`at least about 2250 mg,or at least about 2500 mgazacitidine.
`
`[0033]
`
`In one embodiment, the amounts ofthe cytidine analog in the oral formulations
`
`include a therapeutically effective amount. Contemplated therapeutic indications are
`
`provided herein. The precise therapeutically effective amounts of the cytidine analog in the
`
`pharmaceutical compositions provided herein will vary depending on,e.g., the age, weight,
`
`disease and condition of the patient, and may be determined by one of ordinary skill in the art
`
`using methods known in the art. For example, in particular embodiments, pharmaceutical
`compositions may contain sufficient quantities of a cytidine analog to provide a daily dosage
`equivalentto about 150 mg/m’(based onpatient body surface area) or about 4 mg/kg (based
`on patient body weight) as single or divided (2-3) daily doses.
`
`NY1I-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0008
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0008
`
`

`

`In one embodiment, the oral dosage forms and compositionsofthe cytidine
`[0034]
`analog provided herein maybe usedto treat patients having hematologic disorders. In
`particular embodiments, the oral dosage forms and compositionsof azacitidine provided
`herein maybe usedtotreat patients having hematologic disorders. Hematologic disorders
`include abnormal growth of blood cells which can lead to dysplastic changesin blood cells
`and hematologic malignancies such as various leukemias. Examples of hematologic
`disorders include, but are not limited to, acute myeloid leukemia (AML), acute promyelocytic
`leukemia, acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML),
`myelodysplastic syndromes (MDS), andsickle cell anemia.
`[0035]
`Acute myeloid leukemia (AML)is the most commontypeofacute leukemiathat
`occurs in adults. Several inherited genetic disorders and immunodeficiencystates are
`associated with an increased risk of AML. Theseinclude disorders with defects in DNA
`stability, leading to random chromosomal breakage, such as Bloom's syndrome, Fanconi's
`anemia, Li-Fraumenikindreds, ataxia-telangiectasia, and X-linked agammaglobulinemia.
`[0036]
`Acute promyelocytic leukemia (APML)represents a distinct subgroup of AML.
`This subtype is characterized by promyelocytic blasts containing the 15;17 chromosomal
`translocation. This translocation leadsto the generation of the fusion transcript comprised of
`
`the retinoic acid receptor and a sequence PML.
`[0037]
`Acute lymphoblastic leukemia (ALL)is a heterogenerousdisease with distinct
`clinical features displayed by various subtypes. Reoccurring cytogenetic abnormalities have
`been demonstrated in ALL. The most common cytogenetic abnormality is the 9;22
`translocation. The resultant Philadelphia chromosomerepresents poor prognosis of the
`
`|
`
`patient.
`Chronic myelogenous leukemia (CML)is a clonal myeloproliferative disorder of a
`[6038]
`pluripotent stem cell. CMLis characterized by a specific chromosomal abnormality
`involving the translocation of chromosomes 9 and 22, creating the Philadelphia chromosome.
`.
`lonizing radiation is associated with the development of CML.
`[0039]|The myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic
`stem cell disorders grouped together becauseofthe presenceofdysplastic changesin one or
`more of the hematopoietic lineages including dysplastic changes in the myeloid, erythroid,
`and megakaryocytic series. These changesresult in cytopenias in one or moreofthe three
`lineages. Patients afflicted with MDStypically develop complicationsrelated to anemia,
`neutropenia (infections), or thrombocytopenia (bleeding). Generally, from about 10% to
`
`NYI-4143779v1
`
`-8-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0009
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0009
`
`

`

`about 70% of patients with MDSdevelop acute leukemia. MDSaffects approximately
`
`40,000-50,000 people in the U.S. and 75,000-85,000 patients in Europe. 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
`
`acute myeloid leukemia (AML). MDSpatients have a median survival of four monthsto five
`
`years depending onrisk stratification. Higher-risk patients have a median survivaloffive to
`
`14 months. Altering the natural history of the disease and providing increased survival is one
`
`of the most important treatment goals in higher-risk MDS.
`
`[0040]
`
`In one embodiment, MDSis a condition to treat with the dosage forms or
`
`compositions provided herein, and includes the following myelodysplastic syndrome
`
`subtypes: refractory anemia, refractory anemia with ringed sideroblasts (if accompanied by
`
`neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess
`
`blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic
`
`leukemia. In another embodiment, the condition to treat is higher-risk MDS.
`
`[0041]
`
`In another embodiment, provided herein is a method for delivering a cytidine
`
`analog to a patient comprising administering the patient in need of treatment with a
`
`composition of a cytidine analog. In one embodiment, the composition comprises an oral
`
`formulation of a cytidine analog, wherein the oral formulation of the cytidine analog
`
`comprises: (a) a therapeutically effective amount of a cytidine analog; and (b) a drug release
`
`controlling component capable of releasing the cytidine analog primarily in the stomach,
`
`wherein after ingestion by a patient the cytidine analog is released primarily in the stomach.
`
`In another embodiment, provided herein is a method of formulating a cytidine
`[0042]
`analog for oral delivery, comprising formulating (including, in certain embodiments, coating)
`
`a therapeutically effective amountof a cytidine analog with a drug release controlling
`
`component capable of releasing the cytidine analog primarily in the stomach.
`
`[0043]
`
`In another embodiment, provided herein is a method of increasing the
`
`bioavailability of a cytidine analog comprising administering a pharmaceutical composition
`
`provided herein to a patient orally. Specitically, a pharmaceutical composition provided
`
`herein is provided to a patient, and ingested by the patient, wherein the composition contacts
`
`the biological fluids of the patient's body being absorbed in the upper gastrointestinal tract,
`
`and increases the bioavailability of the cytidine analog. Oral bioavailability of a cytidine
`
`analog composition provided herein can be more than 5%, more than 10%, more than 15%,
`
`more than 20%, more than 25%, more than 30%, or more than 50% greater than the oral
`
`NY1-4143779v1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0010
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0010
`
`

`

`bioavailability of a previous formulation of a cytidine analog. Average maximum plasma
`concentration achievedrelative to the dose administered may be more than 2 fold higher,
`morethan 3 fold higher, more than 5 fold higher, or about 10 fold higherthan the oral
`bioavailability of a previous formulation of a cytidine analog, when a cytidine analog is
`administered orally in the composition provided herein.
`[0044]
`In another embodiment, provided herein are methodsfor treating a patient having
`a disease associated with abnormalcell proliferation, comprising administering the patient
`orally with a pharmaceutical composition provided herein.
`In one embodiment, a
`pharmaceutical composition provided herein allows for enhanced bioavailability of the
`cytidine analog to the patient.
`{0045}
`In some embodiments, indications that may be treated using the pharmaceutical
`compositions provided herein include those involving undesirable or uncontrolled cell
`proliferations. Such indications include benign tumors, various types of cancers such as
`primary tumors and tumor metastasis, hematological disorders (e.g. leukemia,
`myelodysplastic syndrome andsickle cell anemia), restenosis (e.g. coronary, carotid, and
`cerebral lesions), abnormal stimulation of endothelial cells (arteriosclerosis), insults to body
`tissue due to surgery, abnormal woundhealing, abnormal angiogenesis, diseases that produce
`fibrosis of tissue, repetitive motion disorders, disorders oftissues that are not highly
`vascularized, and proliferative responses associated with organ transplants.
`[0046]
`Generally, cells in a benign tumorretain their differentiated features and do not
`divide in a completely uncontrolled manner. A benign tumoris usually localized and
`nonmetastatic. Specific types of benign tumors that can be treated using the compositionsor
`formulations provided herein include hemangiomas, hepatocellular adenoma, cavernous
`hemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct
`adenoma,bile duct cystanoma,fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,
`myxomas, nodular regenerative hyperplasia, trachomas and pyogenic granulomas.
`[0047]
`In a malignant tumor,cells that become undifferentiated do not respondto the
`body's growth control signals, and multiply in an uncontrolled manner. The malignant tumor
`is invasive and capable of spreadingto distant sites (metastasizing). Malignant tumors are
`generally divided into two categories: primary and secondary. Primary tumorsarise directly
`from the tissue in which they are found. A secondary tumor,or metastasis, is a tumor which
`is originated elsewhere in the body but has now spreadto a distant organ. The common
`routes for metastasis are direct growth into adjacent structures, spread through the vascular or
`
`NYI-4143779v1
`
`-10-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0011
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1051-0011
`
`

`

`lymphatic systems, and tracking along tissue planes and body spaces (peritonealfluid,
`
`cerebrospinalfluid, etc.).
`
`[0043]
`
`Specific types of cancers or malignant tumors, either primary or secondary, that
`
`can be treated using compositions provided in certain embodiments herein include, but are
`
`not limited to, leukemia, breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer,
`
`lung cancer, brain cancer, cancerof the larynx, gall bladder, pancreas, rectum, parathyroid,
`
`thyroid,adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell
`
`carcinoma, squamouscell carcinomaofboth ulcerating and papillary type, metastatic skin
`
`carcinoma, osteo sarcoma, Ewing's sarcoma,veticulum cell sarcoma, myeloma, giantcell
`
`tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and
`
`chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia,
`
`medullary carcinoma, pheochromocytoma, mucosal neuronmas,intestinal ganglioneuromas,
`
`hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma,
`
`ovarian tumor, leiomyomatumor, cervical dysplasia and in situ carcinoma, neuroblastoma,
`
`retinoblastoma, medulloblastoma, soft tissue sarcoma, malignant carcinoid, topical skin
`
`lesion, mycosis fungoides, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other
`
`sarcoma, malignant hypercalcemia, renal cell tumor, polycythermia vera, adenocarcinoma,
`
`glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, epidermoid
`
`carcinomas, and other carcinomas and sarcomas.
`
`[0049]
`
`Treatment of abnormal cell proliferation dueto insults to body tissue during
`
`surgery may be possible for a variety of surgical procedures, including joint surgery, bowel
`
`surgery, and cheloid scarring. Diseases that producefibrotic tissue include emphysema.
`Repetitive motion disorders that may be treated include carpal tunnel syndrome. An example
`ofcell proliferative disorders that may be treated is a bone tumor.
`
`Ftiertrereteenetnnpterpe
`
`Theproliferative responses associated with organ transplantation that may be
`[0050]
`treated include those proliferative responses contributing to potential organ rejections or
`associated complications. Specifically, these proliferative responses may occur during
`transplantation ofthe heart, lung, liver, kidney, and other body organs or organ syste