(12)
`
`United States Patent
`Etter et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,846,628 B2
`Sep. 30, 2014
`
`USOO8846628B2
`
`(54) ORAL FORMULATIONS OF CYTIDINE
`ANALOGS AND METHODS OF USE
`THEREOF
`
`(75) Inventors: Jeffrey B. Etter, Boulder, CO (US); Mei
`Lai, Longmont, CO (US); Jay Thomas
`Backstrom, Leawood, KS (US)
`s
`s
`
`(73) Assignee: Celgene Corporation, Summit, NJ (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 260 days.
`
`(21) Appl. No.: 12/466,213
`
`(22) Filed:
`
`May 14, 2009
`
`(65)
`
`Prior Publication Data
`
`US 2009/0286752 A1
`
`Nov. 19, 2009
`
`Related U.S. Application Data
`(60) Provisional application No. 61/053,609, filed on May
`15, 2008, provisional application No. 61/157,875,
`filed on Mar. 5, 2009, provisional application No.
`61/201,145, filed on Dec. 5, 2008.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`AOIN 43/04
`A6 IK3I/70
`C07H 19/12
`A6 IK 9/28
`A6 IK9/20
`A6 IK3I/706
`A6 IK3I/7068
`(52) U.S. Cl
`CPC ............. A61 K9/2013 (2013.01); A61 K9/2846
`(2013.01); A61 K9/2886 (2013.01); A61 K
`3 1/706 (2013.01); A61 K3I/7068 (2013.01):
`A61 K9/2018 (2013.01)
`USPC ............................................ 514/43: 536/28.3
`(58) Field of Classification Search
`None
`See application file for complete search history.
`References Cited
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`FOREIGN PATENT DOCUMENTS
`
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`OTHER PUBLICATIONS
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`
`Primary Examiner — Lawrence E Crane
`(74) Attorney, Agent, or Firm — Jones Day
`
`(57)
`ABSTRACT
`The present disclosure provides pharmaceutical composi
`tions comprising cytidine analogs, for example, 5-azacyti
`dine or decitabine, for oral administration, wherein the com
`positions release the cytidine analog, for example,
`5-azacytidine or decitabine, Substantially in the stomach.
`Also provided are methods of treating diseases and disorders
`using the oral formulations provided herein.
`
`43 Claims, 23 Drawing Sheets
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0001
`
`

`

`US 8,846,628 B2
`Page 2
`
`(56)
`
`References Cited
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`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0002
`
`

`

`US 8,846,628 B2
`Page 3
`
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`
`* cited by examiner
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0003
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 1 of 23
`
`US 8,846,628 B2
`
`
`
`
`
`
`
`Screen:
`AZOcitidine
`Silicified MicroCrystoline Cellulose
`Monnitol
`Crospovidone
`Magnesium Stearote
`
`
`
`
`
`
`
`
`
`Met Witomi ETPCS
`
`Add N33% Slicified
`Microcrystalline Cellulose
`
`Cool and Screen
`
`in G W Bender Mix:
`AZOcitidine
`Vitamin E TPGS-Silicified Microcrystalline Cellulose
`Silicified Microcrystalline Cellulose
`Monnito
`CrospOvidone
`U
`To W Bender Add
`Magnesium Stedrate
`and Mix
`
`Compress Toblet Cores
`
`Seal Coat Tablets in a Cooting
`Pan to Target Weight Goin
`
`Disperse Hydroxypropy
`Cellulose in Ethanol
`
`Disperse Eudrogit and
`Triethyl Citrote into
`isopropanol - Acetone
`
`s Enteric Coot Toblets in O
`
`Coating Pon to Target
`Weight Gain
`
`Package and obel
`Finished Tablets
`
`F.G. 1
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0004
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 2 of 23
`
`US 8,846,628 B2
`
`-- 75 mg/m2 SC (n=18) Cycle 1 Day 1
`---O--- 75 mg/m2 SC (n=18) Cycle 1 Day 7
`
`Linear Scale
`
`-- 75 mg/m2 SC (n=18) Cycle 1 Day 1
`---0--- 75 mg/m2 SC (n=18) Cycle 1 Day 7
`
`Semi-log Scale
`
`
`
`1000
`900
`800
`700
`600
`500 -
`400
`
`500
`200
`100
`O
`
`1 O O O
`
`100
`
`1 O
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0005
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 3 of 23
`
`US 8,846,628 B2
`
`
`
`\
`H.--
`
`1000
`is 900
`5, 800
`s
`700 ||
`600 - \
`500-
`V
`400-
`300 -
`200
`100
`O
`
`s
`
`5 g
`
`—e 75 mg/m2 SC Cycle 1 Day
`---0--- 75 mg/m2 SC Cycle 1 Day 7
`-- 240 mg PO - F3 Cycle 2 Day 1
`------ 240 mg PO - F3 Cycle 2 Day 7
`-- 300 mg PO - F3 Cycle 2 Day 1
`------ 300 mg PO - F3 Cycle 2 Day 7
`-- 360 mg PO - F3 Cycle 2 Day 1
`------ 360 mg PO - F3 Cycle 2 Day 7
`
`linear Scale
`
`1 O O O
`
`100
`
`O
`
`Day 1 SC AUC infm 150+530 ngh/ml
`-- Day 1240 mg P0 AUC infm 460+220 nghr/ml
`--- Day 1 500 mg P0 AUC infm 260+ 100 nghr/ml
`Day 1560 mg P0 AUC inf N 350+ 175 ngh/ml
`1
`2
`3
`4
`5
`Time (hr)
`FG.3
`
`O
`
`6
`
`7
`
`8
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0006
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 4 of 23
`
`US 8,846,628 B2
`
`8SOO paqJOS9.
`
`
`
`eSOG peqJOSeld
`00£
`07%
`
`09%
`
`
`
`8800 ?SIH UJOJ SÁDO
`
`
`
`
`
`r-i- in cracy re
`
`(P/5) UIQ050ue
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0007
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 5 of 23
`
`US 8,846,628 B2
`
`3S00 p30JOS9.
`
`eS00 peqJOSeid
`
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`
`
`
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`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0008
`
`

`

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`Sep. 30, 2014
`
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`
`

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`Sep. 30, 2014
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`
`

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`Sep. 30, 2014
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`
`

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`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0012
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
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`US 8,846,628 B2
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0013
`
`

`

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`
`Sep. 30, 2014
`
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`Apotex v. Cellgene - IPR2023-00512
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`
`

`

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`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0015
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0015
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0016
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0017
`
`

`

`U.S. Patent
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`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0018
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0018
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
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`US 8,846,628 B2
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0019
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0020
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0021
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 19 Of 23
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`US 8,846,628 B2
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`Petitioner Apotex Exhibit 1001-0022
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0023
`
`

`

`U.S. Patent
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`Sep. 30, 2014
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0024
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0024
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
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`US 8,846,628 B2
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0025
`
`

`

`U.S. Patent
`
`Sep. 30, 2014
`
`Sheet 23 of 23
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`US 8,846,628 B2
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0026
`
`

`

`US 8,846,628 B2
`
`1.
`ORAL FORMULATIONS OF CYTDNE
`ANALOGS AND METHODS OF USE
`THEREOF
`
`I. CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims priority to U.S. Provisional Patent
`Application Nos. 61/053,609, filed May 15, 2008: 61/201,
`145, filed Dec. 5, 2008; and 61/157,875, filed Mar. 5, 2009,
`the contents of each of which are incorporated by reference
`herein in their entireties.
`
`II. FIELD
`
`Provided herein are pharmaceutical formulations compris
`ing cytidine analogs, or their salts, Solvates, hydrates, precur
`sors, and/or derivatives thereof, for oral administration in
`Subjects. Also provided are methods for making the formula
`tions and methods for using the formulations to treat diseases
`and disorders including cancer, disorders related to abnormal
`cell proliferation, hematologic disorders, and immune disor
`ders, among others.
`
`III. BACKGROUND
`
`10
`
`15
`
`25
`
`2
`Primary and secondary MDS are defined by taking into
`account patients’ prior history: previous treatments with che
`motherapy, radiotherapy or professional exposure to toxic
`substances are factors delineating secondary MDS (SMDS)
`from primary MDS. Cytogenetically, one difference between
`the two groups is the complexity of abnormal karyotypes;
`single chromosome aberrations 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 11c 23
`and 21q22. The genetic changes in the malignant cells of
`MDS result mainly in the loss of genetic material, including
`probable tumor suppressor genes.
`An international 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., et 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 mar
`row cells of the patients is found in all subtypes. Information
`is available regarding the pathobiology of MDS, certain MDS
`classification systems, and particular methods of treating and
`managing MDS. See, e.g., U.S. Pat. No. 7,189,740 (issued
`Mar. 13, 2007), which is incorporated by reference herein in
`its entirety.
`Nucleoside analogs have been used clinically for the treat
`ment of viral infections and cancer. Most nucleoside analogs
`are classified as anti-metabolites. After they enter the cell,
`nucleoside analogs are successively phosphorylated to
`nucleoside 5'-mono-phosphates, di-phosphates, and tri-phos
`phates.
`5-AZacytidine (National Service Center designation NSC
`102816; CAS Registry Number 320-67-2), also known as
`azacitidine, AZA, or 4-amino-1-f-D-ribofuranosyl-1,3,5-tri
`azin-2(1H)-one, is currently marketed as the drug product
`VIDAZAR). 5-Azacytidine is a nucleoside analog, more spe
`cifically a cytidine analog. 5-AZacytidine is an antagonist of
`its 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 of the cytosine ring in place of a carbon. 5-AZacy
`tidine may be defined as having the molecular formula
`CHNOs, a molecular weight of 244.21 grams per mole,
`and the following structure:
`
`30
`
`35
`
`40
`
`45
`
`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, pros
`tate, ovary, brain, and intestine. The incidence of cancer con
`tinues to climb as the general population ages and as new
`forms of cancer develop. A continuing need exists for effec
`tive therapies to treat subjects with cancer.
`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 vari
`able 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).
`MDS are grouped together because of the presence of
`dysplastic changes in one or more of the hematopoietic lin
`50
`eages including dysplastic changes in the myeloid, erythroid,
`and megakaryocytic series. These changes result in cytope
`nias in one or more of the three lineages. Patients afflicted
`with MDS may develop complications related to anemia,
`neutropenia (infections), and/or thrombocytopenia (bleed
`55
`ing). 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 programmed cell death
`(apoptosis). As the disease progresses and converts into leu
`kemia, a proliferation of leukemic cells overwhelms the
`healthy marrow. The disease course differs, with some cases
`behaving as an indolent disease and others behaving aggres
`sively with a very short 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.
`
`
`
`5-AZacytidine
`
`Other members of the class of cytidine analogs include, for
`example: 1-?3-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);
`
`60
`
`65
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1001-0027
`
`

`

`3
`5-aza-2'-deoxy-2'-
`5-aza-2'-deoxy-2,2'-difluorocytidine:
`fluorocytidine:
`1-3-D-ribofuranosyl-2(1H)-pyrimidinone
`(Zebularine);
`2',3'-dideoxy-5-fluoro-3'-thiacytidine
`(Emtriva); 2'-cyclocytidine (Ancitabine): 1-3-D-arabinofura
`nosyl-5-azacytosine (Fazarabine or ara-AC); 6-azacytidine
`(6-aza-CR);
`5,6-dihydro-5-azacytidine
`(dEH-aza-CR);
`N-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine (Capecit
`abine); N-octadecyl-cytarabine; andelaidic acid cytarabine.
`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 reproduc
`ing established methylation patterns in daughter DNA strands
`of replicating DNA. Inhibition of DNA methyltransferases by
`5-azacytidine or 5-aza-2'-deoxycytidine leads to DNA
`15
`hypomethylation, thereby restoring normal functions to mor
`phologically dysplastic, immature hematopoietic cells and
`cancer cells by re-expression of genes involved in normal cell
`cycle regulation, differentiation and death. The cytotoxic
`effects of these cytidine analogs cause the death of rapidly
`dividing cells, including cancer cells, that are no longer
`responsive to normal cell growth control mechanisms. 5-aza
`cytidine, unlike 5-aza-2'-deoxycytidine, also incorporates
`into RNA. The cytotoxic effects of azacitidine may result
`from multiple mechanisms, including inhibition of DNA,
`RNA and protein synthesis, incorporation into RNA and
`DNA, and activation of DNA damage pathways.
`5-AZacytidine and 5-aza-2'-deoxycytidine have been
`tested in clinical trials and showed significant anti-tumor
`activity, Such as, for example, in the treatment of myelodys
`plastic syndromes (MDS), acute myelogenous leukemia
`(AML), chronic myelogenous leukemia (CML), acute lym
`phocytic 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
`35
`sponsored trials for the treatment of MDS and has been
`approved for treating all FAB subtypes of MDS. See, e.g.,
`Kornblith et al., J. Clin. Oncol. 20(10): 2441-2452 (2002);
`Silverman et al., J. Clin. Oncol. 20010): 2429-2440 (2002).
`5-AZacytidine may alter the natural course of MDS by dimin
`ishing the transformation to AML through its cyt