(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`1111111111111111 IIIIII IIIII 11111111111111111111 IIIII 111111111111111 IIIII IIII IIIIIII IIII IIII IIII
`
`( 43) International Publication Date
`2 December 2004 (02.12.2004)
`
`PCT
`
`(10) International Publication Number
`WO 2004/103358 A2
`
`A61K 31/16,
`(51) International Patent Classification 7:
`31/4045, 31/4745, 31/513, 31/704, 31/7068, 45/06, A61P
`35/00, 35/04
`
`(74) Agent: GRUBB, Philip; Novartis AG, Corporate Intellec(cid:173)
`tual Property, CH-4002 Basel (CH).
`
`(21) International Application Number:
`PCT /EP2004/005433
`
`(22) International Filing Date:
`
`19 May 2004 (19.05.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/472,161
`
`21 May 2003 (21.05.2003) US
`
`(71) Applicant (for all designated States except AT, US): NO(cid:173)
`VARTIS AG [CH/CH]; Lichtstrasse 35, CH-4056 Basel
`(CH).
`
`(71) Applicant (for AT only): NOVARTIS PHARMA GMBH
`[AT/AT]; Brunner Strasse 59, A-1230 Vienna (AT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): ATADJA, Peter,
`Wisdom [CA/US]; 18 Eastbrook Road, Parsippany, NJ
`07054 (US). REMISZEWSKI, Stacy, William [US/US];
`147 Honeysuckle Drive, Washington Township, NJ 07676
`(US). TROGANI, Nancy [US/US]; 1210 Birch Street,
`Boonton, NJ 07005 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`---iiiiiiii
`iiiiiiii -iiiiiiii --
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`- -i
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`iiiiiii
`iiiiiiii
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`Q0
`ln
`~-----------------------------------------
`~ (54) Title: COMBINATION OF HISTONE DEACETYLASE INHIBITORS WITH CHEMOTHERAPEUTIC AGENTS
`,-...I
`~ (57) Abstract: The invention relates to a combination which comprises (a) one or more chemotherapeutic agents and (b) a his-
`0
`tone deacetylase inhibitor ("HDAI") for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of
`0
`proliferative diseases including pre-malignant lesions (e.g. colon polyps) and malignancies, both solid and undifferentiated or other
`M proliferative diseases in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such
`0 a combination and to a method of preventing or treating proliferative diseases including pre-malignant lesions (e.g. colon polyps)
`
`: , and malignancies, both solid and undifferentiated or other proliferative diseases, in a mammal, particularly a human, with such a
`;;, combination. The present invention further also relates to a commercial package or product comprising such a combination.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0001
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`Combination of Histone Deacetylase Inhibitors with Chemotherapeutic Agents
`
`The invention relates to a combination which comprises (a) one or more chemotherapeutic
`
`agents and (b) a histone deacetylase inhibitor ("HDAI") for simultaneous, concurrent,
`
`separate or sequential use, especially for use in the treatment of proliferative diseases
`
`including pre-malignant lesions (e.g. colon polyps) and malignancies, both solid and
`
`undifferentiated or other proliferative diseases in a mammal, particularly a human. The
`
`invention also relates to pharmaceutical compositions comprising such a combination and to
`
`a method of preventing or treating proliferative diseases including pre-malignant lesions (e.g.
`
`colon polyps) and malignancies, both solid and undifferentiated or other proliferative
`
`diseases, in a mammal, particularly a human, with such a combination. The present
`
`invention further also relates to a commercial package or product comprising such a
`
`combination.
`
`Background
`
`Reversible acetylation of histones is a major regulator of gene expression that acts by
`
`altering accessibility of transcription factors to DNA. In normal cells, histone deacetylase
`
`(HOA) and histone acetyltrasferase together control the level of acetylation of histones to
`
`maintain a balance. Inhibition of HOA results in the accumulation of hyperacetylated
`
`histones, which results in a variety of cellular responses. Inhibitors of HOA (HDAI) have
`
`been studied for their therapeutic effects on cancer cells. Recent developments in the field
`
`of HDAI research have provided active compounds, both highly efficacious and stable, that
`
`are suitable for treating tumors.
`
`Accruing evidence suggests that HDAI are even more efficacious when used in
`
`combination with other chemotherapeutic agents. There are both synergistic and additive
`
`advantages, both for efficacy and safety. Therapeutic effects of combinations of
`
`chemotherapeutic agents with HDAI can result in lower safe dosages ranges of each
`
`component in the combination.
`
`The Diseases to be Treated
`
`The combinations of the present invention are useful for treating proliferative diseases.
`
`A proliferative disease is mainly a tumor disease (or cancer) (and/or any metastases). The
`
`inventive combinations are particularly useful for treating a tumor which is a breast cancer,
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0002
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`2
`
`genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma,
`ovarian cancer, pancreas cancer, neuroblastoma, head and/or neck cancer or bladder
`cancer, or in a broader sense renal, brain or gastric cancer; in particular (i) a breast tumor;
`an epidermoid tumor, such as an epidermoid head and/or neck tumor or a mouth tumor; a
`lung tumor, for example, a small cell or non-small cell lung tumor; a gastrointestinal tumor,
`for example, a colorectal tumor; or a genitourinary tumor, for example, a prostate tumor
`( especially a hormone-refractory prostate tumor); or (ii) a proliferative disease that is
`refractory to the treatment with other chemotherapeutics; or (iii) a tumor that is refractory to
`treatment with other chemotherapeutics due to multidrug resistance.
`
`In a broader sense of the invention, a proliferative disease may furthermore be a
`hyperproliferative condition, such as leukemias, hyperplasias, fibrosis ( especially pulmonary,
`but also other types of fibrosis, such as renal fibrosis), angiogenesis, psoriasis,
`atherosclerosis and smooth muscle proliferation in the blood vessels, such as stenosis or
`restenosis following angioplasty.
`
`Other malignancies which may be treated according to this invention includes a
`malignancy that is susceptible to treatment with an HDAI compound, for example, breast
`cancer, lung cancer, ovarian cancer, lymphoma, head and neck cancer and cancer of the
`colon, esophagus, stomach, bladder, prostrate, uterus and cervix.
`
`Where a tumor, a tumor disease, a carcinoma or a cancer are mentioned, also
`metastasis in the original organ or tissue and/or in any other location are implied alternatively
`or in addition, whatever the location of the tumor and/or metastasis.
`
`The Chemotherapeutic Agents
`The term "chemotherapeutic agent(s)" is a broad one, as there are many cancer
`chemotherapeutic agents, having different mechanisms of action. Combinations of these
`with HDAI agents can result in improvements in cancer therapy. Generally,
`chemotherapeutic agents are classified according to the mechanism of action. Many of the
`available agents are antimetabolites of development pathways of various tumors, or react ·
`with the DNA of the tumor cells. There are also agents which inhibit enzymes such as
`topoisomerase I and topoisomerase 11, or which are antimiotic agents.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0003
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`3
`
`By the term "chemotherapeutic agent" is meant especially any chemotherapeutic agent
`
`other than a histone deacetylase inhibitor ("HDAI") or a derivative thereof. It includes but is
`
`not limited to,
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`an aromatase inhibitor,
`
`an antiestrogen, an anti-androgen (especially in the case of prostate cancer) or a
`
`gonadorelin agonist,
`
`a topoisomerase I inhibitor or a topoisomerase II inhibitor,
`
`a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a
`
`platin compound,
`
`v.
`
`a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid
`
`phosphatase activity, a further anti-angiogenic compound or a compound which
`
`induces cell differentiation processes,
`
`vi.
`
`vii.
`
`a bradykinin 1 receptor or an angiotensin II antagonist,
`a cyclooxygenase inhibitor, a bisphosphonate, a rapamycin derivative such as
`everolimus, a heparanase inhibitor (prevents heparan sulphate degradation), e.g. Pl-
`
`88, a biological response modifier, preferably a lymphokine or interferons, e.g.
`
`interferon y, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic
`pathways,
`
`viii. an inhibitor of Ras oncogenic isoforms, e.g. H-Ras, K-Ras or N-Ras, or a farnesyl
`
`ix.
`
`x.
`
`transferase inhibitor, e.g. L-744,832 or DK8G557,
`
`a telomerase inhibitor, e.g. telomestatin,
`
`a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase
`
`inhibitor, e.g. bengamide or a derivative thereof, or a proteosome inhibitor, e.g. PS-
`
`341.
`
`The term "aromatase inhibitor" as used herein relates to a compound which inhibits the
`
`estrogen production, i.e. the conversion of the substrates androstenedione and testosterone
`
`to estrone and estradiol, respectively. The term includes, but is not limited to steroids,
`
`especially atamestane, exemestane and formestane and, in particular, non-steroids,
`
`especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone,
`
`ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark AROMASIN™.
`
`Formestane can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark LENTARON™. Fadrozole can be administered, e.g., in the form as it is marketed,
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0004
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`4
`
`e.g. under the trademark AFEMA™. Anastrozole can be administered, e.g., in the form as it
`
`is marketed, e.g. under the trademark ARIMIDEX™. Letrozole can be administered, e.g., in
`
`the form as it is marketed, e.g. under the trademark FEMARA™ or FEMAR™
`
`Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark ORIMETEN™. A combination of the invention comprising a chemotherapeutic
`
`agent which is an aromatase inhibitor is particularly useful for the treatment of hormone
`
`receptor positive tumors, e.g. breast tumors.
`
`The term "antiestrogen" as used herein relates to a compound which antagonizes the
`
`effect of estrogens at the estrogen receptor level. The term includes, but is not limited to
`
`tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX™.
`
`Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under
`
`the trademark EVlSTA™. Fulvestrant can be formulated as disclosed in US 4,659,516 or it
`
`can be administered, e.g., in the form as it is marketed, e.g. under the trademark
`
`FASLODEX™. A combination of the invention comprising a chemotherapeutic agent which is
`
`an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors,
`
`e.g. breast tumors.
`
`The term "anti-androgen" as used herein relates to any substance which is capable of
`
`inhibiting the biological effects of androgenic hormones and includes, but is not limited to,
`
`bicalutamide (CASODEX™), which can be formulated, e.g. as disclosed in US 4,636,505.
`
`The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix,
`
`goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX™.
`
`Abarelix can be formulated, e.g. as disclosed in US 5,843,901.
`
`The term "topoisomerase I inhibitor" as used herein includes, but is not limited to
`
`topotecan, irinotecan, 9-nitrocamptothecin, 7-(t-butoxy)imino methyl camptothecin
`
`(gimatecan) and the macromolecular camptothecin conjugate PNU:.166148 (compound A1 in
`
`WO99/17804). lrinotecan can be administered, e.g. in the form as it is marketed, e.g. under
`
`the trademark CAMPTOSAR™. Topotecan can be administered, e.g., in the form as it is
`
`marketed, e.g. under the trademark HYCAMTIN™.
`
`The term "topoisomerase 11 inhibitor" as used herein includes, but is not limited to the
`
`anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAEL YX™),
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0005
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`5
`
`daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and
`
`losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide can be
`
`administered, e.g. in the form as it is marketed, e.g. under the trademark ETOPOPHOS™.
`
`Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark
`
`VM 26-BRISTOL™ Doxorubicin can be administered, e.g. in the form as it is marketed, e.g.
`
`under the trademark ADRIBLASTIN™. Epirubicin can be administered, e.g. in the form as it
`
`is marketed, e.g. under the trademark FARMORUBICIN™. ldarubicin can be administered,
`
`e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOS™. Mitoxantrone can
`
`be administered, e.g. in the form as it is marketed, e.g. under the trademark
`
`NOVANTRON™.
`
`The term "microtubule active agent" relates to microtubule stabilizing and microtubule
`
`destabilizing agents including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca
`
`alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine
`
`sulfate, and vinorelbine, discodermolides and epothilones and derivatives thereof, e.g.
`
`epothilone B or a derivative thereof. Paclitaxel may be administered e.g. in the form as it is
`
`marketed, e.g. TAXOL™. Docetaxel can be administered, e.g., in the form as it is marketed,
`
`e.g. under the trademark TAXOTERE™. Vinblastine sulfate can be administered, e.g., in the
`
`form as it is marketed, e.g. under the trademark VINBLASTIN R.P.™. Vincristine sulfate can
`
`be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN™.
`
`Discodermolide can be obtained, e.g., as disclosed in US 5,010,099.
`
`The term "alkylating agent" as used herein includes, but is not limited to
`
`cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel™).
`
`Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark CYCLOSTIN™. lfosfamide can be administered, e.g., in the form as it is
`
`marketed, e.g. under the trademark HOLOXAN™.
`
`The term "antineoplastic antimetabolite" includes, but is not limited to 5-fluorouracil,
`
`capecitabine, gemcitabine, DNA demethylating agents, such as 5-azacytidine and
`
`decitabine, methotrexate and edatrexate. Capecitabine can be administered, e.g., in the
`
`form as it is marketed, e.g. under the trademark XELODA™. Gemcitabine can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZAR™.
`
`The term "platin compound" as used herein includes, but is not limited to carboplatin,
`
`cis-platin and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed,
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0006
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`6
`
`e.g. under the trademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the form
`
`as it is marketed, e.g. under the trademark ELOXATIN™.
`
`The term "compounds targeting/decreasing a protein or lipid kinase activity or further
`
`anti-angiogenic compounds" as used herein includes, but is not limited to protein tyrosine
`
`kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.
`
`compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor
`
`family of receptor tyrosine kinases (EGFR, Erb 82, Erb83, Erb84 as homo- or heterodimers ),
`
`the vascular endothelial growth factor family of receptor tyrosine kinases (VEG FR), the
`
`platelet-derived growth factor-receptors (PDGFR), the fibroblast growth factor-receptors
`
`(FGFR), the insulin-like growth factor receptor 1 (IGF-1 R), the Trk receptor tyrosine kinase
`
`family, the Axl receptor tyrosine kinase family, the Ret receptor tyrosine kinase, the
`
`Kit/SCFR receptor tyrosine kinase, members of the c-Abl family and their gene-fusion
`
`products (e.g. BCR-Abl), members of the protein kinase C (PKC) and Raf family of
`
`serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK or Pl(3) kinase family,
`
`or of the Pl(3)-kinase-related kinase family, and/or members of the cyclin-dependent kinase
`
`family (CDK) and anti-angiogenic compounds having another mechanism for their activity,
`
`e.g. unrelated to protein or lipid kinase inhibition.
`
`Compounds which target, decrease or inhibit the activity of VEGFR are especially
`
`compounds, proteins or antibodies which inhibit the VEGF receptor tyrosine kinase, inhibit a
`
`VEGF receptor or bind to VEGF, and are in particular those compounds, proteins or
`
`monoclonal antibodies generically and specifically disclosed in WO 98/35958, e.g. 1-(4-
`
`chloroanilino )-4-( 4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof,
`
`e.g. the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO
`
`00/27819 and EP O 769 947; those as described by M. Prewett et al in Cancer Research 59
`
`(1999) 5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770,
`
`Dec. 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in
`
`Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202;
`
`Angiostatin™, described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; Endostatin™,
`
`described by M. S. O'Reilly et al, Cell 88, 1997, 277-285; anthranilic acid amides; 2D4190;
`
`2D6474; SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g.
`
`RhuMab.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0007
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`7
`
`By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific
`
`antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they
`
`exhibit the desired biological activity.
`
`Compounds which target, decrease or inhibit the activity of the epidermal growth factor
`
`receptor family are especially compounds, proteins or antibodies which inhibit members of
`
`the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind
`
`to EGF or EGF related ligands, and are in particular those compounds, proteins or
`
`monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g. the
`compound of ex. 39, or in EP O 564 409, WO 99/03854, EP 0520722, EP O 566 226, EP 0
`787 722, EP O 837 063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO
`
`97/38983 and, especially, WO 96/30347 (e.g. compound known as GP 358774), WO
`
`96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g. compound ZM105180); e.g.
`
`trastuzumab (HerpetinR), cetuximab, lressa, OSl-774, Cl-1033, EKB-569, GW-2016, E1.1,
`
`E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3.
`
`Compounds which target, decrease or inhibit the activity of PDGFR are especially
`
`compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative,
`
`e.g. imatinib.
`
`Compounds which target decrease or inhibit the activity of c-Abl family members and
`
`their gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib;
`
`PD180970; AG957; or NSC 680410.
`
`Compounds which target, decrease or inhibit the activity of protein kinase C, Raf,
`
`MEK, SRC, JAK, FAK and PDK family members, or Pl(3) kinase or Pl(3) kinase-related
`
`family members, and/or members of the cyclin-dependent kinase family (CDK) are especially
`
`those staurosporine derivatives disclosed in EP O 296 110, e.g. midostaurin; examples of
`
`further compounds include e.g. UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;
`
`llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; or LY333531/LY379196.
`
`Further anti-angiogenic compounds are e.g. thalidomide {THALOMID) and TNP-470.
`
`Compounds which target, decrease or inhibit the activity of a protein or lipid
`
`phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, e.g.
`
`okadaic acid or a derivative thereof.
`
`Compounds which induce cell differentiation processes are e.g. retinoic acid, a-, y- or
`8-tocopherol or a-, y- or 8-tocotrienol.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0008
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`8
`
`The term cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g.
`
`celecoxib (CelebrexR), rofecoxib (VioxxR), etoricoxib, valdecoxib or a 5-alkyl-2-
`
`arylaminophenylacetic acid, e.g. 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid.
`
`The term "bisphosphonates" as used herein includes, but is not limited to, etridoriic,
`
`clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
`
`"Etridonic acid" can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark DIDRONEL™. "Clodronic acid" can be administered, e.g., in the form as it is
`
`marketed, e.g. under the trademark BONEFOS™. "Tiludronic acid" can be administered,
`
`e.g., in the form as it is marketed, e.g. under the trademark SKELID™. "Pamidronic acid"
`
`can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIA™.
`
`"Alendronic acid" can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark FOSAMAX™. "lbandronic acid" can be administered, e.g., in the form as it is
`
`marketed, e.g. under the trademark BONDRANAT™. "Risedronic acid" can be administered,
`
`e.g., in the form as it is marketed, e.g. under the trademark ACTONEL™. "Zoledronic acid"
`
`can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETA™
`
`The term "matrix metalloproteinase inhibitor" as used herein includes, but is not limited
`
`to collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g.
`
`hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue
`
`marimastat, prinomastat, BMS-279251, BAY 12-9566, TAA211 or AAJ996.
`
`It has been found that the following classes of chemotherapeutic agents are especially
`
`useful in the practice of this invention: antimetabolites, DNA topoisomerase I inhibitors, DNA
`
`topoisomerase II inhibitors, microtubule active agents, and the like. Within the class of
`
`antimetabolites are included agents that are inhibitors of thymidine production; inhibitors of
`
`vascular endothethial growth factor; DNA demethylating agents; or protein-tyrosine kinase
`
`inhibitors.
`
`Representative examples of these classes of chemotherapeutic agents which are
`
`useful in the practice of this invention are illustrated as follows:
`
`DNA topoisomerase I inhibitors: camptothecin or derivatives thereof such as
`
`gimatecan.
`
`DNA topoisomerase II inhibitors: Adriamycin
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0009
`
`

`

`WO 2004/103358
`
`9
`
`PCT /EP2004/005433
`
`Microtubule active agents: Discodermolides and epothilones such as epothilone B and
`
`epothilone D.
`
`Antimetabolites, including:
`
`Thymidine production inhibitors, such as 5-Fluorouracil;
`
`DNA demethylating agents, such as 5-Azacytidine and decitabine;
`
`Vascular endothethial growth factor inhibitors, such as 1-[4-chloroanilino]-
`
`4-[pyridylmethyl]-phthalazine succinate (PTK 787);
`
`Protein-tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec).
`
`Generally speaking the chemotherapeutic agents useful in the combinations of this
`
`invention, viz., any of the chemotherapeutic agents mentioned above, and especially those
`
`which are DNA topoisomerase II inhibitors, microtubule active agents, thymidine production
`
`inhibitors, DNA topoisomerase I inhibitors, and DNA demethylating agents, are used
`
`together with the HDAI compounds in the dosages and with the therapeutic regimes as
`
`employed in the usual course of therapy of each drug alone.
`
`The HDAI Compounds
`
`HDAI compounds of particular interest for use in the inventive combinations are
`
`hydroxamate compounds described by the formula (I)
`
`0
`
`~
`
`HO"'-.
`N
`H
`
`y
`
`X
`
`wherein
`
`~ Rs
`N~~
`
`R4
`
`( I )
`
`n1
`
`n2
`
`ns
`
`R1 is H, halo, or a straight chain C1-Cs alkyl (especially methyl, ethyl or n-propyl, which
`methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or
`
`more substituents described below for alkyl substituents );
`R2 is selected from H, C1-C10 alkyl, (preferably C1-C6 alkyl, e.g. methyl, ethyl or
`-CH2CH2-OH), C4 - Cg cycloalkyl, C4 - Cg heterocycloalkyl, C4 - Cg
`heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl,
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0010
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl), -(CH2)nC(O)R6,
`-(CH2)nOC(O)Rs, amino acyl, HON-C(O)-CH=C(R1)-aryl-alkyl- and -(CH2)nR1;
`R3 and R4 are the same or different and independently H, C1-C6 alkyl, acyl or acylamino,
`or R3 and ~ together with the carbon to which they are bound represent C=O, C=S,
`or C=NRa, or R2 together with the nitrogen to which it is bound and R3 together with
`the carbon to which it is bound can form a C4 - C9 heterocycloalkyl, a heteroaryl, a
`polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl
`polyheterocycle ring;
`R5 is selected from H, C1-C6 alkyl, C4- Cs cycloalkyl, C4 - Cs heterocycloalkyl, acyl, aryl,
`heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl), aromatic
`polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles,
`polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl and non-aryl
`polyheterocycles;
`n, n1, n2 and n3 are the same or different and independently selected from O - 6, when
`n1 is 1-6, each carbon atom can be optionally and independently substituted with Ra
`and/or~;
`X and Y are the same or different and independently selected from H, halo, C1-C4 alkyl,
`such as CH3 and CF3, N02, C(O)R1, ORs, SR9, CN, and NR10R1 1;
`Rs is selected from H, C1-Cs alkyl, C4- Cg cycloalkyl, C4 - Cs heterocycloalkyl,
`cycloalkylalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl, 2-
`phenylethenyl), heteroarylalkyl (e.g., pyridylmethyl), OR12, and NR13R14;
`R1 is selected from OR1s, SR1s, S(O)R1s, S02R11, NR13R14, and NR12S02Rs;
`Ra is selected from H, OR15, NR13R14, C1-C6 alkyl, C4 - Cs cycloalkyl, C4 - C9
`heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g.,
`pyridylmethyl);
`Rs is selected from C1 - C4 alkyl, for example, CH3 and CF3, C(O)-alkyl, for example
`C(O)CH3, and C(O)CF3;
`R10 and R11 are the same or different and independently selected from H, C1-C4 alkyl,
`and -C(O)-alkyl;
`R12 is selected from H, C1-Cs alkyl, C4 - Cs cycloalkyl, C4 - Cs heterocycloalkyl, C4 - C9
`heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl
`(e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);
`R13 and R14 are the same or different and independently selected from H, C1-C6 alkyl,
`C4 - Cg cycloalkyl, C4 - Cs heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl),
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0011
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`11
`
`heteroarylalkyl (e.g., pyridylmethyl), amino acyl, or R13 and R14 together with the
`nitrogen to which they are bound are C4 - Cs heterocycloalkyl, heteroaryl,
`
`polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl
`
`polyheterocycle;
`R15 is selected from H, C1-C6 alkyl, C4 - Cs cycloalkyl, C4 - C9 heterocycloalkyl, aryl,
`heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
`R16 is selected from C1-C6 alkyl, C4- C9 cycloalkyl, C4- C9 heterocycloalkyl, aryl,
`heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
`
`R17 is selected from C1-C5 alkyl, C4 - Cs cycloalkyl, C4 - Cs heterocycloalkyl, aryl,
`
`aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14;
`m is an integer selected from O to 6; and
`Z is selected from 0, NR13, S and S(O),
`
`or a pharmaceutically acceptable salt thereof.
`
`As appropriate, unsubstituted means that there is no substituent or that the only
`
`substituents are hydrogen.
`
`Halo substituents are selected from fluoro, chloro, bromo and iodo, preferably fluoro or
`
`chloro.
`
`Alkyl substituents include straight and branched C1-C5alkyl, unless otherwise noted.
`Examples of suitable straight and branched C1-C6alkyl substituents include methyl, ethyl, n(cid:173)
`propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, and the like. Unless otherwise noted, the alkyl
`
`substituents include both unsubstituted alkyl groups and alkyl groups that are substituted by
`
`one or more suitable substituents, including unsaturation (i.e. there are one or more double
`
`or triple C-C bonds), acyl, cycloalkyl, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and
`OR15, for example, alkoxy. Preferred substituents for alkyl groups include halo, hydroxy,
`alkoxy, oxyalkyl, alkylamino, and aminoalkyl.
`
`Cycloalkyl substituents include C3-Cs cycloalkyl groups, such as cyclopropyl,
`
`cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. Unless otherwise
`
`noted, cycloalkyl substituents include both unsubstituted cycloalkyl groups and cycloalkyl
`groups that are substituted by one or more suitable substituents, including C1-C6 alkyl, halo,
`hydroxy, aminoalkyl, oxyalkyl, alkylamino, and OR15, such as alkoxy. Preferred substituents
`for cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1005-0012
`
`

`

`WO 2004/103358
`
`PCT /EP2004/005433
`
`12
`
`The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl
`
`portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones,
`
`arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
`Heterocycloalkyl substituents include 3 to 9 membered aliphatic rings, such as 4 to 7
`
`membered aliphatic rings, containing from one to three heteroatoms selected from nitrogen,
`
`sulfur, oxygen. Examples of suitable heterocycloalkyl substituents include pyrrolidyl,
`
`tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-
`
`diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. Unless otherwise noted,
`
`the rings are unsubstituted or substituted on the carbon atoms by one or more suitable
`substituents, including C1-C5 alkyl, C4 - Cg cycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl),
`and heteroarylalkyl (e.g., pyridylmethyl), halo, amino, alkyl amino and OR15, for example
`alkoxy. Unless otherwise no