`US008410131B2
`
`c12) United States Patent
`Lane et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,410,131 B2
`Apr. 2, 2013
`
`(54) CANCER TREATMENT
`
`(75)
`
`Inventors: Heidi Lane, Basel (CH); Terence
`O'Reilly, Basel (CH); Jeanette
`Marjorie Wood, Biel-Benken (CH)
`
`(73) Assignee: Novartis Pharmaceuticals
`Corporation, East Hanover, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1189 days.
`
`(21) Appl. No.:
`
`10/468,520
`
`(22) PCT Filed:
`
`Feb.18,2002
`
`(86) PCT No.:
`
`PCT/EP02/01714
`
`§ 371 (c)(l),
`(2), ( 4) Date:
`
`Jan.27,2004
`
`(87) PCT Pub. No.: W002/066019
`
`PCT Pub. Date: Aug. 29, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2004/0147541 Al
`
`Jul. 29, 2004
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 19,2001
`Oct. 17, 2001
`
`(GB)
`(GB)
`
`0104072.4
`0124957.2
`
`(51)
`
`Int. Cl.
`A61K 311436
`(2006.01)
`A61P 35100
`(2006.01)
`(52) U.S. Cl. ....................................................... 514/291
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`(Continued)
`
`Primary Examiner - Kortney L Klinkel
`(74) Attorney, Agent, or Firm -Ann R. Pokalsky, Esq.;
`Dilworth & Barrese, LLP
`
`(57)
`
`ABSTRACT
`Rapamycin derivatives have interesting effects in the treat(cid:173)
`ment of solid tumors, optionally in combination with a che(cid:173)
`motherapeutic agent.
`
`9 Claims, No Drawings
`
`Breckenridge Exhibit 1001
`'131 patent
`Page 001
`
`
`
`US 8,410,131 B2
`Page 2
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`WO
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`
`Breckenridge Exhibit 1001
`'131 patent
`Page 002
`
`
`
`US 8,410,131 B2
`
`1
`CANCER TREATMENT
`
`The present invention relates to a new use, in particular a
`new use for a compound group comprising rapamycin and
`derivatives thereof.
`Rapamycin is a known macrolide antibiotic produced by
`Streptomyces hygroscopicus. Suitable derivatives of rapamy(cid:173)
`cin include e.g. compounds of formula I
`
`wherein
`R 1 is CH3 or C3 _6alkynyl,
`R2 is Hor -CH2-CH20H, and
`Xis =0, (H,H) or (H,OH)
`provided that R2 is other than H when Xis =0 and R 1 is CH3 .
`Compounds of formula I are disclosed e.g. in U.S. Pat. Nos.
`5,665,772; 6,440,990; 5,985,890; and 6,200,985, which are
`incorporated herein by reference. They may be prepared as
`disclosed or by analogy to the procedures described in these
`references.
`Preferred compounds are 32-deoxorapamycin, 16-pent-2-
`ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-di(cid:173)
`hydro-rapamycin, 16-pent-2-yny loxy-32(S)-dihydro-40-0-
`(2-hydroxyethy l)-rapamycin and, more preferably, 40-0-(2-
`hydroxyethyl)-rapamycin (referred thereafter as Compound
`A), disclosed as Example 8 in U.S. Pat. Nos. 5,665,772 and
`6,440,990.
`Compounds of formula I have, on the basis of observed
`activity, e.g. binding to macrophilin-12 (also known as
`FK-506 binding protein or FKBP-12), e.g. as described in
`WO 94/09010, WO 95/16691 or WO 96/41807, been found to
`be useful e.g. as immunosuppressant, e.g. in the treatment of
`acute allograft rejection. It has now been found that Com(cid:173)
`pounds of formula I have potent antiproliferative properties
`which make them useful for cancer chemotherapy, particu(cid:173)
`larly of solid tumors, especially of advanced solid tumors.
`There is still the need to expand the armamentarium of cancer
`treatment of solid tumors, especially in cases where treatment
`with anticancer compounds is not associated with disease
`regression or stabilization.
`In accordance with the particular findings of the present
`invention, there is provided:
`1.1 A method for treating solid tumors in a subject in need
`thereof, comprising administering to said subject a thera(cid:173)
`peutically effective amount of a compound of formula I.
`
`lO
`
`20
`
`2
`1.2 A method for inhibiting growth of solid tumors in a
`subject in need thereof, comprising administering to said
`subject a therapeutically effective amount of a compound
`of formula I.
`1.3 A method for inducing tumor regression, e.g. tumor mass
`reduction, in a subject in need thereof, comprising admin(cid:173)
`istering to said subject a therapeutically effective amount
`of a compound of formula I.
`1.4 A method for treating solid tumor invasiveness or symp-
`toms associated with such tumor growth in a subject in
`need thereof, comprising administering to said subject a
`therapeutically effective amount of a compound of formula
`I.
`15 1.5 A method for preventing metastatic spread of tumours or
`for preventing or inhibiting growth of micrometastasis in a
`subject in need thereof, comprising administering to said
`subject a therapeutically effective amount of a compound
`of formula I.
`By "solid tumors" are meant tumors and/or metastasis
`(whereever located) other than lymphatic cancer, e.g. brain
`and other central nervous system tumors ( eg. tumors of the
`meninges, brain, spinal cord, cranial nerves and other parts of
`central nervous system, e.g. glioblastomas or medulla blas-
`25 tomas); head and/or neck cancer; breast tumors; circulatory
`system tumors (e.g. heart, mediastinum and pleura, and other
`intrathoracic organs, vascular tumors and tumor-associated
`vascular tissue); excretory system tumors (e.g. kidney, renal
`pelvis, ureter, bladder, other and unspecified urinary organs);
`30 gastrointestinal tract tumors (e.g. oesophagus, stomach, small
`intestine, colon, colorectal, rectosigmoid junction, rectum,
`anus and anal canal), tumors involving the liver and intrahe(cid:173)
`patic bile ducts, gall bladder, other and unspecified parts of
`binary tract, pancreas, other and digestive organs); head and
`35 neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and
`other parts of mouth, parotid gland, and other parts of the
`salivary glands, tonsil, oropharynx, nasopharynx, pyriform
`sinus, hypopharynx, and other sites in the lip, oral cavity and
`pharynx); reproductive system tumors (e.g. vulva, vagina,
`40 Cervix uteri, Corpus uteri, uterus, ovary, and other sites asso(cid:173)
`ciated with female genital organs, placenta, penis, prostate,
`testis, and other sites associated with male genital organs);
`respiratory tract tumors (e.g. nasal cavity and middle ear,
`accessory sinuses, larynx, trachea, bronchus and lung, e.g.
`45 small cell lung cancer or non-small cell lung cancer); skeletal
`system tumors (e.g. bone and articular cartilage of limbs,
`bone articular cartilage and other sites); skin tumors (e.g.
`malignant melanoma of the skin, non-melanoma skin cancer,
`basal cell carcinoma of skin, squamous cell carcinoma of
`50 skin, mesothelioma, Kaposi's sarcoma); and tumors involv(cid:173)
`ing other tissues incluing peripheral nerves and autonomic
`nervous system, connective and soft tissue, retroperitoneum
`and peritoneum, eye and adnexa, thyroid, adrenal gland and
`other endocrine glands and related structures, secondary and
`55 unspecified malignant neoplasm of lymph nodes, secondary
`malignant neoplasm of respiratory and digestive systems and
`secondary malignant neoplasm of other sites.
`Where hereinbefore and subsequently a tumor, a tumor
`disease, a carcinoma or a cancer is mentioned, also metastasis
`60 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 is.
`In a series of further specific or alternative embodiments,
`the present invention also provides
`65 1.6 A method for the treatment of a disease associated with
`deregulated angiogenesis in a subject in need thereof, com(cid:173)
`prising administering to said subject a therapeutically
`
`Breckenridge Exhibit 1001
`'131 patent
`Page 003
`
`
`
`US 8,410,131 B2
`
`15
`
`3
`effective amount of rapamycin or a derivative thereof, e.g.
`CCI779, ABT578 or a compound of formula I.
`1.7 A method for inhibiting or controlling deregulated anglo(cid:173)
`genesis in a subject in need thereof, comprising adminis(cid:173)
`tering to said subject a therapeutically effective amount of
`rapamycin or a derivative thereof, e.g. CCI779, ABT578 or
`a compound of formula I.
`1.8 A method for enhancing the activity of a chemotherapeu(cid:173)
`tic agent or for overcoming resistance to a chemotherapeu-
`tic agent in a subject in need thereof, comprising adminis- 10
`tering to said subject a therapeutically effective amount of
`rapamycin or a derivative thereof, e.g. CCI779, ABT578 or
`a compound of formula I, either concomitantly or sequen(cid:173)
`tially with said chemotherapeutic agent.
`1.9 A method according to 1.8 wherein the chemotherapeutic
`agent is an inhibitor of signal transduction pathways
`directed either against host cells or processes involved in
`tumor formation and/ or metastases formation or utilised by
`tumour cells for proliferation, survival, differentiation or 20
`development of drug resistance.
`1.10 A method as indicated above, wherein rapamycin or a
`derivative thereof, e.g. CCI779, ABT578 or a compound of
`formula I is administered intermittently.
`CCI779 is a rapamycin derivative, i.e. 40-[3-hydroxy-2- 25
`(hydroxymethyl)-2-methylpropanoate ]-rapamycin or a phar(cid:173)
`maceutically acceptable salt thereof, and is disclosed e.g. in
`U.S. Pat. No. 5,362,718.ABT578 is a 40-substitutedrapamy(cid:173)
`cin derivative further comprising a diene reduction.
`Examples of diseases associated with deregulated angio- 30
`genesis include without limitation e.g. neoplastic diseases,
`e.g. solid tumors. Angiogenesis is regarded as a prerequisite
`for those tumors which grow beyond a certain diameter, e.g.
`about 1-2 mm.
`In a series of further specific or alternative embodiments,
`the present invention also provides:
`2 .1 A compound of formula I for use in any method as defined
`under 1.1 to 1.5 above.
`2.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I for use in any method as
`defined under 1.6 to 1.10 above or 7 below.
`3 .1 A compound of formula I for use in the preparation of a
`pharmaceutical composition for use in any method as
`defined under 1.1 to 1.5 above.
`3.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I for use in the preparation of a
`pharmaceutical composition for use in any method as
`defined under 1.6 to 1.10 above or 7 below.
`4.1 A pharmaceutical composition for use in any method as
`defined under 1.1 to 1.5 above comprising a compound of 50
`formula I together with one or more pharmaceutically
`acceptable diluents or carriers therefor.
`4.2 A pharmaceutical composition for use in any method as
`defined under 1.6 to 1.10 above or 7 below comprising
`rapamycin or a derivative thereof, e.g. CCI779, ABT578 or 55
`a compound of formula I, e.g. Compound A, together with
`one or more pharmaceutically acceptable diluents or car(cid:173)
`riers therefor.
`5.1 A pharmaceutical combination comprising a) a first agent
`which is rapamycin or a derivative thereof, e.g. CCI779, 60
`ABT578 or a compound of formula I, e.g. Compound A,
`and b) a co-agent which is a chemotherapeutic agent, e.g.
`as defined hereinafter.
`5.2 A pharmaceutical combination comprising an amount of
`a) a first agent which is rapamycin or a derivative thereof,
`e.g. CCI779, ABT578 or a compound of formula I, e.g.
`Compound A, and b) a co-agent which is a chemothera-
`
`4
`peutic agent selected from the compounds defined under
`paragraph (iv) or (v) below, to produce a synergistic thera(cid:173)
`peutic effect.
`6. A method as defined above comprising co-administration,
`e.g. concomitantly or in sequence, of a therapeutically
`effective amount of rapamycin or a derivative thereof, e.g.
`CCI779, ABT578 or a compound of formula I, e.g. Com(cid:173)
`pound A, and a second drug substance, said second drug
`substance being a chemotherapeutic agent, e.g. as indi(cid:173)
`cated hereinafter.
`7. A method for treating post-transplant lymphoproliferative
`disorders or a lymphatic cancer, e.g. for treating tumor
`invasiveness or symptoms associated with such tumor
`growth in a subject in need thereof, comprising co-admin(cid:173)
`istering to said subject, e.g. concomitantly or in sequence,
`of rapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I, e.g. Compound A, and a
`second drug substance, said second drug substance being a
`chemotherapeutic agent, e.g. as indicated hereinafter.
`By "lymphatic cancer" are meant e.g. tumors of blood and
`lymphatic system (e.g. Hodgkin's disease, Non-Hodgkin's
`lymphoma, Burkitt's lymphoma, AIDS-related lymphomas,
`malignant immunoproliferative diseases, multiple myeloma
`and malignant plasma cell neoplasms, lymphoid leukemia,
`myeloid leukemia, acute or chronic lymphocytic leukemia,
`monocytic leukemia, other leukemias of specified cell type,
`leukemia of unspecified cell type, other and unspecified
`malignant neoplasms of lymphoid, haematopoletic and
`related tissues, for example diffuse large cell lymphoma,
`T-cell lymphoma or cutaneous T-cell lymphoma).
`By the term "chemotherapeutic agent" is meant especially
`any chemotherapeutic agent other than rapamycin or a deriva(cid:173)
`tive thereof. It includes but is not limited to,
`i. an aromatase inhibitor,
`35 ii. an antiestrogen, an anti-androgen (especially in the case of
`prostate cancer) or a gonadorelin agonist,
`iii. a topoisomerase I inhibitor or a topoisomerase II inhibitor,
`iv. a microtubule active agent, an alkylating agent, an antine(cid:173)
`oplastic antimetabolite or a platin compound,
`40 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. a bradykinin I receptor or an angiotensin II antagonist,
`45 vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone
`deacetylase inhibitor, a heparanase inhibitor (prevents
`heparan sulphate degradation), e.g. PI-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 famesyl transferase inhibitor, e.g.
`L-744,832 or DK8G557,
`ix. a telomerase inhibitor, e.g. telomestatin,
`x. a protease inhibitor, a matrix metalloprotelnase 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 testoster(cid:173)
`one to estrone and estradiol, respectively. The term includes,
`but is not limited to steroids, especially atamestane, exemes(cid:173)
`tane and formestane and, in particular, non-steroids, espe(cid:173)
`cially aminoglutethimide, roglethimide, pyridoglutethimide,
`65 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
`
`Breckenridge Exhibit 1001
`'131 patent
`Page 004
`
`
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`US 8,410,131 B2
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`5
`AROMASIN™. Formestane can be administered, e.g., in the
`form as it is marketed, e.g. under the trademark LEN(cid:173)
`TAROWM. Fadrozole can be administered, e.g., in the form
`as it is marketed, e.g. under the trademarkAFEMA™. Anas(cid:173)
`trozole 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 ORIMETEWM. 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 com(cid:173)
`pound which antagonizes the effect of estrogens at the estro(cid:173)
`gen receptor level. The term includes, but is not limited to
`tamoxifen, fulvestrant, raloxifene and raloxifene hydrochlo(cid:173)
`ride. Tamoxifen can be administered, e.g., in the form as it is
`marketed, e.g. under the trademark NOLVADEX™. Ralox(cid:173)
`ifene hydrochloride can be administered, e.g., in the form as 20
`it is marketed, e.g. under the trademark EVISTA™. Fulves(cid:173)
`trant can be formulated as disclosed in U.S. Pat. No. 4,659,
`516 or it can be administered, e.g., in the form as it is mar(cid:173)
`keted, e.g. under the trademark FASLODE™. A combination
`of the invention comprising a chemotherapeutic agent which 25
`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, 30
`bicalutamide (CASO DEX™), which can be formulated, e.g.
`as disclosed in U.S. Pat. No. 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 U.S. Pat. No. 4,100,274 and can be 35
`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 U.S. Pat. No. 5,843,901.
`The term "topoisomerase I inhibitor" as used herein
`includes, but is not limited to topotecan, irinotecan, 9-nitro- 40
`camptothecin and the macromolecular camptothecin conju(cid:173)
`gate PNU-166148 (compound Al in W099/17804). Irinote(cid:173)
`can 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 45
`trademark HYCAMTIWM.
`The term "topoisomerase II inhibitor" as used herein
`includes, but is not limited to the anthracyclines such as
`doxorubicin (including liposomal formulation, e.g. CAE(cid:173)
`LYX™), daunorubicin, epirubicin, idarubicin and nemorubi(cid:173)
`cin, 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 55
`trademark VM 26-BRISTOL™ Doxorubicin can be admin-
`istered, e.g. in the form as it is marketed, e.g. under the
`trademark ADRIBLASTIWM. Epirubicin can be adminis(cid:173)
`tered, e.g. in the form as it is marketed, e.g. under the trade(cid:173)
`mark FARMORUBICIWM. Idarubicin 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
`NOVANTROWM.
`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
`
`6
`alkaloids, e.g., vinblastine, especially vinblastine sulfate, vin(cid:173)
`cristine especially vincristine sulfate, and vinorelbine, disco(cid:173)
`dermolides and epothilones and derivatives thereof, e.g.
`epothilone Bora derivative thereof. Paclitaxel may be admin(cid:173)
`istered e.g. in the form as it is marketed, e.g. TAXOL™.
`Docetaxel can be administered, e.g., in the form as it is mar(cid:173)
`keted, 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
`10 sulfate can be administered, e.g., in the form as it is marketed,
`e.g. under the trademark FARMISTIWM. Discodermolide
`can be obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099.
`The term "alkylating agent" as used herein includes, but is
`not limited to cyclophosphamide, ifosfamide, melphalan or
`15 nitrosourea (BCNU or Gliadel™). Cyclophosphamide can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark CYCLOSTIWM. Ifosfamide can be administered,
`e.g., in the form as it is marketed, e.g. under the trademark
`HOLOXAWM.
`The term "antineoplastic antimetabolite" includes, but is
`not limited to 5-fluorouracil, capecitabine, gemcitabine,
`methotrexate and edatrexate. Capecitabine can be adminis(cid:173)
`tered, e.g., in the form as it is marketed, e.g. under the trade(cid:173)
`mark 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. Carbo(cid:173)
`platin can be administered, e.g., in the form as it is marketed,
`e.g. under the trademark CARBO PLAT™. Oxaliplatin can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark ELOXATIWM.
`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 fam(cid:173)
`ily of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4
`as homo- or heterodimers ), the vascular endothelial growth
`factor family of receptor tyrosine kinases (VEGFR), the
`platelet-derived growth factor-receptors (PDGFR), the fibro(cid:173)
`blast growth factor-receptors (FGFR), the insulin-like growth
`factor receptor 1 (IGF-lR), the Trk receptor tyrosine kinase
`family, theAxl receptor tyrosine kinase family, the Ret recep(cid:173)
`tor 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,
`50 SRC, JAK, FAK, PDK or PI(3) kinase family, or of the PI(3)(cid:173)
`kinase-related kinase family, and/or members of the cyclin(cid:173)
`dependent kinase family (CDK) and anti-anglogenic com(cid:173)
`pounds 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
`60 and specifically disclosed in WO 98/35958, e.g. 1-(4-chlo(cid:173)
`roanilino )-4-( 4-pyridylmethyl)phthalazine or a pharmaceuti(cid:173)
`cally acceptable salt thereof, e.g. the succinate, or in WO
`00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO
`00/27819 andEP 0 769 947; those as described by M. Prewett
`65 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,
`December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,
`
`Breckenridge Exhibit 1001
`'131 patent
`Page 005
`
`
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`US 8,410,131 B2
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`7
`3209-3214, and by J. Mordenti eta! 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 5
`amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF
`antibodies or anti-VEGF receptor antibodies, e.g. RhuMab.
`By antibody is meant intact monoclonal antibodies, poly(cid:173)
`clonal antibodies, multispecific antibodies formed from at
`least 2 intact antibodies, and antibodies fragments so long as 10
`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 0 564
`409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, 20
`EP 0 837 063, U.S. Pat. No. 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 CP 358774), WO
`96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g.
`compoundZM105180); e.g. trastuzumab (HerpetinR), cetux- 25
`imab, Iressa, OSI-774, CI-1033, EKB-569, GW-2016, El.1,
`E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3.
`Compounds which target, decrease or inhibit the ac