I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`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
`
`U.S. PATENT DOCUMENTS
`4,100,274 A
`7/1978 Dutta et al.
`111987 Tucker
`4,636,505 A
`4,885,171 A * 12/1989 Surendra et al. .............. 424/122
`5,010,099 A
`4/1991 Gunasekera et al.
`1111991 Sehgal et al.
`................. 424/122
`5,066,493 A
`5,093,330 A
`3/1992 Caravatti et al.
`5,194,447 A *
`3/1993 Kao .............................. 514/542
`5,206,018 A
`4/1993 Sehgal et al.
`................. 424/122
`5,362,718 A
`1111994 Skotnicki et al. ............... 514/63
`5,521,184 A
`5/1996 Zinunermann
`5/1998 Schnur et al.
`5,747,498 A
`5,792,783 A
`8/1998 Tang et al.
`5,843,901 A
`12/1998 Roeske
`5,922,730 A
`7/1999 Hue et al. ...................... 514/291
`5,985,890 A * 1111999 Cottens et al. ................ 514/291
`6,333,348 Bl * 12/2001 Vogel et al. ................... 514/449
`6,569,463 B2
`5/2003 Patel et al.
`.................... 424/497
`9/2003 Rabindran et al. ............ 514/291
`6,617 ,333 B2
`6,641,811 Bl* 1112003 Suthanthiran et al. ..... 424/146.l
`6,878,720 B2
`412005 Altmann et al.
`2002/0022054 Al
`212002 Sawada et al. ................ 424/468
`2002/0061303 Al
`512002 Singh
`
`2002/0098278 Al
`2003/0100886 Al
`2003/0100887 Al
`
`712002 Bates et al. .................... 427/2.1
`5/2003 Segal et al.
`................... 604/509
`5/2003 Scott et al. .................... 604/509
`
`EP
`EP
`EP
`EP
`EP
`EP
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`520722
`12/1992
`566226
`10/1993
`8/1997
`787722
`837063
`4/1998
`1074263
`212001
`1074263
`1112006
`94/09010
`4/1994
`9410202 Al
`5/1994
`9503283 Al
`2/1995
`94/16691
`6/1995
`95/28406
`10/1995
`9630347 Al
`10/1996
`9633980 Al
`10/1996
`9641807
`12/1996
`9702266 Al
`111997
`9730034 Al
`8/1997
`9735575 Al
`10/1997
`9738983 Al
`10/1997
`9747317
`12/1997
`9749688 Al
`12/1997
`98/09970
`3/1998
`9810767 A2
`3/1998
`9811223 Al
`3/1998
`9811908
`3/1998
`9835958 Al
`8/1998
`9917804 Al
`4/1999
`99038654 Al
`8/1999
`0009495
`212000
`0027820
`512000
`0037502
`612000
`10/2000
`0059509
`712001
`01151049
`0149338
`712001
`0187372
`1112001
`0197809
`12/2001
`(Continued)
`
`OTHER PUBLICATIONS
`
`Lien et al. Therapeutic anti-VEGF antibodies. Therapeutic Antibod(cid:173)
`ies, Handbook of Experimental Pharmacology 181. Y. Chernaj ovsky
`et al. (eds). 2008; pp. 131-150.*
`Wikipedia (http://en.wikipedia.org/wiki/ Angiogenesis. *
`Zhu et al. ("Inhibition of tumor growth and metastasis by targeting
`tumor-associated angiogenesis with antagonists to the receptors of
`vascular endothelial growth factor", Investigational New Drugs, 17,
`1999, 195-212).*
`Shi et al. ("Rapamycin enhances apoptosis and increases sensitivy to
`cisplatin in vitro" Cancer Research, 1995, 55, 1982-1988).*
`Fossa et al. ("Survival of patients with advanced urothelial cancer
`treated with cisplatin-based chemotherapy" Britich Journal of Can(cid:173)
`cer 1996, 74, 1655-1659).*
`renal pelvis (medical dictionary definition Dec. 12, 1998, accessed
`via http://www.mondofacto.com /facts/dictionary?renal+pelvis on
`May 19, 2011).*
`
`(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
`
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`02/05791
`1/2002
`0213802
`212002
`0240000
`512002
`10/2002
`02/080975
`10/2002
`02080975
`12/2002
`02/098416
`
`OTHER PUBLICATIONS
`Sokoloff et al. "Current Management of Renal Cell Carcinoma" CA
`Cancer J. Clin. 1996, 46, 284-302.*
`Cho et al. ("Current Status of Targeted Therapy for Advanced Renal
`Cell Carcinoma", Korean Journal of Urology, 2012, 53, 217-228.*
`Arecci et al., "Immunosuppressants FK506 and Rapamycin Function
`as Reversal Agents of the Multidrug Resistance Phenotype", Blood,
`vol. 80, No. 6, pp. 1528-1536 (1992).
`Dayanir et al., "Identification of Tyrosine Residues in Vascular
`Endothelial Growth",JBiolChem, vol. 276, No. 21, pp. 17686-17692
`(2001).
`Eng et al., "Activity of Rapamycin (AY-22,989) Against Transplated
`Tumors", J Antibiotics, vol. XXXXVII, No. 10, pp. 1231-1237
`(1984).
`Law et al., "Farnesyltransferase Inhibitor Induces Rapid Growth
`Arrest and Blocks p70s6k Activation by Multiple Stimuli", J Biol
`Chem, vol. 275, No. 15, pp. 10796-10801 (2000).
`Peng eta!., "Novel Pyrrolo-quinoline Derivatives as Potent Inhibitors
`for PB-Kinase Related Kinases", Bioorg Med Chem, vol. 10, No. 1,
`pp. 167-174 (2002).
`Shi et al., "Rapamycin Enhances Apoptosis and Increases Sensitivity
`to Cisplatin in Vitro", Cancer Res, vol. 55, No. 9, pp. 1982-1988
`(1995).
`Geoerger et al., "Antitumor Activity of the Rapamycin Analog CCI-
`779 in Human Primitive Neuroectodermal Tumor/Medulloblastorna
`Models as Single Agent and in Combination Chemotherapy", Cancer
`Research 61: 1527-1532 (2001).
`Guba et al., "Rapamycin inhibits tumor growth and metastasis by
`antiangiogenesis", Chirugishes Forum Fver Experimentelle und
`Klinische Forschung: 37-39 (2001).
`Zhong et al., "Modulation of Hypoxia-inductible Factor 1-alpha
`Expression by the Epidermal Growth Factor/ Phosphatidylinositol
`3-Kinase/PTEN/AKT/FRAP Pathway in Human Prostate Cancer
`Cells: Implications for Tumor Angiogenesis and Therapeutics"; Can(cid:173)
`cer Research 60: 1541-1545 (2000).
`Zhong et al. "Modulation of Hypoxia-Inducible Factor 1-alpha
`Expression by the Epidermal Growth Factor/ Phosphatidylinositol
`3-Kinase/PTEN/AKT/ FRAP Pathway .
`", Cancer Res. 2000,
`60(6): 1541-1545.
`
`Geoerger et al. "Antitumor Activity of the Rapamycin Analog CCI-
`779 in Human Primitive Neuroectoderrnal Tumor/Medulloblastoma
`Models as SingleAgent and in Combination Chemotherapy", Cancer
`Res 2001, 61( 4): 1527-1532.
`Guba et al. "Rapamycin Inhibits Tumor Growth and Metastasis by
`Antiangiogenesis", Chirurgisches Forum Fuer Experimentelle and
`Klinische Forschung, 2001, 37-39.
`Fukazawa et al., "U0126 Reverses Ki-ms-mediated Transformation
`by Blocking Both Mitogen-activated Protein Kinase and p70 S6
`Kinase Pathways"; Cancer Research 2000, 60: 2104-2107.
`Hallensleben et al., "Identification of a New Metabolite ofMacrolide
`Immunosuppressant, Like Rapamycin and SDZ RAD, Using High
`Performance Liquid Chromatography and Electrospray Tandem
`Mass Spectrometry"; J Am Soc Mass Spectrom 2000, 11: 516-525.
`Majewski et al., The immunosuppressive macrolide RAD inhibits
`growth of human Ebstein-Barr virus-transformed B lymphocytes in
`vitro and in vivo: A potential approact to prevention and treatment of
`posttransplant lymphoproliferative disorders; PNAS 2000, 97(8):
`4285-4290.
`Mordenti et al., "Efficacy and Concentration-Response of Murine
`Anti-VEGF Monoclonal Antibody in Tumor-Bearing Mice and
`Extrapolation to Humans"; Toxicologic Pathology 1999, 27(1):
`14-21.
`O'Reilly et al., "Angiostatin: A Novel Angiogenesis Inhibitor That
`Mediates the Suppression of Metastases by a Lewis Lung Carci(cid:173)
`noma"; Cell 1994, 79: 315-328.
`O'Reilly et al., "Endostatin: An Endogeneous Inhibitor of
`Angiogenesis and Tumor Growth"; Cell 1997, 88: 277-285.
`Prewett et al., "Antivascular Endothelial Growth Factor Receptor
`(Fetal Liver Kinase 1) Monocolnal Antibody Inhibits Tumor
`Angiogenesis and Growth of Several Mouse and Human Tumors";
`Cancer Research 1999, 59: 5209-5218.
`Yuan et al. "Time-dependent vascular regression and permeability
`changes in established human tumor xenografts induced by an anti(cid:173)
`vascular endothelial growth factor/vascular permeability factor anti(cid:173)
`body"; Proc. Natl. Acad. Sci. 1996, 93: 14765-14770.
`Zhu et al., "Inhibition of Vascular Endothelial Growth Factor-in(cid:173)
`duced Receptor Activation with Anti-Kinase Insert Domain-contain(cid:173)
`ing Receptor Single-Chain Antibodies from a Phage Display
`Library"; Cancer Research 1998, 58: 3209-3214.
`Zhaoyou, Modern Oncology 2000, 1st press. (English summary pro(cid:173)
`vided) English summary only considered.
`* cited by examiner
`
`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