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`2012-07-11
`I Lane et al.
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`031671-US-CNT03 (62 C 3)
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`of cited Document
`
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`U.S.PATENTS
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`Remove
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`1
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`6333348
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`HUE et al.
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`EFSWeb2.1.17
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 1
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`INFORMATION DISCLOSURE
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`2012-07-11
`I Lane et al.
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`Examiner Name
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`I
`Attorney Docket Number
`
`031671-US-CNT03 (62 C 3)
`
`9
`
`6569463
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`PATEL et al.
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`10
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`11
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`
`SUTHANTHIRAN et al.
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`1
`
`20020022054
`
`2002-02-21
`
`SAWADA et al.
`
`2
`
`3
`
`4
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`20020098278
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`2003-05-29
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`SEGAL etal.
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`20030100887
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
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`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`( Not for submission under 37 CFR 1.99)
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`Application Number
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`Filing Date
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`First Named Inventor
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`2012-07-11
`I Lane et al.
`
`Examiner Name
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`
`031671-US-CNT03 (62 C 3)
`
`1
`
`1074263
`
`EP
`
`2001-02-07
`
`NEUER et al.
`
`2
`
`9409010
`
`WO
`
`1994-04-28
`
`COTTENS
`
`3
`
`9516691
`
`WO
`
`1995-06-22
`
`COTTENS
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`4
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`9528406
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`WO
`
`1995-10-26
`
`SKOTNICKI et al.
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`5
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`9641807
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`WO
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`1996-12-27
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`COTTENS et al.
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`6
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`9747317
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`1997-12-18 WECKBECKER
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`7
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`WO
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`1998-03-12
`
`HU et al.
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`8
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`0149338
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`WO
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`2001-07-12
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`LI et al.
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`9
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`0151049
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`WO
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`2001-07-19 WASIK et al.
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`10
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`2002-01-24
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`MASSIMINI et al.
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`11
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`WO
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`EFSWeb2.1.17
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
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`(cid:143)
`
`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 3
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`INFORMATION DISCLOSURE
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`
`12
`
`02080975
`
`WO
`
`2002-10-17
`
`GIBBONS et al.
`
`13
`
`02098416
`
`WO
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`2002-12-12
`
`DUKART et al.
`
`14
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`
`WO
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`2002-05-23
`
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`15
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`WO
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`1998-03-26 WOOD et al.
`
`16
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`WO
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`KOPIA et al.
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`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
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`(cid:143)
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`Include name of the author (in CAPITAL LETTERS), title of the article (when appropriate), title of the item
`(book, magazine, journal, serial, symposium, catalog, etc), date, pages(s), volume-issue number(s),
`publisher, city and/or country where published.
`
`T5
`
`1
`
`LIEN et al. "Therapeutic anti-VEGF antibodies. Therapeutic Antibodies, Handbook of Experimental Pharmacology
`181. Y. Chernajovskyetal. (eds). 2008; 131-150.
`
`2
`
`Wikipedia (http://en.wikipedia.org/wiki/Angiogenesis.
`
`GEOERGER et al. "Antitumor Activity of the Rapamycin Analog CCl-779 in Human Primitive Neuroectodermal 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 und Klinische Forschung, 2001, 37-39.
`
`3
`
`4
`
`EFSWeb2.1.17
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`(cid:143)
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`(cid:143)
`
`(cid:143)
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`(cid:143)
`
`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
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`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`( Not for submission under 37 CFR 1.99)
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`Application Number
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`Filing Date
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`First Named Inventor
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`Art Unit
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`2012-07-11
`I Lane et al.
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`Examiner Name
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`Attorney Docket Number
`
`031671-US-CNT03 (62 C 3)
`
`5
`
`6
`
`7
`
`8
`
`9
`
`LAW et al. "Farnesyltransferase Inhibitor Induces Rapid Growth Arrest and Blocks p70s6k Activation by Multiple
`Stimuli", J Biol Chem 2000, 275(15): 10796-10801.
`
`PENG et al. "Novel Pyrrolo-quinoline Derivatives as Potent Inhibitors for P13-Kinase Related Kinases", Bioorg Med
`Chem 2002, 10(1): 167-174.
`
`SHI et al. "Rapamycin Enhances Apoptosis and Increases Sensivity to Cisplatin in Vitro", Cancer Res. 1995, 55(9):
`1982-1988.
`
`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.
`
`SHI et al. "Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro" Cancer Research 1995, 55:
`1982-1988.
`
`10
`
`FOSSA et al. "Survival of patients with advanced urothelial cancer treated with cisplatin-based chemotherapy" British
`Journal of Cancer 1996, 74: 1655-1659.
`
`11
`
`Renal Pelvis (medical dictionary definition 12/12/1998, accessed via http://www.mondofacto.com/facts/dictionary?renal
`+pelvis on May 19, 2011).
`
`12
`
`ARE CCI et al. "lmmunosuppresants FK506 and Rapamycin Function as Reversal Agents of the Multidrug Resistance
`Phenotype", Blood 1992, 80(6): 1528-1536.
`
`13
`
`DAYANIRetal. "Identification of Tyrosine Residues in Vascular Endothelial Growth", J Biol Chem 2001, 276(21):
`17686-17692.
`
`14
`
`ENG et al. "Activity of Rapamycin (AY-22,989) Against Transplanted Tumors", J Antiobotics 1984, XXXVll(10):
`1231-1237.
`
`15
`
`ZHU et al. "Inhibition of tumor growth and metastasis by targeting tumor-associated angiogenesis with antagonists to
`the receptors of vascular endothelial growth factor", lnvestigational New Drugs 1999, 17: 195-212.
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`(cid:143)
`
`EFSWeb2.1.17
`
`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 5
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`INFORMATION DISCLOSURE
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 8
`
`

`

`Case 4-31671A
`
`- 1 -
`
`Treatment of Solid Tumours with Rapamycin Derivatives
`
`This application is a continuation of U.S. Application No. 10/468,520, filed January 27, 2004,
`
`which is a 371 application of PCT/EP2002/01714, filed February 18, 2002, which in its
`
`entirety is herein incorporated by reference.
`
`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 rapamycin include e.g. compounds of
`
`formula I
`
`24
`
`19
`
`21
`
`wherein
`R1 is CH3 or C3-aalkynyl,
`R2 is H or-CH2-CH2-OH, and
`X is =O, (H,H) or (H,OH)
`provided that R2 is other than H when X is =O and R1 is CH3.
`
`Compounds of formula I are disclosed e.g. in U.S. Patent 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 diclosed 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($ )-dihydro-rapamycin, 16-pent-2-ynyloxy-32(8)-dihydro-40-O-(2-
`
`hydroxyethyl)-rapamycin and, more preferably, 40-O-(2-hydroxyethyl)-rapamycin (referred
`
`thereafter as Compound A), disclosed as Example 8 in U.S. Patent Nos: 5,665,772 and
`6,440,990.
`
`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 9
`
`

`

`Case 4-31671A
`
`-2-
`
`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 Compounds of formula I have potent antiproliferative properties which make them useful
`
`for cancer chemotherapy, particularly 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 therapeutically effective amount of a compound of
`
`formula I.
`
`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 administering to said subject a therapeutically effective
`
`amount of a compound of formula I.
`
`1.4 A method for treating solid tumor invasiveness or symptoms 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.
`
`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 blastomas); 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); gastrointestinal tract tumors
`
`(e.g. oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum,
`
`anus and anal canal), tumors involving the liver and intrahepatic bile ducts, gall bladder,
`
`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 10
`
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`Case 4-31671A
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`other and unspecified parts of biliary tract, pancreas, other and digestive organs); head and
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`neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid
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`gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform
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`sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); reproductive system
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`tumors (e.g. vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites
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`associated with female genital organs, placenta, penis, prostate, testis, and other sites
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`associated with male genital organs); respiratory tract tumors (e.g. nasal cavity and middle
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`ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or
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`non-small cell lung cancer); skeletal system tumors (e.g. bone and articular cartilage of
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`limbs, bone articular cartilage and other sites); skin tumors (e.g. malignant melanoma of the
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`skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of
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`skin, mesothelioma, Kaposi's sarcoma); and tumors involving other tissues incluing
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`peripheral nerves and autonomic nervous system, connective and soft tissue,
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`retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other
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`endocrine glands and related structures, secondary and unspecified malignant neoplasm of
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`lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and
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`secondary malignant neoplasm of other sites.
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`Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer is
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`mentioned, also metastasis in the original organ or tissue and/or in any other location are
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`implied alternatively or in addition, whatever the location of the tumor and/or metastasis is.
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`In a series of further specific or alternative embodiments, the present invention also provides
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`1.6 A method for the treatment of a disease associated with deregulated angiogenesis in a
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`subject in need thereof, comprising administering to said subject a therapeutically
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`effective amount of rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a
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`compound of formula I.
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`1.7 A method for inhibiting or controlling deregulated angiogenesis in a subject in need
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`thereof, comprising administering to said subject a therapeutically effective amount of
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`rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a compound of formula I.
`1.8 A method for enhancing the activity of a chemotherapeutic agent or for overcoming
`resistance to a chemotherapeutic agent in a subject in need thereof, comprising
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`administering to said subject a therapeutically effective amount of rapamycin or a
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`derivative thereof, e.g. CCl779, ABT578 or a compound of formula I, either
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`concomitantly or sequentially with said chemotherapeutic agent.
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 11
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`1.9 A method according to 1.8 wherein the chemotherapeutic agent is an inhibitor of signal
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`transduction pathways directed either against host cells or processes involved in tumor
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`formation and/or metastases formation or utilised by tumour cells for proliferation,
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`survival, differentiation or development of drug resistance.
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`1.10 A method as indicated above, wherein rapamycin or a derivative thereof, e.g. CCl779,
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`ABT578 or a compound of formula I is administered intermittently.
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`CCl779 is a rapamycin derivative, i.e. 40- [3-hydroxy-2-(hydroxymethyl)-2-methylpropa(cid:173)
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`noate]-rapamycin or a pharmaceutically acceptable salt thereof, and is disclosed e.g. in USP
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`5,362,718. ABT578 is a 40-substituted rapamycin derivative further comprising a diene
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`reduction.
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`Examples of diseases associated with deregulated angiogenesis include without limitation
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`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.
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`In a series of further specific or alternative embodiments, the present invention also
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`provides:
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`2.1 A compound of formula I for use in any method as defined under 1.1 to 1.5 above.
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`2.2 Rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a compound of formula I for
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`use in any method as defined under 1.6 to 1.10 above or 7 below.
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`3.1 A compound of formula I for use in the preparation of a pharmaceutical composition for
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`use in any method as defined under 1.1 to 1.5 above.
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`3.2 Rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a compound of formula I for
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`use in the preparation of a pharmaceutical composition for use in any method as
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`defined under 1.6 to 1.1 O above or 7 below.
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`4.1 A pharmaceutical composition for use in any method as defined under 1.1 to 1.5 above
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`comprising a compound of formula I together with one or more pharmaceutically
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`acceptable diluents or carriers therefor.
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`4.2 A pharmaceutical composition for use in any method as defined under 1.6 to 1.1 O
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`above or 7 below comprising rapamycin or a derivative thereof, e.g. CCl779, ABT578
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`or a compound of formula I, e.g. Compound A, together with one or more
`pharmaceutically acceptable diluents or carriers therefor.
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`5.1 A pharmaceutical combination comprising a} a first agent which is rapamycin or a
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`derivative thereof, e.g. CCl779, 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.
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 12
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`5.2 A pharmaceutical combination comprising an amount of a) a first agent which is
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`rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a compound of formula I,
`e.g. Compound A, and b) a co-agent which is a chemotherapeutic agent selected from
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`the compounds defined under paragraph (iv) or (v) below, to produce a synergistic
`therapeutic effect.
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`6.
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`A method as defined above comprising co-administration, e.g. concomitantly or in
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`sequence, of a therapeutically effective amount of rapamycin or a derivative thereof,
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`e.g. CCl779, ABT578 or a compound of formula I, e.g. Compound A, and a second
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`drug substance, said second drug substance being a chemotherapeutic agent, e.g. as
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`indicated hereinafter.
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`7.
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`A method for treating post-transplant lymphoproliferative disorders or a lymphatic
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`cancer, e.g. for treating tumor invasiveness or symptoms associated with such tumor
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`growth in a subject in need thereof, comprising co-administering to said subject, e.g.
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`concomitantly or in sequence, of rapamycin or a derivative thereof, e.g. CCl779,
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`ABT578 or a compound of formula I, e.g. Compound A, and a second drug substance,
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`said second drug substance being a chemotherapeutic agent, e.g. as indicated
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`hereinafter.
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`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
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`immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms,
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`lymphoid leukemia, myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic
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`leukemia, other leukemias of specified cell type, leukemia of unspecified cell type, other and
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`unspecified malignant neoplasms of lymphoid, haematopoietic and related tissues, for
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`example diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma).
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`By the term "chemotherapeutic agent" is meant especially any chemotherapeutic agent other
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`than rapamycin or a derivative thereof. It includes but is not limited to,
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`i.
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`ii.
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`iii.
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`iv.
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`an aromatase inhibitor,
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`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
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`platin compound,
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
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`v.
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`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,
`a bradykinin 1 receptor or an angiotensin II antagonist,
`vi.
`vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, 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 famesyl
`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.
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`ix.
`x.
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`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
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`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
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`trademark LENTARON™. Fadrozole can be administered, e.g., in the form as it is marketed,
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`e.g. under the trademark AFEMA™. Anastrozole can be administered, e.g., in the form as it
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`is marketed, e.g. under the trademark ARI Ml DEX™. Letrozole can be administered, e.g., in
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`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
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`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.
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`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
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`Breckenridge Exhibit 1160
`Breckenridge v. Novartis IPR2017-01592
`File History 13/546,686 Application
`Page 14
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`administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX™.
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`Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under
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`the trademark EVISTA™. Fulvestrant can be formulated as disclosed in US 4,659,516 or it
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`can be administered, e.g., in the form as it is marketed, e.g. under the trademark
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`·
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`FASLODEX™. A combination of the invention comprising a chemotherapeutic agent which is
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`an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors,
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`e.g. breast tumors.
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`The term "anti-androgen" as used herein relates to any substance which is capable of
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`inhibiting the biological effects of androgenic hormones and includes, but is not limited to,
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`bicalutamide (CASODEX™), which can be formulated, e.g. as disclosed in US 4,636,505.
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`The term "gonadorelin agonist' as used herein includes, but is not limited to abarelix,
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`goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be
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`administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEX™.
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`Abarelix can be formulated, eg. as disclosed in US 5,843,901.
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`The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan,
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`irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-
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`166148 (compound A1 in WO99/17804)