I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US007781446B2
`
`c12) United States Patent
`Dukart et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 7,781,446 B2
`*Aug. 24, 2010
`
`(54) USE OF CCI-779 AS AN ANTINEOPLASTIC
`AGENT
`
`2002/0183239 Al
`2002/0183240 Al
`
`12/2002 Gibbons
`12/2002 Gibbons
`
`(75)
`
`Inventors: Gary Dukart, Ambler, PA (US); James
`J. Gibbons, Jr., Westwood, NJ (US);
`Lisa Anne Speicher, Havertown, PA
`(US); Philip Frost, Morris Township, NJ
`(US); Carolyn Mary Discafani-Marro,
`Cortlandt Manor, NY (US)
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`
`0 525 960 Al
`WO 02/13802 A2
`
`2/1993
`212002
`
`(73) Assignee: Wyeth LLC, Madison, NJ (US)
`
`OTHER PUBLICATIONS
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 111701,109
`
`(22) Filed:
`
`Feb.1,2007
`
`(65)
`
`Prior Publication Data
`
`US 2007/0142425 Al
`
`Jun.21,2007
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/374,644, filed on
`Feb. 26, 2003, now Pat. No. 7,189,735, which is a
`continuation of application No. 10/010,584, filed on
`Nov. 13, 2001, now abandoned.
`
`(60) Provisional application No. 60/249,077, filed on Nov.
`15, 2000.
`
`(51)
`
`Int. Cl.
`A61K 31144
`(2006.01)
`(52) U.S. Cl. ....................... 514/291; 514/183; 514/311;
`514/312; 514/313
`(58) Field of Classification Search ................. 514/291,
`514/183,311,312,313
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`12/1975 Sehgal et al.
`3,929,992 A
`1111976 Sehgal et al.
`3,993,749 A
`8/1983 Eng
`4,401,653 A
`12/1989 Surendra et al.
`4,885,171 A
`111992 Warner et al.
`5,078,999 A
`111992 Sturm et al.
`5,080,899 A
`3/1992 Caine et al.
`5,100,899 A
`4/1993 Sehgal et al.
`5,206,018 A
`2/1994 Caufield et al.
`5,286,730 A
`2/1994 Caufield et al.
`5,286,731 A
`2/1994 Mitchell et al.
`5,288,711 A
`6/1994 Baeder et al.
`5,321,009 A
`5,362,718 A * 1111994 Skotnicki et al. .............. 514/63
`5,387,589 A
`2/1995 Kulkarni et al.
`5,496,832 A
`3/1996 Armstrong et al.
`5,516,781 A
`5/1996 Morris et al.
`5,561,138 A
`10/1996 Armstrong et al.
`5,728,710 A
`3/1998 Luengo
`6,617 ,333 B2
`9/2003 Rabindran et al.
`
`B. Geoerger, et al., Cancer Research, Feb. 15, 2001,vol. 61, No. 4, pp.
`1527-1532.
`G. Schwartsmann, et al., Annals of Oncology, Oct. 13, 2000, vol. 11,
`No. 3, pp. 235-243.
`S.N. Sehgal, et al., J. Antibiot., 1975, 727, 28.
`C.V. Vezina, et al., J. Antibiot., 1975, 721, 28.
`H.A. Baker, et al., J. Antibiot., 1978, 539, 31.
`Faseb, 1989, 3411, 3.
`Faseb, 1989, 5256, 3.
`R.Y. Caine, et al., Lancet, 1978, 1183.
`R. Martel, et al., Can. J. Physiol. Pharmacol., 1977, 48, 55.
`J. Alexandre, et al., Bull. Cancer, 1999, 808, 86.
`A. Perren, et al., Am. J. Pathology, 1999, 1253, 155.
`J.E. Dancey, et al., ASCO Educational Book, Spring 2000, 68.
`M. Hidalgo, et al., Oncogene, 2000, 6680, 19.
`E.A. Sausville, et al., ASCO Educational Book, Fall, 1998, 112.
`J. Alexandre, et al., CCI-779, anew rapamycin analog, has anti tumor
`activity at doses inducing only mild cutaneous effects andmucostitis;
`early results of an ongoing phase 1 study, Proceedings of the 10th
`NCI/EORTC/ AACR Symposium, 1999 (poster presentation).
`J.J. Gibbons, et al., Proceedings of the American Association for
`Cancer Research, 1999, 30la, 40.
`B. Geoerger, et al., Proceedings of the American Association for
`Cancer Research, 1999, 603a, 40.
`J, Alexandre, et al., Proceedings of the American Association for
`Cancer Research, 2000, 613, 41.
`M. Hidalgo, et al., Proceedings of the 11th NCI/EORTC/ AACR
`Symposium, 2000, 4548s, 6 (Supp.).
`M. Hidalgo, et al., Annals of Oncology, 2000, 133a, 11(4).
`E. Raymond, et al., Proceedings of the 11th NCI/EORTC/ AACR
`Symposium, 2000, Ab, 414.
`E. Raymond, et al., Proceedings of the ASCO, 2000, 187a, 19.
`M. Hidalgo, et al., Phase 1 and Pharmacological Studies with the
`Rapamycin Analog CCI-779 Administered as a 30 Minute Infusion,
`NCI-CTEP, Drug Development Meeting, Oct. 1999.
`M. Abou-Gharbia, Medicinal Chemistry Approaches for Optimiza(cid:173)
`tion of Early Leads in Drug Candidates: The Discovery of
`Calicheamicin, Rapamycin and EAA-090, International Conference
`on Pure and Applied Heterocyclic Chemistry, Mar. 2000.
`
`(Continued)
`
`Primary Examiner-James D Anderson
`(74) Attorney, Agent, or Firm-Howson & Howson LLP;
`David A. Rubin
`
`(57)
`
`ABSTRACT
`
`This invention provides the use of CCI-779 in the treatment of
`neoplasms.
`
`2 Claims, No Drawings
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 001
`
`

`

`US 7, 781,446 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`R. Langreth, et al., The Wall StreetJournal, Nov. 17, 1999, vol. 234.
`Carter, et al., Chemotherapy of Cancer, second edition, 1981, pp.
`362-365, John Wiley & Sons, N.Y., N.Y.
`Alberts, New Perspectives on an Old Friend: optimizing carboplatin
`for the treatment of solid tumors, Oncologist, 1998, 3(1): 15-34,
`Abstract.
`Dorland'S Illustrated Medical Dictionary, 24th Edition, p. 987, 1965.
`P. Robins, Poster Highlights I ,!Drugs, 1999, vol. 2, No. 6, Paragraph,
`CCI-779, XP-001083882.
`Yu, et al., "mTOR, a novel target in breast cancer: the effect of
`CCI-779, an mTORinhibitor, in preclinical models ofbreast cancer",
`Endocr. Relat. Cancer, 8(3):249-258 (Sep. 2001).
`Raymond, et al., "CCI-779, a rapamycin analog with antitumor activ(cid:173)
`ity: a phase I study utilizing a weekly schedule", Proc. Am. Soc. Clin.
`Oncol. 19(abstr. 728) (Annual Meeting, May 20-23, 2000).
`M. Hidalgo, et al., CCI-779, a Rapamycin Analog and Multifaceted
`Inhibitor of Signal Transduction: a Phase I Study, Proceedings of the
`American Society of Clinical Oncology 2000 Annual Meeting, May
`20-23, 2000.
`Schmelzle, et al., "TOR, a central controller of cell growth," Cell, vol.
`103, No. 2, (Oct. 13, 2000) pp. 253-262.
`
`Friedrich, "Von Rippel-Lindau Syndrome, A Pleomorphic Condi(cid:173)
`tion", Cancer, 86(Sl 1):2478-2482 (Jun. 1998)(presented at the
`American Cancer Society Second National Conference on Cancer
`Genetics, San Francisco, CA, Jun. 26-28, 1998; published in journal
`Dec. 1, 1999).
`Hidalgo, "The rapamycin-sensitive signal transduction pathway as a
`target for cancer therapy", Oncogene, 19:6680-6686 (Dec. 27, 2000).
`Maxwell, "The tumor suppressor protein VHL targets hypoxia-in(cid:173)
`ducible factors for oxygen-dependent proteolysis", Nature, 399:271-
`275 (May 20, 1999).
`Zhong, "Modulation of Hypoxia-inducible Factor la Expression by
`the Epidermal Growth Factor/Phosphatidylinositiol 3-Kinase/PTEN/
`AKT/FRAP Pathway in Human Prostate Cancer Cells: Implications
`for Tumor Angiogenesis and Therapeutics", Cancer Research,
`60:1541-1545 (Mar. 15, 2000).
`English-language translation of a Notice of Reexamination issued
`Jul. 27, 2009 in counterpart Chinese Patent Application No.
`01818926.1.
`English-language translation of a Final Rejection mailed May 19,
`2009 in counterpart Japanese Patent Application No. 2002-542375.
`English translation of an Examination Report dated Oct. 18, 2009
`issued in counterpart Chilean Patent Application No. 02739-2001.
`* cited by examiner
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 002
`
`

`

`US 7,781,446 B2
`
`1
`USE OF CCI-779 AS AN ANTINEOPLASTIC
`AGENT
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of U.S. patent applica(cid:173)
`tion Ser. No. 10/374,644, filed Feb. 26, 2003 (now U.S. Pat.
`No. 7,189,735, issued Mar. 13, 2007), which is a continuation
`of U.S. patent application Ser. No. 10/010,584, filed Nov. 13, 10
`2001, which claims the benefit under 35 USC 119( e) of prior
`U.S. Provisional Patent Application No. 60/249,077, filed
`Nov. 15, 2000.
`
`2
`As used in accordance with this invention, the term "treat(cid:173)
`ment" means treating a mammal having a neoplastic disease
`by providing said mammal an effective amount ofCCI-779
`with the purpose ofinhibiting growth of the neoplasm in such
`5 mammal, eradication of the neoplasm, or palliation of the
`neoplasm.
`As used in accordance with this invention, the term "pro(cid:173)
`viding," with respect to providing CCI-779, means either
`directly administering CCI-779, or administering a prodrug,
`derivative, or analog which will form an effective amount of
`CCI-779 within the body.
`As used in accordance with this invention, the term "refrac(cid:173)
`tory neoplasm" refers to neoplasms in patients which typi-
`15 cally had progressed following treatment with standard che(cid:173)
`motherapy that was appropriate for that given neoplasm.
`The preparation ofCCI-779 is described in U.S. Pat. No.
`5,362,718, which is hereby incorporated by reference.
`The antineoplastic activity of CCI-779 was confirmed in a
`preclinical in vitro and in vivo standard pharmacological test
`procedure which measured the ability of CCI-779 to treat
`human renal cell cancer (a rapidly progressive disease with
`very limited treatment options), as well as in two Phase 1
`25 human clinical trials. The procedures used and results
`obtained are briefly described below.
`
`20
`
`BACKGROUND OF THE INVENTION
`
`This invention relates to the use ofrapamycin 4 2-ester with
`3-hydroxy-2-(hydroxymethyl)-2-methylpropionic
`acid
`(CCI-779) as an antineoplastic agent. Rapamycin is a mac(cid:173)
`rocyclic triene antibiotic produced by Streptomyces hvqro-
`scopicus, which was found to have antifungal activity, par(cid:173)
`ticularly against Candida albicans, both in vitro and in vivo
`[C. Vezina et al., J. Antibiot. 28, 721 (1975); S. N. Sehgal et
`al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot.
`31, 539 (1978); U.S. Pat. No. 3,929,992; and U.S. Pat. No.
`3,993,749]. Additionally, rapamycin alone (U.S. Pat. No.
`4,885,171) or in combination with picibanil (U.S. Pat. No.
`4,401,653) has been shown to have antitumor activity.
`The immunosuppressive effects of rapamycin have been
`disclosed in FASEB 3, 3411 (1989). Cyclosporin A and
`FK-506, other macrocyclic molecules, also have been shown
`to be effective as immunosuppressive agents, therefore useful
`in preventing transplant rejection [FASEB 3, 3411 (1989);
`FASEB 3, 5256 (1989); R.Y. Caine eta!., Lancet 1183 (1978);
`and U.S. Pat. No. 5,100,899]. R. Martel eta!. [Can. J. Physiol.
`Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effec(cid:173)
`tive in the experimental allergic encephalomyelitis model, a
`model for multiple sclerosis; in the adjuvant arthritis model, a
`model for rheumatoid arthritis; and effectively inhibited the
`formation oflgE-like antibodies.
`Rapamycin is also useful in preventing or treating systemic
`lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonary
`inflammation [U.S. Pat. No. 5,080,899], insulin dependent
`diabetes mellitus [U.S. Pat. No. 5,321,009], skin disorders,
`such as psoriasis [U.S. Pat. No. 5,286,730], bowel disorders
`[U.S. Pat. No. 5,286,731], smooth muscle cell proliferation
`and intimal thickening following vascular injury [U.S. Pat.
`Nos. 5,288,711 and 5,516,781], adult T-cell leukemia/lym(cid:173)
`phoma [European Patent Application 525,960 Al], ocular
`inflammation [U.S. Pat. No. 5,387,589], malignant carcino-
`mas [U.S. Pat. No. 5,206,018], cardiac inflammatory disease
`[U.S. Pat. No. 5,496,832], and anemia [U.S. Pat. No. 5,561,
`138].
`The preparation and use of hydroxyesters of rapamycin,
`including CCI-779, are disclosed in U.S. Pat. No. 5,362,718.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Preclinical Test Procedures
`In vitro test procedure: Renal tumor lines HTB-44 and
`CRL-1161 were obtained from the American Tissue Culture
`Collection (ATCC), Bethesda, Md. SN12-C line was
`obtained from Dr. J. Fidler, M. D. Anderson Hospital, Hous(cid:173)
`ton, Tex. Cells were plated in MEM (Gibco) supplemented
`with 2 mM glutamine, 1 mM sodium pyruvate, 5 ml penicil(cid:173)
`lin-streptomycin solution, 1 mM non-essential amino acid
`solution, 10% fetal bovine solution. Cells (5xl03
`) were
`plated in 96 well plates with a final volume of 200 ml and
`incubated for 24 hours at 3 7° C. Log dilutions of CCI-779
`beginning at 100 µg/ml were then added to the cultures for 48
`hours. Over the last 5 hours, cells were pulsed with 1 µci
`3H-thymidine (New England Nuclear, 6.7 ci/m Mo!). Cells
`were then harvested and the degree of thymidine uptake deter(cid:173)
`mined by liquid scintillation spectrometry. The IC50 was
`determined as the concentration that produced 50% of the
`maximum uptake ofthymidine in control untreated cells.
`In vivo test procedure: Female Balb/c nu/nu mice were
`obtained from Charles River Labs, Wilmington, Del., at 6-8
`weeks ofage. Mice (n=lO/group )were injected sc with 5xl06
`cells resuspended in a 50% solution of Matrigel (BD Bio(cid:173)
`sciences) and tumors allowed to develop. When tumor size
`reached 100 mg, mice were treated orally with CCI-779 at 25
`mg/kg. CCI-779 was dosed for 5 consecutive days with
`repeated 14 day cycles throughout the duration of the experi(cid:173)
`ment. The formulation used for CCI-779 was a 50% ethanol,
`49% phosal, 1 % tween 80 vehicle for resuspending CCI-779,
`where the stock was resuspended into a 1: 10 dilution of the
`vehicle prior to dosing. Tumor growth was evaluated using a
`vernier caliper and volume (lxwxh) was converted to mass
`using the formula: lxw2/2.
`
`Results:
`Human renal cell tumors were cultured in vitro in the
`presence or absence of CCI-779 for 3 days and the effect on
`growth determined by 3 H-thymidine incorporation of control
`versus treated cells. Table 1 shows that IC50 (50% growth
`inhibitory concentration) for all 3 lines tested was in the low
`nMrange.
`
`This invention provides, the use of CCI-779 as an antine(cid:173)
`oplastic agent, and particularly for neoplasms which are
`refractory to standard therapy, or for whom standard therapy 60
`is not appropriate. In particular CCI-779 is useful in the
`treatment of renal cancer, soft tissue cancer, breast cancer,
`neuroendocrine tumor of the lung, cervical cancer, uterine
`cancer, head and neck cancer, glioblastoma, non-small lung
`cell cancer, prostate cancer, pancreatic cancer, lymphoma, 65
`melanoma, small cell lung cancer, ovarian cancer, endome(cid:173)
`trial cancer, and colon cancer.
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 003
`
`

`

`US 7,781,446 B2
`
`3
`
`TABLE 1
`
`The effect of CCI-779 on the growth of human renal tumor
`cells in vitro
`
`Renal Twnor Line
`
`CCI-779 IC50 (nM)
`
`HTB-44
`CRL-1161
`SN12-C
`
`5.0
`2.0
`5.5
`
`The effect of CCI-779 in two human renal lines (HTB-44
`and CRL-1161) was evaluated in vivo by engrafting tumor
`cells on the flanks of nude mice. Once tumors were estab-
`lished at a size of about 100 mg, mice were treated with
`CCI-779 or a vehicle control. Treatment with CCI-779 at 25
`mg/kg resulted in significant inhibition of tumor cell growth
`in the mice (Table 2).
`
`4
`The following summarizes the results that were obtained:
`In patients having renal cancer on the weekly schedule, 1
`partial response (~50% reduction in tumor size) and 2 minor
`responses (~25% but<50% reduction in tumor size) were
`observed. In renal cancer patients on the dailyx5 schedule, 1
`minor response, 1 unconfirmed minor response, and 1 stable
`disease ( <25% increase to <25% reduction in tumor size)
`lasting approximately 5 months were observed. In patients
`having soft tissue sarcoma on the dailyx5 dosage schedule, 1
`possible partial response, 2 minor responses, and 1 stable
`disease lasting approximately 51h months were observed. In
`patients with breast cancer on the weekly dosage schedule,
`one partial response was observed. In patients with neuroen(cid:173)
`docrine tumor of the lung on the weekly dosage schedule, one
`partial response was observed. In patients having cervical
`cancer on the dailyx5 dosage schedule, one minor response
`was observed. In patients having uterine cancer receiving the
`
`10
`
`15
`
`TABLE2
`
`Effect of CCI-779 on the growth of human renal tumor cells in nude mouse xenografts
`
`Cell Drug
`
`Tumor Mass (mg)
`Da s
`
`Line Treatment
`
`0
`
`7
`
`21
`
`35
`
`49
`
`55
`
`HTB- Control
`44
`CCI
`%TIC
`CRL- Control
`1161 CCI
`%TIC
`
`288 ± 21
`290 ± 15
`101
`273 ± 18
`272 ± 14
`100
`
`616 ± 55
`219 ± 18
`156 ± 13* 252 ± 48*
`71
`41
`355 ± 36
`413 ± 60
`219 ± 16* 226 ± 17*
`62
`60
`
`1095 ± 44
`453 ± 85*
`41
`480 ± 127
`200 ± 21 *
`42
`
`2412 ± 342
`2033 ± 247
`980 ± 155* 1050 ± 183*
`48
`44
`546 ± 170
`507 ± 156
`229 ± 28*
`268 ± 30
`42
`53
`
`*p value - <.05
`% TIC -Treated/Control x 100
`
`35
`
`Clinical Trial:
`Two single agent (CCI-779) Phase I clinical trials have
`been conducted. In the first study, CCI-77 9 was administered
`as a 30 minute i.v. infusion daily for 5 days, every two to three
`weeks. In the second study, CCI-779was administered as a 30
`minute i.v. infusion, once weekly. Both trials were open label,
`ascending dose, single-arm, multicenter studies. Patients
`were allowed to continue treatment as long as the CCI-779
`was tolerated and there was no evidence of obvious disease
`progression. The following eligibility criteria were used:
`Inclusion Criteria
`1. Patients with a histologic diagnosis of advanced cancer
`(solid tumors and, in the first study, lymphomas) who are
`refractory to standard therapy or for whom standard
`therapy is not appropriate.
`2. Measurable or evaluable disease.
`3. At least 3 weeks since prior chemotherapy and/or radia(cid:173)
`tion therapy (6 weeks since nitrosoureas or mitomycin
`C).
`4. At least 4 weeks since any other investigational agent.
`5. Age at least 18 years old.
`6. Adequate bone marrow, renal, and hepatic function.
`7. Serum cholesterol<350 mg/dL and triglycerides 1300
`mg/dL.
`8. ECOG performance status 0-2.
`9. Life expectancy of at least 3 months.
`10. Signed, dated, witnessed written informed consent.
`A total of 63 patients and 24 patients were enrolled in first
`and second studies, respectively. Dose levels ranged from
`0.75-24 mg/m2 and 7.5-220mg/m2
`, with the dailyx5 every 2
`weeks and weekly schedules, respectively.
`
`50
`
`dailyx5 dosage schedule, one unconfirmed minor response
`was observed. In patients having head and neck cancer receiv(cid:173)
`ing the dailyx5 dosage schedule, I stable disease for approxi(cid:173)
`mately 81h months was observed. In patients having non-
`40 small cell lung cancer receiving the dailyx5 dosage schedule,
`one partial response was observed. These results are particu(cid:173)
`larly surprising, considering that the patients in these studies
`had advanced cancers that were generally refractory to stan-
`45 dard treatment, and also considering that these were Phase I
`clinical trials, in which efficacy is often limited, as the pri(cid:173)
`mary objective of a Phase I trial is to determine the safety and
`tolerability of the drug being evaluated.
`Based on the results of the preclinical and clinical test
`procedures, CCI-779 is useful in treating neoplasms, in par(cid:173)
`ticular, refractory neoplasms. More particularly, CCI-779 is
`useful in the treatment of renal carcinoma, soft tissue carci(cid:173)
`noma, breast cancer, neuroendocrine tumor of the lung, cer(cid:173)
`vical cancer, uterine cancer, head and neck cancer, glioblas-
`55 toma, non-small cell lung cancer, prostate cancer, pancreatic
`cancer, lymphoma, melanoma, small cell lung cancer, ovarian
`cancer, endometrial cancer, and colon cancer.
`As typical with chemotherapy, dosage regimens are closely
`monitored by the treating physician, based in numerous fac-
`60 tors including the severity of the disease, response to the
`disease, any treatment related toxicities, age, and health of the
`patient. Based on the results obtained with CCI-779, it is
`projected that initial i.v. infusion dosages will be between
`about 0.1and100 mg/m2 when administered on a daily dos-
`65 age regimen, and between about 1 and 1000 mg/m2 when
`administered on a weekly dosage regimen. Other dosage regi(cid:173)
`mens and variations are foreseeable, and will be determined
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 004
`
`

`

`US 7,781,446 B2
`
`5
`through physician guidance. It is preferred that CCI-779 is
`administered by i.v. infusion or orally, preferably in the form
`of tablets or capsules. Other routes of administration are also
`feasible, such as via implants, parenterally (besides i.v., such
`as intraperitoneal and subcutaneous injections), rectally,
`intranasally, vaginally, and transdermally.
`Dosage regimens are expected to vary according to the
`route of administration. For example, dosages for oral admin(cid:173)
`istration are often up to tenfold greater than for i.v. adminis(cid:173)
`tration. It is anticipated that CCI-779 may be administered as 10
`the sole active chemotherapeutic agent, or may be part of a
`chemotherapeutic regimen containing more than one antine(cid:173)
`oplastic agent. The use of concomitant chemotherapeutic
`agents often allows for dosage reduction of each particular
`agent, thereby increasing the safety margin of the particular 15
`agents.
`Oral formulations containing the active compounds of this
`invention may comprise any conventionally used oral forms,
`including tablets, capsules, buccal forms, troches, lozenges
`and oral liquids, suspensions or solutions. Capsules may con- 20
`tain mixtures of the active compound(s) with inert. fillers
`and/or diluents such as the pharmaceutically acceptable
`starches (e.g. com, potato or tapioca starch), sugars, artificial
`sweetening agents, powdered celluloses, such as crystalline
`and microcrystalline celluloses, flours, gelatins, gums, etc. 25
`Useful tablet formulations may be made by conventional
`compression, wet granulation or dry granulation methods and
`utilize pharmaceutically acceptable diluents, binding agents,
`lubricants, disintegrants, surface modifying agents (including
`surfactants), suspending or stabilizing agents, including, but 30
`not limited to, magnesium stearate, stearic acid, talc, sodium
`lauryl sulfate, microcrystalline cellulose, carboxymethylcel(cid:173)
`lulose calcium, polyvinylpyrrolidone, gelatin, alginic acid,
`acacia gum, xanthan gum, sodium citrate, complex silicates,
`calcium carbonate, glycine, dextrin, sucrose, sorbitol, dical- 35
`cium phosphate, calcium sulfate, lactose, kaolin, mannitol,
`sodium chloride, talc, dry starches and powdered sugar. Pre(cid:173)
`ferred surface modifying agents include nonionic and anionic
`surface modifying agents. Representative examples of sur(cid:173)
`face modifying agents include, but are not limited to, polox- 40
`amer 188, benzalkonium chloride, calcium stearate, ceto(cid:173)
`stearl alcohol, cetomacrogol emulsifying wax, sorbitan
`esters, colloidal silicon dioxide, phosphates, sodium dodecyl(cid:173)
`sulfate, magnesium aluminum silicate, and triethanolamine.
`Oral formulations herein may utilize standard delay or time 45
`release formulations to alter the absorption of the active com(cid:173)
`pound(s ). The oral formulation may also consist of adminis(cid:173)
`tering the active ingredient in water or a fruit juice, containing
`appropriate solubilizers or emulsifiers as needed.
`In some cases it may be desirable to administer the com- 50
`pounds directly to the airways in the form of an aerosol.
`The compounds of this invention may also be administered
`parenterally or intraperitoneally. Solutions or suspensions of
`these active compounds as a free base or pharmacologically
`acceptable salt can be prepared in water suitably mixed with 55
`a surfactant such as hydroxy-propylcellulose. Dispersions
`can also be prepared in glycerol, liquid polyethylene glycols
`and mixtures thereof in oils. Under ordinary conditions of
`storage and use, these preparations contain a preservative to
`prevent the growth of microorganisms.
`
`6
`The pharmaceutical forms suitable for injectable use
`include sterile aqueous solutions or dispersions and sterile
`powders for the extemporaneous preparation of sterile inject(cid:173)
`able solutions or dispersions. In all cases, the form must be
`sterile and must be fluid to the extent that easy syringability
`exists. It must be stable under the conditions of manufacture
`and storage and must be preserved against the contaminating
`action of microorganisms such as bacteria and fungi. The
`carrier can be a solvent or dispersion medium containing, for
`example, water, ethanol, polyol (e.g., glycerol, propylene
`glycol and liquid polyethylene glycol), suitable mixtures
`thereof, and vegetable oils.
`For the purposes of this disclosure, transdermal adminis(cid:173)
`trations are understood to include all administrations across
`the surface of the body and the inner linings of bodily pas(cid:173)
`sages including epithelial and mucosa! tissues. Such admin(cid:173)
`istrations may be carried out using the present compounds, or
`pharmaceutically acceptable salts thereof, in lotions, creams,
`foams, patches, suspensions, solutions, and suppositories
`(rectal and vaginal).
`Transdermal administration may be accomplished through
`the use of a transdermal patch containing the active com(cid:173)
`pound and a carrier that is inert to the active compound, is non
`toxic to the skin, and allows delivery of the agent for systemic
`absorption into the blood stream via the skin. The carrier may
`take any number of forms such as creams and ointments,
`pastes, gels, and occlusive devices. The creams and ointments
`may be viscous liquid or semisolid emulsions of either the
`oil-in-water or water-in-oil type. Pastes comprised of absorp(cid:173)
`tive powders dispersed in petroleum or hydrophilic petroleum
`containing the active ingredient may also be suitable. A vari(cid:173)
`ety of occlusive devices may be used to release the active
`ingredient into the blood stream such as a semi-permeable
`membrane covering a reservoir containing the active ingredi(cid:173)
`ent with or without a carrier, or a matrix containing the active
`ingredient. Other occlusive devices are known in the litera(cid:173)
`ture.
`Suppository formulations may be made from traditional
`materials, including cocoa butter, with or without the addition
`of waxes to alter the suppository's melting point, and glyc(cid:173)
`erin. Water soluble suppository bases, such as polyethylene
`glycols of various molecular weights, may also be used.
`
`The invention claimed is:
`1. A method of treating a refractory neoplasm in a mammal
`in need thereof, which comprises providing to said mammal
`a therapeutically effective amount ofCCI-779, wherein said
`mammal has been previously treated with standard chemo(cid:173)
`therapy and wherein said refractory neoplasm has progressed
`following
`treatment with said standard chemotherapy,
`wherein said refractory neoplasm is renal cancer.
`2. A method of reducing the size of a refractory human
`renal cell tumor in a human patient, which comprises provid(cid:173)
`ing to said human patient a therapeutically effective amount
`of CCI-779, wherein said human patient has been previously
`treated with standard chemotherapy and wherein said refrac(cid:173)
`tory human renal cell tumor has progressed following treat(cid:173)
`ment with said standard chemotherapy.
`
`* * * * *
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 005
`
`

`

`33 Terrace Drive, Westwood, NewJersey, 07675 Dukart
`
`RESIDENCE
`(CITY, AND EITHER STATE OR FOREIGN
`COUNTRY)
`1714 Benjamin Drive, Ambler, Pennsylvania, 19002
`
`A.
`
`509 Covington Road, Havertown, Pennsylvania, 19083
`4 Emerson Court, Morris Township, New Jersey, 07940
`8 Brookside Avenue, Cortlandt Manor, New York, 10567
`
`
`
`=u.
`
`foo»
`
`i
`
`fs
`
`/—/ 6-0O
`S==6
`PROVISIONAL APPLICATION FOR PATENT
`Sr
`eS
`This is a request for filing a PROVISIONAL APPLICATIONFOR PATENTunder 37 CFR 1.53(b)(2)
`4S GS
`3Sa
`
`
`a Docket Number|AM100466 Type a plus + _
`=v
`sign (+) inside
`=>
`—
`a ~ =>=
`S eee==
`="
`? =
`=
`
`LAST NAME
`
`Gibbons, Jr.
`Speicher
`Frost
`Discafani-Marro
`
`Gary
`James
`Lisa
`Philip
`Carolyn
`
`TITLE OF THE INVENTION (280 characters max)
`
`USE OF CCI-779 AS AN ANTINEOPLASTIC AGENT
`
`CORRESPONDENCE ADDRESS
`
`: \
`
`.
`American Home Products Corporation
`Patent Law Department-2B
`
`
`
`i|| Other (specify)
`
`Certificate of Mailing
`
`METHOD OF PAYMENT(check one)
`|| A check or money order is enclosed to cover the Provisional filing fees
`
`PROVISIO
`xX|The Commissioner is hereby authorized to charge
`NAL
`
`filing fees and credit deposit account Number:
`
`O1-1425
`
`FILING
`FEE($)
`
`$150.00
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the
`United States Government.
`
`Yes, the name of the U.S. Government agency and the Government contract numberare:
`
`Respectfully submitted,
`
`SIGNATURE
`
`November 15, 2000
`
`35,288
`
`TYPED OR PRINTED NAME ARNOLD S. MILOWSKY
`
`REG. NO.
`
`TELEPHONE
`[J
`
`(610) 902-2635
`
`Additional inventors are being named on separately numbered sheets attached hereto.
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 006
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 006
`
`

`

`15 November 2000
`2ED1:0CO:ASM:asm
`AM100446
`PATENT
`
`
`
`USE OF CCI-779 AS AN ANTINEOPLASTIC AGENT
`
`BACKGROUND OF THE INVENTION
`This invention relates to the use of rapamycin 42-ester with 3-hydroxy-2-
`(hydroxymethyl)-2-methylpropionic acid (CCI-779) as an antineoplastic agent.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces
`hygroscopicus, which was found to have antifungal activity, particularly against
`Candida albicans, both in vitro and in vivo [C. Vezina et al., J. Antibiot. 28, 721
`(1975); S.N. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Bakeret al., J. Antibiot.
`31, 539 (1978); U.S. Patent 3,929,992; and U.S. Patent 3,993,749]. Additionally,
`rapamycin alone (U.S. Patent 4,885,171) or in combination with picibanil
`(U-S.
`Patent 4,401,653) has been shown to have antitumoractivity.
`The immunosuppressive effects of rapamycin have been disclosed in FASEB
`3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules, also have
`been shown to be effective as immunosuppressive agents,
`therefore useful
`in
`preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989): R.
`Y. Calne et al., Lancet 1183 (1978); and U.S. Patent 5,100,899]. R. Martel et al.
`[Can. J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that rapamycin is effective in
`the experimental allergic encephalomyelitis model, a model for multiple sclerosis; in
`the adjuvant arthritis model, a model for rheumatoid arthritis; and effectively
`inhibited the formation of IgE-like antibodies.
`lupus
`treating systemic
`Rapamycin is
`also useful
`in preventing or
`erythematosus [U.S. Patent 5,078,999], pulmonary inflammation [U.S. Patent
`5,080,899],
`insulin dependent diabetes mellitus
`[U.S. Patent 5,321,009],
`skin
`disorders, such as psoriasis [U.S. Patent 5,286,730], bowel disorders [U.S. Patent
`5,286,731], smooth muscle cell proliferation and intimal
`thickening following
`vascular
`injury
`[U.S.
`Patents
`5,288,711
`and
`5,516,781],
`adult T-cell
`leukemia/lymphoma[European Patent Application 525,960 A1], ocular inflammation
`[U.S. Patent 5,387,589], malignant carcinomas [U.S. Patent 5,206,018], cardiac
`inflammatory disease [U.S. Patent 5,496,832], and anemia [U.S. Patent 5,561,138].
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 007
`
`West-Ward Exhibit 1040
`Dukart USP '446
`Page 007
`
`

`

`15 November 2000
`2ED2:0CO:ASM:asm
`AM100446
`PATENT
`
`-2-
`
`The preparation and use of hydroxyesters of rapamycin, including CCI-779,
`
`are disclosed in U.S. Patent 5,362,718.
`
`DESCRIPTION OF THE INVENTION
`
`This invention provides the use of CCI-779 as an antineoplastic agent, and
`particularly for neoplasms which are refractory to standard therapy, or for whom
`standard therapy is not appropriate.
`In particular CCI-779 is useful in the treatment
`
`of renal cancer, soft tissue cancer, breast cancer, neuroendocrine tumor of the lung,
`cervical cancer, uterine cancer, head and neck cancer, glioblastoma, non-small lung
`cell cancer, prostate cancer, pancreatic cancer, lymphoma, melanoma, small cell lung
`
`cancer, ovarian cancer, colon cancer.
`
`As used in accordance with this invention,
`
`the term "treatment" means
`
`treating a mammal having a neoplastic disease by providing said mammal an
`effective amount of CCI-779 with the purpose of inhibiting growth of the neoplasm
`in such mammal, eradication of the neoplasm,or palliation of the neoplasm.
`
`As used in accordance with this invention, the term “providing,” with respect
`to providing CCI-779, meanseither directly administering CCI-779, or administering
`a prodrug, derivative, or analog which will form an effective amount of CCI-779
`
`within the body.
`
`the term "refractory neoplam"
`As used in accordance with this invention,
`refers to neoplasms in patients which typically h