(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`Intcrn an ona] B urcau
`
`(43) International Publication Date
`23 May 2002 (23.05.2002)
`
`(10) International Publication Number
`
`PCT
`
`W0 02/40000 A2
`
`(51) International Patent ('Ilassi1ication7:
`
`A6lK 3 H00
`
`(21) InternationalApplication Number:
`
`PCT/US01/47324
`
`(22) International Filing Date:
`13 November 2001 (13.11.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/249,077
`
`15 November 2000 (15.11.2000)
`
`US
`
`(71) Applicant: WYETII |,llS/1JS];l*"ive (Jira1dal‘arms, Madi-
`son, NJ 0794041874 (US).
`
`(72) Inventors: DUKART, Gary; 1714 Benjaniin Drive, An1—
`hler, PA 19002 (US). GIBBONS, James, Joseph, .|r.; 33
`Tc1'rncc Drive, Wcstwood, NJ 07675 (US). SPEICHER,
`Lisa, Anne; 509 Covington Road, Havertown. PA 19083
`(US). FROST, Philip; 4Emcrson Court, Morris Township,
`NJ 07960 (US). DISCAFANLMARRO, Carolyn, Mary;
`8 Brookside Avenue, Cortlandt Manor, NY 10567 (US).
`
`(81) Designated States (national): AH, AG, A1,, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, M7,, N(), N'/,, OM, PI], PI,, PT, RO, RU, SI), SH, SG,
`31, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU,
`ZA. ZW.
`
`Designated States (regional): ARIPO patent (GH, GM,
`KB,
`MW, M7,, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FL FR, GB, GR, IE,
`11', LU, MC, NL, my SH, '11:), ()API patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`SN, TD,
`TG),
`
`Declarations under Rule 4.17:
`— as to opplicanfls entixlanzent to applyfor and be granted a
`patent (Rule 4.l7('il,U_/or all dwignatlons
`as to the applicarzt ’s crztitlcnwnt to claim the priority oftlze
`earlier application (Rule 4. l 7(i'izf)) for all designations
`
`~«
`
`Published:
`without international Search report and to be republished
`upon receipt oflhal report
`
`Agents: MILOWSKY, Arnold, S.; Wyeth, Patent Law
`Department, Five Gi1‘fl1(iHF{11‘l11S, Madison, NJ 07940 0874
`et al. (US).
`
`For two-letter cocles and other abbrewations, re;/lzr to the "Guid-
`ance Notes on Codes andAblrreviatians " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`02/40000A2
`
`Q (54) Title: USE OF CCL779 AS AN ANTINEOPLASTIC AGENT
`B (57) Abstract: This invention provides the use ofCCI—779 in the treatment of neoplasms.
`
`West-Ward Phar
`Exhibit 10'
`Page 0
`
`West-Ward Pharm.
`Exhibit 1054
`Page 001
`
`

`

`wo 02/40000
`
`PCT/US01/47324
`
`USE OF CCI-779 AS AN ANTINEOPLASTIC AGENT
`
`This invention relates to the use of rapamycin 42-ester with 3-hydroxy~2-
`
`(hydroxymethyl)~2—methy1propionic acid (CCL779) as an antineoplastic agent.
`
`Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces
`
`hygroscopicus, which was found to have antifungal activity, particularly against
`
`Candida albicans, both in v_it_rg and in _\:_i_'»_7_o_ [C. Vezina et al., J. Antibiot. 28, 721
`
`(1975); SN. Sehgal et al., J. Antibiot. 28, 727 (1975); H. A. Baker et al., J. Antibiot.
`
`31, 539 (1978); U.S. Patent 3,929,992; and U.S. Patent 3,993,749]. Additionally,
`
`rapatnycin alone (U.S. Patent 4,885,171) or in combination with picibanil (US.
`
`Patent 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 innnunosuppressive agents,
`
`therefore useful
`
`in
`
`preventing transplant rejection [FASEB 3, 3411 (1989); FASEB 3, 5256 (1989); R.
`
`Y. Calne et al., Lancet 1183 (1978); and US. Patent 5,100,899]. R. Martel et al. [Can.
`
`J. Physiol. Pharmacol. 55, 48 (1977)] disclosed that raparnycin is effective in the
`
`experimental allergic encephalomyelitis model, a model for multiple sclerosis; in the
`
`adjuvant arthritis model, a model for rheumatoid arthiitis; and effectively inhibited
`
`the fonnation of IgE-like antibodies.
`
`Rapamycin is
`
`also useful
`
`in preventing or
`
`treating systemic
`
`lupus
`
`erythematosus
`
`[U.S. Patent 5,078,999], pulmonary inflainmation [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 intirnal
`
`thickening following
`
`vascular injmy [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 Pharm.
`Exhibit 1054
`Page 002
`
`

`

`WO 02/40000
`
`PCT/USOI/47324
`
`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 CCL779 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—77.9 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
`
`C3.l'1C61', ovarian cancer, COIOII C'c1I1C6I'.
`
`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, means either directly administering CCI—779, or administering
`
`l a prodrug, derivative, or analog which will form an effective amount of CCL779
`
`within the body.
`
`As used in accordance with this invention, the term, "refractory neoplasm"
`
`refers to neoplasms in patients which typically had progressed following treatment
`
`with standard chemotherapy that was appropriate for that given neoplasm.
`
`The preparation of CCL779 is described in US. Patent 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
`
`cg-
`
`West-Ward Pharm.
`Exhibit 1054
`Page 003
`
`

`

`WO 02/40000
`
`PCT/US01/47324
`
`CCI-779 to treat human renal cell cancer (a rapidly progressive disease with very
`
`limited treatment options), as well as in two Phase I human clinical trials. The
`
`procedures used and results obtained are briefly described below.
`
`Preclinical Test Procedures
`
`In vitro test procedure: Renal tumor lines I-ITB—44 and CRl_r1l61 were
`
`obtained from the American Tissue Culture Collection (ATCC), Bethesda, MD.
`
`SN12-C line was obtained from Dr. J. Fidler, M.D. Anderson Hospital, Houston, TX.
`
`Cells were plated in MEM (Gibco) supplemented with 2 111M glutamine,
`
`1 mM
`
`sodium pyruvatc, 5 ml penicillin—streptomyc'1n solution, 1 mM non~essential amino
`
`acid solution, 10% fetal bovine solution. Cells (5 X 103) were plated in 96 well plates
`
`with a final Volume of 200 ml and incubated for 24 hours at 37°C. Log dilutions of
`
`CCI~779 beginning at 100 ug/ml were then added to the cultures for 48 hours. Over
`
`the last 5 hours, cells were pulsed with 1 uci 3H—thyn1idine (New England Nuclear,
`
`6.7 ci/m Mol). Cells were then harvested and the degree of thymidine uptake
`
`determined by liquid scintillation spectrometry. The IC50 was determined as the
`
`concentration that produced 50% of the maximum uptake of thymidine in control
`
`untreated cells.
`
`In vivo test procedure: Female Balb/c nu/nu mice were obtained from Charles
`
`River Labs, Wilmington, DE, at 6-8 weeks of age. Mice (n=10/group)wcrc injected
`
`so with 5 X 106 cells resuspended in a 50% solution Of Matrigel (BD Biosciences) and
`
`tumors allowed to develop. When tumor size reached 100 mg, mice were treated
`
`orally with CCL779 at 25 mg/kg. CCI~779 was dosed for 5 consecutive days with
`
`repeated 14 day cycles throughout the duration of the experiment. 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 (1 X W X h) was converted to mass using the formula:
`
`1 X W2 / 2.
`
`West-Ward Pharm.
`Exhibit 1054
`Page 004
`
`

`

`WO 02/4000()
`
`PCT/USO'l/47324
`
`i1S_e_§.1.1_1t§=
`
`Human renal cell tumors were cultured in vitro in the presence or absence of
`
`CCL779 for 3 days and the effect on growth determined by 3H—thymidine
`
`incorporation of control versus treated cells. Table 1 shows that IC5o (50% growth
`
`inhibitory concentration) for all 3 lines tested was in the low nM range.
`
`Table 1 The effect of CCI-779 on the growth of human renal tumor cells in vitro
`
`Renal Tumor Line
`
`CCI—779 IC__w tnML
`
`I-ITB~44
`CRL-1161
`SNl2—C
`
`5.0
`2.0
`5.5
`
`The effect of CCI-779 in two human renal lines (HTB—44 and CRL—l 161)
`
`were was evaluated in vivo by engrafting tumor cells on the flanks of nude mice. Once
`
`tumors were established 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).
`
`Table 2 Effect of CCI~779 on the growth of human renal tumor cells in nude mouse
`xeuogratts
`
`Cell Line
`
`HTB—44
`
`Drug
`Treatment
`
`0
`
`Control
`CCI
`%T/C
`
`Control
`CCI
`
`% T/C
`
`288i21
`290::l5
`101
`
`2'/3i18
`272i] 4
`
`100
`
`* p value — < .05
`% T/C - Treated/Control x 100
`
`20
`
`Tumor Mass (L15)
`Days
`
`21
`
`35
`
`49
`
`55
`
`616i55
`252i48*
`41
`
`lO95:l:44
`453:t:85"'“
`41
`
`2033212247
`980::l55*
`48
`
`2412:I:3 42
`lO50:t:l83*
`44
`
`413:k60
`226:l:l7*
`
`480:|~.127
`200:l:2 1 *
`
`546:|:l70
`229:l:28*
`
`507:'r:l56
`268:t:30
`
`60
`
`42
`
`.
`
`42
`
`53
`
`West-Ward Pharm.
`Exhibit 1054
`Page 005
`
`

`

`W0 02/4000!)
`
`PCT/USO I/47324
`
`Clinical Trial:
`
`Two single agent (CCI-779) Phase I clinical trials have been conducted. In the
`
`first study, CCI~779 was administered as a 30 minute i.v. infusion daily for 5 days,
`
`every two to three weeks.
`
`In the second study, CCI—779 was 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 CCL779 was tolerated and there was no evidence of obvious disease
`
`progression. The following eligibility criteria were used:
`
`Inclusion Criteria
`
`. 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.
`
`. At least 3 weeks since prior chemotherapy and/or radiation therapy (6 weeks
`
`since nitrosoureas or mitomycin C).
`
`. At least 4 weeks since any other investigational agent.
`
`. Age at least 18 years old.
`
`. Adequate bone marrow, renal, and hepatic function.
`
`. Serum cholesterol 3 350 mg/dL and triglycerides S 300 mg/dL.
`
`. ECOG performance status 0-2.
`
`. Life expectancy of at least 3 months.
`
`10. Signed, dated, witnessed written informed consent.
`
`A total of 63 patients and 24 patients were emolled in first and second studies,
`
`respectively. Dose levels ranged from 0.75~24 mg/I112 and 75-220 mg/m2, with the
`
`daily x 5 every 2 weeks and weekly schedules, respectively.
`
`The following summarizes the results that were obtained:
`
`In patients having renal cancer on the Weekly schedule, 1 partial response (2
`
`50% reduction in tumor size) and 2 minor responses (2 25% but < 50% reduction in
`
`25
`
`30
`
`West-Ward Pharm.
`Exhibit 1054
`Page 006
`
`

`

`WO 02/40000
`
`PCT/USOI/47324
`
`tumor size) were observed. In renal cancer patients on the daily x 5 schedule, 1 minor
`
`response, 1 unconfirmed minor response, and l stable disease (< 25% increase to <
`
`25% reduction in tumor size) lasting approximately 5 months were observed.
`
`In I
`
`patients having sot’: tissue sarcoma on the daily x 5 dosage schedule, 1 possible partial
`
`response, 2 minor responses, and 1 stable disease lasting approximately 5% months
`
`were observed.
`
`In patients with breast cancer on the weekly dosage schedule, one
`
`partial response was observed.
`
`In patients with neuroendocrine tumor of the lung on
`
`the weekly dosage schedule, one partial response was observed.
`
`In patients having
`
`cervical cancer on the daily X 5 dosage schedule, one minor response was observed.
`
`In patients having uterine cancer receiving the daily x 5 dosage schedule, one
`
`unconfirrned minor response was observed.
`
`In patients having head and neck cancer
`
`receiving the daily x 5 dosage schedule, 1 stable disease for approximately 8‘/2 months
`
`was observed.
`
`In patients having non-small cell lung cancer receiving the daily X 5
`
`dosage schedule, one partial response was observed. These results are particularly
`
`surprising, considering that the patients in these studies had advanced cancers that
`
`were generally refractory to standard treatment, and also considering that these were
`
`Phase I clinical trials, in which efficacy is often limited, as the primary 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 particular, refractory neoplasms. More particularly,
`
`CCI-779 is useful in treating treatment of renal carcinoma, soft tissue carcinoma,
`
`breast cancer, ncuroendocrine tumor of the lung, cervical cancer, uterine cancer, head
`
`and neck cancer, glioblastoma, non—small cell lung cancer, prostate cancer, pancreatic
`
`lymphoma, melanoma, small cell lung cancer, ovarian cancer, and colon
`
`cancer,
`C¢’:l.l’lC6I'.
`
`As typical with chemotherapy, dosage regimens are closely monitored by the
`
`treating physician, based on numerous factors including the severity of the disease,
`
`response to the disease, any treatment related toxicities, age, and health of the patient.
`
`West-Ward Pharm.
`Exhibit 1054
`Page 007
`
`

`

`WO 02/40000
`
`PCT/USOI/47324
`
`Based on the results obtained with CCL779, it is projected that initial i.v. infusion
`
`dosages will be between about 0.1 and 100 mg/m2 when administered on a daily
`
`dosage regimen, and between about 1 and 1000 mg/m2 when administered on a
`
`weekly dosage regimen. Other dosage regimens and variations are foreseeable, and
`
`will be determined 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 administration are often up to tenfold greater than for
`
`i.V. administration.
`
`It is anticipated that CCI-779 may be administered as the sole
`
`active chemotherapeutic agent, or may be part of a chemotherapeutic regimen
`
`containing more than one
`
`antineoplastic
`
`agent.
`
`The use of concomitant
`
`chemotherapeutic agents often allows for dosage reduction of each particular agent,
`
`thereby increasing the safety margin of the particular 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
`
`contain mixtures of the active con1pound(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. 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 not limited to, magnesium stearate, stearic acid, talc,
`
`sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium,
`
`polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate,
`
`complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium
`
`West-Ward Pharm.
`Exhibit 1054
`Page 008
`
`

`

`WO 02/40000
`
`PCT/USOI/47324
`
`phosphate, calcium sulfate,
`
`lactose, kaolin, mannitol, sodium chloride,
`
`talc, dry
`
`starches and powdered sugar. Preferred surface modifying agents include nonionic
`
`and anionic surface modifying agents. Representative examples of surface modifying
`
`agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium
`
`stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol
`
`silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate,
`
`and triethanolamine. Oral formulations herein may utilize standard delay or time
`
`release formulations to alter the absorption of the active compound(s). The oral
`
`formulation may also consist of administering the active ingredient in water or a fruit
`
`10
`
`juice, containing appropriate solubilizers or emulsifiers as needed.
`
`In some cases it may be desirable to administer the compounds directly to the
`
`airways in the form of an aerosol.
`
`The compounds of this invention may also be administered parenterally or
`
`intraperitoncally. Solutions or suspensions of these active compounds as a free base
`
`or pharmacologically acceptable salt can be prepared in water suitably mixed with a
`
`surfactant such as hydroxy—propy1cel1_ulosc. Dispersions can also be prepared in
`
`glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary
`
`conditions of storage and use, these preparation contain a preservative to prevent the
`
`growth of microorganisms.
`
`The pharmaceutical forms suitable for injectable use include sterile aqueous
`
`solutions or dispersions and sterile powders for the extemporaneous preparation of
`
`sterile injectable 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 administrations
`
`are
`
`understood to include all administrations across the surface of the body and the inner
`
`West-Ward Pharm.
`Exhibit 1054
`Page 009
`
`West-Ward Pharm.
`Exhibit 1054
`Page 009
`
`

`

`WO 02/40000
`
`PCT/USOI/47324
`
`linings of bodily passages
`
`including epithelial and mucosal
`
`tissues.
`
`Such
`
`administrations 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
`
`transdennal patch containing the active compound and a cairier 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 ointrnents may be viscous liquid or semisolid emulsions of either the
`
`oi1—in-watcr or water-in-oil type. Pastcs comprised of absorptive powders dispersed
`
`in petroleum or hydrophilic petroleum containing the active ingredient may also be
`
`suitable. A variety 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 ingredient with or without a carrier, or a matrix containing the
`
`active ingredient. Other occlusive devices are known in the literature.
`
`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 glycerin. Water soluble suppository bases, such as polyethylene glycols of
`
`various molecular weights, may also be used.
`
`West-Ward Pharm.
`Exhibit 1054
`Page 010
`
`

`

`WO 02/40000
`
`PCT/USOI/47324
`
`1.
`
`A method of treating a neoplasm in a mammal in need thereof, which
`
`comprises providing to said mammal an effective amount of CCI-779.
`
`2.
`
`A method of treating a refractory neoplasm in a mammal in need
`
`thereof, which comprises providing to said mammal an effective amount of CCI~779.
`
`The method according to claim 1, wherein the neoplasm is renal cancer.
`
`4.
`sarcoma.
`
`The method according to claim 1, wherein the neoplasm is soft tissue
`
`The method according] to claim 1, wherein the neoplasm is breast
`
`6.
`
`The method according to claim 1, wherein the neoplasm is a
`
`neuroendocrine tumor of the lung.
`
`7.
`
`The method according to claim 1, wherein the neoplasm is cervical
`
`cancer.
`
`03110 81‘.
`
`9.
`neck cancer.
`
`The method according to claim 1, wherein the neoplasm is uterine
`
`The method according to claim 1, wherein the neoplasm is a head and
`
`10.
`
`The method according to claim 1, wherein the neoplasm is
`
`glioblastorna.
`
`West-Ward Ph .
`Exhibit 1
`Page
`
`West-Ward Pharm.
`Exhibit 1054
`Page 011
`
`

`

`W0 02/4000!)
`
`PCT/USO I/47324
`
`11.
`
`The method according to claim 1, wherein the neoplasm is non-small
`
`cell lung cancer.
`
`12.
`
`14.
`
`15.
`
`16.
`
`lung cancer.
`
`17.
`
`18.
`
`19.
`
`Cancer.
`
`The method according to claim 1, wherein the neoplasm is prostate
`
`The method according to claim 1, wherein the neoplasm is pancreatic
`
`The method according to claim 1, wherein the neoplasm is lymphoma.
`
`The method according to claim 1, wherein the neoplasm is melanoma.
`
`The method according to claim 1, wherein the neoplasm is small cell
`
`The method according to claim 1, wherein. the neoplasm is ovarian
`
`The method according to claim 1, wherein the neoplasm is colon
`
`Use of rapamycin 42-ester with 3—hydroxy-2-(hydroxymethyl)-2-
`
`methylpropionic acid (CCI-779) in the preparation of a medicament for the treatment
`
`of a neoplasm in a mammal.
`
`20.
`
`Use of rapamycin 42~ester with 3-hydroXy~2—(hydroxymethyl)~2-
`
`methylpropionic acid (CCI-779) in the preparation of a medicament for the treatment
`
`of a refractory neoplasm in a mammal.
`
`West-Ward Pharm.
`Exhibit 1054
`Page 012
`
`West-Ward Pharm.
`Exhibit 1054
`Page 012
`
`

`

`WO 02/40000
`
`PCT/US01/47324
`
`21.
`
`Use according to claim 19 wherein the neoplasm is renal cancer, soft
`
`tissue
`
`sarcoma, breast
`
`cancer, neuroendocrine tumor of the
`
`lung,
`
`cervical
`
`cancer,uterine cancer, head and neck cancer, glioblastoma, non~sma11 cell lung cancer,
`
`prostate cancer, pancreatic cancer,
`
`lymphoma, melanoma, small cell lung cancer,
`
`ovarian CZLIICGI.‘ 01‘ 601011 02111661‘.
`
`West-Ward Phar
`Exhibit 10
`
`West-Ward Pharm.
`Exhibit 1054
`Page 013
`
`