United States Patent [191
`Sehgal et al.
`
`[75]
`
`[54] USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`Inventors: Surendra N. Sehgal, Princeton, N.J.;
`Claude Vezina, Oka, Canada
`[73] Assignee: Ayerst, McKenna &: Harrison, Inc.,
`St. Laurent, Canada
`[21] Appl. No.: 784,274
`[22] Filed:
`Oct. 29, 1991
`
`Related U.S. Application Data
`[60] Continuation-in-part of Ser. No. 682,813, Apr. 9, 1991,
`Pat. No. 5,066,493, which is a continuation-in-part of
`Ser. No. 391,334, Aug. 9, 1989, abandoned, which is a
`division of Ser. No. 592,193, Mar. 22, 1984, Pat. No.
`4,885,171, which is a continuation of Ser. No. 126,276,
`Mar. 3, 1980, abandoned, which is a continuation of
`Ser. No. 957,626, Nov. 3, 1978, abandoned.
`Int. Cl.5 ..................... A61K 35/00; A61K 31/66;
`A61K 31/505; AOlN 57/00
`[52] U.S. Cl ..................................... 424/122; 514/110;
`514/274; 514/291
`[58] Field of Search ................ 424/122; 514/110, 274,
`514/291
`
`[51]
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,929,992 2/1976 Sehgal ................................. 424/122
`3,993,749 11/1976 Sehgal ................................. 424/122
`4,316,885 3/1982 Rakhi .................................. 424/122
`4,401,653 8/1983 Eng ..................................... 424/114
`4,650,803 3/1987 Stella et al .......................... 514/291
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US005206018A
`5,206,018
`[11] Patent Number:
`[45] Date of Patent: Apr. 27, 1993
`
`4,885,171 12/1989 Surendra et al .................... 424/122
`5,066,493 11/1991 Sehgal ................................. 424/122
`5,078,999 1/1992 Warner ............................... 424/122
`5,080,899 1/1992 Sturm .................................. 424/122
`
`OTHER PUBLICATIONS
`U.S. patent application. Ser. No. 07/717,773 filed Jun.
`18, 1991-(Miller).
`Abst. dist. at Fifth Intl Conf. of Inflamm. Res. Assoc.
`121, Sep. 23, 1990 (Baeder, W. L.).
`Vezina, C. J. Antibiot. 28, 721-726 (1975).
`Sehgal, S. J. Antibiot. 28, 727-732 (1975).
`Martel. R., Can J. Physiol. Pharmacol., 55, 48 (1977).
`Eng. C. J. Antibiotics 37:1231 (1984).
`FASEB 3:3411 (1989)-(Staruch, M. J.).
`FASEB 3:5256 (1989)-(Dumont, F. J.).
`Med. Sci. Res. 17:877 (1989)-(Morris, R.).
`
`Primary Examiner-Nathan M. Nutter
`Attorney, Agent, or Firm-Arnold S. Milowsky
`ABSTRACT
`[57]
`This invention provides a method of treating, inhibiting
`the proliferation of, reducing the size of, or eradicating
`malignant neoplasms in a mammal in need thereof
`which comprises administering an antineoplastic
`amount of rapamycin to said mammal. In particular,
`rapamycin is useful in treating, inhibiting the prolifera(cid:173)
`tion of, reducing the size of, or eradicating malignant
`mammary and skin carcinomas, and central nervous
`system neoplasms.
`
`12 Claims, No Drawings
`
`Breckenridge Exhibit 1052
`Sehgal '018 patent
`Page 001
`
`

`

`USE OF RAPAMYCIN IN TREATMENT OF
`TUMORS
`
`This a continuation-in-part application of co-pending
`application Ser. No. 07/682,813, filed Apr. 9, 1991 and
`now U.S. Pat. No. S,066,493, which in turn is a con(cid:173)
`tinuation-in-part application of co-pending application
`Ser. No. 07/391,334, filed Aug. 9, 1989 and now aban(cid:173)
`doned, which in. turn is a divisional application of co(cid:173)
`pending application Ser. No. 06/S92,193, filed on Mar.
`22, 1984, now issued as U.S. Pat. No. 4,88S,171, on Dec.
`S, 1989, which in turn is a continuation application of
`co-pending application Ser. No. 06/126,276, filed on
`Mar. 3, 1980, now abandoned, which in turn is a contin(cid:173)
`uation application of co-pending application Ser. No.
`OS/9S7,626, filed Nov. 3, 1978, now abandoned.
`
`SUMMARY OF THE INVENTION
`According to this invention a method is provided for
`treating malignant neoplasms in a mammal which com- 45
`prises administering to said mammal an antineoplastic
`amount of rapamycin. More specifically, rapamycin
`inhibits the proliferation of malignant cells, controls the
`growth of malignant neoplasms, reduces the size of
`malignant neoplasms, eradicates malignant neoplasms, 50
`prolongs the survival time of said mammal, kills malig(cid:173)
`nant cells, and adversely affects malignant cells.
`
`1
`
`5,206,018
`
`2
`formulate the compound in various dosage forms for
`oral or parenteral administration, e.g. tablets or sterile
`solutions. Such formulations are described in U.S. Pat.
`No. 3,929,992, cited above. Rapamycin may also be
`5 administered in combination with a therapeutically ef(cid:173)
`fective amount of an antineoplastic agent commonly
`used in cancer therapy.
`When the antifungal antibiotic of this invention is
`employed as an anticancer agent in warm-blooded ani-
`10 mals, e.g. rats, it may be used alone or in combination
`with a therapeutically effective amount of an antineo(cid:173)
`plastic agent commonly used in cancer therapy and
`with pharmaceutically acceptable carriers, the propor(cid:173)
`tion of which is determined by the solubility and chemi-
`15 cal nature of the compounds, chosen route of adminis(cid:173)
`tration and standard biological practice. For example,
`an antineoplastic effective amount of the antibiotic may
`be administered alone or in combination orally in solid
`BACKGROUND OF THE INVENTION
`form containing such excipients as starch, sugar, certain
`20 types of clay and so forth. Similarly, such an amount
`1. Field of the Invention
`This invention relates to the use of rapamycin as an
`may also be administered orally in the form of solutions
`anti-cancer or anti-tumor agent.
`or suspensions, or the antibiotic may be injected paren-
`terally alone or in combination. For parenteral adminis-
`2. Description of the Prior Art
`Rapamycin is an antifungal antibiotic described by C.
`tration the antibiotic may be used alone or in combina-
`Vezina et al., J. Antibiot., 28, 721 (197S), S. N. Sehgal et 25 tion in the form of a sterile solution or suspension con-
`al., J. Antibiot., 28, 727 (197S) and S. N. Sehgal et al.,
`taining other solutes or suspending agents, for example,
`U.S. Pat. No. 3,929,992, issued Dec. 30, 197S, filed Apr.
`enough saline or glucose to make the solution isotonic,
`12, 1974. Rapamycin is extracted from a streptomycete
`bile salts, acacia, gelatin, sorbitan monooleate, polysor-
`(Streptomyces hygroscopicus) isolated from an Easter
`bate 80 (oleate esters of sorbitol and its anhydrides co-
`Island soil sample and is particularly effective against 30 polymerized with ethylene oxide) and the like.
`Candida albicans both in vitro and in vivo.
`When utilizing rapamycin alone or in combination
`In addition, a recent report by R. R. Martel et al.,
`with a therapeutically effective amount of an antineo-
`Can. J. Physiol., SS, 48 (1977) describes the use ofrapa-
`plastic agent commonly used in cancer therapy for the
`mycin for the prevention of the development of two
`treatment of tumors, the total dose of active agent can
`experimental
`immunopathies [(experimental allergic 35 range from 0.01 to 2SO mg per kg of body weight per
`encephalomyelitis (EAE) and adjuvant arthritis (AA)].
`day with a preferred dosage range from 0.1 to SO mg per
`The latter report also describes the inhibitory effect of
`kg of body weight per day. However, as the dosage of
`rapamycin on the formation of humoral (lgE-like) anti-
`rapamycin to be administered by the method of this
`body. This report concludes that immunosuppressant
`invention will of course vary with the tumor or cancer
`activity of rapamycin appears to be related to inhibition 40 and tolerance of the mammal, and with the nature of the
`of the lymphatic system.
`other antineoplastic agents used in combination. The
`schedule of dosing can range from one to five times per
`day to a single dose given every two to ten days. In(cid:173)
`creasing the frequency of administration is expected to
`reduce the amount of active drug needed per dose. Such
`dosages and scheduling of administration must be deter-
`mined on an individual basis, depending upon the tumor
`or cancer, nutritional state of the mammal, age of the
`mammal, toxicity in each individual, and with the na(cid:173)
`ture of the other antineoplastic agents used in combina(cid:173)
`tion, etc.
`Rapamycin was evaluated in several National Cancer
`Institute standard tumor test procedures. The results
`showed that rapamycin reduces tumor size in and pro(cid:173)
`longs the survival time of tumor-bearing mammals.
`More specifically, rapamycin is useful for controlling
`the following carcinogenic tumors in standard mamma(cid:173)
`lian tumor models: lymphatic leukemia, colon, mam(cid:173)
`mary, melanocarcinoma and ependymoblastoma. The
`effectiveness of rapamycin in this respect was demon(cid:173)
`strated in the laboratory with rodents having trans-
`planted tumors. Details of methods used to evaluate this
`effect are described in various publications; for exam(cid:173)
`ple, R. I. Geran et al., Cancer Chemother. Rep., Part 3,
`3, (No. 2) 1-103 (1972) and references therein. In addi(cid:173)
`tion, the protocols for the antitumor tests are available
`from the National Cancer Institute, Bethesda, Md.,
`U.S.A. These models have been adopted by the Na-
`
`DETAILS OF THE INVENTION
`According to the present method, rapamycin is em- 55
`ployed as the active agent. The isolation and description
`of rapamycin is given in U.S. Pat. No. 3,929,992, cited
`above, herein incorporated by reference.
`Rapamycin is administered, either orally or parenter(cid:173)
`ally, to a carcinogenic tumor bearing mammal for the 60
`purpose of inhibiting the proliferation of malignant
`cells, controling the growth of malignant neoplasms,
`reducing the size of malignant neoplasms, eradicating
`malignant neoplasms, prolonging the survival time of
`said mammal, killing malignant cells, and adversely 65
`affecting malignant cells.
`While rapamycin can be administered above, e.g. as a
`sole component of a filled capsule, it is preferred to
`
`Breckenridge Exhibit 1052
`Sehgal '018 patent
`Page 002
`
`

`

`5,206,018
`
`4
`TABLE 3-continued
`Effect of Rapamycin on Survival Time of CDF 1 Mice
`Implanted with Colon 26 Tumor
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`days
`mg/kg
`T
`(T-C, g)
`C
`12.5
`0.3
`30.4
`19.1
`Treatment:
`Single intraperitooeal injection on days I, Sand 9 in a vehicle of saline with Tween-
`80.
`Evaluation:
`TIC% = Median survival time (MST) in days of treated animals (T)lcontrol
`animals (C) x 100. A TIC% of 125 or greater is considered as a li&nificut prolon(cid:173)
`gation of host survival. Evaluation done on day 60.
`
`Survivors
`on Day S
`10/10
`
`TIC%
`MST
`159
`
`3
`tional Cancer Institute as standard test procedures for
`predicting clinical activity of new chemotherapeutic
`agents.
`Tables 1 to 6 show the effects of therapy with rapa(cid:173)
`mycin on various tumors or cancers in rodents. More 5
`specifically, Table 1 shows the prolongation of survival
`time of female CDF1 mice implanted with lymphatic
`leukemia P388 by administering rapamycin; Table 2
`shows the reduction in size of colon 38 tumors in female
`BDF1 mice by administering rapamycin; Table 3 shows 10
`the prolongation of survival time of male CDF1 mice
`implanted with colon 26 tumors by administering rapa(cid:173)
`mycin; Table 4 shows the reduction in size of CD8F1
`mammary tumors in male CD8F1 rats by administering
`rapamycin; Table 5 shows the prolongation of survival
`time of female BDF1 mice implanted with Bl6 melono(cid:173)
`carcinoma by administering rapamycin; and Table 6
`shows the prolongation of survival time of male Swiss
`mice implanted with ependymoblastoma by administer- 20
`ing rapamycin.
`
`15
`
`TABLE4
`Effect of R.apamycin OD CD8F I
`Mammary Tumors in CD8F1 Rats
`Average
`Dose/ Net Wt. Difference
`Inj.
`of Animals
`mg/kg .
`(T.C, g)
`-6.6
`-6.5
`-4.8
`-4.1
`-2.4
`-0.8
`
`Survivors
`on Day 5
`4/10
`10/10
`10/10
`10/10
`10/10
`10/10
`
`MTW
`da~
`c
`T
`0 3200
`323
`3200
`448
`3200
`755
`3200
`825
`3200
`928
`3200
`
`TIC%
`MTW
`
`10
`14
`23
`25
`29
`
`400
`200
`100
`so
`25
`12.5
`
`25
`
`Treatment:
`Single intraperitoneal injection on days I, 8, IS, 22 and 29 in a vehicle of saline with
`Tween-80.
`30 Evaluation:
`TIC% = Median tumor weight (MTW) estimated from tumor diameter of treated
`animals (T)lcontrol animals (C) X 100. A TIC% of 42 or less is considered as a
`significant inhibitor of tumor growth. Evaluation done on day JO.
`
`TABLE 1
`Effect ofRapamycin on Survival Time ofCDF1 Mice
`Implanted with L~phatic Leukemia P-388 (ascetic)
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`da:ts
`c
`mg/kg
`(T-C, g)
`T
`-1.9
`14.1
`10.2
`-2.4
`13.1
`10.2
`-1.6
`13.7
`10.2
`-1.9
`14.3
`10.2
`-1.6
`13.9
`10.2
`-0.6
`13.9
`· 10.2
`
`Survivors
`on Day 5
`
`6/6
`6/6
`6/6
`6/6
`6/6
`6/6
`
`TIC%
`MST
`138
`128
`134
`140
`136
`136
`
`400
`200
`100
`50
`25
`12.5
`
`Treatment:
`Nine intrapcritoneaJ injections starting on day one in a vehicle of saline with
`Twecn-80 [Trade Mark for a derivative of Z-sorbitan mono-9-ocwlccenoate poly(cid:173)
`(oxy-1,2-ethanediyl)].
`Evaluation:
`T /C% = Median Survival Time (MST) in days of treated animals (T)/control
`animals (C) X 100. A T/C% of 125 or greater is considered as a significant prolon(cid:173)
`gation of host survival. Evaluation done on day 30.
`
`35
`
`40
`
`TABLE 2
`Effect of Rapam:tcin on Colon 38 Tumor Weight in Mice
`Dose/ Ave. Wt. Difference
`MTW
`Inj.
`of Animals
`mg
`mg/kg
`(T-C, g)
`400
`200
`100
`50
`25
`12.5
`
`Survivors
`on Day 5
`
`10/10
`10/10
`10/10
`9/10
`10/10
`10/10
`
`T
`188
`209
`272
`320
`368
`368
`
`c
`810
`810
`810
`810
`810
`810
`
`TIC%
`MTW
`23
`25
`33
`39
`45
`45
`
`-3.4
`-2.0
`-0.8
`-0.8
`-0.4
`0.4
`
`45
`
`TABLE 5
`Effect of Rapam:tcin on Bl6 Melanocarcinoma in BDF1 Mice
`Average
`Dose/ Net Wt. Difference
`Inj.
`of Animals
`mg/kg
`(T-C, g)
`
`Survivors
`on Day 5
`10/10
`10/10
`10/10
`10/10
`10/10
`10/10
`
`MST
`da:ts
`c
`T
`22.0 20.1
`22.3
`20.1
`28.0 20.1
`25.3
`20.1
`28.0 20.l
`29.0 20.1
`
`TIC%
`MST
`109
`110
`139
`125
`139
`144
`
`400
`200
`100
`so
`25
`12.5
`
`-3.3
`-1.5
`-1.2
`-0.7
`0.1
`0.1
`
`Treatment:
`Single intraperitoneal injection on each of days I through 9 in a vehicle of saline
`with Twecn-80.
`Evaluation:
`TIC% = Median Survival Time (MST) in days of treated animals (T) control
`animals (C) X 100. AT IC% of 125 or greater is considered as a significant proloo-
`50 gation of host survival. Evaluation done on day 60.
`
`Treatment:
`Single intraperitoneal injection on days 2, 9 and 16 in a vehicle of saline with Tween
`80.
`Evaluation:
`TIC% = Median tumor weight (MTW) estimated from tumor diameter of treated 55
`animals (T)lcontrol animals (C) X 100. A TIC% of 42 or less is considered as a
`significant inhibitor of tumor growth. Evaluation done on day 20.
`
`TABLE6
`Effect of RaP!!!!:tcin on E~d~oblastoma in Swiss Mice
`Average
`Dose/ Net Wt. Difference
`Inj.
`of Animals
`mg/kg
`(T.C, g)
`200
`-3.3
`100
`-2.2
`so
`-1.3
`25
`-2.0
`12.S
`-1.0
`
`Survivors
`on Day 5
`10/10
`10/10
`9/10
`10/10
`10/10
`
`MST
`da~
`c
`T
`44.0
`18.1
`26.0
`18.1
`34.0
`18.1
`34.0
`18.1
`32.3 18.l
`
`TIC%
`MST
`243
`143
`187
`187
`178
`
`60
`
`Treatment:
`Single intraperitoneal injection on each of days I through 9 in a vehicle of saline
`with Tween-80.
`65 Evaluation:
`TIC% = Median Survival Time (MST) in days of treated animals (T) control
`animals (C) x 100. AT IC% of 125 or greater is considered as a significant prolon(cid:173)
`gation of host survival. Evaluation done on day 60.
`
`TABLE 3
`Effect of Rapamycin on Survival Time of CDF 1 Mice
`Implanted with Colon 26 Tumor
`Dose/ Ave. Wt. Difference
`MST
`Inj.
`of Animals
`da:ts
`(T-C, g)
`T
`C
`mg/kg
`
`Survivors
`on Day 5
`
`400
`200
`100
`50
`25
`
`-2.4
`-1.8
`-1.4
`-0.8
`-0.3
`
`10/10
`10/10
`10/10
`10/10
`10/10
`
`19.1
`26.3
`19.1
`25.8
`19.1
`29.0
`30.6 19.l
`30.3
`19.l
`
`TIC%
`MST
`137
`135
`151
`160
`158
`
`Breckenridge Exhibit 1052
`Sehgal '018 patent
`Page 003
`
`

`

`5,206,018
`
`5
`The standard animal models used can be divided into
`two types based on how the results are expressed. Re(cid:173)
`sults can be expressed as a comparison of the median
`survival time for mammals in the treated (T) group
`(those treated with rapamycin) versus the median sur- 5
`vival time for mammals in the untreated control (C)
`group. The result is given as a percentage of TIC; a
`high percent TIC indicates that the compound that was
`tested was effective in treating the malignant neoplasm
`that was evaluated. Statistically significant results are 10
`observed at either 125 or 130% TIC, depending on the
`neoplasm that was evaluated. Alternatively, the results
`of certain tests for solid tumors can be expressed based
`on the tumor weight of the solid tumor after the evalua(cid:173)
`tion period. The tumor weight in the test (T) animals is 15
`compared with the tumor in the control (C) animals and
`the results are expressed as a percent TIC. When results
`are expressed as a function of tumor weight, a low %
`TIC indicates effective treatment of the neoplasm, as
`the tumors in the test animals are smaller than tumors in 20
`the untreated control animals. A percent TIC of less
`than 42 is considered to be statistically significant.
`The results of the above described National Cancer
`Institute standard tumor test procedures demonstrate
`rapamycin's antineoplastic activity in mammals. As 25
`such rapamycin is useful in treating malignant neo(cid:173)
`plasms. Treating broadly includes, but is not limited to,
`inhibiting the proliferation of malignant cells, control(cid:173)
`ling the growth of malignant neoplasms, reducing the
`size of malignant neoplasms, eradicating malignant neo- 30
`plasms, prolonging the survival time of said mammal,
`killing malignant cells, and adversely affecting malig(cid:173)
`nant cells. Preferred embodiments of this invention, that
`are described below, are based on the specific types of
`malignant neoplasms that rapamycin has been shown to 35
`be effective in treating. The scope of this invention,
`however, is not limited to these specific embodiments,
`as other neoplasms that rapamycin is effective in treat(cid:173)
`ing will be apparent to one skilled in the art.
`Based on the ability of rapamycin to significantly 40
`inhibit tumor growth in the Colon 38 standard test pro(cid:173)
`cedure, as seen by a reduction in tumor size, and in(cid:173)
`crease survival time of the host mammal in the Colon 26
`standard test procedure, rapamycin is useful in treating
`mammalian carcinomas of the colon and rectum. The 45
`use of rapamycin in treating colon cancer is covered in
`U.S. Pat. No. 4,885,171.
`In the CD8F1 mammary tumor test procedure, rapa(cid:173)
`mycin caused a reduction in tumor size at doses of up to
`200 mg/kg. Mammary tumors were reduced in weight 50
`by 71 % at 12.5 mg/kg and by 90% at a dose of 200
`mg/kg, indicating an almost complete eradication of the
`mammary carcinoma. As such, rapamycin is useful in
`treating mammalian breast neoplasms.
`A significant increase in survival time of the host 55
`mammal was observed in the B 16 melanocarcinoma
`standard test procedure for mice that were treated with
`doses of up to 100 mg/kg. As such, rapamycin is useful
`in treating skin carcinomas such as basal cell carcinoma,
`squamous cell carcinoma, malignant melanoma, and the 60
`like.
`The ependymoblastoma standard test procedure is
`predictive of a compound's ability to treat malignant
`central nervous system neoplasms. At a dose of 50
`mg/kg, a% TIC of 187 was obtained, and at a dose of 65
`200 mg/kg, a % TIC of 243 was obtained (median
`survival time of 44.0 days for mammals treated with
`rapamycin versus median survival time of 18.1 days for
`
`6
`untreated control group). At all doses tested, rapamycin
`caused a significant increase in survival time of the host
`mammal in the ependymoblastoma standard test proce(cid:173)
`dure, and is therefore useful in treating malignant cen(cid:173)
`tral nervous system neoplasms. The extremely favor(cid:173)
`able results obtained in this test procedure also indicate
`that rapamycin is capable of reaching the intracranial
`neoplasm by crossing the blood brain barrier. Malignant
`central nervous system neoplasms describes a broad
`class of intracranial neoplasms which include, but are
`not limited to: intracranial meningiomas, sarcomas,
`gliomas, astrocytomas, medulloblastomas, schwan(cid:173)
`nomas, ependymomas, meningiomas, germinomas, and
`the like.
`Rapamycin was weakly active in the P-388 leukemia
`standard test procedure; a maximal% TIC of 140 was
`achieved at a dose of 50 mg/kg. When comparing these
`data to other data obtained for other anti-leukemic com(cid:173)
`pounds described in the literature, rapamycin is not felt
`to be ~ful in treating higher mammalian leukemias.
`Rapamycin also can be used to produce beneficial
`effects in the treatment of malignant neoplasms when
`combined with a therapeutically effective amount of an
`antineoplastic agent commonly used in cancer therapy.
`Such antineoplastic agents
`include
`the alkylating
`agents, for example, busulfan, chlorambucil, cyclophos(cid:173)
`phamide, mechlorethamine hydrochloride, melphalan,
`pipobroman, thiotepa and uracil mustard; antimetabo(cid:173)
`lites, for example, cytarabine, fluorouracil, floxuridine,
`mercaptopurine, methotrexate and thioguanine; miscel(cid:173)
`laneous anticancer agents, for example, dacarbazine,
`hydroxyurea, mitotane, procarbazine hydrochloride,
`quinacrine hydrochloride, vinblastine sulfate and vin(cid:173)
`cristine sulfate; estogens, for example, chlorotrianisene,
`conjugate estogens (e.g. PREMARIN @), diethylstil(cid:173)
`bestrol and the like; androgens, for example, methyltes(cid:173)
`tosterone, testosterone and the like; adrenal corticoster(cid:173)
`oids, for example, prednisone and the like; progesta(cid:173)
`gens, for example, megestrol, hydroxyprogesterone
`caproate and the like; radioactive isotopes; and antibiot(cid:173)
`ics, for example, bleomycin sulfate, doxorubicin hydro(cid:173)
`chloride and the like. Suitable methods of administra(cid:173)
`tion, compositions and dosages of the antineoplastic
`agents are described in medical textbooks; for instance,
`"PHYSICIANS' DESK REFERENCE", 32nd ed.,
`Medical Economics Co., Oradell, N.J. U.S.A., 1978 and
`"AMA DRUG EVALUATIONS", 3rd ed. PSG Pub(cid:173)
`lishing Company, Inc., Littleton, Mass., U.S.A. pp
`1106-1151, 1977. When used in combination, rapamycin
`is administered as described previously; however, a
`lower dose can be used for efficacious results.
`We claim:
`1. A method of treating a malignant neoplasm se(cid:173)
`lected from the group consisting of a mammary carci(cid:173)
`noma, a skin carcinoma, and a central nervous system
`neoplasm in a mammal in need thereof which comprises
`administering an antineoplastic amount of rapamycin to
`said mammal orally or parenterally with the proviso
`that said malignant neoplasm has not been transplanted
`into said mammal.
`2. The method of claim 1 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`carcinoma, squamous cell carcinomas, and malignant
`melanoma.
`3. The method of claim 1 wherein the central nervous
`system neoplasm is an intracranial neoplasm selected
`from the group consisting of a meningioma, sarcoma,
`
`Breckenridge Exhibit 1052
`Sehgal '018 patent
`Page 004
`
`

`

`7
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`4. A method of inhibiting the proliferation of malig(cid:173)
`nant cells selected from the group consisting of a mam(cid:173)
`mary carcinoma, a skin carcinoma, and a central ner- s
`vous system neoplasm in a mammal in need thereof
`which comprises administering an antineoplastic
`amount of rapamycin to said mammal orally or paren(cid:173)
`terally with the proviso that said malignant cells have
`not been transplanted into said mammal.
`5. The method of claim 4 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`carcinoma, squameous cell carcinomas, and malignant
`melanoma.
`6. The method of claim 4 wherein the central nervous 15
`system neoplasm is an intracranial neoplasm selected
`from the group consisting of a meningioma, sarcoma,
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`7. A method of reducing the size of a malignant neo- 20
`plasm selected from the group consisting of a mammary
`carcinoma, a skin carcinoma, and a central nervous
`system neoplasm in a mammal in need thereof which
`comprises administering an antineoplastic amount of
`rapamycin to said mammal orally or parenterally with 25
`the proviso that said malignant neoplasm has not been
`transplanted into said mammal.
`
`10
`
`5,206,018
`
`8
`8. The method of claim 7 wherein the skin carcinoma
`is selected from the group consisting of a basal cell
`carcinoma, squameous cell carcinomas, and malignant
`melanoma.
`9. The method of claim 7 wherein the central nervous
`system neoplasm is an intracranial neopl~m selected
`from the group consisting of a meningioma, sarcoma,
`glioma, astrocytoma, medulloblastoma, schwannoma,
`ependymoma, meningioma, and germinoma.
`10. A method of eradicating a malignant neoplasm
`selected from the group consisting of a mammary carci(cid:173)
`noma, a skin carcinoma, and a central nervous system
`neoplasm in a mammal in need thereof which comprises
`administering an antineoplastic amount of rapamycin to
`said mammal orally or parenterally with the proviso
`that said malignant neoplasm has not been transplanted
`into said mammal.
`11. The method of claim 10 wherein the skin carci(cid:173)
`noma is selected from the group consisting of a basal
`cell carcinoma, squameous cell carcinomas, and malig(cid:173)
`nant melanoma.
`12. The method of claim 10 wherein the central ner(cid:173)
`vous system neoplasm is an intracranial neoplasm se(cid:173)
`lected from the group consisting of a meningioma, sar(cid:173)
`coma, glioma, astrocytoma, medulloblastoma, schwan(cid:173)
`noma, ependymoma, meningioma, and germinoma.
`• • • • •
`
`30
`
`35
`
`40
`
`45
`
`so
`
`SS
`
`60
`
`6S
`
`Breckenridge Exhibit 1052
`Sehgal '018 patent
`Page 005
`
`