", -e
`
`•
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`INVESTOR IN PEOPLE
`
`The Patent Office
`Concept House
`Cardiff Road
`Newport
`South Wales
`NPIO 8QQ
`
`RECtO 1.5 MAY 2002
`
`WIPO
`
`peT
`
`I, the undersigned, being an officer du1y authorised in accordance with Section 74(1) and (4) of
`the Deregulation & Contracting Out Act 1994, to sign and issue certificates on behalf of the
`Comptroller-General, hereby certify that annexed hereto is a true copy of the documents as
`originally filed in connection with the patent application identified therein.
`
`In accordance with the Patents (Companies Re-registration) Rules 1982, if a company named in
`this certificate and any accompanying documents has re-registered under the Companies Act
`1980 with the same name as that with which it was registered immediately before re-registration
`save for the substitution as, or inclusion as, the last part ofthe name of the words "public limited
`company" or their equivalents in Welsh, references to the name of the company in this certificate
`and any accompanying documents shall be treated as references to the name with which it is so
`re-registered.
`
`In accordance with the rules, the words "public limited company" may be replaced by p.1.c., pIc,
`P.L. C. or PLC.
`
`Re-registration under the Companies Act does not constitute a new legal entity but merely
`subjects the company to certain additional company law niles.
`
`Signed
`
`Dated 2 January 2002
`
`An Executive Agency of the Department of Trade and Industry
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 001
`
`

`

`f I
`
`_ . . . . . ~
`
`PatejtsF~ ~t-l.L;';":~'~'
`~ "'l' •• The
`:
`.
`~'0;
`~:n~) 1977
`.: Pa:',
`J 1 9 FEB 2mB
`Office
`
`~ .. :'.
`
`A
`, ....
`~
`~~~ ~
`".9~2.VE D ~!?_'i \..\ ' ..
`\
`Requpst for grant 0 a patent
`(See the rwtes on the bacJ;. afthis form. You can also
`get an explanatory leaflet from the Patent Office to
`help you fiIl in this form)
`
`ft 9 ~FEB t2DOl .
`
`The Patent Office
`Cardiff Road
`. Newport
`Gwent NPlO SQQ
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`S.
`
`Your reference
`
`4-31671P2
`
`Patent application number
`(The Patent Office willfill in this part)
`
`Full name, address and postcode of the
`or of each applicant
`(underline all surnames)
`
`Patent ADP number (if you know it)
`If the applicant is a corporate body,
`countIy I state
`give
`the
`of
`its
`incorporation
`
`0104072.4
`
`NOVARTISAG
`SCHWARZWALDALLEE 215
`4058 BASEL
`SWITZERLAND
`
`o "+\L.Sl\?>1-\b1.
`
`SWITZERLAND
`
`Title of invention
`
`Organic Compounds
`
`B.A. YORKE & CO.
`CHARTERED PATENT AGENTS
`COOMB HOUSE, 7 ST. JOHN"S ROAD
`ISLEWORTH
`MIDDLESEX TW7 6NH
`
`1800001/
`CountIy
`
`Prioril;y application
`number
`(if you 1crww it)
`
`Date of filing
`(day /month/year
`)
`
`Number'of earlier
`application
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`Date of filing
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`Yes
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`Name of your agent (If you have one)
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`<t Address for service" in the United
`Kingdom to which all correspondence
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`ore more earlier patent applications,
`give
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`riling date of the earlier application
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`a) any applicant named in part 3 is not an.
`inventor, or
`
`b) there is an inventor who is not named as
`an applicant, or
`
`c) any named applicant is a corporate
`body_
`
`(see note (d))
`
`Patents Form. 1/77
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 002
`
`

`

`~
`
`...... ' . •
`
`Patents Form 1/77 •
`
`9.
`
`Enter the number of sheets for any of ~.
`the following items you are filing with
`this form. Do not count copies of the
`same document
`
`Continuation sheets of this form
`
`9
`2
`
`Description
`
`CIaim(s)
`
`Abstract
`
`Drawing{s)
`
`10.
`
`If you are also filing any of the
`following, state how many against each
`item.
`
`Priority documents
`
`Translations of priority documents
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`Statement of inventorship and right
`to grant of a patent (patents Fonn
`7/77)
`
`Request for preliminary- exrunina.tion
`and search (patents Form. 9/77)
`
`Request for substantive examination
`(patents Fonn 10/77)
`
`Any other documents
`(please specify)
`
`11.
`
`I/We request the grant of a patent on the basis of this
`application
`
`Date
`
`12. Name and daytime telephone number
`of person to contact in the United
`Kingdom
`
`BA. Yorke & Co.
`Mrs. E. Cheetham
`020 8560 5847
`
`Warning
`After an application for a patent has been filed. the Comptroller of the Patent Office wr.11 consider whether
`publication or communication of the invention should be prohibited or restricted under Section 22 of the Patents
`Act 1977. YoU' will be informed ifit is necessary to prohibit or restrict your invention in this way. Furthermore, if
`you live in the United Kingdom, Section 23 of the Patents Act 1977 stops you from applying for a patent abroad
`without first getting written pennission from the Patent Office unless an application has been filed at least 6
`weeks beforehand in the united Kingdomfor apatentfor the same invention and either rio direction prohibiting
`publication or communication has been givenJ or any such direction has been revoked.
`Notes
`If you need help to fill in this form or you have any questio~, please contact the Patent Office on 0645
`a)
`500505.
`Write your answers in capital letters using black ink or you may type them.
`If there is not enough space for all the relevant details on any part of this form., please continue on a
`separate sheet of paper and write "see continuation sheet" in the relevant part(s). Any continuation sheet
`should be attached to this form.
`Once you have filled in the form you must remember to sign and date it.
`For details of the fee and ways to pay please contact the Patent Office.
`
`b)
`
`c)
`
`d)
`e)
`
`Patents Form. 1/77
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 003
`
`

`

`•
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`- 1 -
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`•
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`Organic Compounds
`
`The present i~vention relates to a new use, in particular a new use for a compound group
`comprising derivatives of rapamycin.
`
`Suitable derivatives of rapamycin include e.g. compounds of formula I
`
`24
`
`wherein
`Rl is CH3 or C3 •salkynyl,
`R2 is H or -CH2-CH2-OH,
`X is =0 or (H,OH)
`provided that R2 is -CH2-CH2-OH when Rl is CH3 and X is =0.
`
`Most of the compounds of formula I are either generically or specifically disclosed in WO.
`94/09010, WO 95/16691 orWO 96/41807, which are incorPorated herein by reference, the
`compound of formula 1 wherein X is =0, Rl is 2-pentynyl and R2 is -CH2-CH2-OH being novel
`and forming part of the invention.
`
`A preferred compound is 40-0-(2-hydroxyethyl)-rapamycin (referred thereafter as
`.
`Compound A). disclosed as Example 8 in WO 94/09010.
`
`Certain compounds of formula I have, on the basis of observed activity, e.g. bi~~.ing to
`macrophilin-12 (also known asFK-506 binding protein or FKBP-12). e.g. as described in
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 004
`
`

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`•
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`- 2-
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`•
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`WO 94/09010, WO 95/16691 orWO 96/41807, been found to be useful e.g. as
`
`immunosuppr~ssantJ e.g. in the treatment of acute allograft rejection. It has now been found
`th~t 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, comp~sing
`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 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.
`
`1.4 A method for preventing m~tastatic spread of tumours or for preventing or inhibiting
`growth of micrometastasis in a subject in need thereof, comprising ad~inistering to
`said subject a therapeutically effective amount of a compound of formula I.
`1.5 A method for the treatment of a disease associated with deregulated angio~enesis in
`a subject in need thereof, comprising administering to said subject a therapeutically
`effective amount of a compound of formula I.
`1.6 A method for inhibiting or controlling deregulated angiogenesis 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. pancreatic tumors; melanomas; lung cancer, e.g. small cell lung
`cancer; breast cancer; epidermoid carcinomas; renal-cell carcinomas; neuroendocrine
`tumors; genitourinary cancer, e.g. cervical, uterine, ovarian, prostate or bladder cancer;
`gastrOintestinal cancer, e.g. gastric or colon cancer; glioblastomas; head and/or neck
`cancer; soft-tissue sarcomas.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 005
`
`

`

`.8
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`•
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`- 3 -
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`•
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`Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a cancer is
`mentioned, also metastasis in the original organ or tissue and/or in any other location are
`implied alternatively or in addition, whatever the location of the tumor and/or metastasis is.
`
`Examples of diseases associated with deregulated angiogenesis include 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.
`
`3.
`4.
`
`5.
`
`As alternative to the above the present invention also provides:
`2.
`A compound of formula I wherein X is =0, R1 is 2-pentynyl and R2 is -CH2-CH2-OH for
`use as a pharmaceutical;
`A compound of formula I for use in any method as defined under 1.1 to 1.6 above;
`A compound of formula I for use in the preparation of a pharmaceutical composition
`for use in any method as defined under 1.1. to 1.6. above;
`A pharmaceutical composition comprising a. compound of formula I wherein X is =0,
`R1 is'2-pentynyl and R2 is -CH2-CH2-OH together with one or more pharmaceutically
`acceptable diluents or carriers therefor;
`A pharmaceutical composition for use in any method as defined under 1.1 to 1.6
`above comprising a compound of formula I together with one or more pharmaceutically
`acceptable diluents or carriers therefor.
`
`6.
`
`Utility of the compounds of formula I in treating solid tumors as hereinabove specified, may
`be demonstrated in animal test methods as well as in clinic, for example in accordance with
`the methods hereinafter described.
`A.
`In Vivo
`A.1 Activity in KB-31 human epidermoid tumor xenografts
`Fragments of KB-31 tumors (approx. 25 mg; Roswell Park Memorial Institute Buffalo,
`NY, USA) are transplanted subcutaneously into the left flank of BALB/c nude mice.
`Treatment is started on day 7 or on day 10 following tumor transplantation. The compound
`to be tested is administered p.o. once per day from day 7/10 to day 25/35, respectively.
`Antitumor activity is expressed as· T/C% (mean increase of tumor volumes of treated.
`
`..
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 006
`
`

`

`·1
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`•
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`•
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`animals divided by the mean increase of tumor volumes of control animals multiplied by
`100). In this assay, when administered at a daily dose ranging from 0.5 mglkg to 2.5 mglkg,
`the compounds of formula I inhibit tumor growth; for example in one representative
`experiment Compound A when administered at a dose of 2,5 mg/kglday results in a final
`TIC cvalue of 25%(T/C for animal controls is 100%).
`
`A.2 Activity in HCT116 human colon carcinoma xenografts
`1x1 0 6 HCT116 cells (Cell line CCL247. ATCC. Rockville MD, USA) are injected
`subcutaneously into the left flank of BALB/c nude mice. Treatment is started on day 7 or on
`day 9 following tumor transplantation. The compound to be tested is administered p.o once
`per day from day 7/9 to day 25/37, respectively. Antitumor activity is expressed as T/C% as
`indicated above. In this assay, when administered at a daily dose ranging from 2.5 mg/kg to
`10 mglkg. the compounds of formula I inhibit tumor growth; for example in one
`, representative experiment Compound A when administered p.o. at a dose of 2,5 or 5
`
`mglkg/day results in final TIC values of 50% and 37%, respectively (TIC for animal controls
`is defined as 100%).
`
`A.3 Activity in CA20948 rat pancreatic tumors
`Tumors are established in male Lewis rats by subcutaneous injection of CA20948
`tumor cell suspension derived from donor rats into the left flank of male Lewis rats.
`Treatment is started on day 4 post inoculation. The compound to be tested is administered
`p.o: once per day (6 days a week) from day 4 to day 12114 post inoculation. Antitumor
`activity is expressed as T/C% as indicated above. In this assay, when administered at a
`daily dose of 0.5 mg/kg to 2.5 mg/kg, the compounds of formula I inhibit tumor growth; for
`example in one representative experiment Compound A when administered p.o. at a daily
`dose of 2.5 mg/kg results in a final TIC value of 23 % (TIC for animal controls is defined as
`100%).
`
`B.
`
`Clinical Trial
`
`Objectives
`Primary:
`
`To charactE?rize the safety profile, including both acute and cumulative toxicities,
`and determine the maximum tolerated dose of a compound of formula I, e.g.
`Compound A, administered by intravenous infusion to adult patients with
`advanced solid tumors who have failed standard systemic therapy or for whom
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 007
`
`

`

`•
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`-5-
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`•
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`standard systemic therapy does not exist
`Secondary: To obtain preliminary evidence of antitumor activity of a compound of formula I,
`e.g. Compound A. administered by intravenous infusion to this population of
`patients.
`To gather information on tumors from tumor biopsy samples where available
`and accessible pre- and post-therapy in order to identify biological factors that
`correlate with efficacy and response.
`
`Design
`
`This is an open-label. dose-escalation study to assess the safety and efficacy of
`a compound of formula I administered by intravenous infusion to adult patients
`with advanced solid tumors who have failed standard systemic therapy or for
`whom standard systemic therapy does not exist.
`The treatment period consists of up to 3 months. Patients experiencing
`unacceptable tOXicity or disease progression are discontinued prematurely.
`
`Patients achieving a complete or partial response, or patients with stable
`disease at the end of 3 months continue further treatment according to an
`extension protocol at the discretion of the investigator and after approval by the
`sponsor. Eligible patients receive additional treatment until disease progression
`
`or unacceptable toxicity are observed .
`. In the absence of dose-limiting toxicity (DL T), dose escalation proceeds as
`follows:
`
`1. First dose escalation: 100% dose increase (unless grade 2 toxicity is
`identified in first cohort, in which case dose escalation is 25% - 67%)
`. 2. Dose escalations following 100% dose increase from first to second
`cohort: 67% dose increases until grade 2 toxicity is identified
`3. Final dose escalations following identification of grade 2 toxicity: 25%-
`67% dose increases, based on consensus reached among the
`
`investigators and the sponsor
`Dose escalation is based on toxicities from the first cycle for each cohort of
`patients. The provisional maximum tolerated dose (MTD) is defined as the dose
`level il'flmediately below that at which DL T is observed in at least two out of 3-6
`patients. The cohort defined as the provisional MTD then enrolls additional
`patients to a total of 12 to confirm the MTD through further evaluation of the
`
`safety. pharmacokinetic, and pharmacodynamic profiles of the compound of
`
`formula J tested.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 008
`
`

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`•
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`-6-
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`•
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`All toxicities are defined according to the revised US National Cancer Institute
`Common Toxicity Criteria.
`
`Patients:
`
`Inclusion Criteria
`The following criteria must be met for inclusion into the study:
`
`i. Male or female patients ~18 years of age.
`
`ii. Histologically documented advanced solid tumor, who have failed stan(cid:173)
`dard systemic therapy and up to 1 additional systemic therapy, or for
`whom standard systemic therapy does not exist.
`iii. At least one measurable, evaluable, or non-evaluable site of disease as
`defined by Southwestern Oncology Group (SWOG) Solid Tumor
`Response Criteria including tumor marker value that is above the
`institutional upper limit of normal.
`
`iVa Women of childbearing potential must have a negative serum I3-HCG
`
`pregnancy test prior to the initiation 'of study drug. Male and female
`patients ~f reproductive potential must agree to employ an effective
`method of birth control throughout the study and for up to 3 months
`following discontinuation of study drug.
`
`V. World Health Organization (WHO) Performance Status Score of ~ 2.
`
`vi. Life expectancy of at least 3 months.
`vii. Written informed consent is obtained prior to any screening procedures.
`
`Exclusion Criteria: Exclusion from the study is required if any of the following
`apply:
`
`i. Female pati.ents who are pregnant or breast-feeding. Postmenopausal
`women must be amenorrheic for at least 12 months to be considered of
`
`non-childbearing potential.
`ii. Patient has a severe and/or uncontrolled medical disease (Le., uncon(cid:173)
`trolled diabetes, congestive heart failure, myocardial infarction within 6
`months of study, chronic renal disease, or active uncontrolled infection).
`iii. Patient has a known brain metastasis.
`iVa Patient has an acute or known chronic liver disease (Le., chronic active
`hepatitis, cirrhosis).
`v. Patient has a known diagnosis of human immunodeficiency virus (HIV)
`
`infection.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 009
`
`

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`·t
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`....., .... -_ -... _a __ ... _ •
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`-7-
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`vi. Patient has received any investigational agent within 30 days prior to
`study entry.
`vii. Patient received chemotherapy within 4 weeks (6 weeks for nitrosoureas
`or mitomycin C) prior to study entry.
`viii. Patient received prior radiation therapy within 4 weeks prior to study
`entry.
`
`ix. Patient previously received radiotherapy to ~ 25% of the bone marrow.
`
`x. Patient had a major surgery within 2 weeks prior to study.entry.
`xi. Patient has a history of non-compliance to medical regimens.
`xii. Patient has impairment of hepatic, renal or hematologic function.
`
`xiii. Patient is < 5 years free of another primary malignancy; however, non(cid:173)
`
`melanomatous skin cancer and cervical carcinoma in situ are excluded
`only if the patient has active disease.
`Treatments: the compound of formula I, e.g. Compound A, may be administer~d orally or
`parenterally, e.g. sub-cutaneous, starting with a dose level of about 0.75 mg.
`bose escalation proceeds according to the scheme outlined above. The study
`defines treatment delays. dose reductions, or withdrawal from treatment for
`
`individuals experiencing hematologic or other toxicities known to result from the
`compound.
`
`Activity is demonstrated as a function of the rate of objective tumor
`Efficacy variables
`response and length of progression-free and overall survival. Baseline tumor
`evaluations include optimal assessment of all measurable, evaluable, and
`
`nonevaluable disease.
`
`Daily dosages required in practising the method of the present invention will, of course, vary
`depending on a variety of factors, for example the particular compound of formula I chosen,
`the particular condition to be treated and the desired effect. In general, however,
`satisfactory results are achieved on administration of a compound of formula I at daily
`dosage rates of the order of ca. 0.5 mg to 20 mg as a single dose or in di,:,ided doses. The
`compounds of formula I may be administered by any conventional route, in particular
`enterally, e.g. orally, e.g. in the form of tablets, capsules, drink solutions or parenterally. e.g.
`in the form of injectable solutions or suspensions. Suitable unit dosage forms for oral
`administration comprise from ca. 0.1 mg to 10 mg active ingredient, e.g. Compound A,
`together with one or more pharmaceutically acceptable diluents or carriers therefor.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 0010
`
`

`

`•
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`-8-
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`•
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`When used in the method according to the invention, the compounds of formula I may be
`administered as the sole active ingredient or together with other chemotherapeutic drugs.
`By the term "other chemotherapeutic", there is meant especially any chemotherapeutic
`ot~er than a compound of formula I. For example, the ~ompounds of formula I may be used
`in combination with e.g. paclitaxel, gemcitabine, cisplatinum, doxorubicin, 5-fluorouracil, a
`hormonal agent or antagonist, e.g. an anti-androgen or mitoxantrone (especially in the case
`of prostate cancer), or an antiestrogen, like letrozole (especially in the case of breast
`cancer), an antimetabolite, a plant alkaloid, a biological response modifier, preferably a
`Iymphokine or interferons, an inhibitor of protein tyrosine kinase and/or serine/threonine
`kinase, or an agent with other or unknown mechanism of action, e.g.any epitholone or
`epitholone derivative. Where the compounds of formula I are administered in conjunction
`
`with other chemotherapeutic drugs, dosages of the co-administered compound will of
`-course vary depending on the type of co-drug employed, on the specific drug employed, on -
`the condition to be treated, and so forth. The terms "co-administration" or "combined
`administration" or the like as utilized herein are meant to encompass administration of the
`selected therapeutic agents to a single patient, and are intended to include treatment
`regimens in which the agents are not necessarily administered by the same route of
`administration or at the same time.
`
`In accordance with the foregoing the present invention provides in a yet further aspect:
`7.
`A pharmaceutical combination comprising a} a first agent which is a compound of
`formula I, e.g. Compound A and b} a co-agent which is a chemotherapeutic agent, e.g.
`
`as defined above.
`
`8.
`
`A method as defined above compriSing co-administration, e.g. concomitantly or in
`sequence, of a therapeutically effective amount of a compound of formula I, e.g.
`Compound A, and a second drug substance, said second drug substance being a
`chemotherapeutic agent, e.g. as indicated above.
`
`Preferred pharmaceutical combinations include e.g. a combination of e.g. Compound A with
`
`e.g. cisplatinum, paclitaxel, gemcrtabine or doxorubicin.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 0011
`
`

`

`•
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`-9-
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`•
`
`Compounds of formula I are well tolerated at dosages required for use in accordance with
`the present invention. For example, the NTEL for Compound A in a 4-week toxicity study is
`0.5 mg/kg/day in rats and 1.5 mg/kglday in monkeys.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 0012
`
`

`

`•
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`-10 -
`
`CLAIMS
`
`•
`
`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
`
`24
`
`wherein
`R1 is CH3 or C3-salkynyl,
`R2 is H or -CH2-CH2-0H,
`X is =0 or (H,OH)
`provided that R2 is -CH2-CH2-OH when R1 is CH3 and X is =0.
`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 as defined in claim 1.
`
`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 as defined in claim 1.
`A method for preventing metastatic spread of tumours or for preventing o~ inhibiting
`growth of micrometastasis in a subject in need thereof, comprising administering to
`said subject a therapeutically effective amount of a compound of formula 1 as defined
`in claim 1.
`A method for the treatment of a disease associated with deregulated angiogenesis in
`a subject in need thereof, comprising administering to said subject a therapeutically
`
`effective amount of a compound of formula I as defined in claim 1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 0013
`
`

`

`•
`
`•
`
`6.
`
`A method for inhibiting or controlling deregulated angiogenesis in a subject in need
`thereof. comprising administering to said subject a therapeutically effective amount of
`a compound of formula I as defined in claim 1 .
`
`7.
`
`8.
`
`9.
`
`A compound of formula I as herein defined wherein X is =0, R1 is 2-pentynyl and R2 is
`-CH2-CH2-OH
`A compound of formula I as herein defined wherein X is =0, R1 is 2-pentyny\ an'd R2 is
`-CH2-CH2-0H for use as a pham:taceutical;
`A compound of formula I as defined in claim 1 for use in a method as defined in any
`one of the claims 1 to 6.
`10. A compound of formula I as defined in claim 1 for use in the preparation of a
`pharmaceutical composition for use in a method as defined in anyone of the claims 1
`to 6.
`11. A pharmaceutical composition comprising a compound of formula I as herein defined
`wherein X is =0, R1 is 2:.pentynyl and R2 is -CH2-CH2-OH 'together with one or more
`pharmaceutically acceptable diluents or carriers therefor.
`12. A pharmaceutical composition for use in a method as defined in anyone of the claims
`1 to 6 comprising a compound of formula las defined in claim 1 together with one or
`
`more pharmaceutically acceptable diluents or carriers therefor.
`13. A pharmaceutical combination comprising a) a first agent which is a compound of
`formula I as defined in claim 1 and b) a co-agent which is a chemotherapeutic agent.
`14. A method according to anyone of the claims 1 to 6 comprising co-administration, e.g.
`concomitantly or in sequence, of a therapeutically effective amount of a compound of
`formula I as defined in claim 1 and a second drug substance, said second drug
`
`substance being a chemotherapeutic agent.
`15. A compound according to claim 9 or 10, a pharmaceutical composition or combination
`according to claim 12 or 13 or a method according to anyone of the claims 1 to 6 or
`14, wherein the compound of formula I is 40-0-(2-hydroxyethyl)-rapamycin.
`
`West-Ward Exhibit 1012
`GB '072 Priority Application
`Page 0014
`
`