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`BYFAX
`
`V
`
`DFW /aja
`11 May 2000
`
`The European Patent Office
`Erhardtstraise 27
`D-8000
`MUNCHEN
`Germany
`
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`. w--==··fy
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`Patents & Trade Marks Dept
`Huntercombe Lane South
`Taplow, Maidenhead
`Berkshire, SL6 0PH
`Tel: +44 (0)1628 604377
`, '.' f,3x: ~.4.1 (0)1~ 628 799098
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`Dear Sirs
`
`.I
`
`....
`
`i ' -
`
`RE: European Patent Application No 95915671.~
`American Home Products Corporation Cas~93171
`
`i
`
`'
`
`-
`
`I refer to the Communication pursuant to Article 96(2) and Rule 51(2) EPC dated 1
`September 1999.
`
`Dealing in turn with the points raised by the Examiner:
`
`It is noted that the new claims filed on 10 October 1996 are based on the
`1.
`original disclosure.
`
`2 and 3.
`
`The Examining Division considers the Documents Dl - D4 as relevant.
`
`US 4650803
`Dl
`=
`WO-A-9205179
`D2
`=
`US 5233036
`D3
`=
`D4
`Tetrahedron Letters 35(1994), 1019-1022
`=
`Novelty over Dl - D4 is acknowledged.
`
`A
`•
`
`The Applicants point out that the problem solved by the present application is
`4.1
`to provide hydroxyesters of rapamycin useful as immunosuppressants but also
`useful in the treatment of diseases including adult T-cell leukemia/lymphoma and
`solid tumors, see page 1 lines 7 and 8. See also page 2 where "anti-tumor" use is
`indicated. Further test data is available to illustrate anti-tumor use (vide infra). A
`compound claimed in this application is undergoing clinical trials as an anti-tumor
`agent.
`
`4.2
`It is noted that D2 is considered the closest prior art. The Examining Division
`also comments that Dl - D4 are all relevant because they appear to be prodrugs of
`rapamycin. This statement is disputed in so far as D2 - D4 are concerned since it
`implies that the side chain is lost during metabolism to give rapamycin which is the
`active entity responsible for the pharmacological effect. However no evidence is
`provided by the Examining Division to show whether or not the compounds of these
`references are prodrugs of rapamycin.
`It appears to be an assumption made by the
`
`John Wyeth & Brother L1m1ted
`Registered 1n England No 135937
`Registered Office. Huntercombe Lane South
`Taplow, Maidenhead, Berkshire, SL6 0PH
`
`I\"\'ESTOR IN PEOPLE
`
`Incorporating Wyeth Laboratories
`SMA Nutrition
`
`

`

`/ '✓
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`= •• :))
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`-2-
`
`Examining Division which insofar as the present compounds are concerned is
`The Applicants consider that the activity in the present compounds
`incorrect.
`resides in the compounds themselves and they do not require conversion to
`rapamycin to exert their biological activity.
`
`•
`
`4.3-5 The Examining Division comments that the compounds disclosed in D2-D4 all
`have qualitatively the same activity. This is not correct in that the compounds of the
`present application have an additional and important activity as anti tumor agents -
`see page 1 line 8 which is substantiated by data included hereinbelow.
`
`The Examining Division appears to suggest that the presence of an inventive step
`could be acknowledged if it is made credible by test results that another problem has
`been solved.
`It appears also that we are required to provide a comparison with the
`closest prior art compound of D2, viz. rapamycin 42-mono-methylsuccinate.
`
`It is pointed out firstly that none of the prior art documents D2-D4 teach anti(cid:173)
`tumor activity. Secondly the Table below demonstrates highly significant anti tumor
`test data for the compound of Example 11 (rapamycin 42-ester with 2,2-bis(cid:173)
`(hydroxymethyl)propionic acid). Since the closest prior art makes no reference to
`anti-tumor activity it is submitted that there is no need to make a comparison.
`
`TABLE
`
`•
`
`Inhibition of growth of human tumor cell lines (in vitro) by
`compound of Example 11
`Tumor type
`Cell line
`Breast Cancer
`BT-474
`SK-BR-3
`MCF7
`Prostate Cancer PC-3
`LNCaP
`DU 145
`LOX
`Melanoma
`Ovarian Cancer A2780 S
`A2780DDP
`HTB 161
`A549
`LX-1
`CaCo2
`HCT-15
`SW948
`MIP 101
`CX-1
`SW620
`
`Lung Cancer
`
`Colon Cancer
`
`ICSQ (gM)"
`0.0006
`0.0007
`0.001
`0.0005
`0.0007
`0.001
`0.001
`0.004
`0.04
`0.07
`0.1
`2.5
`0.004
`0.07
`0.05
`0.08
`4.4
`4.4
`
`

`

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`• • ··· s,
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`-3-
`
`4.8
`COLO 205
`LS 174T
`4.9
`SW480
`5.9
`0.1
`CCRF-CEM
`5.8
`HL-60
`a: IC50 = concentration causing 50% growth inhibition.
`
`Leukemia
`
`Based on the teaching in the application as filed and the data provided herein it is
`submitted that the compounds of the present application do possess an inventive
`step over the prior art being indicated as anti-tumor agents.
`
`The Examining Division has objected to the breadth of scope. Enclosed
`4.6
`herewith are replacement claims which more narrowly define the invention and are
`based on the original specification as filed.
`In particular the features of claim 4 have
`been introduced into claim 1. 42,31-Bis compounds are removed.
`
`The Examining Division has objected to Claim 1 for being unclear due to the
`presence of two provisos. Restriction of Claim 1 to the features of Claim 4 has
`resulted in one proviso being removed and the other being simplified. The use of the
`one proviso is regarded as clear and the meaning is readily comprehensible.
`
`Claim 12 (new claim 11) has been amended to remove functional language.
`The term "reactive derivative" however has been retained since its meaning is readily
`clear from the description on page 5 lines 26 to 30. Those skilled in the art would be
`aware of how to perform an acylation reaction and what the term means.
`
`The Applicants propose to bring the description into line once the claims have
`5.
`been agreed.
`
`A new claim 3 has been added to the claims directed to first pharmaceutical use. A
`second medical use claim has been added as new claim 9 directed to anti tumor
`treatment.
`
`These amendments are made without prejudice to reinstatement of the original
`wording during future prosecution of this application or any application derived
`therefrom, and without prejudice to filing of divisional applications.
`
`,.,,
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`j
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`

`

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`-4-
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`D
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`D
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`D
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`• = .. =<;r
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`The Applicant requests Oral Proceedings (Article 116 EPC) before any notice of
`rejection may issue.
`
`A form 1037 accompanies the confirmatory copy of the fax for acknowledging
`receipt.
`
`Yours faithfully
`
`c;j)(J~
`
`-
`
`Dr D F Wileman
`European Patent Attorney (GA 2141)
`
`-
`
`

`

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`e De
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`- 20 -
`
`CLAIMS
`
`1.
`
`A compound of the structure
`
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`
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`
`• e
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`• • • • • •
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`! Alfl>~CJ3171 tPC:*f
`!
`
`= •• : ••• : • = •• : =--~i
`
`(I)
`
`Meo·······
`
`0
`
`OMe
`
`wherein RI is -COCR7R8R9 and R2 is H;
`R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7
`carbon atoms, -(CR3R4)tDR 10, -CF3, -F, or -C02R 11 ;
`R8 and R9 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or(cid:173)
`(CR3R4)tDR10; or R8 and R9 may be taken together to form X;
`R 10 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7
`carbon atoms, tri-(alkyl of 1-6 carbon atoms)silyl, tri-(alkyl of 1-6 carbon
`atoms)silylethyl, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, tri(cid:173)
`(alkyl of 1-6 carbon atoms)silylethoxymethyl, chloroethyl, or tetrahydropyranyl;
`X is 5-(2,2-di-(alkyl of 1-6 carbon atoms))[l,3]dioxanyl, 5-(2-spiro(cycloalkyl of 3-8
`carbon atoms))[l,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6 carbon atoms))[l,3]dioxanyl,
`4-(2-spiro(cycloalkyl of 3-8 carbon atoms))[l,3]dioxanyl, 4-(2,2-di-(alkyl of 1-6
`carbon
`atoms))[l ,3]dioxalanyl, or 4-(2-spiro(cycloalkyl of 3-8
`carbon
`atoms))[ 1,3 ]dioxalanyl;
`R3 and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7
`carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or -F;
`
`and
`f = 0-6
`with the proviso that RI contains at least one -(CR 3R4)tDR 10 or X group,
`or a pharmaceutically acceptable salt thereof.
`
`

`

`·~
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`- 21 -
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`: 1~¾H)3171 BPC:*:"
`:
`. . . . .
`: • : : : =~0
`• : :
`. . . . ) \
`
`2.
`
`A compound according to claim 1 which is one of the following:
`
`rapamycin 42-ester with (tetrahydropyran-2-yloxy)acetic acid;
`
`rapamycin 42-ester with hydroxyacetic acid;
`
`rapamycin 42-ester with 2,2-dimethyl-3-(tetrahydropyran-2-yloxy)propionic acid;
`
`rapamycin 42-ester with 3-hydroxy-2,2-dimethylpropionic acid;
`
`rapamycin 42-ester with 2,2-dimethyl[ 1,3 ]dioxalane-4-carboxylic acid;
`
`rapamycin 42-ester with 2,3-dihydroxypropionic acid;
`
`rapamycin 42-ester with 2,2-d1methyl[l,3]dioxane-5-carboxylic acid;
`
`rapamycin 42-ester with 3-hydroxy-2-hydroxymethylpropionic acid;
`
`rapamycin 42-ester with 2,2,5-trimethyl[l ,3]dioxane-5-carboxylic acid;
`
`rapamycin 42-ester with 2,2-bis-(hydroxymethyl)propionic acid;
`
`rapamyci n 42-ester with 2,2-dimethy 1-5-(2-trimethylsilanylethoxymethyl)[ 1,3 ]-dioxane-
`5-carboxy lic acid;
`
`or
`
`rapamycin 42-ester with 3-methyl-1,5-dioxa-spiro[5.5]undecane 3-carboxylic acid;
`
`or a pharmaceutically acceptable salt thereof.
`
`3.
`
`A compound of formula I as claimed in Claim 1 for use as a pharmaceutical.
`
`Use of a compound of formula I as claimed in Claim 1 in the preparation of a
`4.
`medicament for treating transplantation rejection or graft vs. host disease in a mammal.
`
`

`

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`- 22 -
`
`••
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`• • • • • •
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`: ~-CEH>3171 ~P<:"!"
`:
`
`: .. : ... : . : .. : : .. :G/7
`
`Use of a compound of formula I as claimed in Claim 1 in the preparation of a
`5.
`medicament for treating a fungal infection in a mammal.
`
`Use of a compound of formula I as claimed in Claim 1 in the preparation of a
`6.
`medicament for treating rheumatoid arthritis in a mammal.
`
`Use of a compound of formula I as claimed in Claim l in the preparation of a
`7.
`medicament for treating restenosis in a mammal.
`
`Use of a compound of formula I as claimed in Claim 1 in the preparation of a
`8.
`medicament for treating pulmonary inflammation in a mammal.
`
`Use of a compound of formula I as claimed in Claim 1 in the preparation of a
`9.
`medicament for treating tumors in a mammal.
`
`A pharmaceutical composition which comprises a compound of the structure (I)
`10.
`as claimed in Claim 1 or claim 2 or a pharmaceutically acceptable salt thereof, and a
`pharmaceutical carrier.
`
`A process for preparing a hydroxy ester of rapamycin of formula I as defined in
`11.
`Claim 1 which comprises acylating rapamycin with an acylating agent of formula
`
`HO-COCR7R8R9
`(II)
`
`or a reactive derivative thereof wherein R7-R9are as defined in Claim 1 providing that
`free hydroxy groups are protected and after the reaction removing any protecting groups
`present as required.
`
`