•
`
`elhei= C 0 ) liB:l£.age; and
`
`, .
`
`R 4 is methyl or R' and R 1 together form C...6 alkylene;
`
`provided rb..a.t R 1 and R 2 are not both H; and
`i?f9~~ ~t_-~o&~l or hyrlroxy~ljC~~J ~. otbef th"'!P ·:~~~etllyl .. or
`ljy~~~~~!
`
`2.
`
`Compounds according to claim 1 selected from the following;
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`l 0.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`12.
`
`40-Q-Benzyl-rapamycin
`
`40-0-( 4 • -Hydroxymethyl)bcnzyl-rapamycin
`
`40-0-(4 .. -{l~-Dihyd..roxyethyl)]bcnzyl-rapamycin
`
`40-0-Allyl-rapamycin
`
`40-0-[3'-{2 .. 2-Dimetbyl-I,3-dioxolan-4(S)-yl)-prop-2'-en-1'-yl]-rapamycin
`
`(2.E. 4'S)-40-0-{4'.S-Dihydroxypent-2'-en-l '-yl)-rapamycin
`
`40-0-(2-Hydroxy)ethoxycarbonylmethyl-rapam.ycin
`
`40-0-(2-Hydroxy)cthyl-r.ipam.ycin
`
`40-0-(3-Hydroxy)propyl-rapamycin
`
`40-0-( 6-Hydroxy)hexyl-rapamycin
`
`40-0-(2-(2-Hydroxy)ethoxy Jethyl-rapamycin
`
`40-0-({3S)-2.2-Dimethyldioxolan-3-yl]mechyl-rapamycin
`
`40-0-[(2S)-2.3-Dibydroxyproir 1-yl]-rapamycin
`
`40-0-(2-Acetoxy)cthyl-rapamycin
`
`40-0-(2-1'1cotinoy!oxy)etb.yl-rapamycin
`
`40-0-[2-o;-Morpholino )acetox:· ]ethyl-r-pamycin
`
`40-0-(2-N-Imidazolylacetoxy)ethyl-rapamycin
`
`4-0-0-[2-(N-Methyl-Ny -pipcrazinyl)acewxy ]etbyl-rapamycin
`
`39-0-Desmetbyl-39.40-0.0-ctbylene-rapamycin
`
`(26R)-26-Dihydro-10-0-(2-bydroxy)ethyl-rapamycin
`
`28-0-Methyl-rapa!Dyci!l
`
`40-0-(2-AIIJ.inoethyl)-rapamycin
`
`
`
`

`
`3.
`
`5.
`
`40-8'2.-Acetaminoethy 1)-rapamycin
`
`40-0-(2-Nicotinamidoethyl)-rapamycin
`
`..,
`
`40-0-{2-(N-Methyl-i.midazo-2 • -ylca:rbcthoxamido )etbyl)-rapamyc:;in
`
`40-0-{2-Elhoxycarbonylaminoethyl)-rapamycin
`
`40-0-(2-Toly lsulfonamidocthyl)-rapamycin
`40-0-[2-(4" ,5'-Dicarboethoxy-1 ·;i: ,3"-triazol-1 '-yl)-ethyl]-rapamycin
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`Compounds according to claim 1 where X and Y are both 0, R 2 is H. R.l is
`methyl. and R 1 is other thar. H.
`
`A pr~Cs.s _ f~{ ~g compounds according· to any ooe of claims 1 through 4
`comprising the steps of ee~ea ef' eate:i:aa:hle e;· (i) reacteg a rapamycin,
`deoxorapamycin, or dihydiorapamycin (optionally in 0-protected form) with an
`organic radical (R 1 ·oi ~::- ~ ~~~ ~-~ · 1 •. optioiiany ·m prorecr~ f~)
`attached co a leaving group @
`teeer s~!aflle eeicii:c: e6 ae\:la=al reaetieR eee~eieHS
`. sac~~!.
`
`(a) x is -~Q'.3~~9- ~E- -~ ~~f:i_on ~~ -~1a.Ce m the presen~ ~! a.n:. aC?~d; ~
`(b) xis_ CF~~: and -~-~~n takt;~ pl~ee in die preseru:e· ~:ca t?a.Se;
`
`6.
`
`A compound according to any one of claims 1-5 for use as a pharmaceutical.
`
`A pharmaceutid composition comprising a compound according to any one of
`
`clai.cls !-3 tO~etber v.ith a pbarnw::eutically a.ccepubJe diluent or earner.
`
`8.
`
`t;sc of a compound according to claims 1-5 in the manufacture of a medicament
`
`for treating or preventing any of the following conditions:
`
`(i) autoimmune diseas~.
`
`(ii) allograft rejection.
`
`
`
`

`
`.,---
`
`(iii) graft vs. host disease>
`(iv) asthma.
`(v) multidrug resistance,
`
`•
`
`(vi) tumors or hypeiproliferari.ve disord~ or
`
`(vii) fungal infections.
`(viii) inflammation.
`
`(ix) infection by pathogens having Mip or Mip-like faC!ors, or
`
`(x) overdose of ma.cropbilin-binding immunosuppzcssants.
`
`..
`.
`Ye el fJFee!:t:les, fJf'Beesses. e::""lel 1:1T::i:J:ities sessta:Btially 8::9 ae&~eee eereir±.
`
`9.
`
`~
`
`-
`
`i I
`'
`
`_t_
`
`- · · - - ·
`
`d
`
`
`
`

`
`' ---. ..
`\
`
`--~
`
`(Amended) CLAIMS
`
`"(I)
`
`y
`
`24
`
`18
`
`20
`
`wherein
`
`X is (H.H) or O;
`
`Y is (H.OH) or O;
`
`R 1 and R 2 are independently selected
`
`H, alkyl, tfiiea:llcyl. arylalkyl, h
`
`roxyalkyl, dihydroxyalkyl,
`
`hydroxyalkylarylalkyl; dihydroxy kylarylalkyl. alkoxyalkyl. acyloxyalkyl,
`
`aminoalkyl, alkylaminoalkyl, alko ycarbonylaminoalkyl, acylaminoalkyl,
`arylsulfonamidoalkyl, allyl, dihydr xyalkylallyl. dioxolanylallyl. and
`hydroxyalkoxyalkyl
`
`
`
`

`
`' ether ( 0 ) liaka:ge; and
`
`\
`R 4 is methyl or R 4 and R 1 together form C 2-6 alkylene;
`
`d R 2 are not both H; and
`provided that R 1
`p~qyi4~4 that alko yalkyl or :hydroX,y_~oxy3llcYI )s c:>ther than ·alkoxymethyl or
`hydrpxyalkoxyme
`
`/
`Compounds according to claim 1 selected from the following:
`
`2.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`\. ..
`
`ymethyl)benzyl-rapamycin
`
`ydroxyethyl)]benzyl-rapamycin
`
`40-0-[3 • -(2,2-Dim thyl-1,3-dioxolan-4(S)-yl)-prop-2'-en-1 '-yl]-rapamycin
`
`(2'E, 4'S)-40-0-(4 5'-Dihydroxypent-2'-en-1 '-yl)-rapamycin
`
`40-0-(2-Hydrdx e
`
`carbonylmethyl-rapamycin
`
`40-0-[(3S)-2,2-Dimeth ldioxolan-3-yl]methyl-rapamycin
`
`40-0-[ (2S)-2,3-Dihydro yprop-1-yl ]-rapamycin
`
`40-0-(2-Acetox y)ethy l-r
`
`40-0-(2-N icotinoy loxy)et
`
`40-0-[2-(N-Morpholino )ac toxy ]ethy 1-rapamycin
`
`40-0-(2-N-lmidazoly lace to
`
`)ethy 1-rapamycin
`
`40-0-[2-(N-Methyl-N' -pipe
`
`inyl)acetoxy]ethyl-rapamycin
`
`39-0-Desmethy 1-39 ,40-0,0- thylene-rapamycin
`
`(26R)-26-Dihydro-40-0-(2-h
`
`roxy)ethyl-rapamycin
`
`28-0-Methyl-rapamycin
`
`40-0-(2-Aminoethy l)-rapamyc1
`
`
`
`

`
`/
`
`....
`
`'
`
`40-0-(2-A~eta'm.inoethy 1)-rapamycin
`40-0-(2-Nicoti amidoethyl)-rapamycin
`
`40-0-(2-(N-Me
`
`1-imidazo-2 • -y lcarbethoxamido )ethy 1)-rapamycin
`
`onylaminoethyl)-rapamycin
`
`40-0-(2-Tolylsulf.
`
`· doethyl)-rapamycin
`
`40-0-[2-(4' ,5'-Di~·t'JS,)Aethoxy-1 '.2· ,3'-triazol-1 '-yl)-ethyl]-rapamycin
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`Compounds according to clam I where X and Y are both 0, R 2 is H, R 4 is
`methyl, and R 1 is other than H.
`
`~
`The cOmpound acco~ claim i. which is 40-0-(2-Hydroxy)ethyl-rapamycin.
`
`A process for making comp unds according to any one of claims_ 1 through 4
`
`--------
`
`deoxorapamycin, or dihydror pamycin (optionally in 0-protected form) with an
`organic radical (R1 or R 2 as efined in claim 1. optionally in protected form)
`
`attached to a leaving group ( ) t:tadeF suitable aeidie eF aeHtFal Feaetion eoaditieas
`
`. such that
`
`(a) X is CC1 3(NH)O- and the eaction takes place in the presence of an acid; or
`(b) X is CF3S03- and the react on takes place in the presence of a base;
`
`and (ii) optionally reducing
`
`or (where necessary) deprotecting the product.
`
`-------
`
`1-5 for use as a pharmaceutical.
`
`rising a compound according to any one of
`
`3.
`
`4.
`
`5.
`
`7.
`
`8.
`
`6.
`
`A compound according to an
`
`A pharmaceutical_ composition co
`
`-----
`
`claims 1-5 together with a pharmac utically acceptable diluent or carrier.
`
`I ·~5 .
`f
`d .
`d.
`f
`se o a compoun accor 1ng to c ms 1- m the manufacture o a me 1cament
`U
`d
`for treating or preventing any of the following conditions:
`
`(i) autoimmune disease,
`
`(ii) allograft rejection.
`
`
`
`

`
`(iii)
`
`(iv) asthma.
`
`(v)
`
`(vi)
`
`(vii) fungal infections
`
`(viii) inflammation.
`
`(x) overdose of macrophilin binding immunosuppressants.
`
`having Mip or Mip-like factors, or
`
`""'~
`
`J>!e • el pre<!>1ets, fl~ lffiHties st>Bst&eti&!ly es aese•ibe<! hereiH.
`
`9.
`
`
`
`

`
`,
`
`,TENT COOPERATION TREA'
`
`r-rom the
`INTERNATIONAL PREl.IMINARY EXAMINING AUTHORITY
`
`To:
`SANDOZ LTD.
`Patents & Trademarks Division
`Lichtstr. 35
`.. ..,----,~~--~=,---
`4002 Basel
`SUISSE
`
`!.i
`
`--
`
`::-:·.;'_ ;(;J~
`
`:
`
`..
`
`. ... -'"--· ~-... ··--............
`
`PCT
`
`NOTIFICATION OF TRANSMITTAL OF
`INTERNATIONAL PRELIMINARY
`EXAMINATION REPORT
`
`(PCT Rule 71.1)
`
`Date of mailing
`(day/month/year)
`
`0 2. 11. 9lt
`
`Applicant"s or agent ·s file reforence
`100-7932
`
`International application No.
`PCT/ EP 93/ 02604"
`
`Applicant
`
`SANDOZ Lm. et al.
`
`I lnJ«n";on>i fol;ng d"o (day/mOMh/y~•) I Priority date (da_v1month/year)
`
`24/09/1993
`
`.
`
`09/10/1992
`
`IMPORTANT NOTIFICATION
`
`t.
`
`·1 hC' applicant i~ hC'rC"hy notified that thi!< International Preliminary Examining Authority transmits herewith the international
`pr<-hmmarv C"v:11nma11nn r<-pon and its annexe!<. ir any. established on the international application.
`
`A copy nr lhC' t<•pn11 ;inrJ 11~ annC'X<'~. ;r anv. i!< hC"inJ? tr:m!<mitted to the" lnl<-rnation::1l Tiur<-au for communic::11ion 10 ::111 the
`t'IC'clC'd Olf1cr<
`
`\\"hcr<- 1r•1•11r1.,I i., ;iny nr lht." <-kcll"J OffwC'<. the ln1crn::111on;il Tiure;iu will prepare an Fnizlish tram<l;ition or the rC'pon (hut
`""' nf "'" :111ur,r<) ."lnd will lran<nHI such t1an<lat1nn to rhn!<e Offic-c-s.
`
`Hf '\U,IU U
`
`11 .. · a1·r!•. "'"' '""" cnlc-r lhC' nat1<'n.:tl l'ha<c- hcf.,rc- C'"ach C'"IC'"clc-d Office- hy pc-rforminl!, cert:iin ::1cl!< (liling transl::1tiom: and
`.. ,,,,,. .. '""'"'"·': f,.,.,., n1ll1111 lll 11l<'llth< fr.,rn !he- p11orll)' d:itc (nr i;itc-r in '.<f'ITIC" Officc~)(Arlicle .19(l})(SC"C'" ::!l!<o the- rc-n1indc-r
`,.,.,,,I»,,, .. 1 .. , •. ""''"'11.:tl Bure-au "''h Fo1n1 rc·1 dll".lOI).
`
`\\ t.crc ;i 11 ;.1 .. J;.11•><> of thr mlcrn:1tio11::1l ::1pplrc:it10n mu<t he rurni!'hed to an elected Office, that tran!<lation 1nust contain a
`11a1,.l;,•1"" nl :>.,, :in1tC""lfC''.< to the m1c-rnat1on::1I preliminary examin;itinn report. It is the applicant·s respon!<ihility lo prepare
`::111<1 I unH•'• '""' h 11 ;in•l:>11on directly tn c-ach c-lec1ed Office concerned.
`
`I "' fur11 .... 1!--i;ul• "" the :1pphc::1hlc time- hmlls ;ind requirements of the elected Offices, see Volumc II of the PCI" Applicant·s
`( fuu!r
`
`~ l·ur"f'('::l•l l'atc-nt Office
`,.,g1
`
`- - - - l·a,- ( · 49-RQ) 2.199-4465
`
`1>-1Ul2~1! '\lumch
`
`·1 d. ( · 4~-1!9 > 2.l~Q.O, Tx: 52.1656 cpmu d
`
`h''"' l'<."l ·11'1·./\ .-11r. !July 1992) 1'2047.1
`
`(10/03/1994)
`
`Authori7.ed officer
`
`Jose Ramon Ambroa
`
`
`
`

`
`-··
`
`•
`
`PATENT COOPERATION TREATY
`
`•
`
`From the INTERNATIONAL SEARCHING AUTHORITY
`
`To:
`SANDOZ LTD.
`Patents & Trademarks
`L1chtstr. 35
`4002 Basel
`SWITZERLAND
`
`D1v1s1on
`--··--·-
`
`•••
`~.·.
`
`'!"" ....
`
`:.: ..
`
`--
`
`-
`
`Applicant's or agent's file reference
`100-1932
`International application No.
`PCT I EP 93/ 02604
`Applicant
`
`SANDOZ LTD. et al.
`
`PCT
`
`NOTIFICATION OF TRANSMITrAL OF
`THE INTERNATIONAL SEARCH REPORT
`OR THE DECLARATION
`
`(PCT Rule 44.1)
`
`-
`
`Date of mailing
`(day/month/year)
`
`2 8. 12. 93
`
`FOR FURTHER ACTION s~ paragraphs 1 and 4 below
`
`International filing date
`(day/month/year)
`
`24/09/93
`
`1. [i} The applicant is hereby notified that the international search report has been established and is transmitted herewith.
`Yilinc of -dments and statement wader Article 19:
`The applicant is entitled, if he so wishes, to amend the claims of the international application (see Rule 46):
`
`When! The time limit for filing such amendments is normally 2 months from the date of transmittal of the
`international search report; however, for more details, see the notes on the accompanying sheet.
`
`Where! To the International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20, Switzerland
`Fascimile No.: (41-22) 740.14.35
`
`For moR ddailcd in5cruc:tions, see the notes on the accompanying sheet.
`
`The applicant is hereby notified that no international search report will be established and that the declaration under
`Article I 7(2)(a) to tha.t effect is transmitted herewith.
`
`3. o
`
`With regard to the prob:st against payment of (an) additional fee(s) under Rule 40.2; the applicant is notified that:
`
`D
`
`D
`
`the protest together with the decision thereon has been transmitted to the International Bureau together with the
`applican1$'s request to forward the texts of both the protest and the decision thereon to the designated Offices.
`
`no decision has ~n made yet on the protest; the applicant will be notified as soon as a decision is made.
`
`4.Furtber actioa(s):
`
`The applicant is reminded of the following:
`
`Shortly after 18 months from the priority date, the international application will be published by the International Bureau.
`If the applicant wishes to avoid or postpone publication, a notice of withdrawal of the international application, or of the
`priority claim, must reach the International Bureau as provided in Rules 90bU.1 and 90bl.r.3, respectively, before the
`completion of the technical preparations for international publication.
`
`Within 19 -cbs from the priority dat.e, a demand for international preliminary examination must be filed if the applicant
`wishes to postpone the entry into the national phase until 30 months from the priority date (in some Offices even later).
`
`Within 20 m-cbs from the priority dale, the applicant must perform the prescribed acts for entry into the national phase
`before all designated Offices which have not been elected within 19 months from the priority dat.e or could not be elected
`because they are not bound by Chapter II.
`
`Name and mailing address of the International Searching Authority Authorized officer
`
`~ European Patent Office, P.B. 5818 Patentlaan 2
`
`N L-2280 HV Rijswijk
`Tel. ( • 31-70) 340-2040. Tx. 31 6S 1 epo nl,
`_....-__Fax: ( + 31-70) 340-3016
`
`·
`
`M. PEIS
`
`Mf
`
`Form PCT/ISA/220 (July 1992)
`
`
`
`

`
`•
`
`NOTES TO FORM Pcr/ISA/220
`
`·•
`
`These notes are intended to give the basic instructions concerning the filing of amendments under article 19. The
`Notes are based on the requirements of the Patent Cooperation Treaty and of the Regulations and the Administrative
`Instructions under that Treaty. In case of disaepancy between these Notes and those requirements, the latter are applicable.
`For more detailed information, see also the PCT Applicant's Guide, a publication of WIPO.
`
`In these notes, •Article•, •Rule•, and •section• refer to the provisions of the PCT, the PCT Regulations and the PCT
`administrative Instructions respectively.
`
`INSTRUCTIONS CONCERNING AMENDMENTS UNDER ARTICLE 19
`
`The applicant has, after having received the international search report. one opportunity to amend the claims of the
`international application. It should however be emphasized that. since all parts of the international application (claims.,
`description and drawings) may be amended during the international preliminary examination procedure, there is usually
`no need to file amendments of the claims under Article 19 except where, e.g. the applicant wants the latter to be published
`for the purposes of provisional protection or has another reason for amending the claims before international pbulica.tion.
`Furthermore, it should be emphasized that provisional protection is available in some States only.
`
`What parts of the international application may be amended!
`The claims only.
`
`The description and the drawings may only be amended during international preliminary examination under
`Chapter II.
`
`When?
`
`Within 2 months from the date of transmittal of the international search report or 16 months from the priority
`dale, whichever time limit expires later. h should be noted, however, that the amendments wil be considered
`as having been received on time if they are received by the International Bureau after the expiration of the
`applicable time limit but before the completion of the technical preparations for international publication
`(Rule 46.l).
`
`Wbcft not to file the lllDeadmeots'!
`
`The amendmenu may only be filed with the International Bureau and not with the receiving Office or the
`International Searching Authority (Rule 46.2).
`
`Where a demand for international preliminary examination has been/is filed. see below.
`
`How!
`
`Elther by cancelling one or more entire claims, by adding one or more new claims or by amending the text of
`one or more of the claims as ftled.
`
`A replacement sheet must be submitted for each sheet of the claims which, on account of an amendment or
`amendmenu, differs from the sheet originally filed.
`
`All the claims appearing on a replacement sheet must be numbered in Arabic numerals. Where a claim is
`canoeUed, no renumbering of the other claims is required. In all cases where claims are renumbered, they must
`be r~umbered con.scc:utively (Administrative Instructions, Section 20S(b)).
`
`Whmt D«k'"DOmllmllU:S ..-./may -=comp_, die ammdmcats!
`
`Leacr (Sedioa 205(b )):
`
`The amcndm~u must be submitted with a letter.
`The ~r will not be published with the international application and the amended claims. It should not be
`confounded with the ·st&tement under Article 19(1)• (see below, under •statement under Article 19(1Y).
`
`The letter must indic:&Le the differences between the claims a.s filed and the claims as amended. It must. in
`p&r\JCUlar, indic:&Le, in connection with each claim appearing in the international application (it being understood
`that identical indic&tions concerning several claims may be grouped),whether
`
`(i)
`
`(ii)
`
`(ill)
`
`(iv)
`
`the claim is unchanged;
`
`the claim is cancelled;
`
`the claim is new;
`the claim replaces one or more claims as filed;
`
`(v)
`
`the claim is the result of the division of a claim as filed.
`
`Notes to Form PCT/ISA/220 (first sheet) (July 1992)
`
`
`
`

`
`NOTES TO FORM Per /ISA/220 (continued)
`
`'lbe foUowi.ng examples illustrate tbe llUUIDer ia wbich 11111eadmeats must be explained ia the
`accompanying letta-:
`
`I.
`
`2.
`
`3.
`
`4.
`
`[Where originally there were 48 claims and aft.er amendment of some claims there are SI]:
`·claims I to 29, JI, 32, 34, JS, 27 to 48 replaced by amended claims bearing the same numbers;
`Claims 30, 33 and 36 unchanged; new claims 49 to SI added.•
`
`[Where originally there were I S claims and after amendment of all claims there are I I];
`•claims I to IS replaced by amended claims I to It.•
`
`[Where originally there were I4 claims and the amendments consist in cancelling some claims and in adding
`new claims]:
`·claims I to 6 and I 4 unchanged; claims 7 to I 3 cancelled; new claims Is. I 6 and I 7 added.• or
`·claims 7 to 13 cancelled; new claims IS, 16 and I7 added; all other claims unchanged.•
`
`[Where various kinds of amendments are made]:
`·claims 1-10 unchanged; claims 1 I TO 13, IS and 19 cancelled; claims 14, IS and 16 replaced by amended
`claim 14; claim 17 subdivided into amended claims IS, 16 and I7; new claims 20 and 21 added.•
`
`•statement under artide 19(1 r (Rule 46.4)
`The amendments may be accompanied by a statement explaining the amendments and indicating any impact .
`that such amendments might have on the description and the drawings which cannot be amended under
`Article 19(I ).
`
`The statement will be published with the international application and the amended claims.
`The statement should be brief, it should not exceed SOO words if in English or if translated into English.
`
`It should not be confouded with and does not replace the letter indicating the differences between the claims
`as filed and as amended. It must be riled on a sepan.te sheet and must be identified as such by a heading,
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`The amendments must be made in the language in which the international application is published. The letter
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`Consequence if 11 demand for iataaatioaal prdimiaary examination bas already been filed?
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`For further details on the requirements of each designir.ted/elected Office, see Volume II of the PCT Applicant's
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`Notes to Form PCT/ISA/220 (second sheet) (July 1992)
`
`
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`

`
`EO/US
`PCT /E P93/02604
`
`P_AiNT COOPERATION TREA.
`
`PCT
`
`To:
`
`From the INTERNATIONAL BUREAU
`
`NOTIFICATION OF ELECTION
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`(PCT Rule 61.2)
`
`United States Patent and Trademark
`Office
`Washington, D.C.
`
`Date of mailing:
`28 April 1994 (28.04.94)
`
`International application No.:
`PCT /E P93/02604
`
`in its capacity as elected Office
`
`Applicant's or agent's file reference:
`100-7932
`
`International filing date:
`24 September 1993 (24.09.93)
`
`Priority date:
`
`09 October 1992 (09. 10. 92)
`
`Applicant:
`
`SANDOZ LTD. et al
`
`1. The designated Office is hereby notified of its election made:
`
`[8J in the demand filed with the International preliminary Examining Authority on:
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`
`D in a notice effecting later election filed with the International Bureau on:
`
`2. The election [8J was
`D was not
`
`made before the expiration of 19 months from the priority date or, where Rule 32 applies, within the time limit under
`Rule 32.2(b).
`
`The International Bureau of WIPO
`34, chemin des Colombettes
`1211 Geneva 20. Switzerland
`
`Facsimile No.: (41-22) 740.14.35
`
`Form PCT/18/331 (July 1992)
`
`Authorized officer:
`
`J. Zahra
`Telephone No.: (41-2 2) 730.91. 11
`
`430217
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`..._ ___ i_'_C_T_/_E_P_9.._3_/_l_l2-u--u--"'_.· _ __,
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`1 U/(19/\.d..;~
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`'.
`
`.. '
`
`=> fil reg; d que stat
`FILE 'REGISTRY' ENTERED AT 11:43:38 ON 26 APR 96
`USE IS SUBJECT TO THE TERMS OF YOUR ~STOMER AGREEMENT
`COPYRIGHT (C) 1996 American Chemical Society (ACS)
`
`19 APR 96
`STRUCTURE FILE UPDATES:
`DICTIONARY FILE UPDATES: 25 APR 96
`
`HIGHEST RN 175414-60-5
`HIGHEST RN 175414-60-5
`
`TSCA INFORMATION NOW CURRENT THROUGH DECEMBER 1995
`
`Please note that search-term pricing does apply when
`conducting SmartSELECT searches.
`
`Ll
`
`STR
`
`N9DE ATTRIBUTES:
`OEFAULT MLEVEL IS ATOM
`DEFAULT ECLEVEL IS LIMITED
`
`..
`GRAPH ,AT 1p~.IBUTES~:
`RING(S) ARE ISOLATED OR EMBEDDED
`NUMBER OF NpDES IS 27
`
`1
`
`}
`
`:
`
`
`
`

`
`STEREO ATTRIBUTES: NONE
`L2
`6B7 SEA FILE=REGISTRY SSS FUL Ll
`
`3912 ITERATIONS
`100.0% PROCESSED
`SEARCH TIME: 00.00.10
`
`6B7 ANSWERS
`
`=> fil ca,caplus
`FILE 'CA' ENTERED AT 11:43:45 ON 26 APR 96
`USE IS SUBJECT TO THE TERMS OF YOUR CUSTOMER AGREEMENT
`COPYRIGHT (C) 1996 AMERICAN CHEMICAL SOCIETY (ACS)
`
`'CAPLUS' ENTERED AT 11:43:45 ON 26 APR 96
`FILE
`USE IS SUBJECT TO THE TERMS OF YOUR CUSTOMER AGREEMENT
`COPYRIGHT (C) 1996 AMERICAN CHEMICAL SOCIETY (ACS)
`
`=> s 12
`L3
`L4
`
`657 FILE CA
`667 FILE CAPLUS .
`
`TOTAL FOR ALL FILES
`L5
`1324 L2
`
`=> s 15(1) ((autoimmun? or auto immun?) (3a) (diseas? or disorder#) or
`allograft? or graft? or transplant? or asthm? or (multidrug# or
`drug#) (3a)resist? or tum? or carcin? or cancer? or neoplas? or fung? or
`inflamm? or infect? or immunosupress? or immun? suppress?)
`L6
`132 FILE CA
`L7
`132 FILE CAPLUS
`
`TOTAL FOR ALL FILES
`LB
`264 L5(L) ((AUTOIMMUN? OR AUTO IMMUN?) (3A) (DISEAS? OR DISORDER#
`) OR ALLOGRAFT? OR GRAFT? OR TRANSPLANT? OR ASTHM? OR
`(MUL
`TIDRUG# OR DRUG#) (3A)RESIST? OR TUM? OR CARCIN? OR CANCER?
`OR NEOPLAS? OR FUNG? OR INFLAMM? OR INFECT? OR IMMUNOSUPR
`ESS? OR IMMUN? SUPPRESS?)
`
`=> s
`L9
`LlO
`
`lB and (treat? or therap? or prevent? or inhibit?)
`105 FILE CA
`105 FILE CAPLUS
`
`TOTAL FOR ALL FILES
`Lll
`210 LB AND (TREAT? OR THERAP? OR PREVENT? OR INHIBIT?)
`
`=> s lB(l) (treat? or therap? or prevent? or inhibit?)
`L12
`51 FILE CA
`L13
`51 FILE CAPLUS
`
`TOTAL FOR ALL FILES
`L14
`102 LB(L) (TREAT? OR THERAP? OR PREVENT? OR INHIBIT?)
`
`=> dup rem 114;~.d 1-51 bib abs hitstr; fil caold
`
`
`
`

`
`PROCESSING COMPLETED FOR L14
`L15
`51 DUP REM L14 (51 DUPLICATES REMOVED)
`
`L15
`AN
`TI
`
`IN
`PA
`so
`
`PI
`DS
`
`DUPLICATE 1
`
`AI
`PRAI
`DT
`LA
`AB
`
`ANSWER 1 OF 51 CA COPYRIGHT 1996 ACS
`124:220512 CA
`Pse of lef lunomide to control and reverse chronic allograft
`rejection and to_ prevent or control xenograft rejection
`Williams, James w.
`USA
`PCT Int. Appl., 44 pp.
`CODEN: PIXXD2
`WO 9601111 Al 960118
`W: AM, AU, BB, BG, BR, BY, CA, CN, CZ, EE, FI, GE, HU, JP, KE, KG,
`KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN, MW, MX, NO, NZ, PL,
`RO, RU, SD, SI, SK, TJ, TT, UA, UZ, VN
`RW: AT, BE, BF, BJ, CF, CG, CH, CI, CM, DE, DK, ES, FR, GA, GB, GR/
`IE, IT, LU, MC, ML, MR, NE, NL, PT, SE, SN, TD, TG
`WO 95-US8~46 950630
`us 94-270908 940705
`Patent
`English
`Methods are disclosed for controlling or reversing chronic rejection
`of allografts in a transplantation patient by administering
`leflunomide.:product alone, or in combination with one or mo~e
`immunosuppressive agents selected from the group consisting of
`cyclosporine A, FK506, rapamycin and corticosteroids. Also
`disclosed .are methods of preventing or controlling acute and chronic
`rejection of xenografts in a transplantation patient.by
`admihister.iihg leflunomide product alone, or in combination with one
`or more imni.unosuppressive agents selected from the g.roup consisting
`of cyclosporine A, FK506, rapamycin and corticosteroids. Th'e effect
`of e.g. leflunomide alone or with cyclosporine A on chronic
`rejection of rat cardiac allografts and on rejection od concordant
`hamster to rat cardiac xenografts is described.
`LT 53123-88-9, Rapamycin
`RL: BAC (Biological activity or effector, except adverse); THU
`'(.Therapeutic use); BIOL (Biological study); USES (Uses) -
`(leflu.nomide or A771726, alone or in immunosuppressant
`combination, to control and reverse chronic allog~aft
`rejection and to prevent or control xenograft
`rejection1
`53126-88-9 CA
`Rapa'inycin (9CI)
`
`RN
`CN
`
`(CA INDEX NAME)
`
`Absolute stereochemistry.
`Double bqnd geometry as shown.
`
`
`
`

`
`PAGE 1-A
`
`Me
`
`Me
`
`Me
`
`Me
`
`s
`
`PAGE 2-A
`
`Me
`
`DUPLICATE 2
`
`L15 ANSWER 2 OF 51 CA COPYRIGHT 1996 ACS
`AN
`124:75919 CA
`TI Cytokine and alloantibody networks in long term cardiac allografts
`in rat recipients treated with rapamycin
`AU Wasowska, Barbara; Wieder, Kenneth J.; Hancock, Wayne W.; Zheng, Xin
`Xiao; Berse, Brygida; Binder, Jochen; Strom, Terry B.;
`Kupiec-Weglinski, Jerzy W.
`CS Harvard Medical School, Division of Immunology, Boston, MA, 02215,
`USA
`J. Immunol. (1996}, 156(1}, 395-404
`CODEN: JOIMA3; ISSN: 0022-1767
`Journal
`English
`Treatment with rapamycin (RPM} prevents accelerated rejection of
`(LEW.times.BN}Fl cardiac allografts in LEW rats presensitized with
`
`SO
`
`