0
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`
`September 09, 2015
`
`THIS IS TO CERTIFY THAT ANNEXED IS A TRUE COPY FROM THE
`RECORDS OF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`OF:
`
`APPLICATION NUMBER: 08/416,673
`FILING DATE: April 07, 1995
`PATENT NUMBER: 5,665, 772
`ISSUE DATE: September 09,1997
`
`By Authority of the
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`f/1 ~-
`
`M. TARVER
`Certifying Officer
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 001
`
`

`
`- 37 -
`
`CLAIMS
`
`" .. ·
`
`0 , ••
`
`(I)
`
`0.....--
`
`24
`
`X is (H,H) or 0;
`
`Y is (H,OH) or 0;
`
`R 1 and R2 are independently selected from
`
`H, alkyl, thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl,
`
`hydroxyalkylarylalkyl, dihydroxyalkylarylalkyl\alkoxyalkyl, acyloxyalkyl,
`\
`aminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, acylaminoalkyl,
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 002
`
`

`
`,_
`.. -· WD 94/09010
`
`•
`
`-38-
`
`• PCT/EP93/02604
`
`~
`
`arylsulfonamidoalky~ allyl, dihydroxyalkylallyl, dioxolanylallyl,
`caralkoxyalkyl, and (R3~Si where each R3 is independently selected from~
`methyl, ethyl, isopropyl, ,!-butyl, and phenyl; wherein "alk-" or "alkyl" refers
`to cl-6 alkyl, branched or linear, preferably c;.3 alkyl, in which the carbon
`chain may be optionally interrupted by an ether (-0-) Hnksge; and
`
`R4 is m thy! or R~ and R 1 together fOim ~ alkylene;
`
`provided th R1 and Rz are not both H; and
`provided that here R1 is carbalkoxyalkyl or (RJ),Si. X andY are not both 0.
`
`2.
`
`Compounds ace
`· g to claim 1 selected from the following:
`1.
`40-0-Benzy:r rapamycin
`2.
`40-0-( 4 • -Hy
`xymethyl)benzyl-mpamycin
`3.
`40-0-[4'-(1,2-
`
`4.
`5.
`6.
`
`~Allyl-rapam cin
`40-0-[3'-(2,2-Dim yl-1.3-dioxolan-4{S)-yl)-prop-2'-en-l'-yl]-rapamycin
`(2'E. 4'5)-40-0-(4'
`'-Dihydroxypent-2'-en-1'-yl)-rapamycin
`40-0-(2-Hydroxy)etbo carbonylmethyl-rapamycin
`40-0-(2-Hydroxy)cthyl-
`9.
`40-0-(3-Hydroxy)propyl-
`amycin
`10. ~0-(6-Hydroxy)hexyl-rap yc:in
`11. 40-0-[2-(2-Hydroxy)ethoxy]e yl-rapamycin
`12. 4Q..0-[(3S)-2.2-Dimethyldioxol
`-3-yl]methyl-rapamycin
`13. ~0-[(25)-2,3-Dihyd:roxypzop-1- }-rapamycin
`14. 40-0-(2-Acetoxy)ethyl-rapamycin
`15. 40-0-(2-Nicotinoyloxy)ethyl-rapamycin
`16. 40-0-[2-(N-Morpholino )acetoxy]ethyl-~amycin
`
`7.
`
`8.
`
`\
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 003
`
`

`
`' ;·
`.. , ..,....,\
`
`·Wd 94/09010
`;.....;'- ..
`
`•
`
`- 39-
`
`• . PCf/EP93/02604
`
`-~
`
`\
`17. 40-0-(2-N-Imidazolylacetoxy )ethyl-rapamycin
`18. 40-0-[2-(N-Methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin
`19. 3~~-Desmethyl-39 ,40-0,0-ethylene-rapamycin
`20.
`(26R\ -26-Dihydro-40-0-(2-hydroxy)ethyl-rapamycin
`
`21.
`
`minoethyl)-rapamycin
`
`40-0-(2-~cetaminoethyl)-rapamycin
`
`22.
`23.
`24. 40-0-(2-N~~-namidoethyl)-rapamycin
`25. 40-0-(2-(N-
`ethyl-imidazo-2 '-ylcarbethoxamido)ethyl)-rapamycin
`26. 40-0-(2-Ethox ~arbon~laminoethy1)-rapamycin
`27. 40-0-(2-Tolylsul.fonamidoethyl)-rapamycin
`28. 40-0-[2 -( 4' ,5 '-D~boethoxy -I ',2' ,3 '-triazol-1 '-y I)-ethyl]-rapamycin
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`Compounds according to clairp 1 where X andY are both 0, R2 isH, R4 is methyl,
`and R 1 is other than H.
`\
`.
`
`40-0-(2-Hydroxy)ethyl-rapamy\
`
`Compounds according to any one ~:!aims 1 through 4 obtained or obtainable by (i)
`reacting a rapamycin, deoxorapam~~:\.' or dihydrorapamycin (optionally in a(cid:173)
`protected form) with an organic radic' attached to a leaving group under suitable
`acidic or neutral reaction conditions, an
`(ii) optionally reducing the producL.
`
`A compound according to any one of clai
`
`1-5 for use as a pharmaceutical.
`
`A pharmaceutical composition comprising a co\pound according to any one of
`claims 1-5 together with a pharmaceutically ac\le diluent or carrier.
`
`Use of a compound according to claims 1-5 in the \ufacture of a medicament for
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 004
`
`

`
`PCf/EP93/02604
`
`•
`
`- 40-
`
`or preventing any of the following conditions:
`
`(i)
`
`(ii)
`
`(iii)
`(iv) asthma,
`
`(v)
`
`ost disease.
`
`..
`
`(vi)
`roliferative disorders, or
`(vii) fungal infections,
`(viii) inflammation,
`
`having Mip or Mip-like factors, or
`
`9.
`
`Novel products, processes, and utilities substantially as described herein.
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 005
`
`

`
`\W
`
`'·-~
`WORLD INTELLECTUAL PROPERTY ORGANIZATION'
`International Bureau
`'
`
`t1lt
`
`PCf
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCl)
`wo 94/09010
`
`(51) International Patent Oassification 5 :
`C07D 498/18, C07F 7/18
`A61K 31/435 I I C07D 498/18
`C07D 311:00, 273:00, 221:00
`
`(11) International Publication Number:
`
`At
`
`(43) International Publication Date:
`
`28 April 1994 (28.04.94)
`
`(21) International Application Number:
`
`PCT /EP93/02604
`
`(22) International Filing Date:
`
`24 September 1993 (24.09.93)
`
`(72) Inventors; and
`(75) Inventors/ Applicants {for US only) : COTTENS, Sylvain
`[CHICH]; In den Reben 12, CH-4108 Witterswil (CH).
`SEDRAN!, Richard [LU/CH]; Herrengrabenweg 15,
`CH-4054 Basle (CH).
`
`(30) Priority data:
`9221220.8
`
`9 October 1992 (09.1 0.92)
`
`GB
`
`(74) Common Representative: SANDOZ LTD.; Patents &
`Trademarks Div., Lichtstrasse 35, CH-4002 Basle (CH).
`
`(71) Applicant {for AT only): SANDOZ-ERFINDUNGEN
`VERWALTUNGSGESELLSCHAFT M.B.H. [AT/AT];
`Brunner Strasse 59, A-1230 Vienna (A 1).
`
`(71) Applicant (for DE only): SANDOZ-PATENT-GMBH [DE/ '
`DE]; Humboldstrasse 3,_D-79539 Lorrach (DE).
`·
`
`(81) Designated States: AU, CA, CZ, FI, HU, JP, KR, NO, NZ,
`PL, RO, RU, SK, US, European patent (AT, BE, CH,
`DE, OK, ES, 'FR, GB, GR, IE, IT, LU, MC, NL, PT,
`SE).
`-
`
`(71) Applicant (for all designated States except AT DE US): SAN(cid:173)
`DOZ LTD. [CHICH]; Lichtstrasse 35, CH-4002 Basle
`(CH).
`
`Published
`With international search report.
`
`(54) Title: 0-ALKYLATED RAPAMYCIN DERIVATIVES AND THEIR USE, PARTICULARLY AS IMMUNOSUPPRES(cid:173)
`SANTS
`
`(57) Abstract
`
`Novel 0-alkylated derivatives of rapamycin of for-
`mula (1), especially 40-0-alkylated derivatives, are found a •a
`to have pharmaceutical utility, particularly as immunosup(cid:173)
`pressants.
`
`50.> , ...... ··
`~~0
`
`i 34
`
`1t
`
`0
`
`- -
`
`13
`
`15
`
`:
`
`(I)
`
`24
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 006
`
`

`
`DECLARATION AND POWER OF ATTORNEY
`FOR UNITED STATES PATENT APPLICATION
`
`Case No.
`
`100-7932/PCT
`
`I
`
`~ '(
`
`'·"
`
`. '
`
`As a below named inventor, I hereby declare that:
`
`My residence, post office address and citizenship are as stated below next to my name,
`
`and
`
`I believe that I am the original, first and sole inventor (if only one name is listed below)
`or an original, first and joint inventor (if more than one name is listed below) of the subject
`
`matter which is claimed and for which a United States patent is sought on the invention
`
`entitled
`
`0-ALKYLATED RAPAMYCIN DERIVATIVES AND THEIR USE, PARTICULARLY
`AS IMMUNOSUPPRESSANTS
`
`the specification of which
`
`[ ]
`
`is attached hereto.
`
`[ ] was_ filed on
`
`19
`
`as application Serial No. 01
`
`and, if these brackets contain an X [
`
`], was amended on
`
`19
`
`[X] was filed as Patent Cooperation Treaty intemation application No. PCT/EP93/02604
`
`on September 24
`
`, 19 9 3
`
`, if these brackets contain an X [ ], was
`
`amended under Patent Cooperation Treaty Article 19 on
`
`and, if these brackets contain an X [
`[ ] entered the national stage in the United States and was accorded Serial No.
`
`] , was amended on
`
`' 19
`, 19
`
`on
`
`was amended on
`
`' 19
`
`, and if these brackets contain an X [
`
`I hereby state tha~. I have reviewed and understand the contents of the above-identified
`
`specifiction including the claims, as amended by any amendment(s) referred to above.
`I acknowledge my duty to disclose all information which is known by me to be material
`
`to patentability as defined in Title 37, Code of Federal Regulations, § 1.56.
`I hereby claim the benefit under Title 35, United States Code, § 119 of any foreign
`
`application(s) for patent or inventor's certificate indicated below and of any Patent
`
`Cooperation Treaty international application(s) designating at least one country other than the
`
`United States indicated below and have also identified any foreign application(s) for
`
`- 1 -
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 007
`
`

`
`Case No. 100-7932/PCT
`
`patent or inventor's certificate and Patent Cooperation Treaty international application(s)
`designating at least one country other than the United States for the same subject matter and
`having a filing date before that of the application for said subject matter the priority of which
`is claimed:
`
`Country:
`
`Number:
`
`Filing Date:
`
`Great Britain
`
`9221220.8
`
`October 9, 1992
`
`Priority Claimed:
`
`[X] Yes[ ] No
`
`[ ] Yes[ ] No
`
`[ ] Yes[ ] No
`
`[ ] Yes[ ] No
`
`[
`
`] Yes[ ] No
`
`[ ] Yes[ ] No
`
`I hereby claim the .benefit under Title 35, United States Code, § 120 of any United
`States application(s) listed below and of any Patent Cooperation Treaty international
`application(s) designating the United States listed below and, insofar as the subject matter of
`each of the claims of this application is not disclosed in said prior app1ication(s) in the
`manner required by the first paragraph of Title 35, United States Code, § 112, I acknowledge
`my duty to disclose all information known to me to be material to patentability as defined in
`Title 37, Code of Federal Regulations, § 1.56 which became available between the filing
`date(s) of the prior application(s) and the national or Patent Cooperation Treaty international
`filing date of this application:
`
`Application
`
`Serial No.
`none
`
`Status (Pending,
`
`Abandoned, Patented)
`
`- 2 -
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 008
`
`

`
`,--j
`
`'
`
`I hereby appoint the following:
`
`ROBERT S. HONOR
`THOMASO.MCGOVERN
`MELVYN M. KASSENOFF
`JOSEPH J. BOROVIAN
`DIANE E. FURMAN
`CARL W. BATTLE
`ANDREW N. PARFOMAK
`JOHN L. CHIATALAS
`CAROL A. LOESCHORN
`MICHAEL P. MORRIS
`THOMAS C. DOYLE
`
`Case No. 100-7932/PCT
`
`~&-No 22.801
`Reg. No. 25,741
`Reg. Nu.-26~89-
`Reg. No. 2.6.63-1-
`Reg. No.__31..-1.04-
`-Reg. No. 3Q73J(cid:173)
`Reg. No. 32 43 1
`Reg. No. 31,818
`_Reg No 35,590 -
`Reg. No. 34,513-
`Reg. No. 22,340
`
`/ /
`
`respectively and individually, as my attorneys and/or agents, with full power of substitution
`
`and revocation, to prosecute this application and to transact all business in the Patent and
`
`Trademarks Office connected therewith. Please address all communications to ROBERT S.
`HONOR, SANDOZ CORPORATION, 59 Route 10, East Hanover, New Jersey 07936-1080,
`
`whose telephone number is 201-503-8485.
`I hereby declare that all statements made herein of my own knowledge are true and that
`all statements made on information and belief are believed to be true; and further that these
`statements were made with the knowledge that willful false statements and the like so made
`
`are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United
`
`States Code and that such willful false statement may jeopardize the validity of the
`
`application or any patent issuing thereon.
`
`Sole inventor or
`first joint inventor:
`.... ;
`
`\
`
`Full name
`
`Sylvain Cottens
`
`·o
`/ _,..{)
`~·i·
`
`Signature
`Date
`Citizenship
`Residence
`
`fflat-~~ I~ ;13'1 \
`Switzerland
`CH-4108 Witterswil,
`In den Reben 12,
`Switzerland
`C-HX
`P.O. Address: same. as above. _
`
`IMPORTANT: Before this declaration is signed, the patent application (the specificateion, the claims and this
`declarations) must be read and understood by each person signing it, and no changes may be made in the
`application after this declaration has been signed.
`
`- 3 -
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 009
`
`

`
`t ,-
`
`100-7932/PCT
`
`Case No.
`oD
`-z, _,....
`f[)i~~\~
`l g )_s-
`
`Second joint inventor,
`if any:
`
`Full name
`
`Richard Sedrani
`
`Signature
`Date
`Citizenship
`Residence
`
`~ill... 11
`Luxembourg
`Herrengrabenweg 15, CH-4054 Basle,
`C--H >(
`Switzerland
`P.O. Address :same as above
`
`Third joint inventor,
`if any:
`
`Fourth joint inventor,
`if any:
`
`Fifth joint inventor
`if any:
`
`Full name
`
`Signature
`Date
`Citizenship
`Residence
`
`P.O. Address:
`
`Full name
`
`Signature
`Date
`Citizenship
`Residence
`
`P.O. Address:
`
`Full name
`
`Signature
`Date
`Citizenship
`Residence
`
`P.O. Address:
`
`- 4-
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 010
`
`

`
`f~ ··"
`
`.
`
`'
`
`DO/EO BIBLIOGRAPHIC DATA ENTRY
`
`SERIAL NUMBER:
`08 / 416673
`IA NUMBER:
`PCT/ £P93 / 02604
`FAMILY NAME:
`COTTENS
`GIVEN NAME:
`SYLVAIN
`PRIORITY CLAIMED (Y/NJ:
`Y
`NO BASIC FEE CY/N);
`N
`ATTORNEY DOCKET NUMBER:
`100-7932/PCT
`CORRESPONDENTS NAME/ADDRESS:
`ROBERT S. HONOR
`SANDOZ PATENT DEPT
`59 ROUTE 10
`E. HANOVER~ N.J. 07936-1080
`
`RECEIPT DATE:
`04 / 07 /
`IA FILING DATE:
`09 / 24 /
`DELAY WAIVED (Y/NJ:
`N
`DEMAND RECEIVED (Y/N)~
`Y
`PRIORITY DATE:
`10 / 09
`/
`US DESIGNATED ONLY CY/N):
`CtJUNTRY:
`
`APPLICATION TITLES:
`0-ALKLATED RAPAMYCIN DERIVATIVES AND THEIR US£, PARTICULARLY AS
`IMMUNOSUPPRESSENTS
`
`OK TO UPDATE? <Y OR NJ Y
`
`N
`
`95
`93 .
`
`•
`•
`•
`•
`t32 •
`EPX •
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 011
`
`

`
`BAR CODE
`
`lllllllllllllllllllllllllllllllll
`
`U.S. PATENT APPLICATION
`
`SERIAL NUMBER
`
`RUNG DATE
`
`ClASS
`
`GROUP ART UNIT
`
`08/416,673
`
`04/07/95
`
`514
`
`1205
`
`SYLVAIN COTTENS, WITTERSWIL, SWITZERLAND; RICHARD SEDRAN!, BASLE,
`SWITZERLAND.
`
`**CONTINUING DATA*********************
`VERIFIED
`THIS APPLN IS A 371 OF
`
`PCT/EP93/02604 09/24/93
`
`**FOREIGN/PCT APPLICATIONS************
`VERIFIED
`GREAT BRITAIN
`9221220.8
`
`10/09/92
`
`CHX
`
`0
`
`8
`
`1
`
`$1,090.00
`
`100-7932/PCT
`
`ALING FEE
`RECEIVED
`
`DOCKET NO.
`
`ROBERT S HONOR
`SANDOZ CORPORATION
`59 ROUTE 10
`EAST HANOVER NJ 07936-1080
`
`0-ALKYLATED RAPAMYCIN DERIVATIVES AND THEIR USE, PARTICULARLY AS
`IMMUNOSUPPRESSANTS
`
`This is to certify that annexed hereto is a true copy from the records of the United States
`Patent and Trademark Office of the application wh1ch is identified above.
`
`By authority of the
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`Date
`
`Certifying Officer
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 012
`
`

`
`PATENT APPLICATION SERIAL Qo? / 4 1 6 6 7 3
`
`U.S. DEPARTMENT OF COMMERCE
`PATENT AND TRADEMAlUC OFFICE
`FEE RECORD SHEET
`
`---
`
`.::""?~·
`
`MS19049 04/12/95
`19039 05/22/95
`19040 05/22/95
`
`08416673
`08416673
`08416673
`
`.,.$~18086 05/30/95 08416673
`·-Hs19046 t0i23/9:i-Oa416673___ -
`
`PT0-1556
`(5/81)
`
`19-0134 190 960
`19--0134 190 960
`19-0134 190 970
`
`980.00CH
`980. OOCR ~
`,
`980.00CH VK-
`1 ~0 ~ "f
`. t~-0134 _ ~a~- 9?0" __ -~~~ooc~(J I$:
`
`19-om 190 · 968
`
`uo.oot\ift>
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 013
`
`

`
`PATENT APPLICATION~~ 1 ~AMI NATION RECORD
`
`Effective -
`
`1 , 1994
`
`-~
`
`,
`', ~ :7r3;;Ft
`
`CLAIMS AS FILED - PART I
`(Column 1)
`
`12)
`
`SMALL ENTITY
`
`OR
`
`FOR
`
`NUMBER FILED
`
`NUMBER EXTRA
`
`RATE
`
`FEE
`
`BASIC FEE
`
`TOTAL CLAIMS
`
`INDEPENDENT CLAIMS
`
`4111&
`~,,
`
`0
`
`~~ /minus20=
`
`minus 3=
`
`*
`
`*
`
`MULTIPLE DEPENDENT CLAIM PRESENT
`
`* If the difference in column 1 is less than zero, enter ·o· in column 2
`
`-\
`
`365.00
`
`y
`
`{
`
`x$11=
`
`x38=
`
`+120=
`
`TOTAL
`
`OR
`
`OR
`
`OR
`
`OTHER THAN
`SMALL ENTITY
`
`RATE ~b
`
`f~V.VV
`
`x$22='
`
`,x76=
`OR
`OR +240= l:2¥V
`\&:~
`TOTAL ro::x JJ
`OTH~~~A~
`
`CLAIMS AS AMENDED - PART II
`(Column 1)
`(Column 2)
`CLAIMS
`REMAINING
`AFTER
`AMENDMENT
`
`HIGHEST
`NUMBER
`PREVIOUSLY
`PAID FOR
`
`(Column 3)
`
`PRESENT
`EXTRA
`
`*
`
`*
`
`Minus
`
`**
`
`Minus
`
`***
`
`=
`
`=
`
`c(
`1-
`z
`w
`:::E Total
`c
`z w
`:::E
`c(
`
`SMALL ENTITY OR
`
`SMALL ENTITY
`
`RATE
`
`x$11=
`
`x38=
`
`ADD I-
`TIONAL
`FEE
`
`RATE
`
`ADD I-
`TIONAL
`FEE
`
`OR x$22=
`
`OR
`
`x76=
`
`FIRST PRESENTATION OF MULTIPLE DEPENDENT CLAIM
`
`(Column 1)
`
`'
`
`CLAIMS
`REMAINING
`AFTER
`AMENDMENT
`
`(Column 2)
`
`(Column 3)
`
`HIGHEST
`NUMBER
`PREVIOUSLY
`PAID FOR
`
`PRESENT
`EXTRA
`
`*
`
`*
`
`Minus
`
`**
`
`Minus
`
`***
`
`=
`
`=
`
`m
`1-
`z
`w
`:::E Total
`c
`z
`w
`:::E
`c(
`
`FIRST PRESENTATION OF MULTIPLE DEPENDENT CLAIM
`
`(Column 1)
`
`CLAIMS
`REMAINING
`AFTER
`AMENDMENT
`
`(Column 2)
`
`(Column 3)
`
`HIGHEST
`NUMBER
`PREVIOUSLY
`PAID FOR
`
`PRESENT
`EXTRA
`
`RATE
`
`+120=
`TOTAL
`ADDIT. FEE
`
`RATE
`
`x$11=
`
`x38=
`
`+120=
`
`TOTAL
`ADDIT. FEE
`
`OR +240=
`
`TOTAL
`OR ADDIT. FEE
`
`ADD I-
`TIONAL
`FEE
`
`RATE
`
`ADD I-
`TIONAL
`FEE
`
`OR
`
`x$22=
`
`OR
`
`x76=
`
`OR +240=
`
`TOTAL
`OR ADDIT. FEE
`
`RATE
`
`ADD I-
`TIONAL
`FEE
`
`.
`ADD I-
`TIONAL
`FEE
`
`x$11=-
`
`x38=
`
`+120=
`
`OR x$22=
`
`OR x76=
`
`OR +240=
`
`0
`1-
`z
`w
`:::E Total
`c
`z
`w
`:::E
`c(
`
`*
`
`*
`
`Minus
`
`**
`
`Minus
`
`***
`
`=
`
`=
`
`FIRST PRESENTATION OF MULTIPLE DEPENDENT CLAIM
`
`* If the entry in column 1 is less than the entry in column 2, write "0" in column 3.
`TOTAL
`TOTAL
`** If the "Highest Number Previously Paid For" IN THIS SPACE is less than 20, enter "20."
`OR ADDIT. FEE
`ADDIT. FEE
`***If the Highest Number Previously Paid For" IN THIS SPACE is less than 3, enter "3."
`The Highest Number Previously Paid For" (Total or Independent) is the highest number found in the appropriate box in column 1.
`
`FORM PT0-875
`(Rev. 10/94)
`
`Patent and Trademark Office, U.S. DEPARTMENT OF COMMERCE
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 014
`
`

`
`W094/090JO •• ~-
`
`•'
`
`-
`
`0-ALKYLAIEQ RAPAMYCltLD.ERIYATIV.ES_ANO_T.HEIR_u.s.E., PARTICULARLY AS IMMUNO-
`,--SUPPRESSANTS
`. · ·
`·
`·
`-~
`;;··~ ~
`IV ,: .
`This invention comprises novel alkylated derivatives of rapamycin having
`pharmaceutical utility. especially as immunosuppressants.
`
`-
`
`Rapamycin is a known macrolide antibiotic produced by Streptomvces
`hve-roscopicus, having the structure depicted in Formula A:
`
`41
`
`36
`
`0
`
`0---
`
`5
`
`J
`
`(A)
`
`24
`
`See. e.g., McAlpine, J.B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am.
`Chern. Soc. (1991) 113: 7433; US Patent No. 3 929 992. Rapamycin is an extremely
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 015
`
`

`
`W094/09010
`
`PCf /EP93/02604
`
`- 2 -
`
`potent immunosuppressant and has also been shown to have antitumor and antifungal
`activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable
`bioavailability as well as its high toxicity. Moreover, rapamycin is highly insoluble, making
`it difficult to formulate stable galenic compositions.
`
`It has now surprisingly been discovered that cenain novel derivatives of rapamycin
`(the Novel Compounds) have an improved pharmacologic profile over rapamycin, exhibit
`greater stability and bioavailability, and allow for greater ease in producing galenic
`formulations. The Novel Compounds are alkylated derivatives of rapamycin having the
`strucnrre of Formula I:
`
`41
`
`So ,, ....
`
`,,
`3
`: 34
`=
`2
`6 7~0
`II
`N
`8
`
`0
`
`(I)
`
`0---
`
`18
`
`20
`
`24
`
`--
`
`wherein
`
`3
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 016
`
`

`
`W094/09010
`
`PCT /EP93/02604
`
`-3-
`
`X is (lUI) or 0;
`
`Y is (H.OH) or 0;
`
`R 1 and Rz are independently selected from
`H. alkyl~ thioalkyl, arylalkyl, hydroxyalkyl, dihydroxyalkyl.
`hydroxyalkylarylalkyl. dihydroxyalkylaxylalkyl. alkoxyali.."Y 1~ acyloxyalk:yl,
`aminoalkyl, alkylaminoalkyl. a!.koxycarbonylaminoalkyl, acylaminoalkyl,
`arylsulfonamidoalkyl, allyl, dihydroxyalkylallyl, dioxolanylallyl,
`carbalkoxyalk:yl. and (R3):3Si where each R3 is independently selected from H.
`methyl, ethyl, isopropyl, !-butyl. and phenyl; wherein "alk-" or "alkyl" refers
`to c;.6 alkyl, branched or linear preferably cl.l alkyl, in which the carbon
`chain may be optionally inren:u:pted by an ether ( -0-) linkage; and
`
`R4 is methyl, or R4 and R1 together fOim ~ alkylene;
`
`provided that R 1 and R~ are not both H; and
`provided that where R1 is (R3
`):3Si or carbalkoxyalkyl, X andY are not both 0.
`
`Preferred Novel Compounds include the following:
`40-0-Benzyl-rapamycin
`40-0-(4' -Hydroxymethyl)benzyl-rapamycin
`40-0-[ 4' -(1,2-Dihydroxyet:hyl)]benzyl-rapamycin
`40-0-Allyl-rapamycin
`40-0-[3'-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2'-en-l'-yl]-rapamycin
`(2'E, 4tS)-40-0-(4' ,5'-Dihydroxypent-2'-en-1' -yl)-rapamycin
`40-0-(2-Hydroxy)eihoxycarbonylmerhyl-zapamycin
`40-0-(2-Hydroxy)ethyl-rapamycin
`
`1.
`
`2.
`
`3.
`
`4.
`5.
`6.
`
`7.
`
`8.
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 017
`
`

`
`wo 94/09010
`
`PCf /EP93/02604
`
`- 4 -
`
`40-0-(3-Hydroxy )propyl-rapamycin
`40-0-(6-Hydroxy)hexyl-rapamycin
`40-0-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin
`40-0-[(35)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin
`40-0-[(25)-2,3-Dihydroxyprop-1-yl]-rapamycin
`40-0-(2-Acetoxy)ethyl-rapamycin
`40-0-(2-Nicotinoyloxy)ethyl-rapamycin
`40-0-[2-(N-Morpholino)acetoxy]ethyl-rapamycin
`/ 40-0-(2-N-Imidazolylacetoxy)ethyl-rapamycin
`40-0-[2-(N-Methyl-N' -piperazinyl)acetoxy]ethyl-rapamycin
`39-0-Desmethyl-39,40-0,0-ethylene-rapamycin
`(26R)-26-Dihydro-40-0-(2-hydroxy)ethyl-rapamycin
`28-0-Methyl-rapamycin
`
`40-0-(2-Aminoethyl)-rapamycin
`40-0-(2-Acetaminoethyl)-rapamycin
`40-0-(2-Nicotinamidoethyl)-rapamycin
`40-0-(2-(N-Methyl-imidazo-2 '-y lcarbethoxamido )ethyl)-rapamycin
`40-0-(2-Ethoxycarbonylaminoethyl)-rapamycin
`40-0-(2-Tolylsulfonamidoethyl)-rapamycin
`40-0-[2-(4' ,5' -Dicarboethoxy-1 ',2' ,3 '-triazol-1 '-yl)-ethyl}-rapamycin
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`27.
`
`28.
`
`The Novel Compounds for immunosuppressive use are preferably the
`40-0-substituted rapamycins where X andY are both 0, R2 isH, R4 is methyl, and R 1 is
`other than H; most preferably where R 1 is selected from hydroxyalkyl, hydroxyalkoxyalkyl,
`acylaminoalkyl, and aminoalkyl; especially 40-0-(2-hydroxy)ethyl-rapamycin, 40-0-(3-
`hydroxy)propyl-rapamycin, 40-0-[2-(2-hydroxy)ethoxy}ethyl-rapamycin, and
`40-0-(2-acetaminoethyl)-rapamycin).
`
`Preferably, a-substitution at C40 or 0,0-disubstitution at C28 and C40 is performed
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 018
`
`

`
`wo 94/09010
`
`PCT /EP93/02604
`
`- 5 -
`
`according to the following general process: Rapamycin (or dihydro or deoxorapamycin) is
`reacted with an organic radical attached to a leaving group (e.g., RX where R is the organic
`radical, e.g., an alkyl, allyl, or benzyl moiety, which is desired- as the 0-substiruent, and X is
`the leaving group, e.g., CC13C(NH)O or CF3S03) under suitable reaction conditions,
`preferably acidic or neutral conditions, e.g., in the presence of an acid like
`oifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid or their
`respective pyridinium or substituted pyridinium salts when X is CC13C(NH)O or in the
`presence of a base like pyridine, a substituted pyridine, diisopropylethylamine or
`pentamethylpiperidine when X is CF3S03•
`0-substirutions at C28 only are accomplished in
`the same manner, but with prior protection at C40. Funher modifications are possible. For
`example, where the substituent is allyl, the isolated, monosubstituted double bond of the
`allyl moiety is highly amenable to funher modification.
`
`The 9-deoxorapamycin compounds are preferably produced by reducing a rapamycin
`using hydrogen sulfide, by reacting rapamycin with diphenyldiselenide and ttibutylphosphine
`or by other suitable reduction reaction.
`
`The 26-dihydro-rapamycins are preferably produced by reducing rapamycins or
`9-deoxorapamycins from keto to hydroxy at C26 by a mild reduction reaction, such as a
`borohydride reduction reaction.
`
`The Novel Compounds are particularly useful for the following conditions:
`
`a)
`Treatment and prevention of organ or tissue transplant rejection, e.g. for the
`treatment of recipients of e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic,
`skin or corneal transplants. They are also indicated for the prevention of graft-versus-host
`disease, such as following bone marrow transplantation.
`b)
`Treatment and prevention of autoimmune disease and of inflammatory
`conditions, in particular inflammatory conditions with an etiology including an autoimmune
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 019
`
`

`
`W094/09010
`
`••
`
`PCT/EP93/02604
`
`- 6-
`
`component such as anhritis (for example rheumatoid anhriris, anhritis chronica progrediente
`and anhritis deformans) and rheumatic diseases. Specific autoimmune diseases for which
`the compounds of the invention may be employed include, autoinunune hematological
`disorders (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and
`idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, sclerodoma,
`W_egener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis,
`psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel
`disease (including e.g. ulcerative colitis and Crohn's disease) endocrine ophthalmopathy,
`Graves disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes
`(diabetes mellitus type 1), uveitis (anterior and posterior), keratoconjunctivitis sicca and
`vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic anhritis, glomerulonephritis
`(with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or
`minimal change nephropathy) and juvenile dermatomyositis.
`c)
`Treaonent and prevention of asthma.
`d)
`Treaonent of multi-drug resistance (MDR). The Novel Compounds suppress
`P-glycoproteins (Pgp), which are the membrane transpon molecules associated with MDR.
`MDR is particularly problematic in cancer patients and AIDS patients who will not respond
`to conventional chemotherapy because the medication is pumped out of the cells by Pgp.
`The Novel Compounds are therefore useful for enhancing the efficacy of other
`chemotherapeutic agents in the treaonent and control of multidrug resistant conditions such
`as multidrug resistant cancer or multidrug resistant AIDS.
`e)
`Treaonent of proliferative disorders, e.g. rumors, hyperproliferative skin
`disorder and the like.
`Treaonent of fungal infections.
`f)
`Treaonent and prevention of inflammation, especially in potentiating the action
`
`g)
`
`of steroids.
`
`h)
`Treaonent and prevention of infection, especially infection by pathogens
`having Mip or Mip-like factors.
`i)
`Treaonent of overdoses of FK-506, rapamycin, immunosuppressive Novel
`
`1
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 020
`
`

`
`W094/09010
`
`-
`
`- 7 -
`
`PCT /EP93/02604
`
`Compounds, and other macrophilin binding immunosuppressants.
`
`The invention thus provides the Novel Compounds described herein, for use as novel
`intermediates or as pharmaceuticals, methods of treating or preventing the above-described
`disorders by administering an effective amount of a Novel Compound to a patient in need
`thereof, use of a Novel Compound in the manufacture of a medicament for treattnent or
`prevention of the above-described disorders, and pharmaceutical compositions comprising a
`Novel Compound in combination or association with a pharmaceutically acceptable diluent
`or carrier.
`
`Most of the Novel Compounds described herein are highly immunosuppressive,
`especially those Novel Compounds which are 0-substituted at C40, and these Novel
`Compounds are particularly useful in indications a and b, but not in indication i. Those of
`the Novel Compounds which are less immunosuppressive, especially those which are a(cid:173)
`substituted at C28 only. are particularly useful in indications h and i, but are less preferred
`in indications a or b.
`
`The Novel Compounds are utilized by administration of a pharmaceutically effective
`dose in pharmaceutically acceptable fonn to a subject in need of treattnent. Appropriate
`dosages of the Novel Compounds will of course vary, e.g. depending on the condition to be
`treated (for example the disease type or the nature of resistance), the effect desired and the
`mode of administration.
`
`In general however satisfactory results are obtained on administration orally at
`dosages on the order of from 0.05 to 5 or up to lOmg/kglday, e.g. on the order of from 0.1
`to 2 or up to 7.5 mg/kglday administered once or, in divided doses 2 to 4x per day, or on
`administration parenterally, e.g. intravenously, for example by i.v. drip or infusion, at
`dosages on the order of from 0.01 to 2.5 up to 5 mglkglday, e.g. on the order of from 0.05
`or 0.1 up to 1.0 mg/kglday. Suitable daily dosages for patients are thus on the order of 500
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 021
`
`

`
`W094/09010 •
`
`PCT /EP93/02604
`
`- 8 -
`
`mg p.o., e.g. on the order of from 5 to 100 mg p.o., or on the order of from 0.5 to 125 up to
`250 mg i.v~. e.g. on the order of from 2.5 to 50 mg i.v ..
`
`Alternatively and even preferably, dosaging is arranged in patient specific manner to
`provide pre-determined trough blood levels, e.g. as determined by RIA technique. Thus
`patient dosaging may be adjusted so as to achieve regular on-going trough blood levels as
`measured by RIA on the order of from 50 or 150 up to 500 or lOOOng/ml, i.e. analogously to
`methods of dosaging currently employed for Ciclosporin immunosuppressive therapy.
`
`The Novel Compounds may be administered as the sole active ingredient or together
`with other drugs. For example, in immunosuppressive applications such as prevention and
`treaonent of graft vs. host disease, transplant rejection, or autoimmune disease, the Novel
`Compounds may be used in combination with Ciclosporin, FK-506, or their
`immunosuppressive derivatives; corticosteroids; azathioprene; immunosuppressive
`monoclonal antibodies, e.g., monoclonal antibodies to CD3, CD4, CD25, CD28, or CD45;
`and7or other immunomodulatory compounds. For anti-inflammatory applications, the Novel
`Compounds can be used together with anti-inflammatory agents, e.g., corticosteroids. For
`anti-infective applications, the Novel Compounds can be used in combination with other
`anti-infective agents, e.g., anti-viral drugs or antibiotics.
`
`The Novel Compounds are administered by any conventional route, in particular
`enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or
`parenterally, for example in the form of injectable solutions or suspensions. Suitable unit
`dosage forms for oral administration comprise, e.g. from 1 to 50 mg of a compound of the
`invention, usually 1 to 10 mg. Pharmaceutical compositions comprising the novel
`compounds may be prepared analogously to pharmaceutical compositions comprising
`rapamycin, e.g., as described in EPA 0 041 795, which would be evident to one skilled in
`the art.
`
`9
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 022
`
`

`
`. WO 94/09010
`
`• PCT /EP93/02604
`
`- 9 -
`
`The phannacological activity of the Novel Compounds are demonstrated in, e.g., the
`following tests:
`
`1. Mixed lvmphocvte reaction (Ml..R)
`The Mixed Lymphocyte Reaction was originally developed in connection with
`allografts, to assess the tissue compatibility between potential organ donors and recipients,
`and is one of the best established models of immune reaction in vitro. A murine model
`MLR, e.g., as described by T.Meo in "Immunological Methods", L. Lefkovits and B. Peris,
`Eds., Academic Press, N.Y. pp. 227-239 (1979), is used to demonstrate the
`immunosuppressive effect of the Novel Compounds. Spleen cells (0.5 x 106
`) from Balb/c
`mice (female, 8-10 weeks) are co-incubated for 5 days with 0.5 x 106 irradiated (2000 rads)
`or mitomycin C treated spleen cells from CBA mice (female, 8-10 weeks). The irradiated
`allogeneic cells induce a proliferative response in the Balb/c spleen cells which can be
`measured by labeled precursor incorporation into the DNA. Since the stimulator cells are
`irradiated (or mitomycin C treated) they do not respond to the Balb/c cells with proliferation
`but do retain their antigenicity. The anti proliferative effect of the Novel Compounds on the
`Balb/c cells is measured at various dilutions and the concentration resulting in 50%
`inhibition of cell proliferation (IC~0) is calculated. The inhibitory capacity of the test sample
`may be compared to rapamycin and expressed as a relative IC~0 (i.e. IC~0 test sample/IC50
`rapamycin).
`
`2.
`
`IL-6 mediated proliferation
`The capacity of the Novel Compounds to interfere with growth factor associated
`signalling pathways is assessed using an interleukin-6 (Il...-6)-dependent mouse hybridoma
`cell line. The assay is performed in 96-well microtiter plates. 5000 cells/well are cultivated
`in serum-free medium (as described by M. H. Schreier and R. Tees in Immunological
`Methods, I. Lefkovits and B. Pemis, eds., Academic Press 1981, VoL II, pp. 263-275),
`supplemented with 1 ng recombinant ll...-6/ml. Following a 66 hour incubation in the
`absence or presence of a test sample, cells are pulsed with 1 JJCi (3-H)-thymidine/well for
`
`;o.
`
`Par Pharm., Inc.
`Exhibit 1002
`Page 023
`
`

`
`wo 94/09010 •
`
`Per /EP93/02604
`
`- 10-
`
`another 6 hours, harvested and counted by liquid scintillation. (3-H)-thymidine incorporation
`into DNA correlates with the increase in cell number and is thus a measure of cell
`proliferation. A dilu