`
`UNITED STATES DEPARTMENT OF COMMERCE
`
`United States Patent and Trademark Office
`
`September 09, 2015
`
`
`
`By Authority of the
`Under Secretary of Commercefor Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`THIS IS TO CERTIFY THAT ANNEXEDIS A TRUE COPY FROM THE
`
`RECORDSOF THIS OFFICE OF THE FILE WRAPPER AND CONTENTS
`
`OF:
`
`APPLICATION NUMBER: 12/094,173
`FILING DATE: May 19, 2008
`PATENT NUMBER: 9,006,224
`ISSUE DATE: April 14, 2015
`
`NM. “lar
`
`M. TARVER
`
`Certifying Officer
`
`West-Ward Pharm.
`Exhibit 1002
`Page 001
`
`
`
`
`
`Be ETP. ey
`
`J
`
`AND POWER OF ATTORNEY FOR UNITED STATES PATENT APPLICATION
`
`Original
`
`O Supplemental
`
`Ol
`
`Substitute
`
`As a below named inventor, | hereby declare that:
`My residence, post office address and citizenship are as stated below hext to my name, and
`| believe | am the original, first and scle Inventor (if only one nameis listed below) or an original, first
`andjoint inventor (if more than one name Is Hsted below) of the subject matter whichis claimed and for
`which a United Slates patent ls sought on the Invention entitled
`
`Neuroendocrine tumor treatment >
`
`the specification of which:
`
`i|is attached herete,
`
`o
`
`was filed on
`
`(day/month/year}
`
`as Application No.
`
`and, if this box (01) contains an *
`O | was amanded on .
`
`(day/monti/year)
`
`E
`
`was filed as Patent Cooperation Treaty international Application No.
`PCT/EP2006/068656
`on
`20.11.2006
`(day/monthyear)
`
`and,if this box (11) contains an *
`
`0D
`
`entered the national slage in the United States and was accorded Application No.
`
`and, if this box (1) contains an *
`
`0
`
`was amended, subsequent to entry into the national stage, on
`.
`
`.
`{day/manth/year}
`
`| hereby state that | have reviewed and understand the contents of the above-identified specification,
`including the clalms, as amended by any amendment(s} specifically referred to above and,if this
`application was filed as a Patent Cooperation Treaty Intemational application, by any amendments
`made during the international stage {Including any made under Patent Cooperation Treaty Rute 91,
`Articie 19 and Article 34).
`
`| acknowledge my duty to disclose information which is material to patentability as defined in 37 C.F.R.
`1.56, Including,
`for continuationin-part applications, material
`information which became availabie
`between the filing date of
`the prior application and the national ar Patent Cooperation Treaty
`international filing date of the continuation-fn-part application.
`
`West-Ward Pharm.
`Exhibit 1002
`Page 002
`
`West-Ward Pharm.
`Exhibit 1002
`Page 002
`
`
`
`| hereby claim the benefit under 35 U.S.C. 119(a)-(d) or (7) or 365{b) of any foreign application(s) for
`patent, inventor's certificate or plant breeder's right certificate listed below and under 35 U.S.C. 365{a)
`of any Patent Cooperation Treaty international application(s) designating at least one country other
`than the United States listed below and have also jisted below any foreign application(s) far patent,
`inventor's certificate or plant breeder's night certificate and Patent Cooperation Treaty Intemational
`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 the pricrity of which is claimed for that subject
`matter:
`
`COUNTRY/REGION
`OR P.G.T.
`
`:
`
`APPLICATION No.
`
`FILING DATE
`(day/month/year)
`
`.
`
`PRIORITY CLAIMED
`
`Great Britain
`
`Great Britaln —
`Great Britain
`
`Great Britain
`
`GreatBritain
`
`Great Britain
`
`0523658.3
`
`0601082.1
`0602747.8
`
`0607942.0
`
`0609272.0
`
`0609912.1
`
`European Procedure
`
`06120660.3
`
`21.11.2005
`
`19.01.2006
`10.02.2006
`
`—
`
`21.04.2006
`
`10.05.2006
`
`18.05.2006
`
`14.09.2006
`
`Hl Yes
`
`El Yes
`El Yes
`
`fl Yes
`
`Tf) Yes
`
`Hl Yes
`
`El Yes
`
`O No
`
`O No
`O No
`
`O No
`
`O No
`
`O No
`
`O No
`
`| hereby claim the benefit under 35 U.S.C. 119{e) of any United States provisional application(s) listed
`below:
`
`APPLICATION NO.
`
`FILING DATE
`day/month/year
`
`! hereby claim the benefit under 35 U.S.C. 120 of any United States application(s} listed below and
`under 36 U.S.C. 365(c) of any Patent Cooperation Treaty international application(s} designating the
`United States listed balow:
`
`United States
`Application No.
`
`United States
`Filing Date
`{(day/month/year)
`
`Status (Pending,
`Abandoned or U.S.
`Patent No.
`
`day/month/year
`
`International
`Application Na.
`and Filing Date
`
`West-Ward Pharm.
`Exhibit 1002
`Page 003
`
`West-Ward Pharm.
`Exhibit 1002
`Page 003
`
`
`
`| hereby appoint all of the registered practitoners associated with Customer No. 001095, respactivaty
`and indWidually, as my attomeys and agents, with full power of substitution and revocation,
`to
`prosecute this application and to transactall business in the Patent and Trademark Office connected
`therewith.
`
`| hereby authorize the registered practitioners associated with
`lf this box (0) contains an x H,
`Customer No. 001095 and any others acting on my behalt to take any action relating to this application
`based on communications from Corporate Intellactual Property of Novartis Intemational AG, Basle,
`Switzerland, or an affiliate thereof cr a succassor thereto, without direct communication from ma.
`Please send all correspondence relating to this apptication to the address associated with Customer
`No. 001085.
`
`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 inie; and further that these statements were made
`with the knowledge that wilitul false statements and the like so made are punishable by fine or
`imprisonment, or both, under 18 U.S.C. 1001 and that such wilHul false statements may jeopardize the
`validity of the application or any patantissuing thereon.
`
`
`Full name of sole
`or first joint inventor
`
`Peter Wayne MARKS
`
`Inventor'ssignature
`
`eoas etfh. m4
`4
`
`Data
`
`AZé HE
`-
`
`{day/rnonth‘/year)
`
`
`
`
`Residence
`
`Woodbridge, CT 06525-1913, US
`
`Citizenship
`
`,
`
`USA
`
`Post Office Address
`
`145 Rimmon Read
`Woodbridge, CT 06525-1913
`us
`Full name of second
`joint inventor,If any
`
`David LEBWOHL
`
`Inventor's signature
`
`Abtrel Lebel).
`
`Date Ze BEC 200fer
`
`{day/month/year)
`
`Residence
`
`Citizenship
`
`Madison, New Jersey 07940 US
`
`USA
`
`66 Pomeroy Road
`. Post Office Address
`Madison, Now Jersey 07640
`us
`
`IMPORTANT: Befora this declaration is signed, the patent application (the specification, the claims
`and this declaration) must be read and understood by each person signingit, and no changes may be
`madein the application after this declaration has been signed.
`
`West-Ward Pharm.
`Exhibit 1002
`Page 004
`
`West-Ward Pharm.
`Exhibit 1002
`Page 004
`
`
`
`Date of Deposit
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR LID
`
`Express Mail Label Number
`
`Form PTO-1390-MOD
`
`
`
`
`(REV 10-96)
`
`U.S. Deparment of Commerce Patent and Trademark Office
`ATTORNEY’S DOCKET NUMBER
`
`
`34678-US-PCT
`
`
`U.S. APPLICATION NO. urknown, see 37 CFR 4.5)
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`
`
`CONCERNING A FILING UNDER 35 U.S.C. 371
`
`
`
`INTERNATIONAL APPLICATION NO. INTERNATIONALFILING DATE|PRIORITY DATE CLAIMED
`
`
`PCT/EP2006/068656
`20 November 2006 (20.11.06)
`21 November 2005 (21.11.05)
`
`
`TITLE OF INVENTION
`
`
`
`
`NEUROENDOCRINE TUMOR TREATMENT USING MTOR INHIBITORS
`APPLICANT(S) FOR DO/EO/US
`MARKSET AL.
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EQ/US)the following items and other information:
`
`HO&OOO
`
`This is a FIRST submissionof items concerning a filing under 35 U.S.C. 371.
`This is a SECOND or SUBSEQUENTsubmission of items concerning a filing under 35 U.S.C. 371,
`This express request to begin national examination procedures (35 U.S.C. 371(f)) at any time rather than delay
`examination until the expiration of the applicable time limit set in 35 U.S.C. 371(b} and PCT Articles 22 and 39(1).
`A proper Demand forInternational Preliminary Examination was made by the 19th month from the earliest claimed priority
`date.
`A copy of the International Application as filed (85 U.S.C. 371(c}{2))
`a. LJ
`is transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`has been transmitted by the International Bureau. (See Form PCT/IB/308)
`c. L]
`isnot required, as the application wasfiled in the United States Receiving Office (RO/US).
`A translation of the International Application into English (35 U.S.C. 371(c)(2)).
`Amendmentsto the claims of the International Application under PCT Article 19 (35 U.S.C.371 (c)(3)).
`
`a. (1$are transmitted herewith {required only if not transmitted by the International Bureau).
`b. CL] have been transmitted by the International Bureau.
`c. C1 have not been made: however, the time limit for making such amendments has NOT expired,
`d.
`have not been made and will not be made.
`A translation of the amendmentsto the claims under PCT Arlicile 19 (35 U.S.C. 374 (c)(3)).
`An executed Declaration and Powerof Attorney (original or copy) (35 U.S.C. 371(c)(4)).
`A translation of the annexesto the Internationa! Preliminary Examination Repon under PCT Article 36 (35 U.S.C,
`371 (c)(5)).
`
`OBI
`
`Items 11. to 16. below concern document(s) or information included.
`
`11. EJ An Information Disclosure Statement under 37 CFR 1.97 and 1.99.
`
`12. [1 Anassignment document jor recording. A separate cover sheet in compliance with 37 CFR 3.29 and 3.31is included.
`13. —] A FIRSTpreliminary amendment.
`(1 ASECOND or SUBSEQUENTpreliminary amendment.
`
`14. EJ An Application Data Sheet under 37 CFR 1.76.
`
`15. [] A substitute specification.
`
`16. L) A change of powerof attorney and/or addressletter.
`
`17. LJ A computer-readable form of the sequencelisting in accordance with PCT Rule 13ter.2 and 37 CFR 1.821-1.925.
`18. [1 A second copy of the published International Application under 35 U.S.C. 154(d){4),
`19. [] Asecond copy of the English language translation ofthe International application under 35 U.S.C, 154(d}(4).
`20. (] Otheritems or information:
`
`West-Ward Pharm.
`Exhibit 1002
`Page 005
`
`West-Ward Pharm.
`Exhibit 1002
`Page 005
`
`
`
`U.S. APPLICATION NO. Gf known, see 37 CFR 1.5)
`
`INTERNATIONAL APPLICATION NO.
`PCT/EP2006/068656
`
`$
`
`$
`
`
`
`
`
`930 po
`
`ATTORNEY'S DOCKET NUMBER
`
`
`
`34678-US-PCT
`
`The following fees are submitted:
`CALCULATIONS errouse
`ONLY
`
`
`
`
`
`21.
`[4] Basic national fee... 2... ccc cece eee ee eee
`$310
`
`
`
` 22. Examination Fee
`
`
`LJ
`If Internationa! preliminary examination report was prepared by USPTO
`and all claims satisfy provisions of PCT Article 39(13-(4)...............
`
`hd All other situations, . 2.0.0... ec eeee cee eens
`
`
`23. Search fee
`CI
`If Search fee (37 CFR 1.445{a)(2)) has been paid on the international
`
`
`application to the USPTOasan International Searching Authority... ... .
`
`
`If International Search Report was prepared and provided to the Office. ..
`[4]
`$410
`LJ All other situations... 2... ccc cee cence eee c ee eeeeuee
`$
`
`TOTAL OF 21, 22 AND 23=
`
`
`Additional fee for specification and drawingsfiled in paper over 100 sheets (excluding sequencelisting or computer
`program listing filed in an electronic medium). The fee is $260 for each additional 50 sheets of paperor fraction
`thereof.
`
`
`
`
`
`Numberof each additional 50 or fraction
`Total Sheets
`thereof (round up to a whole number)
`
`Extra sheets
`
`40-100=|] 0 50 =
`
`RATE
`
`x
`
`$
`
`260
`
`
`
`
`
`
`
`
`
`
`Surcharge of $130 for furnishing the oath of dectaration [ater than
`months from ihe earliest claimed priority
`date (37 CFR 1.492(e)).
`
`CLAIMS
`Total claims
`Ld
`[$s
`
`L130
`
`filed (Note 37 CFR 1.9, 1.27, 1.28).
`
`
`
` Processing fee of $130 for furnishing the English translation later than
`+
`earliest claimed priority date (87 CFR 1.49211).
`
`
`
`
`
`
`
`Feefor recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be accompanied
`
`
`by an appropriate cover sheet (37 CFR 3.28, 3.31). $40 per propert
`+
`
`
`
`
`TOTAL FEES ENCLOSED =
` Amount to
`
`
`be: refunded
`
`
`
`
`
`
`Acheack in the amountof $
`(2)
`a,
`to cover the above fees is enclosed.
`
`b. EJ
`Please charge Deposit Account No. 19-0134 in the nameof Novartis in the amount of $1,770 to caver the above fees. A
`duplicate copy of this form is enclosed.
`
`
`
`
`
`
`
`
`
`
`
`
`
` East Hanover, NJ 07936-1080
`
`TOTAL NATIONALFEE =|$ 1,770
`
`[|] 30 months from the
`
`Cc.
`
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpaymentto
`Deposit Account No. 19-0134 in the name of Novartis.
`
`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR 1.137(a)}
`or (b)) must be filed and granted to restore the application to pending status.
`
`Send all correspondence to the address associated with
`Customer No. 001095, which is currently:
`
`d
`
`
`
`
`
`
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`
`ghton
`Gregoary/@.
`Attorney for Applicants
`Reg. No. 47,666
`(862) 778-2614
`
`
`
`
`
`Page 2 cf 2
`
`West-Ward Pharm.
`Exhibit 1002
`Page 006
`
`West-Ward Pharm.
`Exhibit 1002
`Page 006
`
`
`
`Date of Deposit
`
`FILING BY “EXPRESS MAIL” UNDER 37 CFR LID
`
`Express Mail Label Number
`
`Form PTO-1390-MOD
`
`
`
`
`(REV 10-96)
`
`U.S. Deparment of Commerce Patent and Trademark Office
`ATTORNEY’S DOCKET NUMBER
`
`
`34678-US-PCT
`
`
`U.S. APPLICATION NO. urknown, see 37 CFR 4.5)
`TRANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`
`
`CONCERNING A FILING UNDER 35 U.S.C. 371
`
`
`
`INTERNATIONAL APPLICATION NO. INTERNATIONALFILING DATE|PRIORITY DATE CLAIMED
`
`
`PCT/EP2006/068656
`20 November 2006 (20.11.06)
`21 November 2005 (21.11.05)
`
`
`TITLE OF INVENTION
`
`
`
`
`NEUROENDOCRINE TUMOR TREATMENT USING MTOR INHIBITORS
`APPLICANT(S) FOR DO/EO/US
`MARKSET AL.
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/EQ/US)the following items and other information:
`
`HO&OOO
`
`This is a FIRST submissionof items concerning a filing under 35 U.S.C. 371.
`This is a SECOND or SUBSEQUENTsubmission of items concerning a filing under 35 U.S.C. 371,
`This express request to begin national examination procedures (35 U.S.C. 371(f)) at any time rather than delay
`examination until the expiration of the applicable time limit set in 35 U.S.C. 371(b} and PCT Articles 22 and 39(1).
`A proper Demand forInternational Preliminary Examination was made by the 19th month from the earliest claimed priority
`date.
`A copy of the International Application as filed (85 U.S.C. 371(c}{2))
`a. LJ
`is transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`has been transmitted by the International Bureau. (See Form PCT/IB/308)
`c. L]
`isnot required, as the application wasfiled in the United States Receiving Office (RO/US).
`A translation of the International Application into English (35 U.S.C. 371(c)(2)).
`Amendmentsto the claims of the International Application under PCT Article 19 (35 U.S.C.371 (c)(3)).
`
`a. (1$are transmitted herewith {required only if not transmitted by the International Bureau).
`b. CL] have been transmitted by the International Bureau.
`c. C1 have not been made: however, the time limit for making such amendments has NOT expired,
`d.
`have not been made and will not be made.
`A translation of the amendmentsto the claims under PCT Arlicile 19 (35 U.S.C. 374 (c)(3)).
`An executed Declaration and Powerof Attorney (original or copy) (35 U.S.C. 371(c)(4)).
`A translation of the annexesto the Internationa! Preliminary Examination Repon under PCT Article 36 (35 U.S.C,
`371 (c)(5)).
`
`OBI
`
`Items 11. to 16. below concern document(s) or information included.
`
`11. EJ An Information Disclosure Statement under 37 CFR 1.97 and 1.99.
`
`12. [1 Anassignment document jor recording. A separate cover sheet in compliance with 37 CFR 3.29 and 3.31is included.
`13. —] A FIRSTpreliminary amendment.
`(1 ASECOND or SUBSEQUENTpreliminary amendment.
`
`14. EJ An Application Data Sheet under 37 CFR 1.76.
`
`15. [] A substitute specification.
`
`16. L) A change of powerof attorney and/or addressletter.
`
`17. LJ A computer-readable form of the sequencelisting in accordance with PCT Rule 13ter.2 and 37 CFR 1.821-1.925.
`18. [1 A second copy of the published International Application under 35 U.S.C. 154(d){4),
`19. [] Asecond copy of the English language translation ofthe International application under 35 U.S.C, 154(d}(4).
`20. (] Otheritems or information:
`
`West-Ward Pharm.
`Exhibit 1002
`Page 007
`
`West-Ward Pharm.
`Exhibit 1002
`Page 007
`
`
`
`U.S. APPLICATION NO. Gf known, see 37 CFR 1.5)
`
`INTERNATIONAL APPLICATION NO.
`PCT/EP2006/068656
`
`$
`
`$
`
`
`
`
`
`930 po
`
`ATTORNEY'S DOCKET NUMBER
`
`
`
`34678-US-PCT
`
`The following fees are submitted:
`CALCULATIONS errouse
`ONLY
`
`
`
`
`
`21.
`[4] Basic national fee... 2... ccc cece eee ee eee
`$310
`
`
`
` 22. Examination Fee
`
`
`LJ
`If Internationa! preliminary examination report was prepared by USPTO
`and all claims satisfy provisions of PCT Article 39(13-(4)...............
`
`hd All other situations, . 2.0.0... ec eeee cee eens
`
`
`23. Search fee
`CI
`If Search fee (37 CFR 1.445{a)(2)) has been paid on the international
`
`
`application to the USPTOasan International Searching Authority... ... .
`
`
`If International Search Report was prepared and provided to the Office. ..
`[4]
`$410
`LJ All other situations... 2... ccc cee cence eee c ee eeeeuee
`$
`
`TOTAL OF 21, 22 AND 23=
`
`
`Additional fee for specification and drawingsfiled in paper over 100 sheets (excluding sequencelisting or computer
`program listing filed in an electronic medium). The fee is $260 for each additional 50 sheets of paperor fraction
`thereof.
`
`
`
`
`
`Numberof each additional 50 or fraction
`Total Sheets
`thereof (round up to a whole number)
`
`Extra sheets
`
`40-100=|] 0 50 =
`
`RATE
`
`x
`
`$
`
`260
`
`
`
`
`
`
`
`
`
`
`Surcharge of $130 for furnishing the oath of dectaration [ater than
`months from ihe earliest claimed priority
`date (37 CFR 1.492(e)).
`
`CLAIMS
`Total claims
`Ld
`[$s
`
`L130
`
`filed (Note 37 CFR 1.9, 1.27, 1.28).
`
`
`
` Processing fee of $130 for furnishing the English translation later than
`+
`earliest claimed priority date (87 CFR 1.49211).
`
`
`
`
`
`
`
`Feefor recording the enclosed assignment (37 CFR 1.21(h)). The assignment must be accompanied
`
`
`by an appropriate cover sheet (37 CFR 3.28, 3.31). $40 per propert
`+
`
`
`
`
`TOTAL FEES ENCLOSED =
` Amount to
`
`
`be: refunded
`
`
`
`
`
`
`Acheack in the amountof $
`(2)
`a,
`to cover the above fees is enclosed.
`
`b. EJ
`Please charge Deposit Account No. 19-0134 in the nameof Novartis in the amount of $1,770 to caver the above fees. A
`duplicate copy of this form is enclosed.
`
`
`
`
`
`
`
`
`
`
`
`
`
` East Hanover, NJ 07936-1080
`
`TOTAL NATIONALFEE =|$ 1,770
`
`[|] 30 months from the
`
`Cc.
`
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpaymentto
`Deposit Account No. 19-0134 in the name of Novartis.
`
`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR 1.137(a)}
`or (b)) must be filed and granted to restore the application to pending status.
`
`Send all correspondence to the address associated with
`Customer No. 001095, which is currently:
`
`d
`
`
`
`
`
`
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`
`ghton
`Gregoary/@.
`Attorney for Applicants
`Reg. No. 47,666
`(862) 778-2614
`
`
`
`
`
`Page 2 cf 2
`
`West-Ward Pharm.
`Exhibit 1002
`Page 008
`
`West-Ward Pharm.
`Exhibit 1002
`Page 008
`
`
`
`CASE 34678-US-PCT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`IN RE PCT NATIONAL STAGE APPLICATION OF
`
`MARKSET AL.
`
`INTERNATIONAL APPLICATION NO: PCT/EP2006/068656
`
`FILED: 20 NOVEMBER 2006
`
`U.S. APPLICATION NO: Not yet known
`
`35 USC §371 DATE: Herewith
`
`FOR: NEUROENDOCRINE TUMOR TREATMENT USING MTOR
`INHIBITORS
`
`MS: Amendment
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`INFORMATION DISCLOSURE STATEMENT
`
`Sir:
`
`This paperis being filed within three months of the date of entry of the national stage as
`set forth in 37 C.F.R. §1.491 of the international application. Therefore, no fees are required.
`If
`a fee is deemedto be required, the Commissioneris hereby authorized to charge such fee to
`Deposit Account No. 19-0134.
`
`In accordance with 37 C.F.R. §1.56, applicants wish to calf the Examiner's attention to
`the referencescited on the attached form(s) PTO-1449.
`
`The listed references werecited in the international stage search report. Since these
`references are of recordin the instant PCT application PCT/EP2006/068656, copies are not
`enclosed herewith.
`
`West-Ward Pharm.
`Exhibit 1002
`Page 009
`
`West-Ward Pharm.
`Exhibit 1002
`Page 009
`
`
`
`The Examineris requested to consider the foregoing information in relation to this
`application and indicate that each reference was considered by returning a copyof the initialed
`PTO 1449 form(s}.
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`(B62) 778-2614
`
`Date:
`
`Respectfully submitted,
`
`Gregéry & Houghton
`Attorney for Applicants
`Reg. No. 47,666
`
`West-Ward Pharm.
`Exhibit 1002
`Page 010
`
`West-Ward Pharm.
`Exhibit 1002
`Page 010
`
`
`
`
` (51) International Patent Classification§:
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(11) International Publication Number:
`WO 97/47317
`.
`(43) International Publication Date:
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intemational Bureau
`
`A6IK 38/31
`
`18 December 1997 (18.12.97}
`
`
`
`hyperproliferation.
`
`
`
`(22) International Filing Date:
`
`11 June 1997 (11.06.97)
`
`(21) International Application Number: PCT/EP97/03036|(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, HU,IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, L¥, MD, MG, MK, MN, MW, MX, NO, NZ,
`PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT,
`UA, UG, U5, DZ, VN, YU, ZW, ARIPO patent (GH, KE,
`LS, MW, SD, SZ, UG, ZW}, Eurasian patent (AM, AZ, BY,
`KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, CH,
`DE, DK, ES, Fi, FR, GB, GR, JE, IT, LU, MC, NL, PT,
`SE}, OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML,
`MR, NE, §N, TD, TG).
`
`(30) Priority Data:
`9612171.0
`9619310,7
`
`1 June 1996 (11.06.96)
`16 September 1996 (16.09.96)
`
`GB
`GB
`
`(71) Applicant (for af! designated States except US}: NOVARTIS
`AG [CH/CH]; Schwarzwaldallee 215, CH-4058 Basel (CH).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only: WECKBECKER, Gisbert
`[DE/CH}]; Loeliring 31, CH-4105 Biel-Benken (CH).
`
`Published
`With international search report.
`
`(74) Agent: ROTH, Bemhard, M.: Novartis AG, Palent- und
`Markenabteilung, Klybeckstrasse 14], CH-4002 Basel (CH),
`
`(54) Title: COMBINATION OF A SOMATOSTATIN ANALOGUE AND A RAPAMYCIN
`
`(37) Abstract
`
`A combination of a compound of the somatostatin class and a rapamycin macrolide is useful for the prevention or treatment of cell
`
`West-Ward Pharm.
`Exhibit 1002
`Page 011
`
`West-Ward Pharm.
`Exhibit 1002
`Page 011
`
`
`
`Zimbabwe
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing intemational applications under the PCT.
`Albania
`ES
`L5
`Lesotho
`Slovenia
`SI
`Spain
`FI
`Armenia
`Finland
`SK
`Slovakia
`LT
`Lithuania
`Austria
`Lu
`FR
`France
`SN
`Luxembourg
`Senegal
`Australia
`Gabon
`L¥
`GA
`SZ
`Latvia
`Swaziland
`GB
`MC
`Chad
`Monaco
`TD
`Azerbaijan.
`United Kingdom
`GE
`MoD
`TG
`Bosnia and Herecgoving
`Georgia
`Republic of Moklova
`Togo
`Barbados
`GH
`Ghana
`MG
`TI
`Madagascar
`Tajikistan
`CN
`Guinea
`MK
`TM
`Turkmenistan
`Belgeum
`The former Yugosley
`Burkina Paso
`Greece
`GR
`TR
`Republic of Macedonia
`Turkey
`HU
`Mali
`TT
`Aulgaria
`Hungary
`Trinidad and Tobago
`Benin
`[E
`Ireland
`VA
`Ukraine
`Mongolia
`Brazil
`IL
`Larael
`Mauritania
`uG
`Uganda
`Belarus
`Is
`iceland
`US
`Malawi
`United States of America
`Canada
`IT
`Mexico
`Uzbekistan
`UZ
`ftaly
`JP
`¥N
`Viet Nam
`Japan
`Central African Republic
`Niger
`KE
`Netherlands
`Conga
`YU
`Kenya
`Yugoslavia
`KG
`Switeerland
`zw
`Kyrgyzstan
`Norway
`Coxe d'Ivoire
`KP
`New Zealand
`Democratic People's
`Cameroon
`Poland
`Republic of Korea
`China
`Republic of Korea
`Portugal
`Cube
`Romania
`Kazakstan
`Saint Lucia
`Rugsian Federation
`Czech Republic
`Lipchtenstem
`Sudan
`Germany
`Denmark
`Sti Lanka
`Sweden
`Estonia
`Liberia
`Singapore
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`rT
`RO
`RL
`sD
`SE
`
`West-Ward Pharm.
`Exhibit 1002
`Page 012
`
`West-Ward Pharm.
`Exhibit 1002
`Page 012
`
`
`
`WO 97/4737
`
`PCT/EP97/03036
`
`COMBINATIO
`
`F
`
`OMATO
`
`IN ANALOGUE
`
`AND A RAPAMYCI
`
`The present invention relates to a pharmaceutical combination and its use in the
`treatment of disorders associated with excess benign and malignant cell proliferation, e.g.
`
`tumors or intirnal celi proliferation.
`
`There is a continuing need for the development of drugs having increased
`
`effectiveness in inhibiting or slowing down undesired cell proliferation, particularly in the
`
`cancer field and in vasculopathies.
`
`Accordingly, there is provided a pharmaceutical combination compnsing 4
`
`compound of the somatostatin class, and a rapamycin macrolide.
`
`The somatostatin class is a known class of small peptides comprising the naturally
`
`occurring somatostatin-14 and analogues having somatostatin related activity, ¢.g. as
`disclosed by A.S. Dutta in Small Peptides, Vol.19, Elsevier (1993). By “somatostatin
`analogue” as used herein is meant any straight-chain or cyclic polypeptide having a
`structure based on that of the naturally occurring somatostatin-]4 wherein one or more
`
`amino acid units have been omitted and/or replaced by one or more other amino radical(s)
`
`and/or wherein one or more functional groups have been replaced by one or more other
`functional groups and/or one or more groups have been replaced by one or several other
`isosteric groups. In general, the term covers all modified derivatives of the native
`somatostatin-I4 which exhibit a somatostatin related activity, e.g. they bind to at least one
`
`somatostatin receptor (hSST-1, hSST-2, hSST-3, hSST-4 or hSST-5), preferably in the
`nMolar range, more preferably to at least the hSST-2 receptor in the nMolar range.
`
`Cyclic, bridge cyclic and straight-chain somatostatin analogues or derivatives are
`known and have been described together with processes for their production e.g. in US
`
`Patent Specifications 4,310,518 and 4,235,886, in European Patent Specifications EP-
`A-1295; 23,192; 29,310; 29,579; 30,920; 31,303; 63,308; 70,021; 83,305; 215,171;
`203,031: 214,872; 143,307; 298,732; 277,419; 389,180; 395,417; 450,480A2; in Belgian
`Patent Specification BE-A-900,089; and in WO 91/09056; WO 97/01579; WO 97/14715,
`
`West-Ward Pharm.
`Exhibit 1002
`Page 013
`
`West-Ward Pharm.
`Exhibit 1002
`Page 013
`
`
`
`WO 97/47317
`
`PCT/EP97/03036
`
`the contents thereof, in particular with respect to the compounds, being incorporated
`herein by reference.
`
`Preferred somatostatin analogues are e. g. compounds of formula |
`
`CH,-S-Y,
`-
`~~,
`_N-CH-CO-B-C-D-E-NH-CH-G
`
`Y,-S-CH,
`
`A’
`
`A
`
`d)
`
`wherein
`
`Ais C,,alkyl, C,.,.phenylalkyl or a group of formula RCO-,
`
`whereby
`
`i)
`
`i)
`
`a)
`
`b)
`
`Ris hydrogen, C,.,,alkyl, phenyl! or C,,,phenylalkyl, or
`
`RCO- is
`
`a D-phenylalanine residue optionally ring-substituted by halogen, NO,, NH,, OH,
`C\alkyl! and/or C,alkoxy, or
`
`the residue of a natural or a synthetic o-amino-acid other than defined under a)
`above, or of a corresponding D-amino acid, or
`
`©)
`
`a dipeptide residue in which the individual amino acid residues are the same or
`
`different and are selected from those defined under a) and/or b) above,
`the G-amino group of amino acid residues a) and b) and the N-terminal amino group of
`dipeptide residues c) being optionally mono-or di-C,_,,alkylated or substituted by
`C,galkanoy!;
`
`A’
`
`is hydrogen or C,_,alkyl,
`
`Y, and Y, represent together a direct bond or each of Y, and Y, is hydrogen
`
`B
`
`is -Phe- optionally ring-substituted by halogen, NO,, NH,, OH, C,.,alkyl and /or
`
`West-Ward Pharm.
`Exhibit 1002
`Page 014
`
`West-Ward Pharm.
`Exhibit 1002
`Page 014
`
`
`
`WO 97/47317
`
`PCT/EP97/03036
`
`C,,alkoxy (including pentafluoroalanine), naphthylalanine or pyridylalanine,
`
`C
`
`ts (L)-Trp- or (D)}-Trp- optionally o-N-methylated and optionally benzene-
`ring-substituted by halogen, NO,, NH,, OH, C,jalky] and/or C,,alkoxy,
`
`Dis Lys, 4-aminocyclohexylAla or 4-aminocyclohexylGly
`
`Eis Thr. Ser, Val, Tyr, Ile, Leu or an aminobutyric or aminoisobutyric acid residue
`
`G
`
`is a group of formula
`
`COOR, -CHORCONS
`
`R
`
`Y’
`
`Il
`
`12
`
`Ryg
`
`or
`
` -CON
`
`X
`
`wherein
`
`R,
`R,,
`
`R,,
`R,._
`R,,_
`
`is hydrogen or C,,alkyl,
`is hydrogen orthe residue of a physiologically acceptable, physiologicatly
`hydrolysable ester, e.g. formyl, C,,,alkylcarbonyl, benzoyl,
`is hydrogen, C,,alkyl, phenyl or C,,phenyl-alkyl.
`is hydrogen, C,,alkyl or a group of formula -CH{(R,;}-X,,
`is CH,OH, -(CH,),-OH, -(CH,),-OH, -CH(CH,)OH, isobutyl, butyl, benzyl,
`naphthy!-methy! or indol-3-yl-methyl, and
`
`X,
`
`is a group of formula
`
`-COOR,, -CHOR,,or -CO-N
`
`Xia
`N
`
`R
`
`15
`
`West-Ward Pharm.
`Exhibit 1002
`Page 015
`
`West-Ward Pharm.
`Exhibit 1002
`Page 015
`
`
`
`WO 97/47317
`
`PCT/EP97/03036
`
`wherein
`
`R, and R,, have the meanings given above,
`
`R,,
`
`Ri,
`
`R,,
`
`is hydrogen or C, ,alkyl and
`
`is hydrogen, C,,alkyl, phenyl] or C,.,9phenylalkyl, and
`
`is hydrogen or hydroxy,
`
`with the proviso that
`
`when R,,
`
`is -CH(R,,)-X, then R,,
`
`is hydrogen or methyl,
`
`wherein the residues B, D and E have the L-configuration, and the residues in the 2- and
`
`7-position each independently have the (L)- or (D)- configuration,
`
`in free form or tn pharmaceutically acceptable salt or complex form.
`
`Individual compounds of formula I suitable in accordance with the present invention are
`the following somatostatin analogues:
`
`=a
`
`. (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol
`
`also known as octreotide
`
`b. (pyPhe-C'ys-Tyr-(DyTrp-Lys-Val-Cys-ThiNH,
`
`OO
`c. (D)Phe-Cys-Tyr-(D)Trp-Lys- Vai-Cys-TrpNH,
`
`also known as vapreotide
`
`en|
`d. (D)Trp-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH,
`
`e. (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH,
`
`f. 3-(2-(Naphthyl)-(D)Ala-Cys-Tys-(D)Trp-Lys-Val-Cys-ThtNH,
`
`also known as lanreotide
`
`West-Ward Pharm.
`Exhibit 1002
`Page 016
`
`West-Ward Pharm.
`Exhibit 1002
`Page 016
`
`
`
`WO 97/47317
`
`PCT/EP97/03036
`
`g- (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-B-Nal-NH,
`
`h. 3.(2-naphthyl)-Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-B-Nal-NH,
`
`i,
`
`(Dyphe-Cys-BNal-(D)Trp-Lys-Val-Cys-Thr-NH,
`
`Lo
`
`(D)Phe-Cys-Tyr-(D)Trp-Lys-Leu-Cys-Thr-NH,
`
`. (DyPhe-Cys-Tyr-(D)Trp-Lys-Cys-Thr-NH,.
`
`~
`
`A preferred compound of formula I is octreotide.
`
`Compounds of formula I may exist e.g. in free form, salt form or in the form of
`complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric
`acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides
`and acetates. Complexes are e.g. formed from compoundsof the invention on addition of
`inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or
`
`an addition of polymeric organic substances.
`
`Further somatostatin analogues suitable for use in accordance with the present
`
`invention are:
`
`cyclo [-Asn-Phe-Phe-DTrp-Lys-Thr-Phe-Gaba-],
`cyclo(Asu-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Tyr-Thr-Ser), and
`
`(D)Nal-Glu-Tyr-(D)Trp-Lys-Val-Lys-Thr-NH,
`
`According to an alternatively preferred embodimentof the mvention,the somatostatin
`componentof the combination is a somatostatin analogue comprising the amino acid
`sequence of formula (ID)
`
`West-Ward Pharm.
`Exhibit 1002
`Page 017
`
`West-Ward Pharm.
`Exhibit 1002
`Page 017
`
`
`
`WO 97/47317
`
`PCT/EP97/03036
`
`-(D/L)Trp-Lys-X,-X,-
`
`(II)
`
`wherein X, is a radical of formula (a) or (b}
`
`(a)
`
`(b)
`
`‘NH-CH-CO-
`CH-O-CH,-R,
`
`] C
`
`H,
`
`or
`
`“NH-CH-CO-
`
`CH,
`
`R,
`
`wherein R,
`
`is optionatiy substituted phenyl,
`
`R, ts -Z,-CH;-R,, -CH,-CO-O-CH,-R,,
`
`<O)- O-GH,-R,
`
`or
`
`OH
`
`CH,-R,
`
`wherein Z, is © or S,
`
`and
`
`X,
`
`is an G-amino acid having an aromatic residue on the C,, side chain, or an
`amino acid unit selected from Dab, Dpr, Dpm, His,(Bzl)HyPro, thieny]-
`Ala, cyclohexyl-Ala and 1,-butyl-Ala,
`the residue Lys of said sequence corresponding to the residue Lys? of the native
`somatostatin-14,
`
`the contents
`Such somatostatin analogues are e.g, disclosed in WO/ 97/01579,
`thereof, in particular with respect to the specifically exemplified compounds, being
`
`West-Ward Pharm.
`Exhibit 1002
`Page 018
`
`West-Ward Pharm.
`Exhibit 1002
`Page 018
`
`
`
`WO $7/47317
`
`PCT/EP97/03036
`
`incorporated herein by reference.
`
`Preferably the sequence of formula II as defined above corresponds to the residues
`
`at positions 8 through 11 of the somatostatin-14. More preferably the somatostatin
`analogue as disclosed above comprises a hexapeptide unit, the residues at positions 3
`through 6 of said hexapeptide unit comprising the sequence of formula II. More
`
`particularly the hexapeptide unit is cyclic, e.g. having a direct peptide linkage between the
`a-carbonyl group of the residue at position 6 and the G-amino group of the residue at
`
`position 1.
`
`While Lys, X; and X, in th