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`RICA
`
`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: 12/094,1 73
`
`FILING DATE: May 19, 2008
`
`PATENT NUMBER: 9,006,224
`
`ISSUE DATE: April 14, 2015
`
`By Authority of the
`
`Under Secretary of Commerce for Intellectual Property
`and Director of the United States Patent and Trademark Office
`
`/M.//2o1__/
`
`M. TARVER
`
`Certifying Officer
`
`ARGENTUM
`Exhibit 1002
`
`000001
`
`
`
`.3; 69¢’;
`
`T
`
`AND PO
`
`R OF ATTORNEY FOR UNITED STAT S PATENT A PLI
`
`Tl N
`
`Original
`
`El Supplemental
`
`El
`
`Substitute
`
`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 I am the original, first and sole lnventor'(if only one name is listed below) or an original, tirst
`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
`
`Nauroandocn.-ine tumor treatane-nt '
`
`the specification of which:
`
`Cl
`
`[I
`
`[S]
`
`is attached hereto.
`
`was filed on
`
`-
`(dayimonthiyeer)
`
`as Application No.
`
`and, if this box (El) contains an 3
`l:'l
`_ was amended on .
`
`(daylmonthlyea r)
`
`was filed as Patent Cooperation Treaty international Application No.
`PCTIEPZODBIDGBBSB
`on
`20.11 .2006
`(daylmontrtfyear)
`
`and, if this box (El) contains an 3
`
`El
`
`entered the national stage in the United States and was accorded Application No.
`
`and, If this box (Cl) contains an 3
`
`III
`
`was amended, subsequent to entry into the national stage, on
`-
`
`_
`tdayimonthlyeari
`
`I hereby state that I have reviewed and understand the contents of the above-identified specification.
`including the cialms, as amended by any amendment(s) specifically referred to above and. if H135
`application was flied as a Patent Cooperation Treaty Intematlonal application, by any amendments
`made during the international stage (Including any made under Patent Cooperation Treaty Rule 91,
`Article 19 and Article 34).
`
`I act-tnowledge my duty to disclose infomtation which is material to patentabiiity as defined In 37 C.F.R.
`1.56.
`including,
`for continuation-in-part applications, material
`infonnation which became available
`between the filing date of
`the prior application and the national or Patent Cooperation Treaty
`international filing date of the continuation-in-part application.
`
`000002
`
`
`
`I hereby claim the benefit under 35 U.S.C. 119(a)~(d) or (f) or 3659:) of any foreign application(s) for
`patent, inventor's oenifcate or plant breeders right certificate listed below and under 35 U.S.C. 365(a)
`of any Patent Cooperation Treaty international applicetion(a) designating at least one country other
`than the United States listed below and have also iisted below any foreign applioatlonie) for patent
`inventors certificate or plant breeder's right certificate and Patent Cooperation Treaty lntematlonal
`appl:'cation(a) 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 pn'on'ty of which is claimed for that subject
`matter:
`
`COUNTRYIREGION
`OR P.C.T.
`
`'
`
`- APPLICATION No.
`
`FILING DATE
`(daytmon
`ar)
`
`,
`
`PRIORITY CLAIMED
`
`Great Britain
`
`05236583
`
`Great Brlhiln _
`Great Britain
`
`Great Britain
`
`Great Brllaln
`
`Great Britain
`
`0601082.1
`06-02747.8
`
`06-07942.0
`
`0609272.0'
`
`0609912.1
`
`EUFOPGEI1 PH‘-‘|=0dIIfl
`
`051206503
`
`21 .1 1 .2005
`
`1 9.01.2006
`10.02.2006
`
`.
`
`21.04.2006
`
`1 0.05.2006
`
`18.05.2006
`
`14.09.2006
`
`Yes
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`Yes
`
`EEEEEEE
`
`No
`
`No
`No
`
`No
`
`No
`
`No
`
`No
`
`onnnono
`
`I hereby claim the benefit under 35 U.S.C. 119(e) of any United States provisional appllcaliOn(B) listed
`below:
`
`APPLICATION NO.
`
`FILING DATE
`cla lrnonthl er
`
`I hereby claim the benefit under 35 U.S.C. 120 oi any United States applic.-at1on(s) listed below and
`under 35 U.S.C. 365(0) of any Patent Cooperation Treaty international appllcaflonle) designating the
`United States listed below:
`
`United States
`Appllcafion No.
`
`United States
`Filing Date
`(d5W|'n0|1W¥63f)
`
`Status (Pending,
`Abandoned or U.S.
`Patent No.
`
`lntemational
`Application No.
`and Filing Date
`da Imon er
`
`000003
`
`
`
`I hereby appoint all of the registered practitioners associated with Customer No. 001095. respectively
`and individually. as my attorneys and agents. with full power of substitution and revocation.
`to
`prosecute this application and to transact all business in the Patent and Trademark Oltice connected
`therewith.
`
`this box (El) contains an x , i hereby authorize the registered practitioners associated with
`If
`Customer No. 001095 and any others actin on my behalf to take any action relating to this application
`based on communications from Corporate Intellectual Property of Novarfls International AG. Basie,
`Switzertand. or an affiliate thereof or a successor thereto, without direct communication from me.
`
`Please send all correspondence relating to this application to the address associated with Customer
`No. 001095.
`
`I hereby declare that all statements made herein of my own knowledge are true and that all statements
`made on information and belief are betle-Jed 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 18 U.S.C. 1001 and that such willful false statements mayjeoperdize the
`validity of the appflcation or any patent issuing thereon.
`
`Full Mme of sole
`or first Joint inventor
`
`_
`Peter Wayne MARKS
`
`inventorssignature
`
`_/Q
`
`Date
`
`Residence
`
`Woodbrldge, CT 06525-1913. US
`
`Citizenship
`
`'
`
`USA
`
`Post Oflice Address
`
`145 Rimmon Road
`Woodbridge. CT 06525-1913
`US
`
`Full name of second
`joint inventor. If any
`
`David LEBWOHL
`
`lnventor‘s signature
`
`Residence
`
`Citizenship
`
`Madison. New Jersey 07940 Us
`
`USA
`
`, Post Oftice Address
`
`55 Pomaroy Road
`Madison. New Jerley 07040
`US
`
`Date. 23" fifc 2:90};-
`
`(d ayfrnontltlyeer)
`
`IMPORTANT: Before this declaration is signed. the patent application (the specification. the claims
`and this declaration) 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.
`
`000004
`
`
`
`FILING BY “EXPRESS MAIL” UNDER 3'? CFR 1.10
`
`Express Mail Label Number
`
`Date of Deposit
`
`Form PTO—139G-MOD
`‘REV ‘W’
`
`U. S Deparlrrientcfcomrnerce Patent and Trademark Office
`
`TFIANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/E0/US)
`CONCERNING A FILING UNDER 35 u.s.c. 371
`INTERNATIONAL APPLICATION NO.
`INTERNATIONAL FILING DATE
`PCT/EP20D6/068656
`20 November 2006 (20.1 1.06)
`TITLE OF INVENTION
`NEUROENDOCRINE TUMOR TREATMENT USING MTOR INHIBITORS
`APPLICANTIS) FOR DOIEO/US
`MARKS ET AL.
`
`ATTQRNE\(’s DOCKET NUMBER
`346'78—US—PCT
`U-3 APPLICATION NO‘ «-rrwwn-seesrcrnr-5»
`
`PRIORITY DATE CLAIMED
`21 November 2005 (21.11.05)
`
`Applicant herewith submits to the United States Designatedr'Elected Oflice (DOIEOIUSJ the following items and other information:
`
`This is a FIRST submission of items concerning a filing under 35 U.S.C. 371.
`This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`This express request to begin national examination procedures (35 U.S.C. 371(0) 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).
`date.
`A proper Demand for International Preliminary Examination was made by the 19th month from the earliest claimed priority
`A copy of the International Application as filed (35 U.S.C. 371(c)(2))
`a. El
`is transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`has been transmitted by the International Bureau. (See Form PCTf|Br'30B)
`c. El
`is not required, as the application was filed in the United States Receiving Office (FIOIUSI.
`A translation of the international Application into English (35 U.S.C. 371(c)(2)).
`Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C.371(c)(3)).
`a. [I are transmitted herewith (required only if not transmitted by the international Bureau).
`b. E] have been transmitted by the International Bureau.
`c.
`I:I have not been made; however, the time limit for making such amendments has NOT expired.
`cl.
`have not been made and will not be made.
`A translation of the amendments to the claims under PCT Ar1icle 19 (35 U.S.C. 371 (c)(3)).
`An executed Declaration and Power of Attorney (original or copy) (35 U.S.C. 371(c)(4)).
`A translation of the annexes to the International Preliminary Examination Report under PCT Article 36 (35 U.S.C.
`3?1(C)(5)).
`
`Items 11. to 16. below concern documenl(sI or information included.
`
`11. E An Information Disclosure Statement under 37 CFR 1.97 and 1.93.
`
`12.
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`20.
`
`IZIIZIIIIEIEIIIIIZIZIEIZI
`
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.23 and 3.31 is included.
`A FIRST preliminary amendment.
`A SECOND or SUBSEQUENT preliminary amendment.
`
`An Application Data Sheet under 37 CFR 1.76.
`
`A substitute specification.
`
`A change of power of attorney andfor address letter.
`
`A computer-readable form of the sequence listing in accordance with PCT Fiule 13rer.2 and 37 CFR 1.821—1.EI25.
`
`A second copy of the published International Application under 35 U.S.C. 154(d){4).
`
`A second copy of the English language translation of the international application under 35 U.S.C. 154(d)(4).
`Other items or information:
`
`000005
`
`
`
`US. AF'F'LlCATlON NO. (rt lmowrt, see 37 CFR 1.5)
`INTEFENATIONAL APPLICATION NO.
`— vcrrsrzooeroasasa
`The following fees are submitted:
`
`ATTOFINEVS DOCKET NUMBER
`ms-us-rcr
`CALCULATIONS no use
`
`21. E Basic national fee.
`22. Examination Fee
`
`.
`
`.
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`.
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`.
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`.
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`.
`
`.
`
`.
`
`$310
`
`E]
`
`if international preliminary examination report was prepared by USPTO
`and all claims satisfy provisions of PCT Article 33(1)-(4) .
`.
`.
`.
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`.
`.
`.
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`E All other situations.
`
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`
`23. Search fee
`
`C]
`
`If Search fee (3? CFR 1.445(a)(2)) has been paid on the international
`.
`.
`application to the USPTO as an International Searching Authority.
`.
`.
`.
`E if International Search Report was prepared and provided to the Office. .
`E] All other situations .
`.
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`
`
`Additional fee for specification and drawings filed in paper over 100 sheets (excluding sequence listing or computer
`program listing filed in an electronic medium). The fee is $260 for each additional 50 sheets of paper or fraction
`thereof.
`
`TOTAL OF 21, 22 AND 23 :
`
`Total Sheets
`
`Extra sheets
`
`Number of each additional 50 or fraction
`thereof (round u - to a whole number)
`40-100=1
`
`RATE
`
`E] 30
`
`Surcharge of $130 for furnishing the oath of declaration later than
`months from the earliest claimed riori
`date (37 CFR 1.492(e)).
`CLAIMS
`NUMBER FILED
`NUMBER EXTRA
`12
`Total claims j O X
`nde ndent claims
`370
`$
`+
`MULTIPLE DEPENDENT CLAlM(S) (if a n licable}
`_ TOTAL OF ABOVE CALCULATIONS =
`Reduction of 112 for filing by small entity, if applicable. Verified Small Entity Statement must also be
`filed (Note 37 CFR 1.9, 1.27.128).
`
`RATE
`
`$
`
`50
`
`09J3Cl
`
`1,770
`
`1,770
`
`1,770
`
`5969
`
`$
`
`$
`
`3
`
`1,770
`Amount to
`be: refunded
`char ed
`
`SUBTOTAL :
`Processing fee of $130 for furnishing the English translation later than L] 30 months from the
`earliest claimed priority date (3? CFR 1.492(1)).
`
`+
`TOTAL NATIONAL FEE =
`Fee for recording the enclosed assignment (3? CFR 1.21 (h)). The assignment must be accompanied
`to an a roriate cover sheet (37 CFR 3.28, 3.31). $40 er roert
`«-
`TOTAL FEES ENCLOSED =
`
`III
`
`A check in the amount of $
`
`to cover the above fees is enclosed.
`
`E Please charge Deposit Account No. 19-0134 in the name of Novarlis in the amount of $1,770 to cover the above fees. A
`duplicate copy of this form is enclosed.
`
`a.
`b.
`
`C.
`
`The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any overpayment to
`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 CFH 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:
`
`7
`4~
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`
`ghton
`.
`Gregory
`Attorney for Applicants
`Reg. No. 47,666
`(862) 778-2614
`
`Page 2 of 2
`
`000006
`
`
`
`FILING BY “EXPRESS MAIL” UNDER 3'? CFR 1.10
`
`Express Mail Label Number
`
`Date of Deposit
`
`Form PTO—139G-MOD
`‘REV ‘W’
`
`U. S Deparlrrientcfcomrnerce Patent and Trademark Office
`
`TFIANSMITTAL LETTER TO THE UNITED STATES
`DESIGNATED/ELECTED OFFICE (DO/E0/US)
`CONCERNING A FILING UNDER 35 u.s.c. 371
`INTERNATIONAL APPLICATION NO.
`INTERNATIONAL FILING DATE
`PCT/EP20D6/068656
`20 November 2006 (20.1 1.06)
`TITLE OF INVENTION
`NEUROENDOCRINE TUMOR TREATMENT USING MTOR INHIBITORS
`APPLICANTIS) FOR DOIEO/US
`MARKS ET AL.
`
`ATTQRNE\(’s DOCKET NUMBER
`346'78—US—PCT
`U-3 APPLICATION NO‘ «-rrwwn-seesrcrnr-5»
`
`PRIORITY DATE CLAIMED
`21 November 2005 (21.11.05)
`
`Applicant herewith submits to the United States Designatedr'Elected Oflice (DOIEOIUSJ the following items and other information:
`
`This is a FIRST submission of items concerning a filing under 35 U.S.C. 371.
`This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`This express request to begin national examination procedures (35 U.S.C. 371(0) 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).
`date.
`A proper Demand for International Preliminary Examination was made by the 19th month from the earliest claimed priority
`A copy of the International Application as filed (35 U.S.C. 371(c)(2))
`a. El
`is transmitted herewith (required only if not transmitted by the International Bureau).
`b.
`has been transmitted by the International Bureau. (See Form PCTf|Br'30B)
`c. El
`is not required, as the application was filed in the United States Receiving Office (FIOIUSI.
`A translation of the international Application into English (35 U.S.C. 371(c)(2)).
`Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C.371(c)(3)).
`a. [I are transmitted herewith (required only if not transmitted by the international Bureau).
`b. E] have been transmitted by the International Bureau.
`c.
`I:I have not been made; however, the time limit for making such amendments has NOT expired.
`cl.
`have not been made and will not be made.
`A translation of the amendments to the claims under PCT Ar1icle 19 (35 U.S.C. 371 (c)(3)).
`An executed Declaration and Power of Attorney (original or copy) (35 U.S.C. 371(c)(4)).
`A translation of the annexes to the International Preliminary Examination Report under PCT Article 36 (35 U.S.C.
`3?1(C)(5)).
`
`Items 11. to 16. below concern documenl(sI or information included.
`
`11. E An Information Disclosure Statement under 37 CFR 1.97 and 1.93.
`
`12.
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`20.
`
`IZIIZIIIIEIEIIIIIZIZIEIZI
`
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.23 and 3.31 is included.
`A FIRST preliminary amendment.
`A SECOND or SUBSEQUENT preliminary amendment.
`
`An Application Data Sheet under 37 CFR 1.76.
`
`A substitute specification.
`
`A change of power of attorney andfor address letter.
`
`A computer-readable form of the sequence listing in accordance with PCT Fiule 13rer.2 and 37 CFR 1.821—1.EI25.
`
`A second copy of the published International Application under 35 U.S.C. 154(d){4).
`
`A second copy of the English language translation of the international application under 35 U.S.C. 154(d)(4).
`Other items or information:
`
`000007
`
`
`
`US. AF'F'LlCATlON NO. (rt lmowrt, see 37 CFR 1.5)
`INTEFENATIONAL APPLICATION NO.
`— vcrrsrzooeroasasa
`The following fees are submitted:
`
`ATTOFINEVS DOCKET NUMBER
`ms-us-rcr
`CALCULATIONS no use
`
`21. E Basic national fee.
`22. Examination Fee
`
`.
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`$310
`
`E]
`
`if international preliminary examination report was prepared by USPTO
`and all claims satisfy provisions of PCT Article 33(1)-(4) .
`.
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`E All other situations.
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`23. Search fee
`
`C]
`
`If Search fee (3? CFR 1.445(a)(2)) has been paid on the international
`.
`.
`application to the USPTO as an International Searching Authority.
`.
`.
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`E if International Search Report was prepared and provided to the Office. .
`E] All other situations .
`.
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`
`Additional fee for specification and drawings filed in paper over 100 sheets (excluding sequence listing or computer
`program listing filed in an electronic medium). The fee is $260 for each additional 50 sheets of paper or fraction
`thereof.
`
`TOTAL OF 21, 22 AND 23 :
`
`Total Sheets
`
`Extra sheets
`
`Number of each additional 50 or fraction
`thereof (round u - to a whole number)
`40-100=1
`
`RATE
`
`E] 30
`
`Surcharge of $130 for furnishing the oath of declaration later than
`months from the earliest claimed riori
`date (37 CFR 1.492(e)).
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`
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`
`$
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`50
`
`09J3Cl
`
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`
`1,770
`
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`
`5969
`
`$
`
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`
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`
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`Amount to
`be: refunded
`char ed
`
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`earliest claimed priority date (3? CFR 1.492(1)).
`
`+
`TOTAL NATIONAL FEE =
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`to an a roriate cover sheet (37 CFR 3.28, 3.31). $40 er roert
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`A check in the amount of $
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`to cover the above fees is enclosed.
`
`E Please charge Deposit Account No. 19-0134 in the name of Novarlis in the amount of $1,770 to cover the above fees. A
`duplicate copy of this form is enclosed.
`
`a.
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`
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`
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`
`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFH 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:
`
`7
`4~
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`
`ghton
`.
`Gregory
`Attorney for Applicants
`Reg. No. 47,666
`(862) 778-2614
`
`Page 2 of 2
`
`000008
`
`
`
`CASE 34678-US—PCT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`IN RE PCT NATIONAL STAGE APPLICATION OF
`
`MARKS ET AL.
`
`INTERNATIONAL APPLICATION NO: PCTfEP2006/068656
`
`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
`
`This paper is 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 deemed to be required, the Commissioner is hereby authorized to charge such fee to
`Deposit Account No. 190134.
`
`In accordance with 37 C.F.R. §‘I .56, applicants wish to call the Examiner’s attention to
`
`the references cited on the attached form(s) PTO—14-49.
`
`The listed references were cited in the international stage search report. Since these
`
`references are of record in the instant PCT appiication PCT/EP2006/068656, copies are not
`enclosed herewith.
`
`000009
`
`
`
`The Examiner is requested to consider the foregoing information in relation to this
`
`application and indicate that each reference was considered by returning a copy of the initialed
`PTO 1449 form(s).
`
`Novartis Pharmaceuticals Corp.
`Patents Pharma
`One Health Plaza, Building 104
`East Hanover, NJ 07936-1080
`(862) 778-2614
`
`Date:
`
`Respectfully submitted,
`
`-
`on
`. Hou
`Greg y
`Attorney for Applicants
`Reg. No. 47,666
`
`000010
`
`
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`lntemationai Bureau
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`A61K 3831
`
`(11) International Publication Number:
`
`W0 9'7/47317
`
`(43) International Publication Date:
`
`IS December [997 (i3.l2.97}
`
`(21) International Application Number:
`
`PCTVEP97/03036
`
`(22) International Filing Date:
`
`11 June 1997 (I 1.06.97)
`
`(30) Priority Data:
`'96 l 2 l 7 I .0
`9619310.?
`
`ll June 1996 (1106.96)
`16 September 1996 (l6.09.96)
`
`GE
`GE
`
`(71) Applicant (for ail designated States except US): NOVARTIS
`AG ICHICH]: Schwarzwalclallcc 215, CH-4058 Basel (CH).
`
`(72) Inventor; and
`('15) Inventor];-Xpplicanl {for US only): WE-DCKBECKER, Gisbcrt
`[DEICH]; Locliring 3!, CH-4105 Biz-.1-Bcnken (CH).
`
`('74) Agent: ROTH. Bernhard. M.; Novanis AG, PaIcnt- und
`Markbnabtcilung, Klybcclcslrassc 141, CH-4002 Basal (CH).
`
`(81) Designated States: AL. AM, AT, AU, AZ, BA, BB, BG, BR,
`BY. CA. CH, CN, CU. CZ, DE. DK. EE. ES, Fl. GB, GE,
`GH. 1-IU, IL, IS, JP, KE. KG. KP. KR, KZ, LC. LK, LR,
`LS. LT. LU. LV. MD, MG, MK. MN, MW, MX. NO, NZ,
`PL, PT, RO, RU. SD. SE, SG. SI. SK. TI, TM, TR. TI‘.
`UA, UG, US, UZ, VN, YU. ZW, ARIPU patent (GH, KE.
`LS, MW, SD, 82. UG, ZW). Eurasian pau:n1(AM. AZ, BY,
`KG, KZ, MD, RU, TJ, TM), European patent (AT, BE, CH,
`DE. DK. ES. Fl, FR. GB. GR, IE. IT. LU, MC. NL, PT.
`SE), OAPI patent (BF. BL CF, CG. CI, CM. GA. GM. ML,
`MR, NE, SN, TD. TG).
`
`Published
`‘With inrernarinnai search report.
`
`(54) Title: COMBINATION OF A SOMATOSTATIN ANALOGUE AND A RAPAMYCIN
`
`(57) Abstract
`
`A combination of a compound of the somatostatin class and a rapamycin macrolide is useful for thc prevention or treatment of call
`hyperproliferation.
`
`000011
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`MC
`MD
`MG
`MK
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing intcmationai applications under the PCT‘.
`Albania
`ES
`LS
`Lesotho
`Slovenia
`SI
`Spain
`Fl
`Armenia
`Finland
`SK
`Slovakia
`LT
`Lilhuunia
`Amlria
`LU
`FR
`France
`Luxembourg
`Senegal
`Australia
`Gabon
`GA
`Lalvia
`Swaziland
`GE
`Chad
`Monaco
`Azerbaijan
`United Kingdom
`GE
`Bosnia mo Hcrelsgu-villa
`Georgia
`Republic of Moldova
`Togo
`Bubodoa
`GH
`Ghana
`Madagascar
`Tajikiatari
`GN
`Guinea
`Turkmenistan
`Belgium
`The funnei Yugoslav
`Burlrina Faao
`Greece
`GR
`Republic of Macedonia
`Turkey
`IIU
`Mali
`Bulgaria
`Hungary
`Trinidad and Tobago
`Benin
`[E
`Ireland
`Ukraine
`Mongolia
`Brazil
`[L
`laniel
`Maurilallia
`Uganda
`Beiai-us
`IS
`Iceland
`Malawi
`Unired Snare: of America
`Canada
`IT
`Mexico
`Uzbekistan
`Italy
`JP
`Vic! Nam
`Japan
`Central African Republic
`Niger
`KE
`Netherlands
`Ccmgu
`Kenya
`Yugoslavia
`KG
`Switzerland
`Zimbabwe
`Kyrgyulan
`Norway
`com d'Ivoire.
`KP
`New Zealand
`De:-ruocralic People's
`Caniem-on
`Poland
`Republic of Korea
`China
`Republic of Korea
`Poruigal
`Cuba
`Romania
`Kazaislan
`Saint Lucia
`Russian Federation
`Czech ‘Republic
`Lieazhlcnslcin
`Sudan
`Germany
`Denmark
`Sr‘: Lsnlra
`Swetn
`llelorlia
`Liberia
`Singapore
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`Pl.
`PT
`RO
`RI]
`SD
`SE
`SC
`
`SZ
`TD
`1'13
`1'5
`TM
`TR
`TT
`UA
`U6
`US
`UZ
`VN
`YU
`ZW
`
`000012
`
`
`
`W0 97!-473“
`
`PCTI'EP9'H(}3036
`
`COMBINATIO
`
`F
`
`OM TO
`
`IN NALOGUE NDARAPAMYCI
`
`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 intimal cell 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 phannaceutical combination comprising a
`
`compound of the somatostatin class. and a rapamycin macrolide.
`
`The somatostatin class is a known class of small peptides comprising the naturally
`
`occurring somatostatin-l4 and analogues having somatostatin related activity, e.g. as
`
`disclosed by AS. Dutta in Small Peptides. Vol.19, Elsevier (3993). 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-l4 wherein one or more
`
`amino acid units have been omitted andlor replaced by one or more other amino radica](s)
`
`andJor wherein one or more functional groups have been replaced by one or more other
`
`functional groups andfor 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—l4 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 hSS'I'-5), preferably in the
`
`nMolar range, more preferably to at least the hSST-2 receptor in the nM0lar 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 4.310,5l8 and 4,235,886, in European Patent Specifications EP-
`
`A-1295; 23,l92; 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 91109056; WO 97101579; W0 97i'l47l5.
`
`000013
`
`
`
`wo 97/47317
`
`PCT/EP97l(l3036
`
`the contents thereof, in particular with respect to the compounds. being incorporated
`
`herein by reference.
`
`Preferred somatostatin anaiogues are e. g. compounds of formula I
`
`Y2'S" H2
`(‘II-ll-S-Y1
`:N-CH-co-B-C-D-E-NH- H-G
`
`A,
`
`A
`
`wherein
`
`A is Cmalkyl. C,_mphenylalkyl or a group of formula RCO-,
`
`whereby
`
`i)
`
`ii)
`
`R is hydrogen. C,,,,alkyl, phenyl or C-,_,uphenylalky1, or
`
`RCO- is
`
`a)
`
`a D-phenylalanine residue optionally ring-substituted by halogen, N02, NH2, OH.
`
`C,_3aikyl and/or Cwalkoxy; or
`
`the residue of a natural or a synthetic ot-amino-acid other than defined under a)
`
`above, or of a corresponding D-amino acid, or
`
`c)
`
`a dipeptide residue in which the individual amino acid residues are the same or
`
`different and are selected from those defined under a) andlor b) above,
`
`the (1—amino group of amino acid residues a) and b) and the N-terminal amino group of
`
`dipeptide residues c) being optionally mono- or di-Cmalkylated or substituted by
`
`C,_,alkanoyl;
`
`A‘
`
`is hydrogen or C,_3allcyl,
`
`Y, and Y2 represent together a_ direct bond or each of Y, and Y, is hydrogen
`
`B
`
`is -Phe- optionally ring—substitutcd by halogen, N02. NH}, OH, Cmalkyl and /or
`
`000014
`
`
`
`W0 9'”47317
`
`PCTfEP9‘7/03036
`
`Cmalkoxy (including pentafluoroalanine), naphthylalanine or pyriclylalanine,
`
`is (L)-TIp— or (D)-Trp- optionally ot—N-methylated and optionally benzene-
`
`ring-substitutcd by halogen, N02. NI-12. OH. C,_,alkyl and/or C,_3alkoxy,
`
`is Lys, 4—aminocyclohexylA1a or 4-aminocyclohe:-:ylGly
`
`is Thr. Ser, Val, Tyr. Ile. Leu or an aminobutyric or aminoisobutyric acid residue
`
`is a group of formula
`
`/R11
`—COORT —CI-12030, -CON.‘
`
`R12
`
`wherein
`
`is hydrogen or Cmalkyl,
`
`is hydrogen or the residue of a physiologically acceptable, physiologically
`
`hydrolysable ester, e.g. forrnyl, Cmzalkylcarbonyl, benzoyl,
`
`is hydrogen. C..3alky1, phenyl or Cmphenyl-alkyl.
`
`is hydrogen, Cmalkyl or a group of formula —CH(R,3)—X,,
`
`is CH:OH, -(CI-12);.-OH, -(CH,)3—OH, -CH(CH3)OH, isobutyl, butyl, benzyl.
`
`naphthyl-methyl or indol—3—yl-methyl, and
`
`is a group of formula
`
`-cook, -CH 10121 cor -CO-N
`
`000015
`
`
`
`W0 97/47317
`
`PCTfEP97I03036
`
`wherein
`
`R7 and Rm have the meanings given above,
`
`R”
`
`is hydrogen or Cmalkyl and
`
`R”
`
`is hydrogen, C,_3a1kyl, phenyl or C,_,ophenylalkyl, and
`
`R”,
`
`is hydrogen or hydroxy,
`
`with the proviso that
`
`when R, is -CH(R,3)-X, then R“ is hydrogen or methyl,
`
`wherein the residues B. D and B have the L-configuration, and the residues in Lhe 2- and
`
`7—position each independently have the (L)— or (D)- configuration.
`
`in free form or in 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-Ciys—Phe-(D)Trp—Lys—Thr-gys-Thr—ol
`also known as octreotide
`
`. (D)Phe-(iys-Tyr-(D)Trp-Lys-Val—Cys—ThrNI-I,
`
`.
`
`(D)Phe—Cy5—Tyr-(D)Trp-Ly5—Val-Cys-TrpNI-[1
`
`also known as vapreotide
`
`. (D)Trp—Cys-Phe-(D)Trp-Lys—Thr-Cys-ThrNH,
`
`. (D)Phe-Cys-Phe-(D)Trp-Lys—Thr-gys-ThrNI-[2
`
`. 3—(2-(Naphthyl)—(D)Ala-éys-Tyr-(D)Trp-Lys-Val-glys-ThrNH,
`also known as lanreotide
`
`000016
`
`
`
`wo 97247317
`
`pcrnmvxososs
`
`.
`
`(D)Phe—Cys—Tyr-(D)Trp-Lys—Val—&ys-B-Nal—NH2
`
`. 3—(2-naphthy})-Ala-éys-Tyr-(D)Trp-Lys—Val-Cys-fi-Na]-NH;
`
`'.
`
`(D)Phe-(1.:ys—B—Nal—(D)Trp-Lys-Val-Eys—Thr—Nl-I3
`
`'.
`
`(D)Phe-Cys~Tyr-(D}Trp-Lys-Leu-Cys-Thr-NH,
`
`'. (D)Phe—Cys-Tyr-(D)Trp-Lys-Eys-'I'hr~NH2.
`
`A preferred compound of fonnula I is octreotide.
`
`Compounds of formula. I may exist e.g. in free form, salt fonn or in the form of
`
`complexes thereof. Acid addition salts may be fonned 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 compounds of the invention on addition of
`
`inorganic substances, e.g. inorganic salts or hydroxides such as Ca— and Zn-salts. andfor
`
`an addition of polymeric organic substances.
`
`Further somatostatin analogues suitable for use in accordance with the present
`
`invention are:
`
`cyclo [-Asn—Phe-Phe—D'I‘rp-Lys-Thr-Phe-Gaba-].
`
`cyclo(Asu-Ly5-Asn-Phe-Phe-Trp-Lys—Thr-Tyr-Thr-Ser), and
`
`(D)N al—Glu-Tyr-(D)Trp-Lys-Val-Lys-Thr-NH,
`
`According to an alternatively preferred embodiment of the invention. the somatostatin
`
`component of the combination is a somatostalin analogue comprising the amino acid
`
`sequence of formula (II)
`
`000017
`
`
`
`W0 W47317
`
`PCTlEP97I03U36
`
`—(D/L)Trp-Ly5—X2-X3-
`
`wherein X3 is a radical of formula (a) or (b}
`
`-NH-|'.l':H-CO-
`CH-o-CH,-R,
`
`I C
`
`H3
`
`-NH-C[!H-C0-
`CH2
`
`R2
`
`wherein R,
`
`is optionally substituted phenyl,
`
`R2 is -Z,-Cl-I,-R,. -CH2-CO-O-CH,-R,,
`
`—@— O-CH2-R,
`
`{-33%OH
`
`wherein Z, is O or S,
`
`and
`
`X,
`
`is an a-amino acid having an aromatic residue on the Cu side chain. or an
`
`amino acid unit selected from Dab. Dpr, Dpm, His,(Bzl}I-IyPm, thieny1-
`
`Ala, cyclohcxyl-Ala and I.-butyl-Ala,
`
`the residue Lys of said sequence corresponding to the residue Lys’ of the native
`somatostatin-14.
`
`Such somatostatin analogues are c.g. disclosed in WOI 97I0l579,
`
`the contents
`
`thereof, in particular with respect to the specifically exemplified compounds, being
`
`000018
`
`
`
`W0 97/47317
`
`PCT/1:1=97ro3o3-5
`
`incorporated herein by reference.
`
`Preferably the sequence of formula II as defined above corresponds to the residues
`
`at positions 8 through 31 of the somatostatin-l4. 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
`
`0t~carbonyl group of the residue at position 6 and the o'.—arnino group of the residue at
`
`position 1.
`
`While Lys, X3 and X3 in the sequence of formula II have the L-configuration, Trp
`
`may have the D- or L-configuration, preferably the D-configuration.
`
`X3 is preferably a residue of formula fa) or (b), R: being preferably -Z,-Cl-I,-R, or
`
`@ o-cH,-a,
`
`_
`
`When X, comprises an aromatic residue on the Cflside chain, it may suitably be a
`
`natural or unnatural ot—arnino acid, e.g. Phe, Tyr, Trp, Nal, Pal. benzothienyl-Ala, Tic and
`
`thyronin. preferably Phe or Nal, more preferably Phe. X, is preferably an ct-amino acid
`
`bearing an aromatic residue on the Cu side chain.
`
`When R,
`
`is substituted phenyl, it may suitably be substituted by halogen, methyl,
`
`ethyl, methoxy or ethoxy eg. in ortho and/or par