Clustered multi-antigenic carbohydrate constructs, methods for their preparation, and uses thereof 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2004208884 A1 2004-10-21 [US20040208884]US7824687 B2 2010-11-02 [US7824687] / 2004-10-212010-11-02
申请号/申请日
2003US-10728041 / 2003-12-03
发明人
DANISHEFSKY SAMUEL J;KEDING STACY J;
申请人
SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH;
主分类号
IPC分类号
A01N-043/04A61K-031/70A61K-031/715A61K-038/00A61K-038/14A61K-039/00A61K-039/385A61K-047/48C07H-015/04C07H-015/10C07H-015/18C07K-001/107C07K-004/00C07K-005/078C07K-009/00C07K-014/435C08B-037/00
摘要
(US7824687) The present invention provides novel clustered multi-antigenic constructs having the structure: and methods for the synthesis thereof.  In still another aspect, the present invention provides methods for the treatment of cancer, preferably for the prevention of recurrence of cancer, and methods for inducing antibodies in a subject, comprising administering to a subject in need, an effective amount of any of the inventive constructs as disclosed herein, either in conjugated form or unconjugated and in combination with a suitable immunogenic carrier.
机翻摘要
暂无翻译结果,您可以尝试点击头部的翻译按钮。
地址
代理人
代理机构
;
优先权号
1999US-60150088 1999-08-20 2000US-09641742 2000-08-18 2002US-10209618 2002-07-31 2003US-10728041 2003-12-03 2003WO-US22657 2003-07-18
主权利要求
(US7824687) What is claimed is: 1.  A clustered multi-antigenic construct having the structure:   wherein q is 0 or 1;   each occurrence of s is independently an integer from 1-20;   t' is an integer from 2-6;   RX1 is hydrogen, alkyl, acyl, aryl, heteroaryl, -alkyl(aryl), -alkyl(heteroaryl), a nitrogen protecting group, an amino acid or a protected amino acid;   R is hydrogen or an immunogenic carrier;   each occurrence of the spacer is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl or peptidic moiety;   the linker is either a free carboxylic acid,  -- O -- , (carboxamido)alkyl carboxamide, MBS, primary carboxamide, mono- or dialkyl carboxamide, mono- or diarylcarboxamide, linear or branched chain (carboxy)alkyl carboxamide, linear or branched chain (alkoxycarbonyl)alkyl-carboxamide, linear or branched chain (carboxy)arylalkylcarboxamide, linear or branched chain (alkoxycarbonyl)alkylcarboxamide, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester;   each occurrence of L1 is independently a substituted or unsubstituted aliphatic or heteroaliphatic moiety;   each occurrence of A is independently a carbohydrate determinant having the structure:    wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent pyranose moieties and the sum of b and c is 2, the sum of d and f is 2, and the sum of g and i is 2, and with the proviso that x, y and z are not simultaneously 0; wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group; wherein each occurrence of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group; wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:    wherein Y and Z are independently NH or O; wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2; with the proviso that the v and w bracketed structures represent pyranose moieties and the sum of 1 and k is 2, and the sum of s and u is 2, and with the proviso that v and w are not simultaneously 0; wherein R'0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group; wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group; wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group; wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group; and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group;   with the proviso that all occurrences of A on the multi-antigenic glycopeptide are not the same;   with the limitation that each occurrence of A independently comprises a carbohydrate domain, or elongated version thereof, that is present on tumor cells. 2. The construct of claim 1 wherein t' is  >= 2 and within each bracketed structure s, independently, each occurrence of A is the same. 3. The construct of claim 1, wherein occurrences of A from one bracketed structure s to the next are different. 4. The construct of claim 1, wherein A, for each occurrence, is independently selected from the group consisting of Globo-H, fucosyl GM1, KH-1, glycophorin, N3, Tn, TF, STN, (2,3)ST, 2,6-STn, Gb3, Ley and Lex. 5. The construct of claim 1, wherein each occurrence of L1 is independently a moiety having the structure  -- O(CH2)n --  wherein n is an integer from 1-10; or a natural amino acid side chain, wherein a hydrogen radical of the natural amino acid side chain has been removed and replaced with a carbohydrate moiety A as defined in claim 1. 6. The construct of claim 5, wherein each occurrence of L1 is independently a moiety having the structure  -- O(CH2)n --  wherein n is an integer from 1-10. 7. The construct of claim 6, wherein n is 3. 8. The construct of claim 1, having the structure:   wherein each occurrence of RA is independently H or methyl; and   wherein each occurrence of RB is independently an alkyl glycoside moiety having the structure:    wherein n is an integer from 0-9;   wherein A, for each occurrence, is independently selected from the group consisting of Globo-H, fucosyl GM1, glycophorin, N3, Tn, TF, STN, (2,3)ST, 2,6-STn, Gb3, Ley and Lex. 9. The construct of claim 1, wherein RX1 is an acyl moiety. 10. The construct of claim 9, wherein RX1 is an amino acid residue. 11. The construct of claim 1, wherein the spacer, for each occurrence, is independently a substituted or unsubstituted C1-6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO2, COCO, CONRZ1, OCONRZ1, NRZ1NRZ2, NRZ1NRZ2CO, NRZ1CO, NRZ1CO2, NRZ1CONRZ2, SO, SO2, NRZ1SO2, SO2NRZ1, NRZ1SO2NRZ2, O, S, or NRZ1; wherein each occurrence of RZ1 and RZ2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; a peptidyl moiety or a bivalent aryl or heteroaryl moiety. 12. The construct of claim 1, wherein the spacer, for each occurrence, is independently  -- (CHRsp)n -- , where n is 1-8 and each occurrence of Rsp is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, -alkyl(aryl), -alkyl(heteroaryl),  -- ORsp1,  -- SRsp1 or  -- NRsp1Rsp2 where Rsp1 and Rsp2 are independently hydrogen or lower alkyl; a peptidyl moiety comprising one or more alpha -amino acid residues, or a bivalent aryl moiety having the structure:   13. The construct of claim 1, wherein each occurrence of the spacer is independently a dipeptidyl moiety. 14. The construct of claim 1, wherein t' is 3, each occurrence of the spacer that is not directly attached to the linker is independently a dipeptidyl moiety and the glycopeptide has the structure:   wherein L1 is as defined in claim 1; wherein Rsp is independently hydrogen alkyl, cycloalkyl, aryl, heteroaryl, -alkyl(aryl), -alkyl(heteroaryl)  -- ORsp1, or  -- NRsp1Rsp2 where Rsp1 and Rsp2 are independently hydrogen or lower alkyl; a peptidyl moiety comprising one or more alpha -amino acid residues, or a bivalent aryl moiety having the structure:    s1, s2 and s3 are independently integers from 2-5; A1-A3 are carbohydrate domains, as defined for A in claim 1, and are different from each other; and RX2 is hydrogen, alkyl, acyl, aryl, heteroaryl, -alkyl(aryl), -alkyl(heteroaryl) or a nitrogen protecting group. 15. The construct of claim 14 having the structure:   wherein R, RX2, Rsp, s1, s2 and s3 and A1-A3 are as defined in claim 14; each occurrence of n is independently an integer from 1-10; and each occurrence of Raa is hydrogen, lower alkyl, aryl, heteroaryl, -alkyl(aryl) or -alkyl(heteroaryl). 16. The construct of claim 15, wherein each occurrence of n is 1 and each occurrence of Raa is hydrogen or methyl. 17. The construct of claim 15, wherein each occurrence of n is independently an integer from 1-10 and each occurrence of Raa is hydrogen. 18. The construct of claim 15, wherein each occurrence of Rsp is independently a natural amino acid side chain. 19. The construct of claim 18, wherein each occurrence of Rsp is hydrogen. 20. The construct of claim 1 having the structure:   wherein q is 0 or 1; the spacer, for each occurrence, is independently a substituted or unsubstituted C1-6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO2, COCO, CONRZ1, OCONRZ1, NRZ1NRZ2, NRZ1NRZ2CO, NRZ1CO, NRZ1CO2, NRZ1CONRZ2, SO, SO2, NRZ1SO2, SO2NRZ1, NRZ1SO2NRZ2, O, S, or NRZ1; wherein each occurrence of RZ1 and RZ2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; a peptidyl moiety or a bivalent aryl or heteroaryl moiety; the linker is either a free carboxylic acid,  -- O -- , (carboxamido)alkyl carboxamide, MBS, primary carboxamide, mono- or dialkyl carboxamide, mono- or diarylcarboxamide, linear or branched chain (carboxy)alkyl carboxamide, linear or branched chain (alkoxycarbonyl)alkyl-carboxamide, linear or branched chain (carboxy)arylalkylcarboxamide, linear or branched chain (alkoxycarbonyl)alkylcarboxamide, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester; and the carrier is an immunogenic carrier. 21. The construct of claim 1, 14, 15 or 20, wherein the linker is  -- O -- ,  -- NRG-,  -- NRG(aliphatic)NRJ -- ,  -- NRG(heteroaliphatic)NRJ -- , -(aliphatic)NRJ -- , -(heteroaliphatic)NRJ -- ,  -- O(aliphatic)NRJ -- ,  -- O(heteroaliphatic)NRJ -- ,  -- NRG(aliphatic)NRJ(C.dbd.O)(CRHRI)kS -- ,  -- NRG(heteroaliphatic)NRJ(C.dbd.O)(CRHRI)kS -- , -(aliphatic)NRJ(C.dbd.O)(CRHRI)kS -- , -(heteroaliphatic)NRJ(C.dbd.O)(CRHRI)kS -- ,  -- O(aliphatic)NRJ(C.dbd.O)(CRHRI)kS -- ,  -- O(heteroaliphatic)NRJ(C.dbd.O)(CRHRI)kS -- , an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester, wherein each occurrence of k is independently 1-5; wherein each occurrence of RG, RH, RI or RJ is independently hydrogen, a linear or branched, substituted or unsubstituted, cyclic or acyclic moiety, or a substituted or unsubstituted aryl moiety, and wherein each aliphatic or heteroaliphatic moiety is independently substituted or unsubstituted, linear or branched, cyclic or acyclic. 22. The construct of claim 21, wherein the linker is  -- O -- ,  -- NRG(CRHRI)kNRJ -- ,  -- NRG(CRHRI)kNRJ(C.dbd.O)(CRHRI)kS -- ,  -- NRG -- ,  -- (CRHRJ)kNRI -- ,  -- O(CRHRI)kNRJ, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester, wherein each occurrence of k is independently 1-5, wherein each occurrence of RG, RH, RI or RJ is independently hydrogen, a linear or branched, substituted or unsubstituted, cyclic or acyclic moiety, or a substituted or unsubstituted aryl moiety. 23. The construct of claim 1, 14, 15 or 20, wherein q is 1 and the crosslinker is a fragment having the structure:   whereby said structure is generated upon conjugation of maleimidobenzoic acid N-hydroxy succinimide ester with a linker. 24. The construct of claim 1, 14 or 15, wherein R is hydrogen and q is 0. 25. The construct of claim 1, 14 or 15, wherein R is an immunogenic carrier. 26. The construct of claim 25 wherein the immunogenic carrier is a protein, peptide or lipid. 27. The construct of claim 26 wherein the carrier is KLH, polylysine, HSA or BSA. 28. The construct of claim 1, 14 or 15, wherein q is 0 and R is a lipid immunogenic carrier having the structure:   wherein m', n' and p' are each independently integers between about 8 and 20; and RV is hydrogen, substituted or unsubstituted linear or branched chain lower alkyl or substituted or unsubstituted phenyl. 29. The construct of claim 20, wherein q is 0 and the carrier is a lipid immunogenic carrier having the structure:   wherein m', n' and p' are each independently integers between about 8 and 20; and RV is hydrogen, substituted or unsubstituted linear or branched chain lower alkyl or substituted or unsubstituted phenyl. 30. The construct of claim 28 wherein m', n' and p' are each 14 and the lipid is tripalmitoyl-S-glycerylcysteinylserine. 31. The construct of claim 1, 14 or 15, wherein each occurrence of A is independently Globo-H, fucosyl GM1, KH-1, glycophorin, Ley, Lex, N3, Tn, STN, 2,6-STn, (2,3)ST, Gb3 or TF. 32. The construct of claim 1, 14, 15 or 20, wherein the linker is a moiety having the structure  -- NH(CH2)t''NHC(.dbd.O)(CH2)vS -- ; wherein t'' and v are each independently integers from 1-6. 33. The construct of claim 1, 14 or 15, wherein n and q are each 0, R is hydrogen and the linker is a moiety having the structure  -- NH(CH2)t''NHC(.dbd.O)(CH2)vS --  wherein t'' and v are each independently integers from 1-6. 34. The construct of claim 1, 14 or 15, wherein n is 0, q is 1, R is KLH, the linker is a moiety having the structure  -- NH(CH2)t''NHC(.dbd.O)(CH2)vS --  wherein t'' and v are each independently integers from 1-6, and the crosslinker is a moiety having the structure:   35. The construct of claim 32 wherein t'' is 3 and v is 1. 36. A method for the synthesis of clustered multi-antigenic constructs having the structure:   wherein q is 0 or 1;   each occurrence of s is independently an integer from 2-20;   t' is an integer from 2-6;   RX1 is hydrogen, alkyl, acyl, aryl, heteroaryl, -alkyl(aryl), -alkyl(heteroaryl), a nitrogen protecting group, an amino acid or a proctected amino acid;   R is hydrogen or an immunogenic carrier;   each occurrence of the spacer is independently a substituted or unsubstituted aliphatic, heteroaliphatic, aryl, heteroaryl or peptidic moiety;   the linker is either a free carboxylic acid,  -- O -- , (carboxamido)alkyl carboxamide, MBS, primary carboxamide, mono- or dialkyl carboxamide, mono- or diarylcarboxamide, linear or branched chain (carboxy)alkyl carboxamide, linear or branched chain (alkoxycarbonyl)alkyl-carboxamide, linear or branched chain (carboxy)arylalkylcarboxamide, linear or branched chain (alkoxycarbonyl)alkylcarboxamide, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester;   each occurrence of L1 is independently a substituted or unsubstituted aliphatic or heteroaliphatic moiety;   each occurrence of A is independently a carbohydrate domain having the structure:    wherein a, b, c, d, e, f, g, h, i, x, y and z are independently 0, 1, 2 or 3, with the proviso that the x, y and z bracketed structures represent pyranose moieties and the sum of b and c is 2, the sum of d and f is 2, and the sum of g and i is 2, and with the proviso that x, y and z are not simultaneously 0; wherein R0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group; wherein each occurrence of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is independently hydrogen, OH, ORi, NHRi, NHCORi, F, CH2OH, CH2ORi, a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group; wherein each occurrence of Ri is independently hydrogen, CHO, COORii, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group or a saccharide moiety having the structure:    wherein Y and Z are independently NH or O; wherein k, l, r, s, t, u, v and w are each independently 0, 1 or 2; with the proviso that the v and w bracketed structures represent pyranose moieties and the sum of l and k is 1 or 2, and the sum of s and u is 2, and with the proviso that v and w are not simultaneously 0; wherein R'0 is hydrogen, a linear or branched chain alkyl, acyl, arylalkyl or aryl group; wherein each occurrence of R10, R11, R12, R13, R14 and R15 is independently hydrogen, OH, ORiii, NHRiii, NHCORiii, F, CH2OH, CH2ORiii, or a substituted or unsubstituted linear or branched chain alkyl, (mono-, di- or tri)hydroxyalkyl, (mono-, di- or tri)acyloxyalkyl, arylalkyl or aryl group; wherein each occurrence of R16 is hydrogen, COOH, COORii, CONHRii, a substituted or unsubstituted linear or branched chain alkyl or aryl group; wherein each occurrence of Riii is hydrogen, CHO, COORiv, or a substituted or unsubstituted linear or branched chain alkyl, acyl, arylalkyl or aryl group; and wherein each occurrence of Rii and Riv are each independently H, or a substituted or unsubstituted linear or branched chain alkyl, arylalkyl or aryl group; and wherein each glycosidic moiety is either alpha - or beta -linked to an amino acid;   with the limitation that each occurrence of A independently comprises a carbohydrate domain, or elongated version thereof, that is present on tumor cells;   wherein within each bracketed structure s, independently, each occurrence of A is the same   wherein said method comprises steps of:   (a) providing a glycoamino acid having the structure:    wherein A is a carbohydrate domain as described above;   (b) reacting s occurrences of said glycoamino acid under suitable conditions to generate a glycopeptide having the structure:    wherein s is an integer from 2-20; each occurrence of A is the same within the bracketed glycopeptide s; R' is hydrogen or a protecting group; and R'' is hydrogen, a protecting group, an amino acid or a protected amino acid;   (c) reacting said glycopeptide with a spacer under suitable conditions to generate a spacer construct having the structure:    (d) Repeating steps (a) through (c) t'-1 times to generate t'-1 spacer constructs each independently having the structure:    wherein, for each spacer construct, s, L1, R'' and the spacer moiety may be the same or different; and each spacer construct comprises a different carbohydrate domain A;   (e) Reacting the spacer construct formed in step (c) with the spacer constructs of step (d) under suitable conditions to generate a construct having the structure:    wherein Rx is a protecting group; each occurrence of A is the same within each bracketed structure s; and each bracketed structure s comprises a different carbohydrate domain A; and   (f) Reacting the constructs of step (e) with a linker and optionally a crosslinker and/or an immunogenic carrier under suitable conditions to form the clustered multi-antigenic construct having the structure:    wherein q, linker, crosslinker and R are as defined above. 37. A pharmaceutical composition comprising: a construct of claim 1, wherein R is an immunogenic carrier; and   a pharmaceutically suitable carrier. 38. The pharmaceutical composition of claim 37, wherein the immunogenic carrier is bovine serum albumin, polylysine or keyhole limpet hemocyanin. 39. The pharmaceutical composition of claim 37, wherein the construct does not comprise a crosslinker and the immunogenic carrier is a lipid having the structure:   wherein m', n' and p' are each independently integers between about 8 and 20; and RV is hydrogen, substituted or unsubstituted linear or branched chain lower alkyl or substituted or unsubstituted phenyl. 40. The pharmaceutical composition of claim 39, wherein m', n' and p' are each 14 and the lipid is tripalmitoyl-S-glycerylcysteinylserine. 41. The pharmaceutical composition of claim 37 or 38, or 40, further comprising one or more immunological adjuvants. 42. The pharmaceutical composition of claim 41, wherein at least one of said one or more immunological adjuvants is a saponin adjuvant. 43. The pharmaceutical composition of claim 42, wherein the saponin adjuvant is GPI-0100. 44. The pharmaceutical composition of claim 41, wherein at least one of said one or more immunological adjuvants is bacteria or liposomes. 45. The pharmaceutical composition of claim 44, wherein the immunological adjuvant is Salmonella minnesota cells, or bacille Calmette-Guerin. 46. The pharmaceutical composition of claim 42, wherein saponin adjuvant is QS-21. 47. A method of treating cancer in a subject suffering therefrom comprising: administering to a subject a therapeutically effective amount of a clustered multi-antigenic construct of claim 1, wherein R is an immunogenic carrier, and a pharmaceutically suitable carrier. 48. The method of claim 47, wherein said method comprises preventing the recurrence of cancer in a subject. 49. The method of claim 47 or 48, wherein the cancer is a solid tumor. 50. The method of claim 47 or 48, wherein the subject is in clinical remission, or where the subject has been treated by surgery, has limited unresected disease. 51. A method of inducing antibodies in a subject, wherein the antibodies are capable of specifically binding with tumor cells, which comprises administering to the subject an amount of a clustered multi-antigenic construct of claim 1 effective to induce the antibodies, wherein R is an immunogenic carrier. 52. A method of inducing antibodies in a subject, wherein the antibodies are capable of specifically binding with tumor cells, which comprises administering to the subject: an amount of a clustered multi-antigenic construct of claim 1; wherein R is an immunogenic carrier; and wherein the amount of construct is effective to induce the antibodies. 53. The method of claim 52, wherein the method further comprises administering an immunological adjuvants. 54. The method of claim 47, 51 or 52, wherein the clustered multi-antigenic construct has the structure:   wherein q is 0 or 1; the spacer, for each occurrence, is independently a substituted or unsubstituted C1-6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by CO, CO2, COCO, CONRZ1, OCONRZ1, NRZ1NRZ2, NRZ1NRZ2CO, NRZ1CO, NRZ1CO2, NRZ1CONRZ2, SO, SO2, NRZ1SO2, SO2NRZ1, NRZ1SO2NRZ2, O, S, or NRZ1; wherein each occurrence of RZ1 and RZ2 is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; a peptidyl moiety or a bivalent aryl or heteroaryl moiety; the linker is either a free carboxylic acid,  -- O -- , (carboxamido)alkyl carboxamide, MBS, primary carboxamide, mono- or dialkyl carboxamide, mono- or diarylcarboxamide, linear or branched chain (carboxy)alkyl carboxamide, linear or branched chain (alkoxycarbonyl)alkyl-carboxamide, linear or branched chain (carboxy)arylalkylcarboxamide, linear or branched chain (alkoxycarbonyl)alkylcarboxamide, an oligoester fragment comprising from 2 to about 20 hydroxy acyl residues, a peptidic fragment comprising from 2 to about 20 amino acyl residues, or a linear or branched chain alkyl or aryl carboxylic ester; and the carrier is an immunogenic carrier.
法律状态
(US7824687) LEGAL DETAILS FOR US2004208884  Actual or expected expiration date=2027-09-15    Legal state=ALIVE    Status=GRANTED     Event publication date=2003-12-03  Event code=US/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=US US10728041  Application date=2003-12-03  Standardized application number=2003US-10728041     Event publication date=2003-12-03  Event code=US/EXMR  Event type=Administrative notifications  USPTO Examiner Name Primary Examiner: CANELLA, KAREN A    Event publication date=2003-12-03  Event code=US/ART  Event type=Administrative notifications  USPTO Art Group  ART=1643     Event publication date=2003-12-03  Event code=US/SMALL  Event type=Administrative notifications  Appl Has Filed a Verified Statement of Micro to Small Entity Status Business Entity Status: SMALL    Event publication date=2003-12-03  Event code=US/AIA  Event type=Administrative notifications  First Inventor File Indicated:  AIA=No     Event publication date=2003-12-03  Event code=US/DK  Event type=Examination events  Attorney Docket Number Docket Nbr: 2003080-0142 (SK-893-B-US    Event publication date=2003-12-03  Event code=US/CUST  Event type=Examination events  Attorney/Agent Customer Number Customer Nbr: 63411    Event publication date=2004-01-12  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2004-03-18  Event code=US/INCD  Event type=Examination events  Event type=OAO  Notice Mailed--Application Incomplete--Filing Date Assigned    Event publication date=2004-06-18  Event code=US/AS  Event type=Change of name or address  Event type=Reassignment  Assignment Owner: SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH, NEW  Effective date of the event=2004-06-08  ASSIGNMENT OF ASSIGNORS INTEREST ASSIGNORS:DANISHEFSKY, SAMUEL J. KEDING, STACY J. REEL/FRAME:015467/0869     Event publication date=2004-07-30  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2004-10-21  Event code=US/A1  Event type=Examination events  Application published  Publication country=US  Publication number=US2004208884  Publication stage Code=A1  Publication date=2004-10-21  Standardized publication number=US20040208884     Event publication date=2005-01-31  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2005-06-28  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2006-09-27  Event code=US/RESTREQ  Event type=Examination events  Event type=Corrections  Event type=OAO  Restriction/Election Requirement    Event publication date=2006-12-19  Event code=US/AINEA  Event type=OAI  Event type=Examination events  Informal or Non-Responsive Amendment after Examiner Action    Event publication date=2006-12-19  Event code=US/ELC  Event type=Examination events  Event type=OAI  Response to Election / Restriction Filed    Event publication date=2006-12-19  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2007-04-12  Event code=US/ELC  Event type=Examination events  Event type=OAI  Response to Election / Restriction Filed    Event publication date=2007-07-09  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2007-10-15  Event code=US/AINEA  Event type=OAI  Event type=Examination events  Informal or Non-Responsive Amendment after Examiner Action    Event publication date=2007-10-15  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2008-01-18  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2008-04-14  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2008-10-14  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2008-10-14  Event code=US/136G  Event type=OAO  Request for Extension of Time - Granted    Event publication date=2009-01-21  Event code=US/CTFR  Event type=Examination events  Event type=OA  Event type=OAO  Final Rejection    Event publication date=2009-03-24  Event code=US/DC  Event indicator=Neg  Event type=Examination events  Terminal Disclaimer Filed    Event publication date=2009-03-24  Event code=US/CTFAR  Event type=Examination events  Event type=OAI  Response after Final Action    Event publication date=2009-04-21  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2009-07-22  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2009-08-19  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2009-09-16  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2009-09-18  Event code=US/NOAM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Mail Notice of Allowance    Event publication date=2009-12-17  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2009-12-17  Event code=US/RCEX  Event type=Examination events  Event type=RCE  Event type=OAI  Request for Continued Examination (RCE)    Event publication date=2010-01-05  Event code=US/DRCECAP  Event type=RCE  Event type=OAO  Disposal for a RCE / CPA / R129    Event publication date=2010-03-02  Event code=US/NOAM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Mail Notice of Allowance    Event publication date=2010-05-27  Event code=US/RCEX  Event type=Examination events  Event type=RCE  Event type=OAI  Request for Continued Examination (RCE)    Event publication date=2010-05-27  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2010-05-29  Event code=US/DRCECAP  Event type=RCE  Event type=OAO  Disposal for a RCE / CPA / R129    Event publication date=2010-06-11  Event code=US/NOAM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Mail Notice of Allowance    Event publication date=2010-09-14  Event code=US/APRDY  Event indicator=Pos  Event type=Examination events  Application Is Considered Ready for Issue    Event publication date=2010-10-13  Event code=US/PAT  Event indicator=Pos  Event type=Event indicating In Force  Patented Case    Event publication date=2010-10-13  Event code=US/ISSM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Event type=Restitution or restoration  Issue Notification Mailed    Event publication date=2010-11-02  Event code=US/B2  Event indicator=Pos  Event type=Event indicating In Force  Granted patent as second publication  Publication country=US  Publication number=US7824687  Publication stage Code=B2  Publication date=2010-11-02  Standardized publication number=US7824687     Event publication date=2010-11-02  Event code=US/354  Event indicator=Pos  Event type=Extension of term of duration of protection  Patent term extended under  35 U.S.C 154(b) until/for Delays (A,B,C): 1712  Overlap Delays: 0  Non Overlap Delays: 1712   PTO Office Delays: 0  Applicant Delays: 330  Adjustment total:  Number of days of extension=1382    Event publication date=2012-08-28  Event code=US/CC  Event type=Corrections  Event type=Restitution or restoration  Certificate of Correction - Post Issue Communication    Event publication date=2013-11-12  Event code=US/NMFP  Event type=Payment or non-payment notifications  Publication of First Notice of Maintenance Fees Payable. PAYMENT NOTICE YEAR:  Year of payment of annual fees=3     Event publication date=2014-04-30  Event code=US/FPAY  Event indicator=Pos  Event type=Event indicating In Force  Event type=Payment or non-payment notifications  Fee payment recorded   Annual fees payment date=2014-04-30     Year of payment of annual fees=4     Event publication date=2017-11-14  Event code=US/NMFP  Event type=Payment or non-payment notifications  Publication of First Notice of Maintenance Fees Payable. PAYMENT NOTICE YEAR:  Year of payment of annual fees=7     Event publication date=2018-04-19  Event code=US/M2552  Event type=Payment or non-payment notifications  Payment of Maintenance Fee, 8th Yr, Small Entity    Event publication date=2018-04-19  Event code=US/MAFP  Event indicator=Pos  Event type=Payment or non-payment notifications  Maintenance Fee Payment   Annual fees payment date=2018-04-19     Year of payment of annual fees=8  PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552)
专利类型码
A1B2
国别省市代码
若您需要申请原文,请登录。

最新评论

暂无评论。

登录后可以发表评论

意见反馈
返回顶部