# US 6,001,364 A · Hetero-polyoxime compounds and their preparation by parallel assembly > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 6,001,364 A - Document ID: US6001364A - Status: Granted - Kind: A - Application number: 08/105,904 - Filed: 1993-08-31 - Granted: 1999-12-14 - Earliest claimed: 1993-05-05 - Assignees: Gryphon Sciences - Inventors: Keith Rose; Robin E. Offord - Web page: https://patentgrep.com/patent/US6001364A ## CPC - C07K 1/1077: {by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids} - A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes - A61P 37/04: Immunostimulants - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Provided by this invention are defined compositions of hetero-polyoximes of defined structure comprising a baseplate structure having a plurality of oxime bonds, wherein each oxime bond links a specifically active molecule to the baseplate. Also provided are novel baseplates having a plurality of oxime forming complementary reactive groups and novel specifically reactive molecules having an oxime forming complementary reactive group. Also provided by this invention are methods of preparing these novel compositions of matter by chemoselectively ligating via oxime bond formation a complementary orthogonal reactive group on the baseplate to a complementary reactive orthogonal group on a specifically active molecule. Methods of using these defined compositions of matter as well as pharmaceutical compositions comprising these defined compositions of matter and methods of their use are also provided by this invention. ## Claims ### Claim 1 A homogeneous hetero-polyoxime composition, wherein the hetero-polyoxime comprises a first organic baseplate molecule linked via a plurality of at least three oxime linkages to a plurality of second organic molecules, said oxime linkages being formed by reaction of an orthogonal reactive group on each said second organic molecule with a complementary first orthogonal reactive group on said baseplate, wherein said first orthogonal reactive groups and said second orthogonal reactive groups are independently selected from the group consisting of an aldehyde group, a keto and an amino-oxy group, and wherein at least one of said second organic molecules attached to the baseplate is different from another second organic molecule attached to said baseplate. ### Claim 2 (depends on 1) The composition of claim 1, wherein each oxime linkage is in the same orientation. ### Claim 3 (depends on 1) The composition of claim 1, wherein said baseplate is formed at least in part from amino acid residues. ### Claim 4 (depends on 1) The composition of claim 1, wherein at least one complementary orthogonal reactive group present on the baseplate comprises an aldehyde group. ### Claim 5 (depends on 4) The composition of claim 4, wherein at least one orthogonal reactive group on a second organic molecule comprises amino-oxy-acetyl. ### Claim 6 (depends on 1) The composition of claim 1, wherein a complementary orthogonal reactive group of at least one of the second organic molecules is an aldehyde or an amino-oxy group. ### Claim 7 (depends on 1) The composition of claim 1, wherein at least one of the second organic molecules is selected from the group consisting of peptides, lipids, oligosaccharides, nucleic acid sequences, and polymers formed by a combination thereof. ### Claim 8 (depends on 1) The composition of claim 1, wherein said hetero-polyoxime is immunogenic. ### Claim 9 (depends on 1) The composition of claim 1, wherein at least one of said second organic molecules comprises a polypeptide having a complementarity determining region of a native antibody. ### Claim 10 (depends on 1) The composition of claim 1, further comprising a molecule linked to the baseplate and selected from the group consisting of metal chelating agents, detectable markers, lipophilic anchors, imaging agents, and therapeutic agents. ### Claim 11 (depends on 1) The composition of claim 1, wherein at least one of said second organic molecules comprises a member selected from the group consisting of metal chelating agents, detectable markers, lipophilic anchors, imaging agents, and therapeutic agents. ### Claim 12 (depends on 1) The composition of claim 1, wherein at least one of the second organic molecules further comprises an imaging agent or detectable marker. ### Claim 13 (depends on 1) A pharmaceutical composition, comprising the homogeneous composition of claim 1 and a pharmaceutically acceptable carrier. ### Claim 14 (depends on 13) A pharmaceutical composition of claim 13, wherein said homogeneous composition is immunogenic and is present in an immunogenically effective amount. ### Claim 15 (depends on 14) A method of inducing an immune response in an animal, which comprises administering to the animal an immunologically effective amount of the composition of claim 14. ### Claim 16 A homogeneous hetero-polyoxime composition produced by a process comprising the steps of: 1) obtaining a first organic baseplate molecule having present therein a plurality of at least three first orthogonal reactive groups capable of oxime linkage formation, 2) obtaining a second organic molecule having present therein a second orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, 3) obtaining a third organic molecule having present therein a third orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, wherein said third organic molecule and said second organic molecule are different, wherein said first orthogonal reactive groups, said second orthogonal reactive groups and said third orthogonal reactive groups are independently selected from the group consisting of an aldehyde group, a keto group and an amino-oxy group and wherein said second orthogonal reactive groups and said third orthogonal reactive groups are not complementary to the same first orthogonal reactive groups, 4) mixing the baseplate molecules and the second organic molecules under conditions allowing essentially quantitative oxime linkage formation between the second orthogonal reactive group of said second organic molecule and at least one of said first orthogonal reactive groups on the baseplate molecules but not between the second orthogonal reactive group of said second organic molecules and first orthogonal reactive groups on the baseplate molecules complementary to the third orthogonal reactive group on said third organic molecule, whereby oxime linkage formation occurs between the second orthogonal reactive group of said second organic molecule and at least one of said first orthogonal reactive group on said baseplate molecule, 5) mixing the baseplate molecules and the third organic molecules, either contemporaneously or sequentially with said mixing in step 4), under conditions allowing essentially quantitative oxime linkage formation between the third orthogonal reactive group of said third organic molecules and at least one of said first orthogonal reactive groups on the baseplate molecules but not between the third orthogonal reactive group of said third organic molecules and the first orthogonal reactive groups on the baseplate molecules complementary to the second orthogonal reactive group on said second organic molecules, whereby oxime linkage formation occurs between the third orthogonal reactive group of said third organic molecule and at least one of said first orthogonal reactive group on said baseplate molecule, 6) optionally repeating steps 2 and 4 with one or more additional organic molecules having present therein an orthogonal reactive group capable of oxime linkage formation with its complementary first orthogonal reactive groups on the baseplate, and 7) separating the hetero-polyoxime product from unreacted organic molecules. ### Claim 17 A method of producing a homogeneous hetero-polyoxime composition comprising the steps of: 1) obtaining a first organic baseplate molecule having present therein a plurality of at least three first orthogonal reactive groups capable of oxime linkage formation, 2) obtaining a second organic molecule having present therein a second orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, 3) obtaining a third organic molecule having present therein a third orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, wherein said third organic molecule and said second organic molecule are different, wherein said first orthogonal reactive groups, said second orthogonal reactive groups and said third orthogonal reactive groups are independently selected from the group consisting of an aldehyde group, a keto group and an amino-oxy group and wherein said second orthogonal reactive groups and said third orthogonal reactive groups are not complementary to the same first orthogonal reactive groups, 4) mixing the baseplate molecules and the second organic molecules under conditions allowing essentially quantitative oxime linkage formation between the second orthogonal reactive group of said second organic molecule and at least one of said first orthogonal reactive groups on the baseplate molecules but not between the second orthogonal reactive group of said second organic molecules and first orthogonal reactive groups on the baseplate molecules complementary to the third orthogonal reactive group on said third organic molecule, whereby oxime linkage formation occurs between the second orthogonal reactive group of said second organic molecule and at least one of said first orthogonal reactive group on said baseplate molecule, 5) mixing the baseplate molecules and the third organic molecules, either contemporaneously or sequentially with said mixing in step 4), under conditions allowing essentially quantitative oxime linkage formation between the third orthogonal reactive group of said third organic molecules and at least one of said first orthogonal reactive groups on the baseplate molecules but not between the third orthogonal reactive group of said third organic molecules and the first orthogonal reactive groups on the baseplate molecules complementary to the second orthogonal reactive group on said second organic molecules, whereby oxime linkage formation occurs between the third orthogonal reactive group of said third organic molecule and at least one of said first orthogonal reactive group on said baseplate molecule, 6) optionally repeating steps 2 and 4 with one or more additional organic molecules having present therein an orthogonal reactive group capable of oxime linkage formation with its complementary first orthogonal reactive groups on the baseplate, and 7) separating the hetero-polyoxime product from unreacted organic molecules. ### Claim 18 (depends on 17) The method of claim 17, wherein each mixing step occurs at a pH equal to or less than 5. ### Claim 19 A method of producing a homogeneous hetero-polyoxime composition comprising the steps of: 1) obtaining a first organic baseplate molecule having present therein a plurality of at least three first orthogonal reactive groups capable of oxime linkage formation, 2) obtaining a second organic molecule having present therein a second orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, 3) obtaining a third organic molecule having present therein a third orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, wherein said third organic molecule and said second organic molecule are different, and wherein said first orthogonal reactive groups, said second orthogonal reactive groups and said third orthogonal reactive groups are selected from the group consisting of an aldehyde group, a keto group and an amino-oxy group, 4) mixing the baseplate molecules and the second organic molecules under conditions allowing essentially quantitative oxime linkage formation between the second orthogonal reactive group of said second organic molecule and at least one of said first orthogonal reactive groups on the baseplate molecules, whereby oxime linkage formation occurs between the second orthogonal reactive group of said second organic molecule and at least one of said first orthogonal reactive group on said baseplate molecule, 5) isolating a homogeneous oximation product of step 4, 6) mixing said isolated homogeneous oximation product and the third organic molecules, under conditions allowing essentially quantitative oxime linkage formation between the third orthogonal reactive group of said third organic molecules and at least one first orthogonal reactive groups remaining on the homogeneous oximation product, whereby oxime linkage formation occurs between the third orthogonal reactive group of said third organic molecule and at least one of said first orthogonal reactive group on said baseplate molecule, 7) optionally repeating steps 2, 4 and 5 with one or more additional organic molecules having present therein an orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate, and 8) separating the hetero-polyoxime product from unreacted organic molecules. ### Claim 20 (depends on 19) The homogeneous hetero-polyoxime composition produced by the method of claim 19. ### Claim 21 A method of producing a library of hetero-polyoxime compounds comprising the steps of: 1) obtaining a first organic baseplate molecule having present therein a plurality of at least three first orthogonal reactive groups capable of oxime linkage formation, 2) obtaining a plurality of second organic molecules, each having present therein a second orthogonal reactive group capable of oxime linkage formation with at least one of said first orthogonal reactive groups on the baseplate molecule, wherein said plurality of second organic molecules comprises at least two different second organic molecules, wherein said first orthogonal reactive groups, and said second orthogonal reactive groups are selected from the group consisting of an aldehyde group, a keto group and an amino-oxy group, 3) mixing the baseplate molecule and the plurality of second organic molecules under conditions allowing essentially quantitative oxime linkage formation between the second orthogonal reactive group on the second organic molecules and the complementary first orthogonal reactive groups on the baseplate molecule, whereby oxime linkage formation occurs between the second orthogonal reactive group of said second organic molecule and the complementary first orthogonal reactive group on said baseplate molecule, and 4) isolating the library produced. ### Claim 22 (depends on 21) The library produced by the method of claim 21. ### Claim 23 (depends on 21) The method of claim 21 wherein each of the plurality of second organic molecules has the same second orthogonal reactive group. ### Claim 24 (depends on 23) The library produced by the method of claim 23. ### Claim 25 (depends on 21) The method of claim 21, wherein the plurality of second organic molecules has at least two different second orthogonal reactive groups and wherein the baseplate molecule has the corresponding complementary first orthogonal reactive groups. ### Claim 26 (depends on 25) The library produced by the method of claim 25.