US 12,024,484 C1 (13,193rd)
Lipid formulations for gene editing
Kallanthottathil G. Rajeev, Wayland, MA (US); and Souvik Biswas, Woburn, MA (US)
Filed by Verve Therapeutics, Inc., Boston, MA (US)
Assigned to VERVE THERAPEUTICS, INC., Boston, MA (US)
Reexamination Request No. 90/019,885, Mar. 21, 2025.
Reexamination Certificate for Patent 12,024,484, issued Jul. 2, 2024, Appl. No. 18/180,306, Mar. 8, 2023.
Application 90/019,885 is a continuation of application No. PCT/US21/50511, filed on Sep. 15, 2021.
Claims priority of provisional application 63/078,738, filed on Sep. 15, 2020.
Claims priority of provisional application 63/220,340, filed on Jul. 9, 2021.
Ex Parte Reexamination Certificate issued on Feb. 23, 2026.
Int. Cl. C07C 229/12 (2006.01)
CPC C07C 229/12 (2013.01)
AS A RESULT OF REEXAMINATION, IT HAS BEEN DETERMINED THAT:
Claim 20 was previously cancelled.
Claims 4, 7, 11, 14, 19 and 29 are cancelled.
Claims 1-3, 5, 6, 8-10, 12 and 15 are determined to be patentable as amended.
Claims 13, 16-18 and 30, dependent on an amended claim, are determined to be patentable.
Claims 21-28 were not reexamined.
1. An amino lipid having a structure of Formula (I*), or a pharmaceutically acceptable salt or solvate thereof,

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wherein
R1 is hydrogen, C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, C3-C30 heteroalkyl, C3-C30 heteroalkenyl, C3-C30 heteroalkynyl, C3-C10 cycloalkyl, —C0-C10 alkylene-L-R6 , or —C2-C10 alkenylene-L-R6, wherein each of the alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and cycloalkyl is independently substituted or unsubstituted;
R2 is hydrogen, C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, C3-C30 heteroalkyl, C3-C30 heteroalkenyl, C3-C30 heteroalkynyl, C3-C10 cycloalkyl, —C0-C10 alkylene-L-R6 , or —C2-C10 alkenylene-L-R6, wherein each of the alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and cycloalkyl is independently substituted or unsubstituted;
[ wherein R1 and R2 are the same;
X is —C(═O)O—, —OC(═O)—, or —OC(═O)NR4—;
Y is —C(═O)O—, —OC(═O)—, or —OC(═O)NR4—; ]
each of X, Y, and Z is independently —C(═O)NR4—, —NR4C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, NR4C(═O)O—, —OC(═O)NR4—, —NR4C(═O)NR4—, —NR4C(═NR4)NR4—, —C(═S)NR4—, —NR4C(═S)—, —C(═S)O—, —OC(═S)—, OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —NR4C(═S)NR4—, —C(═O)S—, —SC(═O)—, —OC(═O)S—, —NR4C(═O)S—, —SC(═O)NR4—, —C(═S)S—, —SC(═S)—, —SC(═S)O—, —SC(═O)S—, —SC(═S)S—, —NR4C(═S)S—, —SC(═S)NR4—, —R11C(═O)N(R4)R9—, —NR7C(═O)R9—, —R11C(═O)OR9—, —R11OC(═O)R9—, —R11OC(═O)OR9—, —R11N(R4)C(═NR4)R9—, R11C(═S)N(R4)R9—, —R11N(R4)C(═S)R9—, —R11C(═S)OR9—, —R11OC(═S)R9—, —R11OC(═S)OR9—, —R11N(R4)C(═S)OR9—, —R11OC(═S)N(R4)R9—, —R11N(R4)C(═S)N(R4)R9—, —R11C(═O)SR9—, —R11SC(═O)R9—, —R11OC(═O)SR9—, —R11N(R4)C(═O)SR9—, —R11SC(═O)N(R4)R9—, —R11C(═S)SR9—, —R11SC(═S)R9—, —R11SC(═S)OR9—, —R11SC(═O)SR9—, —R11SC(═S)SR9—, —R11N(R4)C(═S)SR9—, —R11SC(═S)N(R4)R9—, —R11OR9—, —R11SR9—, —O—, —S— or a bond;
each of L is independently —C(═O)NR4—, —NR4C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)—, —OC(═O)O—, —NR4C(═O)O—, —OC(═O)NR4—, [ or ] —NR4C(═O)NR4— , —NR4C(═NR4)NR4—, —C(═S)NR4—, —NR4C(═S)—, —C(═S)O—, —OC(═S)—, —OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —NR4C(═S)NR4—, —C(═O)S—, —SC(═O)—, —OC(═O)S—, —NR4C(═O)S—, —SC(═O)NR4—, —C(═S)S—, —SC(═S)—, —SC(═S)O—, —SC(═O)S—, —SC(═S)S—, —NR4C(═S)S—, —SC(═S)NR4—, —O—N—CR4—, —CR4═N—O—, —O—, —S—, —R11C(═O)N(R4)R9—, —R11OC(═O)OR9—, —R11N(R4)C(═O)R9—, —R11C(═O)OR9—, —R11OC(═O)R9—, —R11N(R4)C(═O)OR9—, —R11OC(═O)N(R4)R9—, —R11N(R4)C(═O)N(R4)R9—, —R11N(R4)C(═NR4)N(R4)R9—, —R11N(R4)C(═S)R9—, —R11C(═S)OR9—, —R11OC(═S)R9—, —R11OC(═S)OR9—, —R11N(R4)C(═S)OR9—, —R11OC(═S)N(R4)R9—, —R11N(R4)C(═S)N(R4)R9—, —R11C(═O)SR9—, —R11SC(═O)R9—, —R11OC(═O)SR9—, —R11N(R4)C(═O)SR9—, —R11SC(═O)N(R4)R9—, —R11C(═S)SR9—, —R11SC(═S)R9—, —R11SC(═S)OR9—, —R11SC(═O)SR9—, —R11SC(═S)SR9—, —R11N(R4)C(═S)SR9—, —R11SC(═S)N(R4)R9, —R11O—N═CR9—, —R11C(R10)═N—OR9—, —R11OR9—, —R11SR9—, —C1-C10 alkylene-C(═O)O—, —C1-C10 alkylene-OC(═O)—, —C1-C10 alkylene-O—, or a bond, wherein the alkylene is substituted or unsubstituted;
R3 is —C0-C10 alkylene-NR7R8 , —C0-C10 alkylene-heterocycloalkyl, or —C0-C10 alkylene-heteroaryl, wherein the alkylene-heterocycloalkyl and the alkylene-heteroaryl comprises a nitrogen, and wherein the alkylene, heterocycloalkyl and heteroaryl is independently substituted or unsubstituted;
each of R4 is independently hydrogen or CH3 , substituted or unsubstituted C1-C16 alkyl or substituted or unsubstituted C1-C16 heteroalkyl;
R5 is hydrogen or substituted or unsubstituted —C0-C10 alkylene-L-R4;
each of R6 is independently hydrogen, C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, Cy-C3-30 alkyl, Cy-C3-30 alkenyl, or Cy-C3-30 alkynyl, wherein the alkyl, the alkenyl and alkynyl are each independently substituted or unsubstituted;
each of Cy is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
each of R7 and R8 is independently hydrogen or substituted or unsubstituted C1-C16 alkyl, substituted or unsubstituted C1-C16 heteroalkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a substituted or unsubstituted C2-C6 heterocyclyl; and
each of R9 is independently hydrogen or substituted or unsubstituted C1-C16 alkylene, or unsubstituted C1-C16 heteroalkylene;
each of R10 is independently hydrogen or substituted or unsubstituted C1-C16 alkylene, or unsubstituted C1-C16 heteroalkylene; and each of R11 is independently substituted or unsubstituted C1-C16 alkylene, or unsubstituted C1-C16 heteroalkylene;
each of n, m, and q is independently 0, 1, 2, 3, 4, or 5.
2. The amino lipid of claim 1, wherein the amino lipid has a structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof,

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wherein
each of R1 and R2 is independently C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, C3-C30 heteroalkyl, C3-C30 heteroalkenyl, C3-C30 heteroalkynyl, C3-C10 cycloalkyl, —C0-C10 alkylene-L-R6, or —C2-C10 alkenylene-L-R6, wherein each of the alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and cycloalkyl is independently substituted or unsubstituted;
each of X, Y, and Z is independently —C(═O)NR4—, —NR4C(═O)—, —C(═O)O—, —OC(═O)—, —OC (═O)O—, —NR4C(═O)O—, —OC(═O)NR4—, —NR4C(═O)NR4—, —NR4C(═NR4)NR4—, —C(═S)NR4—, —NR4C(═S)—, —C(═S)O—, —OC(═S)—, —OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —NR4C(═S)NR4—, —C(═O)S—, —SC (═O)—, —OC(═O)S—, —NR4C(═O)S—, —SC(═O)NR4—, —C(═S)S—, —SC(═S)—, —SC(═S)O—, —SC(═O)S—, —SC(═S)S—, —NR4C(═S)S—, —SC(═S)NR4—, —O—, —S—, —C1-C10 alkylene—O—, or a bond, wherein the alkylene is substituted or unsubstituted;
each of L is independently —C(═O)NR4—, —NR4C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —NR4C(═O)O—, —OC(═O)NR4—, —NR4C(═O)NR4—, —NR4C(═NR4)NR4—, —C(═S)NR4—, —NR4C(═S)—, —C(═S)O—, —OC(═S)—, —OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —NR4C(═S)NR4—, —C(═O)S—, —SC(═O)—, —OC(═O)S—, —NR4C(═O)S—, —SC (═O) NR4—, —C(═S)S—, —SC(═S)—, —SC(═S)O—, —SC(═O)S—, —SC(═S)S—, —NR4C(═S)S—, —SC(═S)NR4—, —O—N═CR4—, —CR4═N—O—, —O—, —S—, —C1-C10 alkylene—O—, —C1-C10 alkylene—C(═O)O—, —C1-C10 alkylene—OC(═O)—, or a bond, wherein the alkylene is substituted or unsubstituted;
R3 is —C0-C10 alkylene—NR7R8 or —C0-C10 alkylene-heterocycloalkyl, wherein the alkylene-heterocycloalkyl comprises a nitrogen, and wherein the alkylene and heterocycloalkyl are each independently substituted or unsubstituted;
each of R4 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl;
each of R6 is independently C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, Cy-C3-30 alkyl, Cy-C3-30 alkenyl, or Cy-C3-30 alkynyl, wherein the alkyl, the alkenyl and alkynyl are each independently substituted or unsubstituted;
each of Cy is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and
each of R7 and R8 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a substituted or unsubstituted C2-C6 heterocyclyl.
3. The amino lipid of claim 1, wherein the amino lipid has a structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof,

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wherein
each of X and Y are the same [ ; ] and are selected from the group consisting of: —OC(═O)—, —OC(═O)O—, —OC(═O)NR4,—C(═S)O—, —OC(═S)—, —OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —SC(═O)—, —OC(═O)S—, —SC(═S)O—, —O—, —C1-C10 alkylene—O—, and a bond, wherein the alkylene is substituted or unsubstituted
R1 and R2 are the same and are selected from the group consisting of: hydrogen, C1-C30 alkyl, C1-C30 heteroalkyl, and Cy-C3-30 alkyl, wherein the alkyl and heteroalkyl are each independently substituted or unsubstituted;
each of R4 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl;
each of Cy is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and
each of R7 and R8 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a substituted or unsubstituted C2-C6 heterocyclyl [ ;] ,
A is —O—, —CH2—, —S—, or —NR12—;
R12 is hydrogen, C1-C10 alkyl, or C1-C10 heteroalkyl, wherein the alkyl and heteroalkyl are each independently substituted or unsubstituted;
Cy is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
p is 1, 2, 3, 4, 5 or 6.
5. The amino lipid of claim 3, wherein each of R1 and R2is

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6. The amino lipid of claim 3, wherein the amino lipid is

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.
8. The amino lipid of claim 7 [ 1] , wherein L is independently —C (=O)O—or —OC (=O)—.
9. The amino lipid of claim 7 [ 1] , wherein R6 is linear or branched C6-C20 alkyl.
10. The amino lipid of claim 7 [ 1] , wherein R6 is Cy—C3-30 alkyl, Cy-C3-30 alkenyl, or Cy—C3-30 alkynyl.
12. The amino lipid of claim 7 [ 1] , wherein each R7 and R8 is independently substituted or unsubstituted C1-C6 alkyl.
15. An amino lipid having a structure of Formula (II*), or a pharmaceutically acceptable salt or solvate thereof,

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wherein
each of R1 and R2 is independently hydrogen, C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, C3-C30 heteroalkyl, C3-C30 heteroalkenyl, C3-C30 heteroalkynyl, C3-C10 cycloalkyl, —C0 -C10 alkylene-L-R6 , or —C1-C10 alkenylene-L-R6, wherein each of the alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, and cycloalkyl is independently substituted or unsubstituted;
each of X , [ and ] Y , and Z is independently —C(═O)—NR4—, —C(═O)—, —NR4C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —NR4C(═O)O—, [ or ] —OC(═O)NR4— , —NR4C(═O)NR4—, —NR4C(═NR4)NR4—, —C(═S)NR4,—NR4C(═S)—, —C(═S)O—, —OC(═S)—, —OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —NR4C(═S)NR4—, —C(═O)S—, —SC(═O)—, —OC(═O)S—, —NR4C(═O)S—, —SC (═O) NR4—, —C (═S)S—, —SC(═S)—, —SC(═S)O—, —SC(═O)S—, —SC(═S)S—, —NR4C(═S)S—, —SC(═S)NR4—, —O—, —S—, or a bond;
[ Z is —C(═O)NR4—, —C(═O)—, —NR4C(═O)—, —C (═O)O—, —OC(═O)—, —OC(═O)O—, —NR4C(═O)O—, or —OC(═O)NR4—; ]
each of L is independently —C(═O)NR4—, —NR4C(═O)—, —C(═O)O—, —OC(═O)—, —OC(═O)O—, —NR4C(═O)O—, —OC(═O)NR4—, [ or ] —NR4C(═O)NR4— , -NR4C(═NR4)NR4—, —C(═S)NR4—, —NR4C(═S)—, —C(═S)O—, —OC(═S)—, —OC(═S)O—, —NR4C(═S)O—, —OC(═S)NR4—, —NR4C(═S)NR4—, —C(═O)S—, —SC(═O)—, —OC(═O)S—, —NR4C(═O)S—, —SC(═O)NR4—, —C(═S)S—, —SC(═S)—, —SC(═S)O—, —SC(═O)S—, —SC(═S)S—, —NR4C(═S)S—, —SC(═S)NR4—, —O—N═CR4—, —CR4═N—O—, —O—, —S—, —C1-C10 alkylene—O—, —C1-C10 alkylene—C(═O)O—, —C1-C10 alkylene—OC(═O)—, or a bond, wherein the alkylene is substituted or unsubstituted;
R3 is hydrogen, —C1-C6 alkyl, —C0-C10 alkylene-NR7R8,-C0-C10 alkylene-heterocycloalkyl, or —C0-C10 alkylene-heterocycloaryl, wherein the alkyl, alkylene, heterocycloalkyl and heterocycloaryl is independently substituted or unsubstituted [ —C1-C6 alkylene-NR7R8 ] ;
each of R4 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl;
each of R6 is independently C3-C30 alkyl, C3-C30 alkenyl, C3-C30 alkynyl, Cy-C3-30 alkyl, Cy-C3-30 alkenyl, or Cy-C3-30 alkynyl, wherein the alkyl, the alkenyl and alkynyl are each independently substituted or unsubstituted;
each of Cy is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl [ C6-C20 alkyl ] ;
each of R7 and R8 is independently hydrogen or substituted or unsubstituted C1-C6 alkyl, or R7 and R8 taken together with the nitrogen to which they are attached form a substituted or unsubstituted C2-C6 heterocyclyl;
each of a and b is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and m is 0, 1, 2, 3, 4, or 5.