# US 12,180,138 B2 · Lipid nanoparticle compositions for delivering circular polynucleotides

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- Number: US 12,180,138 B2
- Document ID: US12180138B2
- Status: Granted
- Kind: B2
- Application number: 18/501,955
- Filed: 2023-11-03
- Published: 2024-04-11
- Granted: 2024-12-31
- Earliest claimed: 2021-11-08
- Assignees: Orna Therapeutics, Inc.
- Applicants: Orna Therapeutics, Inc.
- Inventors: Allen T. Horhota; Junghoon Yang; Kevin J. Kauffman; Thomas Barnes; Robert Alexander Wesselhoeft; Amy M. Becker; Gregory Motz
- Web page: https://patentgrep.com/patent/US12180138B2

## CPC

- C07C 229/12: to carbon atoms of acyclic carbon skeletons
- A61K 9/1272: comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543})
- A61K 9/5123: {Organic compounds, e.g. fats, sugars}
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/24: containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
- A61K 47/28: Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 48/0033: {the non-active part being non-polymeric}
- C07C 219/06: having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C 229/22: the carbon skeleton being further substituted by oxygen atoms
- C07C 229/24: having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)

## Abstract

Disclosed herein are novel lipids that can be used in combination with other lipid components, such as helper lipids, structural lipids, and cholesterols, to form lipid nanoparticles for delivery of therapeutic agents, such as nucleic acids (e.g., circular polynucleotides), both in vitro and in vivo.

## Claims

### Claim 1

An ionizable lipid represented by Formula (13*):
or a pharmaceutically acceptable salt thereof, wherein:
n* is an integer from 1 to 7;
Ra is hydrogen;
Rb is hydrogen or C1-C6 alkyl;
R1 and R2 are each independently unsubstituted, linear, or branched C6-C30 alkyl or —(CH2)qC(O)(CH2)rCH(R8)(R9), wherein one of R1 and R2 is an unsubstituted, linear or branched C6-C30 alkyl,
wherein:
q is an integer from 0 to 12,
r is 0,
R8 is R10, and
R9 and R10 are independently unsubstituted linear C1-C12 alkyl or unsubstituted linear C2-C12 alkenyl.

### Claim 2 (depends on 1)

The ionizable lipid of claim 1, wherein the ionizable lipid is represented by Formula (13a-1), Formula (13a-2), or Formula (13a-3):
wherein n is 1, 2, 3, 4, or 5.

### Claim 3 (depends on 1)

The ionizable lipid of claim 1, wherein q is 3, 4, 5, or 6.

### Claim 4 (depends on 1)

The ionizable lipid of claim 1, wherein Rb is hydrogen.

### Claim 5 (depends on 1)

The ionizable lipid of claim 1, wherein Rb is C1-C6 alkyl.

### Claim 6 (depends on 1)

The ionizable lipid of claim 1, wherein R9 and R10 are the same.

### Claim 7 (depends on 1)

The ionizable lipid of claim 1, wherein R9 and R10 are different.

### Claim 8 (depends on 1)

The ionizable lipid of claim 1, wherein R9 and R10 are each independently unsubstituted linear C4-C8 alkyl.

### Claim 9 (depends on 1)

The ionizable lipid of claim 1, wherein R9 and R10 are each independently unsubstituted linear C6-C8 alkyl.

### Claim 10 (depends on 1)

The ionizable lipid of claim 1, wherein R1 is unsubstituted, linear, or branched C6-C30 alkyl.

### Claim 11 (depends on 1)

The ionizable lipid of claim 1, wherein R2 is —(CH2)qC(O)O(CH2)rCH(R8)(R9).

### Claim 12 (depends on 1)

The ionizable lipid of claim 1, wherein R1 and R2 are each independently selected from:

### Claim 13 (depends on 12)

The ionizable lipid of claim 12, wherein R1 and R2 are the same.

### Claim 14 (depends on 12)

The ionizable lipid of claim 12, wherein R1 and R2 are different.

### Claim 15 (depends on 1)

The ionizable lipid of claim 1, wherein the ionizable lipid is:
or is a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The ionizable lipid of claim 1, wherein the ionizable lipid is:
or is a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The ionizable lipid of claim 1, wherein the ionizable lipid is:
or is a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The ionizable lipid of claim 1, wherein the ionizable lipid is:
or is a pharmaceutically acceptable salt thereof.

### Claim 19

An ionizable lipid represented by Formula (13):
or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2, 3, or 4;
Ra is hydrogen;
R1 is unsubstituted linear C6-C30 alkyl;
R2 is —(CH2)qC(O)O(CH2)rCH(R8)(R9),
wherein:
q is 3, 4, 5, or 6,
r is 0,
R8 is R10, and
R9 and R10 are independently unsubstituted linear C2-C8 alkyl.

### Claim 20 (depends on 19)

The ionizable lipid of claim 19, wherein R9 and R10 are the same.

### Claim 21 (depends on 19)

The ionizable lipid of claim 19, wherein R9 and R10 are different.

### Claim 22 (depends on 19)

The ionizable lipid of claim 19, wherein R9 and R10 are each independently unsubstituted linear C4-C8 alkyl.

### Claim 23 (depends on 19)

The ionizable lipid of claim 19, wherein R9 and R10 are each independently unsubstituted linear C6-C8 alkyl.

### Claim 24 (depends on 19)

A pharmaceutical composition comprising the ionizable lipid of claim 19.

### Claim 25 (depends on 24)

The pharmaceutical composition of claim 24, wherein the pharmaceutical composition further comprises a RNA polynucleotide.

### Claim 26 (depends on 25)

The pharmaceutical composition of claim 25, wherein the RNA polynucleotide is a linear RNA polynucleotide.

### Claim 27 (depends on 25)

The pharmaceutical composition of claim 25, wherein the RNA polynucleotide is a circular RNA polynucleotide.

### Claim 28 (depends on 24)

The pharmaceutical composition of claim 24, wherein the pharmaceutical composition further comprises:
a helper lipid, wherein the helper lipid is DOPE or DSPC,
cholesterol, and
a PEG-lipid, wherein the PEG-lipid is DSPE-PEG (2000) or DMG-PEG (2000).