# US 11,999,675 B2 · Ionizable cationic lipids

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- Number: US 11,999,675 B2
- Document ID: US11999675B2
- Status: Granted
- Kind: B2
- Application number: 16/983,121
- Filed: 2020-08-03
- Published: 2021-01-14
- Granted: 2024-06-04
- Earliest claimed: 2012-03-29
- Assignees: Translate Bio, Inc.
- Applicants: Translate Bio, Inc.
- Inventors: Frank DeRosa; Braydon Charles Guild; Michael Heartlein
- Web page: https://patentgrep.com/patent/US11999675B2

## CPC

- C07C 211/21: Monoamines
- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- 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 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 38/1816: {Erythropoietin [EPO]}
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/85: for animal cells
- C12Y 302/01023: Beta-galactosidase (3.2.1.23), i.e. exo-(1-->4)-beta-D-galactanase
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Disclosed herein are novel compounds, pharmaceutical compositions comprising such compounds and related methods of their use. The compounds described herein are useful, e.g., as liposomal delivery vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and subsequent transfection of said target cells, and in certain embodiments are characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids.

## Claims

### Claim 1

A method of treating disease in a subject, wherein the method comprises administering an effective amount of a lipid nanoparticle to the subject, wherein said lipid nanoparticle comprises
mRNA encoding a therapeutic enzyme or protein;
a cationic lipid having the following structure
and
one or more helper lipids, non-cationic lipids, and/or PEG-modified lipid components.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mRNA comprises a chemical modification.

### Claim 3 (depends on 1)

The method of claim 1, wherein the mRNA comprises one or more locked nucleic acids (LNA).

### Claim 4 (depends on 1)

The method of claim 1, wherein the therapeutic enzyme or protein or enzyme is selected from the group consisting of human growth hormone, erythropoietin, α1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

### Claim 5 (depends on 1)

The method of claim 1, wherein the one or more PEG-modified lipid is DMG-PEG2000, the one or more helper lipid is DOPE, and/or the one or more non-cationic lipid is cholesterol.

### Claim 6 (depends on 5)

The method of claim 5, wherein the one or more PEG-modified lipid is DMG-PEG2000, the one or more helper lipid is DOPE, and the one or more non-cationic lipid is cholesterol.

### Claim 7 (depends on 1)

The method of claim 1, wherein the one or more non-cationic lipids are selected from the group consisting of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine), DLPE (1,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPS (1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine), ceramides, sphingomyelins, and cholesterol.

### Claim 8 (depends on 1)

The method of claim 1, wherein the one or more PEG-modified lipid comprises a poly(ethylene)glycol chain of up to 5 kDa covalently attached to a lipid comprising one or more C6-C20 alkyls.

### Claim 9 (depends on 1)

The method of claim 1, wherein the one or more PEG-modified lipid is a PEG-modified ceramide comprising C14 or C18 acyl chains.

### Claim 10

A method of treating disease in a subject, wherein the method comprises administering an effective amount of a lipid nanoparticle to the subject, wherein said lipid nanoparticle comprises
mRNA encoding a therapeutic enzyme or protein;
a cationic lipid having the following structure
and
one or more helper lipids, non-cationic lipids, and/or PEG-modified lipid components.

### Claim 11 (depends on 10)

The method of claim 10, wherein the mRNA comprises a chemical modification.

### Claim 12 (depends on 10)

The method of claim 10, wherein the mRNA comprises one or more locked nucleic acids (LNA).

### Claim 13 (depends on 10)

The method of claim 10, wherein the therapeutic enzyme or protein is selected from the group consisting of human growth hormone, erythropoietin, α1-antitrypsin, acid alpha glucosidase, arylsulfatase A, carboxypeptidase N, α-galactosidase A, alpha-L-iduronidase, iduronate-2-sulfatase, iduronate sulfatase, N-acetylglucosamine-1-phosphate transferase, N-acetylglucosaminidase, alpha-glucosaminide acetyltransferase, N-acetylglucosamine 6-sulfatase, N-acetylgalactosamine-4-sulfatase, beta-glucosidase, galactose-6-sulfate sulfatase, beta-galactosidase, beta-glucuronidase, glucocerebrosidase, heparan sulfamidase, heparin-N-sulfatase, lysosomal acid lipase, hyaluronidase, galactocerebrosidase, ornithine transcarbamylase (OTC), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), arginase 1 (ARG1), cystic fibrosis transmembrane conductance regulator (CFTR), survival motor neuron (SMN), Factor VIII, Factor IX and low density lipoprotein receptors (LDLR).

### Claim 14 (depends on 10)

The method of claim 10, wherein the one or more PEG-modified lipid is DMG-PEG2000, the one or more helper lipid is DOPE, and/or the one or more non-cationic lipid is cholesterol.

### Claim 15 (depends on 14)

The method of claim 14, wherein the one or more PEG-modified lipid is DMG-PEG2000, the one or more helper lipid is DOPE, and the one or more non-cationic lipid is cholesterol.

### Claim 16 (depends on 10)

The method of claim 10, wherein the one or more non-cationic lipids are selected from the group consisting of DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine), DLPE (1,2-dilauroyl-sn-glycero-3-phosphoethanolamine), DPPS (1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine), ceramides, sphingomyelins, and cholesterol.

### Claim 17 (depends on 10)

The method of claim 10, wherein the one or more PEG-modified lipid comprises a poly(ethylene)glycol chain of up to 5 kDa covalently attached to a lipid comprising one or more C6-C20 alkyls.

### Claim 18 (depends on 10)

The method of claim 10, wherein the one or more PEG-modified lipid is a PEG-modified ceramide comprising C14 or C18 acyl chains.