# US 11,433,144 B2 · Biodegradable lipids for delivery of nucleic acids

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- Number: US 11,433,144 B2
- Document ID: US11433144B2
- Status: Granted
- Kind: B2
- Application number: 17/141,744
- Filed: 2021-01-05
- Published: 2021-12-02
- Granted: 2022-09-06
- Earliest claimed: 2014-05-30
- Assignees: Translate Bio, Inc.
- Applicants: Translate Bio, Inc.
- Inventors: Frank DeRosa; Michael Heartlein
- Web page: https://patentgrep.com/patent/US11433144B2

## CPC

- A61K 48/0033: {the non-active part being non-polymeric}
- 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 38/1816: {Erythropoietin [EPO]}
- A61K 38/4846: {Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)}
- A61K 48/0025: {wherein the non-active part clearly interacts with the delivered nucleic acid}
- A61K 48/0041: {the non-active part being polymeric}
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- C07D 319/12: not condensed with other rings
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12Y 304/21022: Coagulation factor IXa (3.4.21.22)
- C12N 2310/11: Antisense
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

The present invention provides, in part, a biodegradable compound of formula I, and sub-formulas thereof:Formula (I) or a pharmaceutically acceptable salt thereof, where each X independently is O or S, each Y independently is O or S, and each R1 independently is defined herein; and a liposome composition comprising the cationic lipid of formula I or a sub-formula thereof, and methods of delivering agents, such as nucleic acids including mRNA, in vivo, by administering to a subject the liposome comprising the cationic lipid of formula I or a sub-formula thereof, where the agent is encapsulated within the liposome.

## Claims

### Claim 1

A lipid nanoparticle comprising:
messenger RNA (mRNA) encoding a protein;
one or more non-cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids; and
a compound of formula III:
or a pharmaceutically acceptable salt thereof.

### Claim 2

A lipid nanoparticle comprising:
messenger RNA (mRNA) encoding a protein;
one or more non-cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids; and
a compound of formula IV:
or a pharmaceutically acceptable salt thereof.

### Claim 3

A lipid nanoparticle comprising:
messenger RNA (mRNA) encoding a protein;
one or more non-cationic lipids, one or more cholesterol-based lipids and/or one or more PEG-modified lipids; and
a compound of formula V:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The lipid nanoparticle of claim 1, wherein the lipid nanoparticle is a liposome.

### Claim 5 (depends on 1)

The lipid nanoparticle of claim 1, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phospho-ethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)).

### Claim 6 (depends on 1)

The lipid nanoparticle of claim 1, wherein the one or more PEG-modified lipids comprise a poly(ethylene) glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length.

### Claim 7 (depends on 4)

The lipid nanoparticle of claim 4, wherein the liposome has a size less than about 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, or 50 nm.

### Claim 8 (depends on 1)

The lipid nanoparticle of claim 1, wherein the protein encoded by the mRNA is a cytosolic protein, a secreted protein, or an enzyme.

### Claim 9 (depends on 1)

The lipid nanoparticle of claim 1, wherein the mRNA comprises one or more modified nucleotides.

### Claim 10 (depends on 9)

The lipid nanoparticle of claim 9, wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine.

### Claim 11 (depends on 1)

The lipid nanoparticle of claim 1, wherein the mRNA is unmodified.

### Claim 12 (depends on 2)

The lipid nanoparticle of claim 2, wherein the lipid nanoparticle is a liposome.

### Claim 13 (depends on 2)

The lipid nanoparticle of claim 2, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phospho-ethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)).

### Claim 14 (depends on 2)

The lipid nanoparticle of claim 2, wherein the one or more PEG-modified lipids comprise a poly(ethylene) glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length.

### Claim 15 (depends on 12)

The lipid nanoparticle of claim 12, wherein the liposome has a size less than about 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, or 50 nm.

### Claim 16 (depends on 2)

The lipid nanoparticle of claim 2, wherein the protein encoded by the mRNA is a cytosolic protein, a secreted protein, or an enzyme.

### Claim 17 (depends on 2)

The lipid nanoparticle of claim 2, wherein the mRNA comprises one or more modified nucleotides.

### Claim 18 (depends on 17)

The lipid nanoparticle of claim 17, wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine.

### Claim 19 (depends on 2)

The lipid nanoparticle of claim 2, wherein the mRNA is unmodified.

### Claim 20 (depends on 3)

The lipid nanoparticle of claim 3, wherein the lipid nanoparticle is a liposome.

### Claim 21 (depends on 3)

The lipid nanoparticle of claim 3, wherein the one or more non-cationic lipids are selected from DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine), DOPE (1,2-dioleyl-sn-glycero-3-phosphoethanolamine), DOPC (1,2-dioleyl-sn-glycero-3-phosphotidylcholine), DPPE (1,2-dipalmitoyl-sn-glycero-3-phospho-ethanolamine), DMPE (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine), DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)).

### Claim 22 (depends on 3)

The lipid nanoparticle of claim 3, wherein the one or more PEG-modified lipids comprise a poly(ethylene) glycol chain of up to 5 kDa in length covalently attached to a lipid with alkyl chain(s) of C6-C20 length.

### Claim 23 (depends on 20)

The lipid nanoparticle of claim 20, wherein the liposome has a size less than about 250 nm, 200 nm, 150 nm, 100 nm, 75 nm, or 50 nm.

### Claim 24 (depends on 3)

The lipid nanoparticle of claim 3, wherein the protein encoded by the mRNA is a cytosolic protein, a secreted protein, or an enzyme.

### Claim 25 (depends on 3)

The lipid nanoparticle of claim 3, wherein the mRNA comprises one or more modified nucleotides.

### Claim 26 (depends on 25)

The lipid nanoparticle of claim 25, wherein the one or more modified nucleotides comprise pseudouridine, N-1-methyl-pseudouridine, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolopyrimidine, 3-methyl adenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5 propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and/or 2-thiocytidine.

### Claim 27 (depends on 3)

The lipid nanoparticle of claim 3, wherein the mRNA is unmodified.