# US 10,117,941 B2 · Lipids and compositions for the delivery of therapeutics

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- Number: US 10,117,941 B2
- Document ID: US10117941B2
- Status: Granted
- Kind: B2
- Application number: 15/603,069
- Filed: 2017-05-23
- Published: 2018-02-15
- Granted: 2018-11-06
- Earliest claimed: 2008-11-10
- Assignees: Arbutus Biopharma Corporation
- Applicants: Arbutus Biopharma Corporation
- Inventors: Muthiah Manoharan; Kallanthottathil G. Rajeev; Muthusamy Jayaraman; David Butler; Jayaprakash K. Nair; Martin Maier; Laxman Eltepu
- Web page: https://patentgrep.com/patent/US10117941B2

## CPC

- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- 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 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- 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 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61K 47/28: Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07C 229/08: the nitrogen atom of the amino group being further bound to hydrogen atoms
- C07C 229/30: the carbon skeleton being acyclic and unsaturated
- C07C 237/16: the carbon skeleton being acyclic and unsaturated
- C07C 251/38: to carbon atoms of a saturated carbon skeleton
- C07C 251/78: to carbon atoms of an unsaturated carbon skeleton
- C07C 271/12: to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C 271/20: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 323/25: the carbon skeleton being acyclic and saturated
- C07D 203/10: Radicals substituted by singly bound oxygen atoms
- C07D 317/28: Radicals substituted by nitrogen atoms (nitro radicals C07D317/16)
- C07D 317/44: ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D 317/46: condensed with one six-membered ring
- C07D 317/72: spiro-condensed with carbocyclic rings
- C07D 319/06: not condensed with other rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 491/113: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention provides lipids that are advantageously used in lipid particles for the in vivo delivery of therapeutic agents to cells. In particular, the invention provides lipids having the following structure wherein R1 and R2 are each independently for each occurrence optionally substituted C10-C30 alkyl, optionally substituted C10-C30 alkenyl, optionally substituted C10-C30 alkynyl, optionally substituted C10-C30 acyl, or -linker-ligand; R3 is H, optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, alkylhetrocycle, alkylphosphate, alkylphosphorothioate, alkylphosphorodithioate, alkylphosphonates, alkylamines, hydroxyalkyls, ω-aminoalkyls, ω-(substituted)aminoalkyls, ω-phosphoalkyls, ω-thiophosphoalkyls, optionally substituted polyethylene glycol (PEG, mw 100-40K), optionally substituted mPEG (mw 120-40K), heteroaryl, heterocycle, or linker-ligand; E is O, S, N(Q), C(O), N(Q)C(O), C(O)N(Q), (Q)N(CO)O, O(CO)N(Q), S(O), NS(O)2N(Q), S(O)2, N(Q)S(O)2, SS, O═N, aryl, heteroaryl, cyclic or heterocycle; and, Q is H, alkyl, ω-aminoalkyl, ω-(substituted)aminoalky, ω-phosphoalkyl or ω-thiophosphoalkyl.

## Claims

### Claim 1

A lipid having the structure
or a salt or isomer thereof.

### Claim 2 (depends on 1)

A lipid particle comprising a lipid of claim 1.

### Claim 3 (depends on 2)

The lipid particle of claim 2, wherein the particle further comprises a neutral lipid and a lipid capable of reducing aggregation.

### Claim 4

A lipid particle consisting essentially of
a. a lipid having the structure
or a salt or isomer thereof;
b. a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM;
c. a sterol; and
d. PEG-DMG or PEG-DMA,
in a molar ratio of about 20-60% lipid: 5-25% neutral lipid: 25-55% sterol: 0.5-15% PEG-DMG or PEG-DMA.

### Claim 5 (depends on 2)

The lipid particle of claim 2, further comprising a therapeutic agent.

### Claim 6 (depends on 5)

The lipid particle of claim 5, wherein the therapeutic agent is a nucleic acid.

### Claim 7 (depends on 6)

The lipid particle of claim 6, wherein the nucleic acid is a plasmid.

### Claim 8 (depends on 6)

The lipid particle of claim 6, wherein the nucleic acid is an immunostimulatory oligonucleotide.

### Claim 9 (depends on 6)

The lipid particle of claim 6, wherein the nucleic acid is selected from the group consisting of an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

### Claim 10 (depends on 5)

The lipid particle of claim 5, wherein the therapeutic agent is siRNA.

### Claim 11 (depends on 5)

The lipid particle of claim 5, wherein the therapeutic agent is mRNA.

### Claim 12 (depends on 4)

The lipid particle of claim 4, wherein the sterol is cholesterol.

### Claim 13 (depends on 2)

A pharmaceutical composition comprising a lipid particle of claim 2 and a pharmaceutically acceptable excipient, carrier, or diluent.

### Claim 14 (depends on 5)

A pharmaceutical composition comprising a lipid particle of claim 5 and a pharmaceutically acceptable excipient, carrier, or diluent.