# US 11,078,484 B2 · Multimeric oligonucleotides having decreased kidney clearance

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- Number: US 11,078,484 B2
- Document ID: US11078484B2
- Status: Granted
- Kind: B2
- Application number: 15/889,975
- Filed: 2018-02-06
- Published: 2018-08-09
- Granted: 2021-08-03
- Earliest claimed: 2017-02-06
- Assignees: Mpeg La, LLC
- Applicants: Mpeg La, LLC
- Inventors: Jonathan Miles Brown; Kristin K. H. Neuman; Hans-Peter Vornlocher; Philipp Hadwiger
- Web page: https://patentgrep.com/patent/US11078484B2

## CPC

- 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 31/713: Double-stranded nucleic acids or oligonucleotides
- A61P 13/12: of the kidneys
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/351: Conjugate
- C12N 2310/3519: Fusion with another nucleic acid
- C12N 2310/51: in polymeric form, e.g. multimers, concatemers
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N 2320/53: reducing unwanted side-effects
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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

## Abstract

The present invention relates to methods of administering to a subject multimeric oligonucleotides having monomeric subunits joined by linkers. The multimeric oligonucleotides have a molecular weight of at least about 45 kD and other characteristics, such that their clearance due to glomerular filtration is reduced. The present invention also relates to such multimeric oligonucleotides and methods of synthesizing such multimeric oligonucleotides.

## Claims

### Claim 1

A method of administering a multimeric oligonucleotide to a subject in need thereof, the method comprising administering an effective amount of the multimeric oligonucleotide to the subject, the multimeric oligonucleotide comprising subunits , wherein:
each of the subunits is independently a single or double stranded oligonucleotide, and each of the subunits is joined to another subunit by a covalent linker ●;
the multimeric oligonucleotide has a molecular weight and/or size configured to decrease its clearance due to glomerular filtration; and
the molecular weight of the multimeric oligonucleotide is at least about 45 kD; and the decreased clearance due to glomerular filtration results in increased in vivo circulation half-life of the multimeric oligonucleotide.

### Claim 2 (depends on 1)

The method of claim 1, wherein the number of subunits contained in the multimeric oligonucleotide is m, m being an integer selected to enable the multimeric oligonucleotide to have the molecular weight and/or size configured to decrease its clearance due to glomerular filtration.

### Claim 3 (depends on 1)

The method of claim 1, in which the multimeric oligonucleotide comprises Structure 21:
and n is an integer ≥0.

### Claim 4 (depends on 1)

The method of claim 1, in which the subunits are single-stranded oligonucleotides.

### Claim 5 (depends on 3)

The method of claim 3, wherein n is ≥1.

### Claim 6 (depends on 1)

The method of claim 1, in which the subunits are double-stranded oligonucleotides.

### Claim 7 (depends on 3)

The method of claim 3, wherein:
when n=0, the clearance of the multimeric oligonucleotide due to glomerular filtration is decreased relative to that of a monomeric subunit and/or a dimeric subunit
of the multimeric oligonucleotide; and
when n ≥1, the clearance of the multimeric oligonucleotide due to glomerular filtration is decreased relative to that of a monomeric subunit , a dimeric subunit
and/or a trimeric subunit
of the multimeric oligonucleotide.

### Claim 8 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration is determined by measuring the in vivo circulation half-life of the multimeric oligonucleotide after administering the multimeric oligonucleotide to the subject.

### Claim 9 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration is determined by measuring the time required for the serum concentration of the multimeric oligonucleotide to decrease to a predetermined value.

### Claim 10 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration is determined by measuring the serum concentration of the multimeric oligonucleotide at a predetermined time after administering the multimeric oligonucleotide to the subject.

### Claim 11 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration is determined by measuring the area under a curve of a graph representing serum concentration of the multimeric oligonucleotide over time after administering the multimeric oligonucleotide to the subject.

### Claim 12 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration increases in vivo bioavailability of the multimeric oligonucleotide.

### Claim 13 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration increases in vivo cellular uptake of the multimeric oligonucleotide.

### Claim 14 (depends on 1)

The method of claim 1, in which the decreased clearance due to glomerular filtration increases in vivo therapeutic index/ratio of the multimeric oligonucleotide.

### Claim 15 (depends on 3)

The method of claim 3, wherein n is an integer greater than or equal to 1, and at least one of the monomeric subunits comprises a single strand having one of the covalent linkers ● joined to its 3′ terminus and another of the covalent linkers joined to its 5′ terminus.

### Claim 16 (depends on 2)

The method of claim 2, wherein m is greater than or equal to 2.

### Claim 17 (depends on 2)

The method of claim 2, wherein m is greater than or equal to 3.

### Claim 18 (depends on 2)

The method of claim 2, wherein m is greater than or equal to 4.

### Claim 19 (depends on 2)

The method of claim 2, wherein m is 4, 5, 6, 7, or 8.

### Claim 20 (depends on 2)

The method of claim 2, wherein m is greater than or equal to 4 and less than or equal to 17.

### Claim 21 (depends on 2)

The method of claim 2, wherein m is greater than or equal to 4 and less than or equal to 8.

### Claim 22 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide further comprises one or more targeting ligands.

### Claim 23 (depends on 1)

The method of claim 1, wherein at least one of the subunits is a targeting ligand.

### Claim 24 (depends on 22)

The method of claim 22, wherein the targeting ligand is an aptamer.

### Claim 25 (depends on 22)

The method of claim 22, wherein the targeting ligand comprises N-Acetylgalactosamine (GalNAc), cholesterol, tocopherol, folate, 2-[3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA), or anisamide.

### Claim 26 (depends on 22)

The method of claim 22, wherein the targeting ligand comprises a sugar, peptide, or other nucleic acid.

### Claim 27 (depends on 22)

The method of claim 22, wherein the targeting ligand comprises a cell specific peptide or protein, aptamer, cell growth factor, vitamin, monosaccharide, polysaccharide, arginine-glycine-aspartic acid (RGD), or asialoglycoprotein receptor ligand.

### Claim 28 (depends on 27)

The method of claim 27, wherein the targeting ligand is transferrin.

### Claim 29 (depends on 27)

The method of claim 27, wherein the targeting ligand is folic acid.

### Claim 30 (depends on 27)

The method of claim 27, wherein the targeting ligand is GalNAc.

### Claim 31 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide is conjugated to a biologically active moiety that is a protein, peptide, amino acid, other nucleic acid, targeting ligand, carbohydrate, polysaccharide, lipid, other organic compound, or inorganic compound.

### Claim 32 (depends on 31)

The method of claim 31, wherein the biologically active moiety has gene editing activity.

### Claim 33 (depends on 32)

The method of claim 32, wherein the biologically active moiety having gene editing activity is an oligonucleotide.

### Claim 34 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide comprises Structure 54:
wherein each subunit is independently a double-stranded oligonucleotide , wherein d is an integer greater than or equal to 1, and wherein each covalent linker ● is on the same strand.

### Claim 35 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide comprises Structure 28:

### Claim 36 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide comprises Structure 30:

### Claim 37 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide does not comprise PEG.

### Claim 38 (depends on 1)

The method of claim 1, comprising two or more different covalent linkers.

### Claim 39 (depends on 1)

The method of claim 1, wherein at least one of the covalent linkers ● joins three or more monomeric subunits .

### Claim 40 (depends on 1)

The method of claim 1, wherein the multimeric oligonucleotide comprises Structure 29:

### Claim 41 (depends on 1)

The method of claim 1, where the multimeric oligonucleotide comprises

### Claim 42 (depends on 2)

The method of claim 2, wherein each monomeric subunit is independently a double stranded oligonucleotide, and wherein m is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

### Claim 43 (depends on 2)

The method of claim 2, wherein each monomeric subunit is independently a double stranded oligonucleotide, wherein m is 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and wherein each covalent linker is on the same strand.

### Claim 44 (depends on 1)

The method of claim 1, where the multimeric oligonucleotide comprises