# US 12,599,680 B1 · Treatments for ocular neovascularization

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- Number: US 12,599,680 B1
- Document ID: US12599680B1
- Status: Granted
- Kind: B1
- Application number: 19/300,498
- Filed: 2025-08-14
- Granted: 2026-04-14
- Earliest claimed: 2021-04-27
- Assignees: 4D Molecular Therapeutics Inc.
- Applicants: 4D Molecular Therapeutics Inc.
- Inventors: Christian Burns; Melissa Calton; Meredith Leong; Paul Szymanski
- Web page: https://patentgrep.com/patent/US12599680B1

## CPC

- A61K 48/0066: {Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61K 48/0083: {characterised by an aspect of the administration regime}
- A61P 27/02: Ophthalmic agents
- C07K 14/005: from viruses
- C07K 14/71: for growth factors; for growth regulators
- C07K 16/22: against growth factors {; against growth regulators}
- 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)}
- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- C12N 15/1138: {against receptors or cell surface proteins}
- C12N 15/62: DNA sequences coding for fusion proteins
- C12N 15/86: Viral vectors
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/32: fusions with soluble part of a cell surface receptor, "decoy receptors"
- C07K 2319/55: containing a fusion with a toxin, e.g. diphteria toxin
- C12N 2310/11: Antisense
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2320/31: Combination therapy
- C12N 2750/14122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12N 2750/14171: Demonstrated in vivo effect
- C12N 2800/22: Vectors comprising a coding region that has been codon optimised for expression in a respective host
- C12N 2830/00: Vector systems having a special element relevant for transcription
- C12N 2830/42: being an intron or intervening sequence for splicing and/or stability of RNA
- C12N 2840/20: translation of more than one cistron
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Provided herein are compositions and methods for the treatment of ocular neovascular diseases such as wet age-related macular degeneration.

## Claims

### Claim 1

A synthetic ribonucleic acid (RNA) molecule, wherein the synthetic RNA molecule comprises a sense strand comprising a nucleotide sequence set forth as SEQ ID NO:19 and an antisense strand comprising a nucleotide sequence set forth as SEQ ID NO:20.

### Claim 2 (depends on 1)

The synthetic RNA molecule according to claim 1, wherein the RNA is a small hairpin RNA (shRNA) or an artificial microRNA (miRNA).

### Claim 3 (depends on 1)

A nucleic acid comprising a nucleotide sequence to be transcribed to an RNA, wherein the RNA comprises a synthetic RNA molecule according to claim 1.

### Claim 4 (depends on 3)

The nucleic acid of claim 3 wherein the nucleic acid comprises (i) a nucleotide sequence to be transcribed to an artificial miRNA comprising a sense sequence comprising the nucleotide sequence set forth as SEQ ID No: 19 and an antisense sequence comprising the nucleotide sequence set forth as SEQ ID No: 20 and further comprises (ii) a nucleotide sequence encoding a first anti-angiogenic polypeptide that inhibits the activity of VEGF-A, wherein the nucleotide sequence of (i) and (ii) are operably linked to an expression control sequence.

### Claim 5 (depends on 4)

The nucleic acid according to claim 4, wherein the first anti-angiogenic polypeptide is aflibercept.

### Claim 6 (depends on 5)

The nucleic acid according to claim 5, wherein the nucleotide sequence encoding aflibercept comprises the nucleotide sequence of SEQ ID NO:50 or a sequence at least 90% identical thereto.

### Claim 7 (depends on 6)

The nucleic acid according to claim 6, wherein the nucleotide sequence encoding the first anti-angiogenic polypeptide and the nucleotide sequence encoding said artificial miRNA are under the control of the same ubiquitous promoter.

### Claim 8 (depends on 7)

The nucleic acid according to claim 7, wherein the promoter is a CAG or CBA promoter.

### Claim 9 (depends on 8)

The nucleic acid according to claim 8, wherein the promoter is a CAG promoter and wherein the nucleotide sequence encoding the artificial miRNA is located within the hybrid chicken β-actin and rabbit β-globin intron of the CAG promoter.

### Claim 10 (depends on 9)

The nucleic acid according to claim 9, wherein the nucleic acid comprises the nucleotide sequence set forth in SEQ ID No: 69 or a sequence at least 90% identical thereto.

### Claim 11 (depends on 10)

The nucleic acid according to claim 10, wherein the nucleic acid comprises the nucleotide sequence set forth as SEQ ID NO:69.

### Claim 12 (depends on 5)

A vector comprising the nucleic acid according to claim 5.

### Claim 13 (depends on 11)

A vector comprising the nucleic acid according to claim 11.

### Claim 14 (depends on 13)

The vector according to claim 13, wherein the vector is a recombinant adeno-associated virus (rAAV) vector.

### Claim 15 (depends on 14)

The vector according to claim 14, wherein the rAAV comprises a capsid protein comprising an amino acid sequence at least 90% identical to SEQ ID NO:48.

### Claim 16 (depends on 15)

The vector according to claim 15, wherein the rAAV comprises a capsid comprising a capsid protein comprising an amino acid sequence at least 95% identical to SEQ ID NO:48 and a heterologous nucleic acid comprising the sequence set forth as SEQ ID No: 69 or a sequence at least 95% identical thereto.

### Claim 17 (depends on 16)

The vector according to claim 16, wherein the rAAV comprises a capsid protein comprising the amino acid sequence set forth as SEQ ID NO:48 and a heterologous nucleic acid sequence comprising the sequence set forth as SEQ ID NO:69.

### Claim 18 (depends on 17)

A host cell comprising the vector according to claim 17.

### Claim 19 (depends on 17)

A pharmaceutical composition comprising the vector according to claim 17 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

A method for the treatment of an ocular disease associated with VEGF-A in a subject in need of such treatment, the method comprising intraocularly administering to the subject a pharmaceutical composition according to claim 19.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the pharmaceutical composition is administered by intravitreal injection.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the pharmaceutical composition comprises 1× 108 to 1× 1015 vector particles or 1× 1010 to 5× 1013 vector particles.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the disease associated with VEGF-A is selected from the group consisting of wet age-related macular degeneration; macular edema following retinal vein occlusion; retinal neovascularization resulting from retinal vein occlusion; diabetic macular edema, diabetic retinopathy, myopic macular degeneration, branch retinal vein occlusion, hemi-retinal vein occlusion, and central retinal vein occlusion; retinopathy of prematurity; idiopathic choroidal neovascularization; myopia macular degeneration and secondary retinal and choroidal neovascularization; retinal telangiectasia; neovascular glaucoma; vitreous hemorrhage; retinal and choroidal neovascularization secondary to retinal diseases, including but not limited to uveitis, trauma, retinal degenerative disorders, genetic retinal and/or choroidal disease, tumors of the eye, corneal and iris neovascularization.

### Claim 24 (depends on 23)

The method according to claim 23, wherein the disease associated with VEGF-A is selected from wet age-related macular degeneration; diabetic macular edema; macular edema following retinal vein occlusion; diabetic retinopathy; and myopic choroidal neovascularization.