# US 10,058,574 B2 · Compositions comprising bacterial strains

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- Number: US 10,058,574 B2
- Document ID: US10058574B2
- Status: Granted
- Kind: B2
- Application number: 15/592,178
- Filed: 2017-05-10
- Published: 2017-11-09
- Granted: 2018-08-28
- Earliest claimed: 2015-06-15
- Assignees: 4D Pharma Research Limited
- Applicants: 4D Pharma Research Limited
- Inventors: George Grant; Angela Margaret Patterson; Imke Mulder; Seanin McCluskey; Emma Raftis
- Web page: https://patentgrep.com/patent/US10058574B2

## CPC

- A61K 35/74: Bacteria (therapeutic use of a bacterial protein A61K38/00)
- A23C 9/12: Fermented milk preparations; Treatment using microorganisms or enzymes
- A23L 33/135: Bacteria or derivatives thereof, e.g. probiotics
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 39/0216: {Bacteriodetes, e.g. Bacteroides, Ornithobacter, Porphyromonas}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 1/205: Bacterial isolates
- A23V 2002/00: Food compositions, function of food ingredients or processes for food or foodstuffs
- A61K 2039/52: {Bacterial cells; Fungal cells; Protozoal cells}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/58: {raising an immune response against a target which is not the antigen used for immunisation}
- C12R 2001/01: Bacteria or Actinomycetales {; using bacteria or Actinomycetales}
- 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)
- A23C: DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; PREPARATION THEREOF (preservation thereof A23B11/00)
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- 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)
- A23V: INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- C12R: INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention provides compositions comprising bacterial strains for treating and preventing inflammatory and autoimmune diseases.

## Claims

### Claim 1

A pharmaceutical composition that comprises a therapeutically effective amount of a bacteria strain of the genus Bacteroides;
wherein the bacteria strain is lyophilized;
wherein the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, diluent, or carrier;
wherein the therapeutically effective amount of the bacteria strain comprises from about 1×103 to about 1×1011 CFU/g of the bacteria strain with respect to total weight of the pharmaceutical composition; and
wherein the bacteria strain comprises a polynucleotide sequence of a 16S rRNA gene that has at least 95% sequence identity to the polynucleotide sequence of SEQ ID NO:4, as determined by a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12, a gap extension penalty of 2, and a Blocks Substitution Matrix (BLOSUM) of 62.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the bacteria strain comprises the polynucleotide sequence of SEQ ID NO:4.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is effective to reduce a level of at least one pro-inflammatory cytokine.

### Claim 4 (depends on 3)

The pharmaceutical composition of claim 3, wherein the at least one pro-inflammatory cytokine comprises an IL-17 cytokine selected from the group consisting of: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.

### Claim 5 (depends on 3)

The pharmaceutical composition of claim 3, wherein the at least one pro-inflammatory cytokine comprises a cytokine selected from the group consisting of: IFN-γ, IL-1β, RANTES, MIP-1α, IL-8, and IL-6.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition contains a single bacteria strain.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the bacteria strain is viable and capable of at least partially colonizing an intestine of a human subject.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein at least 50% of the bacteria strain as measured by an amount of CFU, remains viable after about 1 year of storage when the pharmaceutical composition is stored in a closed container at 25° C. at 95% relative humidity.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a lyophilized composition.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a lyoprotectant which is the pharmaceutically acceptable excipient, diluent, or carrier.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a prebiotic compound selected from the group consisting of: a fructo-oligosaccharide, a short-chain fructo-oligosaccharide, inulin, an isomalt-oligosaccharide, a transgalacto-oligosaccharide, a pectin, a xylo-oligosaccharide, a chitosan-oligosaccharide, a beta-glucan, an arable gum modified starch, a polydextrose, a D-tagatose, an acacia fiber, carob, an oat, and a citrus fiber.

### Claim 12

A method of treating a condition mediated by the Th17 pathway in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition that comprises a bacteria strain of the genus Bacteroides;
wherein the administering is effective to produce a decrease in production of at least one pro-inflammatory cytokine in the subject, thereby treating the condition mediated by the Th17 pathway in the subject; and
wherein the bacteria strain is lyophilized;
wherein the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, diluent, or carrier;
wherein the therapeutically effective amount of the bacteria strain comprises from about 1×103 to about 1×1011 CFU/g of the bacteria strain with respect to total weight of the pharmaceutical composition; and
wherein the bacteria strain comprises a polynucleotide sequence of a 16S rRNA gene that has at least 95% sequence identity to the polynucleotide sequence of SEQ ID NO:4, as determined by a Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12, a gap extension penalty of 2, and a Blocks Substitution Matrix (BLOSUM) of 62.

### Claim 13 (depends on 12)

The method of claim 12, wherein the pharmaceutical composition comprises a single bacteria strain.

### Claim 14 (depends on 12)

The method of claim 12, wherein the at least one pro-inflammatory cytokine comprises a cytokine of the Th17 pathway.

### Claim 15 (depends on 12)

The method of claim 12, wherein the at least one pro-inflammatory cytokine comprises an IL-17 cytokine selected from the group consisting of: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.

### Claim 16 (depends on 12)

The method of claim 12, wherein the at least one pro-inflammatory cytokine comprises a cytokine selected from the group consisting of: IFN-γ, IL-1β, RANTES, MIP-1α, IL-8, and IL-6.

### Claim 17 (depends on 12)

The method of claim 12, wherein the condition mediated by the Th17 pathway is selected from the group consisting of: uveitis; a cancer; multiple sclerosis; an arthritis; neuromyelitis optica; psoriasis; systemic lupus erythematosus; an inflammatory bowel disease; celiac disease; an asthma; allergic asthma; neutrophilic asthma; chronic obstructive pulmonary disease (COPD); scleritis; vasculitis; Behcet's disease; atherosclerosis; atopic dermatitis; emphysema; periodontitis; allergic rhinitis; and allograft rejection.

### Claim 18 (depends on 17)

The method of claim 17, wherein the condition mediated by the Th17 pathway is an asthma; and wherein the treating comprises reducing neutrophilia or eosinophilia.

### Claim 19 (depends on 17)

The method of claim 17, wherein the condition mediated by the Th17 pathway is an arthritis selected from the group consisting of rheumatoid arthritis, osteoarthritis, psoriatic arthritis, spondyloarthritis, ankylosing spondylitis, and juvenile idiopathic arthritis; and wherein the method reduces joint swelling.

### Claim 20 (depends on 12)

The method of claim 12, wherein the bacteria strain comprises the polynucleotide sequence of SEQ ID NO:4.

### Claim 21 (depends on 12)

The method of claim 12, wherein the subject has the condition, or has been identified as being at risk of the condition.

### Claim 22 (depends on 12)

The method of claim 12, further comprising administering an additional therapeutic agent to the subject.

### Claim 23 (depends on 12)

The method of claim 12, wherein the administering of the pharmaceutical composition comprises oral, rectal, nasal, buccal, sublingual, intraperitoneal, or subcutaneous administration.

### Claim 24 (depends on 12)

The method of claim 12, wherein the administering comprises providing one or more doses of 1 g, 3 g, 5 g, or 10 g of the pharmaceutical composition.

### Claim 25 (depends on 1)

The pharmaceutical composition of claim 1, wherein the bacteria strain is non-spore forming.

### Claim 26 (depends on 1)

The pharmaceutical composition of claim 1, wherein the polynucleotide sequence of the 16S rRNA gene has at least 98% sequence identity to the polynucleotide sequence of SEQ ID NO:4, as determined by the Smith-Waterman homology search algorithm using the affine gap search with the gap open penalty of 12, the gap extension penalty of 2, and the BLOSUM of 62.

### Claim 27 (depends on 12)

The method of claim 12, wherein the polynucleotide sequence of the 16S rRNA gene has at least 98% sequence identity to the polynucleotide sequence of SEQ ID NO:4, as determined by the Smith-Waterman homology search algorithm using the affine gap search with the gap open penalty of 12, the gap extension penalty of 2, and the BLOSUM of 62.

### Claim 28 (depends on 1)

The pharmaceutical composition of claim 1, wherein the bacteria strain is strain 675 deposited under accession number NCIMB 42408.

### Claim 29 (depends on 1)

The pharmaceutical composition of claim 1, wherein the polynucleotide sequence of the 16S rRNA gene has at least 99% sequence identity to the polynucleotide sequence of SEQ ID NO:4, as determined by the Smith-Waterman homology search algorithm using the affine gap search with the gap open penalty of 12, the gap extension penalty of 2, and the BLOSUM of 62.

### Claim 30 (depends on 1)

The pharmaceutical composition of claim 1, wherein the bacteria strain is of the species Bacteroides coprocola.

### Claim 31 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is comprised in a capsule.

### Claim 32 (depends on 12)

The method of claim 12, wherein the polynucleotide sequence of the 16S rRNA gene has at least 99% sequence identity to the polynucleotide sequence of SEQ ID NO:4, as determined by the Smith-Waterman homology search algorithm using the affine gap search with the gap open penalty of 12, the gap extension penalty of 2, and the BLOSUM of 62.

### Claim 33 (depends on 12)

The method of claim 12, wherein the bacteria strain is of the species Bacteroides coprocola.

### Claim 34 (depends on 12)

The method of claim 12, wherein the bacteria strain is strain 675 deposited under accession number NCIMB 42408.

### Claim 35 (depends on 12)

The method of claim 12, wherein the pharmaceutical composition is comprised in a capsule.

### Claim 36 (depends on 12)

The method of claim 12, wherein the pharmaceutical composition comprises a lyoprotectant which is the pharmaceutically acceptable excipient, diluent, or carrier.