# US 10,946,091 B2 · Compositions and methods for treating Crohn's disease and related conditions and infections

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,946,091 B2
- Document ID: US10946091B2
- Status: Granted
- Kind: B2
- Application number: 16/392,274
- Filed: 2019-04-23
- Published: 2019-08-15
- Granted: 2021-03-16
- Earliest claimed: 2012-06-04
- Assignees: Gaurav Agrawal
- Applicants: Gaurav Agrawal
- Inventors: Gaurav Agrawal
- Web page: https://patentgrep.com/patent/US10946091B2

## CPC

- A61K 39/39533: {against materials from animals}
- A23C 9/123: using only microorganisms of the genus lactobacteriaceae; Yoghurt (A23C9/13 takes precedence)
- A23G 3/36: characterised by the composition {containing organic or inorganic compounds}
- A23G 3/364: {containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins}
- A23G 4/06: characterised by the composition {containing organic or inorganic compounds}
- A23G 4/12: containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins (containing dairy products A23G4/16)
- A23G 9/32: characterised by the composition {containing organic or inorganic compounds}
- A23G 9/36: containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins (characterised by the dairy products used A23G9/40)
- A61K 31/133: having hydroxy groups, e.g. sphingosine
- A61K 31/4164: 1,3-Diazoles
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/498: Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/40: bacterial
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- C07K 16/241: {Tumor Necrosis Factors}
- A23C 9/13: using additives
- A23C 9/1315: {Non-milk proteins or fats; Seeds, pulses, cereals or soja; Fatty acids, phospholipids, mono- or diglycerides or derivatives therefrom; Egg products}
- A23C 9/1322: {Inorganic compounds; Minerals, including organic salts thereof, oligo-elements; Amino-acids, peptides, protein-hydrolysates or derivatives; Nucleic acids or derivatives; Yeast extract or autolysate; Vitamins; Antibiotics; Bacteriocins}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- 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)
- A23G: COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

In alternative embodiments, the invention provides a “triple combination” therapy for treating, ameliorating and preventing Crohn's Disease (or Crohn syndrome, terminal or distal ileitis or regional enteritis) or related disorders and conditions in mammals, such as paratuberculosis in mammals, or Johne's disease, including genetically-predisposed and chronic disorders, where the microbial or bacterial flora of the bowel is at least one causative or symptom-producing factor; and compositions for practicing same. In alternative embodiments, methods and compositions of the invention comprise or comprise use of therapies, medications, formulations and pharmaceuticals comprising active agents that can suppress or eradicate the microbiota super-infection that causes Crohn's Disease or paratuberculosis infection in mammals. In alternative embodiments, the methods and uses of the invention for treating, ameliorating and preventing Crohn's Disease and complications of Crohn's Disease, or related disorders and conditions in mammals, such as paratuberculosis in mammals, or Johne's disease, comprises administration to an individual (human or mammal) in need thereof: (1) an anti-TNFα composition, or a composition capable of down-modulating TNFα activity; (2) a Hyperbaric Oxygen Treatment, or HBOT; and (3) an anti Mycobacterium avium sub species paratuberculosis (MAP) (an anti-MAP) agent, composition or therapy.

## Claims

### Claim 1

A therapeutic combination comprising:
(1) at least one anti-TNFα composition or drug; or, at least one composition or drug capable of down-modulating or down-regulating a TNFα activity; and
(2) at least two anti-Mycobacterium avium sub species paratuberculosis (MAP) (an anti-MAP) agents.

### Claim 2 (depends on 1)

The therapeutic combination of claim 1, wherein the at least one anti-TNFα composition or drug, or the at least one composition or drug capable of down-modulating or down-regulating a TNFα activity, comprises: a protein, a peptide or an antibody capable of specifically binding to a TNFα or a TNFα-receptor or TNFα downstream effector.

### Claim 3 (depends on 1)

The therapeutic combination of claim 1, wherein the at least two anti-MAP agents comprise rifabutin and clofazimine.

### Claim 4 (depends on 1)

The therapeutic combination of claim 1, comprising administration to an individual or a patient in need thereof:
(1) at least one anti-TNFα composition or drug, or at least one composition or a drug capable of down-modulating or down-regulating a TNFα activity; and
(2) at least three anti-Mycobacterium avium sub species paratuberculosis (MAP) (an anti-MAP) agents.

### Claim 5 (depends on 4)

The therapeutic combination of claim 4, wherein the at least three anti-Mycobacterium avium sub species paratuberculosis (MAP) (an anti-MAP) agents comprise:
(a) rifabutin, clofazimine and clofazimine;
(b) rifabutin, clofazimine and clarithromycin;
(c) rifabutin, clofazimine and metronidazole 5-nitroimidazole;
(d) rifabutin, clofazimine and tinidazole; or
(e) rifabutin, clofazimine and ciprofloxacin.

### Claim 6 (depends on 1)

The therapeutic combination of claim 1, wherein the therapeutic combination is manufactured or formulated as:
(a) a chewable delivery vehicle, a gum, a gummy, a candy, a lozenge, an ice cream or an ice, or a yogurt, or a unit dosage of an anti-MAP or an anti-TNFα composition, drug, formulation, pharmaceutical or pharmaceutical preparation is formulated as a pediatric unit dosage; or
(b) a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation, or re-formulated for final delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteral formulation.

### Claim 7 (depends on 1)

The therapeutic combination of claim 1, further comprising:
a flavoring or a sweetening agent, aspartamine, stevia, monk fruit, sucralose, saccharin, cyclamate, xylitol, vanilla, artificial vanilla or chocolate or strawberry flavor, artificial chocolate essence, or a mixture or combination thereof;
a preservative, benzoic acid, or potassium sorbate;
at least one probiotic or prebiotic;
at least one congealing agent, wherein optionally the congealing agent comprises an arrowroot or a plant starch, a powdered flour, a powdered potato or potato starch, an absorbant polymer, and/or a corn flour or a corn starch;
at least one an anti-inflammatory agent, wherein optionally the inflammatory agent comprises or is a 4 or a 5-amino-salicylate, an olsalazine, a mesalazine, a sulfasalazine, and/or a balsalazide, or a combination thereof;
an additive selected from one or more of a saline, a media, a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a contrast agent, a dispersal agent, a buffer or a buffering agent, a sweetening agent, a debittering agent, a flavoring agent, a pH stabilizer, an acidifying agent, a preservative, a desweetening agent and/or coloring agent, vitamin, mineral and/or dietary supplement, or a prebiotic nutrient;
a drug, wherein optionally the drug comprises an antibiotic, or
at least one Biofilm Disrupting Compound, wherein optionally the biofilm disrupting compound comprises an enzyme, a deoxyribonuclease (DNase), N-acetylcysteine, an auranofin, an alginate lyase, glycoside hydrolase dispersin B; a Quorum-sensing inhibitor, a ribonucleic acid III inhibiting peptide, Salvadora persica extracts, Competence-stimulating peptide, Patulin and penicillic acid; peptides—cathelicidin-derived peptides, small lytic peptide, PTP-7, Nitric oxide, neo-emulsions; ozone, lytic bacteriophages, lactoferrin, xylitol hydrogel, synthetic iron chelators, cranberry components, curcum in, silver nanoparticles, Acetyl-11-keto-.beta.-boswellic acid (AKBA), barley coffee components, probiotics, sinefungin, S-adenosylmethionine, S-adenosyl-homocysteine, Delisea furanones, N-sulfonyl homoserine lactones or any combination thereof.

### Claim 8 (depends on 1)

The therapeutic combination of claim 1, formulated as a delayed or gradual enteric release composition or formulation, and optionally the formulation comprises a gastro-resistant coating designed to dissolve at a pH of 7 in the terminal ileum, or an active ingredient is coated with an acrylic based resin, or a poly(meth)acrylate, or a methacrylic acid copolymer B, NF, which dissolves at pH 7 or greater.

### Claim 9 (depends on 1)

The therapeutic combination of claim 1, wherein a unit dosage of the at least one anti-MAP agent or the at least one anti-TNFα composition, drug, formulation, pharmaceutical or pharmaceutical preparation is formulated as unit dosage of between about 10 mg and 1100 mg, or is about 10, 20, 30, 40, 50, 60, 70, 75, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 750, 800, 900, 1000 or 1100 or more mg per unit dose.

### Claim 10 (depends on 1)

The therapeutic combination of claim 1, wherein a unit dosage of the at least one anti-MAP or the at least one anti-TNFα composition, drug, formulation, is for: a bid (twice a day), tid (three times a day), four times a day, five times a day or six times a day or more, administration.

### Claim 11 (depends on 1)

A product of manufacture comprising or having contained therein the therapeutic composition of claim 1.

### Claim 12 (depends on 11)

The product of manufacture of claim 11, wherein the product of manufacture is a delivery vehicle, a container, a syringe, a device or a bag.

### Claim 13 (depends on 1)

The therapeutic combination of claim 1, wherein the TNFα activity comprises causing an autophagy or an apoptosis in a cell.

### Claim 14 (depends on 1)

The therapeutic combination of claim 1, wherein the therapeutic combination is manufactured or formulated as a pharmaceutical or a pharmaceutical preparation.

### Claim 15 (depends on 2)

The therapeutic combination of claim 2, wherein the antibody is or comprises: an infliximab; an adalimumab; a certolizumab, certolizumab pegol; a golimumab; a basiliximab; a daclizumab; an omalizumab; or, any combination thereof.

### Claim 16 (depends on 7)

The therapeutic combination of claim 7, wherein:
(a) the prebiotic comprises inulin, lactulose, extracts of artichoke, chicory root, oats, barley, various legumes, garlic, kale, beans or flax or an herb,
(b) the probiotic comprises a cultured or stool-extracted microorganism or bacteria, or a bacterial component, or
(c) the bacteria or bacterial component comprises or is derived from a bacterium of the genus Bacteroidetes, Firmicutes, Lactobacilli, or Bifidobacteria, or an E. coli or a Strep fecalis bacterium.

### Claim 17 (depends on 1)

The therapeutic combination of claim 1, wherein a unit dosage of the at least one anti-MAP agent or the at least one anti-TNFα composition, drug, formulation, is formulated for administration at a daily or once a day dosage of about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 600, 700, 750, 800, 900, 1000 or 1100 or more mg per day, or between about 100 and 1100 mg per day.

### Claim 18 (depends on 10)

The therapeutic combination of claim 10, wherein the unit dosage and daily dosage are adjusted to be: about 1000 mg/70 kg a day, or about 14 mg/kg a day, for an adult median dose per day or five times a day for adult use, or for a 70 kg individual would be 200 mg per unit dose; or for a pediatric dosage about 350 mg/25 kg a day, or about 15 to 16 mg/kg, a day; or, five times a day for pediatric use, or for a 25 kg individual, would be 70 mg per unit dose.