Claims for Patent: 10,036,759

Summary for Patent: 10,036,759

Title:	Pathway specific markers for diagnosing irritable bowel syndrome
Abstract:	The present invention provides methods for aiding in the diagnosis of irritable bowel syndrome (IBS) in an individual. In particular, the present invention is useful for determining whether the individual does not have either celiac disease or inflammatory bowel disease (IBD), and has IBS and/or a subtype thereof. Thus, the present invention provides an accurate diagnostic prediction of IBS and is useful for guiding treatment decisions.
Inventor(s):	Westin; Stefan (Carlsbad, CA), Selvaraj; Fabiyola (San Diego, CA), Princen; Fred (La Jolla, CA), Singh; Sharat (Rancho Santa Fe, CA)
Assignee:	Nestec S.A. (Vevey, CH)
Application Number:	15/646,838
Patent Claims:	1. A method for aiding in the diagnosis of irritable bowel syndrome (IBS) and/or a clinical subtype thereof in a subject, said method comprising: (a) detecting in a sample a first panel of markers to rule-out a diagnosis of inflammatory bowel disease (IBD) and celiac disease (CD); (i) wherein ruling-out CD includes detecting in said sample obtained from said subject the presence or absence of one or more of the following markers: an anti-gliadin IgA antibody, an anti-gliadin IgG antibody, an anti-tissue transglutaminase (tTG) antibody, or an anti-endomysial antibody to obtain a CD score, and applying a decision tree or a set of rules to said CD score to obtain a decision whether said sample is a CD sample or a non-CD sample; (ii) wherein ruling-out IBD includes detecting in said sample the presence or level or genotype of one or more of the following markers to obtain an IBD score: (A) the presence or level of a serological marker selected from the group consisting of ASCA-A, ASCA-G, ANCA, pANCA, anti-OmpC antibody, anti-CBir1 antibody, anti-FlaX antibody, or anti-A4-Fla2 antibody; or (B) the presence or level of an inflammation marker selected from the group consisting of VEGF, ICAM, VCAM, SAA, or CRP; or (C) the genotype of a genetic marker selected from the group consisting of ATG16L1, ECM1, NKX2-3, or STAT3; and (b) detecting in said sample a second panel of markers, which second panel includes: (c) at least one bacterial antigen antibody marker to obtain a microbiome score, and one bile acid malabsorption marker to obtain a malabsorption score to rule-in a diagnosis of IBS. 2. The method of claim 1, wherein said method further comprises obtaining one or more of the following (a)-(i) scores: (a) detecting in said sample the level of at least one mast cell marker to obtain a mast cell score; or (b) detecting in said sample the level of at least one inflammatory cell marker to obtain an inflammatory score; or (c) detecting in said sample the level of at least one bile acid malabsorption (BAM) marker to obtain a BAM score; or (d) detecting in said sample the level of at least one kynurenine marker to obtain an oxidative stress score; or (e) detecting in said sample the level of at least one serotonin marker to obtain a serotonin score; or (f) if said sample is a non-CD sample, then applying a random forest statistical analysis to said IBD score to obtain a decision whether the sample is an IBD sample or a non-IBD sample; or (g) if said sample is a non-IBD sample, then applying a statistical algorithm to one or more of the following: said microbiome score, said mast cell score, said inflammatory score, said BAM score, said oxidative stress score, and said serotonin score to obtain a disease score; or (h) determining a diagnosis of IBS in said subject based on a statistical algorithm that generates a probability of having IBS based on the disease score and a diagnostic model comprising a microbiome score, a mast cell score, an inflammatory score, a bile acid malabsorption score, an oxidative stress score, and a serotonin score from a retrospective cohort of patients. 3. The method of claim 1, wherein the at least one bacterial antigen antibody marker is selected from the group consisting of an anti-Fla1 antibody, anti-Fla2antibody, anti-FlaA antibody, anti-FliC antibody, anti-FliC2antibody, anti-FliC3antibody, anti-YBaN1antibody, anti-ECFliC antibody, anti-Ec0FliC antibody, anti-SeFljB antibody, anti-CjFlaA antibody, anti-CjFlaB antibody, anti-SfFliC antibody, anti-CjCgtA antibody, anti-Cjdmh antibody, anti-CjGT-A antibody, anti-EcYidX antibody, anti-EcEra antibody, anti-EcFrvX antibody, anti-EcGabT antibody, anti-EcYedK antibody, anti-EcYbaN antibody, anti-EcYhgN antibody, anti-RtMaga antibody, anti-RbCpaF antibody, anti-RgPilD antibody, anti-LaFrc antibody, anti-LaEno antibody, anti-LjEFTu antibody, anti-BfOmpa antibody, anti-PrOmpA antibody, anti-Cp10bA antibody, anti-CpSpA antibody, anti-EfSant antibody, anti-LmOsp antibody, anti-SfET-2 antibody, anti-Cpatox antibody, anti-Cpbtox antibody, anti-EcSta2antibody, anti-Ec0Stx2A antibody, anti-CjcdtB/C antibody, anti-CdtcdA/B antibody, and combinations thereof. 4. The method of claim 2, wherein the at least one mast cell marker is selected from the group consisting of .beta.-tryptase, histamine, prostaglandin E2(PGE2), and combinations thereof. 5. The method of claim 2, wherein the at least one inflammatory marker is selected from the group consisting of CRP, ICAM, VCAM, SAA, GRO.alpha., and combinations thereof. 6. The method of claim 2, wherein the at least one bile acid malabsorption marker is selected from the group consisting of 7.alpha.-hydroxy-4-cholesten-3-one, FGF19, and a combination thereof. 7. The method of claim 2, wherein the at least one kynurenine marker is selected from the group consisting of kynurenine (K), kynurenic acid (KyA), anthranilic acid (AA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), xanthurenic acid (XA), quinolinic acid (QA), tryptophan, 5hydroxytryptophan (5-HTP), and combinations thereof. 8. The method of claim 2, wherein the at least one serotonin markers is selected from the group consisting of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), serotonin-O-sulfate, serotonin-O-phosphate, and combinations thereof. 9. The method of claim 2, wherein the diagnostic model is established using a retrospective cohort with known outcomes of IBS and healthy controls. 10. The method of claim 2, wherein the diagnostic model is established using a retrospective cohort with known outcomes of a clinical subtype of IBS and healthy controls. 11. The method of claim 2, wherein the method further comprises classifying a diagnosis of IBS as IBS-constipation (IBS-C), IBS diarrhea (IBS-D), IBS-mixed (IBS-M), IBS-alternating (IBS-A), or post-infectious (IBS-PI). 12. The method of claim 2, wherein the level of said mast cell marker, said inflammatory cell marker, said BAM marker, said kynurenine marker or said serotonin marker is independently detected with a hybridization assay, amplification-based assay, immunoassay, immunohistochemical assay, or a mobility assay. 13. The method of claim 12, wherein the hybridization assay comprises an ELISA or a collaborative enzyme enhanced reactive-immunoassay. 14. The method of claim 2, wherein the sample is selected from the group consisting of whole blood, plasma, serum, saliva, urine, stool, tears, any other bodily fluid, a tissue sample, and a cellular extract thereof. 15. The method of claim 14, wherein the sample is serum. 16. The method of claim 2, wherein at least two members selected from the following group are measured: microbiome score, a mast cell score, an inflammatory score, a bile acid malabsorption score, an oxidative stress score, and a serotonin score. 17. The method of claim 16, wherein at least three members selected from the following group are measured: microbiome score, a mast cell score, an inflammatory score, a bile acid malabsorption score, an oxidative stress score, and a serotonin score. 18. The method of claim 16, wherein at least four members selected from the following group are measured: microbiome score, a mast cell score, an inflammatory score, a bile acid malabsorption score, an oxidative stress score, and a serotonin score. 19. The method of claim 16, wherein at least five members selected from the following group are measured: microbiome score, a mast cell score, an inflammatory score, a bile acid malabsorption score, an oxidative stress score, and a serotonin score. 20. The method of claim 16, wherein all members of the following group are measured: microbiome score, a mast cell score, an inflammatory score, a bile acid malabsorption score, an oxidative stress score, and a serotonin score.

Details for Patent 10,036,759

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Jubilant Hollisterstier Llc	N/A	positive skin test control-histamine	Injection	103891	03/13/1924		2033-05-24