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Ep 3071235 B1 (19) TZZ¥Z_ ¥_T (11) EP 3 071 235 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/702 (2006.01) A61K 31/716 (2006.01) 13.12.2017 Bulletin 2017/50 A61K 31/733 (2006.01) A61K 31/7016 (2006.01) A61K 45/06 (2006.01) A61P 1/00 (2006.01) (21) Application number: 16704085.6 (86) International application number: (22) Date of filing: 13.01.2016 PCT/US2016/013305 (87) International publication number: WO 2016/122889 (04.08.2016 Gazette 2016/31) (54) GLYCAN THERAPEUTICS AND RELATED METHODS THEREOF GLYCANTHERAPEUTIKA UND ENTSPRECHENDE VERFAHREN COMPOSITIONS THÉRAPEUTIQUES DE GYLCANE ET PROCÉDÉS ASSOCIÉS (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • VON MALTZAHN, Geoffrey A. GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Somerville, Massachusetts 02145 (US) PL PT RO RS SE SI SK SM TR • SILVERMAN, Jared Designated Extension States: Brookline MA 02445 (US) BA ME • YAMANAKA, Yvonne J. Palo Alto, CA 94304-2446 (US) (30) Priority: 26.01.2015 US 201562108039 P • MILWID, Jack 23.04.2015 US 201562152005 P Winchester, MA 01890 (US) 23.04.2015 US 201562152011 P • GEREMIA, John M. 23.04.2015 US 201562152007 P Watertown 23.04.2015 US 201562152017 P MA 02138 (US) 23.04.2015 US 201562152016 P 10.09.2015 US 201562216997 P (74) Representative: Bühler, Dirk 10.09.2015 US 201562216993 P Maiwald Patentanwalts GmbH 10.09.2015 US 201562216995 P Elisenhof 10.09.2015 US 201562217002 P Elisenstraße 3 06.10.2015 US 201562238110 P 80335 München (DE) 06.10.2015 US 201562238112 P (56) References cited: (43) Date of publication of application: WO-A1-2004/052121 WO-A1-2009/082214 28.09.2016 Bulletin 2016/39 US-A1- 2004 235 789 US-A1- 2005 004 070 (73) Proprietor: Kaleido Biosciences, Inc. Bedford, MA 01730 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 071 235 B1 Printed by Jouve, 75001 PARIS (FR) EP 3 071 235 B1 Description BACKGROUND 5 [0001] The microbiota of humans is complex, and varies by individual depending on genetics, age, sex, stress, nutrition and diet. The microbiota perform many activities and may influence the physiology of the host. Changing the numbers and species of gut microbiota can alter community function and interaction with the host. A limited number of probiotic bacteria is known in the art, and some association with health benefits documented when taken by humans. Some foods are considered ’prebiotic’ foods that contain substances that may promote the growth of certain bacteria that are thought 10 to be beneficial to the human host. The results of clinical tests with these substances are conflicted with respect to their efficacy, and their influence on human health is generally described as being modest. Thus, there is a need for novel therapeutic inputs that can stimulate beneficial microbiota shifts and improve human health. [0002] US 2004/235789 A1, US 2005/004070 A1, WO 2004/052121 A1 and WO 2009/082214 A1 disclose oligosac- charide compositios for us in the treatment of various diseases. 15 SUMMARY OF THE INVENTION [0003] The present invention provides pharmaceutical compositions, methods and pharmaceutical claims as defined in the appended claims. 20 [0004] More generally, the present disclosure feartures, in one aspect, methods of modulating the abundance of a bacterial taxa in a human subject’s gastrointestinal microbiota, the method comprising administering to the human subject a pharmaceutical composition comprising a glycan therapeutic preparation in an amount effective to modulate the abundance of the bacterial taxa, wherein i) the glycan therapeutic preparation comprises a mixture of branched glycans, wherein the average degree of branching (DB, branching points per residue) of the glycans in the preparation is at least 25 0.01 (e.g., at least 0.05, or at least 0.1), ii) at least 50% of the glycans in the preparation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, and iii) the ratio of alpha- to beta-glycosidic bonds present in the glycans of the preparation is between about 1:1 to about 5:1 overall. In some embodiments of the present disclosure, the bacterial taxa comprises at least a first and a second bacterial taxa. [0005] In some embodiments, the preparation comprises branched oligosaccharides. In some embodiments, the av- 30 erage degree of branching in the preparation (DB) is at least 0.05 (e.g., at least 0.1). [0006] In some embodiments, at least one, at least two, at least three, at least four, or more of the glycosidic bonds independently comprise a 1->2 glycosidic bond, a 1->3 glycosidic bond, a 1->4 glycosidic bond, or a 1->6 glycosidic bond. In some embodiments, one or more, two or more, or three or more glycosidic bonds are present in both alpha and beta configuration. 35 [0007] In some embodiments, a glycan unit comprises at least one, at least two, at least three, or more of a monosac- charide selected from the group of a tetrose, a pentose, a hexose, and a heptose. In some embodiments, a glycan unit comprises at least one, at least two, at least three, or more of a monosaccharide selected from the group of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, and rhamnose. [0008] In some embodiments, at least a plurality of the glycans, e.g., at least 10, 20, 30 40, 50, 60, 70, 80, 90, 95, or 40 99 % (by weight or number), or substantially all, of the glycans in the preparation, do not comprise more than a preselected reference level, of a repeating unit of glycan units, e.g., a repeating unit of 2, 3, 4 or more glycan units. In an embodiment, the preselected reference level is 10, 20, 30, 40, 50, or 60% of the total glycan units in a glycan. By way of example, in an embodiment, a glycan made up of 20 saccharide monomers, less than 50% of those 20 monomers are repeating units of a 2 or 3 glycan repeat. 45 [0009] In some embodiments, the glycan therapeutic preparation is synthetic and not isolated from a natural oligosac- charide or polysaccharide source. [0010] In some embodiments of the present disclosure, the abundance of the bacterial taxa (e.g., of each of a first and a second bacterial taxa) in the human subject’s gastrointestinal microbiota is modulated by at least about 5%, 10%, 25% 50%, 75%, 100%, 250%, 500%, 750%, or by at least 1000%. In some embodiments, the modulation comprises an 50 increase or a decrease in the abundance of the bacterial taxa (e.g., of each of a first and a second bacterial taxa) in the human subject’s gastrointestinal microbiota. [0011] In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a commensal bacterial taxa. In other embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a pathogenic bacterial taxa. 55 [0012] In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a genus selected from the group of Akkermansia, Alistipes, Anaerofilum, Bacteroides, Bilophila, Blautia, Bifidobacterium, Butyrivibrio, Campylobacter, Candidatus, Citrobacter, Clostridium, Collinsella, Coprococcus, Desulfovibrio, Dialister, Dorea, Entero- bacter, Enterococcus, Escherichia, Eubacterium, Faecalibacterium, Fusobacterium, Haemophilus, Klebsiella, Lachno- 2 EP 3 071 235 B1 spira, Lactobacillus, Odoribacter, Oscillospira, Parabacteroides, Peptococcus, Peptostreptococcus, Phascolarctobac- terium, Porphyromonas, Portiera, Prevotella, Providencia, Pseudomonas, Roseburia, Ruminococcus, Salmonella, Shig- ella, Staphylococcus, Streptococcus, Subdoligranulum, Vibrio, and Yersinia. In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a genus selected from the group of Prevotella, Akkermansia, 5 Bacteroides, Clostridium (Erysipelotrichaceae), Clostridium (Clostridiaceae), Bifidobacterium, Aggregatibacter, Clostrid- ium (Peptostreptococcaveae), Parabacteroides, Lactobacillus, and Enterococcus. In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a genus selected from the group of Akkermansia, Bacteroides, Bifidobacterium, Lactobacillus, and Parabacteroides. In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a genus selected from the group of Akkermansia and Blautia. 10 [0013] In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) comprises a taxa predominant in the small intestine or large intestine. In some embodiments, the bacterial taxa (e.g., a first and a second bacterial taxa) predominant in the small intestine comprises a genus selected from the group of Achromobacter, Agrobacterium, Blautia, Burkholderia, Coprococcus, Cryocola, Enterococcus, Eubacterium, Holdemania, Lactococcus, Mycobacterium, Pseudoramibacter, Ralstonia, Sphingomonas, Streptococcus, and Turicibacter. In some embodiments, the bacterial 15 taxa (e.g., a first and a second bacterial taxa) predominant in the large intestine comprises a genus selected from the group of Anaerotruncus, Akkermansia, Bacteroides, Bilophila, Butyricimonas, Odoribacter, Parabacteroides, Phascol- arctobacterium, Prevotella, and Ruminococcus. [0014] In some embodiments, the pharmaceutical composition further comprises a polyphenol preparation. In some embodiments, the polyphenol preparation comprises a plant polyphenol isolated from a plant source material. In some 20 embodiments, the plant source material comprises blueberry, cranberry, grape, peach, plum, pomegranate, soy, red wine, black tea, or green tea. [0015] In some embodiments, the modulating the abundance of a bacterial taxa (e.g., a first and a second bacterial taxa) treats a dysbiosis, e.g., a dysbiosis described herein.
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