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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 5 November 2015 (05.11.2015) P O PCT (51) International Patent Classification: C12Q 1/02 (2006.0 1) C12Q 1/04 (2006.0 1) A61B 5/00 (2006.01) C12Q 1/68 (2006.01) A61K 35/66 (2015.01) G01N 33/68 (2006.01) A61K 35/741 (2015.01) (21) International Application Number: PCT/IL20 15/050442 (22) International Filing Date: 28 April 2015 (28.04.2015) (25) Filing Language: English WO 2015/166492 A3 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (30) Priority Data: TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 61/984,944 28 April 2014 (28.04.2014) US TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 62/048,065 9 September 2014 (09.09.2014) US DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 62/050,939 16 September 2014 (16.09.2014) US LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicant: YEDA RESEARCH AND DEVELOPMENT SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, CO. LTD. [IL/IL]; at the Weizmann Institute of Science, GW, KM, ML, MR, NE, SN, TD, TG). P.O. Box 95, 7610002 Rehovot (IL). Declarations under Rule 4.17 : (72) Inventors: ELINAV, Eran; 16 HaGefen Street, 7680400 — of inventorship (Rule 4. 1 7(iv)) Mazkeret Batia (IL). SEGAL, Eran; 40 Nachshon Street, 4730168 Ramat-HaSharon (IL). Published: (26) Publication Language: English (74) Agents: G. E. EHRLICH (1995) LTD. et al; 11 Menachem Begin Road, 5268 104 Ramat Gan (IL). — with international search report (Art. 21(3)) [Continued on next page] (54) Title: MICROBIOME RESPONSE TO AGENTS (57) Abstract: A method of determining tolerance to an agent in a healthy subject is disclosed. The method comprises: (a) determining a signature of a microbiome in a sample of the healthy subject who has been subjected to the agent or condition; and (b) comparing the signature of the microbiome of the healthy subject to at least one reference signa ture of a pathological microbiome, wherein when the signature of the microbiome of the healthy sub ject is statistically significantly similar to the refer ence signature of the pathological microbiome, it is indicative that the healthy subject is intolerant to the agent. < o o before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) with sequence listing part of description (Rule 5.2(a)) (88) Date of publication of the international search report: 23 December 2015 A . CLASSIFICATION INV. O F SUBJECT MATTER A61B5/00 G01N33/68 C12Q1/02 C12Q1/68 A61K35/66 A61K35/741 C12Q1/04 ADD. According to International Patent Classification (IPC) o r t o both national classification and IPC B . FIELDS SEARCHED Minimum documentation G06F C12Q Documentation Electronic searched searched C . DOCUMENTS Category* system followed during the international WPI CONSIDERED Citation of document, by classification symbols) G01N other than minimum documentation data base consulted EPO-Internal , (classification A61K A61B to the extent that such documents are included search (name of data base and, where practicable, Data, BIOSIS, COMPENDEX, in the fields searched search terms used) FSTA, INSPEC EMBASE, T O B E RELEVANT with indication, where appropriate, of the relevant passages Relevant to claim No. A. N. PAYNE ET AL: "Gut mi crobi al adaptati on t o di etary consumpti on of fructose, arti f i ci al sweeteners and sugar al cohol s : impl i cati ons for host-mi crobe i nteracti ons contri buti ng t o obesi ty" , OBESITY REVI EWS, vol . 13 , no. 9 , 1 1 June 2012 (2012-06-11) pages 799-809 , XP055205060, ISSN : 1467-7881 , DOI : 10. 1111/J . 1467-789X. 2012 . 01009 . x ci ted i n the appl i cati on the whol e document abstract tabl e 3 on page 803 page 803 , l eft col umn , l ast paragraph r i ght col umn , l ast paragraph page 807 , l eft col umn 1-50 , - -/X| Further documents * Special categories are listed in the continuation of cited documents of Box C . : "A" document defining the general state of the art which is not considered to be of particular relevance "E" earlier application filing date o r patent but published o n o r after the international "L" documentwhich may throw doubts o n priority claim(s) orwhich is cited to establish the publication date of another citation o r other special reason (as specified) "O" document means referring to a n oral disclosure, use, exhibition o r other "P" document published prior to the international the priority date claimed filing date but later than Date of the actual completion search of the international "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand the principle o r theory underlying the invention "X" document of particular relevance; the claimed invention cannot be considered novel o r cannot b e considered to involve a n inventive step when the document is taken alone "Y" document of particular relevance; the claimed invention cannot be considered to involve a n inventive step when the document is combined with one o r more other such documents, such combination being obvious to a person skilled in the art "&" document search report 20/10/2015 of the ISA/ European Patent Office, P.B. 5818 Patentlaan N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 member of the same patent family Date of mailing of the international 10 August 2015 Name and mailing address See patent family annex. Authorized officer 2 Gal 1-Truchot, A C(Continuation). Category* X DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant passages THERESA E COWAN ET AL: "Arti f i c i a l sweetener consumpti on d i fferenti al l y affects the gut mi crobi ota-host metabol i c i nteracti ons - - Cowan et a l . 27 (1) : 224. 7 - - The FASEB Journal " , Relevant to claim No. 1 , 5 ,6, 8-14, 19 , 22 ,24, 25 ,27 , 39 ,44,45 THE FASEB JOURNAL, vol . 27 , 1 Apri l 2013 (2013-04-01) 224. 7 , XP055205066, ISSN : 0892-6638 c i ted i n the appl i cati on the whol e document Y , page 2010/172874 Al (TURNBAUGH PETER J [US] 8 July 2010 (2010-07-08) c i ted i n the appl i cati on the whol e document abstract c l aims 18, 23 page 19 , paragraph 94 - page 20, paragraph 99 exampl e 2 , pages 22-23 c l aim 2 1 20,21 TH0MPS0N-CHAG0YAN 0 C ET AL: " Faecal mi crobi ota and short-chai n fatty aci d 1 ,6,7 , 1 1 , 12 , 14-18, 24-26, 39-45 US ET AL) X l evel s i n faeces from i nfants wi t h cow ' s mi l k protei n a l l ergy" , INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY, KARGER AG, CH , Y vol . 156, no. 3 , 1 January 2011 (2011-01-01) , pages 325-332 , XP009166971 , ISSN : 1018-2438 the whol e document abstract sentence bri dgi ng pages 325-326 page 327 , l eft col umn , l ast paragraph r i ght col umn , thi r d paragraph : " FISH of bacteri a l cel l s " page 327 , r i ght col umn , l ast paragraph : "Determi nati on of Faecal SCFA" page 328, r i ght col umn , paragraph 2 "Bacteri a l Counts ( FISH-FC) " and tabl e 3 on page 328 page 328, r i ght col umn , l ast paragraph page 329 , r i ght col umn , l ast paragraph and tabl e 4 on page 330 -/-- 20,21 C(Continuation). Category* X, P X, P DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant passages AL: "The rol e of commensal bacteri a i n the regul ati on of sensi t i zati on t o food a l l ergens" , FEBS LETTERS, ELSEVI ER, AMSTERDAM, NL, vol . 588, no. 22 , 1 May 2014 (2014-05-01) pages 4258-4266, XP029083055 , ISSN : 0014-5793 , D0I : 10. 1016/J . FEBSLET.2014.04.026 the whol e document Relevant to claim No. 1 ,5-22 , 24-27 , 39-45 CAO SEVERINE ET , J0THAM SUEZ ET AL: "Arti f i c i a l sweeteners i nduce g l ucose i ntol erance by a l teri ng the gut mi crobi ota" , 1 ,5-22 , 24-27 , 39-45 NATURE, 17 September 2014 (2014-09-17) , XP055205484, ISSN : 0028-0836, D0I : 10. 1038/naturel3793 the whol e document X, P SUEZ J ET AL: "Non-cal ori c arti f i c i a l sweeteners and the mi crobi ome: Fi ndi ngs and chal l enges" , GUT MICROBES 20150401 TAYLOR AND FRANCIS INC. USA, vol . 6 , no. 2 , 1 Apri l 2015 (2015-04-01) , pages 149-155 , XP008177160, ISSN : 1949-0976, D0I : 10. 1080/19490976.2015 . 1017700 the whol e document 1 ,5-22 , 24-27 , 39-45 X, P MARI E S. A. PALMNAS ET AL: 1 , 5 ,6, 8-10, 13 , 14,24, 25 ,39 " Low-Dose Aspartame Consumpti on Di fferenti al l y Affects Gut Mi crobi ota-Host Metabol i c Interacti ons i n the Di et-Induced Obese Rat" , PL0S ONE, vol . 9 , no. 10, 14 October 2014 (2014-10-14) , page el09841 , XP055205532 , D0I : 10. 1371/journal .pone. 0109841 the whol e document X, P THAISS CHRIST0PH A ET AL: "Transki ngdom Control of Mi crobi ota Di urnal Osci l l ati ons Promotes Metabol i c Homeostasi s " , CELL, CELL PRESS, US, vol . 159 , no. 3 , 16 October 2014 (2014-10-16) , pages 514-529 , XP029084863 , ISSN : 0092-8674, D0I : 10. 1016/J . CELL.2014.09 .048 the whol e document -/-- 1, 5 , 7 , 1 1 , 12 , 14-21 , 24-26, 39-45 C(Continuation). Category* DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document, with indication, where appropriate, of the relevant passages THAISS C A ET AL: " A day i n the l i f e of the meta-organi sm: Di urnal rhythms of the i ntesti nal mi crobi ome and i t s host" , GUT MICROBES 20150422 TAYLOR AND FRANCIS INC. USA, vol . 6 , no. 2 , 22 Apri l 2015 (2015-04-22) , pages 137-142 , XP008177161 , ISSN : 1949-0976, D0I : 10. 1080/19490976.2015 . 1016690 the whol e document Relevant to claim No. I ,5,7, I I , 12 , 14-21 , 24-26, 39-45 International INTERNATIONAL SEARCH REPORT Box No. II search report has not been established in respect o f certain claims under Article (2) (a) for the following reasons: Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: 23, 38 Claims Nos.: because they relate to parts of the international application that d o not comply with the prescribed an extent that n o meaningful international search can be carried out, specifically: FURTHER INFORMATION □ Claims Nos.: because they are dependent Box No. Ill requirements to such sheet PCT/ISA/21Q claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Observations where unity of invention is lacking (Continuation of item 3 of first sheet) This International Searching Authority found multiple inventions see addi tional 1. 1 No. Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international □ application PCT/I L2015/05Q442 in this international application, as follows: sheet As all required additional search fees were timely paid by the applicant, this international search report covers all searchable ' claims. 2. I I As all searchable claims could be searched without effort justifying a n additional fees, this Authority did not invite payment o f additional fees. ' As only some o f the required additional search fees were timely paid by the applicant, this international ' only those claims for which fees were paid, specifically claims Nos. : I I No required additional search fees were timely paid by the applicant. Consequently, this international restricted to the invention first mentioned in the claims; it is covered by claims Nos.: 1, 5 , 22-27, 39-45 (completely) Remark on Protest search report is ly) ' The additional search fees were accompanied ' payment o f a protest fee. ' The additional search fees were accompanied by the applicant's protest but the applicable ' fee was not paid within the time limit specified in the invitation. I INo protest Form PCT/ISA/21 0 (continuation ; 6-21(partial search report covers accompanied of first sheet (2)) (April 2005) by the applicant's protest and, where applicable, the the payment o f additional search fees. protest International Application No. FURTHER INFORMATION CONTINUED FROM PCT/ISA/ PCTV I L2015/ 050442 210 Thi s Internati onal Searchi ng Authori t y found mul t i pl e (groups of) i nventi ons i n thi s i nternati onal appl i cati on , a s fol l ows : 1. cl aims : 1, 5 , 22-27 , 39-45 (compl etely) ; 6-21 (parti al ly) methods of determi ni ng tol erance t o an agent i n a heal thy subject, based on a si gnature of a mi crobi ome; ki t thereof 2 . cl aims : 2-4(compl etely) ; 6-21 (parti al ly) methods of determi ni ng an effect of an agent on a mi crobi ome 3 . cl aims : 28-38 methods of restori ng the tol erance of a subject t o an agent compri si ng admi ni steri ng a probi oti c or an anti bi oti c composi t i on 4 . cl aims : 46-50 methods of provi di ng an anti bi oti c or probi oti c treatment International FURTHER INFORMATION CONTINUED FROM PCT/ISA/ Application No. PCTV I L2015/ 050442 210 Conti nuati on of Box I I . Cl aims Nos . : 23 , 38 Cl aims 23 and 38 refer t o mi crobes di scl osed i n Tabl e 4 . However, i n the present appl i cati on , Tabl e 4 (on page 125) di spl ays cl i ni cal parameters such a s BMI and wai st-hi p rati o but no mi crobe or mi crobe ' s cl ass i s di scl osed. Therefore, cl aims 23 and 38 are total l y uncl ear and l ack support (Arti cl e s 5 and 6 PCT) . Thi s l ack of cl ari t y was so severe that no search coul d be performed on thei r subject-matter. The appl i cant ' s attenti on i s drawn t o the fact that cl aims rel ati ng t o i nventi ons i n respect of whi ch no i nternati onal search report has been establ i shed need not be the subject of an i nternati onal prel imi nary exami nati on (Rul e 66. 1(e) PCT) . The appl i cant i s advi sed that the EPO pol i cy when acti ng a s an Internati onal Prel imi nary Exami ni ng Authori t y i s normal l y not t o carry out a prel imi nary exami nati on on matter whi ch has not been searched. Thi s i s the case i rrespecti ve of whether or not the cl aims are amended fol l owi ng recei pt of the search report or duri ng any Chapter I I procedure. I f the appl i cati on proceeds i nto the regi onal phase before the EPO, the appl i cant i s remi nded that a search may be carri ed out duri ng exami nati on before the EPO (see EPO Gui del i nes C-IV, 7 .2) , shoul d the probl ems whi ch l ed t o the Arti cl e 17 (2) decl arati on be overcome. Patent document cited in search report US 2010172874 Publication date Al 08-07-2010 Patent family member(s) 2102350 2010172874 2014093478 2008076696 Publication date A2 Al Al A2 23-09-2009 08-07-2010 03-04-2014 26-06-2008