WO 2011/024999 Al
Contents
1.2. Sambrook et al Molec ular Oloning
3. ra s erb p 5 9 BCR AB Cp G CpG
4. WO 2011 024999 16 PCT JP2010 064715 0045 0046 0047 TT D NED HC L U S
5. DNA
6. CdE EE 5 09 2dm 1 1 m WO 2011 024999 3 PCT JP2010 064715 0009 ool 0 0011 0012 001
7. DNA 0 05 WO 2011 024999 6 PCT JP2010 064715 0023 0024 0025 0026 007 2 DNA
8. p fsa mir 34b c ir 34D C micro RNA 3 4o micro RNA 34 hir 34D C mi ro RNA fsa mir 34D C COMB DNA T Ys CpG D WO 2011 024999 24 PCT JP2010 064715 0088 0089 009 0 009
9. MR TB HASE RR SOGCOSB 5 3 i ii iii ARE iv RE v PETRE RY vi vi i vV d d i
10. 0001 WO 2011 024999 8 PCT JP2010 064715 0032 7 2
11. WO 2011 024999 35 PCT JP2010 064715 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 2m 1 Oml
12. DNA DNA CpG DNAR x FILA WAX FILME clk f CpG6 CpG CpG6 DNA DNA CpG6 DNA WO 2011 024999 23 PCT JP
13. Bs WO 2011 024999 5 PCT JP2010 064715 0018 0019 002 0 0021 092
14. LET A C 2 1 2 WO 20
15. lt lt Som WII RNA cDNA lt WO 2011 024999 22 PCT JP2010 064715 0069 007
16. 1000m lt 15 Hom 17 90m 20m I CHS O g DNA 2 g DNA 5 g DNA
17. PET 10 PET PET
18. S KRP1 DNA lt S KRP1 DNA 4596 lt S KRP1 DNA 5 9 WO 2011 024999 19 PCT JP2010 064715 067 S KRP2 p NA SKP2 p NA 1096 lt
19. RE DNA 2 0 06 3 998 2 0 02 r 89 6 WS
20. E L lt 1 10 30 11 2010 ISA Jp 100 89153 WR SI 4 3 O3 3581 1101 Am 3252 PCT JP2010 0 64715 c EE EE JP 2007 534404 A
21. U O UU EE RUTZ Dok Zon 3
22. MEDLINE BIOSIS STN JSTPIUS TMEDPIUS TST7580 lllreamll c 1 12 d HABER 1998 56 5 E 117 121 118 12 Hk OF 1 12 TOMIKI Y et al CANCER CELL EXFOLIATION BY PREOPERATIVE COLONOSCOPIC EXAMINATION Digestive Endoscopy 2000 Vol 12 p 327 330 TSUBJECTS AND METHODS Fig 1 MX RESULT E C T Go lt lt
23. NB I lt WO 2011 024999 12 PCT JP2010 064715 0037 0038 0089 0 0
24. lt DNA DT AR DNA
25. 2 0mm S KRP1 DNA 5 9 S KRP2 D INA 09 lt
26. 2 0 11 2 009 6 Ba 5 2 9 8 8 7 3 4 3 6 6 Sai Borman r Bormann 28 Bormann 3 Bormann 4 WO 2011 024999 27 PCT JP2010 064715
27. 5m1 C F260AZI 1cm R WO 2011 024999 30 PCT JP2010 064715 ol 08 ol c9 0110 0111 0112 0113 0114 DNA DNA QAG FNtE O Fpitect bisulfite kit piTect Bisulfite m pllect Bisulfite Handboo kJ TE bisulfite DNA 1 PCR primer S RP1 S RP2 DKK 2 microRNA34b C DNA
28. AFP C A CA 9 9 YVUPILTN lt APC K RAS H RAS N RAS srbB p53 P16 BCR ABL CH R RASS 7 P3 U SRP 773 U MINT 7 7 U MGMT RUNX 7 7 U SMAD7 y U PROM7 732 U 2 38 Bii 4 T BVEKLVTO CMV lt DNA S RP1 S RP2 DKK2 hsa mir 34b c p16INK4A BA RA U gt MLH1 14 3 3 sigma BNIP3 CH R CiiTA JGFBP7 Histone H3K27 H RK
29. lt lt 2m1 Oml lt 3 ml 8ml lt 4m1l 6m1l
30. SFRP1 SFRP2 DKK2 hsa mir 34b c p16lNK4A B KA hMrH1 14 3 3 sigma BH3 Only 7 P BNIP3 JEFF CH R MHC clas 1 IIITA BRA IG BP7 Histone H3K27 HRK CACNA G COX2 D NAR Ras RASS 7 CpG DNA WO 20
31. 0 4 Be 3 3 S r 0 09 lt WO 2011 024999 2 PCT JP2010 064715 0004 0005 0006 0007 0008
32. X WO 2011 024999 4 PCT JP2010 064715 0014 0015 0016 0017 END X P TRA RY 18F P
33. 2 2 WO 2011 024999 28 PCT JP2010 064715 ol 01 ol 02 ol 08 DNA DNA EL amp 2 2 DNA DNA 5 00yp rr 24 g 2 2 8 5 524g 2 DNA 16 53716 8 8 g 7 08y 3 00g 2 DNA DNA DNA
34. NanoDrop ND 1000 t WO 2011 024999 29 PCT JP2010 064715 01 04 01 6 01 06 01 07 2 12 596 33 3 96 lt 2 31 696 61 19 lt 2
35. 0060 p NA 20mm 2 0mm h mir 34b c p NA 59 20mm rnsa mir 34b c p WO 2011 024999 20 PCT JP2010 064715 0061 0062 0063 0064 INA 596 DKK2 DNA 09
36. mir34b c S RP1 S KRP2 DKK2 DNA 596 WO 2011 024999 34 PCT JP2010 064715 0124
37. 2 DNA mir 34b c S RPI S RP2 DKK2 Sensitivity SDecificity AUC R OC Best cut off 5ensitivity specificity 5 20mm 20mm DNA ROC CHS 20mm m ir 34b c ES RP1 DNA ROC
38. ABH WE AUC ROC AUCs F054 ODER 1 0 ROC SEI AIG T 0 ROC WO 2011 024999 25 PCT JP2010 064715 003 X1 Al KRR t EOS RR RER Vo Sp Sing B LUM SD 63 3 pp 047 68 21 24 E S 5 amp 2 18 CES BR h
39. 1 3 1 2 4 3 5 2m Om 4 6 5 7 DNA 6 8 D NA SFRP1 SFRP2 DKK2 hs mir 34b c p161 NK4A B RA FHMLH1 14 3 3 sigma BNIP3 CH R CUTA JGFBP7 H istone H3K27 HRK CACNAIG COX2 D NA5 RASS 27 57x 3 amp ER em D NA 7 9 D NA S RP1 S RP2 DKK2 hs mir 34D C D NA s TO 9
40. 2 0mm nmir 34b c DKK 2 DNA ROC Sensitivity WO 2011 024999 14 PCT JP2010 064715 TES 1 SpeCificity 6 DNA Tumor size 20m lt 2 0mm hiR34b c 15 lt miR34 b c DNA 159 SRPI 51 lt S RP1 DNA 5196 DKK2 1 lt DKK2 DNA 1096 S RP2 10 DS RP2 DNA 1096 Yes No
41. S RP1 DNA 41 2 11 P 0 0043 microRNA34b c DNA 23 38 5 33 P 0 20 S RP1 DNA 32 6 11 P 0 089 ERE microRNA34b c DNA 17 17 JERR CH 33 P 0 OO m mp S RPIOx DNA n 33 39 mp 57 17 P 0 023 0 microRNA34b cC DNA m 15 62 mp 29 36 P 0 0477 micro RNA34b c DNA P lt 0 001 R 0
42. DNA 14 1 8 SFRP1 SFRP2 DKK2 hsa mir 34b c p161NK4A E hMLH1 14 3 3 sigma BNIP3 CHFR CIITA IGFBP7 Histone H3K27 HRK CACNA1G COX2 DFNA5 RASSF2 D N A 1 4 19 SFRP1 SFRP2 DKK2 hsa mir 34b c DN A 2 0 SFRP1 DNA 4596 WO 2011 024999 23 24 25 26 27 28 29 0 31 37 PCT JP2010 064715 4 2 S RP1 p NA 5 4 2 S RP2
43. 4 CYTYC ThinPrep RAE PreservC yt Solution Vials Oml prefilled Box of 50 vials EXBS 0340 LAY UR 5 PRISM version 5 for windows CpG site t 6 ROC mir34b C S RP1 S RP2 DKK2 DNA ROC R4 mir34b C S RP1 S RP2 DKK2 NA 17 89 6 15 339
44. 2007 11 29 US 2005 0261553 A1 amp GB 409474 D amp EP 1740085 A amp wo 2005 117685 Al amp CA 2555180 A amp CN 1905832 A srsp 2005 63 4 5 707 719 pa G 1 Research 2009 08 01 Vol 17 No 4 p 304 311 wo 20071132844 ai JS 2 M SR L 2007 11 22 amp US 2010 0068702 A amp EP 2022861 A1 amp KR 10 2009 0020595 A amp CN 101443462 A PC JP201 07064715 Sh U 1 2 8 3 PCT 17 2 4 1 E 14 33 O 14 33 X
45. pNA 0 6 4 2 S RP2 p NA 3 3 4 2 DKK2 p NA 0 4 2 DKK2 p NA 9 4 2 mir 34b c p NA 5 9 6 4 2 OVINA CE mir 34b c pNA 8 9 4 2 20mm mir 34b c p NA 7
46. 06g DNA bisulfite PCR MS PCR Comb ined bisulfite restriction assay COBRA MS SN P bis ulfite S S CP DMH differential methylation hybr idization MethyLight Pyrosequencin9 061 2 60nm DAPI 4 6 WO 2011 024999 18 PCT JP2010 064715 062 0063 0054 0055 0056 Mupid seme STAIN eye 33258 H33258 Quant iT V N PicoGreen dsDNA Reagent Invitrogen Quant iT RiboGreen ME RNA Reagent Invitrogen Gel Indicator RNA Staining Solution SYBR Green lld SYBR Gold GelRed
47. T nvas ive Cancers Non inva sive tumors Yes Nei No P lt P lt 0 001 0 19 R7 2 DNA DNA mir 34b c S RP1 S RP2 DKK2
48. rr 2 12 REF roue ton SSC L A 73 WO 2011 024999 9 PCT JP2010 064715 4 r5 14 76 4 5 77 e
49. DNA 4 5ml S DTA 0 9 S DS 0 5ml 20mg ml K Coae No 903 5 gm 55 HA UltraPure Buffer Saturated Phenol In vitrogen life technologies 5ml 2700 rpm 4 5 2 2 5m Ambion CatWg 510 O 09 6 9ml 4 C 2 2 7 00 rpm 4 5 7 0 Oom I ERAR 27 00 rpm 4 S3 2 00m I 5X DNA DNA DNA
50. SAPPORO SS SR YAMANO Hiroo JP JP TO101495 MEDICAL UNIVERSITY JP JP T 0600061 54 Title SPECIMEN FOR DETECTING INFILTRATIVE LARGE INTESTINE TUMORS 54 57 Abstract Provided is a method for noninvasively obtaining an index for R1 diagnosing the infiltration or invasive depth of a large intestine tumor The method is characterized in that a specimen by which the infiltrative large intes 1 tine tumor can be detected is obtained by spraying a cleaning solvent onto the target large intestine mucous layer to separate the mucous from said mucous layer and recovering the separated mucous along with the cleaning solvent E 74 81 WO 2011 024999 A IMAN ADA UUN UNU INUNDI TNNT 2 2 2 1 Akita JP
51. py ose quencer DNA primer CpG site K RAS 12 13 K RAS QIAGR KRAS PyroMark K WO 2011 024999 31 PCT JP2010 064715 0115 0116 RAS v2 0 4 x 24 97 0452 PyroMark KRAS v2 O Handboo ki S RP1 S RP2 DKK2 mir34b c DNA S RP1 DNA 52 55 11 P lt 0 001 microRNA34b cC DNA T26 39 5 33 P 0 0007
52. 78 ema Sail Oml 4 7 79 DNA 4 8 20 SFRP1 SFRP2 DKK2 hs mir 34b c p16INK4A BA RA nMLHi 14 3 3 sigma BNIP3 CH R CUTA 1FBP7 Histone H3K27 HRK CACNA1G COX2 D NA5 RASS DNA 4 9 2 S RP1 S RP2 DKK2 hs mir 34D C DNA 2 0 22 S RP1 DNA 459 6 4 42 2 3 S RP1 DNA 5 r9 WO 2011 024999 10 PCT JP2010 064715 4 42 2 4 S RP2 pNA
53. 15 16 17 18 19 20 21 22 14 1 4 1 5 1 6 2ml 10ml 1 4 gt 1 7
54. 0018 2 2 4 lt 4 8 QC 2 0C lt s 0C 0 8 OC 4 009 PCR NASBA Nucleic Acid Sequence Based Amplification TMA Transcr iption Mediated Amplification LOR Ligase Chain Re action SDA Strand displacement amplification LAMP Loop me diated isothermal amplification 1CAN Isothermal and chimeric pr imer initiated amplification of nucleic acids branched DNA RNase
55. DNA DNA 6 2 0mm Yes 20mm No 9 D NA p N A nmir34b c S RP1 S RP2 DK K2 DNA mir34b c S RP1 S RP2 DNA 396
56. Sei KUZUWA Kiyoshi et ai T 1620067 8 2 1 T amp T Tokyo JP HE 7 AE AG AL AM Ao AT AU AZ BA BB BG BH 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 IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN Mw MX Y MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU 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 ARIPO BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ T n AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MI NL NO PL PT Ro SE SI SK SM TR OAPI BF BJ CF CG CL CM GA GN GQ GW ML MR NE SN TD TG 21 3 L 5 2 a WO 2011 024999 1 PCT JP2010 064715 0001 009 000 B d amp
57. Wash DNA biopsy DNA 959 R Pearson T WO 2011 024999 15 PCT JP2010 064715 0041 0042 0045 L 0044 P 1 SE
58. 2 3 2 3 2 DNA 12 28 P 1 24m8 N 87 15 86 9633 mg N 365 THY ABB AR BE TE SA iA ia K I BO CC Gsm DNA 2 DNA K RAS DNA NT tube
59. 4 2 3 11 20mm mir 34b c pb NA 59 DKK2 pb NA 0 141 M 32 20mm S RP1 p NA 5 9 D2 S KRP2 pb NA 09 4 12 33 4 413 2 WO 2011 024999 11 PCT JP2010 064715 0083 0034 0085 0056
60. AFP C A CA19 9 Tn ra s erbB p53 BCR AB lt 1
61. S KP2 p NA 3396 008 DKK2 p NA lt DKK2 p NA 1096 lt DKK2 p NA 119 009 mir 34b c p NA nmir 34b c p NA 596 mir 34b c p NA s 9
62. primer mir 34b c DNA 2 DNA 3 DNA S KRP1 4 DNA 5 DNA 7 DNA S KRP2 8 DNA 9 DNA 10 DNA DKK2 11 DNA 12 DNA 13 14 DNA PCR assay genaturation step ODC 30 annealing ste p 60C 30 extension step 72 C 30 50
63. 0 4 42 2 5 S RP2 pb NA 3 3 4 42 26 DKK2 pNA 09 6 1 4 2 1 27 DKK2 pb NA 9 141 2 2 s mir 34Db c pNA 59 6 4 2 29 mir 34b c pb NA 8 9 141 412 3 0 20mm mir 34b c pNA 59 6
64. CACNA1G C 2 D NAD RASS DNA PBS K WO 2011 024999 17 PCT JP2010 064715 Chomczynski P Sacchi N Anal Biochem 162 156 159 1987 4 20G 10 20 lt 29
65. 0099 ol 00 Nik TNM 3 9 om 5m 1 om AK 4 6 NT tube 5m 2 om 1 1 om 2 2 37 A
66. 4 5 DNA 6 DNA S RP1 S RP2 DKK2 nsa mir 34b c pl 6INK4A BH KA UY HMLH1 14 3 3 sigma BNIP3 CH R CUTA IGFBP7 Histone H3K27 HRK CACNA1G COX2 D NA5 RASSF2 DNA 7 DNA S RP1 S RP2Z DKK2 nsa mir 34b c7 5 DNA s 9 2 0 g DNA WO 2011 024999 36 PCT JP2010 064715 13 14
67. B RN 0 1500rpm 0 21 5 15 10 47 6 0 W 4 26 6 Ni 2 2 o Method 1 Method 2 adenoca rcinoma
68. PCT 17 2 a G PCT 39 1Gv 2 J aW Ai ASS TERNA U OR 3 p Hou PCT 6 4 a 2 3 IT 1 3 1 r O AMA HEA
69. 10 Name and mailing address of the ISA Authorized office r Japanese Patent Office Facsimile No Telephone No International application No PCT JP2010 064715 INTERNATIONAL SEARCH REPORT C Contmuation DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document with indication where appropriate of the relevant passages Relevant to claim No X JP 2007 534404 A UCL Biomedica PLC 13 29 November 2007 29 11 2007 claims drawings US 2005 0261553 Al amp GB 409474 D EP 1740085 A amp WO 2005 117685 A1 CA 2555180 A amp CN 1905832 A A SUZUKI et al Atarashii Daicho Gan Yokusei 1 313 Idenshi SFRP Japanese Journal of Clinical Medicine 2005 vol 63 no 4 pages 707 to 719 A FUJII et al Kaiyosei Daichoen ni Okeru DNA 1 13 Methyl ka wa Hatsugen no Bunshi Marker to Narieru ka G I Research 01 August 2009 01 08 2009 vol 17 no 4 pages 304 to 311 A WO 2007 132844 Al Sapporo Medical University 1 13 22 November 2007 22 11 2007 amp US 2010 0068702 A amp EP 2022861 Al amp KR 10 2009 0020595 A amp CN 101443462 A INTERNATIO NAL SEARCH REPORT International application No PCT JP2010 064715 Box No II Observations where certain claims were found unsearchable Continuation of item 2 of first sheet This international search report has not been established m respect of certain claims under Article 17 2 a for the following reasons 1 X1 Claims Nos 1
70. 4296 0 1 000 3 K RAS 4 2 77 79 K R AS K RAS WO 2011 024999 32 PCT JP2010 064715 0117 0118 0119 012 0 0121 3 hyperplastic polyp adenoma early cancer protruded type 0 I gt Jilat type I Ia LST depressed type I Ic y 1I Ia I Io Parly sancer submucos al yer AdVvaced cance r borrmann R WHO
71. 80 prese pee Se S 7 0 A SA gt e D Be X aod t CA Rat 2 22 rniR 34t c ES RE eege NS P 0 0501 ESTAFA 3100 t 3482 a04 zx SX TTE nas 804 HE e e S K Put SS gt SFRP1 TS ipai Tar EN LO gt D ES 40 E 20 D o Q methylation o o T Ven II S ROOD T d o s Bo Z sets D SFRP2 D ats ae 40 EN Kb sais tuo Ze ey L 20 ton Kei We ei 100 DKKZ methylation iC NI N 98 N 187 Siopsy samples Normal PCT JP2010 064715 PLORI NS ce 5 ros gt DN Pagg PxQ 801 D kd LN s k D WE LES E Ka ett ef es e H See X De t eee IC NI Normal N 36 N 34 N 6 Washing fluids WO 2011 024999 4 4 sensitivity sensitivity sensitivity D 0 8 CH a e 3 e 4 6 miR34b c 0 2 Specificity 0 765 3 06 8 op PCT JP2010 064715 SFRP1 Ka E AUC 0 796 04 AUG 0 736 Best cut off 17 8 S Best cut off 45 096 Sensitivity 0 833 7 amp 2 Sensitivity 0 750 a4 68 Q8 1 specificity SFRP2 Specificity 0 765 d Specificity 0 708 o e LA 04 08 08 1 i specificity DKK2 Z 08 E AUC 0 688 04 AUC 0 702 Best cut off 33 0 o i Beat cutoff 11 0 Sensitivity 0 583 9 2 Sensitivity 0 805 03 06 Q8 t 1 specificity SIZE lt 20mm mi
72. m 16 E H Rt SE HLS 1 Sp rng Bormann 1 Bormann 2 1 Bormann 34 Bormann 148 t 0 t BSKT Z wt BEY SI H ZI LO EN Kaf ung AKR TR mR DEER SA TARA i i H ISO X 20mm S 10 7 2 9 0mmni A t D 0094 22 ERC E RARA ER TO RU S DNA EEN EE ALIE E H 37 8 RER UA 1 ER TAR PR MALR 2 SR Sg ES MUS 2 Em ES EES DNAS 21284 18 17 08x 18 3 GEN 4552 nm 130 1688 NT SSES 2 pro 17 uod amp RAR i eu 20 18 oi po RAR i E ER ES BT Ride 182 31 12 5 33 3X 45 9 31 6 BF 1 SO S WO 2011 024999 26 PCT JP2010 064715 0095 0096 0097 0005 X3 RF EREMOSR LAR zt LUELLA RSE AR DE RO e 2 E EE i 28 FAR HER ag MAM vg E Sa BA a SS to se sl sg 52 98 187 x6 M 6 674 667 L 672 68 6397 61 67 TT 5 20M 4 WU 126 XS x A de 36 BLE 9 Moa 3 BROAS 20mmd 9 Tin om dk eM MEM amp 20mm 43 21 28 Bo Weg RER 15 ss o xis e te RARE Oa OM BERERE 25 7 AROS 0 070 H LM i L 82 36 4 BA L ERA 2EES BR 9 6 g 14 SRNR 2 7 2 8 kE Ok 33 62
73. 0 0071 0072 0073 0074 0075 0976 0077 _WRIEBRTCH ITE MSMOKRBICBES LC LMC E ELKRBORR BBE REGEBIEXABSEGEEHIO RBA BEE ORKA A DNA DNA
74. 1 0092 CpG e DNA R A G Sg NR A R NIF G KOC Receiver Opera ting Characteristic CUrve ROC ROC SE sensitivity 1 BRE Specificity 1
75. 11 024999 13 PCT JP2010 064715 3 DNA miR 34bD c S RP1 S RP2 DKK2 CpG DNA Biopsy samples Wash ing fuids NI N Oma D N NS P lt P lt 0 0001 0 019 4 ROC Receiver Operating Characteristic Cmrve ROC
76. 11 024999 7 PCT JP2010 064715 098 DNA ah 0 9 1 Ahlquist DA et al Gastroenterology 2000 Nov 119 5 12 19 27 2 0sborn NK st al Gastroenterology 200b Jan3128 1 192 26 OBO
77. 2010 064715 0078 0079 00 0 00 1 002 003 00 4 005 00 6 007 CpG DNA DNA CcG X DNA DNA RES MBA CSS LUC UU LST S 2 SHRM
78. 4 33 because they relate to subject matter not required to be searched by this Authority namely Claims 14 33 involves a step of spraying a cleaning liquid onto the raucous liquid layer ofa large intestine and removing the mucous liquid and therefore pertain to method for surgery of the human body continued to extra sheet ie L Claims Nos because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out specifically 3 L_I Claims Nos because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6 4 a Box No Ill Observations where unity of invention is lacking Continuation of item 3 of first sheet This International Searching Authority found multiple inventions in this international application as follows L_I Asall required additional search fees were timely paid by the applicant this international search report covers all searchable claims emm LI As all searchable claims could be searched without effort justifying additional fees this Authority did not invite payment of additional fees nn L_I Asonly some of the required additional search fees were timely paid by the applicant this international search report covers only those claims for which fees were paid specifically claims Nos j E No required additional search fccs wer
79. 5 lt 3 59
80. 5 96 4 m 20mm WO 2011 024999 38 PCT JP2010 064715 32 33 mir 34b c p NA 59 DKK2 p NA 7 09 6 4 2 ROA 20mm S RP1 pb NA 5 9 S RP2 pNA 09 6 4 2 ROA 4 3 2 1 6 PCT JP2010 064715 WO 2011 024999 1 2 6 WO 2011 024999 2 2 1 BRE 2 PCT JP2010 064715 3 6 WO 2011 024999 3 3 NS Sep mm
81. 6 119 7 20mm 2 0mm ROC WO 2011 024999 33 PCT JP2010 064715 0122 0125 20mm 20mm ROC 5 2 0mm mir 34b c S KRP1 DNA ROC 5 20mm mir 34b c DKK2 D NA ROC 5 2 Omm miR34b S RP D NA lt 2 0mm miR34b c DKK2 D NA 8
82. A Laboratory Manual 2nd ed Old Spring Harb WO 2011 024999 21 PCT JP2010 064715 0055 0056 L 0057 L 0655 or Laboratory Press 1989 Sambrook et al Molecular Cloni n9 A Laboratory Manual 3rd ed Qld Sp rns Harbor Press 2 00 Ausubel t al Qrrent Protocols in Molecular Biology Greene Publishing Associates 1992 2 000 Ausubel al Short Protocols in Molecular Biology A Compendium of Methods from COrrent Protocols in Molecular Biology 4th Ed Wiley Sons 1999 Harlow and Lane Antibodies A Laborato ry Manual Old Spring Harbor Laboratory Press 199 0 Harl ow andIane Using Antibodies A Laboratory Manual Qld Sprin g Harbor LaboratoryPress 1999 7x
83. SUL IX I Further documents are listed in the continuation of Box C LJ See patent inily annex Special categories of cited documents g later document published after the international filing date or ponty document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention earlier application or patent but published on or after the international X document of particular relevance the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim s or which is step when the document is taken alone cited to establish the publication date of another citation or other d document of particular relevance the claimed invention cannot be special reason as specified considered to involve an inventive step when the document is document referring to an oral disclosure use exhibition or other means combined with one or more other such documents such combination document published prior to the international filing date but later than being obvious to a person skilled in the art the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 10 November 2010 10 11 10 30 November 2010 30 11
84. UBJECT MATTER GOIN33 50 2006 01 A6IB1 00 2006 01 i C12M3 00 2006 01 i C1201 02 2006 0 i C1201 68 2006 01 i According to International Patent Classification IPC or to both national classification and IPC B FIELDS SEARCHED Minimum documentation searched classification system followed by classification symbols G01N33 50 A61BI 00 C12M3 00 C12QI 02 C12Q1 68 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Jitsuyo Shinan Koho 1922 1996 Jitsuyo Shinan Toroku Koho 1996 2010 Kokai Jitsuyo Shinan Koho 1971 2010 Toroku Jitsuyo Shinan Koho 1994 2010 Electronic data base consulted during the international search name of data base and where practicable search terms used MEDLINE BIOSIS STN JSTPlus JMEDPlus JST758 0 JDreamll C DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document with indication where appropriate of the relevant passages Relevant to claim No X ISHIBASHI et al Determining the telomerase 1 12 activity of exfoliated cells in intestinal lavage solution to detect colorectal carcinoma Japanese Journal of Clinical Medicine 1998 vol 56 no 5 pages 117 to 121 page 118 2 method X TOMIKI Y et al CANCER CELL EXFOLIATION BY 1 12 PREOPERATIVE COLONOSCOPIC EXAMINATION Digestive Endoscopy 2000 Vol 12 p 327 330 SUBJECTS AND METHODS fig 1 RE
85. d 34b c mame SERPA D ode GE 0 04 08 08 1 specificity sensitivity 0 04 G6 08 1 e e N 1 specificity SIZE 20mms miR34b c DKK 1 specificity 5 6 WO 2011 024999 PCT JP2010 064715 6 6 N Test Yes postive No iC negative P value N 38 Jl miR34b c 1595 AP Yes 25 28 Notes Nz10 No 410 Dkk2 10 lt L za gt m N 68 s Pz0 005 Ko nig Tumor size e E 20mms P 0 005 Yes 29 38 No 6 31 N 8 P 0 001 Z 8 SFRP2 10 lt R ped Yes 5 6 PESCE Ps0 035 No 1 23 Pz0 002 6 6 WO 2011 024999 PCT JP2010 064715 E07 7 IC Ni Ps 9221 so P 0 4307 R 0 2728 R 009419 H biopsy Pz0 2160 Rz0 2423 L ae D de art eaor e cepe Sa ez D hiopsy biopsy biopsy SFRP2 ao Peti 0340 F 0 2645 R 0 1888 S Zeg a A eek np rev ech 2 Errar wa race t aa ert E ei m Ree 29 40 s 89 op Siapay 804 P0024 nog P 0 0834 894 Hat D R 0 2285 R 0 2382 Rd 2417 E s 9 S 49 x as e E 42 40 ef 7 2 ae E x adi 3 A Qs MA a 29 m a 20 pa nin a A E A E gi ri E n ez e l rt e wr Sa an 80 0 100 Oo biopsy 20 30 Sp 80 199 biopsy INTERNATIONAL SEARCH REPORT International application No PCT JP2010 064715 A CLASSIFICATION OF S
86. e timely paid by the apphcant Consequently this international search report is restricted to the invention first mentioned in the claims it is covered by claims Nos Remark on Protest ISS The additional search fees were accompanied by the applicant s protest and where applicable the payment of a protest fee The additional search fees were accompanied by the applicant s protest but the applicable protest fee was not paid within the time limit specified in the invitation L1 No protest accompanied the payment of additional search fees INTERNATIONAL SEARCH REPORT International application No PCT JP2010 064715 Continuation of Box No II 1 of continuation of first sheet 2 and thus relate to a subject matter on which this International Searching Authority is not required to carry out a search under the provisions of PCT Article 17 2 a i and PCT Rule 39 1 iv PCT JP2010 0647153 IPC IntCl GOIN33 50 2006 01 i A61B1 00 2006 01 i C12M3 00 2006 01 1 C12Q1 02 2006 01 i C12Q1 68 2006 01 i B IPC IntCl G01N33 50 A61B1 00 C12M3 00 C12Q1 02 C12Q1 68 co
87. wo 2011 024999 A1 Ibai 12 19 G lnii inni piin bnn 10 43 2011 3 3 03 03 2011 WO 2011 024999 Al 51 1 17T 29 1 GOIN 33 50 2006 01 C120 1 02 2006 01 Hokkaido JP A61B 1 00 2006 01 C120 1 68 2006 01 72 CO ND 5 BAS QD PCT JP20 10 0647 15 TOYOTA Minoru JP JP T0608556 1 17T B 22 2010 8 30 30 08 2010 Hokkaido JP YAMAMOTO Eiichiro Q5 JP JP 0608556 1 pes Be 17T B HoKKaido JP 26 IE KAMIMAE Seiko JP JP T0608556 30 MS Se B 61 238 106 2009 8 28 28 08 2009 US F Hokkaido JP 8 5 SUZUKI Hiromu B JP JP T 0608556 1 71 HERA lt 17T BH HoKKaido JP
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