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(12) United States Patent (10) Patent No.: US 9,163,284 B2 Liu Et Al

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(12) United States Patent (10) Patent No.: US 9,163,284 B2 Liu Et Al USOO91 63284B2 (12) United States Patent (10) Patent No.: US 9,163,284 B2 Liu et al. (45) Date of Patent: Oct. 20, 2015 (54) METHODS FOR IDENTIFYING ATARGET 2013,01582.45 A1 6, 2013 Russell et al. SITE OF ACAS9 NUCLEASE 2014, OO17214 A1 1/2014 Cost 2014f0065711 A1 3/2014 Liu et al. 2014.0068797 A1 3/2014 Doudna et al. (71) Applicant: President and Fellows of Harvard 2014/O127752 A1 5, 2014 Zhou et al. College, Cambridge, MA (US) 2014/0234289 A1* 8, 2014 Liu et al. .................... 424/94.61 2014/0273O37 A1 9, 2014 Wu (72) Inventors: David R. Liu, Lexington, MA (US); 2014/0273226 A1 9, 2014 Wu Vikram Pattanayak, Cambridge, MA 2014/0273230 A1 9/2014 Chen et al. 2014/0295556 A1 10/2014 Joung et al. (US) 2014/03494.00 A1 11/2014 Jakimo et al. 2014/0356867 A1 12/2014 Peter et al. (73) Assignee: President and Fellows of Harvard 2014/0357523 A1 12/2014 Zeiner et al. College, Cambridge, MA (US) 2015, 0010526 A1 1/2015 Liu et al. (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 AU 2012244264 11, 2012 U.S.C. 154(b) by 0 days. CN 103233028 A 8, 2013 CN 103388006 A 11, 2013 (21) Appl. No.: 14/320,370 CN 103614415 A 3, 2014 CN 103.642836 A 3, 2014 (22) Filed: Jun. 30, 2014 CN 103668472 A 3, 2014 CN 103820441 A 5, 2014 (65) Prior Publication Data CN 103820454. A 5, 2014 CN 10391 1376. A T 2014 US 2015/OO44191A1 Feb. 12, 2015 CN 103923.911 A T 2014 CN 104004778 A 8, 2014 CN 104.109687. A 10/2014 Related U.S. Application Data CN 104178461 A 12/2014 WO WO 2007/O2SO97 A2 3, 2007 (60) Provisional application No. 61/864.289, filed on Aug. WO WO 2007.136815 A2 11/2007 9, 2013. WO WO 2007 143574 A1 12/2007 WO WO 2009,134808 A2 11/2009 (51) Int. Cl. WO WO 2010/054108 A2 5, 2010 CI2O I/68 (2006.01) WO WO 2010/0541.54 A2 5, 2010 CI2N 9/22 (2006.01) WO WO 2010.075424 A2 T 2010 (52) U.S. Cl. WO WO 2010, 129023 A2 11/2010 CPC ................ CI2O I/6874 (2013.01); C12N 9/22 (Continued) (2013.01) (58) Field of Classification Search OTHER PUBLICATIONS None See application file for complete search history. Guilanger et al. (Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification, Nature (56) References Cited Biotech., col. 32, No. 6, pp. 577-583, Apr. 25, 2014).* (Continued) U.S. PATENT DOCUMENTS 6,453,242 B1 9/2002 Eisenberg et al. 6,503,717 B2 1/2003 Case et al. Primary Examiner — Stephanie K Mummert 6,534,261 B1 3/2003 Cox, III et al. 6,599,692 B1 7/2003 Case et al. Assistant Examiner — Aaron Priest 6,607,882 B1 8/2003 Cox, III et al. 6,824,978 B1 1 1/2004 Cox, III et al. (74) Attorney, Agent, or Firm — Wolf, Greenfield & Sacks, 6,933,113 B2 8, 2005 Case et al. P.C. 6,979,539 B2 12/2005 Cox, III et al. 7,013,219 B2 3, 2006 Case et al. 7,163,824 B2 1/2007 Cox, III et al. (57) ABSTRACT 7.919,277 B2 4/2011 Russell et al. 8,361,725 B2 1/2013 Russell et al. Some aspects of this disclosure provide Strategies, methods, 8,546,553 B2 10/2013 Terns et al. 8,680,069 B2 3/2014 de Fougerolles et al. and reagents for determining nuclease target site preferences 8,697.359 B1 * 4/2014 Zhang ............................ 435, 6.1 and specificity of site-specific endonucleases. Some methods 8,846,578 B2 9/2014 McCray et al. provided herein utilize a novel “one-cut’ strategy for screen 2008/O124725 A1 5/2008 Barrangou et al. 2008. O1822.54 A1 7/2008 Hall et al. ing a library of concatemers comprising repeat units of can 2009,0130718 A1 5, 2009 Short didate nuclease target sites and constant insert regions to 2010/0076057 A1 3/2010 Sontheimer et al. identify library members that can been cut by a nuclease of 2010/0093617 A1 4/2010 Barrangou et al. interest via sequencing of an intact target site adjacent and 2010, 0104690 A1 4/2010 Barrangou et al. 2011/O189776 A1 8, 2011 Terns et al. identical to a cut target site. 2011/0217739 A1 9, 2011 Terns et al. 2012fO141523 A1 6/2012 Castado et al. 2013,0130248 A1 5, 2013 Haurwitz et al. 24 Claims, 55 Drawing Sheets US 9,163.284 B2 Page 2 (56) References Cited WO WO 2014/099744 A1 6, 2014 WO WO 2014/O99750 A2 6, 2014 FOREIGN PATENT DOCUMENTS WO WO 2014/113493 A1 T 2014 WO WO 2014/124226 A1 8, 2014 WO WO 2011/O17293 A2 2, 2011 WO WO 2014f127287 A1 8, 2014 WO WO 2011/O53982 A2 5, 2011 WO WO 2014, 128659 A1 8, 2014 WO WO 2012/O54726 A1 4/2012 WO WO 2014f130955 A1 8, 2014 WO WO 2012/1389.27 A2 10, 2012 WO WO 2014f131833 A1 9, 2014 WO WO 2012/158985 A2 11/2012 WO WO 2014, 143381 A1 9, 2014 WO WO 2012/158986 A2 11/2012 WO WO 2014, 144094 A1 9, 2014 WO WO 2012, 164565 A1 12/2012 WO WO 2014f1441:55 A1 9, 2014 WO WO 2013/O12674 A1 1, 2013 WO WO 2014, 144288 A1 9, 2014 WO WO 2013,066438 A2 5, 2013 WO WO 2014, 144592 A2 9, 2014 WO WO2O13066438 A2 * 5, 2013 WO WO 2014, 144761 A2 9, 2014 WO WO 2013,098244 A1 T 2013 WO WO 2014f145599 A2 9, 2014 WO WO 2013/126794 A1 8, 2013 WO WO 2014/150624 A1 9, 2014 WO WO 2013, 130824 A1 9, 2013 WO WO 2014/152432 A2 9, 2014 WO WO 2013/141680 A1 9, 2013 WO WO 2014/153470 A2 9, 2014 WO WO 2013, 142378 A9 9, 2013 WO WO 2014, 164466 A1 10/2014 WO WO 2013, 142578 A2 9, 2013 WO WO 2014, 165349 A1 10/2014 WO WO 2013, 169398 A2 11/2013 WO WO 2014, 165825 A2 10/2014 WO WO 2013, 1698O2 A1 11, 2013 WO WO 2014, 172458 A1 10/2014 WO WO 2013, 176772 A2 11/2013 WO WO 2014f172470 A 10, 2014 WO WO 2013, 176915 A1 11/2013 WO WO 2014, 182700 A1 11, 2014 WO WO 2013, 17691.6 A1 11, 2013 WO WO 2014, 184143 A1 11, 2014 WO WO 2013, 181440 A1 12/2013 WO WO 2014, 184741 A1 11, 2014 WO WO 2013, 186754 A2 12/2013 WO WO 2014, 184744 A1 11, 2014 WO WO 2013, 188037 A2 12/2013 WO WO 2014, 186585 A2 11/2014 WO WO 2013, 188522 A2 12/2013 WO WO 2014, 186686 A2 11/2014 WO WO 2013, 188638 A2 12/2013 WO WO 2014, 190181 A1 11, 2014 WO WO 2014/O11237 A1 1, 2014 WO WO 2014, 191128 A1 12/2014 WO WO 2014/011901 A2 1, 2014 WO WO 2014, 191518 A1 12/2014 WO WO 2014/O18423 A2 1, 2014 WO WO 2014, 191521 A2 12/2014 WO WO 2014/022120 A1 2, 2014 WO WO 2014, 191525 A1 12/2014 WO WO 2014/0227 O2 A2 2, 2014 WO WO 2014, 191527 A1 12/2014 WO WO 2014/036219 A2 3, 2014 WO WO 2014, 197568 A2 12/2014 WO WO 2014/0395.13 A2 3, 2014 WO WO 2014, 197748 A2 12/2014 WO WO 2014/O39523 A1 3, 2014 WO WO 2014/039684 A1 3f2014 OTHER PUBLICATIONS WO WO 2014/0396.92 A2 3, 2014 M WO WO 2014/O397O2 A2 3, 2014 Pattanayak et al. (Revealing off-target cleavage specificities of zinc WO WO 2014/039872 A1 3, 2014 finger nucleases by in vitro selection, Nature Methods, vol. 8, No. 9. WO WO 2014/O3997O A1 3, 2014 pp. 765-770, Aug. 11, 2011).* WO WO 2014/041327 A1 3, 2014 WO WO 2014/043143 A1 3, 2014 Jinek et al. (A Programmable Dual-RNA-Guided DNA WO WO 2014/0471.03 A2 3, 2014 Endonuclease in Adaptive Bacterial Immunity, Science, vol. 337 No. WO WO 2014/059173 A2 4, 2014 6096 pp. 816-821, Jun. 28, 2012).* WO WO 2014/059255 A1 4/2014 Carroll (ACRISPR Approach to Gene Targeting, Mol Ther. Sep. WO WO 2014/065596 A1 5, 2014 2012:20(9): 1658-60).* WO WO 2014/066505 A1 5, 2014 Barrangou (RNA-mediated programmable DNA cleavage, Nature WO WO 2014/068.346 A2 5, 2014 Biotechnology 30, 836-838, Sep. 10, 2012).* WO WO 2014/070887 A1 5, 2014 Cong et al. 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