IP Library › Granted Patent US 12,473,543
Granted Patent B2
US 12,473,543 · App. 17/603,917 · Granted Nov 18, 2025

Adenine base editors with reduced off-target effects

Inventors: David R. Liu (Cambridge, MA); Holly A. Rees (Cambridge, MA)
Assignees: The Broad Institute, Inc.; President and Fellows of Harvard College
C12N9/78C12N9/22C12N15/102C07K2319/09C07K2319/80C12N2310/20C12N2320/31
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,473,543
App. No.
17/603,917
Granted
Nov 18, 2025
Kind
B2
Abstract

The present disclosure provides novel adenine base editors that retain ability to edit DNA efficiently but show greatly reduced off-target effects, such as reduced RNA editing activity, as well as lower off-target DNA editing activity and reduced indel by product formation. Also provided are base editing methods comprising contacting a nucleic acid molecule with an adenine base editor and a guide RNA that has complementarity to a target sequence. Further provided are complexes comprising a guide RNA bound to a base editor provided herein; and kits and pharmaceutical compositions for the administration of adenine base editor variants to a host cell.

Claims (26)

1 . A fusion protein comprising a first adenosine deaminase and a second adenosine deaminase, wherein the first adenosine deaminase

(a) is catalytically inactive, or

(b) has decreased adenosine deaminase activity as compared to the second adenosine deaminase;

wherein the first adenosine deaminase comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of any one of SEQ ID NOs: 86-94, and wherein the first adenosine deaminase comprises any amino acid residue except for E in a position that corresponds to position 59 of SEQ ID NO: 86; and

wherein the second adenosine deaminase comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of any one of SEQ ID NOs: 86-94, 96 and 110, wherein the second adenosine deaminase comprises any amino acid residue except for A, V, or T, in a position that corresponds to position 106 of SEQ ID NO: 86.

2 . The fusion protein of claim 1 , wherein the first and/or the second adenosine deaminase is capable of deaminating adenine of a deoxyadenosine in deoxyribonucleic acid (DNA).

3 . The fusion protein of claim 1 , wherein the first and/or second adenosine deaminase is a TadA deaminase derived from an E. coli, S. aureus, B. subtilis, S. typhimurim, S. putrefaciens, H. influenza, C. crescentus , or a G. sulfurreducens bacterium.

4 . The fusion protein of claim 1 , wherein the first adenosine deaminase comprises an A in a position that corresponds to position 59 of SEQ ID NO: 86.

5 . The fusion protein of claim 1 , wherein the first adenosine deaminase comprises the amino acid sequence of SEQ ID NO: 95 or 107.

6 . The fusion protein of claim 1 , wherein the second adenosine deaminase comprises an amino acid sequence that is at least 85%, 90%, 95%, 98%, 99%, or 99.5% identical to the amino acid sequence of any one of SEQ ID NOs: 86-94, 96, and 110, with the exception of an amino acid substitution to a residue other than A, V, and T in position 106 of the amino acid sequence of SEQ ID NO: 86 or in a position in the amino acid sequence of any one of SEQ ID NOs: 86-94, 96, and 110 that corresponds to position 106 of SEQ ID NO: 86.

7 . The fusion protein of claim 6 , wherein the second adenosine deaminase comprises a Q, F, W, or M in a position that corresponds to position 106 of SEQ ID NO: 86.

8 . The fusion protein of claim 6 , wherein the second adenosine deaminase comprises a W in a position that corresponds to position 106 of SEQ ID NO: 86.

9 . The fusion protein of claim 1 , wherein the second adenosine deaminase comprises a Q, F, W, K, or M in a position that corresponds to position 108 of SEQ ID NO: 86.

10 . The fusion protein of claim 1 , wherein the fusion protein further comprises a nucleic acid programmable DNA binding protein (napDNAbp) domain.

11 . The fusion protein of claim 10 , wherein the napDNAbp domain is a nuclease dead Cas9 (dCas9), a Cas9 nickase (nCas9), or a nuclease active Cas9.

12 . The fusion protein of claim 1 further comprising one or more nuclear localization sequences (NLS).

13 . The fusion protein of claim 10 , wherein the fusion protein comprises the structure: NH 2 -[first adenosine deaminase]-[second adenosine deaminase]-[napDNAbp domain]-COOH; NH 2 -[second adenosine deaminase]-[first adenosine deaminase]-[napDNAbp domain]-COOH; NH 2 -[napDNAbp domain]-[first adenosine deaminase]-[second adenosine deaminase]-COOH; NH 2 -[napDNAbp domain]-[second adenosine deaminase]-[first adenosine deaminase]-COOH; NH 2 -[first adenosine deaminase]-[napDNAbp domain]-[second adenosine deaminase]-COOH; or NH 2 -[second adenosine deaminase]-[napDNAbp domain]-[first adenosine deaminase]-COOH, wherein each “]-[” in the structure indicates the optional presence of a linker sequence.

14 . The fusion protein of claim 1 , wherein the fusion protein comprises an amino acid sequence that is at least 85% identical to any one of the amino acid sequences of SEQ ID NOs: 216-228.

15 . The fusion protein of claim 1 , wherein the fusion protein comprises any one of the amino acid sequences of SEQ ID NOs: 216-228.

16 . A complex comprising the fusion protein of claim 10 and a guide RNA bound to the napDNAbp domain of the fusion protein.

17 . A method comprising contacting a nucleic acid molecule with the fusion protein of claim 10 and a guide RNA, wherein the guide RNA is between 15 and 100 nucleotides long and comprises a sequence of at least 10 contiguous nucleotides that is complementary to a target sequence.

18 . A polynucleotide encoding the fusion protein of claim 1 .

19 . A vector comprising the polynucleotide of claim 18 .

20 . A cell comprising the fusion protein of claim 1 .

21 . The fusion protein of claim 1 , wherein the second adenosine deaminase comprises the amino acid sequence of any one of SEQ ID NOs: 97-106.

22 . The fusion protein of claim 1 , wherein the second adenosine deaminase further comprises a Q, F, W, or M in a position that corresponds to position 47 of SEQ ID NO: 86.

Assignments (5)
LICENSE Recorded Apr 3, 2025
From: BROAD INSTITUTE, INC.
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 070725/0143 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2022
From: HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061059/0512 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2022
From: REES, HOLLY A.
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 061059/0616 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 12, 2022
From: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
To: THE BROAD INSTITUTE, INC.
Reel/Frame 061060/0904 →
CONFIRMATORY ASSIGNMENT Recorded Sep 12, 2022
From: LIU, DAVID R.
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 061409/0017 →
Continuity (2)
Provisional Application 62835490 · Apr 17, 2019
Related Publication 20220307003A1 · Sep 29, 2022
References Cited (400)
US 4182449A · Kozlow · 1980 [cited by applicant]
US 4186183A · Steck et al. · 1980 [cited by applicant]
US 4217344A · Vanlerberghe et al. · 1980 [cited by applicant]
US 4235871A · Papahadjopoulos et al. · 1980 [cited by applicant]
US 4261975A · Fullerton et al. · 1981 [cited by applicant]
US 4485054A · Mezei et al. · 1984 [cited by applicant]
US 4501728A · Geho et al. · 1985 [cited by applicant]
US 4663290A · Weis et al. · 1987 [cited by applicant]
US 4737323A · Martin et al. · 1988 [cited by applicant]
US 4774085A · Fidler · 1988 [cited by applicant]
US 4797368A · Carter et al. · 1989 [cited by applicant]
US 4837028A · Allen · 1989 [cited by applicant]
US 4873316A · Meade et al. · 1989 [cited by applicant]
US 4880635A · Janoff et al. · 1989 [cited by applicant]
US 4889818A · Gelfand et al. · 1989 [cited by applicant]
US 4897355A · Eppstein et al. · 1990 [cited by applicant]
US 4906477A · Kurono et al. · 1990 [cited by applicant]
US 4911928A · Wallach · 1990 [cited by applicant]
US 4917951A · Wallach · 1990 [cited by applicant]
US 4920016A · Allen et al. · 1990 [cited by applicant]
US 4921757A · Wheatley et al. · 1990 [cited by applicant]
US 4946787A · Eppstein et al. · 1990 [cited by applicant]
US 4965185A · Grischenko et al. · 1990 [cited by applicant]
US 5017492A · Kotewicz et al. · 1991 [cited by applicant]
US 5047342A · Chatterjee · 1991 [cited by applicant]
US 5049386A · Eppstein et al. · 1991 [cited by applicant]
US 5079352A · Gelfand et al. · 1992 [cited by applicant]
US 5139941A · Muzyczka et al. · 1992 [cited by applicant]
US 5173414A · Lebkowski et al. · 1992 [cited by applicant]
US 5223409A · Ladner et al. · 1993 [cited by applicant]
US 5244797A · Kotewicz et al. · 1993 [cited by applicant]
US 5270179A · Chatterjee · 1993 [cited by applicant]
US 5374553A · Gelfand et al. · 1994 [cited by applicant]
US 5405776A · Kotewicz et al. · 1995 [cited by applicant]
US 5436149A · Barnes · 1995 [cited by applicant]
US 5449639A · Wei et al. · 1995 [cited by applicant]
US 5478745A · Samulski et al. · 1995 [cited by applicant]
US 5496714A · Comb et al. · 1996 [cited by applicant]
US 5512462A · Cheng · 1996 [cited by applicant]
US 5580737A · Polisky et al. · 1996 [cited by applicant]
US 5614365A · Tabor et al. · 1997 [cited by applicant]
US 5652094A · Usman et al. · 1997 [cited by applicant]
US 5658727A · Barbas et al. · 1997 [cited by applicant]
US 5668005A · Kotewicz et al. · 1997 [cited by applicant]
US 5677152A · Birch et al. · 1997 [cited by applicant]
US 5767099A · Harris et al. · 1998 [cited by applicant]
US 5780053A · Ashley et al. · 1998 [cited by applicant]
US 5830430A · Unger et al. · 1998 [cited by applicant]
US 5834247A · Comb et al. · 1998 [cited by applicant]
US 5835699A · Kimura · 1998 [cited by applicant]
US 5844075A · Kawakami et al. · 1998 [cited by applicant]
US 5849548A · Haseloff et al. · 1998 [cited by applicant]
US 5851548A · Dattagupta et al. · 1998 [cited by applicant]
US 5855910A · Ashley et al. · 1999 [cited by applicant]
US 5856463A · Blankenborg et al. · 1999 [cited by applicant]
US 5962313A · Podsakoff et al. · 1999 [cited by applicant]
US 5981182A · Jacobs, Jr. et al. · 1999 [cited by applicant]
US 6015794A · Haseloff et al. · 2000 [cited by applicant]
US 6057153A · George et al. · 2000 [cited by applicant]
US 6063608A · Kotewicz et al. · 2000 [cited by applicant]
US 6077705A · Duan et al. · 2000 [cited by applicant]
US 6099857A · Gross · 2000 [cited by applicant]
US 6156509A · Schellenberger · 2000 [cited by applicant]
US 6183998B1 · Ivanov et al. · 2001 [cited by applicant]
US 6355415B1 · Wagner et al. · 2002 [cited by applicant]
US 6416997B1 · Mir-Shekari et al. · 2002 [cited by applicant]
US 6429298B1 · Ellington et al. · 2002 [cited by applicant]
US 6453242B1 · Eisenberg et al. · 2002 [cited by applicant]
US 6479264B1 · Louwrier · 2002 [cited by applicant]
US 6503717B2 · Case et al. · 2003 [cited by applicant]
US 6534261B1 · Cox, III et al. · 2003 [cited by applicant]
US 6558671B1 · Slingluff et al. · 2003 [cited by applicant]
US 6589768B1 · Kotewicz et al. · 2003 [cited by applicant]
US 6599692B1 · Case et al. · 2003 [cited by applicant]
US 6607882B1 · Cox, III et al. · 2003 [cited by applicant]
US 6610522B1 · Kotewicz et al. · 2003 [cited by applicant]
US 6689558B2 · Case et al. · 2004 [cited by applicant]
US 6716973B2 · Baskerville et al. · 2004 [cited by applicant]
US 6824978B1 · Cox, III et al. · 2004 [cited by applicant]
US 6933113B2 · Case et al. · 2005 [cited by applicant]
US 6979539B2 · Cox, III et al. · 2005 [cited by applicant]
US 7013219B2 · Case et al. · 2006 [cited by applicant]
US 7045337B2 · Schultz et al. · 2006 [cited by applicant]
US 7067650B1 · Tanaka · 2006 [cited by applicant]
US 7070928B2 · Liu et al. · 2006 [cited by applicant]
US 7078208B2 · Smith et al. · 2006 [cited by applicant]
US 7083970B2 · Schultz et al. · 2006 [cited by applicant]
US 7163824B2 · Cox, III et al. · 2007 [cited by applicant]
US 7192739B2 · Liu et al. · 2007 [cited by applicant]
US 7223545B2 · Liu et al. · 2007 [cited by applicant]
US 7329807B2 · Vadrucci et al. · 2008 [cited by applicant]
US 7354761B2 · Schultz et al. · 2008 [cited by applicant]
US 7368275B2 · Schultz et al. · 2008 [cited by applicant]
US 7419669B2 · Kosmatopoulos et al. · 2008 [cited by applicant]
US 7442160B2 · Liu et al. · 2008 [cited by applicant]
US 7476500B1 · Liu et al. · 2009 [cited by applicant]
US 7476734B2 · Liu · 2009 [cited by applicant]
US 7479573B2 · Chu et al. · 2009 [cited by applicant]
US 7488718B2 · Scheinberg et al. · 2009 [cited by applicant]
US 7491494B2 · Liu et al. · 2009 [cited by applicant]
US 7510706B2 · Yonemitsu et al. · 2009 [cited by applicant]
US 7541450B2 · Liu et al. · 2009 [cited by applicant]
US 7556940B2 · Galarza et al. · 2009 [cited by applicant]
US 7557068B2 · Liu et al. · 2009 [cited by applicant]
US 7595179B2 · Chen et al. · 2009 [cited by applicant]
US 7638300B2 · Schultz et al. · 2009 [cited by applicant]
US 7670807B2 · Lampson et al. · 2010 [cited by applicant]
US 7678554B2 · Liu et al. · 2010 [cited by applicant]
US 7713721B2 · Schultz et al. · 2010 [cited by applicant]
US 7771935B2 · Liu et al. · 2010 [cited by applicant]
US 7794931B2 · Breaker et al. · 2010 [cited by applicant]
US 7807408B2 · Liu et al. · 2010 [cited by applicant]
US 7851658B2 · Liu et al. · 2010 [cited by applicant]
US 7915025B2 · Schultz et al. · 2011 [cited by applicant]
US 7919277B2 · Russell et al. · 2011 [cited by applicant]
US 7993672B2 · Huang et al. · 2011 [cited by applicant]
US 7998904B2 · Liu et al. · 2011 [cited by applicant]
US 7999071B2 · Schlom et al. · 2011 [cited by applicant]
US 8012739B2 · Schultz et al. · 2011 [cited by applicant]
US 8017323B2 · Liu et al. · 2011 [cited by applicant]
US 8017755B2 · Liu et al. · 2011 [cited by applicant]
US 8030074B2 · Schultz et al. · 2011 [cited by applicant]
US 8067556B2 · Hogrefe et al. · 2011 [cited by applicant]
US 8114648B2 · Schultz et al. · 2012 [cited by applicant]
US 8173364B2 · Schultz et al. · 2012 [cited by applicant]
US 8173392B2 · Schultz et al. · 2012 [cited by applicant]
US 8183012B2 · Schultz et al. · 2012 [cited by applicant]
US 8183178B2 · Liu et al. · 2012 [cited by applicant]
US 8206914B2 · Liu et al. · 2012 [cited by applicant]
US 8354380B2 · Liu et al. · 2013 [cited by applicant]
US 8361725B2 · Russell et al. · 2013 [cited by applicant]
US 8394604B2 · Liu et al. · 2013 [cited by applicant]
US 8420104B2 · Charneau et al. · 2013 [cited by applicant]
US 8440431B2 · Voytas et al. · 2013 [cited by applicant]
US 8440432B2 · Voytas et al. · 2013 [cited by applicant]
US 8450471B2 · Voytas et al. · 2013 [cited by applicant]
US 8492082B2 · De Franciscis et al. · 2013 [cited by applicant]
US 8546553B2 · Terns et al. · 2013 [cited by applicant]
US 8569256B2 · Heyes et al. · 2013 [cited by applicant]
US 8586363B2 · Voytas et al. · 2013 [cited by applicant]
US 8673612B2 · Klatzmann et al. · 2014 [cited by applicant]
US 8680069B2 · de Fougerolles et al. · 2014 [cited by applicant]
US 8691729B2 · Liu et al. · 2014 [cited by applicant]
US 8691750B2 · Constien et al. · 2014 [cited by applicant]
US 8697359B1 · Zhang · 2014 [cited by applicant]
US 8697439B2 · Mangeot et al. · 2014 [cited by applicant]
US 8697853B2 · Voytas et al. · 2014 [cited by applicant]
US 8709466B2 · Coady et al. · 2014 [cited by applicant]
US 8728526B2 · Heller · 2014 [cited by applicant]
US 8729038B2 · Gruber et al. · 2014 [cited by applicant]
US 8741279B2 · Kasahara et al. · 2014 [cited by applicant]
US 8748667B2 · Budzik et al. · 2014 [cited by applicant]
US 8758810B2 · Okada et al. · 2014 [cited by applicant]
US 8759103B2 · Kim et al. · 2014 [cited by applicant]
US 8759104B2 · Unciti-Broceta et al. · 2014 [cited by applicant]
US 8771728B2 · Huang et al. · 2014 [cited by applicant]
US 8790664B2 · Pitard et al. · 2014 [cited by applicant]
US 8795965B2 · Zhang · 2014 [cited by applicant]
US 8822663B2 · Schrum et al. · 2014 [cited by applicant]
US 8835148B2 · Janulaitis et al. · 2014 [cited by applicant]
US 8846578B2 · McCray et al. · 2014 [cited by applicant]
US 8871445B2 · Cong et al. · 2014 [cited by applicant]
US 8889418B2 · Zhang et al. · 2014 [cited by applicant]
US 8900814B2 · Yasukawa et al. · 2014 [cited by applicant]
US 8945839B2 · Zhang · 2015 [cited by applicant]
US 8975232B2 · Liu et al. · 2015 [cited by applicant]
US 8993233B2 · Zhang et al. · 2015 [cited by applicant]
US 8999641B2 · Zhang et al. · 2015 [cited by applicant]
US 9023594B2 · Liu et al. · 2015 [cited by applicant]
US 9023649B2 · Mali et al. · 2015 [cited by applicant]
US 9034650B2 · Padidam · 2015 [cited by applicant]
US 9068179B1 · Liu et al. · 2015 [cited by applicant]
US 9150626B2 · Liu et al. · 2015 [cited by applicant]
US 9163271B2 · Schultz et al. · 2015 [cited by applicant]
US 9163284B2 · Liu et al. · 2015 [cited by applicant]
US 9181535B2 · Liu et al. · 2015 [cited by applicant]
US 9200045B2 · Liu et al. · 2015 [cited by applicant]
US 9221886B2 · Liu et al. · 2015 [cited by applicant]
US 9228207B2 · Liu et al. · 2016 [cited by applicant]
US 9234213B2 · Wu · 2016 [cited by applicant]
US 9243038B2 · Liu et al. · 2016 [cited by applicant]
US 9267127B2 · Liu et al. · 2016 [cited by applicant]
US 9290773B2 · Edgerton · 2016 [cited by applicant]
US 9296790B2 · Chatterjee et al. · 2016 [cited by applicant]
US 9322006B2 · Liu et al. · 2016 [cited by applicant]
US 9322037B2 · Liu et al. · 2016 [cited by applicant]
US 9340799B2 · Liu et al. · 2016 [cited by applicant]
US 9340800B2 · Liu et al. · 2016 [cited by applicant]
US 9359599B2 · Liu et al. · 2016 [cited by applicant]
US 9388430B2 · Liu et al. · 2016 [cited by applicant]
US 9394537B2 · Liu et al. · 2016 [cited by applicant]
US 9434774B2 · Liu et al. · 2016 [cited by applicant]
US 9458484B2 · Ma et al. · 2016 [cited by applicant]
US 9512446B1 · Joung et al. · 2016 [cited by applicant]
US 9526784B2 · Liu et al. · 2016 [cited by applicant]
US 9534210B2 · Park et al. · 2017 [cited by applicant]
US 9580698B1 · Xu et al. · 2017 [cited by applicant]
US 9593356B2 · Haugwitz et al. · 2017 [cited by applicant]
US 9610322B2 · Liu et al. · 2017 [cited by applicant]
US 9637739B2 · Siksnys et al. · 2017 [cited by applicant]
US 9663770B2 · Rogers et al. · 2017 [cited by applicant]
US 9695446B2 · Mangeot et al. · 2017 [cited by applicant]
US 9737604B2 · Jin et al. · 2017 [cited by applicant]
US 9738693B2 · Telford et al. · 2017 [cited by applicant]
US 9753340B2 · Saitou · 2017 [cited by applicant]
US 9765304B2 · Klatzmann et al. · 2017 [cited by applicant]
US 9771574B2 · Liu et al. · 2017 [cited by applicant]
US 9777043B2 · Anderson et al. · 2017 [cited by applicant]
US 9783791B2 · Hogrefe et al. · 2017 [cited by applicant]
US 9816093B1 · Donohoue et al. · 2017 [cited by applicant]
US 9840538B2 · Telford et al. · 2017 [cited by applicant]
US 9840690B2 · Karli et al. · 2017 [cited by applicant]
US 9840699B2 · Liu et al. · 2017 [cited by applicant]
US 9840702B2 · Collingwood et al. · 2017 [cited by applicant]
US 9850521B2 · Braman et al. · 2017 [cited by applicant]
US 9873907B2 · Zeiner et al. · 2018 [cited by applicant]
US 9879270B2 · Hittinger et al. · 2018 [cited by applicant]
US 9914939B2 · Church et al. · 2018 [cited by applicant]
US 9932567B1 · Xu et al. · 2018 [cited by applicant]
US 9938288B1 · Kishi et al. · 2018 [cited by applicant]
US 9944933B2 · Storici et al. · 2018 [cited by applicant]
US 9982279B1 · Gill et al. · 2018 [cited by applicant]
US 9999671B2 · Liu et al. · 2018 [cited by applicant]
US 10011868B2 · Liu et al. · 2018 [cited by applicant]
US 10040830B2 · Chatterjee et al. · 2018 [cited by applicant]
US 10053725B2 · Liu et al. · 2018 [cited by applicant]
US 10059940B2 · Zhong · 2018 [cited by applicant]
US 10077453B2 · Liu et al. · 2018 [cited by applicant]
US 10113163B2 · Liu et al. · 2018 [cited by applicant]
US 10150955B2 · Lambowitz et al. · 2018 [cited by applicant]
US 10167457B2 · Liu et al. · 2019 [cited by applicant]
US 10179911B2 · Liu et al. · 2019 [cited by applicant]
US 10189831B2 · Arrington et al. · 2019 [cited by applicant]
US 10202593B2 · Liu et al. · 2019 [cited by applicant]
US 10202658B2 · Parkin et al. · 2019 [cited by applicant]
US 10227581B2 · Liu et al. · 2019 [cited by applicant]
US 10323236B2 · Liu et al. · 2019 [cited by applicant]
US 10336997B2 · Liu et al. · 2019 [cited by applicant]
US 10358670B2 · Janulaitis et al. · 2019 [cited by applicant]
US 10392674B2 · Liu et al. · 2019 [cited by applicant]
US 10407474B2 · Liu et al. · 2019 [cited by applicant]
US 10407695B2 · Charneau et al. · 2019 [cited by applicant]
US 10407697B2 · Doudna et al. · 2019 [cited by applicant]
US 10465176B2 · Liu et al. · 2019 [cited by applicant]
US 10508298B2 · Liu et al. · 2019 [cited by applicant]
US 10583201B2 · Chen et al. · 2020 [cited by applicant]
US 10597679B2 · Liu et al. · 2020 [cited by applicant]
US 10612011B2 · Liu et al. · 2020 [cited by applicant]
US 10640767B2 · Maianti et al. · 2020 [cited by applicant]
US 10682410B2 · Liu et al. · 2020 [cited by applicant]
US 10704062B2 · Liu et al. · 2020 [cited by applicant]
US 10745677B2 · Maianti et al. · 2020 [cited by applicant]
US 10858639B2 · Liu et al. · 2020 [cited by applicant]
US 10912833B2 · Liu et al. · 2021 [cited by applicant]
US 10930367B2 · Zhang et al. · 2021 [cited by applicant]
US 10947530B2 · Liu et al. · 2021 [cited by applicant]
US 10954548B2 · Liu et al. · 2021 [cited by applicant]
US 10968253B2 · Ohlmann et al. · 2021 [cited by applicant]
US 11046948B2 · Liu et al. · 2021 [cited by applicant]
US 11053481B2 · Liu et al. · 2021 [cited by applicant]
US 11124782B2 · Liu et al. · 2021 [cited by applicant]
US 11142760B2 · Slaymaker et al. · 2021 [cited by applicant]
US 11214780B2 · Liu et al. · 2022 [cited by applicant]
US 11268082B2 · Liu et al. · 2022 [cited by applicant]
US 11299755B2 · Liu et al. · 2022 [cited by applicant]
US 11306324B2 · Liu et al. · 2022 [cited by applicant]
US 11319532B2 · Liu et al. · 2022 [cited by applicant]
US 11447770B1 · Liu et al. · 2022 [cited by applicant]
US 11542496B2 · Liu et al. · 2023 [cited by applicant]
US 11542509B2 · Maianti et al. · 2023 [cited by applicant]
US 11560566B2 · Liu et al. · 2023 [cited by applicant]
US 11578343B2 · Liu et al. · 2023 [cited by applicant]
US 11643652B2 · Liu et al. · 2023 [cited by applicant]
US 11661590B2 · Liu et al. · 2023 [cited by applicant]
US 11702651B2 · Liu et al. · 2023 [cited by applicant]
US 11732274B2 · Liu et al. · 2023 [cited by applicant]
US 11795443B2 · Liu et al. · 2023 [cited by applicant]
US 11795452B2 · Liu et al. · 2023 [cited by applicant]
US 11820969B2 · Maianti et al. · 2023 [cited by applicant]
US 11898179B2 · Maianti et al. · 2024 [cited by applicant]
US 11912985B2 · Liu et al. · 2024 [cited by applicant]
US 11920181B2 · Liu et al. · 2024 [cited by applicant]
US 11932884B2 · Liu et al. · 2024 [cited by applicant]
US 11999947B2 · Liu et al. · 2024 [cited by applicant]
US 12006520B2 · Liu et al. · 2024 [cited by applicant]
US 12031126B2 · Liu et al. · 2024 [cited by applicant]
US 12043852B2 · Liu et al. · 2024 [cited by applicant]
US 12084663B2 · Maianti et al. · 2024 [cited by applicant]
US 12157760B2 · Liu et al. · 2024 [cited by applicant]
US 12215365B2 · Liu et al. · 2025 [cited by applicant]
US 12281303B2 · Liu et al. · 2025 [cited by applicant]
US 12281338B2 · Liu et al. · 2025 [cited by applicant]
US 20030082575A1 · Schultz et al. · 2003 [cited by applicant]
US 20030087817A1 · Cox et al. · 2003 [cited by applicant]
US 20030096337A1 · Hillman et al. · 2003 [cited by applicant]
US 20030103939A1 · Engelhardt et al. · 2003 [cited by applicant]
US 20030108885A1 · Schultz et al. · 2003 [cited by applicant]
US 20030119764A1 · Loeb et al. · 2003 [cited by applicant]
US 20030167533A1 · Yadav et al. · 2003 [cited by applicant]
US 20030203480A1 · Kovesdi et al. · 2003 [cited by applicant]
US 20040003420A1 · Kuhn et al. · 2004 [cited by applicant]
US 20040028687A1 · Waelti · 2004 [cited by applicant]
US 20040115184A1 · Smith et al. · 2004 [cited by applicant]
US 20040156861A1 · Figdor et al. · 2004 [cited by applicant]
US 20040197892A1 · Moore et al. · 2004 [cited by applicant]
US 20040203109A1 · Lal et al. · 2004 [cited by applicant]
US 20050100890A1 · Davidson et al. · 2005 [cited by applicant]
US 20050136429A1 · Guarente et al. · 2005 [cited by applicant]
US 20050222030A1 · Allison · 2005 [cited by applicant]
US 20050260626A1 · Lorens et al. · 2005 [cited by applicant]
US 20060088864A1 · Smolke et al. · 2006 [cited by applicant]
US 20060104984A1 · Littlefield et al. · 2006 [cited by applicant]
US 20060216702A1 · Compans et al. · 2006 [cited by applicant]
US 20060246568A1 · Honjo et al. · 2006 [cited by applicant]
US 20070015238A1 · Snyder et al. · 2007 [cited by applicant]
US 20070049533A1 · Liu et al. · 2007 [cited by applicant]
US 20070264692A1 · Liu et al. · 2007 [cited by applicant]
US 20070269817A1 · Shapero · 2007 [cited by applicant]
US 20070298118A1 · Lotvall et al. · 2007 [cited by applicant]
US 20080008697A1 · Mintier et al. · 2008 [cited by applicant]
US 20080051317A1 · Church et al. · 2008 [cited by applicant]
US 20080124725A1 · Barrangou et al. · 2008 [cited by applicant]
US 20080182254A1 · Hall et al. · 2008 [cited by applicant]
US 20080220502A1 · Schellenberger et al. · 2008 [cited by applicant]
US 20080241917A1 · Akita et al. · 2008 [cited by applicant]
US 20080268516A1 · Perreault et al. · 2008 [cited by applicant]
US 20090111119A1 · Doyon et al. · 2009 [cited by applicant]
US 20090130718A1 · Short · 2009 [cited by applicant]
US 20090202622A1 · Fleury et al. · 2009 [cited by applicant]
US 20090215878A1 · Tan et al. · 2009 [cited by applicant]
US 20090234109A1 · Han et al. · 2009 [cited by applicant]
US 20100076057A1 · Sontheimer et al. · 2010 [cited by applicant]
US 20100093617A1 · Barrangou et al. · 2010 [cited by applicant]
US 20100104690A1 · Barrangou et al. · 2010 [cited by applicant]
US 20100105134A1 · Quay et al. · 2010 [cited by applicant]
US 20100273857A1 · Thakker et al. · 2010 [cited by applicant]
US 20100305197A1 · Che · 2010 [cited by applicant]
US 20100316643A1 · Eckert et al. · 2010 [cited by applicant]
US 20110016540A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110059160A1 · Essner et al. · 2011 [cited by applicant]
US 20110059502A1 · Chalasani · 2011 [cited by applicant]
US 20110104787A1 · Church et al. · 2011 [cited by applicant]
US 20110123509A1 · Jantz et al. · 2011 [cited by applicant]
US 20110177495A1 · Liu et al. · 2011 [cited by applicant]
US 20110189775A1 · Ainley et al. · 2011 [cited by applicant]
US 20110189776A1 · Terns et al. · 2011 [cited by applicant]
US 20110206672A1 · Little · 2011 [cited by applicant]
US 20110217739A1 · Terns et al. · 2011 [cited by applicant]
US 20110301073A1 · Gregory et al. · 2011 [cited by applicant]
US 20120129759A1 · Liu et al. · 2012 [cited by applicant]
US 20120141523A1 · Castado et al. · 2012 [cited by applicant]
US 20120159653A1 · Weinstein et al. · 2012 [cited by applicant]
US 20120244601A1 · Bertozzi et al. · 2012 [cited by applicant]
US 20120270273A1 · Zhang et al. · 2012 [cited by applicant]
US 20120322861A1 · Byrne et al. · 2012 [cited by applicant]
US 20130022980A1 · Nelson et al. · 2013 [cited by applicant]
US 20130053426A1 · Seow et al. · 2013 [cited by applicant]
US 20130059931A1 · Petersen-Mahrt et al. · 2013 [cited by applicant]
US 20130108657A1 · Yee et al. · 2013 [cited by applicant]
US 20130117869A1 · Duchateau et al. · 2013 [cited by applicant]
US 20130130248A1 · Haurwitz et al. · 2013 [cited by applicant]
US 20130158245A1 · Russell et al. · 2013 [cited by applicant]
US 20130165389A1 · Schellenberger et al. · 2013 [cited by applicant]
US 20130212725A1 · Kuhn et al. · 2013 [cited by applicant]
US 20130309720A1 · Schultz et al. · 2013 [cited by applicant]
US 20130344117A1 · Mirosevich et al. · 2013 [cited by applicant]
US 20130345064A1 · Liu et al. · 2013 [cited by applicant]
US 20140004280A1 · Loomis · 2014 [cited by applicant]
US 20140005269A1 · Ngwuluka et al. · 2014 [cited by applicant]
US 20140017214A1 · Cost · 2014 [cited by applicant]
US 20140018404A1 · Chen et al. · 2014 [cited by applicant]
US 20140044793A1 · Goll et al. · 2014 [cited by applicant]
US 20140065711A1 · Liu et al. · 2014 [cited by applicant]
US 20140068797A1 · Doudna et al. · 2014 [cited by applicant]
US 20140127752A1 · Zhou et al. · 2014 [cited by applicant]
US 20140128449A1 · Liu et al. · 2014 [cited by applicant]
US 20140141094A1 · Smyth et al. · 2014 [cited by applicant]
US 20140141487A1 · Feldman et al. · 2014 [cited by applicant]
US 20140179770A1 · Zhang et al. · 2014 [cited by applicant]
US 20140186843A1 · Zhang et al. · 2014 [cited by applicant]
US 20140186919A1 · Zhang et al. · 2014 [cited by applicant]
US 20140186958A1 · Zhang et al. · 2014 [cited by applicant]
US 20140201858A1 · Ostertag et al. · 2014 [cited by applicant]
US 20140234289A1 · Liu et al. · 2014 [cited by applicant]
US 20140248702A1 · Zhang et al. · 2014 [cited by applicant]
US 20140273037A1 · Wu · 2014 [cited by applicant]
US 20140273226A1 · Wu · 2014 [cited by applicant]
US 20140273230A1 · Chen et al. · 2014 [cited by applicant]
US 20140273234A1 · Zhang et al. · 2014 [cited by applicant]
US 20140283156A1 · Zador et al. · 2014 [cited by applicant]
US 20140295556A1 · Joung et al. · 2014 [cited by applicant]
US 20140295557A1 · Joung et al. · 2014 [cited by applicant]
US 20140342456A1 · Mali et al. · 2014 [cited by applicant]
US 20140342457A1 · Mali et al. · 2014 [cited by applicant]
US 20140342458A1 · Mali et al. · 2014 [cited by applicant]
US 20140349400A1 · Jakimo et al. · 2014 [cited by applicant]
US 20140356867A1 · Peter et al. · 2014 [cited by applicant]
US 20140356956A1 · Church et al. · 2014 [cited by applicant]
US 20140356958A1 · Mali et al. · 2014 [cited by applicant]
US 20140356959A1 · Church et al. · 2014 [cited by applicant]