IP Library › Granted Patent US 12,522,807
Granted Patent B2
US 12,522,807 · App. 17/259,147 · Granted Jan 13, 2026

RNA programmable epigenetic RNA modifiers and uses thereof

Inventors: David R. Liu (Cambridge, MA); Christopher Gerard Wilson (Waltham, MA); Peter J. Chen (Somerville, MA)
Assignees: The Broad Institute, Inc.; President and Fellows of Harvard College
C12N9/1007C12N9/0071C12N9/22C12N15/11C12Y114/11C12Y201/01001A61K38/00C07K2319/00C07K2319/09C07K2319/095C12N2310/20
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Quick Facts
Patent No.
US 12,522,807
App. No.
17/259,147
Filed
Jan 8, 2021
Granted
Jan 13, 2026
Kind
B2
Art Unit
1656
USPC
424/192.1
Abstract

The disclosure provides programmable methylation “writers” and demethylation “erasers” for editing the methylation state of RNA targets, e.g., an RNA transcriptome. In particular, the disclosure provides RNA methylation editor polynucleotide contracts and vectors comprising (i) an RNA programmable RNA binding domain (RNApRNAbd); and (ii) an effector domain, wherein the effector domain is capable of adding or removing a methyl group in an RNA. The disclosed RNA methylation editor constructs are capable of achieving limited off-target modifications in RNA molecules. Further, the disclosure provides methods for making and using the programmable methylation editors to modifying the methylation state of RNA. The disclosure further provides complexes comprising a methylation writer protein and a guide RNA molecule and complexes comprising a demethylation eraser protein and a guide RNA molecule. The disclosure further provides pharmaceutical compositions and cells comprising the disclosed fusion proteins and complexes.

Claims (31)

1 . A fusion protein comprising: (i) an RNA programmable RNA binding domain (RNApRNAbd), wherein the RNApRNAbd is a Type VI CRISPR-Cas protein; and (ii) an effector domain, wherein the effector domain is a truncated methyltransferase consisting of an amino acid sequence that is at least 80% identical to the amino acid sequence of residues 273-580 of SEQ ID NO: 3 (METTL3).

2 . The fusion protein of claim 1 , wherein the effector domain is capable of making an N 6 -methyladenosine (m 6 A) modification in an RNA.

3 . The fusion protein of claim 1 , wherein the effector domain is capable of adding a methyl group in an RNA.

4 . The fusion protein of claim 1 , wherein the RNApRNAbd comprises a Cas13b or a Cas13d protein.

5 . The fusion protein of claim 1 , wherein the RNApRNAbd is nuclease inactive (dRNApRNAbd).

6 . The fusion protein of claim 1 , wherein the RNApRNAbd comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of any one of SEQ ID NOs: 1 and 2.

7 . The fusion protein of claim 1 , wherein the fusion protein further comprises a nuclear localization sequence (NLS) or a nuclear export sequence (NES).

8 . The fusion protein of claim 1 , wherein the RNApRNAbd and the effector domain are fused via a linker that comprises an amino acid sequence selected from the group consisting of GGGGS (SEQ ID NO: 13), GGS, SGGS (SEQ ID NO: 15), SGGSSGGS (SEQ ID NO: 22), SGSETPGTSESATPES (SEQ ID NO: 16), and SGGSSGGSSGSETPGTSESATPESSGGSSGGS (SEQ ID NO: 23).

9 . The fusion protein of claim 1 , wherein the RNApRNAbd comprises the amino acid sequence of any one of SEQ ID NOs: 1 and 2.

10 . The fusion protein of claim 1 , wherein the fusion protein comprises an amino acid sequence at least 80% identical to any one of SEQ ID NOs: 24-25.

11 . A complex comprising the fusion protein of claim 1 and a guide RNA (gRNA) bound to the RNApRNAbd of the fusion protein.

12 . A method comprising contacting an RNA molecule with the fusion protein of claim 1 .

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

14 . A vector comprising the polynucleotide of claim 13 .

15 . A pharmaceutical composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable carrier.

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

17 . The fusion protein of claim 7 , wherein the fusion protein comprises the structure:

NH 2 -[NLS]-[RNApRNAbd]-[NLS]-[effector domain]-COOH, or

NH 2 -[RNApRNAbd]-[NES]-[effector domain]-COOH; and

wherein each instance of “]-[” comprises an optional linker.

18 . The fusion protein of claim 3 , wherein the RNA is an mRNA, a tRNA, or an rRNA.

19 . The fusion protein of claim 1 , wherein the effector domain is a truncated methyltransferase consisting of the amino acid sequence of residues 273-580 of SEQ ID NO: 3 (METTL3).

20 . The fusion protein of claim 1 , wherein the fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 24-25.

21 . A fusion protein comprising an amino acid sequence at least 80% identical to any one of SEQ ID NOs: 26-27.

22 . The fusion protein of claim 21 , wherein the fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 26-27.

23 . A complex comprising the fusion protein of claim 21 and a guide RNA (gRNA) bound to the fusion protein.

24 . A method comprising contacting an RNA molecule with the fusion protein of claim 21 .

25 . A polynucleotide encoding the fusion protein of claim 21 .

26 . A vector comprising the polynucleotide of claim 25 .

27 . A pharmaceutical composition comprising the fusion protein of claim 21 and a pharmaceutically acceptable carrier.

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

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 10, 2021
From: LIU, DAVID R.
To: HOWARD HUGHES MEDICAL INSTITUTE
Reel/Frame 057442/0845 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 10, 2021
From: HOWARD HUGHES MEDICAL INSTITUTE
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 057442/0981 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 10, 2021
From: CHEN, PETER J.
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 057443/0361 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 10, 2021
From: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
To: THE BROAD INSTITUTE, INC.
Reel/Frame 057443/0558 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 10, 2021
From: WILSON, CHRISTOPHER GERARD
To: THE BROAD INSTITUTE, INC.
Reel/Frame 057443/0768 →
Continuity (3)
Provisional Application 62868804 · Jun 28, 2019
Provisional Application 62695777 · Jul 9, 2018
Related Publication 20220033785A1 · Feb 3, 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 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 · 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 9526724B2 · Oshlack 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 · Liu 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 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 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 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 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 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]
US 20140357523A1 · Zeiner et al. · 2014 [cited by applicant]
US 20140377868A1 · Joung et al. · 2014 [cited by applicant]
US 20150010526A1 · Liu et al. · 2015 [cited by applicant]
US 20150031089A1 · Lindstrom · 2015 [cited by applicant]
US 20150031132A1 · Church et al. · 2015 [cited by applicant]