IP Library › Granted Patent US 12,662,667
Granted Patent B2
US 12,662,667 · App. 17/246,460 · Granted Jun 23, 2026

CRISPR enzymes and systems

Inventors: Eugene Koonin (Bethesda, MD); Feng Zhang (Cambridge, MA); Yuri I. Wolf (Bethesda, MD); Sergey Shmakov (Moscow, RU); Konstantin Severinov (New Brunswick, NJ); Ekaterina Semenova (New Brunswick, NJ); Leonid Minakhin (New Brunswick, MD); Kira S. Makarova (Bethesda, MD); Silvana Konermann (Cambridge, MA); Julia Joung (Cambridge, MA); Jonathan S. Gootenberg (Cambridge, MA); Omar O. Abudayyeh (Cambridge, MA)
Assignees: The Broad Institute, Inc.; Massachusetts Institute of Technology; President and Fellows of Harvard College; Rutgers, the State University of New Jersey; The United States of America, as represented by the Secretary, Department of Health and Human Services; Skolkovo Institute of Science and Technology
C12N15/102A61K48/005C12N9/22C12N15/11C12N15/8213C12N2310/20C12N2800/80
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 12,662,667
App. No.
17/246,460
Filed
Apr 30, 2021
Granted
Jun 23, 2026
Kind
B2
Art Unit
1636
USPC
800/9
Abstract

The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA or RNA-targeting systems comprising a novel DNA or RNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.

Claims (23)

1 . A formed CRISPR-Cas complex, consisting of one or more engineered heterologous nucleic acid components and a Type V Cas polypeptide consisting essentially of a nuclease lobe consisting of an RuvC domain and a heterologous polypeptide functional domain linked to the Type V Cas polypeptide; wherein the RuvC domain is connected to the nuclease lobe by one or more bridge helices, wherein the Type V Cas polypeptide comprises an arginine rich cluster and an inactive zinc finger region, wherein the one or more engineered heterologous nucleic acid components comprise a tracr sequence and direct sequence-specific binding of said CRISPR-Cas complex to a target sequence of a polynucleotide, and wherein the Type V Cas polypeptide does not comprise an HNH domain.

2 . The formed CRISPR-Cas complex of claim 1 , wherein the CRISPR-Cas complex directs cleavage at the target sequence of the polynucleotide.

3 . The formed CRISPR-Cas complex of claim 1 , wherein the one or more engineered heterologous nucleic acid components are engineered to hybridize with a target sequence adjacent to a protospacer motif (PAM) in a genome of a eukaryotic cell.

4 . A vector system comprising one or more viral vectors, wherein the one or more viral vectors encode the Type V Cas polypeptide and the one or more engineered heterologous nucleic acid components of claim 1 .

5 . The vector system of claim 4 , wherein a polynucleotide sequence in the one or more viral vectors encoding the Type V Cas polypeptide is codon optimized for expression in a eukaryotic cell.

6 . The vector system of claim 4 , wherein the one or more engineered heterologous nucleic acid component comprises two separate components, a direct repeat component and a spacer component.

7 . The vector system of claim 4 , wherein the one or more engineered heterologous nucleic acid components are engineered to hybridize with a target sequence adjacent to a protospacer motif (PAM) in a genome of a eukaryotic cell.

8 . The vector system of claim 4 , wherein the viral vector is an adenoviral vector, a lentiviral vector, or an adeno-associated viral vector.

9 . The vector system of claim 4 , wherein the one or more engineered heterologous nucleic acid component comprises two separate components, a direct repeat component and a spacer component.

10 . The formed CRISPR-Cas complex of claim 1 , comprising an mRNA encoding the Cas polypeptide, wherein the mRNA is comprised in a lipid nanoparticle, a liposome, an exosome, or a microvesicle.

11 . The formed CRISPR-Cas complex of claim 1 , wherein the functional domain is a deaminase.

12 . The formed CRISPR-Cas complex of claim 1 , wherein the one or more engineered heterologous nucleic acid component comprises two separate components, a direct repeat component and a spacer component.

13 . The formed CRISPR-Cas complex of claim 1 , wherein the heterologous nucleic acid component comprises two separate components, a direct repeat component and a spacer component.

14 . The formed CRISPR-Cas complex of claim 1 , comprising one or more viral vectors encoding the Type V Cas polypeptide, wherein the viral vector is an adenoviral vector, a lentiviral vector, or an adeno-associated viral vector.

15 . A method of targeting a polynucleotide, comprising contacting a sample comprising a polynucleotide with a CRISPR-Cas complex consisting of 1) a Type V Cas polypeptide consisting essentially of a nuclease lobe consisting of an RuvC domain and a heterologous polypeptide functional domain linked to the Type V Cas polypeptide, wherein the RuvC domain is connected to the nuclease lobe by one or more bridge helices, wherein the Type V Cas polypeptide comprises an arginine rich cluster, and an inactive zinc finger, wherein the Type V Cas polypeptide does not comprise an HNH domain, and 2) one or more engineered heterologous nucleic acid components comprise a tracr sequence and are capable of directing sequence-specific binding of the CRISPR-Cas complex to a target sequence of the polynucleotide.

16 . The method of claim 15 , wherein the target sequence is in a eukaryotic cell.

17 . The method of claim 16 , wherein contacting the eukaryotic cell with the CRISPR-Cas complex results in modification of a gene or gene product, or modification in an expression of a gene product.

18 . The method of claim 15 , wherein contacting an eukaryotic cell with the CRISPR-Cas complex results in cleavage of the target sequence.

19 . The method of claim 15 , wherein the one or more engineered heterologous nucleic acid components comprise two separate components, a direct repeat component and a spacer component.

20 . A method of targeting a polynucleotide, comprising contacting a sample comprising, 1) a catalytically inactive Type V Cas polypeptide linked to one or more heterologous polypeptide functional domains, wherein the Type V Cas polypeptide consists essentially a nuclease lobe consisting of a mutated RuvC domain, wherein the Type V Cas polypeptide does not comprise an HNH domain, wherein the mutated RuvC domain is connected to the nuclease lobe by one or more bridge helices, wherein the Type V Cas polypeptide comprises an arginine rich cluster, and an inactive zinc finger, and 2) one or more heterologous engineered nucleic acid components that comprise a tracr sequence and that form a CRISPR-Cas complex with the Cas polypeptide and that is capable of directing sequence-specific binding of said complex to a target sequence of a polynucleotide.

21 . The method of claim 20 , wherein the target sequence is in a eukaryotic cell.

22 . The method of claim 21 , wherein contacting the eukaryotic cell with the CRISPR-Cas complex results in modification of a gene or gene product, or modification in expression of a gene product.

23 . The method of claim 20 , wherein the one or more engineered heterologous nucleic acid components comprise two separate components, a direct repeat component and a spacer component.

Assignments (11)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: ABUDAYYEH, OMAR O.
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 056126/0199 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: GOOTENBERG, JONATHAN
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 056126/0512 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: JOUNG, JULIA
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 056126/0670 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: KONERMANN, SILVANA
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 056126/0926 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: KOONIN, EUGENE
To: THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Reel/Frame 056127/0201 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: MAKAROVA, KIRA S.
To: THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Reel/Frame 056127/0606 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: WOLF, YURI I.
To: THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Reel/Frame 056127/0862 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: ZHANG, FENG
To: THE BROAD INSTITUTE, INC.; MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 056128/0212 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: SEMENOVA, EKATERINA; MINAKHIN, LEONID
To: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY
Reel/Frame 056128/0758 →
PARTIAL ASSIGNMENT Recorded May 4, 2021
From: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY
To: SKOLKOVO INSTITUTE OF SCIENCE AND TECHNOLOGY
Reel/Frame 056157/0652 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2021
From: SEVERINOV, KONSTANTIN
To: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY
Reel/Frame 056177/0453 →
Continuity (5)
Continuation 15842073 · Dec 14, 2017
Continuation In Part PCTUS2016038238 · Jun 17, 2016
Provisional Application 62245264 · Oct 22, 2015
Provisional Application 62181663 · Jun 18, 2015
Related Publication 20210348156A1 · Nov 11, 2021
References Cited (400)
US 4186183A · Alving et al. · 1980 [cited by applicant]
US 4217344A · Handjani 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 4769061A · Comai · 1988 [cited by applicant]
US 4774085A · Fidler · 1988 [cited by applicant]
US 4797368A · Carter et al. · 1989 [cited by applicant]
US 4810648A · Stalker · 1989 [cited by applicant]
US 4837028A · Allen · 1989 [cited by applicant]
US 4873316A · Meade et al. · 1989 [cited by applicant]
US 4897355A · Eppstein et al. · 1990 [cited by applicant]
US 4940835A · Shah et al. · 1990 [cited by applicant]
US 4946787A · Eppstein et al. · 1990 [cited by applicant]
US 4975374A · Goodman et al. · 1990 [cited by applicant]
US 5049386A · Eppstein et al. · 1991 [cited by applicant]
US 5173414A · Lebkowski et al. · 1992 [cited by applicant]
US 5210015A · Gelfand et al. · 1993 [cited by applicant]
US 5266317A · Tomalski et al. · 1993 [cited by applicant]
US 5273894A · Strauch et al. · 1993 [cited by applicant]
US 5276268A · Strauch et al. · 1994 [cited by applicant]
US 5445934A · Fodor et al. · 1995 [cited by applicant]
US 5494813A · Hepher et al. · 1996 [cited by applicant]
US 5543158A · Gref et al. · 1996 [cited by applicant]
US 5561236A · Leemans et al. · 1996 [cited by applicant]
US 5563055A · Townsend et al. · 1996 [cited by applicant]
US 5580859A · Felgner et al. · 1996 [cited by applicant]
US 5589466A · Felgner et al. · 1996 [cited by applicant]
US 5593972A · Weiner et al. · 1997 [cited by applicant]
US 5637489A · Strauch et al. · 1997 [cited by applicant]
US 5646024A · Leemans et al. · 1997 [cited by applicant]
US 5648477A · Leemans et al. · 1997 [cited by applicant]
US 5686281A · Roberts · 1997 [cited by applicant]
US 5712107A · Nichols · 1998 [cited by applicant]
US 5739082A · Donn · 1998 [cited by applicant]
US 5824790A · Keeling et al. · 1998 [cited by applicant]
US 5843728A · Seed et al. · 1998 [cited by applicant]
US 5846946A · Huebner et al. · 1998 [cited by applicant]
US 5851828A · Seed et al. · 1998 [cited by applicant]
US 5855913A · Hanes et al. · 1999 [cited by applicant]
US 5858358A · June et al. · 1999 [cited by applicant]
US 5883223A · Gray · 1999 [cited by applicant]
US 5906936A · Eshhar et al. · 1999 [cited by applicant]
US 5908810A · Donn · 1999 [cited by applicant]
US 5908975A · Caimi et al. · 1999 [cited by applicant]
US 5912170A · Seed et al. · 1999 [cited by applicant]
US 5912172A · Eshhar et al. · 1999 [cited by applicant]
US 5985309A · Edwards et al. · 1999 [cited by applicant]
US 6004811A · Seed et al. · 1999 [cited by applicant]
US 6007845A · Domb et al. · 1999 [cited by applicant]
US 6013861A · Bird et al. · 2000 [cited by applicant]
US 6248876B1 · Barry et al. · 2001 [cited by applicant]
US 6284240B1 · Seed et al. · 2001 [cited by applicant]
US 6284479B1 · Nichols · 2001 [cited by applicant]
US 6352694B1 · June et al. · 2002 [cited by applicant]
US 6392013B1 · Seed et al. · 2002 [cited by applicant]
US 6410014B1 · Seed et al. · 2002 [cited by applicant]
US 6489458B2 · Hackett et al. · 2002 [cited by applicant]
US 6534055B1 · June et al. · 2003 [cited by applicant]
US 6603061B1 · Armstrong et al. · 2003 [cited by applicant]
US 6734341B2 · Singletary et al. · 2004 [cited by applicant]
US 6750059B1 · Blakesley et al. · 2004 [cited by applicant]
US 6753162B1 · Seed et al. · 2004 [cited by applicant]
US 6768044B1 · Boudec et al. · 2004 [cited by applicant]
US 6797514B2 · Berenson et al. · 2004 [cited by applicant]
US 6867041B2 · Berenson et al. · 2005 [cited by applicant]
US 6887466B2 · June et al. · 2005 [cited by applicant]
US 6905680B2 · June et al. · 2005 [cited by applicant]
US 6905681B1 · June et al. · 2005 [cited by applicant]
US 6905874B2 · Berenson et al. · 2005 [cited by applicant]
US 7022896B1 · Weeks et al. · 2006 [cited by applicant]
US 7112665B1 · Leemans et al. · 2006 [cited by applicant]
US 7144575B2 · June et al. · 2006 [cited by applicant]
US 7148203B2 · Hackett et al. · 2006 [cited by applicant]
US 7160682B2 · Hackett et al. · 2007 [cited by applicant]
US 7175843B2 · June et al. · 2007 [cited by applicant]
US 7206639B2 · Jacobsen et al. · 2007 [cited by applicant]
US 7232566B2 · June et al. · 2007 [cited by applicant]
US 7259015B2 · Kingsman et al. · 2007 [cited by applicant]
US 7303910B2 · Bebbington et al. · 2007 [cited by applicant]
US 7351585B2 · Mitrophanous et al. · 2008 [cited by applicant]
US 7572631B2 · Berenson et al. · 2009 [cited by applicant]
US 7741465B1 · Eshhar et al. · 2010 [cited by applicant]
US 7745651B2 · Heyes et al. · 2010 [cited by applicant]
US 7776321B2 · Cascalho et al. · 2010 [cited by applicant]
US 7799565B2 · MacLachlan et al. · 2010 [cited by applicant]
US 7803397B2 · Heyes et al. · 2010 [cited by applicant]
US 7838658B2 · MacLachlan et al. · 2010 [cited by applicant]
US 7868149B2 · Boukharov et al. · 2011 [cited by applicant]
US 7901708B2 · MacLachlan et al. · 2011 [cited by applicant]
US 7915399B2 · MacLachlan et al. · 2011 [cited by applicant]
US 7982027B2 · MacLachlan et al. · 2011 [cited by applicant]
US 7985739B2 · Kay et al. · 2011 [cited by applicant]
US 8044019B2 · Uno et al. · 2011 [cited by applicant]
US 8058069B2 · Yaworski et al. · 2011 [cited by applicant]
US 8088379B2 · Robbins et al. · 2012 [cited by applicant]
US 8101741B2 · MacLachlan et al. · 2012 [cited by applicant]
US 8106022B2 · Manoharan et al. · 2012 [cited by applicant]
US 8188263B2 · MacLachlan et al. · 2012 [cited by applicant]
US 8211422B2 · Eshhar et al. · 2012 [cited by applicant]
US 8227432B2 · Hackett et al. · 2012 [cited by applicant]
US 8236943B2 · Lee et al. · 2012 [cited by applicant]
US 8283333B2 · Yaworski et al. · 2012 [cited by applicant]
US 8313772B2 · Rozema et al. · 2012 [cited by applicant]
US 8372951B2 · Chang et al. · 2013 [cited by applicant]
US 8399645B2 · Campana et al. · 2013 [cited by applicant]
US 8404658B2 · Hajjar et al. · 2013 [cited by applicant]
US 8454972B2 · Nabel et al. · 2013 [cited by applicant]
US 8575305B2 · Gait et al. · 2013 [cited by applicant]
US 8614194B1 · Chen et al. · 2013 [cited by applicant]
US 8642295B2 · De Laat et al. · 2014 [cited by applicant]
US 8697359B1 · Zhang · 2014 [cited by applicant]
US 8697854B2 · Schendel et al. · 2014 [cited by applicant]
US 8709843B2 · Shakuda · 2014 [cited by applicant]
US 8771945B1 · Zhang · 2014 [cited by applicant]
US 8771985B2 · Cui et al. · 2014 [cited by applicant]
US 8795965B2 · Zhang · 2014 [cited by applicant]
US 8865406B2 · Zhang et al. · 2014 [cited by applicant]
US 8871445B2 · Cong et al. · 2014 [cited by applicant]
US 8889356B2 · Zhang · 2014 [cited by applicant]
US 8889418B2 · Zhang et al. · 2014 [cited by applicant]
US 8895308B1 · Zhang et al. · 2014 [cited by applicant]
US 8906616B2 · Zhang et al. · 2014 [cited by applicant]
US 8906682B2 · June et al. · 2014 [cited by applicant]
US 8911993B2 · June et al. · 2014 [cited by applicant]
US 8916381B1 · June et al. · 2014 [cited by applicant]
US 8932814B2 · Cong et al. · 2015 [cited by applicant]
US 8945839B2 · Zhang · 2015 [cited by applicant]
US 8975071B1 · June 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 9101584B2 · June et al. · 2015 [cited by applicant]
US 9102760B2 · June et al. · 2015 [cited by applicant]
US 9102761B2 · June et al. · 2015 [cited by applicant]
US 9790490B2 · Zhang · 2017 [cited by examiner]
US 11180751B2 · Koonin · 2021 [cited by examiner]
US 11634755B2 · Zhang · 2023 [cited by examiner]
US 11639523B2 · Zhang · 2023 [cited by examiner]
US 11773432B2 · Zhang · 2023 [cited by examiner]
US 11781172B2 · Zhang · 2023 [cited by examiner]
US 20030087817A1 · Cox et al. · 2003 [cited by applicant]
US 20040013648A1 · Kingsman et al. · 2004 [cited by applicant]
US 20040142476A1 · Evans et al. · 2004 [cited by applicant]
US 20040171156A1 · Hartley et al. · 2004 [cited by applicant]
US 20050019923A1 · Uchegbu et al. · 2005 [cited by applicant]
US 20050287127A1 · Li et al. · 2005 [cited by applicant]
US 20060030837A1 · McKenna et al. · 2006 [cited by applicant]
US 20060281180A1 · Radcliffe et al. · 2006 [cited by applicant]
US 20070025970A1 · Kingsman et al. · 2007 [cited by applicant]
US 20070054961A1 · Maden et al. · 2007 [cited by applicant]
US 20070093878A1 · Edge et al. · 2007 [cited by applicant]
US 20070266453A1 · Anderson et al. · 2007 [cited by applicant]
US 20080267903A1 · Uchegbu et al. · 2008 [cited by applicant]
US 20080267929A1 · Li et al. · 2008 [cited by applicant]
US 20090007284A1 · Radcliffe et al. · 2009 [cited by applicant]
US 20090017543A1 · Wilkes et al. · 2009 [cited by applicant]
US 20090018016A1 · Duck et al. · 2009 [cited by applicant]
US 20090029861A1 · Feng et al. · 2009 [cited by applicant]
US 20090100536A1 · Adams et al. · 2009 [cited by applicant]
US 20090111106A1 · Mitrophanous et al. · 2009 [cited by applicant]
US 20090144850A1 · Van et al. · 2009 [cited by applicant]
US 20090222937A1 · Arnould et al. · 2009 [cited by applicant]
US 20090271881A1 · Arnould et al. · 2009 [cited by applicant]
US 20100229252A1 · Perez-Michaut · 2010 [cited by applicant]
US 20100311124A1 · Liu et al. · 2010 [cited by applicant]
US 20100317109A1 · Maden et al. · 2010 [cited by applicant]
US 20110016540A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110023139A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110023144A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110023145A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110023146A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110023153A1 · Weinstein et al. · 2011 [cited by applicant]
US 20110091441A1 · Gouble et al. · 2011 [cited by applicant]
US 20110117189A1 · Mazzone et al. · 2011 [cited by applicant]
US 20110142917A1 · Alpert et al. · 2011 [cited by applicant]
US 20110182867A1 · Orkin et al. · 2011 [cited by applicant]
US 20110195123A1 · Shemi · 2011 [cited by applicant]
US 20110225664A1 · Smith · 2011 [cited by applicant]
US 20110230839A1 · Bahrami et al. · 2011 [cited by applicant]
US 20110293571A1 · Widdowson et al. · 2011 [cited by applicant]
US 20110293703A1 · Mahon et al. · 2011 [cited by applicant]
US 20120159653A1 · Weinstein et al. · 2012 [cited by applicant]
US 20120164118A1 · Trobridge et al. · 2012 [cited by applicant]
US 20120251560A1 · Dahlman et al. · 2012 [cited by applicant]
US 20120251618A1 · Schrum et al. · 2012 [cited by applicant]
US 20120295960A1 · Palfi et al. · 2012 [cited by applicant]
US 20120328580A1 · Edge et al. · 2012 [cited by applicant]
US 20130071414A1 · Dotti et al. · 2013 [cited by applicant]
US 20130145487A1 · Cedrone · 2013 [cited by applicant]
US 20130202678A1 · Yu et al. · 2013 [cited by applicant]
US 20130236946A1 · Gouble · 2013 [cited by applicant]
US 20130244279A1 · De Fougerolles et al. · 2013 [cited by applicant]
US 20130245107A1 · De Fougerolles et al. · 2013 [cited by applicant]
US 20130252281A1 · De Fougerolles et al. · 2013 [cited by applicant]
US 20130253040A1 · Miller et al. · 2013 [cited by applicant]
US 20130302401A1 · Ma et al. · 2013 [cited by applicant]
US 20140170753A1 · Zhang · 2014 [cited by applicant]
US 20140179006A1 · Zhang · 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 20140189896A1 · Zhang et al. · 2014 [cited by applicant]
US 20140227787A1 · Zhang · 2014 [cited by applicant]
US 20140234972A1 · Zhang · 2014 [cited by applicant]
US 20140242664A1 · Zhang et al. · 2014 [cited by applicant]
US 20140242699A1 · Zhang · 2014 [cited by applicant]
US 20140242700A1 · Zhang et al. · 2014 [cited by applicant]
US 20140248702A1 · Zhang et al. · 2014 [cited by applicant]
US 20140256046A1 · Zhang et al. · 2014 [cited by applicant]
US 20140273231A1 · Zhang et al. · 2014 [cited by applicant]
US 20140273232A1 · Zhang et al. · 2014 [cited by applicant]
US 20140273234A1 · Zhang et al. · 2014 [cited by applicant]
US 20140287938A1 · Zhang et al. · 2014 [cited by applicant]
US 20140310830A1 · Zhang et al. · 2014 [cited by applicant]
US 20140335620A1 · Zhang et al. · 2014 [cited by applicant]
US 20140342456A1 · Mali et al. · 2014 [cited by applicant]
US 20140356959A1 · Church et al. · 2014 [cited by applicant]
US 20140357530A1 · Zhang et al. · 2014 [cited by applicant]
US 20150031132A1 · Church et al. · 2015 [cited by applicant]
US 20150184139A1 · Zhang et al. · 2015 [cited by applicant]
US 20150232881A1 · Glucksmann et al. · 2015 [cited by applicant]
US 20160208243A1 · Abudayyeh et al. · 2016 [cited by applicant]
US 20170211142A1 · Smargon et al. · 2017 [cited by applicant]
US 20170349914A1 · Cox et al. · 2017 [cited by applicant]
US 20180010134A1 · Sharp et al. · 2018 [cited by applicant]
US 20180044662A1 · Platt et al. · 2018 [cited by applicant]
US 20180057810A1 · Zhang et al. · 2018 [cited by applicant]
CN 104004782A · 2014 [cited by applicant]
EP 0242246A1 · 1987 [cited by applicant]
EP 0333033A1 · 1989 [cited by applicant]
EP 0719338B1 · 2003 [cited by applicant]
EP 0571427B1 · 2003 [cited by applicant]
EP 0728213B1 · 2004 [cited by applicant]
EP 1519714A1 · 2005 [cited by applicant]
EP 0663956B1 · 2005 [cited by applicant]
EP 1664316A1 · 2006 [cited by applicant]
EP 1766035A1 · 2007 [cited by applicant]
EP 1781593A2 · 2007 [cited by applicant]
EP 1887079A1 · 2008 [cited by applicant]
EP 1950303A1 · 2008 [cited by applicant]
EP 2099905A1 · 2009 [cited by applicant]
EP 2099915A1 · 2009 [cited by applicant]
EP 1794306B1 · 2009 [cited by applicant]
EP 2764103A2 · 2014 [cited by applicant]
EP 2771468A1 · 2014 [cited by applicant]
EP 2784162A1 · 2014 [cited by applicant]
JP 2006304779A · 2006 [cited by applicant]
WO 9116024A1 · 1991 [cited by applicant]
WO 9117424A1 · 1991 [cited by applicant]
WO 9215322A1 · 1992 [cited by applicant]
WO 9302197A1 · 1993 [cited by applicant]
WO 9319181A1 · 1993 [cited by applicant]
WO 9324641A2 · 1993 [cited by applicant]
WO 9400992A1 · 1994 [cited by applicant]
WO 9404693A2 · 1994 [cited by applicant]
WO 9409144A1 · 1994 [cited by applicant]
WO 9411188A1 · 1994 [cited by applicant]
WO 9411520A2 · 1994 [cited by applicant]
WO 9504826A1 · 1995 [cited by applicant]
WO 9526407A1 · 1995 [cited by applicant]
WO 9531553A1 · 1995 [cited by applicant]
WO 9535026A1 · 1995 [cited by applicant]
WO 9601904A1 · 1996 [cited by applicant]
WO 9615248A1 · 1996 [cited by applicant]
WO 9619581A1 · 1996 [cited by applicant]
WO 9621023A1 · 1996 [cited by applicant]
WO 9627674A1 · 1996 [cited by applicant]
WO 9630517A1 · 1996 [cited by applicant]
WO 9634968A2 · 1996 [cited by applicant]
WO 9638567A2 · 1996 [cited by applicant]
WO 9639154A1 · 1996 [cited by applicant]
WO 9703211A1 · 1997 [cited by applicant]
WO 9720936A1 · 1997 [cited by applicant]
WO 9726362A1 · 1997 [cited by applicant]
WO 9732985A1 · 1997 [cited by applicant]
WO 9741228A2 · 1997 [cited by applicant]
WO 9742328A1 · 1997 [cited by applicant]
WO 9744472A1 · 1997 [cited by applicant]
WO 9745545A1 · 1997 [cited by applicant]
WO 9747806A1 · 1997 [cited by applicant]
WO 9747807A1 · 1997 [cited by applicant]
WO 9747808A1 · 1997 [cited by applicant]
WO 9820145A2 · 1998 [cited by applicant]
WO 9822604A1 · 1998 [cited by applicant]
WO 9827212A1 · 1998 [cited by applicant]
WO 9832326A2 · 1998 [cited by applicant]
WO 9839460A1 · 1998 [cited by applicant]
WO 9840503A1 · 1998 [cited by applicant]
WO 9912950A2 · 1999 [cited by applicant]
WO 9924585A1 · 1999 [cited by applicant]
WO 9924586A1 · 1999 [cited by applicant]
WO 9924593A1 · 1999 [cited by applicant]
WO 9953072A1 · 1999 [cited by applicant]
WO 9958654A2 · 1999 [cited by applicant]
WO 9958688A2 · 1999 [cited by applicant]
WO 9958690A2 · 1999 [cited by applicant]
WO 9966050A1 · 1999 [cited by applicant]
WO 0004173A1 · 2000 [cited by applicant]
WO 0008175A2 · 2000 [cited by applicant]
WO 0008184A1 · 2000 [cited by applicant]
WO 0008185A1 · 2000 [cited by applicant]
WO 0011192A2 · 2000 [cited by applicant]
WO 0014249A1 · 2000 [cited by applicant]
WO 0022140A1 · 2000 [cited by applicant]
WO 0028052A2 · 2000 [cited by applicant]
WO 0047727A2 · 2000 [cited by applicant]
WO 0073422A1 · 2000 [cited by applicant]
WO 0077229A2 · 2000 [cited by applicant]
WO 0112782A2 · 2001 [cited by applicant]
WO 0112826A2 · 2001 [cited by applicant]
WO 0114569A2 · 2001 [cited by applicant]
WO 0119975A2 · 2001 [cited by applicant]
WO 0198509A2 · 2001 [cited by applicant]
WO 0231826A2 · 2002 [cited by applicant]
WO 0234923A2 · 2002 [cited by applicant]
WO 0246387A2 · 2002 [cited by applicant]
WO 02079410A2 · 2002 [cited by applicant]
WO 02083911A1 · 2002 [cited by applicant]
WO 02101059A2 · 2002 [cited by applicant]
WO 03020763A2 · 2003 [cited by applicant]
WO 03033540A2 · 2003 [cited by applicant]
WO 03071860A2 · 2003 [cited by applicant]
WO 2004033685A1 · 2004 [cited by applicant]
WO 2004044004A2 · 2004 [cited by applicant]
WO 2004056999A1 · 2004 [cited by applicant]
WO 2004074322A1 · 2004 [cited by applicant]
WO 2004078983A2 · 2004 [cited by applicant]
WO 2004090140A2 · 2004 [cited by applicant]
WO 2005002359A2 · 2005 [cited by applicant]
WO 2005012515A2 · 2005 [cited by applicant]
WO 2005012529A1 · 2005 [cited by applicant]
WO 2005030941A1 · 2005 [cited by applicant]
WO 2005030942A1 · 2005 [cited by applicant]
WO 2005095617A2 · 2005 [cited by applicant]
WO 2005095618A2 · 2005 [cited by applicant]
WO 2005095619A1 · 2005 [cited by applicant]
WO 2005095632A2 · 2005 [cited by applicant]
WO 2005107437A2 · 2005 [cited by applicant]
WO 2005113595A2 · 2005 [cited by applicant]
WO 2005114215A2 · 2005 [cited by applicant]
WO 2005123927A1 · 2005 [cited by applicant]
WO 2006000830A2 · 2006 [cited by applicant]
WO 2006018319A1 · 2006 [cited by applicant]
WO 2006032538A1 · 2006 [cited by applicant]
WO 2006045633A1 · 2006 [cited by applicant]
WO 2006063862A1 · 2006 [cited by applicant]
WO 2006072603A2 · 2006 [cited by applicant]
WO 2006103107A1 · 2006 [cited by applicant]
WO 2006108702A1 · 2006 [cited by applicant]
WO 2006125962A2 · 2006 [cited by applicant]
WO 2006133827A2 · 2006 [cited by applicant]
WO 2007009823A1 · 2007 [cited by applicant]
WO 2007039314A2 · 2007 [cited by applicant]
WO 2007039315A1 · 2007 [cited by applicant]
WO 2007039316A1 · 2007 [cited by applicant]
WO 2007107326A1 · 2007 [cited by applicant]
WO 2008038002A2 · 2008 [cited by applicant]
WO 2008039818A2 · 2008 [cited by applicant]
WO 2008076556A2 · 2008 [cited by applicant]
WO 2009144079A1 · 2009 [cited by applicant]
WO 2010061186A2 · 2010 [cited by applicant]
WO 2011028929A3 · 2011 [cited by applicant]
WO 2011146862A1 · 2011 [cited by applicant]
WO 2012079000A1 · 2012 [cited by applicant]
WO 2012135025A2 · 2012 [cited by applicant]
WO 201404724 · 2012 [cited by applicant]
WO 2013039889A1 · 2013 [cited by applicant]
WO 2013040371A2 · 2013 [cited by applicant]
WO 2013046247A1 · 2013 [cited by applicant]
WO 2013122472A1 · 2013 [cited by applicant]
WO 2013126794A1 · 2013 [cited by applicant]
WO 2013130824A1 · 2013 [cited by applicant]
WO 2013163628A2 · 2013 [cited by applicant]
WO 2013166321A1 · 2013 [cited by applicant]
WO 2013176915A1 · 2013 [cited by applicant]
WO 2014011987A1 · 2014 [cited by applicant]
WO 2014018423A2 · 2014 [cited by applicant]
WO 2014018863A1 · 2014 [cited by applicant]
WO 2014059173A2 · 2014 [cited by applicant]
WO 2014066505A1 · 2014 [cited by applicant]
WO 2014083173A1 · 2014 [cited by applicant]
WO 2014093595A1 · 2014 [cited by applicant]
WO 2014093622A2 · 2014 [cited by applicant]
WO 2014093635A1 · 2014 [cited by applicant]
WO 2014093655A2 · 2014 [cited by applicant]
WO 2014093661A2 · 2014 [cited by applicant]
WO 2014093694A1 · 2014 [cited by applicant]
WO 2014093701A1 · 2014 [cited by applicant]
WO 2014093709A1 · 2014 [cited by applicant]
WO 2014093712A1 · 2014 [cited by applicant]
WO 2014093718A1 · 2014 [cited by applicant]
WO 2014118272A1 · 2014 [cited by applicant]
WO 2014134165A1 · 2014 [cited by applicant]
WO 2014172606A1 · 2014 [cited by applicant]
WO 2014184744A1 · 2014 [cited by applicant]
WO 2014191128A1 · 2014 [cited by applicant]
WO 2014204723A1 · 2014 [cited by applicant]
WO 2014204724A1 · 2014 [cited by applicant]