IP Library › Granted Patent US 12,371,504
Granted Patent B2
US 12,371,504 · App. 17/475,216 · Granted Jul 29, 2025

Trispecific proteins and methods of use

Inventors: Holger Wesche (San Francisco, CA); Bryan D. Lemon (Mountain View, CA); Richard J. Austin (San Francisco, CA)
Assignee: Harpoon Therapeutics, Inc.
C07K16/2878A61K39/395A61P35/00C07K16/18C07K16/2809C07K2317/21C07K2317/24C07K2317/31C07K2317/56C07K2317/565C07K2317/569C07K2317/622C07K2317/732C07K2317/76C07K2317/92C07K2319/30C07K2319/31
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Quick Facts
Patent No.
US 12,371,504
App. No.
17/475,216
Granted
Jul 29, 2025
Kind
B2
Abstract

Provided herein are B cell maturation agent (BCMA) targeting trispecific proteins comprising a domain binding to CD3, a half-life extension domain, and a domain binding to BCMA. Also provided are pharmaceutical compositions thereof, as well as nucleic acids, recombinant expression vectors and host cells for making such BCMA targeting trispecific proteins. Also disclosed are methods of using the disclosed BCMA targeting trispecific proteins in the prevention, and/or treatment diseases, conditions and disorders.

Claims (34)

1. A method for treating a cancer in a human subject having the cancer, comprising administering to the subject a pharmaceutical composition comprising a B cell maturation agent (BCMA) binding trispecific protein that comprises:

(a) a first domain (A) which is a single chain variable fragment (scFv) that specifically binds to a human CD3ε;

(b) a second domain (B) which is a single domain antibody that specifically binds to a human serum albumin protein; and

(c) a third domain (C) which is a single domain antibody that specifically binds to a human BCMA comprising the sequence of SEQ ID NO: 468,

wherein the third domain comprises complementarity determining regions CDR1, CDR2, and CDR3,

wherein the CDR1 comprises the amino acid sequence of SEQ ID NO: 76, the CDR2 comprises the amino acid sequence of SEQ ID NO: 190, and the CDR3 comprises the amino acid sequence of SEQ ID NO: 304, and

wherein the cancer expresses BCMA.

2. The method of claim 1 , wherein the cancer is a leukemia, a lymphoma, a multiple myeloma, or a metastasis thereof.

3. The method of claim 1 , wherein the cancer is a multiple myeloma.

4. The method of claim 3 , wherein the multiple myeloma is a smoldering multiple myeloma, a non-secretory myeloma, or an osteosclerotic myeloma.

5. The method of claim 1 , wherein the third domain comprises the following formula: f1-r1-f2-r2-f3-r3-f4,

wherein, r1 is the CDR1; r2 is the CDR2; and r3 is the CDR3; and wherein f1, f2, f3 and f4 are framework regions selected so that said third domain comprises an amino acid sequence that is from about 80% to about 99% identical to the amino acid sequence set forth in SEQ ID NO: 346 or SEQ ID NO: 598.

6. The method of claim 5 , wherein f1 comprises SEQ ID NO: 461 or 462, f2 comprises SEQ ID NO: 463, f3 comprises SEQ ID NO: 464 or 465, and f4 comprises SEQ ID NO: 466 or 467.

7. The method of claim 1 , wherein the BCMA binding trispecific protein further comprises linkers L1 and L2, wherein the domains of the protein are linked in the order H 2 N-(A)-L1-(C)-L2-(B)—COOH, H 2 N—(B)-L1-(A)-L2-(C)—COOH, H 2 N—(C)-L1-(B)-L2-(A)-COOH, H 2 N—(C)-L1-(A)-L2-(B)—COOH, H 2 N-(A)-L1-(B)-L2-(C)—COOH or H 2 N—(B)-L1-(C)-L2-(A)-COOH.

8. The method of claim 7 , wherein the domains are linked in the order H 2 N—(C)-L1-(B)-L2-(A)-COOH.

9. The method of claim 1 , wherein the third domain comprises a sequence that is at least 80% identical to SEQ ID NO: 383.

10. The method of claim 1 , wherein the third domain comprises a sequence that is at least 90% identical to SEQ ID NO: 383.

11. The method of claim 1 , wherein the third domain comprises a sequence that is at least 95% identical to SEQ ID NO: 383.

12. The method of claim 1 , wherein the third domain comprises a sequence that is at least 99% identical to SEQ ID NO: 383.

13. The method of claim 1 , wherein:

the first domain (A) comprises heavy chain complementary determining regions HC CDR1, HC CDR2, and HC CDR3 and light chain complementary determining regions LC CDR1, LC CDR2, and LC CDR3; and wherein the HC CDR1 comprises the amino acid sequence of GFTFNKYAIN (amino acid residues 278-287 of SEQ ID NO: 520), the HC CDR2 comprises the amino acid sequence of RIRSKYNNYATYYADQVK (amino acid residues 302-319 of SEQ ID NO: 520), and the HC CDR3 comprises the amino acid sequence of HANFGNSYISYWAY (amino acid residues 353-366 of SEQ ID NO: 520); and wherein the LC CDR1 comprises the amino acid sequence of ASSTGAVTSGNYPN (amino acid residues 415-428 of SEQ ID NO: 520), the LC CDR2 comprises the amino acid sequence of GTKFLVP (amino acid residues 444-450 of SEQ ID NO: 520), and the LC CDR3 comprises the amino acid sequence of TLWYSNRWV (amino acid residues 483-491 of SEQ ID NO: 520); and

the second domain (B) comprises complementarity determining regions CDR1, CDR2, and CDR3, and wherein the CDR1 comprises the amino acid sequence of GFTFSKFGMS (amino acid residues 154-163 of SEQ ID NO: 520), the CDR2 comprises the amino acid sequence of SISGSGRDTLYADSVK (amino acid residues 178-193 of SEQ ID NO: 520), and the CDR3 comprises the amino acid sequence of GGSLSV (amino acid residues 227-232 of SEQ ID NO: 520).

14. The method of claim 13 , wherein the BCMA binding trispecific protein comprises a sequence that is at least 80% identical to SEQ ID NO: 520.

15. The method of claim 13 , wherein the BCMA binding trispecific protein comprises a sequence that is at least 90% identical to SEQ ID NO: 520.

16. The method of claim 13 , wherein the BCMA binding trispecific protein comprises a sequence that is at least 95% identical to SEQ ID NO: 520.

17. The method of claim 13 , wherein the BCMA binding trispecific protein comprises a sequence that is at least 99% identical to SEQ ID NO: 520.

18. The method of claim 1 , wherein the BCMA binding trispecific protein has an elimination half-time of at least 12 hours, wherein the elimination half-time is measured in the human subject after the BCMA binding trispecific protein is administered to the human subject.

19. The method of claim 18 , wherein the BCMA binding trispecific protein has an elimination half-time of at least 20 hours, wherein the elimination half-time is measured in the human subject after the BCMA binding trispecific protein is administered to the human subject.

20. The method of claim 1 , wherein the BCMA binding trispecific protein is less than about 80 kDa.

21. The method of claim 20 , wherein the BCMA binding trispecific protein is less than about 75 kDa.

22. The method of claim 12 , wherein the third domain comprises the amino acid sequence of SEQ ID NO: 383.

23. The method of claim 17 , wherein the BCMA binding trispecific protein comprises the amino acid sequence of SEQ ID NO: 520.

24. The method of claim 1 , wherein the first domain comprises heavy chain complementary determining regions HC CDR1, HC CDR2, and HC CDR3 and light chain complementary determining regions LC CDR1, LC CDR2, and LC CDR3; and wherein the HC CDR1 comprises the amino acid sequence of GFTFNKYAIN (amino acid residues 278-287 of SEQ ID NO: 520), the HC CDR2 comprises the amino acid sequence of RIRSKYNNYATYYADQVK (amino acid residues 302-319 of SEQ ID NO: 520), and the HC CDR3 comprises the amino acid sequence of HANFGNSYISYWAY (amino acid residues 353-366 of SEQ ID NO: 520); and wherein the LC CDR1 comprises the amino acid sequence of ASSTGAVTSGNYPN (amino acid residues 415-428 of SEQ ID NO: 520), the LC CDR2 comprises the amino acid sequence of GTKFLVP (amino acid residues 444-450 of SEQ ID NO: 520), and the LC CDR3 comprises the amino acid sequence of TLWYSNRWV (amino acid residues 483-491 of SEQ ID NO: 520).

25. The method of claim 1 , wherein the second domain (B) comprises complementarity determining regions CDR1, CDR2, and CDR3, and wherein the CDR1 comprises the amino acid sequence of GFTFSKFGMS (amino acid residues 154-163 of SEQ ID NO: 520), the CDR2 comprises the amino acid sequence of SISGSGRDTLYADSVK (amino acid residues 178-193 of SEQ ID NO: 520), and the CDR3 comprises the amino acid sequence of GGSLSV (amino acid residues 227-232 of SEQ ID NO: 520).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 14, 2021
From: WESCHE, HOLGER; LEMON, BRYAN D.; AUSTIN, RICHARD J.
To: HARPOON THERAPEUTICS, INC.
Reel/Frame 057481/0928 →
Continuity (3)
Continuation 16159554 · Oct 12, 2018
Provisional Application 62572381 · Oct 13, 2017
Related Publication 20220112297A1 · Apr 14, 2022
References Cited (400)
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 4943533A · Mendelsohn et al. · 1990 [cited by applicant]
US 5061620A · Tsukamoto et al. · 1991 [cited by applicant]
US 5199942A · Gillis · 1993 [cited by applicant]
US 5225539A · Winter · 1993 [cited by applicant]
US 5350674A · Boenisch et al. · 1994 [cited by applicant]
US 5399346A · Anderson et al. · 1995 [cited by applicant]
US 5530101A · Queen et al. · 1996 [cited by applicant]
US 5565332A · Hoogenboom et al. · 1996 [cited by applicant]
US 5580859A · Felgner et al. · 1996 [cited by applicant]
US 5585089A · Queen et al. · 1996 [cited by applicant]
US 5585362A · Wilson et al. · 1996 [cited by applicant]
US 5589466A · Felgner et al. · 1996 [cited by applicant]
US 5759808A · Casterman et al. · 1998 [cited by applicant]
US 5766886A · Studnicka et al. · 1998 [cited by applicant]
US 5773292A · Bander · 1998 [cited by applicant]
US 5800988A · Casterman et al. · 1998 [cited by applicant]
US 5811097A · Allison et al. · 1998 [cited by applicant]
US 5840526A · Casterman et al. · 1998 [cited by applicant]
US 5843439A · Anderson et al. · 1998 [cited by applicant]
US 5844093A · Kettleborough et al. · 1998 [cited by applicant]
US 5858358A · June et al. · 1999 [cited by applicant]
US 5859205A · Adair et al. · 1999 [cited by applicant]
US 5874541A · Casterman et al. · 1999 [cited by applicant]
US 5883223A · Gray · 1999 [cited by applicant]
US 5977318A · Linsley et al. · 1999 [cited by applicant]
US 6005079A · Casterman et al. · 1999 [cited by applicant]
US 6015695A · Casterman et al. · 2000 [cited by applicant]
US 6051227A · Allison et al. · 2000 [cited by applicant]
US 6107090A · Bander · 2000 [cited by applicant]
US 6120766A · Hale et al. · 2000 [cited by applicant]
US 6136311A · Bander · 2000 [cited by applicant]
US 6210669B1 · Aruffo et al. · 2001 [cited by applicant]
US 6303121B1 · Kwon · 2001 [cited by applicant]
US 6326193B1 · Liu et al. · 2001 [cited by applicant]
US 6331415B1 · Cabilly et al. · 2001 [cited by applicant]
US 6352694B1 · June et al. · 2002 [cited by applicant]
US 6355476B1 · Kwon et al. · 2002 [cited by applicant]
US 6362325B1 · Kwon · 2002 [cited by applicant]
US 6407213B1 · Carter et al. · 2002 [cited by applicant]
US 6534055B1 · June et al. · 2003 [cited by applicant]
US 6548640B1 · Winter · 2003 [cited by applicant]
US 6569997B1 · Kwon · 2003 [cited by applicant]
US 6670453B2 · Frenken et al. · 2003 [cited by applicant]
US 6682736B1 · Hanson et al. · 2004 [cited by applicant]
US 6692964B1 · June et al. · 2004 [cited by applicant]
US 6759518B1 · Kontermann et al. · 2004 [cited by applicant]
US 6767711B2 · Bander · 2004 [cited by applicant]
US 6797514B2 · Berenson et al. · 2004 [cited by applicant]
US 6808710B1 · Wood 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 6887673B2 · Kunkel 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 6905685B2 · Kwon · 2005 [cited by applicant]
US 6905874B2 · Berenson et al. · 2005 [cited by applicant]
US 6974863B2 · Kwon · 2005 [cited by applicant]
US 6984720B1 · Korman et al. · 2006 [cited by applicant]
US 7034121B2 · Carreno et al. · 2006 [cited by applicant]
US 7060808B1 · Goldstein et al. · 2006 [cited by applicant]
US 7067318B2 · June et al. · 2006 [cited by applicant]
US 7144575B2 · June et al. · 2006 [cited by applicant]
US 7163680B2 · Bander · 2007 [cited by applicant]
US 7172869B2 · June et al. · 2007 [cited by applicant]
US 7175843B2 · June et al. · 2007 [cited by applicant]
US 7214493B2 · Kunkel et al. · 2007 [cited by applicant]
US 7232566B2 · June et al. · 2007 [cited by applicant]
US 7247301B2 · van de Winkel et al. · 2007 [cited by applicant]
US 7262276B2 · Huang et al. · 2007 [cited by applicant]
US 7288638B2 · Jure-Kunkel et al. · 2007 [cited by applicant]
US 7488802B2 · Collins et al. · 2009 [cited by applicant]
US 7595378B2 · van de Winkel et al. · 2009 [cited by applicant]
US 7605238B2 · Korman et al. · 2009 [cited by applicant]
US 7666414B2 · Bander · 2010 [cited by applicant]
US 7723484B2 · Beidler et al. · 2010 [cited by applicant]
US 7807162B2 · Silence · 2010 [cited by applicant]
US 7812135B2 · Smith et al. · 2010 [cited by applicant]
US 7850971B2 · Maddon et al. · 2010 [cited by applicant]
US 7939072B2 · Yarden et al. · 2011 [cited by applicant]
US 7943743B2 · Korman et al. · 2011 [cited by applicant]
US 8008449B2 · Korman et al. · 2011 [cited by applicant]
US 8114965B2 · Maddon et al. · 2012 [cited by applicant]
US 8153768B2 · Kunz et al. · 2012 [cited by applicant]
US 8168757B2 · Finnefrock et al. · 2012 [cited by applicant]
US 8188223B2 · Beirnaert et al. · 2012 [cited by applicant]
US 8236308B2 · Kischel et al. · 2012 [cited by applicant]
US 8354509B2 · Carven et al. · 2013 [cited by applicant]
US 8388967B2 · Smith et al. · 2013 [cited by applicant]
US 8470330B2 · Schuelke et al. · 2013 [cited by applicant]
US 8552156B2 · Takayanagi et al. · 2013 [cited by applicant]
US 8609089B2 · Langermann et al. · 2013 [cited by applicant]
US 8623356B2 · Christopherson et al. · 2014 [cited by applicant]
US 8629244B2 · Kolkman et al. · 2014 [cited by applicant]
US 8703135B2 · Beste et al. · 2014 [cited by applicant]
US 8709424B2 · Schebye et al. · 2014 [cited by applicant]
US 8779105B2 · Korman et al. · 2014 [cited by applicant]
US 8784821B1 · Kufer et al. · 2014 [cited by applicant]
US 8846042B2 · Zhou · 2014 [cited by applicant]
US 8900587B2 · Carven et al. · 2014 [cited by applicant]
US 8907071B2 · Sullivan et al. · 2014 [cited by applicant]
US 8937164B2 · Descamps et al. · 2015 [cited by applicant]
US 8986972B2 · Stull et al. · 2015 [cited by applicant]
US 9089615B2 · Stull et al. · 2015 [cited by applicant]
US 9089616B2 · Stull et al. · 2015 [cited by applicant]
US 9089617B2 · Stull et al. · 2015 [cited by applicant]
US 9090683B2 · Stull et al. · 2015 [cited by applicant]
US 9107961B2 · Stull et al. · 2015 [cited by applicant]
US 9126984B2 · Crosignani et al. · 2015 [cited by applicant]
US 9127071B2 · Yoshida et al. · 2015 [cited by applicant]
US 9133271B1 · Stull et al. · 2015 [cited by applicant]
US 9155803B1 · Stull et al. · 2015 [cited by applicant]
US 9169316B2 · Baty et al. · 2015 [cited by applicant]
US 9309327B2 · Humphreys et al. · 2016 [cited by applicant]
US 9327022B2 · Zhang et al. · 2016 [cited by applicant]
US 9334318B1 · Stull et al. · 2016 [cited by applicant]
US 9340621B2 · Kufer · 2016 [cited by applicant]
US 9345787B2 · Hemminki et al. · 2016 [cited by applicant]
US 9352051B1 · Stull et al. · 2016 [cited by applicant]
US 9353182B2 · Stull et al. · 2016 [cited by applicant]
US 9358304B1 · Stull et al. · 2016 [cited by applicant]
US 9359442B2 · Hoffee et al. · 2016 [cited by applicant]
US 9422368B2 · Spee et al. · 2016 [cited by applicant]
US 9480757B2 · Stull et al. · 2016 [cited by applicant]
US 9481724B2 · Ravetch et al. · 2016 [cited by applicant]
US 9486537B2 · Stull et al. · 2016 [cited by applicant]
US 9624185B1 · Xu · 2017 [cited by applicant]
US 9642918B2 · Bruederle et al. · 2017 [cited by applicant]
US 9708412B2 · Baeuerle et al. · 2017 [cited by applicant]
US 9764042B1 · Stull et al. · 2017 [cited by applicant]
US 9770518B1 · Stull et al. · 2017 [cited by applicant]
US 9775916B1 · Stull et al. · 2017 [cited by applicant]
US 9855343B2 · Stull et al. · 2018 [cited by applicant]
US 9861708B2 · Stull et al. · 2018 [cited by applicant]
US 9867887B1 · Stull et al. · 2018 [cited by applicant]
US 9878053B2 · Stull et al. · 2018 [cited by applicant]
US 9920115B2 · Dubridge et al. · 2018 [cited by applicant]
US 9931420B2 · Stull et al. · 2018 [cited by applicant]
US 9931421B2 · Stull et al. · 2018 [cited by applicant]
US 9937268B2 · Stull et al. · 2018 [cited by applicant]
US 10066016B2 · Dubridge et al. · 2018 [cited by applicant]
US 10100106B2 · Dubridge et al. · 2018 [cited by applicant]
US 10137204B2 · Stull et al. · 2018 [cited by applicant]
US 10428120B2 · Kontermann et al. · 2019 [cited by applicant]
US 10543271B2 · Wesche et al. · 2020 [cited by applicant]
US 10544221B2 · Dubridge et al. · 2020 [cited by applicant]
US 10730954B2 · Wesche et al. · 2020 [cited by applicant]
US 10752694B2 · Kufer · 2020 [cited by examiner]
US 10815311B2 · Wesche et al. · 2020 [cited by applicant]
US 10844134B2 · Baeuerle et al. · 2020 [cited by applicant]
US 10849973B2 · Dubridge et al. · 2020 [cited by applicant]
US 10927180B2 · Wesche et al. · 2021 [cited by applicant]
US 10954311B2 · Baeuerle et al. · 2021 [cited by applicant]
US 11111311B2 · Yoshida et al. · 2021 [cited by applicant]
US 11136403B2 · Wesche et al. · 2021 [cited by applicant]
US 20020015704A1 · Bander · 2002 [cited by applicant]
US 20020051780A1 · Lindhofer et al. · 2002 [cited by applicant]
US 20020081296A1 · Theill et al. · 2002 [cited by applicant]
US 20030031673A1 · Bander · 2003 [cited by applicant]
US 20030092892A1 · Frenken et al. · 2003 [cited by applicant]
US 20040101519A1 · June et al. · 2004 [cited by applicant]
US 20050042664A1 · Wu et al. · 2005 [cited by applicant]
US 20050048617A1 · Wu et al. · 2005 [cited by applicant]
US 20050095244A1 · Jure-Kunkel et al. · 2005 [cited by applicant]
US 20050100543A1 · Hansen et al. · 2005 [cited by applicant]
US 20050175606A1 · Huang et al. · 2005 [cited by applicant]
US 20060034810A1 · Riley et al. · 2006 [cited by applicant]
US 20060046971A1 · Stuhler et al. · 2006 [cited by applicant]
US 20060121005A1 · Berenson et al. · 2006 [cited by applicant]
US 20060228364A1 · Dennis et al. · 2006 [cited by applicant]
US 20060252096A1 · Zha et al. · 2006 [cited by applicant]
US 20070014794A1 · Carter et al. · 2007 [cited by applicant]
US 20070178082A1 · Silence et al. · 2007 [cited by applicant]
US 20070269422A1 · Beirnaert et al. · 2007 [cited by applicant]
US 20080069772A1 · Stuhler et al. · 2008 [cited by applicant]
US 20080260757A1 · Holt et al. · 2008 [cited by applicant]
US 20090041789A1 · Elsaesser-Beile et al. · 2009 [cited by applicant]
US 20090117108A1 · Wang et al. · 2009 [cited by applicant]
US 20090136485A1 · Chu et al. · 2009 [cited by applicant]
US 20090136494A1 · Ponath et al. · 2009 [cited by applicant]
US 20090259026A1 · Tomlinson et al. · 2009 [cited by applicant]
US 20100022452A1 · Silence · 2010 [cited by applicant]
US 20100028330A1 · Collins et al. · 2010 [cited by applicant]
US 20100122358A1 · Bruggemann et al. · 2010 [cited by applicant]
US 20100150918A1 · Kufer et al. · 2010 [cited by applicant]
US 20100166734A1 · Dolk · 2010 [cited by applicant]
US 20100189651A1 · Stagliano et al. · 2010 [cited by applicant]
US 20100189727A1 · Rodeck et al. · 2010 [cited by applicant]
US 20100266531A1 · Hsieh et al. · 2010 [cited by applicant]
US 20100291112A1 · Kellner et al. · 2010 [cited by applicant]
US 20100311119A1 · Hermans et al. · 2010 [cited by applicant]
US 20110129458A1 · Dolk et al. · 2011 [cited by applicant]
US 20110150892A1 · Thudium et al. · 2011 [cited by applicant]
US 20110165621A1 · Dreier et al. · 2011 [cited by applicant]
US 20110262439A1 · Kufer et al. · 2011 [cited by applicant]
US 20110275787A1 · Kufer et al. · 2011 [cited by applicant]
US 20110313135A1 · Vanhove et al. · 2011 [cited by applicant]
US 20120039899A1 · Olsen et al. · 2012 [cited by applicant]
US 20120039906A1 · Olive · 2012 [cited by applicant]
US 20120114649A1 · Langermann et al. · 2012 [cited by applicant]
US 20120231024A1 · Elsaesser-Beile et al. · 2012 [cited by applicant]
US 20120237977A1 · Daugherty et al. · 2012 [cited by applicant]
US 20120263677A1 · Eagle et al. · 2012 [cited by applicant]
US 20120328619A1 · Fey et al. · 2012 [cited by applicant]
US 20130017199A1 · Langermann · 2013 [cited by applicant]
US 20130017200A1 · Scheer et al. · 2013 [cited by applicant]
US 20130136744A1 · Bouche et al. · 2013 [cited by applicant]
US 20130183321A1 · Smith et al. · 2013 [cited by applicant]
US 20130266568A1 · Brinkmann et al. · 2013 [cited by applicant]
US 20130267686A1 · Brinkmann et al. · 2013 [cited by applicant]
US 20130273055A1 · Borges et al. · 2013 [cited by applicant]
US 20130315906A1 · Lowman et al. · 2013 [cited by applicant]
US 20130330335A1 · Bremel et al. · 2013 [cited by applicant]
US 20140004121A1 · Fanslow, III et al. · 2014 [cited by applicant]
US 20140004575A1 · Ito et al. · 2014 [cited by applicant]
US 20140023664A1 · Lowman et al. · 2014 [cited by applicant]
US 20140044728A1 · Takayanagi et al. · 2014 [cited by applicant]
US 20140045195A1 · Daugherty et al. · 2014 [cited by applicant]
US 20140065152A1 · Kwon · 2014 [cited by applicant]
US 20140072565A1 · Kwon · 2014 [cited by applicant]
US 20140072566A1 · Kwon · 2014 [cited by applicant]
US 20140073767A1 · Lee et al. · 2014 [cited by applicant]
US 20140088295A1 · Smith et al. · 2014 [cited by applicant]
US 20140093511A1 · Lonberg et al. · 2014 [cited by applicant]
US 20140161828A1 · Armitage et al. · 2014 [cited by applicant]
US 20140205601A1 · Beirnaert et al. · 2014 [cited by applicant]
US 20140220002A1 · Ponte et al. · 2014 [cited by applicant]
US 20140242075A1 · Parren et al. · 2014 [cited by applicant]
US 20140302037A1 · Borges et al. · 2014 [cited by applicant]
US 20140308285A1 · Yan et al. · 2014 [cited by applicant]
US 20140322218A1 · Xiao et al. · 2014 [cited by applicant]
US 20140348841A1 · Schebye et al. · 2014 [cited by applicant]
US 20150037334A1 · Kufer et al. · 2015 [cited by applicant]
US 20150056206A1 · Zhou · 2015 [cited by applicant]
US 20150064169A1 · Wang et al. · 2015 [cited by applicant]
US 20150079088A1 · Lowman et al. · 2015 [cited by applicant]
US 20150079093A1 · Stuhler · 2015 [cited by applicant]
US 20150079109A1 · Li et al. · 2015 [cited by applicant]
US 20150093336A1 · Van Ginderachter et al. · 2015 [cited by applicant]
US 20150174268A1 · Li et al. · 2015 [cited by applicant]
US 20150175697A1 · Bonvini et al. · 2015 [cited by applicant]
US 20150183875A1 · Cobbold et al. · 2015 [cited by applicant]
US 20150225367A1 · Crosignani et al. · 2015 [cited by applicant]
US 20150232557A1 · Tan et al. · 2015 [cited by applicant]
US 20150274836A1 · Ho et al. · 2015 [cited by applicant]
US 20150274844A1 · Blankenship et al. · 2015 [cited by applicant]
US 20150328332A1 · Stull et al. · 2015 [cited by applicant]
US 20160017058A1 · Kim et al. · 2016 [cited by applicant]
US 20160024174A1 · Odunsi et al. · 2016 [cited by applicant]
US 20160032011A1 · Zhang et al. · 2016 [cited by applicant]
US 20160032019A1 · Xiao et al. · 2016 [cited by applicant]
US 20160039942A1 · Cobbold et al. · 2016 [cited by applicant]
US 20160046724A1 · Brogdon et al. · 2016 [cited by applicant]
US 20160068605A1 · Nemeth et al. · 2016 [cited by applicant]
US 20160115241A1 · Yan et al. · 2016 [cited by applicant]
US 20160130331A1 · Stull et al. · 2016 [cited by applicant]
US 20160185875A1 · Cheng et al. · 2016 [cited by applicant]
US 20160194399A1 · Irving et al. · 2016 [cited by applicant]
US 20160215063A1 · Bernett et al. · 2016 [cited by applicant]
US 20160229913A1 · Bosques et al. · 2016 [cited by applicant]
US 20160251438A1 · Lucas et al. · 2016 [cited by applicant]
US 20160251440A1 · Roobrouck et al. · 2016 [cited by applicant]
US 20160257721A1 · Lieber et al. · 2016 [cited by applicant]
US 20160263087A1 · Crosignani et al. · 2016 [cited by applicant]
US 20160319040A1 · Dreier et al. · 2016 [cited by applicant]
US 20160340444A1 · Baeuerle et al. · 2016 [cited by applicant]
US 20160355842A1 · Parks et al. · 2016 [cited by applicant]
US 20170029502A1 · Raum et al. · 2017 [cited by applicant]
US 20170037130A1 · Raum et al. · 2017 [cited by applicant]
US 20170037149A1 · Raum et al. · 2017 [cited by applicant]
US 20170051068A1 · Pillarisetti et al. · 2017 [cited by applicant]
US 20170152316A1 · Cobbold et al. · 2017 [cited by applicant]
US 20170158771A1 · Glennie et al. · 2017 [cited by applicant]
US 20170204164A1 · Himmler et al. · 2017 [cited by applicant]
US 20170274094A1 · Stull et al. · 2017 [cited by applicant]
US 20170275373A1 · Kufer et al. · 2017 [cited by applicant]
US 20170306014A1 · Cornen et al. · 2017 [cited by applicant]
US 20170334979A1 · Dubridge et al. · 2017 [cited by applicant]
US 20170334997A1 · Dubridge et al. · 2017 [cited by applicant]
US 20170349660A1 · Saville et al. · 2017 [cited by applicant]
US 20170362310A1 · Shoemaker · 2017 [cited by applicant]
US 20170369563A1 · Dubridge et al. · 2017 [cited by applicant]
US 20180016323A1 · Brandenburg et al. · 2018 [cited by applicant]
US 20180036306A1 · Jones et al. · 2018 [cited by applicant]
US 20180134789A1 · Baeuerle et al. · 2018 [cited by applicant]
US 20180148508A1 · Wang et al. · 2018 [cited by applicant]
US 20180318417A1 · Schuetz et al. · 2018 [cited by applicant]
US 20180326060A1 · Wesche et al. · 2018 [cited by applicant]
US 20180327511A1 · Satoh et al. · 2018 [cited by applicant]
US 20180346601A1 · Dettling et al. · 2018 [cited by applicant]
US 20190016811A1 · Lucas et al. · 2019 [cited by applicant]
US 20190023786A1 · Broderick et al. · 2019 [cited by applicant]
US 20190031749A1 · Dubridge et al. · 2019 [cited by applicant]
US 20190046656A1 · Stull et al. · 2019 [cited by applicant]
US 20190062427A1 · Rosenthal et al. · 2019 [cited by applicant]
US 20190092862A1 · Cui et al. · 2019 [cited by applicant]
US 20190127483A1 · Li · 2019 [cited by applicant]
US 20190225702A1 · Baeuerle et al. · 2019 [cited by applicant]
US 20190247510A1 · Stull et al. · 2019 [cited by applicant]
US 20200115461A1 · Evnin et al. · 2020 [cited by applicant]
US 20200148771A1 · Paeuerle et al. · 2020 [cited by applicant]
US 20200155520A1 · Colburn et al. · 2020 [cited by applicant]
US 20200231672A1 · Dubridge et al. · 2020 [cited by applicant]
US 20200270362A1 · Wesche et al. · 2020 [cited by applicant]
US 20200289646A1 · Wesche et al. · 2020 [cited by applicant]
US 20200352998A1 · Albertson et al. · 2020 [cited by applicant]
US 20210047439A1 · Wesche et al. · 2021 [cited by applicant]
US 20210095047A1 · Baeuerle et al. · 2021 [cited by applicant]
US 20210100902A1 · Dubridge et al. · 2021 [cited by applicant]
US 20210171649A1 · Wesche et al. · 2021 [cited by applicant]
US 20210179735A1 · Baeuerle et al. · 2021 [cited by applicant]
US 20210261671A1 · Wesche et al. · 2021 [cited by applicant]
US 20210269530A1 · Lin et al. · 2021 [cited by applicant]
US 20210284721A1 · Stagliano · 2021 [cited by applicant]
US 20210284728A1 · Lin et al. · 2021 [cited by applicant]
US 20210292421A1 · Lin et al. · 2021 [cited by applicant]
US 20210355219A1 · Lin et al. · 2021 [cited by applicant]
US 20210380715A1 · Yoshida et al. · 2021 [cited by applicant]
US 20220017626A1 · Wesche et al. · 2022 [cited by applicant]
US 20220054544A1 · Lin et al. · 2022 [cited by applicant]
US 20220098311A1 · Wesche et al. · 2022 [cited by applicant]
US 20220267462A1 · Wesche et al. · 2022 [cited by applicant]
CA 2992797A1 · 2017 [cited by applicant]
CA 2994579A1 · 2017 [cited by applicant]
CA 3040823A1 · 2018 [cited by applicant]
CN 1563092A · 2005 [cited by applicant]
CN 101646689A · 2010 [cited by applicant]
CN 101809035A · 2010 [cited by applicant]
CN 104520324A · 2015 [cited by applicant]
CN 105968201A · 2016 [cited by applicant]
CN 105968204A · 2016 [cited by applicant]
CN 108026174A · 2018 [cited by applicant]
CN 109593786A · 2019 [cited by applicant]
EP 0239400A2 · 1987 [cited by applicant]
EP 0519596A1 · 1992 [cited by applicant]
EP 0592106A1 · 1994 [cited by applicant]
EP 1378520A1 · 2004 [cited by applicant]
EP 1736484A1 · 2006 [cited by applicant]
EP 2336179A1 · 2011 [cited by applicant]
EP 2581113A1 · 2013 [cited by applicant]
EP 2817338A2 · 2014 [cited by applicant]
EP 3093293A1 · 2016 [cited by applicant]
EP 3093294A1 · 2016 [cited by applicant]
EP 3095797A1 · 2016 [cited by applicant]
EP 3146979A1 · 2017 [cited by applicant]
EP 3337517A2 · 2018 [cited by applicant]
EP 3193929B1 · 2019 [cited by applicant]
EP 3556400A1 · 2019 [cited by applicant]
FR 901228A · 1945 [cited by applicant]
JP 2005501517A · 2005 [cited by applicant]
JP 2007535915A · 2007 [cited by applicant]
JP 2008278814A · 2008 [cited by applicant]
JP 2015501135A · 2015 [cited by applicant]
JP 2015528003A · 2015 [cited by applicant]
JP 2019052750A · 2019 [cited by applicant]
WO WO9109967A1 · 1991 [cited by applicant]
WO WO9307105A1 · 1993 [cited by applicant]
WO WO9404678A1 · 1994 [cited by applicant]
WO WO9937681A2 · 1999 [cited by applicant]
WO WO0043507A1 · 2000 [cited by applicant]
WO WO0130381A2 · 2001 [cited by applicant]
WO WO0190190A2 · 2001 [cited by applicant]
WO WO0196584A2 · 2001 [cited by applicant]
WO WO0222685A2 · 2002 [cited by applicant]
WO WO02055082A1 · 2002 [cited by applicant]
WO WO02085945A2 · 2002 [cited by applicant]
WO WO03025020A1 · 2003 [cited by applicant]
WO WO03035694A2 · 2003 [cited by applicant]
WO WO03064606A2 · 2003 [cited by applicant]
WO WO2004003019A2 · 2004 [cited by applicant]
WO WO2004035607A2 · 2004 [cited by applicant]
WO WO2004041867A2 · 2004 [cited by applicant]
WO WO2004042404A1 · 2004 [cited by applicant]
WO WO2004049794A2 · 2004 [cited by applicant]
WO WO2004056312A2 · 2004 [cited by applicant]
WO WO2004099249A2 · 2004 [cited by applicant]
WO WO2005003168A2 · 2005 [cited by applicant]
WO WO2005009465A1 · 2005 [cited by applicant]
WO WO2005040220A1 · 2005 [cited by applicant]
WO WO2005095456A1 · 2005 [cited by applicant]
WO WO2006020258A2 · 2006 [cited by applicant]
WO WO2006072625A2 · 2006 [cited by applicant]
WO WO2006072626A1 · 2006 [cited by applicant]
WO WO2006105021A2 · 2006 [cited by applicant]
WO WO2006121168A1 · 2006 [cited by applicant]
WO WO2006122786A2 · 2006 [cited by applicant]
WO WO2006122787A1 · 2006 [cited by applicant]
WO WO2007005874A2 · 2007 [cited by applicant]
WO WO2007024715A2 · 2007 [cited by applicant]
WO WO2007042261A2 · 2007 [cited by applicant]
WO WO2007042573A2 · 2007 [cited by applicant]
WO WO2007062466A1 · 2007 [cited by applicant]
WO WO2007113648A2 · 2007 [cited by applicant]
WO WO2007115230A2 · 2007 [cited by applicant]
WO WO2008028977A2 · 2008 [cited by applicant]
WO WO2008084106A1 · 2008 [cited by applicant]
WO WO2009009116A2 · 2009 [cited by applicant]
WO WO2009025846A2 · 2009 [cited by applicant]
WO WO2009030285A1 · 2009 [cited by applicant]
WO WO2009035577A1 · 2009 [cited by applicant]