US 11,666,040 B2
Humanized non-human animals with restricted immunoglobulin heavy chain loci
Lynn Macdonald, Harrison, NY (US); Sean Stevens, Del Mar, CA (US); Andrew J. Murphy, Croton-on-Hudson, NY (US); Margaret Karow, Santa Rosa Valley, CA (US); and John McWhirter, Hastings-on-Hudson, NY (US)
Assigned to Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed by Regeneron Pharmaceuticals, Inc., Tarrytown, NY (US)
Filed on Apr. 15, 2020, as Appl. No. 16/849,782.
Application 16/849,782 is a continuation of application No. 16/703,116, filed on Dec. 4, 2019.
Application 16/703,116 is a continuation of application No. 16/222,951, filed on Dec. 17, 2018, granted, now 10,542,735, issued on Jan. 28, 2020.
Application 16/222,951 is a continuation of application No. 13/788,997, filed on Mar. 7, 2013, granted, now 10,238,093, issued on Mar. 26, 2019.
Claims priority of provisional application 61/663,131, filed on Jun. 22, 2012.
Claims priority of provisional application 61/658,466, filed on Jun. 12, 2012.
Prior Publication US 2020/0281175 A1, Sep. 10, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. A01K 67/027 (2006.01); C12P 21/02 (2006.01); C07K 16/46 (2006.01)
CPC A01K 67/0278 (2013.01) [A01K 67/0276 (2013.01); C07K 16/461 (2013.01); C12P 21/02 (2013.01); A01K 2207/15 (2013.01); A01K 2217/072 (2013.01); A01K 2217/075 (2013.01); A01K 2217/15 (2013.01); A01K 2227/105 (2013.01)] 46 Claims
 
1. A mouse having in its germline genome:
(a) an unrearranged human genomic sequence comprising a single human VH gene segment, one or more DH gene segments, and one or more JH gene segments, wherein the single human VH gene segment, one or more DH gene segments, and one or more JH gene segments are operably linked to a mouse immunoglobulin heavy chain constant region gene at the endogenous immunoglobulin heavy chain locus, wherein insertion of the unrearranged human genomic sequence disrupts the function of an endogenous ADAM6 protein, and wherein the disruption of the endogenous ADAM6 function is associated with a reduction in fertility in male mice; and
b) a nucleic acid sequence that encodes a mouse ADAM6 protein that is functional in a male mouse, wherein the mouse ADAM6 protein is expressed if the mouse is a male mouse such that the male mouse is fertile;
wherein B cells of the mouse express antibodies in response to exposure to an antigen, wherein each antibody includes two immunoglobulin light chains paired with two immunoglobulin heavy chains, wherein each heavy chain comprises a human heavy chain variable domain expressed from a human heavy chain variable region sequence including a VH gene segment that is identical to, or a somatically hypermutated version of, the single human VH gene segment.