DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-100, 102-114, 117-120 have been canceled. Claims 101, 115, 116 remain pending.
Specification
The title will have to be changed to more closely reflect the fact that the claims are drawn to a genetically modified mouse that makes a humanized antibody, specifically that has a humanized immunoglobulin light chain sequence and an inactivated IgG1 gene.
Election/Restrictions
Applicants elected Group I, claims 101,103,105-108,113, without traverse in the reply filed on 4-17-23.
Claims 115 and 116 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4-17-23.
Claim 101 remains under consideration.
Applicant's arguments filed 4-22-26 have been fully considered but they are not persuasive.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Allowable subject matter
The formatting of item 1) of claim 101 is acceptable and allowable. Support is described on pg 9-12 of the response filed 6-26-25.
Claim Rejections - 35 USC § 112
Written Description
Claim 101 remains rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Pending rejection
A) The specification lacks written description for a mouse whose germline genome comprises the “replacement” in item 2) in claim 101.
Claim 101 is drawn to
A genetically modified mouse whose germline has a genome that comprises:
(1) a replacement of:
i) a plurality of unrearranged endogenous immunoglobulin (Ig) variable heavy chain (VH) gene segments,
ii) all unrearranged endogenous Ig diversity heavy chain (DH) gene segments, and
iii) all unrearranged endogenous Ig joining heavy chain (JH) gene segments, with:
a) a plurality of unrearranged human Ig VH gene segments, and
b) all unrearranged human Ig DH gene segments, and
c) all unrearranged human Ig JH gene segments,
such that the unrearranged human Ig VH, DH, and JH gene segments are operably linked to an endogenous IgG1 gene that comprises a deleted or inactivated nucleotide sequence encoding its CH1 domain, wherein the unrearranged human Ig VH, DH, and JH gene segments rearrange in a B cell such that the mouse functionally expresses:
an IgG1 antibody comprising a human heavy chain variable domain operably linked to an endogenous IgG1 constant domain with a deleted or inactivated CH1 domain; and
(2) a replacement of:
i) all unrearranged endogenous Ig variable light chain kappa (VK) gene segments,
ii) all unrearranged endogenous Ig joining light chain kappa (JK) gene segments with
a rearranged human VK:JK variable region gene selected from the group consisting of a VK1-39JK5 gene and a VK3-20JK1 gene such that the rearranged human VK:JK variable region gene is operably linked to an endogenous K light chain constant region gene, and
such that each B cell of the mouse expressing a K light chain functionally expresses only a K light chain encoded by the rearranged human VK:JK variable region gene operably linked to the endogenous K light chain constant region gene.
The specification lacks written description for any rearranged human VK:JK variable region gene as required in item 2 of claim 101 because “VK” and “JK” indicates the presence of variable and joining gene segments. The variable kappa and joining kappa gene segments have been rearranged, recombination signal sequences (RSSs) that flank them have been removed, and the two gene segments have been joined together. Calling it a “variable region gene” in the claim, however, is inaccurate because the rearranged gene contains both variable and joining gene segments. Accordingly, the concept lacks written description.
The specification lacks written description for a “rearranged [Ig] VK1-39JK5 gene” or “rearranged [Ig] VK3-20JK1 gene” as required in item 2 of claim 101. Fig. 2 shows the genome of a mouse in which all endogenous Ig variable and joining light chain kappa gene segments have been removed and replaced with “human VK1-39JK5” or “human VK3-20JK1”, but the specification does not teach the structure of the genes, whether they were “rearranged”, whether RSSs flanking VK1-39 or JK5 remain, whether RSSs flanking VK3-20 or JK1 remain. Accordingly, the concept lacks written description.
The concept of a “rearranged [Ig] VK1-39JK5 gene” or “rearranged [Ig] VK3-20JK1 gene” being operably linked to any “endogenous K light chain constant region gene” in item 2 of claim 101 is found in Fig. 2.
The concept of each B-cell that expresses [an Ig] kappa light chain expressing only a VK:JK variable region gene operably linked to the endogenous kappa light chain constant region gene in item 2 of claim 101 lacks written description. The specification does not teach B-cells that express [an Ig] kappa light chain express only an Ig comprising a VK1-39 or VK3-20 domain operably linked to an endogenous kappa light chain constant domain. The specification does not teach the B-cells only contain a “rearranged [Ig] VK1-39JK5 gene” or “rearranged [Ig] VK3-20JK1 gene” operably linked to any “endogenous K light chain constant region gene. Accordingly, the concept lacks written description.
Response to arguments
Applicants point to para 32, 73, 140, 152 and the description of Fig. 2 none of which are persuasive for reasons set forth in the rejection.
Enablement
Claim 101 remains rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for A genetically modified mouse whose germline has a genome comprising a replacement of:
i) a plurality of unrearranged endogenous variable heavy chain (VH) gene segments,
ii) all unrearranged endogenous diversity heavy chain (DH) gene segments, and
iii) all unrearranged endogenous joining heavy chain (JH) gene segments,
with:
a) a plurality of unrearranged human light chain variable kappa (Vκ) gene segments, and
b) all unrearranged human light chain joining kappa (Jκ) gene,
such that the unrearranged human heavy chain Vκ and Jκ gene segments are operably linked to a modified endogenous IgG gene that comprises a deleted or inactivated nucleotide sequence encoding its CH1 domain, wherein the unrearranged human Ig VH, DH and JH gene segments rearrange in a B cell such that the mouse functionally expresses:
an IgG1 antibody comprising a human heavy chain variable domain operably linked to an endogenous IgG1 with a deleted or inactivated CH1 domain.
(see patented claim in parent application),
does not reasonably provide enablement for item 2) of claim 101). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
Pending rejection
A) The specification does not enable making/using a mouse whose germline genome comprises the light chain of item 2) in claim 101.
The claim and its scope, the teachings in the specification, and the examples are recited above.
The specification lacks written description for any rearranged human VK:JK variable region gene as required in item 2 of claim 101 because “VK” and “JK” indicates the presence of variable and joining gene segments. The variable kappa and joining kappa gene segments have been rearranged, recombination signal sequences (RSSs) that flank them have been removed, and the two gene segments have been joined together. Calling it a “variable region gene” in the claim, however, is inaccurate because the rearranged gene contains both variable and joining gene segments. Accordingly, the concept is not enabled.
The specification lacks written description for a “rearranged [Ig] VK1-39JK5 gene” or “rearranged [Ig] VK3-20JK1 gene” as required in item 2 of claim 101. Fig. 2 shows the genome of a mouse in which all endogenous Ig variable and joining light chain kappa gene segments have been removed and replaced with “human VK1-39JK5” or “human VK3-20JK1”, but the specification does not teach the structure of the genes, whether they were “rearranged”, whether RSSs flanking VK1-39 or JK5 remain, whether RSSs flanking VK3-20 or JK1 remain. Accordingly, the concept is not enabled.
The concept of each B-cell that expresses [an Ig] kappa light chain expressing only a VK:JK variable region gene operably linked to the endogenous kappa light chain constant region gene in item 2 of claim 101 lacks written description. The specification does not teach B-cells that express [an Ig] kappa light chain express only an Ig comprising a VK1-39 or VK3-20 domain operably linked to an endogenous kappa light chain constant domain. The specification does not teach the B-cells only contain a “rearranged [Ig] VK1-39JK5 gene” or “rearranged [Ig] VK3-20JK1 gene” operably linked to any “endogenous K light chain constant region gene. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use the replacement in item 2 of claim 101.
Response to arguments
Applicants point to para 32, 73, 140, 152 and the description of Fig. 2 none of which are persuasive for reasons set forth in the rejection.
Indefiniteness
Claim 101 remains rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The concept of an Ig light chain encoded by a “VL:JL variable region gene” in claim 101 makes the claim indefinite. “VK” and “JK” indicate the presence of variable and joining gene segments. The variable kappa and joining kappa gene segments have been rearranged, recombination signal sequences (RSSs) that flank them have been removed, and the two gene segments have been joined together. Calling it a “variable region gene” in the claim, however, is inaccurate because the rearranged gene contains both variable and joining gene segments. It is also unclear when something is a “VL:JL gene” – it is unclear whether the segments have RSSs or not or when they have been aligned into a “gene”. Accordingly, the concept makes the claim indefinite.
The concept of a “rearranged [Ig] VK1-39JK5 gene” or “rearranged [Ig] VK3-20JK1 gene” as required in item 2 of claim 101 makes the claim indefinite. Fig. 2 shows the genome of a mouse in which all endogenous Ig variable and joining light chain kappa gene segments have been removed and replaced with “human VK1-39JK5” or “human VK3-20JK1”, but the specification does not teach the structure of the “human VK1-39JK5” or “human VK3-20JK1” genes, whether they were “rearranged”, whether RSSs flanking VK1-39 or JK5 remain, whether RSSs flanking VK3-20 or JK1 remain. Accordingly, the concept makes the claim indefinite.
Response to arguments
Applicants argue the claim is clear. Applicants’ argument is not persuasive for reasons set forth above.
Macdonald (8754287) taught a mouse with a germline modification comprising an endogenous IgG constant region gene that has: a) a deletion of a CH1 domain; b) at least one human heavy chain variable gene segment, and c) an intact IgM constant region gene, wherein the mouse expresses an IgG comprising a human variable domain. The art at the time of filing did not reasonably teach or suggest a mouse with the genetic modification claimed.
Macdonald (10143186) taught a genetically modified mouse, but it does not appear to have the same structure or function as those in item B) of claim 101.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Inquiry concerning this communication or earlier communications from the examiner should be directed to Michael C. Wilson who can normally be reached at the office on Monday through Friday from 9:30 am to 6:00 pm at 571-272-0738.
Patent applicants with problems or questions regarding electronic images that can be viewed in the Patent Application Information Retrieval system (PAIR) can now contact the USPTO’s Patent Electronic Business Center (Patent EBC) for assistance. Representatives are available to answer your questions daily from 6 am to midnight (EST). The toll free number is (866) 217-9197. When calling please have your application serial or patent number, the type of document you are having an image problem with, the number of pages and the specific nature of the problem. The Patent Electronic Business Center will notify applicants of the resolution of the problem within 5-7 business days. Applicants can also check PAIR to confirm that the problem has been corrected. The USPTO’s Patent Electronic Business Center is a complete service center supporting all patent business on the Internet. The USPTO’s PAIR system provides Internet-based access to patent application status and history information. It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public.
For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199.
If attempts to reach the examiner are unsuccessful, the examiner's supervisor, Tracy Vivlemore, can be reached on 571-272-2914.
The official fax number for this Group is (571) 273-8300.
Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
Prosecution Insights