DETAILED CORRESPONDENCE
Application Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment to the claims filed on 02/09/2026 in response to the Non-Final Rejection mailed on 10/08/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claim 9 is cancelled.
4. New claims 29-36 are added.
5. Claims 1-5, 8, 10-11, 13-14, 16-17, 21, 23-25 and 28-36 are pending.
6. Applicant’s remarks filed on 02/09/2026 in response to the Non-Final Rejection mailed on 10/08/2025 have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Information Disclosure Statement
7. The IDSs filed on 11/13/2025 and 01/08/2026 have been considered by the examiner and copies of the Form PTO/SB/08 are attached to the office action.
Claim Rejections - 35 USC § 112(b)
8. The rejection of claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lack of antecedent basis is withdrawn in view of applicants’ amendment to claim 1 to recite “a modified mouse ES cell”.
9. Claims 16, 29, and 35 are newly 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. This new grounds of rejection is necessitated by applicants’ amendment to the claims to add new claims 29 and 35.
Regarding claim 29 (claims 16 and 35 dependent therefrom), there is insufficient antecedent basis for the limitation “the insert nucleic acid”. It is suggested that applicants clarify the meaning of the claims.
Claim Rejections - 35 USC § 102
10. The rejection of claim 9 under 35 U.S.C. 102(a)(2) as being anticipated by McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025) is withdrawn in view of applicants’ amendment to the claims to cancel claim 9.
11. The rejection of claims 1, 8, 10-11, 13-14, and 23 under 35 U.S.C. 102(a)(2) as being anticipated by McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims and to incorporate new claims 32 and 36, which is necessitated by applicants’ amendment to the claims to add new claims 32 and 36.
Claims 1, 8, 10-11, 13-14, 23, 32, and 36 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025).
12. With respect to claims 1 and 36, McWhirter et al. teach a method for antibody production comprising providing a mouse ES cell that has been modified to comprise a targeted genetic modification comprising a disruption of a target protein or domain thereof producing a modified mouse ES cell, immunizing the mouse with a predetermined antigen, removing B-lymphocytes from the mouse and selecting one or more B lymphocytes expressing antibodies that bind to the antigen; and isolating an antibody expressed by the B lymphocytes [see Abstract; paragraphs 0206, 0225, 0276-0280, 0282-0283]. Regarding the limitations of contacting a mouse ES cell with: a Cas9 protein; a CRISPR RNA that hybridizes to a CRISPR target sequence at the genomic locus of interest; a tracrRNA; and an incoming nucleic acid sequence that is flanked by: (i) a 5’ homology arm that is homologous to a 5’ target sequence at the genomic locus of interest; and (ii) a 3’ homolog arm that is homologous to a 3’ target sequence at the genomic locus of interest, it is acknowledged that McWhirter et al. does not teach these limitations; however, these are product by process limitations. MPEP 2113.I states "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”. In the instant case, the structure of the mouse ES cell need only comprise a targeted genetic modification comprising disruption of a target protein, which the teachings of McWhirter et al. meet. Claim 36 only serves to further limit the method by which the modified mouse ES cell is made. Accordingly, the teachings of McWhirter et al. read on the limitations of the claims.
With respect to claim 8, McWhirter et al. teach isolating nucleic acids from the B lymphocytes [see paragraph 0225].
With respect to claim 10, McWhirter et al. teach the method of exchanging the heavy chain constant region nucleotide sequence of the nucleic acid encoding the antibody with a nucleotide sequence encoding a human heavy chain constant region [see paragraphs 0206, 0225, 0276-0280, 0282-0283].
With respect to claim 11, McWhirter et al. teach the method further comprising affinity maturing the variable region and inserting the isolated nucleic acid into an expression vector or host [see paragraphs 0195 and 0225].
With respect to claim 13, McWhirter et al. teach the method wherein the antibody expressed by the B lymphocytes is a IgG-type antibody [see paragraph 0212-0214].
With respect to claim 14, McWhirter et al. teach the method further comprising a step of immortalizing the B lymphocytes and producing hybridomas of the selected B lymphocytes [see paragraphs 0225 and 0282].
With respect to claim 23, McWhirter et al. teach the method wherein the targeted genomic modified comprises a knockout of a target protein [see paragraphs 0277-0282].
With respect to claim 32, McWhirter et al. teach the method further comprising a step of immortalizing the B lymphocytes and producing hybridomas of the selected B lymphocytes [see paragraphs 0225 and 0282].
RESPONSE TO REMARKS: Beginning on p. 8 of applicants’ remarks, applicants contend that instant claim 1is a method claim directed to the production of antibodies and not a product by process claim.
This argument is found to be not persuasive for the reasons set forth above and below. The examiner agrees that the claims are a method claim; however, the recitation “wherein the modified mouse ES cell has been produced by contacting a mouse ES cell with…” followed by limitations of how the cell is modified are product by process limitations embedded within the method claim. The structure of the modified mouse ES cell need only to require the genome to be modified to comprise a targeted genetic modification comprising a disruption of a target protein or domain thereof thereby producing a modified mouse ES cell. A modified mouse ES cell with said structure produced by another process such as that taught in McWirter et al. would not be structurally distinct from one produced by another process such as that recited in the claims.
Claim Rejections - 35 USC § 103
13. The rejection of claims 2-5, 16-17, 21, 24-25, and 28 under 35 U.S.C. 103 as being unpatentable over McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025) in view of Lee et al. (US Patent Application Publication 2014/0309487 A1, priority to 04/16/2013; cited on PTO-892 mailed on 10/08/2025) is withdrawn in view of applicants’ persuasive remarks that the priority document of which Lee et al. claims priority to does not contemplate mouse ES cells.
14. Claims 3-4, 16-17, 21, 24-25, 28-29, and 33-35 are newly rejected under 35 U.S.C. 103 as being unpatentable over McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025) in view of Bradley et al. (US Patent Application Publication 2012/0204278 A1; cited on IDS filed on 01/08/2026). This new grounds of rejection is necessitated by applicants’ filing of the IDS on 01/08/2026.
15. The relevant teachings of McWhirter et al. as applied to claims 1, 8, 10-11, 13-14, 23, 32, and 36 are set forth above.
With respect to claims 3-4, 16-17, 21, 24-25, 28-29, and 33-35, McWhirter et al. teach a method for antibody production comprising providing a mouse ES cell that has been modified to comprise a targeted genetic modification comprising a disruption of a target protein or domain thereof producing a modified mouse ES cell, immunizing the mouse with a predetermined antigen, removing B-lymphocytes from the mouse and selecting one or more B lymphocytes expressing antibodies that bind to the antigen; and isolating an antibody expressed by the B lymphocytes [see Abstract; paragraphs 0206, 0225, 0276-0280, 0282-0283].
With respect to claim 5, McWhirter et al. teach the method wherein the mouse ES cell comprises a deletion of one or more mouse antibody gene segments [see paragraphs 0206, 0225, 0276-0280, 0282-0283].
With respect to claim 16, McWhirter et al. teach the method wherein the targeted genomic modification comprises insertion of one or more of human antibody kappa light chain variable domain [see paragraphs 0250-0255].
With respect to claim 17, McWhirter et al. teach the method wherein the targeted genomic modification comprises deletion of one or more mouse antibody heavy and light lambda and kappa chain variable domains and insertion of human antibody kappa and lambda heavy and light chain variable domains [see paragraphs 0250-0288].
With respect to claim 21, McWhirter et al. teach the method wherein the targeted genomic modification comprises insertion of one or more human antibody gene segments [see paragraphs 0250-0288].
With respect to claim 25, McWhirter et al. teach the method wherein an indel is created at the genomic locus wherein the indel results in a knock-out or disruption of a target protein or domain thereof [see paragraphs 0250-0288].
With respect to claim 33, McWhirter et al. teach the method wherein the targeted genomic modification comprises deletion of one or more mouse antibody heavy and light lambda and kappa chain variable domains and insertion of human antibody kappa and lambda heavy and light chain variable domains [see paragraphs 0250-0288].
With respect to claim 34, McWhirter et al. teach the method wherein the targeted genomic modification comprises deletion of one or more mouse antibody heavy and light lambda and kappa chain variable domains and insertion of human antibody kappa and lambda heavy and light chain variable domains [see paragraphs 0250-0288].
With respect to claim 35, McWhirter et al. teach the method wherein the target genomic modification comprises insertion of one or more human antibody gene segments [see paragraphs 0250-0288].
However, McWhirter et al. does not teach the method of claim 3, wherein the incoming nucleic acid is at least 10 kb in size; the method of claim 4, wherein the targeted genomic modification comprises deletion of a region of the genomic locus of interest wherein the deletion is at least 20 kb; the method of claim 28, wherein the targeted genomic modification comprises deletion of a region of the genomic locus of interest wherein the deletion is at least 1 kb; and the method of claim 29, wherein the targeted genomic modification comprises insertion of the insert nucleic acid at the genomic locus of interest wherein the insertion is at least 20 kb;
Bradley et al. teach similar methods for the generation of chimeric human-nonhuman antibodies in mouse embryonic stem cells comprising the deletion of a region of the genomic locus of interest and insertion of human fragment that is at least 20 kb in length [see Abstract; paragraphs 0010-0028; 0064; 0231-0244].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of McWhirter et al. and Bradley et al. according to the teachings of McWhirter et al. and Bradley et al. to include insertion sizes of at least 20kb because McWhirter et al. teach methods for modifying a targeted genomic locus in mouse ES cells to generate human antibodies. Bradley et al. teach similar methods of generating human antibodies in mouse embryonic stem cells by insertion of large fragments of human antibodies into the genome of mouse embryonic stem cells. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of McWhirter et al. and Bradley et al. because Bradley et al. acknowledges that large fragments encoding human antibodies can be inserted into mouse ES cells. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Double Patenting
16. The nonstatutory double patenting rejection of claim 9 over claims 1-19 of U.S. Patent No. 11,920,182 in view of McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025) is withdrawn in view of applicants’ amendment to the claims to cancel claim 9.
17. The nonstatutory double patenting rejection of claims 1-5, 8, 10-11, 13-14, 16-17, 21, 23-25, and 28 over claims 1-19 of U.S. Patent No. 11,920,182 in view of McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to incorporate new claims 29-36 which is necessitated by applicants’ amendment to the claims to add new claims 29-36.
Claims 1-5, 8, 10-11, 13-14, 16-17, 21, 23-25, and 28-36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 11,920,128 in view of McWhirter et al. (US Patent Application Publication 2015/0059009 A1, filing date 02/08/2010; cited on PTO-892 mailed on 10/08/2025).
Claims 1-19 of the ‘128 patent recite a method for modifying a genome at a genomic locus of interest in a non-human mammal zygote, the method comprising assembling in vitro a ribonucleoprotein complex, comprising contacting a purified CRISPR/Cas9 protein and at least two single guide RNAs that hybridize to a CRISPR target sequence at the same genomic locus of interest; and injecting the RNP complex into the non-human mammal zygote; and injecting an incoming nucleic acid that comprises: (i) a 5’ homology arm that is homologous to a 5’ target sequence at the genomic locus of interest and is homologous to a region 5’ of a first protospacer adjacent motif (PAM sequence contained within the genomic locus of interest; and (ii) a 3’ homology arm that is homologous to a 3’ target sequence at the genomic locus of interest and is homologous to a region 3’ of a second PAM sequence contained within the genomic locus of interest; and (iii) optionally an insert nucleic acid sequence; wherein the method uses Cas9 mediated nucleic acid cleavage to create 5’ and 3’ cut ends in the region between the 5’ target sequence and the 3’ target sequence; wherein, following the injection step: (a) which injection step comprises injecting an incoming nucleic acid, the genome of the zygote is modified to comprise a targeted genetic modification comprising a deletion of a genomic locus of interest, wherein the targeted genetic modification is a deletion of from 1 kb to at least 100 kb; and/or (b) which injection step comprises injecting an incoming nucleic acid, the genome of the zygote is modified to comprise a targeted genetic modification comprising insertion of the insert nucleic acid sequence at the genomic locus of interest.
However, the recitations of claims 1-19 of the ‘128 patent do not recite “immunizing the mouse with a predetermined antigen; removing B-lymphocytes from the mouse and selecting one or more B lymphocytes expressing antibodies that bind to the antigen; and isolating an antibody expressed by the B lymphocytes.
McWhirter et al. teach a method for antibody production comprising providing a mouse ES cell that has been modified to comprise a targeted genetic modification comprising a disruption of a target protein or domain thereof producing a modified mouse ES cell, immunizing the mouse with a predetermined antigen, removing B-lymphocytes from the mouse and selecting one or more B lymphocytes expressing antibodies that bind to the antigen; and isolating an antibody expressed by the B lymphocytes [see Abstract; paragraphs 0206, 0225, 0276-0280, 0282-0283].
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the recitations of the ‘128 patent with the teachings of McWhirter et al. because the ‘128 patent recite methods for modifying genome locus of interest in a non-human mammal using a CRISPR/Cas system. McWhirter et al. teach genetic modifications of mouse ES cells can be used for targeted insertion of humanized antibody production. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the recitations of the ‘128 patent and McWhirter et al. because McWhirter et al. acknowledges that genetic modifications of mouse ES cells can be used for targeted insertion of humanized antibody production. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Applicants’ remarks filed on 02/09/2026 have been fully considered by the examiner, and found to be not persuasive for the reasons set forth above regarding McWhirter. The examiner thanks applicants for the typographical error regarding the patent number and the corresponding number has been corrected.
Conclusion
18. Status of the claims:
Claims 1-5, 8, 10-11, 13-14, 16-17, 21, 23-25 and 28-36 are pending.
Claims 1-5, 8, 10-11, 13-14, 16-17, 21, 23-25 and 28-36 are rejected.
No claims are in condition for an allowance.
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 01/08/2026 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(b). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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