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 07/02/2025 in response to the Restriction Requirement mailed on 04/02/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 are pending.
Election/Restrictions
4. Applicant’s election without traverse of Group I in the reply filed on 07/02/2025 is acknowledged.
5. Claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 are pending and examined on the merits.
Priority
6. Acknowledgement is made of this continuation of U.S. Non-provisional Application No. 16/516996, filed on 07/19/2019, which is a continuation of U.S. Non-provisional Application No. 15/094624, filed on 04/08/2016, which is a continuation of U.S. Non-provisional Application No. 14/490549, filed on 09/18/2014, which claims foreign priority under 35 U.S.C. 119(a)-(d) to Great Britain patent application No. 1321210.5 and 1316560, filing date 12/02/2013 and 09/18/2013, respectively. The certified copies have been filed in the parent ‘549 application, filed on 06/10/2016.
Information Disclosure Statement
7. The IDS filed on 07/02/2025 has been considered by the examiner and a copy of the Form PTO/SB/08 is attached to the office action.
Drawings
8. The Drawings filed on 11/17/2023 are acknowledged and accepted by the examiner.
Claim Rejections - 35 USC § 112(b)
9. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 are 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.
Regarding claim 1 (claims 2-5, 8-001, 13-14, 16-17, 21, 23-25, and 28 dependent therefrom), there is insufficient antecedent basis for the limitation “the modified mouse ES cell”.
Duplicate Claim Warning
11. Applicant is advised that should claim 8 be found allowable, claim 9 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 102
12. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
13. Claim(s) 1, 8-11, 13-14, and 23 is/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; examiner cited).
14. Claims 1, 8-11, 13-14, and 23 are drawn to a method for antibody production, comprising the steps of: (a) providing a mouse or progeny thereof developed from the modified mouse ES cell, wherein the modified mouse ES cell has been produced by 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; wherein following the contacting step, the genome of the mouse ES cell is modified to comprise a targeted genetic modification comprising a disruption of a target protein or domain thereof thereby producing a modified mouse ES cell and developing the mouse from the modified mouse ES cell; (b) immunizing the mouse with a predetermined antigen; (c) removing B lymphocytes from the mouse and selecting one or more B lymphocytes expressing antibodies that bind to the antigen; and (d) isolating an antibody expressing by the B-lymphocytes.
15. With respect to claim 1, 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. 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 9, 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].
Claim Rejections - 35 USC § 103
16. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
17. Claim(s) 2-5, 16-17, 21, 24-25, and 28 is/are 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; examiner cited) in view of Lee et al. (US Patent Application Publication 2014/0309487 A1, priority to 04/16/2013; examiner cited).
18. The relevant teachings of McWhirter et al. as applied to claims 1, 8-11, 13-14, and 23 are set forth above.
With respect to claim 2, 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].
However, McWhirter et al. does not teach the method of claim 2, wherein the step comprises 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; 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; and/or insertion of the insert nucleic acid at the genomic locus of interest wherein the insertion is at least 20 kb; the method of claim 24, wherein step (a) comprises the use of at least two CRISPR RNAs; each of which hybridizes to a CRISPR target sequence at the same genomic locus of interest; and 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.
Lee et al. teach a method for modifying a genome at a genomic locus comprising introducing into the rat pluripotent stem cells a large targeting vector (LTVEC) comprising an insert nucleic acid flanked by a 5′ homology arm homologous to a first nucleic acid sequence at a genomic locus of interest and a 3′ homology arm homologous to a second nucleic acid sequence at the genomic locus of interest to produce the targeted genetic modification via homologous recombination, wherein the sum total of the 5′ and the 3′ homology arms is at least 10 kb; and, wherein the insert DNA nucleic acid: (i) comprises a polynucleotide of interest comprising a genomic nucleic acid sequence that encodes a human immunoglobulin heavy chain variable region sequence; wherein introducing step further comprises introducing a Cas nuclease agent or a nucleic acid encoding the Cas, wherein the nuclease agent promotes homologous recombination between the LTVEC and the genomic locus of interest in the pluripotent stem cells and wherein the nuclease agent comprises the CRISPR/Cas system, wherein the CRISPR/Cas system comprises a Cas9 nuclease and a guide RNA [see Abstract; paragraphs 0006-0010; 0012; 0016-0017] In some embodiment, it may comprise a guide RNA (including CRISPR-RNA (cr-RNA) and trans-activating CRISPR RNA (tracrRNA) [see paragraphs 0006-0010; 0012; 0016-0017; 0229]. It is further disclosed that the targeted genetic modification comprises deletion of an endogenous rat nucleic acid sequence, wherein the deletion ranges from about 5 kb to about 3 Mb [see paragraph 0254]. Lee further teaches that the immunoglobulin locus is an immunoglobulin heavy chain locus and/ or an immunoglobulin light chain locus. wherein the immunoglobulin locus is an immunoglobulin heavy chain locus or an immunoglobulin light chain locus, wherein the immunoglobulin light chain locus is a λ or κ immunoglobulin light chain locus [see paragraph 0106]. Lee exemplified genetic modification of rat ES cell but also contemplated modifying stem cell from mouse [see paragraphs 0006-0010; 0012; 0016-0017; 0229].
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 Lee et al. to modify the methods of McWhirter et al. using the CRISPR/Cas system of Lee et al because McWhirter et al. teach deletion of target genes in mouse ES cells and insertion of humanized antibody genes for the production of humanized antibodies. Lee et al. teach that CRISPR/Cas system can be efficiently used to introduced targeted modifications in stem cells to targeted discovery and validation of therapeutic agents more quickly and easily. One of ordinary skill in the art would have had a reasonable expectation of success, a reasonable level of predictability and would have been motivated to combine the teachings of McWhirter et al. and Lee et al. because Lee et al. acknowledge that CRISPR/Cas systems provide efficient systems for targeted modifications in stem cells for validation of therapeutic agents in a quick manner. 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
19. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
20. Claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable 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; examiner cited).
Claims 1-19 of the ‘182 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 ‘182 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 ‘182 patent with the teachings of McWhirter et al. because the ‘182 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 ‘182 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.
Conclusion
21. Status of the claims:
Claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 are pending.
Claims 1-5, 8-11, 13-14, 16-17, 21, 23-25, and 28 are rejected.
No claims are in condition for an allowance.
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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