Notice of Pre-AIA or AIA 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 .
Double Patenting
2. 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.
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3. Claims 1-4, 7-9, 14 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 11-12, 14-17, 19-20, 22-23, 26 and 29-39 of copending Application No. 17631130, and claims 1-5, 7-8, 10, 12, 14-17, 19, 27-28, 41-42 and 45-46 of copending Application No. 18706875 each in view of Gehre et al (Efficient strategies to detect genome editing and integrity in CRISPR-Cas9 engineered ESCs, BioRxiv, 635151, published 10 May 2019).
Regarding claim 1 of the instant application, claims 1 and 12of copending application 17631130 and claims 1, 28, 41 and 42 of copending application 18706875 each teach all of the limitations of the instant claim, except the limitations of exposing a population of cells to a gene editing method and comparing the sequences of amplification products to at least one reference sequence to identify at least one mutation.
However, Gehre teaches these limitations in the abstract, pg. 3 ¶ 1, FIG 1, and pg. 12 ¶ 4.
It would have been obvious to one having ordinary skill in the art to have modified the library preparation and sequence method taught in any of the copending applications to include the limitations regarding gene editing and mutation detection taught by Gehre to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make these modifications because Gehre specifically teaches that it is important to evaluate the risks of off-target effects introduced by CRISPR-Cas9 treatment (pg. 9 ¶ 1). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the formation of sequencing libraries.
Regarding claim 2 of the instant application, Gehre teaches the correct mutation at the desired target site via CRISPR-Cas9 editing (pg. 6 ¶ 1).
Regarding claim 3 of the instant application, Gehre teaches that rearrangements occurred on other chromosomes than the CRISPR target site (i.e., the at least 1 mutation is not present in the target sequence; pg. 9 ¶ 1).
Regarding claim 4 of the instant application, Gehre teaches that the gene editing method comprises the use of CRISPR (abstract and pg. 9 ¶ 1).
Regarding claim 7 of the instant application, Gehre teaches that the reference sequence is a mouse genome (pg. 12 ¶ 4).
Regarding claim 8, Gehre teaches comparing CRISPR altered cells to a wild type cell line at the CRISPR target site, i.e., the reference sequence is a specificity determining sequence which promotes introduction of the mutation into the target sequence (the target site of the CRISPR gRNA; pg. 6 ¶ 2).
Regarding claim 9, Gehre teaches these errors occur independently of the exact CRISPR guide sequence (i.e., they are present in a region of a sequence differing from the specificity-determining sequence by at least 1 base; pg. 6 ¶ 2).
Regarding claim 14 of the instant application, claim 5 of copending application 17631130, and claim 45 of copending application 18706875 each teach this limitation.
Regarding instant claim 23, claim 37 of copending application 17631130 each teach this limitation. For each other copending application, Gehre teaches that the edited cells are embryonic stem cells (i.e., fetal cells; abstract).
This is a provisional nonstatutory double patenting rejection.
4. Claims 5-6 and 16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 11-12, 14-17, 19-20, 22-23, 26 and 29-39 of copending Application No. 17631130 and claims 1-5, 7-8, 10, 12, 14-17, 19, 27-28, 41-42 and 45-46 of copending Application No. 18706875 each in view of Gehre et al (Efficient strategies to detect genome editing and integrity in CRISPR-Cas9 engineered ESCs, BioRxiv, 635151, published 10 May 2019), and further in view of Church et al (United States Patent Application No. US20190062739, published 28 February 2019).
Regarding claim 5 of the instant application, the method of claim 1 is discussed fully above and incorporated here. Neither the issued patent nor Gehre teach that the gene editing technique comprises the use of a gene therapy method.
However, Church teaches a gene editing technique coupled with a transcriptional regulator protein used to treat a mitochondrial disease (i.e., a gene therapy method; [0009] – [0010]).
It would have been obvious to one having ordinary skill in the art to have modified the claims of each of the copending applications to have included the limitations taught by Church to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make these modifications in order treat a particular disease. The ordinary artisan would have recognized that the known techniques in the cited references could have been combined with the claims of the issued patent with predictable results, because the known techniques of the cited references predictably result in the gene editing of cells using CRISPR-Cas9.
Regarding claim 6 of the instant application, Church teaches a method of editing the mitochondrial DNA of a cell ([0023]).
Regarding claim 16 of the instant application, Church teaches that the editing efficiency is 0.6% ([0023]).
This is a provisional nonstatutory double patenting rejection.
5. Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 11-12, 14-17, 19-20, 22-23, 26 and 29-39 of copending Application No. 17631130 and claims 1-5, 7-8, 10, 12, 14-17, 19, 27-28, 41-42 and 45-46 of copending Application No. 18706875 each in view of Gehre et al (Efficient strategies to detect genome editing and integrity in CRISPR-Cas9 engineered ESCs, BioRxiv, 635151, published 10 May 2019), and further in view of Nishida (United States Patent Application No. US20210024906, effectively filed 21 November 2018).
Regarding claim 11 of the instant application, the method of claim 1 is discussed fully above and incorporated here. None of the copending applications nor Gehre teach that the reference sequence is the sequence of a CRISPR RNA (crRNA) or a single guide RNA (sgRNA).
However, Nishida teaches the whole genome sequencing of cells to assess genome-wide off-target effects of CRISPR editing and that the off-target sites were identified by comprising matched sequences proximal to the PAM (i.e., the amplification products were compared to a crRNA or sgRNA; [0162]).
It would have been obvious to one having ordinary skill in the art to have modified the method taught by each of the copending applications in combination with Gehre with the genome wide off-target assessment based on crRNA or sgRNA sequence taught by Nishida to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this combination because Gehre specifically teaches the importance of studying off-target effects related to CRISPR gene editing. In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in the analysis of genome-wide off-target CRISPR editing effects.
6. Claim 21 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 11-12, 14-17, 19-20, 22-23, 26 and 29-39 of copending application No. 17631130 and claims 1-5, 7-8, 10, 12, 14-17, 19, 27-28, 41-42 and 45-46 of copending Application No. 18706875 each in view of Gehre et al (Efficient strategies to detect genome editing and integrity in CRISPR-Cas9 engineered ESCs, BioRxiv, 635151, published 10 May 2019), and each further in view of Kassahn et al (Somatic Point Mutation Calling in Low Cellularity Tumors, PLoS ONE, 8, 11, e74380, published 8 November 2013).
None of the copending applications nor Gehre teach identifying a false positive mutation previously sequenced by an alternate off-target detection method.
However, Kassahn teaches a method wherein multiple mutation calling strategies were tested to identify false positive errors and then benchmarked against the previously sequenced cell line COLO-829 (pg.2, column 1, ¶ 2).
It would have been obvious to one having ordinary skill in the art to have modified the method of off target mutation analysis taught by the combination of each of the copending applications and Gehre with the mutation comparison method taught by Kassahn to arrive at the instantly claimed invention with a reasonable expectation of success. The ordinary artisan would have been motivated to make this combination in order to benchmark the instant method against the current state of the art method as taught by Kassahn (pg. 2, column 1, ¶ 2). In addition, one having ordinary skill in the art would have recognized that the known techniques in the cited references could have been combined with predictable results because the known techniques in the cited references predictably result in sequencing and mutation calling.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
7. Rejections made in the Office Action filed 01 October 2025 under U.S.C. 112(b) have been overcome by amendments to claims 8 and 9 and cancellation of claims 19, 26, 29, 33 and 41.
The NSDP rejection in view of US Patent No. 11905553 and provisional NSDP rejections in view of copending applications 18860539, 18580720, 18559286 and 18882493 have been overcome by amendments made to instant claim 1.
The provisional NSDP rejection in view of 17798468 is withdrawn because that application has gone abandoned.
Regarding the remaining double patenting rejections, the response requests that the Examiner hold the provisional rejection in abeyance until otherwise allowable subject matter is identified in the instant application. However, a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional. As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. MPEP §804(I)(b)(1). Therefore, for the reasons set forth above and those already of record, the provisional nonstatutory double patenting rejection is modified to address the amended claims, and maintained.
8. 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.
Conclusion
9. No claims are allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN ELLIS YOUNG whose telephone number is (703)756-5397. The examiner can normally be reached M-F 0730 - 1700.
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/BRIAN ELLIS YOUNG/Examiner, Art Unit 1684
/JULIET C SWITZER/Primary Examiner, Art Unit 1682