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 .
Applicant arguments and amendments have been thoroughly reviewed and considered. Claims 11-13 have been added. Claim 10 remains withdrawn. Claims 1-9 and 11-13 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Claim Objections
Claims 1, 6, and 9 were rejected for minor informalities. In light of Applicant’s amendments to the claims submitted 4/16/2026, these objections have been withdrawn. See also new ground of objection below.
35 USC 112(b) Rejections
Claims 1-9 were rejected for various indefiniteness issues. These rejections have been withdrawn, but see new grounds of rejection below.
35 USC 103 Rejections
Claims 1-5 and 7-9 were rejected under 35 U.S.C. 103 as being unpatentable over Bau et al. (WO 2019/178346 A1), in view of Sorge et al. (US 2007/0292865 A1), and in view of Swarts et al. (Nucleic Acids Research, 2015).
Claim 6 was rejected under 35 U.S.C. 103 as being unpatentable over Bau et al. (WO 2019/178346 A1), in view of Sorge et al. (US 2007/0292865 A1), in view of Swarts et al. (Nucleic Acids Research, 2015), and further in view of Fisher Scientific (“New England Biolabs, Inc Q5 Hot Start High-Fidelity 2X Master Mix,” 2015).
Applicant’s arguments and amendments have been thoroughly reviewed and considered. These rejections have been withdrawn. See “Response to Applicant’s Arguments” and “Free of the Prior Art” below.
Response to Applicant’s Arguments
Regarding the 35 USC 103 Rejections, Applicant argues that Bau teaches away from simultaneous PCR and cleavage reactions (Remarks, page 8). Additionally, Sorge, which teaches simultaneous PCR and cleavage reactions, utilizes a different nuclease than what is used in the instant invention, and the nucleases of Sorge are of a different class than those claimed, and so operates in a different manner to those claimed. As a result, Applicant argues that “a person skilled in the art would have no motivation to combine Bau with Sorge (Remarks, page 9). Swarts, which does teach a claimed nuclease, but allegedly does so under isothermal conditions, and so is not shown to be compatible with a PCR system. Applicant also states that the claimed reaction conditions that are taught by Bau are in a “separate reaction,” and so cannot readily be applied to a system with simultaneous amplification and cleavage (Remarks, page 10). Finally, Applicant discusses the unexpected technical effects of their invention (Remarks, pages 11-12).
Though the Examiner does not agree with all of Applicant’s points, overall, Applicant’s arguments regarding the combination of Bau, Sorge, and Swarts were persuasive to overcome the 35 USC 103 Rejections. The amendments to claim 1 required further search and consideration, and no prior art could be found that, alone or in combination, met all the claimed limitations of claim 1.
Thus, the prior art rejections are withdrawn.
With regard to Applicant’s allegations of unexpected technical effects, Applicant points to the enrichment results of Examples 5-7 of the instant specification. Though the enrichment achieved in these examples is high, the recitation of these examples alone is not enough to provide evidence of unexpected results. Applicant is directed to MPEP 716.02, which discusses the necessary evidence in such circumstances. Such evidence includes an explanation of why Applicant believes the achieved results are unexpected (e.g. achieving a greater than expected result) and comparison with the closest prior art.
Claim Interpretation
In instant claim 5, particular levels of complementarity in the binding regions established in claim 1 are recited. For each particular level of complementarity/mismatch, the claim states “thereby causing…” With this wording, it will be interpreted that the inherent structure of the binding regions leads to the functional limitation described by the “thereby” statements.
Claim Objections
Claim 9 is objected to because of the following informalities: in line 2, “in the nucleic acid sample” should read “in the pre-amplified nucleic acid sample” to better match the language of step (b) of claim 1. Appropriate correction is required.
Claim 12 is objected to because of the following informalities: based on the genes recited in claim 13, it is believed that the second recitation of “PIK3CA-E545K” should read “EGFR-delE746-A750.” Additionally, each mutation recitation should have “a” or “an” in front of it (“a KRAS-G12D”, “a PIK3CA-E454K”, and “an EGFR-delE746-A750”). Appropriate correction is required.
Claim 13 is objected to because of the following informalities: similar to in claim 12, each mutation recitation should have “a” or “an” in front of it (“a KRAS-G12D”, “a PIK3CA-E454K”, and “an EGFR-delE746-A750”). Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 11-13 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.
Claim 11 is rejected because it recites “the mismatch sites introduced by the gDNA” in line 2, but “mismatched sites introduced by the gDNA” are not recited in claim 1, from which this claim depends. Claim 1 only recites “mismatched base pairs.” Additionally, the general recitation of the gDNA “introducing” mismatches is also not recited in claim 1. In claim 1, mismatches exist between the gDNA and the target region for the target/non-target sequence, but the gDNA does not necessarily cause the mismatches.
Claims 12-13 are rejected due to their dependence on rejected claim 11.
Free of the Prior Art
Claims 1-9 and 11-13 are free of the prior art. No prior art could be found that analyzes target and non-target nucleic acid sequences in the manner claimed, particularly using one of the claimed Argonaute proteins, where an amplification-cleavage reaction results in a 500-fold or greater increase of a target sequence.
Song et al. (bioRxiv, 2019) teaches a NAVIGATER enrichment method that utilizes Argonaute cleavage followed by PCR (Abstract and Figure 1). However, cleavage and PCR do not occur simultaneously (see pages 14-15). Table 3 of the reference also shows a comparison of allele enrichment methods, many of which involve cleavage followed by amplification or sequencing, and none produce the required fold enrichment described in the instant claims.
Song et al. (US 2007/0292865 A1; cited in a previous Office Action) teaches simultaneous amplification and cleavage (see Examples 11 and 12), but does not teach the claimed cleavage enzyme, the use of guide RNA, and does not appear to enrich mutant/variant targets in the presence of similar, non-target sequences.
No prior art could be found the recites simultaneous amplification and cleavage with an Argonaute enzyme in the manner claimed to produce the claimed enrichment.
Conclusion
Claims 1-8 are allowable. Claim 9 is objected to. Claims 11-13 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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