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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 12, 2026 has been entered.
Application Status and Withdrawn Rejections
Applicant’s amendments filed May 12, 2026, amending claim 52 and canceling claims 56-59 is acknowledged. Claims 52-54 are pending and under examination.
The amendment to claim 52 requiring “a tracrRNA consisting of a hairpin and a second stem” overcomes the §103 rejections in the previous office action. The previous §103 rejections are withdrawn.
The limitation of claim 57 was incorporated into claim 52. Thus, claim 52 is identical to canceled claim 57. As recited below, claim 52 is rejected for incorporating new matter using a maintained rejection of claim 57 in the previous office action.
Priority
As indicated in the office action mailed December 12, 2024, the first disclosure of methods for excising, purifying and sequencing a cleaved target nucleic acid is in US provisional application 61/818,382, filed May 1, 2013. However, the first disclosure of single guide RNAs having a tracrRNA with at least two hairpin/stems in addition to the hybridized tracrRNA/crRNA segment (see interpretation in paragraph 7 below) is in US provisional application 61/903232 (FIG 5), filed November 12, 2013. Therefore, the effective filing date of the claims 52-54 is November 12, 2013.
Claim Interpretation
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Claim 52 recites a single guide with 1) a 5’ spacer sequence, 2) a minimum CRISPR repeat sequence, 3) a minimum tracrRNA sequence, 4) a single guide connector sequence connecting the minimum CRISPR repeat sequence and the minimum tracrRNA sequence, and 5) a 3’ tracrRNA consisting of a hairpin region and a second stem. FIG. 1B and paragraph [00285] of the Specification, which are reproduced below, are used to interpret the structure of the claimed single guide RNA.
The Specification doesn’t define “duplex”, “hairpin” or “stem” and it appears that they are used interchangeably. Accordingly, “hairpin” and “stem” are interpreted as being substantially the same. Thus, the claimed single guide RNA (sgRNA) in claim 52 must include (a) a spacer sequence (element 140), (b) minimum crRNA and tracrRNA sequences, which can optionally hybridize, connected by a linker (elements 145-147, 150, 155), and (c) a tracrRNA consisting of ONLY two hairpins/stems in addition to the tracrRNA sequence (element 147) that forms a duplex with the crRNA-derived sequence. Because claim 52 uses closed terminology to claim “a tracrRNA consisting of a hairpin region and a second stem”, the claimed single guide RNA must only contain element 170 and either element 165, if it forms a hairpin, or element 180, but not both element 165 and 180. Additionally, any single-stranded elements must be absent after the minimum tracrRNA sequence (element 147) to the 3’ end of the guide RNA molecule, e.g., elements 160 and 175 must be absent.
Claim Rejections - 35 USC § 112(a) – New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 52-54 are 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. This is a maintained NEW MATTER rejection.
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
In the instantly rejected claims, the new limitation of “wherein the tracrRNA consists of the hairpin region and the second stem in claim 52 appears to represent new matter. “Consists” is interpreted as closed language that restricts the tracrRNA portion of the single guide RNA from comprising any additional nucleotides other than nucleotides that form a hairpin and stem. No specific basis for this limitation was identified in the specification, nor did a review of the specification by the examiner find any basis for the limitation. There is no recitation in the Specification of a tracrRNA “consisting” of only specific structures. Additionally, all of the depictions of sgRNA backbone secondary structures in FIGs 22, 24, 25 and 26 have at least one unpaired or non-hybridized nucleotides outside of the spacer and minimum crRNA/tracrRNA region. Since no basis has been identified, claims 52-54 are rejected as incorporating new matter.
Response to Arguments
Applicant argues that the present specification provides written description support for tracrRNA consisting of a hairpin region and a second stem by referencing FIG 1A and its description in paragraph [00284], specifically element 130 for a single RNA guide can comprise one or more hairpins. Applicant argues that by reciting “one or more hairpins”, the specification provides for the exclusion of some hairpins in the tracrRNA portion of the gRNA (Remarks, ¶ spanning pages 4-5). Applicant also references Fig 1B (recreated above), and paragraphs [00332]-[00333]) that the 3’ tracrRNA sequence can comprise more than one duplexed region, thereby allowing the exclusion of one or more hairpins (page 5, ¶1). This argument has been fully considered but is not persuasive because it does not address the merits of the rejection. The rejection is based on excluding any single-stranded stretches or unpaired nucleotides in between any hairpins/stems. Both FIG 1A and FIG 1B show the 3’ tracrRNA sequences with single-stranded sections and unpaired nucleotides in between hairpins/stems. The tracrRNA variants in FIGs. 22 and 24 have single-stranded portions after the minimum crRNA/tracrRNA duplexes.
Nishimasu solves the crystal structure of SpCas9 complexed with a single guide RNA and DNA (Nishimasu et al., Cell (2014), 156: 935-949). In the report, Nishimasu demonstrates that the portion of the sgRNA from the tracrRNA sequence can be divided into an anti-repeat, three tracrRNA stem loops, and a single-stranded “linker” that connects stem loops 1 and 2 (Fig 4A; page 941, ¶1). Removing all of the tracrRNA except stem loop 1 of the tracrRNA reduced complex formation and/or activity of the complex by 75% (Fig 4D). Nishimasu does not attempt to remove all linker nucleotides, so it was unclear, even after the effective filing date of the claimed invention, if the 3’ tracrRNA sequences could consist of only hairpin/stem sequences, without any single-stranded linker stretches.
Nevertheless, because the Specification does not provide for any 3’ tracrRNA sequences that are missing single-stranded stretches, the claims are rejected for new matter.
Conclusion
No claims are allowable.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(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 CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
Prosecution Insights