DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 10 October 2025 have been entered. Claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, 469, and 471-473 were previously pending in the application. Claim 474 has been added by Applicant. Claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, 469, and 471-474 are currently pending in the application. Claims 1, 97, 452, 453, 454, 463, 464, and 472 are independent claims. The election of the following species remains in effect: SEQ ID NOs: 302 and 3530 expanded to include the subject matter of claim 458.
Claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, 469, and 471-474 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a CON of 35 International Application No. PCT/US2019/036160, filed 07 June 2019, which claims priority to U.S. Provisional Application No. 62/682,838, filed 08 June 2018, and U.S. Provisional Application No. 62/682,820, filed 08 June 2018.
Thus, the earliest possible priority for the instant application is 08 June 2018.
Specification
Applicant’s amendment to the specification filed 10 October 2025 has been entered.
Claim Objections
The objection to amended claim 472 for reciting “from 5 to 3:”, is withdrawn in view of the amendment to claim 472.
Claim Rejections - 35 USC § 112(b)
The rejection of amended claim 16 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting "the modification in the hairpin region" is withdrawn in view of Applicant’s amendments to claim 16.
The rejection of amended claim 471 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “modifications at least H1-1 to H1-5 and H2-1 to H2-12” is withdrawn in view of Applicant’s amendments to claim 471.
**The following new rejection is necessitated by amendments to the claims.**
Amended claim 469 is 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 469 recites the limitation "the mRNA" in line 2. There is insufficient antecedent basis for this limitation in the claim. Claim 469 depends on claim 454, which no longer recites an mRNA. As such, the metes and bounds of the claim cannot be determined.
Claim Rejections - 35 USC § 103
The rejection of amended, previously presented, original, and new claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, 469, and 471-473 under 35 U.S.C. 103 as being unpatentable over May et al. (US20150376586A1, IDS, published 31 December 2015, cited in a prior office action); in view of Yin et al. (2017, Nature Biotechnology, 35(12), 1179-1187, IDS); Wang et al. (2017, Chemical Reviews, Vol. 117, 9874-9906, cited in a prior office action); and Mir et al. (2018, BioRxiv [preprint], deposited 28 March 2018, cited in a prior action), is withdrawn over amended claim 469, maintained over amended, previously presented, and original claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, and 471-473, and newly applied to new claim 474. Applicant's amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
Applicant amended independent claim 1 to recite wherein the hairpin region lacks 5-10 of the nucleotides within the hairpin 1 region or within the hairpin 1 region and the nucleotide between the hairpin 1 region and the hairpin 2 region.
May was cited for teaching a guide RNA (gRNA)/ nucleic acid-targeting nucleic acid which is a short-single guide RNA (short-sgRNA) comprising a guide region and a conserved portion of an sgRNA comprising a hairpin region [¶ 0023, 0108, Figures 1 and 3], wherein the hairpin region lacks 5-10 nucleotides compared to the hairpin region corresponding to nucleotides 49-76 of SEQ ID NO: 400 [¶ 0036, 0338-0339, Figures 1 and 3, SEQ ID NO: 1467, which deletes the consecutive nucleotides 54-61 according to SEQ ID NO: 400 of the instant application and which has 100% sequence identity to SEQ ID NO: 302 of the instant application] and wherein the short- sgRNA comprises a 5' end modification or a 3' end modification [¶ 0079, 0081, 0087-0088]. The sequence of SEQ ID NO: 1467 disclosed by May comprises a deletion of the nucleotides comprising hairpin 1 corresponding to nucleotides 54-61 of SEQ ID NO: 400 of the instant application. The 5-10 lacking nucleotides of the sgRNA taught by May (e.g., the 8 nt missing from SEQ ID NO: 1467 of May compared to SEQ ID NO: 400 of the instant application) are consecutive, within the hairpin 1 region, and comprise nucleotides H1-6 to H1-12 and the 1 nucleotide between H1-12 and H2-1 (e.g., [see May Figure 3A for reference positions within the sgRNA]. As such, the sgRNA of May comprises a hairpin region lacking 7 nucleotides within the hairpin 1 region and the 1 nucleotide between the hairpin 1 region and the hairpin 2 region.
Note that the amendment to claim 14 requires the 5-10 nucleotides lacking from the hairpin region are within the hairpin 1 region, but does not require that no additional nucleotides are lacking from the hairpin region. The sgRNA taught by May lacks 7 of the hairpin 1 nucleotides, which meets the limitation for lacking 5-10 hairpin 1 nucleotides recited in claim 14.
Regarding Applicant’s amendments to independent claim 97 note that the amended claim now recites a short sgRNA comprising a modified sequence at least 70% identical to any of a list of recited sequences, wherein the sequences as recited comprise specific modification patterns. Note that amended claim 97 does not recite the elected species of SEQ ID NO: 302, but that at least SEQ ID NOs: 306, 307, 328, 341, and 342 are sequences with the same length and 100% sequence identity match to the elected species of SEQ ID NO: 302. Additionally, SEQ ID NOs: 206, 207, 228, 241, and 242 recite sequences corresponding to the defined sequences of SEQ ID No: 302, wherein they only lack the variable targeting sequences denoted as “N” in SEQ ID NO: 302, and so are comprised by the elected species of SEQ ID NO: 302. SEQ ID NO: 354 merely recites additional N’s compared to SEQ ID NO: 302, but as recited in claim 97 encompasses a variable number of N’s presented in SEQ ID NO: 302. As such, amended claim 97 has not been withdrawn from further prosecution on the merits and any of the modification patterns depicted in amended claim 97 for SEQ ID NOs: 206, 207, 241, 242, 306, 307, 328, 341, 342, or 354 are encompassed by the elected species.
Further, regarding the modification patterns recited in amended claim 97, note that claim 97 recites “a modified sequence at least 99, […] or 70% identical to any one of” the recited sequences, which has been interpreted to encompass wherein the modifications and/or the sequence is at least 70% identical to the modified sequence recited, such that an identical sequence can comprise up to 30% variation in the modification pattern.
Additionally, the sequence and modification pattern of SEQ ID NO: 206, as recited in claim 97, was previously addressed in the prior action for its recitation in amended claim 443, and sets forth a modification pattern which includes 2’-OMe modification of all 12 upper stem nucleotides and 2’-OMe + phosphorothioate at the three 3’ terminal nucleotides. Although the recited sequence comprises a modification pattern comprising 2’-O-Me modification at all of the upper stem nucleotides, only 70% or more of them must be modified to comply with the limitations of this claim.
Wang was cited for teaching the motivation to modify the last 3 nucleotides of the gRNA sequence according to the pattern recited for the SEQ ID NO: 206 to improve the stability and editing efficiency when co-delivered with a Cas9 protein or Cas9-encoding nucleic acid [page 9895 column 1 paragraph 2, page 9896 column 1 paragraph 2].
Additionally, Yin was cited for teaching the motivation to incorporate 2’-O-Me modifications in the upper stem loop nucleotides at all of the upper stem loop nucleotides to improve cleavage efficiency and to increase RNA resistance to degradation [abstract, column 2 ¶ 2, column 9 ¶ 3- column 10 ¶ 1, Figure 1, 3-4].
Regarding new claim 474, , as discussed above for claim 97, May, Wang, and Yin provide the motivations and teachings for the sequence and modification pattern of SEQ ID NO: 206 as recited in the claim.
As such, Applicant’s amendments do not overcome a finding of obviousness over May, Yin, Wang, and Mir under 35 U.S.C. 103.
Applicant argues that:
Yin does not motivate modifying the upper stem loop and teaches away from altering the hairpin;
Mir does not motivate modifying the upper stem loop;
Wang does not remedy the deficiencies of May, Yin, and Mir; and
the amendment to claim 97 provides modifications not taught by May.
However, that is not agreed.
In response to applicant’s arguments against the references individually, it is noted that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In addition, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Specifically, regarding Applicant’s argument 1), Yin was cited for teaching testing modifications within the invariable region of the sgRNAs, such that sgRNAs comprising 2’-OMe modifications at either eight or every nucleotide of the stem loop (e.g., 2’OMe_loops, SG-2’OMe, and SG-2’OMe-PS) have the highest efficiency of all tested modification variants and also have higher efficiency than the unmodified sgRNA [Figure 1]. Yin further teaches the combination of modifications within the variable (guide) sequence in combination with modifications in the invariable region, in which the sgRNA comprising 2’-OMe modifications at every nucleotide of the upper stem region (e.g., e-sgRNA) outperformed both the native sgRNA and the 5’ & 3’ end labeled sgRNA in cleavage efficiency (e.g., on-target indel formation) in both human cells and in mice [Figures 3-4]. Yin also teaches that chemical modifications of RNAs, including 2’-O-Me modification, can improve therapeutic efficacy by reducing susceptibility to nuclease degradation and that the modification of e-sgRNA facilitate function in part by increasing RNA resistance to degradation [abstract, column 2 ¶ 2, column 9 ¶ 3- column 10 ¶ 1]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to incorporate 2’-O-Me modifications in the upper stem loop nucleotides, including at least 8 and up to all of the upper stem loop nucleotides, to improve cleavage efficiency and to increase RNA resistance to degradation.
Note that any teaching if Yin that a 2’ F modification in the hairpin loops decreased the activity of sgRNAs in cells is not equivalent to a teaching that the absence of some residues from the hairpin loops would likewise decrease the activity of the sgRNAs in the cells. Therefore, an ordinarily skilled artisan at the time of filing would not have been dissuaded from modifying the upper stem loop nucleotides of May based on the teachings of Yin.
Regarding Applicant’s argument 2), note that Mir was cited for teaching the motivation to heavily and/or fully modify a gRNA, including modifications of the hairpin regions H1-1 to H1-6 and H2-1 to H2-12, to increase potency, increase stability, and ease chemical synthesis. As discussed above, Yin was cited for teaching the motivation to incorporate 2’-O-Me modifications in the upper stem loop nucleotides, including at least 8 and up to all of the upper stem loop nucleotides, to improve cleavage efficiency and to increase RNA resistance to degradation.
Regarding Applicant’s argument 3), note that Wang was cited for teaching the motivation to modify the first 3 nucleotides of the gRNA sequence according to the pattern recited in claim 437 option (1) to improve the stability and editing efficiency when co-delivered with a Cas9 protein or Cas9-encoding nucleic acid, and was not relied on for teaching modifications of the upper stem region.
Regarding Applicant’s argument 4), as discussed above, the combination of May, Yin, Wang, and Mir teach the sequence and modification pattern for at least that recited for SEQ ID NO: 206 in amended claim 97.
Therefore, Applicant’s arguments do not overcome a finding of obviousness over May, Yin, Wang, and Mir under 35 U.S.C. 103, and the rejection is maintained.
**The following new rejection is necessitated by Applicant’s amendments to the claims.**
Amended claim 469 is newly rejected under 35 U.S.C. 103 as being unpatentable over May et al. (US20150376586A1, IDS, published 31 December 2015, cited in a prior office action); in view of Yin et al. (2017, Nature Biotechnology, 35(12), 1179-1187, IDS, cited in a prior action); Wang et al. (2017, Chemical Reviews, Vol. 117, 9874-9906, cited in a prior office action); and Mir et al. (2018, BioRxiv [preprint], deposited 28 March 2018, cited in a prior action); as applied to amended, previously presented, original, and new claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, and 471-474; and further in view of Dombrowski [US20200354702A1, published 12 November 2020, with priority to U.S. Provisional Application No. 62/566,144, filed 29 September 2017].
Dombrowski teaches a sequence encoding a Cas9 protein open reading frame using low A codons, which includes the start and stop codons (e.g., SEQ ID NO: 111), which has the same length as and 100% identity to the nucleic acid sequence of instant SEQ ID NO: 3530 [Table 1, 26, Figure 25].
PNG
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224
718
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Greyscale
Dombrowski further teaches that mRNAs for the low A and low A/U codon schemes (e.g., SEQ ID NOs: 111 and 112) showed the highest Cas9 expression of their tested ORFs [0439]. Therefore, an ordinarily skilled artisan at the time of filing the instant application would have been motivated to use the sequence of Dombrowski SEQ ID NO: 111, having the same length and sequence as instant SEQ ID NO: 3530, to express high levels of Cas9.
Given the motivation taught by Dombrowski to use the sequence of instant SEQ ID NO: 3530, it would have been prima facie obvious to an ordinarily skilled artisan at the time of filing the instant application to modify the sgRNA composition of May, Yin, Wang, and Mir comprising a nucleic acid encoding a nuclease such that the nucleic acid comprises the sequence of instant SEQ ID NO: 3530 encoding a Cas9 nuclease with a reasonable expectation of success.
Note that none of applicant’s arguments apply to this new grounds of rejection, in that none address the limitations recited in amended claim 469.
Double Patenting
The rejection of amended, previously presented, and original claims 1, 5, 13-14, 16, 25, 97, 437, 443, 452-458, 463-466, 469, and 471-473 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 34-36, 39, 41-42, 46, 48, 56, 58-64, 70-72, 79-81, and 86-89 of copending Application No. 17/836,265, hereafter referred to as the ‘265 application, in view of May et al. (US20150376586A1, IDS, published 31 December 2015), is maintained and newly applied to new claim 474.
Note that this rejection is made with respect to the ‘265 application claims amendment filed 23 September 2025.
Applicant amended the claims to add the limitation that the hairpin region lacks 5-10 of the nucleotides within the hairpin 1 region or within the hairpin 1 region and the nucleotide between the hairpin 1 region and the hairpin 2 regions into claim 1, which was previously recited as an option of claim 14. Claim 1 of the ‘265 application currently recites wherein the hairpin 1 region lacks 6-8 nucleotides of H1-1 to H1-12, and wherein one or more of positions H1-1, H1-2, or H1-3 is deleted. As such, the lacking hairpin region nucleotides of the ‘265 application claims are a species of the lacking hairpin region nucleotides of the instant application. As such, Applicant’s amendments to the claims do not amend the claims in such a way as to overcome the finding of unpatentability over the ‘265 application.
Applicant argues that the provisional nonstatutory double patenting rejection is the only rejection remaining in the application, and so should be withdrawn because the instant application is the earlier filed Application.
However, this is not agreed.
Provisional nonstatutory double patenting rejections do not require that the co-pending application have a prior effective filing date. As set forth in MPEP 804(I)(B)(1), if two (or more) pending applications are filed, in each of which a rejection of one claimed invention over the other on the ground of provisional nonstatutory double patenting (NSDP) is proper, the provisional NSDP rejection will be made in each application (emphasis added). Additionally, a complete response to a nonstatutory double patenting (NDP) 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 (MPEP 804 (I)(B)(1)). Such a response is required even when the nonstatutory double patenting rejection is provisional.
As discussed above, both 112(b) indefiniteness and 103 obviousness rejections remain in the instant application, and as such the provisional nonstatutory double patenting rejection is not the last remaining rejection.
Therefore, Applicant’s arguments do not overcome the provisional nonstatutory double patenting rejection of record.
Conclusion
No claim is allowed.
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 Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634