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 .
Claim status
In the reply filed 8/04/2025, Applicant has amended Claims 78 and 82, and canceled claims 108-110.
Claims 78, 82, and 85 are under consideration.
Priority
The instant application was filed 01/05/2024 and claims priority to provisional application 63/578,625, filed 8/24/2023, 63510866, filed 6/28/2023, 63507968, filed 6/13/2023, and 63450947, filed 3/08/2023.
In regard to amended claim 82, a review of the provisional application No. 63/450,947 did disclose fRNA with reprogrammable target spacer consisting of 21 nucleotides (p. 8, Example 4); thus, claim 82 is being given the filing date of 3/08/2023.
Withdrawn Objection to Specification
The prior objections specification because it referred to color drawings is withdrawn in light of Applicant’s amended specification filed 8/04/2025.
Withdrawn Claim Rejections - 35 USC § 101
The prior rejection of Claims 78, 82, and 85 under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more is withdrawn in light of Applicant’s claim amendments to incorporate at least one mutation in a poly U stretch within a stem-loop region of the fRNA, which does not have a naturally occurring counterpart.
Withdrawn 35 USC § 102
The prior rejection of Claims 78, 82, and 85 under 35 U.S.C. 102(a)(2) as being anticipated by Zhang et al. (WO2023/114872, filed 12/14/2022, published 6/22/2023), as evidenced by Saito et al. (Nature, 2023, (620):660-692, prior art of record) is withdrawn in light of Applicant’s amendment of Claim 78 to incorporate at least one mutation in a poly U stretch within a stem-loop region of the fRNA, which Zhang does not anticipate.
The prior rejection of Claims 78, 82, and 85 under 35 U.S.C. 102(a)(2) as being anticipated by Ladha et al. (WO2023/240261, filed 6/09/2023, with priority to 63/452,316 filed 3/15/2023 and 63/351,326 filed 6/10/2022, prior art of record), as evidenced by Legendre et al. (GenBank NC_014649, Acanthamoeba polyphaga mimivirus, complete genome. Direct submission 11/17/2010) and Schargel et al. (Nature Struct & Mol Bio, 2024, 32:243-246) is withdrawn in light of Applicant’s amendment of Claim 78 to incorporate at least one mutation in a poly U stretch within a stem-loop region of the fRNA, which Ladha does not anticipate.
Claim Rejections - 35 USC § 103
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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 78, 82, and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (WO2023/114872, filed 12/14/2022, published 6/22/2023, prior art of record), as evidenced by Saito et al. (Nature, 2023, (620):660-692, prior art of record), in view of Zhang, Strecker and Ladha (WO2021/257997, filed 6/18/2021, published 12/23/2021, prior art of record)
The applied reference has a common Applicant (i.e., Massachusetts Institute of Technology) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
In regard to claim 78, Zhang (WO2023) teaches and claims a composition comprising
a Fanzor protein from Naegleria lovaniensis of “Nlov” comprising SEQ ID NO:630 ([0097, 0102, 0129] see Example 10, as well as Claims 1-18 of Zhang), which is 100% identical to SEQ ID NO:3281 of instant Application (SCORE search 4/28/2025, rag.file, Result #1). Specifically, in regard to RuvC domain structure, the NlovFz2 polypeptide naturally has a rearranged RuvC-II domain with respect to the catalytic glutamic acid (E) and glycine (G) residues relative to canonical positions in TnpB domains, a NLS domain, and a HTH domain (see evidentiary reference of Saito et al. for the N. lovaniensis type 2 Fanzor “NlovFz2” in Fig. 1, extended data Fig. 2, and Supplemental Table 1); and
an engineered fRNA (alias omega RNA) comprising a scaffold and reprogrammable target spacer sequence that is capable of forming a complex the Nlov Fanzor protein and directing the Fanzor protein to a target sequence, and wherein the complex binds a TAM sequence 5’ of the target sequence ([0102, 0129, 01381-01382], Example 10, Figs. 23 & 50). In regard to the fRNA being “engineered”, the term “engineered” is not specifically defined by Applicant’s specification, and the term reasonably encompasses fRNA/omegaRNAs that are isolated from their genomic position, as such, Zhang (WO2023) teaches the cognate fRNA for the indicated Nlov Fanzor and it is programmed for targeting in yeast and human cells (Example 10, [01382].
In regard to claim 82, as stated supra, Zhang (WO2023) teaches the sequence of the fRNA for Nlov Fanzor and it comprises 21 nucleotides. Note the transitional phrase “comprises” is open-ended and allows for additional nucleotides. Furthermore, Saito evidences the fRNA for the NlovFz2 is also at least 21 nucleotides (Fig. 1c of Saito).
In regard to claim 85, as stated supra, Zhang (WO2023) teaches the Nlov Fanzor nuclease cleave DNA next to the 5’ TAM.
However, Zhang (WO2023) is silent with respect to a polyU stretch in the stem-loop region of the fRNA being mutated. Note the phrase “stem-loop region” has not been defined by Applicant’s specification and has been interpreted at a polyU stretch within and/or adjacent to the stem-loop formed by the guide RNA scaffold.
With respect to claim 78, Zhang et al. (WO2021) (same inventor as Zhang (WO2023)) teach compositions comprising novel CRISPR nuclease of the TnpB family, wherein a polyU stretch in the stem-loop region of the guide RNA is mutated [0197, 0280].
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to composition comprising the Nlov Fanzor and fRNA as taught by Zhang (WO2023) and mutate a polyU stretch in the stem-loop region as taught by Zhang (WO2021) with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Zhang (WO2021) because mutating a sequence in the poly-U stretch reduces or prevents early or premature termination of the guide RNA production [0197, 0280].
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 8/04/2025 are acknowledged.
Applicant argues that Zhang (2023) is silent to a poly-U stretch in the stem-loop region of the fRNA being mutated, and one of ordinary skill would not have been motivated to mutate the poly-U stretch at taught by Zhang (2021) with a reasonable expectation of success.
First, Applicant argues there would have been no motivation to combine the teachings of Zhang (2023) with Zhang (2021). Specifically, Applicant argues that Zhang (2021) are directed to the TnpB family of CRISPR nucleases, which are different from Fanzor nucleases and one would not have been motivated to modify a Fanzor guide RNA scaffold based on the TnpB guide RNA scaffold. Continuing, Applicant argues that Zhang (2021) does not teach the polyU stretch is mutated specifically in a stem-loop region, and there would be no motivation to choose this region in the guide RNA scaffold. Furthermore, Applicant argues that the Examiner has relied upon impermissible hindsight for motivation to combine Zhang 2023 and Zhang 2021.
Second, Applicant argues there would have been no reasonable expectation of success to combine the teachings of Zhang (2023) with Zhang (2021). Specifically, Applicant argues that instant specification states that that despite the similarities between TnpB and Fanzor nucleases, Fanzors have not been surveyed comprehensively in eukaryotic cells and have not been demonstrates to be active nucleases either in biochemical or cellular contexts. The specification explains that although Fanzor nucleases originated from TnpB systems, the properties of these eukaryotic RNA-guide nuclease are surprisingly and notable different from those of the prokaryotic ones. Due to this unpredictability and novelty, a person of ordinary skill in the art would not have been able to predict a functional Fanzor guide RNA with a polyU mutation in the step loop region.
Applicant's arguments have been fully considered but they are not found persuasive.
In regard to the motivation to combine Zhang (2023) with Zhang (2021) and the Examiner’s alleged use of hindsight reasoning, 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. In re McLaughlin, 443 F.2d 1392; 170 USPQ 209 (CCPA 1971). In instant case, Zhang (2023) teaches the Fanzor nuclease and an engineered fRNA. Furthermore, Zhang (2023) goes on to explain that Fanzor nucleases are the eukaryotic counterparts to the TnpB nucleases of prokaryotes (see Fig. 3 of Zhang, 2023). Zhang (2023) provides alignment and crystal structures comparing Fanzor, Cas12a, and TnpB nuclease (see Fig. 7 of Zhang, 2023), and evidences that “Fanzor retains the overall structure of the REC domain and bridge helix domain, both of which are important for RNA guide and target DNA binding.” [0086]). Thus, one of ordinary skill in the art would have been motivated to turn to the relate art directed to TnpB nucleases of Zhang (2021), who is the same inventor of Zhang (2023). In regard to choosing to modify a position in the poly-U sequence in the stem-loop region, as stated supra, Zhang (2021) teaches the motivation to do so in order to prevent premature termination of the guide RNA transcription by U6 Pol-III enzymes. Since Zhang (2023) teaches the use of the same U6 Pol-III enzyme was well known for making guide RNAs [0503, 01297], it would have been obvious to have applied the teachings for TnpB guide RNAs to Fanzor guide RNAs. Specifically, in regard to the placement of the poly-U substitution in the “stem-loop region”, as stated in the pending rejections, the Examiner has interpreted phrase “stem-loop region” as not the same as “stem-loop” structure itself, and the phrase reasonably encompasses sequences in the region adjacent to the stem-loop structure. Furthermore, it was well known that guide RNAs formed multiple stem loops separated by short single stranded regions between stem-loops, and that stem-loops are more energetically favorable than single stranded RNA, thus the majority of the sequence of the guide RNA occurs in a stem-loop structure, and from a small genus of options to substitute a residue in the poly-U, it would have been predictably obvious to have the poly-U substitution in the stem-loop region .
In regard to Applicant’s second arguments, contrary to the statements of Applicant’s disclosure that Fanzors have not been demonstrated to be active nucleases either in biochemical or cellular contexts, Applicant is reminded that the absence of proof is not proof of absence, and just because Applicant’s were unaware of functional Fanzors in the prior art does not mean that there were no demonstrations of functional Fanzors prior to Applicant’s effective filing date. Specifically, Zhang (2023) discloses in Example 10 that the N. lovaniensis (Nlov) Fanzor in a TAM screening assay [01382]. Thus, functional Fanzor nucleases with their guide fRNAs were known before the time of filing of instant application.
[AltContent: textbox ([img-media_image1.png])]In regard to the successful modification of the Fanzor guide RNA (fRNA), as stated supra, Zhang (2023) discloses the structure of the fRNA for N. lovaniensis in Example 10, [01381], see Fig. 50 excerpt adjacent. Thus, the positions of the poly-U tract in the stem-loop region for modification would have been immediately apparent to one of ordinary skill in the art, and one could have made the mutation by simple cloning or RNA synthesis techniques with a reasonable expectation of success.
Finally, the reasonable expectation of succus of making and using poly-U modified fRNAs is supported by the fact that Zhang (2023) establishes that RNA folding software for predicting stem-loop regions [0206], as well as high through-put assays for determining the activity of a Fanzor nuclease with its optimal fRNA for a particular target were well established, routine and conventional (see Figs 4 and 5 of Zhang, 2023). Thus one of ordinary skill in the art would had arrived at functional complex with a modified poly-U fRNA with a reasonable expectation of success.
Claims 78, 82, and 85 are rejected under 35 U.S.C. 103 as being unpatentable over Ladha et al. (WO2023/240261, filed 6/09/2023, with priority to 63/452,316 filed 3/15/2023 and 63/351,326 filed 6/10/2022, prior art of record), as evidenced by Legendre et al. (GenBank NC_014649, Acanthamoeba polyphaga mimivirus, complete genome. Direct submission 11/17/2010) and Schargel et al. (Nature Struct & Mol Bio, 2024, 32:243-246), in view of Zhang, Strecker and Ladha (WO2021/257997, filed 6/18/2021, published 12/23/2021)
In regard to claim 78, Ladha teaches and claims a composition comprising
a Fanzor (alias TnpB ortholog) protein from Acanthamoeba polyphaga mimivirus of “APmv-2 TnpB/Fanzor ISvMimi_1” comprising SEQ ID NO:104 (Table A, p.497 of WO2023240261, see also Sequence Listing, p. 153, as well as Claim 19 of 63/351,326 priority document). Specifically, in regard to RuvC domain structure, the APmv-2 TnpB/Fanzor ISvMimi_1 is a type 2 Fanzor polypeptide naturally has a rearranged RuvC-II domain with respect to the catalytic glutamic acid (E) and glycine (G) residues relative to canonical positions in TnpB domains (see comparison of relevant portions of Ladha’s SEQ ID NO:104 below to “ApmHNuc_1/187-379” of Applicant’s Fig. 22A):
RuvC-I RuvC-II RuvC-III
NSCGIDPG KICIGKLNV…VVNVNEYL-TTK ADRDENAAKNI
Canonical E->G Alternate E
In regard to the APmv-2 TnpB/Fanzor ISvMimi_1 having NLS and HLH domains, these domains are inherent to the taught sequence as evidenced by Applicant’s specification (see Figs. 3C “Ismini” as well as 8C & 10A “ApmHNuc”), as well as the post-filing art of Schargel et al. (2025) who crystalized the APmv-2 TnpB/Fanzor2 and evidences that it naturally comprises an unordered NLS domain and HTH domain (Figs 1 & 2 of Schargel, and note the first 53 amino acids comprising the NLS of the ApmFz2 of Schargel are 100% identical to SEQ ID NO:104 of Ladha).
an engineered fRNA (alias reRNA) comprising a scaffold and programmed target spacer sequence that is capable of forming a complex the Fanzor protein and directing the Fanzor protein to a target sequence, and wherein the complex binds a TAM sequence 5’ of the target sequence ([00135, 00147, 00244, 0247, 0250-0252, 0269-0270, 1212], claims 1 & 19, 37 of WO2023240261, see also Summary, [0001, 0003-0004, 0085, 0106, 0131] as well as Claims 1, 17 of 63/351,326 priority document). In regard to the fRNA being “engineered”, the term “engineered” is not specifically defined by Applicant’s specification, and the term reasonably encompasses fRNA/reRNAs that are isolated from their genomic position, as such, Ladha teaches the cognate reRNA for the indicated TnpB orthologue is cloned under the control of a U6 promoter ([1210-1212] of WO2023240261, see also [0317-0319] of 63/351,326 priority document), while the prior art of Legendre et al. (2011) evidences that the nucleic acid sequences for cloning the reRNA (i.e., “right end RNA”) from APmv-2 TnpB/Fanzor ISvMimi_1 were available to one of ordinary skill preparing the composition of Ladha (see “YP_0903987301” of GenBank deposit NC_014649.1 by Legendre).
In regard to claim 82, as stated supra, Legendre evidences that the APmv-2 TnpB/Fanzor ISvMimi_1 scaffold was available, which comprises 21 nucleotides. Note the transitional phrase “comprises” is open-ended and allows for additional nucleotides. Furthermore, Ladha teaches a genus of reRNA scaffolds comprising spacers that comprise 3’ extensions programmed toward a target sequence ([00247-0252] of WO2023240261, see also [0106] of 63/351,326 priority document).
In regard to claim 85, as stated supra, Ladha teaches the TnpB/Fanzor nuclease cleave DNA next to the 5’ TAM.
However, although Ladha teaches the TnpB gRNA are modified in one or more positions such as in an internal polyuridinylate sequence ([0257 of WO2023240261, see also [0121] of 63/351,326 priority document), they are silent with respect to a polyU stretch in the stem-loop region of the fRNA being mutated. Note the phrase “stem-loop region” has not been defined by Applicant’s specification and has been interpreted at a polyU stretch within and/or adjacent to the stem-loop formed by the guide RNA scaffold.
With respect to claim 78, Zhang, Strecker and Ladha (same inventor as Ladha 2023) teach compositions comprising novel CRISPR nuclease of the TnpB family, wherein a polyU stretch in the stem-loop region of the guide RNA is mutated [0197, 0280].
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to composition comprising the APmv-2 TnpB/Fanzor ISvMimi_1 and fRNA as taught by Ladha and mutate a polyU stretch in the stem-loop region as taught by Zhang et al. with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Zhang et al. because mutating sequence in the poly-U stretch reduces or prevents early or premature termination of the guide RNA production [0197, 0280].
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 8/04/2025 are acknowledged.
Applicant argues that Ladha is silent to a poly-U stretch in the stem-loop region of the fRNA being mutated, and one of ordinary skill would not have been motivated to mutate the poly-U stretch at taught by Zhang (2021) with a reasonable expectation of success.
First, Applicant argues there would have been no motivation to combine the teachings of Ladha with Zhang (2021). Specifically, Applicant argues that Zhang (2021) does not teach the polyU stretch is mutated specifically in a stem-loop region, and there would be no motivation to choose this region in the guide RNA scaffold, let alone within the stem-loop region of a Fanzor guide RNA. Therefore the Office has relied upon impermissible hindsight.
Second, Applicant argues there would have been no reasonable expectation of success to combine the teachings of Ladha with Zhang (2021) due to the surprisingly and notable difference between eukaryotic Fanzor nuclease from those of the prokaryotic TnpB homologues. Due to this unpredictability and novelty, a person of ordinary skill in the art would not have been able to predict a functional Fanzor guide RNA with a polyU mutation in the step loop region.
Applicant's arguments have been fully considered but they are not found persuasive. The response to the arguments directed to the state of the art for unpredictability and novelty of functional Fanzor nucleases has been addressed above.
In regard to the motivation to combine Ladha with Zhang, Strecker and Ladha (2021) and the Examiner’s alleged use of hindsight reasoning, 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. In re McLaughlin, 443 F.2d 1392; 170 USPQ 209 (CCPA 1971). In instant case, Ladha teaches the Fanzor nuclease and an engineered fRNA (i.e., reRNA). Furthermore, Ladha considers the APmv-1-3 Fanzor nucleases as “TnpB-like proteins” or “TnpB/Fanzor” proteins ([00147] of WO2023/240261, see also p. 153, Sequence Table of 63/351,326 priority document), thereby indicating that the similarity between these nucleases was sufficient enough to apply modifications to either one of these homologues. Thus, the readers of Ladha would not consider the scientific leap from Fanzors to TnpB as being unpredictable.
Furthermore, despite Applicant’s arguments directed to distinguishing between Fanzors and TnpB nucleases, Applicant’s specification evidences for the APmv-2 TnpB/Fanzor2 ISvMimi of Ladha that the Acanthamoeba polyphaga mimivirus fRNA was in fact similar to the wRNA of the TnpB families (see excerpt from p. 189, Example 21, and from p.189, Example 22):
“In the alignment of ApmFNuc loci, the predicted fRNA structure was highly conserved, with the conservation extending upstream into the coding region of ApmFNuc, indicating possible cofolding with this portion of the coding region and potential RNA processing site (Fig. 19I and Fig. 26G). This apparent RNA structure conservation is reminiscent of the OMEGA families, where both the IscB and TnpB families show limited structural variation (Altae-Tran et al. 2021), and processing of the upstream region of the mRNA releases functional guide RNAs (Nety et al. 2023)…Notably, ApmFNuc protein was unstable when expressed alone and required coexpression with its fRNA for protein stabilization and accumulation (FIG. 27), similar to the instability of TnpB in the absence of ωRNA”.
Overall, the statements from Applicant’s disclosure reflecting the state of the art do not provide objective scientific evidence that there was too big of a scientific leap in applying modifications derived from TnpBs to Fanzors. Accordingly, one of ordinary skill in the art would have been motivated to turn to the relate art directed to TnpB nucleases of Zhang and Ladha (2021), who is the same inventor of Ladha (2023), to seek out modifications of the Fanzor fRNA (i.e., reRNA).
In regard to choosing to modify a position in the poly-U sequence in the stem-loop region, as stated supra, Zhang (2021) teaches the motivation to do so in order to prevent premature termination of the guide RNA transcription by U6 Pol-III enzymes. Since Ladha teaches using the same U6 Pol-III enzyme, it would have been obvious to have applied the teachings for TnpB guide RNAs to Fanzor guide RNAs. Specifically, in regard to the placement of the poly-U substitution in the “stem-loop region”, as stated in the pending rejections, the Examiner has interpreted phrase “stem-loop region” as not the same as “stem-loop” structure itself, and the phrase reasonably encompasses sequences in the region adjacent to the stem-loop structure. Furthermore, it was well known that guide RNAs formed multiple stem loops separated by short single stranded regions between stem-loops, and that stem-loops are more energetically favorable than single stranded RNA, thus the majority of the sequence of the guide RNA occurs in a stem-loop structure, and from a small genus of options to substitute a residue in the poly-U, it would have been predictably obvious to have the poly-U substitution in the stem-loop region.
In regard to Applicant’s second arguments, as stated supra, Ladha teaches right-end (re) derived reRNAs (i.e., fRNA), which are genomically adjacent to the RNA-directed nucleases at the right of end of the transposable elements. Since, Ladha identifies the APmv-2 TnpB/Fanzor ISvMimi_1 sequence, and it was already annotated in the APmv genome (see “YP_0903987301” of GenBank deposit NC_014649.1 by Legendre), there was a reasonable expectation of success in making and using the engineered fRNA (i.e., reRNA).
Furthermore, the cited prior art of Zhang (2021) establishes that is was routine and conventional to identify putative gRNAs for a novel CRISPR homologue, wherein once a transcript is identified (i.e., the sequence for AmpFNuc/APmv-2 as disclosed by Ladha), sequences are mapped to their locus in the genome of the source organism (i.e,. the known and published genome of AmpF as evidenced by Legende), and putative gRNAs are identified and their structure is predicted (p. 354, tracrRNA Determination, [1151-1152], see Fig. 5). In fact, Zhang (2021) teaches that RNA folding software was well known, and optimal folding may be determined by any suitable polynucleotide folding algorithm [0186], and explicitly cites the University of Vienna-RNA folding software used in instant Application for the folding of the AmpFNuc fRNA of Fig. 34A. Thus one of ordinary skill in the art would had arrived at functional complex with a modified poly-U fRNA (i.e., reRNA) with a reasonable expectation of success.
Finally, Applicant has not established either criticality or the unpredictability in making and using polyU mutated fRNA. For example, Fig. 34A of the specification [AltContent: textbox ([img-media_image2.png])]shows the fRNA secondary structure for ApmFNuc as predicted by viennaRNA folding software. In this figure, Applicant contemplates U->C substitutions at positions 196 and 198 (i.e., mutations 5 and 6, respective), but these are not reduced to practice. Furthermore, Figure 34A indicates that U->A and U->C substitutions have occurred at positions 183-186 (mutations 1-4, respectively).
[AltContent: textbox ([img-media_image3.png])] However, as evidenced by Legendre, these appear not be Applicant-made substations in the APmv-2 TnpB/Fanzor ISvMimi_1 scaffold, but correspond to the naturally occurring sequence as deposited in NC_014649. Accordingly, Applicant did not establish the unpredictability to make and use any of the claimed substitutions in the taught fRNAs, and provided no evidence that making such substitutions was unpredictable or would have required undue experimentation to one of ordinary skill in the art. Furthermore, when testing the ApmFNuc Fanzor with its fRNAs, Applicant demonstrates that every combination of fRNA produces a functional nuclease (Fig. 35A of the specification).
Finally, any conclusions of unpredictability have to be made in the context of simply producing a functional ribonucleoprotein complex in vitro. In instant case, the Fanzor nuclease was known, the fRNA (i.e., reRNA) regions were known, and folding software and high through-put assays for their screening upon poly-U substitution were routine and conventional. According, the claims at issue would have been found obvious since there had been ample suggestion in the prior art that the claimed composition would have worked in vitro. Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit has concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.
Withdrawn Double Patenting
The prior provisional rejection of Claims 78, 82, 85, on the grounds of nonstatutory double patenting as being unpatentable over claims 1-20, and 22-24 of copending Application No. 18/406,071, is withdrawn in light of the abandonment of copending Application.
The prior provisional rejection of Claims 78, 82, 85, on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 2, 10, 12-13, and 18 of copending Application No. 18/719,352, is withdrawn in light of Applicant’s amendment of Claim 78 to incorporate at least one mutation in a poly U stretch within a stem-loop region of the fRNA, which copending application does not claim.
Double Patenting
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 78, 82, and 85 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 2, 10, 12-13, and 18 of copending Application No. 18/719,352, in view of Zhang, Strecker and Ladha (WO2021/257997, filed 6/18/2021, published 12/23/2021). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented
The subject matter claimed in the instant application is disclosed in the referenced application as follows: the Fanzor polypeptides and fRNA of cited application makes obvious the composition of instant application. It is clear that elements of the cited application claims are to be found in instant claims with respect to the Fanzor being from Tables 1, 6-14, or Figs, 20, 35, or 56.
The difference between the cited application claims and the instant claims lies in the fact that the cited application do not claim a modified polyU tract in the stem-loop region.
With respect to claim 78, Zhang et al. teach compositions comprising novel CRISPR nuclease of the TnpB family, wherein a polyU stretch in the stem-loop region of the guide RNA is mutated [0197, 280].
Accordingly, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to have claimed the Fanzor composition of cited application and mutate a polyU stretch in the stem-loop region as taught by Zhang et al. with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so as taught by Zhang et al. because mutating sequence in the poly-U stretch reduces or prevents early or premature termination of the guide RNA production [0197, 0280].
Since the instant application claims are obvious over cited application claims in view of Zhang et al., said claims are not patentably distinct.
RESPONSE TO ARGUMENTS
Applicant's arguments filed on 8/04/2025 are acknowledged, and ask that instant provisional rejection be held in abeyance until allowable subject matter has been identified.
Conclusion
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
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/ARTHUR S LEONARD/ Examiner, Art Unit 1631