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 was filed in this application after appeal to the Patent Trial and Appeal Board, but prior to a decision on the appeal. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on November 6, 2025 has been entered.
Status of Claims/Rejections
Claims 1-2, 4, 6, 8, 10, 13, 17, 59-60, 62-64, 66-68, and 70-72 are currently pending in the instant application. Claim 2 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Accordingly, claims 1, 4, 6, 8, 10, 13, 17, 59-60, 62-64, 66-68, and 70-72 are under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn, and the following rejection is the only rejection applied in this application.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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, 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.
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 1, 4, 6, 8, 10, 13, 17, 59-60, 62-64, 66-68, and 70-72 are rejected under 35 U.S.C. 103 as being unpatentable over Maianti et al. (WO 2018/165504 A1, of record) in view of Ran et al. (Nature, 2015, 520:186-191, of record).
Maianti exemplifies a genome editing system for editing mouse SCN9a (mSCN9a) comprising S. pyogenes Cas9 and a gRNA targeted to exon 11 of mSCN9a, wherein the gRNA is preceded by the NGG PAM sequence, wherein exon 11 is one of five target exons (exon 10, exon 11, exon 14, exon 17, and exon 22) for Cas9-mediated programmable genome editing of SCN9A for pain reduction, wherein Maianti also expressly exemplifies mouse SCN9a genomic deletions using the gRNAs targeting exon 11. See Figures 6A-6C.
Maianti discloses the nucleotide sequence of exon 11 of human SCN9A at page 189.
Maianti teaches that disruption of SCN9A in DRG neurons can reduce pain transmission and that chronic pain can be suppressed “by genome editing treatment of a small number of DRG neurons”, wherein genome editing is provided by a composition comprising a Cas9-encoding sequence and a guide RNA nucleotide sequence, further comprising a tracrRNA sequence, wherein the Cas9-encoding sequence comprises a nuclear localization signal (NLS) and the Cas9-encoding sequence can correspond to Cas9 from S. aureus, which recognizes a PAM sequence of NNGRRT, wherein Y is a pyrimidine and N is any nucleobase. See paragraphs 0052-0054, 0123-0124, 0172, 0228, and 0230; Figure 1C
Maianti does not teach making a single polynucleotide or a viral particle comprising both the Cas9-encoding sequence and an SCN9A-targeting gRNA sequence. Maianti also does not disclose SEQ ID NO:11 (5’-AAGCAGAAUUAUGGGCCUCUCA) as the gRNA sequence.
Ran teaches that “the restrictive cargo size (~4.5 kb, excluding the inverted terminal repeats) of AAV presents an obstacle for packaging the commonly used Streptococcus pyrogenes Cas9 (SpCas9, ~4.2 kb) and its single guide RNA (sgRNA) in a single vector”, while “smaller Cas9 enzymes” especially Staphylococcus aureus (SaCas9), provide “efficient delivery by AAV” because the “small size of SaCas9 enables packaging of” necessary elements for genome editing “into a single AAV vector within the 4.5-kb packaging limit.” (emphasis added). See pages 186 and 189.
Ran teaches that “Staphylococcus aureus (SaCas9) produced indels with efficiencies comparable to those of SpCas9” and that “SaCas9 achieves the highest editing efficiency in mammalian cells with guides between 21 and 23 nucleotides long”, wherein “SaCas9 cleaves genomic targets most efficiently with NNGRRT”, which is the SaCas9 PAM sequence (emphasis added). See page 187.
Ran demonstrates in vivo genome editing by incorporating “SaCas9 and its sgRNA into an AAV vector” or by packaging sgRNA into “AAV-SaCas9”, which “is able to mediate efficient and rapid editing”. See pages 189-190.
Ran illustrates a nucleotide sequence alignment between a 21-mer target preceded by NNGRRT PAM sequence and a 21-mer “SaCas9” guide RNA that is designed to be homologous to the target sequence, which is fused to a “tracrRNA” or “SaCas9 sgRNA scaffold”, which is 100% identical to SEQ ID NO:41 claimed in the instant case. See Figure 2a copied below.
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It would have been obvious to one of ordinary skill in the art before the effective filing date to make an “AAV-SaCas9” comprising a 22-mer gRNA that is homologous to a 22-mer sequence preceded by the NNGRRT PAM sequence within exon 11 of human SCN9A. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to make a single AAV vector that is able to package both a Cas9-encoding sequence and a gRNA fused to “SaCas9 sgRNA scaffold” for providing a decreased expression level of SCN9A for pain reduction purpose, because making a Cas9/gRNA-based genome editing system targeting exon 11 of SCN9A was an art-recognized goal for pain reduction purpose as evidenced by the teachings of Maianti including the actually synthesized/tested mSCN9A exon 11-targeting SpCas9 systems in Figures 6A-6C, and because it was known in the art that “small size of SaCas9 enables packaging” of genome editing elements “into a single AAV vector”, thereby overcoming the art-recognized “obstacle for packaging the commonly used Streptococcus pyrogenes Cas9 (SpCas9, ~4.2 kb) and its single guide RNA (sgRNA) in a single vector” as taught by Ran, who also taught that the gRNA sequence for Staphylococcus aureus Cas9 (SaCas9) can be “between 21 and 23 nucleotides long”, wherein “SaCas9 cleaves genomic targets most efficiently with NNGRRT”, which is the PAM sequence for SaCas9. Now, the entire nucleotide sequence of exon 11 of human SCN9A was known in the art as disclosed by Maianti, and the methodology for identifying a gRNA sequence for SaCas9 was known in the art as evidenced by Ran, who provided a detailed illustration in Figure 2a copied above, thus one of ordinary skill in the relevant art was reasonably equipped with the technical skills and ability to identify gRNA sequences preceding “NNGRRT” PAM sequence within exon 11 of human SCN9A. As such, one of ordinary skill in the relevant art would have readily identified three “NNGRRT” sequences following a nucleotide sequence of “between 21 and 23 nucleotides long” within exon 11 of human SCN9A thus would have identified a finite number of gRNA sequences of “between 21 and 23 nucleotides long” preceding the three “NNGRRT” sequences shown below, wherein a box is added for the 6-mer PAM sequence and a dotted line is added for the 22-mer preceding the “GAGAGT” SaCas9 PAM sequence.
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“When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that not of innovation but of ordinary skill and common sense.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
It is noted that the RNA sequence (5’-AAGCAGAAUUAUGGGCCUCUCA) corresponding to the 22-mer indicated with a dotted line above is 100% identical to SEQ ID NO:11 elected by applicant.
In view of the foregoing, the genome-editing system of claims 1, 4, 6, 8, 10, 13, 17, 59-60, 62-64, 66-68, and 70-72 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on November 6, 2025 have been fully considered but they are not persuasive. Applicant alleges that the examiner “dismisses Applicant’s evidence about the unpredictability of using computational prediction of gRNA sequence as in Ran.” Contrary to applicant’s allegation, the examiner did not dismiss applicant’s arguments regarding Ran. Note that the fact that applicant found applicant’s arguments unpersuasive is not the same as applicant’s arguments being dismissed. See the detailed response at pages 4-5 of the last Office action as provided by the examiner explaining why applicant’s arguments pertaining to Ran’s gRNA design are not found persuasive to show the alleged unpredictability that is sufficient to render the rejected claims nonobvious.
Applicant argues that the claims are not obvious because neither of the two cited references “shows any editing of the human SNC9A gene” as claimed. In response, the examiner is at a loss as to why a cited reference is legally required to “show” actual practice of the claimed subject matter because the examiner is not aware of any legal requirement that obviousness under §103 requires an actual reduction to practice. Applicant is invited to provide a legal basis for requiring an experimental showing for a claimed product in a patent application for rendering obvious the claimed product under §103.
Applicant argues that the claims are not obvious because the rejection’s rationale is “too simplistic.” In response, it is noted that the examiner is not aware of any legal basis that use of “too simplistic” rationale is prohibited for obviousness under §103. Applicant is invited to provide a legal basis that a “too simplistic” rationale is legally prohibited for obviousness under §103. Furthermore, applicant’s personal opinion that the obviousness rationale is “too simplistic” does nothing to rebut the obviousness rationale because applicant’s personal opinion fails to show errors in using and following the prior art teachings for designing an effective gRNA for a target sequence known and available in the art, especially when the benefits/advantages of identifying and using a gRNA for SaCas9 in place of the conventionally used SpCas9, which uses and requires a different PAM sequence, were expressly taught by Ran as expressly set forth in the rejection above and of record. That is, applicant’s personal opinion is insufficient to discredit or rebut the objective, scientifically-based teachings of the prior art.
Applicant alleges that Ran taught that “experimentation was necessary to confirm whether gRNA sequences had any activity.” It appears applicant has misinterpreted the claimed subject matter. Note that the rejected claims are merely directed to a product, not a method, wherein the claims merely recite the intended use “for modifying a human sodium voltage-gated channel alpha subunit 9 (SCN9A) gene” in the preamble.
Note that “[T]he patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure.” Catalina Mkt. Int’l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir. 2002). Further, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation.” Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997).
Again, as noted above, applicant is invited to provide a legal basis for requiring an experimental showing for a claimed product in a patent application for rendering obvious the claimed product under §103. It is noted that applicant did not specifically point out any specific passages in Ran that allegedly teaches that “experimentation was necessary to confirm whether gRNA sequences had any activity.” Hence, the examiner cannot verify applicant’s assertion.
Applicant provides a brief overview of Ran’s teachings including working examples and arrives at the conclusion that Ran’s teachings “show that mere knowledge of the NNGRRT PAM sequence and an approximate length of a gRNA is far too simplistic and insufficient to reasonably predict editing in the human SCN9A gene using the claimed gRNAs” and is also “insufficient to predict the on- and off-target efficiencies in iPSCs and iPSC-derived sensory neurons (iSNs)” as demonstrated by the specification. Again, applicant’s personal opinion that the obviousness of applicant’s elected SEQ ID NO:11 is “too simplistic” is insufficient to point out the scientific or factual errors in obtaining the claimed product by following the credible, scientifically established teachings disclosed in Ran for gRNA design. Regarding applicant’s argument that the gRNA design rules taught by Ran are “insufficient to predict” human SCN9A editing in iPSCs and iSNs, applicant’s attention is directed to the fact that for obviousness under §103, “all that is required is a reasonable expectation of success”, and it does not require “absolute predictability of success”. See In re O ’Farrell, 853 F.2d 894, 7 USPQ2d 1673 (Fed. Cir. 1988) at 1681. Applicant did not provide any objective, factual evidence showing that one of ordinary skill in the relevant art would not have had a “reasonable”, not “absolute”, expectation/predictability that the gRNA targeted to the publicly available human SCN9A exon 11 sequence, which is a mere 288-mer containing only three art-recognized SaCas9 PAM sequence (NNGRRT), wherein making a genome editing system for editing targeting exon 11 of the mouse counterpart SCN9A was art-recognized goal as evidenced by Maianti, who demonstrated successful editing of SCN9A by targeting exon 11. Note that it is unclear whether “insufficient to predict” as asserted by applicant means lack of a reasonable expectation of predictability. If so, applicant’s argument is not supported by any factual, objective evidence showing the alleged lack of a reasonable expectation of success/predictability in making the claimed product, despite the fact that the examiner was able to manually identify the claimed gRNA sequence by faithfully following the credible teachings of the cited art as set forth in the rejection above. Furthermore, applicant’s attention is again directed to the fact that the claims rejected in the instant rejection are a mere product, not a method. Regarding the editing in iPSCs and iSNs pointed out by applicant, applicant’s attention is directed to the fact that the rejected product claims do not require any editing in iPSCs and iSNs. Hence, the specification’s disclosure relied on and pointed out by applicant is not commensurate in scope with the rejected product claims. Note that the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” See MPEP §716.02.
Applicant argues that the “a considerable amount of experimentation was required” to arrive at the rejected claims by pointing out “1,471 putative off-target sites” for the “40 prioritized gRNAs” including SEQ ID NOs:11-20 claimed in the instant case, wherein 9 out of the 10 sequences showed “no off-target activity.” In response, it is noted that not all “40” gRNAs are targeted to SCN9A, much less exon 11 of SCN9A, for use with SaCas9. Further, it is unclear how the number of off-targets for the combination of 40 different gRNA sequences targeting different genes (SCN9A and SCN10A) for two different Cas9 enzymes (SpCas9 and SaCas9) can possibly show the nonobviousness of the single gRNA (SEQ ID NO:11) rendered obvious in the instant rejection. Further, the lack of an off-target site by SEQ ID NO:11 corroborates the operability and credibility of Ran’s gRNA selection method for use with SaCas9, which was known to be preferable and more advantageous compared to SpCas9. Furthermore, the lack of an off-target site by SEQ ID NO:11 corroborates the teachings of Maianti that demonstrate that targeting exon 11, one of five targeted exons, of mouse counterpart SCN9A resulted in successful editing. Note that the alleged “considerable amount of experimentation” is merely routine screening assays recognized and conventionally performed in the relevant art as evidenced by Maianti and Ran. Further, applicant’s arguments addressing “40” gRNAs and the total number of off-target sites by the “40” gRNAs do not whatsoever persuasively rebut the instant obviousness rejection, wherein exon 11 of SCN9A was one of five target exons (exon 10, exon 11, exon 14, exon 17, and exon 22) for gene editing as disclosed by Maianti, and wherein use of SaCas9 (thus designing gRNAs using the NNGRRT PAM sequence) rather than SpCas9 (using the NGG PAM sequence) was deemed more desirable as taught by Ran. That is, the “40” gRNAs do not rebut the obviousness rationale set forth in the rejection. Now, when the two specific teachings of the cited art are taken into consideration, applicant should consider the activity of gRNAs suggested and utilized in the obviousness rejection satisfying the aforementioned specific teachings provided by the cited art, wherein there is only one gRNA targeting one of exons 10, 11, 14, 17, and 22 of SCN9A for SaCas9 out of the “40” gRNAs, wherein the one gRNA is SEQ ID NO:11. Hence, applicant’s attempts to assert the nonobviousness of the claims by using off-target site numbers provided by gRNAs other than SEQ ID NO:11 and the art-recognized routine gRNA screening assays are not found pertinent to the obviousness rationale set forth in the instant rejection thus found unpersuasive.
Applicant argues that “Liu and Schmitz” previously submitted provide “evidence” that prediction of gRNA’s on-target and off-target activity “is far from trivial.” In response, applicant’s attention is directed to the fact that the rejected claims are merely directed to a product, and furthermore, the rejected claims do not require any limitations pertaining to off-target activity. Furthermore, as noted above, gRNA activity screening was routine and conventional, regardless of whether applicant deems such screening activity as “far from trivial.” See Figures 7-11 of Maianti and Figures 3d and 4f as well as Extended Data Figures 6 and 8-9 of Ran that show the screening results for multiple gRNAs for their specificity and efficiency including evaluation of off-target sites. Again, for obviousness under §103, “all that is required is a reasonable expectation of success”, and it does not require “absolute predictability of success”. Applicant did not provide any persuasive rebuttal evidence showing that one of ordinary skill in the relevant art knowledgeable of the teachings of Maianti and Ran would not have had a reasonable expectation of success in obtaining the claimed product comprising SEQ ID NO:11. Note that “Liu and Schmitz” do not support that one of ordinary skill in the relevant art knowledgeable of the teachings of Maianti and Ran would not have had a reasonable expectation of success in obtaining the claimed product comprising SEQ ID NO:11.
Applicant argues that the examiner’s obviousness rationale for SEQ ID NO:11 “ignores reality” thus “the claims are not obvious.” In response, applicant’s personal opinion is not found sufficient or persuasive to rebut the instant rejection. Note that the arguments of counsel cannot take the place of evidence in the record. See MPEP §2145: “An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”
Applicant argues that Ran’s teachings do not render SEQ ID NO:11 obvious because SEQ ID NO:11 does not begin with a “G”, wherein Ran’s Extended Data Figure 3c taught the “G” base as the first nucleotide “improves editing efficiency.” In response, it is noted that there is no teaching in Ran that a gRNA must have a “G” base as the first nucleotide in order to have the editing activity. In fact, Ran teaches that the guide length of 22 nucleotides in length for SaCas9 provides a high level of indel %, and furthermore, the use of NNGRR(T) PAM sequence provides a significantly higher level of indel %. See Figure 2b and 2d. In the instant case, SEQ ID NO:11 is 22 nucleotides in length designed by identifying the NNGRRT PAM sequence within exon 11 of human SCN9A. Indeed, Ran expressly demonstrates that a gRNA designed with NNGRR(T), wherein the first nucleotide of the gRNA is a “T” provided about 15% of target (EMX1) editing, which is not significantly different from the about 20% of target editing provided by a gRNA having a “G” base at position 1 and designed with NNGRR(T). See Figure 3d. Hence, it is clear that there is no teaching in Ran that a gRNA must have a “G” base as the first nucleotide for gRNA activity. Since SEQ ID NO:11 rendered obvious in the instant rejection fully satisfies Ran’s design rules that are shown to provide higher/highest level of gene editing when using SaCas9, one of ordinary skill in the art would have had a reasonable, if not absolute, expectation that SEQ ID NO:11 would inherently confer the intended use “for modifying a human sodium voltage-gated channel alpha subunit 9 (SCN9A) gene”, absent objective, not personal opinion, evidence to the contrary.
In view of the foregoing, the instant rejection is hereby reiterated.
Conclusion
No claim is allowed.
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.
Note that the newly added “human” does not render the instantly claimed subject matter any different from previously examined on the merits because the gRNA elected and examined in the instant application is directed to a “human” sequence as evidenced by the express statement in the rejection above (same as the previous rejection of record) regarding the teachings of Maianti et al. such that “Maianti discloses the nucleotide sequence of exon 11 of human SCN9A at page 189.” (emphasis now added).
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 DANA H SHIN whose telephone number is (571)272-8008. The examiner can normally be reached Monday-Thursday: 8am - 6:30pm.
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/DANA H SHIN/Primary Examiner, Art Unit 1635