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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114.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 June 22, 2026 has been entered.
Status of Claims/Rejections
Claims 29 and 34-36 are currently pending in the instant application. Claim 36 is withdrawn from further consideration as being drawn to a nonelected invention. Accordingly, claims 29 and 34-35 are under examination on the merits in the instant application.
Any rejections not repeated in this Office action are withdrawn. The following objections/rejections are the only objections/rejections applied in this application.
Specification
The disclosure, see page 46, is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show the colors (e.g., “red”, “blue”) in Figures 1B, 2-3, 4B, and 5A as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Note that the petition to accept color drawings filed on May 12, 2025 was not accepted thus dismissed. See the decision mailed on May 21, 2025.
Since the aforementioned petition is not accepted, the drawings concurrently filed with the aforementioned petition are not entered. Hence, the amended Figures with sequence identifiers included in the color drawings are not entered.
Applicant’s attention is directed to the fact that Figures 1B and 4B contain pairs of nucleotide sequences, wherein the bottom sequence in the 3’ to 5’ orientation are not identified with SEQ ID NOs in the aforementioned color drawings that are not entered.
Applicant is required to submit the following as instructed below:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers for all nucleotide sequence in Figures 1B, 2-3, 4B, and 5A into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Claim Objections
Claim 35 is objected to because of the following informalities: Claim 35 appears to contain four lines. It appears that the last two lines reproduced below should be deleted.
PNG
media_image1.png
64
712
media_image1.png
Greyscale
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 34 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 34 recites that the target nucleic acid sequence of claim 29 “is within a sequence encoding an ORF 63/70.” It is noted that this limitation in claim 34 is indistinguishable from “the target nucleic acid sequence is within a sequence encoding an open reading frame (ORF) 63” already recited in claim 29 because ORF63 of VZV is known to coexist with ORF70, which is a duplicate of ORF63 in reverse orientation as already having long been known in the prior art (see (Journal of Virology, 2001, 75:8224-8239, of record). That is, ORF63 and ORF70 are interchangeable and synonymously used so much so that the instant specification discloses “ORF 63/70” and does not separately disclose “ORF63” and “ORF70”. See page 23. Hence, the wherein limitation of claim 34 is deemed identical to the limitation that is already recited in claim 29, thereby failing to further limit the subject matter of claim 29.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 29 and 34-35 are rejected under 35 U.S.C. 103 as being unpatentable over Cullen et al. (WO 2015/126927 A1, of record) in view of Sommer et al. (Journal of Virology, 2001, 75:8224-8239, of record) and Stevenson et al. (Journal of Virology, 1996, 70:658-662, of record).
Cullen teaches making a construct comprising a Cas9-encoding nucleic acid and a guide RNA targeting a target sequence of a varicella zoster virus (VZV). See claims 1-3.
Cullen teaches that “Cas9 has the ability to directly recognize a short DNA sequence, 5’-NGG-3’ for the commonly used Streptococcus pyogenes (Spy) Cas9 protein, called the protospacer adjacent motif (PAM)” and that “sequence specificity for Spy Cas9 relies both on the PAM and on full complementarity to the 3’ ~13 nt of the ~20 nt variable region of the sgRNA”, wherein “the Cas9 protein directly cleaves both strands of the target”. See page 10.
Cullen exemplifies an sgRNA targeting HPV-18 E6 ORF, wherein the sgRNA sequence-encoding sequence comprises 5’-GCGCTTTGAGGATCCAACA (see page 32), which is designed to target a 23-mer (5’-CGCGCTTTGAGGATCCAACACGG) comprising a 20-mer sequence followed by the 5’-CGG PAM sequence as evidenced by Figure 3C with “the PAM underlined.” (see page 5). See Figure 3C reproduced below.
PNG
media_image2.png
158
604
media_image2.png
Greyscale
Cullen teaches that two sgRNAs designed to target E6 and two sgRNAs designed to target E7 provided target inhibition when tested in cells thus “all four HPV-18 E6- or E7-specific sgRNAs can effectively silence the expression of a cognate target gene.” See page 36.
Cullen does not teach that the VZV-targeting guide RNA comprises SEQ ID NO:5 (5’-CGTGCCATCGAGCGATACGCGGG) in ORF63.
Sommer teaches that the “evidence that ORF63 is indispensable for lytic infection, considered along with the observation that ORF63 transcripts are predominant in latently infected ganglia and that ORF63 protein is also made during latency, suggest that the ORF63 protein plays a critical role in all stages of VZV pathogenesis.” See pages 8234-8235.
Sommer demonstrates reduced infectivity of VZV by a construct having deleted ORF63 and ORF70, wherein ORF63 is “duplicated” as ORF70 in reverse orientation, wherein “failure to generate virus was due to the dual ORF63/70 deletion”. See abstract; page 8224; Figure 1; Table 1.
Stevenson teaches, consistent with Sommer, that the protein product of VZV ORF63 is “localized to the nucleus of infected cells and exhibits immediate-early expression.” See page 658.
Stevenson teaches “a requirement for sequences carboxy terminal to amino acid 210 in the localization of 63 to the cell nucleus.” See page 661.
Stevenson discloses the amino acid sequence of ORF63 protein product as well as the corresponding nucleotide sequence encoding the ORF63 protein in Figure 1B, wherein the amino acid comprising “sequences carboxy terminal to amino acid 210” and the corresponding nucleotide sequence encoding the “sequences carboxy terminal to amino acid 210” is reproduced below, wherein Spy Cas9 “NGG” PAM sequences following 20-mer sequences within the nucleotide sequence encoding carboxy terminal to amino acid 210 (thus from amino acid 211) are boxed and the 20-mer at nucleotide positions 688-707 preceding the “GGG” PAM sequence is underlined by the examiner.
PNG
media_image3.png
245
744
media_image3.png
Greyscale
It would have been obvious to one of ordinary skill in the art before the effective filing date to target 5’-CGTGCCATCGAGCGATACGCGGG in the ORF63 of VZV when making Cullen’s VZV-targeting construct. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to enable Cullen’s guide RNA to have the function of impairing “all stages of VZV pathogenesis” for providing “failure to generate virus”, because ORF63/70 of VZV was known to play “a critical role in all stages of VZV pathogenesis” as taught by Sommer, who also reported “failure to generate virus was due to the dual ORF63/70 deletion”, thereby suggesting that it was an art-recognized goal to target/inhibit ORF63/70 of VZV for reducing VZV infectivity and pathogenesis, and because ORF63 protein was taught to be predominantly localized to the nucleus in infected cells for immediate-early expression with the nuclear localization signal being located in the carboxyl terminal to amino acid 210 as taught by Sommer and Stevenson, thereby suggesting that targeting or disrupting the nuclear localization signal region located downstream of amino acid 210 would inhibit the infectivity of VZV in the nucleus of infected cells, wherein the entire nucleotide sequence encoding the nuclear localization signal region of VZV ORF63 was known and available in the art as disclosed by Stevenson. Now, when selecting a gRNA sequence targeting the nuclear localization signal region of VZV ORF63, one of ordinary skill in the art would have followed the teachings/guidance provided and exemplified in Cullen such that a 23-mer target sequence comprises the 5’-NGG PAM sequence at positions 21-23 is selected, wherein one of ordinary skill in the art would have reasonably identified a finite number (a total of 14) of clearly identifiable 23-mer target sequences with an NGG PAM sequence as notated above (the PAM sequences are boxed), wherein the finite number of 23-mer target sequences comprising the 5’-NGG PAM sequence include the 23-mer sequence of 5’-CGTGCCATCGAGCGATACGCGGG comprising the 5’-GGG PAM sequence as identified hereinabove by the examiner in the reproduced Figure 1B of Stevenson, wherein the entire 23-mer sequence is 100% identical to SEQ ID NO:5 claimed in claim 35. Now, since ORF63 was known to be “duplicated” as ORF70 in reverse orientation as disclosed by Sommer, and since the CRISPR/Cas9 system was known to cleave “both strands of the target” as disclosed by Cullen, one of ordinary skill in the art would have reasonably expected that a gRNA designed to target the above sequence in VZV ORF63 would cleave not only the above sequence but also the complementary sequence in VZV ORF70 that is duplicated in reverse orientation, thereby targeting VZV ORF 63/70.
In view of the foregoing, claims 29 and 34-35 taken as a whole would have been prima facie obvious before the effective filing date.
Response to Arguments
Applicant's arguments filed on June 22, 2026 have been fully considered but they are not persuasive. Applicant argues that the claims are not obvious because there is no suggestion to specifically select SEQ ID NO:5 as the gRNA sequence among the 14 potential sequence options. In response, it is noted that the instant obviousness rejection is not based on the rationale of exclusively selecting SEQ ID NO:5 only. Rather, the obviousness of the rejected claims is based on the art-recognized goal and the prima facie obviousness in selecting and pursing all 14 gRNA sequences satisfying the art-recognized gRNA selection criteria within the art-recognized VZC ORF target sequence, wherein the 14 sequences do include SEQ ID NO:5, wherein making multiple gRNAs within the intended target was routinely performed as evidenced by Cullen. In fact, claims 29 and 34 do not even require SEQ ID NO:5. Since SEQ ID NO:5 is a clearly identifiable gRNA sequence among a total number of 14 sequences, the nucleic acid of claim 35 is nothing but prima facie obvious for the reasons explained in the rejection above.
Applicant argues that the claims are not obvious because there is no guidance as to which sequence would be effective and because not all 14 sequences “will be equally effective”. In response, the examiner is not aware of any legal basis that all species within a finite number of predictable, identified solutions must be “equally” effective for obviousness under §103, especially when the rejected claims in the instant case do not even require any particular level of effectiveness or efficacy. Now, 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. It was known and demonstrated in the prior art that gRNAs properly designed to target an intended gene are reasonably, if not absolutely, expected to provide target expression inhibition as evidenced by Cullen’s disclosure that “all four HPV-18 E6- or E7-specific sgRNAs can effectively silence the expression of a cognate target gene” thus “all four sgRNAs appeared to function equivalently”. See page 36. Hence, a reasonable expectation that any and all 14 properly designed gRNAs including the sequence of SEQ ID NO:5 against the NLS region of VZV ORF63/70 would be effective in providing the intended function of the gRNAs was established in view of the prior art, absent objective evidence to the contrary.
Applicant argues that the examiner’s previous argument stating that “the rejected claims do not require inactivating VZV replication” (see page 9 of the final Office action mailed on May 28, 2025) “further undermines the obviousness rejection” because the rejection relies on Sommer’s teachings for the motivation to “reduce VZV infectivity.” In response, applicant’s attention is directed to the fact that “reducing VZV infectivity and pathogenesis” (the motivation provided in the rejection) is not the same as the unclaimed feature of “inactivating VZV replication” improperly imposed by applicant. As such, there is no teaching in Sommer or any other cited references that “undermines” the obviousness rationale set forth previously, which is reiterated hereinabove. Again, applicant’s attention is directed to the fact that no rejected claim requires “inactivating VZV replication” thus such unrecited feature need not be taught by the cited art. However, even if the instantly rejected claims were to expressly require inactivation of VZV replication, not merely inhibit the expression of VZV in cells or reduce VZV infectivity, such functional limitation would have been reasonably deemed inherent and expected in view of Cullen’s teaching that the sgRNAs designed to target a region comprising the NGG PAM site “inactivate the endogenous HPV-18 E6 and E7 genes integrated into the HeLa cell genome” as evidenced by “the presence of indels in both the HPV-18 E6 and E7 gene at the predicted Cas9 target site” (see page 36) further in light of Sommer’s teaching that “failure to generate virus was due to the dual ORF63/70 deletion”. Again, obviousness under §103 requires only a reasonable level of predictability/expectation of success.
Applicant alleges that the examiner improperly used impermissible hindsight by manually identifying 14 sequences in the rejection. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper 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. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant’s attention is directed to the fact that the examiner utilized art-recognized, disclosed gRNA design rule without impermissibly relying on the instant specification.
Applicant argues that the instant co-inventors made “contribution to the art” by “the identification of specific, effective gRNA target sequences for VZV ORF63, which required inventive selection”. In response, it is noted that applicant did not provide any persuasive rebuttal argument that one of ordinary skill in the relevant art knowledgeable of the teachings of the instantly cited references would not have obtained, with a reasonable expectation of success, the 14 sequences including SEQ ID NO:5 identified in the rejection. Applicant’s personal opinion that the instant co-inventors made “contribution” via “inventive selection” is not supported by any objective, factual evidence demonstrating that an “inventive selection” methodology that is truly invented by the instant co-inventors was actually used in order to obtain SEQ ID NO:5 claimed in claim 35, whereas arriving at SEQ ID NO:5 would not have been possible with the prior art gRNA selection/design methodology. It is very interesting to note on the record that the instant specification itself expressly discloses that the disclosed gRNA sequences including SEQ ID NO:5 “were designed and selected using available online tools”. See pages 45-46. Hence, the examiner is bewildered by applicant’s unfounded allegation that the instantly claimed subject matter involved the instant co-inventors’ “inventive selection”, which thus made “contribution to the art”. Furthermore, applicant’s argument pertaining to “the universe of possible sequences” is irrelevant to the instant ground of rejection, which clearly sets forth the reason/motivation to target the specific, relatively small region (NLS) of the VZV ORF63/70 with the clearly identified, finite number of 14 sequences.
In view of the foregoing, applicant’s arguments are not found persuasive.
Conclusion
No claim is allowed.
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.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DANA H SHIN/Primary Examiner, Art Unit 1635
Prosecution Insights