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 .
Application Status
This action is written in response to applicant’s correspondence received 29 January 2026. Claims 1, 3, 6, 9-13, and 16-20 are currently pending. Accordingly, claims 1, 3, 6, 9-13, and 16-20 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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.
The factual inquiries 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.
Claim(s) 1, 3, 6, 9-13, and 16-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hsu (PG Pub No. US 2019/0338363 A1) in view of Connell ("Molecular mechanisms of RNA targeting by Cas13-containing type VI CRISPR–Cas systems." Journal of molecular biology 431.1 (2019): 66-87), Bostwock (PG Pub No. WO 2021/222065 A1), Bostwick sequence alignment (accessed 16 June 2026), and XM_005589554.2 (Genbank Accession No. XM_005589554.2; published 25 January 2016).
Regarding claims 1 and 13, Hsu is drawn to an invention concerned with CRISPR/Cas methods for targeting RNA molecules (Abstract). Hsu teaches a method of modifying or more target RNA molecules in a eukaryotic cell via the use of a CRISPR-Cas13 system comprising (a) a Cas13d protein and (b) a guide nucleic acid that can hybridize with and direct the system to a target RNA of interest ([0008]-[0009]). Hsu teaches that the system may be utilized to downregulate any target RNA of interest ([0300]). Hsu teaches that CRISPR-Cas13 systems are beneficial to utilize in order to knock down target RNAs because they do not require modification of the transcript, unlike previous RNAi technologies that require genomic modification of the transcript to include a tag ([0005]-[0006]). Hsu further teaches that Cas13d guide RNA sequences could be designed and their ability to target RNAs of interest tested ([0528]).
Hsu does not teach or suggest that the gene of interest includes at least one of an ApoE4 allele or an ApoE3 allele (Claims 1 and 13). Hsu does not teach or suggest that the targeting system complementary region includes the claimed SEQ ID NO: 47 (Claims 1 and 13).
Connell is drawn towards a review study concerned with the molecular mechanisms of RNA targeting by Cas13 systems (Abstract). Connell teaches that CRISPR/Cas13 systems comprise (a) a polynucleotide sequences encoding a nuclease that can form a complex with (b) a guide RNA that includes a complementary region to an RNA molecule of interest (pg. 67; see Fig. 1). Connell teaches that certain species of Cas13b proteins require a protospacer flanking site (PFS) as opposed to a PAM seen in other CRISPR systems (pg. 76). Connell teaches that mRNA molecules to which Cas13b proteins from Bergeyella zoohelcum and Prevotella buccae are targeted to require both a D (A, U, or G) 5’ PFS and a NAN or NNA 3’ PFS present within the reverse complement of the guide RNA for optimal RNA targeting (pg. 76-77; see Type VI-B of Fig. 3d below).
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Figure 1. Fig. 3d of Connell
Bostwock is drawn towards a study concerned with methods for inhibiting the expression of an APOE RNA in order to treat subjects having an APOE-associated neurodegenerative disease (Abstract). Bostwock teaches the use of an APOE gene comprising 1179 nucleotides that further comprises a region that is reverse complementary to, and comprises 100% identity to, the claimed SEQ ID NO: 47 and is described in GenBank Accession No. XM_005589554.2 (pg. 26; see SEQ ID NO: 9 in attached sequence alignment). Bostwock teaches that the term APOE gene encompasses APOE3 and APOE4 alleles (pg. 27).
XM_005589554.2 is drawn towards the GenBank entry referenced in the SEQ ID NO: 9 of Bostwock. XM_005589554.2 teaches that the SEQ ID NO: 9 of Bostwock is an mRNA molecule encoding an APOE gene and that the region of Bostwock being reverse complementary to, and having 100% identity to, the claimed SEQ ID NO: 47 is flanked by a 5’ G and a 3’ NNA motif (pg. 2; see highlighted base pairs 464-487 of XM_005589554.2 below alongside attached sequence alignment).
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Figure 2. Position of reverse complement of SEQ ID NO: 47 within XM_005589554.2
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Figure 3. Sequence alignment of the claimed SEQ ID NO: 47 to base pairs 464-487 of XM_005589554.2
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the Cas13d protein of Hsu for a Cas13b protein because it would have merely amounted to a simple substitution of one known element for another to obtain predictable results. Because the claimed SEQ ID NO: 47 is adjacent to a flanking Cas13b D (A, U, or G) 5’ PFS and a NNA 3’ PFS that is recognized by Cas13b and allows for cleavage of the mRNA, one of ordinary skill in the art would have expected the Cas13b to have been able to similarly knockdown target RNA comprising the claimed SEQ ID NO: 47. Additionally, because the Cas13 proteins were used in a similar manner, namely the knockdown of target RNA, then one of ordinary skill in the art would have expected that utilizing a Cas13b protein instead of a Cas13d protein would have predictably resulted in the downregulation of target RNA.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have tried to target the claimed SEQ ID NO: 47, present within an APOE gene, with the CRISPR-Cas13b system because it would have merely amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. Because the art identified a need to treat APOE-associated diseases through the repression of APOE RNA, then one of ordinary skill in the art would have attempted to design a CRISPR-Cas13b system that could target APOE RNA in order to similarly repress APOE RNA expression. Since a person of ordinary skill in the art would have recognized that RNA cleavage by Cas13b requires both a D (A, U, or G) 5’ PFS and a NNA 3’ PFS, then one of ordinary skill in the art would have recognized that the regions flanked by the required PFSs are finite within the SEQ ID NO: 9 of Bostwock and that targeting the potential regions matching the sequence restraints would have predictably resulted in the downregulation of the APOE RNA expression. Additionally, since Hsu already teaches that Cas13 guide RNAs may be designed and tested, then one of ordinary skill in the art would have recognized that designing Cas13b guide RNAs to target the potential target sequences present within the SEQ ID NO: 9 of Bostwock would have resulted in the predictable outcome of downregulating the APOE RNA expression.
Regarding claims 3, 10, 16, and 18, the obviousness of utilizing a Cas13b protein (i.e., a CRISPR-Cas13 gene editing system comprising a Cas13 protein) is discussed above as applied to claim 1.
Regarding claims 6 and 17, Bostwock teaches that the SEQ ID NO: 9 comprising the target sequence rendered obvious above is an APOE gene, and that the term APOE gene encompasses APOE3 and APOE4 alleles (pg. 27).
Regarding claims 9 and 17, Hsu teaches that the Cas13 guide RNA comprises a guide sequences and a direct repeat sequence (i.e., a scaffold) which facilitates interaction between the Cas13 and the guide molecule ([0412]).
Regarding claim 11, Hsu teaches that the CRISPR system may comprise a Cas13 fused to a deaminase domain ([0475]).
Regarding claim 12, Hsu teaches the use of a vector encoding the Cas13 nuclease and guide molecule, wherein the Cas13 and guide molecule are operably linked to different promoters (i.e., first and second regulatory sequences) ([0419]).
Regarding claim 19, Hsu teaches the use of a Cas13 nuclease comprising 87.7% identity to the claimed SEQ ID NO: 64 ([0010]; see SEQ ID NO: 218 in previously attached sequence alignment).
Regarding claim 20, Hsu teaches that pharmaceutically acceptable carriers (i.e., excipients) can be utilized to deliver the Cas13 protein to a subject ([0311]-[0312]).
Response to Arguments
Applicant's arguments filed 29 January 2026 have been fully considered but they are not persuasive.
Because Applicant’s amendments necessitated the newly filed rejections above, Applicant’s arguments pertaining to the previously pending claims are not found persuasive because Applicant has not provided any arguments pertaining to the newly recited rejection above.
Insofar as Applicant’s arguments are applicable to the newly recited rejections necessitated by amendment, Applicant alleges that the specific gRNAs in the instant specification achieve the surprising result of efficient and beneficial knockdown of ApoE4 while minimizing the knockdown effects of ApoE3 that was not taught nor suggested by Hsu (Remarks; pg. 16).
With regard to the claimed SEQ ID NOs: 13-14, 27, 31, 38, 44-45, 47, and 54, applicant has provided adequate support for the utilization of the claimed guide RNA to preferentially knockdown ApoE4 and not Apoe3 to the same extent (Instant specification; pg. 51-52 and 53-43; see Table 4 for the claimed SEQ ID NOs and Table 6 for the knockdown comparison between ApoE3 and ApoE4).
With regard to the claimed SEQ ID NOs: 40 and 42, it is noted that the claimed SEQ ID NOs did not achieve the surprising result as alleged by Applicant. SEQ ID NOs: 40 and 42 knocked down ApoE3 mRNA to a greater extent than ApoE4 (Instant specification; pg. 53-54).
Accordingly, the alleged unexpected results are not commensurate in scope with the claimed invention because the claimed invention claims SEQ ID NOs: 40 and 42 that did not knockdown ApoE4 to a greater degree than ApoE3. Per MPEP 716.02(d), “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980).” Accordingly, since Applicant has not demonstrated the alleged unexpected results over the entire claimed range of SEQ ID NOs, the argument is not found persuasive.
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 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 KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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