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 .
This action is in response to the amendment filed 01/20/2026, in which claims 1 and 20 were amended, claim 2 was canceled, claims 3-17 were previously presented and claim 21 was newly added. Claims 1, 3-17, 20 and 21 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Response to Amendments - Claim Rejections - 35 USC § 112
The previous rejection of claim 20 under 35 U.S.C. 112(a) has been withdrawn in view of Applicant’s amendments to the claims filed on 01/20/2026.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1, 3-6, 8-17, 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable by Flynn (US 2017/0035860 A1) in view of Simone et al (US 2019/0314398 A1). This rejection was made in the Office action mailed 10/20/2025 and has been rewritten to address the amendment to the claims in the reply filed 01/20/2026.
Regarding claims 1, 3 and 21, Flynn teaches gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene [0111]. Flynn teaches that after tissue derivation, the CRISPR/Cas9 gene will be cloned into the delivery vector separate or together with the designed sgRNA against selected regions of the MAPT gene [0150].
Flynn does not teach the specific sequence of the sgRNA used that would comprise similarity to the expression regulatory region of the human MAPT gene.
Simone teaches methods of targeting a target gene using a therapeutic RNA for the repression or enhancement of expression of the target gene, such as the MAPT gene, and the region of the MAPT gene that the therapeutic RNA is targeting is the MAPT-ASl, t-NATl region which corresponds to SEQ ID NO: 11 and is 100% identical to instant SEQ ID NO: 55 (See Appendix I) [0032-0039 and 0065-0069]. Simone teaches the use of the therapeutic RNA is used for the treatment of Alzheimer’s disease by the reduction or enhancement of expression of a target gene [0178-0179].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Flynn to include the specific targeting of a tau nucleic acid such as the MAPT gene as taught by Simone because Flynn teaches it is within the ordinary skill in the art to use gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene and Simone teaches methods of targeting the MAPT gene for repression of expression for treatment of Alzheimer’s disease.
One would have been motivated to make such a modification in order to receive the expected benefit of reduced expression of the MAPT gene for the treatment of Alzheimer’s disease as taught by Simone.
Regarding claims 4 and 5, Flynn teaches gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene [0111]. Flynn teaches that after tissue derivation, the
CRISPR/Cas9 gene will be cloned into the delivery vector separate or together with the designed sgRNA against selected regions of the MAPT gene [0150].
Regarding claim 6, Flynn teaches gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene [0111]. Flynn teaches that after tissue derivation, the CRISPR/Cas9 gene will be cloned into the delivery vector separate or together with the designed sgRNA against selected regions of the MAPT gene [0150].
Regarding claims 8-10, Flynn teaches the MAPT CRISPR/Cas9 constructs comprising the U6 promoter and guide RNA vector and CMV humanized Cas9 vector, in human HEK293 cells [0110].
Regarding claims 11 and 12, Flynn teaches the MAPT CRISPR/Cas9 constructs comprising the U6 promoter and guide RNA vector and CMV humanized Cas9 vector, in human HEK293 cells [0110].
Regarding claims 13-17, Flynn teaches the CRISPR/Cas9 gene is cloned into the delivery vector such as AAV or lentivirus together with the designed sgRNA against selected regions of the MAPT gene [0145]. Flynn teaches the delivery vehicle that will be utilized for Cas9/CRISPR delivery will be an adeno-associated virus (AAV) [0142]. Flynn teaches Adeno-associated viral vectors are excellent vehicles to transfer genes into the nervous system due to their property to transduce also post-mitotic cells, their ability to be grown to very high titers (up to 1013 virion particles per ml), and their relatively large insert capacity (insert capacity of - 7.5 kb) [0143].
Flynn does not teach that the AAV is specifically an AAV9 vector.
Simone teaches adeno-associated virus (AAV) vectors deliver DNA to a transduced cell and the AAV vector is pseudotyped to increase transduction efficiency and/or to increase target cell specificity, such as an AAV9 [0198]. Simone teaches the t-NAT for targeting of the MAPT gene was comprised in an AAV9-t-NAT vector for delivery to tauopathy mouse models [0298].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Flynn to include the specific AAV9 vector delivery system as taught by Simone because Flynn teaches it is within the ordinary skill in the art to use gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene within an AAV vector for delivery to a cell and Simone teaches using AAV9 for specific targeting of cells for improved delivery.
One would have been motivated to make such a modification in order to receive the expected benefit of enhanced transduction and specific cell delivery of the AAV9 vector as taught by Simone.
Regarding claim 20, Flynn teaches a method of treating Alzheimer’s Disease by administering a vector that targets the MAPT gene (Page 37, Claims 1-3). Flynn teaches gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene [0111]. Flynn teaches that after tissue derivation, the CRISPR/Cas9 gene will be cloned into the delivery vector separate or together with the designed sgRNA against selected regions of the MAPT gene [0150].
Flynn does not teach the specific sequence of the sgRNA used that would comprise similarity to the expression regulatory region of the human MAPT gene.
Simone teaches methods of targeting a target gene using a therapeutic RNA for the repression or enhancement of expression of the target gene, such as the MAPT gene, and the region of the MAPT gene that the therapeutic RNA is targeting is the MAPT-ASl, t-NATl region which corresponds to SEQ ID NO: 11 and is 100% identical to instant SEQ ID NO: 55 (See Appendix I) [0032-0039 and 0065-0069]. Simone teaches the use of the therapeutic RNA is used for the treatment of Alzheimer’s disease by the reduction or enhancement of expression of a target gene [0178-0179].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Flynn to include the specific targeting of a tau nucleic acid such as the MAPT gene as taught by Simone because Flynn teaches it is within the ordinary skill in the art to use gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene and Simone teaches methods of targeting the MAPT gene for repression of expression for treatment of Alzheimer’s disease.
One would have been motivated to make such a modification in order to receive the expected benefit of reduced expression of the MAPT gene for the treatment of Alzheimer’s disease as taught by Simone.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Flynn (US 2017/0035860 A1) in view of Simone et al (US 2019/0314398 A1) as applied to claims 1, 3-6, 8-17, 20 and 21 above, and further in view of Raikwar et al (Molecular Neurobiology (2019) 56: pgs 378–393). This rejection was made in the Office action mailed 10/20/2025 and has been rewritten to address the amendment to the claims in the reply filed 01/20/2026.
The teachings of Flynn and Simone are described above and applied as before.
Regarding claim 7, Flynn teaches gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene [0111]. Flynn teaches that after tissue derivation, the CRISPR/Cas9 gene will be cloned into the delivery vector separate or together with the designed sgRNA against selected regions of the MAPT gene [0150]. While, Simone teaches methods of targeting a target gene using a therapeutic RNA for the repression or enhancement of expression of the target gene, such as the MAPT gene, and the region of the MAPT gene that the therapeutic RNA is targeting is the MAPT-ASl, t-NATl region which corresponds to SEQ ID NO: 11 and is 100% identical to instant SEQ ID NO: 55 (See Appendix I) [0032-0039 and 0065-0069]. Simone teaches the use of the therapeutic RNA is used for the treatment of Alzheimer’s disease by the reduction or enhancement of expression of a target gene [0178-0179].
Flynn and Simone do not teach the Cas9 is derived from Staphylococcus aureus.
Raikwar teaches confocal microscopy of murine BV2 microglial cell line transduced with an adeno-associated virus (AAV) coexpressing Staphylococcus aureus (Sa) Cas9 and a GMF-specific guide RNA (GMF-sgRNA) revealed few cells expressing SaCas9 while lacking GMF expression, thereby confirming successful GMF gene editing (Page 378, Abstract). Raikwar teaches the large size (1368 amino acids) of the Streptococcus pyogenes nuclease SpCas9 and due to the AAV packaging limitations, it is not possible to simultaneously coexpress SpCas9 as well as GMF-specific sgRNA using a single AAV vector (Page 382, Column 1 bridging Column 2). Raikwar teaches to overcome this limitation, the smaller (1053 amino acids) CRISPR-Cas9 nuclease derived from Staphylococcus aureus SaCas9 that can be easily packaged along with GMF sgRNA in a single AAV vector was utilized (Page 382, Column 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Flynn and Simone to include the Staphylococcus aureus derived Cas9 as taught by Raikwar because Flynn teaches it is within the ordinary skill in the art to use gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene, Simone teaches methods of targeting the MAPT gene for repression of expression for treatment of Alzheimer’s disease and Raikwar teaches the smaller (1053 amino acids) CRISPR-Cas9 nuclease derived from Staphylococcus aureus SaCas9 that can be easily packaged along with GMF sgRNA in a single AAV vector was utilized.
One would have been motivated to make such a modification in order to receive the expected benefit of easier and more efficient packaging and delivery of the SaCas9 construct as taught by Raikwar.
Response to Arguments - Claim Rejections - 35 USC § 103
The rejections of claims 1, 3-17, 20 and 21 under 35 U.S.C. 103 has been maintained in view of Applicant' s amendment to the claims filed on 01/20/2026. Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues the nucleotide sequence of Simone SEQ ID NO: 11 is 449 nucleotides in length and only a part thereof (21-nt) is identical to SEQ ID NO: 55 of the present application as well as both are directed to the MAPT gene, therefore, such as coincidence can readily occur.
However, Simone teaches methods of targeting a target gene using a therapeutic RNA for the repression or enhancement of expression of the target gene, such as the MAPT gene, and the region of the MAPT gene that the therapeutic RNA is targeting is the MAPT-ASl, t-NATl region which corresponds to SEQ ID NO: 11 and is 100% identical to instant SEQ ID NO: 55 (See previous Appendix I) [0032-0039 and 0065-0069]. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Flynn to include the specific targeting of a tau nucleic acid such as the MAPT gene as taught by Simone because Flynn teaches it is within the ordinary skill in the art to use gene regulation using a mutant dCas9 construct where the Cas9 protein is fused to a KRAB repressor domain wherein a guide RNA is used to target an exon within the MAPT gene and Simone teaches methods of targeting the MAPT gene for repression of expression for treatment of Alzheimer’s disease. One would have been motivated to make such a modification in order to receive the expected benefit of reduced expression of the MAPT gene for the treatment of Alzheimer’s disease by using a guide RNA for targeting the specific sequence as taught by Flynn and Simone.
Applicant continues to argue that the rejection of claim 7 under 35 U.S.C. 103 should be withdrawn as well in view of the amendments to claim 1 which they believe deems them allowable.
This is not persuasive because the amendments to claim 1 do not render them allowable.
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 ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637
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