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 26 August 2025. Claims 1-7, 9, 11, 20-23, 26, 40-45, 57-59, 91, 105, 119, 137, 150, 153, and 162 are currently pending. Claims 7, 9, 11, 22-23, 26, 40-45, 57-59, 91, 105, 119, 137, 150, 153, and 162 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1-6 and 20-21 are examined herein. The restriction requirement mailed 13 January 2025 is still deemed proper. Applicant's elected Group I and SEQ ID NO: 6 without traverse in the reply filed 13 March 2025.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments 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) 1-5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG Pub No. WO 2018/027078 A1, published 8 Feb 2018) in view of Joung (PG Pub No. US 2020/0308571 A1, earliest effective filing date of 4 Feb 2019).
Regarding claim 1, Liu is drawn to an invention concerned with methods that utilize fusion proteins comprising a Cas9 domain (i.e., a programmable DNA binding domain) and adenosine deaminases (i.e., adenosine base editors) that deaminate adenosine in target DNA (i.e., effect a single nucleobase modification) (Abstract). Liu teaches the use of a guide RNA that can direct the Cas9 domain to a target nucleic acid of interest ([00231]). Liu teaches a method of treating a disease or disorder comprising administering the fusion protein to a subject ([00352]). Liu teaches that ALS (i.e. a neurological disorder) can be treated by the method ([00353)]). Liu teaches that the deamination of the target nucleic acid can result in the introduction or removal of a splice site at a target nucleic acid (i.e., effect a single nucleobase modification at a splice site of a target gene) (pg. 621; see Claims 206-207).
Liu does not teach or suggest the use of an adenosine deaminase that comprises a V82S amino acid alteration as referenced to SEQ ID NO: 2 (Claims 1-2).
However, one of ordinary skill in the art would have considered the teachings of Joung as both references are common fields of endeavor pertaining to the use of Cas9 fusion proteins.
Joung is drawn to an invention concerned with engineered adenine base editor variants with reduced RNA editing activity (Abstract). Joung teaches the use of fusion proteins comprising a Cas9 polypeptide fused to an engineered adenosine deaminase ([005]). Joung teaches the use of an engineered TadA (i.e., an adenosine deaminase domain) having 100% sequence identity to the claimed SEQ ID NO: 2 ([0071]; see SEQ ID NO: 22 attached sequence alignment). Joung teaches that the TadA can comprise a residue change at position V82 with any substitution other than the WT amino acid in order to generate a TadA with an RRE phenotype ([0067]). Joung teaches that the RRE phenotype comprises a base editor with reduced RNA editing activity while still preserving DNA editing activity (i.e. Joung teaches that the activity levels of TadA mutants may be measured) ([0006]). Joung teaches that the TadA may be successfully mutated at multiple positions of interest in order to generate a TadA with an RRE phenotype ([0151)).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to substitute the adenosine deaminase of Liu for the adenosine deaminase of Joung and try to mutate the TadA of Joung such that it comprised a V82S mutation. A person of ordinary skill in the art would have been motivated to do so in order to utilize an adenosine deaminase that had reduced off-target RNA editing activity. A person of ordinary skill in the art would have had a reasonable expectation of success in the substitution because both Liu and Joung teach the use of adenosine deaminases that can be fused to a Cas9 molecule in order to edit a target nucleic acid of interest.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to mutate the TadA of Joung such that it comprised a V82S mutation. Joung teaches that there had been a recognized need in the art to mutate the TadA at position V82 in order to generate a TadA that has reduced off-target RNA editing activity. Joung teaches that that there was a finite number of amino acid substitutions (i.e., 19 possible substitutions) at each of the positions of interest that could successfully generate an RRE phenotype in a TadA. Joung also teaches that one of ordinary skill in the art would have pursued the potential solutions and tested the activity levels of different mutations within the TadA.
Regarding claim 3, Liu teaches that the method may be utilized to alter the splicing of a target gene (1.e., result in alternative splicing of a transcript encoded by the target gene) ([00359]).
Regarding claim 4, Liu teaches that mutations may be utilized to result in the expression of a truncated protein lacking the function of the full-length protein ([00349]).
Regarding claim 5, Liu teaches that the method may be utilized to generate a premature stop codon within the coding region of a target gene (i.e., reduce the expression of a target gene in a subject) ([00359]).
Claim(s) 6 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG Pub No. WO 2018/027078 A1, published 8 Feb 2018) in view of Joung (PG Pub No. US 2020/0308571 A1, earliest effective filing date of 4 Feb 2019) as applied to claims 1-5 above, and further in view of Lundberg (PG Pub No. US 2019/0330604 A1, filed 15 June 2017).
Regarding claims 6 and 20, Liu in view of Joung renders obvious claims 1-5 as described above.
Liu in view of Joung does not teach or suggest that the target gene is a SOD1 gene (Claim 6). Liu in view of Joung does not teach or suggest that the guide polynucleotide comprises positions 1-20 of SEQ ID NO: 6 (Claim 20).
However, one of ordinary skill in the art would have considered the teachings of Lundberg as both references are common fields of endeavor pertaining to the treatment of ALS via the utilization of CRISPR systems.
Lundberg is drawn to a study concerned with methods and materials for treatment of ALS by modulating the expression of a SOD1 gene via CRISPR-Cas systems (Abstract). Lundberg teaches the use of a guide RNA comprising positions 1-20 of SEQ ID NO: 6 ([0025]; see SEQ ID NO: 10788 in attached sequence alignment). Lundberg teaches that the guide RNA can be used to treat a SOD1 related condition such as ALS ([0007]). Lundberg teaches that the CRISPR-Cas system can induce a mutation that results in a premature stop codon in a target gene ([0091]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the guide RNA of Liu in view of Joung for a guide RNA that targets and induces a premature stop coding within a SOD1 gene in order to treat ALS, as described by Lundberg. A person of ordinary skill in the art would have been motivated to do so in order to treat ALS by modulating the expression of a SOD1 gene. A person of ordinary skill in the art would have had a reasonable expectation of success because both Lundberg and Liu in view of Joung teach the use of guide RNAs that can complex with CRISPR proteins in order to treat ALS.
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG Pub No. WO 2018/027078 A1, published 8 Feb 2018) in view of Joung (PG Pub No. US 2020/0308571 A1, earliest effective filing date of 4 Feb 2019) as applied to claims 1-5 above, and further in view of Jaskula-Ranga (PG Pub No. WO 2018/009534 A1).
Regarding claim 21, Liu in view of Joung renders obvious claims 1-5 as described above.
Liu in view of Joung does not teach or suggest that the target gene is a AR gene and wherein the neurological disease is SMBA (Claim 21).
However, one of ordinary skill in the art would have considered the teachings of Jaskula-Ranga as both references are common fields of endeavor pertaining to the treatment of neurological conditions via CRISPR.
Jaskula-Ranga is drawn to a study concerned with compositions and methods comprising improvements of a CRISPR-Cas9 system (Abstract). Jaskula-Ranga teaches that a target polynucleotide for the CRISPR-Cas9 can be an androgen receptor (AR) gene (pg. 68 and 71). Jaskula-Ranga teaches that SBMA can be a disease treated by the CRISPR-Cas9 system (pg. 78).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the target gene of Liu in view of Joung for an AR gene that can be targeted in order to treat SBMA, as described by Jaskula-Ranga. A person of ordinary skill in the art would have been motivated to do so in order to treat SBMA. A person of ordinary skill in the art would have had a reasonable expectation of success because both Jaskula-Ranga and Liu in view of Joung teach the use of functional CRISPR-Cas9 systems that can be utilized to treat neurological conditions.
Response to Arguments
Applicant’s amendments, field 26 August 2025, have been fully considered and are deemed persuasive. Accordingly, the previously filed rejections under 35 USC 112(b), 102, and 103 have been withdrawn. However, Applicant’s amendments have necessitated the newly filed rejections above.
Because Applicant’s arguments are directed towards the previously pending rejections of record, the arguments are 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