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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 06/22/2026 is acknowledged.
Claims 40-44 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse.
Claims 1-12 and 21-33 are canceled. Claims 34-44 are added. Claims 40-44 are drawn to a non-elected species. Claims 13-20 and 34-39 are pending and under consideration.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 13, 16-17, and 34-39 is/are rejected under 35 U.S.C. 102a1 as being anticipated by Ali (Development (2014) 141, 2216-2224 doi:10.1242/dev.106377; IDS) as evidenced by NCBI Genbank Accession NM_008553 (10/13/2018, https://www.ncbi.nlm.nih.gov/nuccore/1407718787?sat=47&satkey=621552 accessed on 08/19/2026).
Claim 13 is drawn to a nucleic acid encoding a mutant basic-helix-loop-helix (bHLH) transcription factor wherein the mutant bHLH factor comprises a mutation of one or more phosphoacceptor sites wherein the mutant factoe exhibits reduced inhibition of finction relative to wild-type.
With regard to claim 13, Ali teaches mutating SP phosphoacceptor sites in both mutant and human Ascl1 (a bHLH TF; claim 37). Ali teaches mutations in different combinations of SP sites to AP, up to 6 in mouse (mouse Ascl1-SA6, claim 39) and 5 in human (claim 34-36; see Supplementary Figure 1). Ali teaches lentiviral (claim 16-17; nucleic acid) vectors encoding the SP-AP mutant proteins (arr page 2223, para 1, for example).
With regard to claim 38, the Ascl1 mutant of Ali has 1-5 (human) or 1-6 (mouse) mutations (altered amino acids) relative to wildtype. Claim 38 requires that the sequence be at least 80% identical to SEQ ID NO:1 (human) or SEQ ID NO:2 (mouse).
Genbank NM_008553 teaches the nucleotide sequence encoding wild-type mouse Ascl1 protein, which 100% aligns with the claimed SEQ ID NO:2. If all 6 serines from the 6 SPs were changed to AP, as taught by Ali, 225/241 amino acids would be identical, which is 97.4% identity. The alignment of SEQ ID NO:2 (Qy) with the wildtype protein sequence (Db) is below and the nucleic acid and protein sequences associated with NM_008553 are attached.
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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.
A) Claim(s) 13-15, 18 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ali (Development (2014) 141, 2216-2224 doi:10.1242/dev.106377; IDS) and Liu (The Journal of Neuroscience, June 24, 2015 • 35(25):9336 –9355; IDS) as evidenced by Higgs (J Neurophysiol 125: 1482–1500, 2021, pages 1482-1500).
Ali meets the limitations of claim 13 as set forth above. Ali teaches use of an inducible lentiviral vector to express mutant Ascl protein in mammalian fibroblasts to determine the ability of the mutant protein to transdifferentiate from fibroblasts into neural cells. Ali found that the mutant form of Ascl1 enhances neuronal maturation and doubled the conversion efficienct Ali does not teach use of an AAV vector or the GFAP promoter.
However, Liu taught assessing the ability of Ascl1 to transdifferentiate astrocytes (glial cells) into neurons. Liu discusses the ability of transcription factors to directly convert fibroblasts to neurons but it remained poorly understood how astrocyte-to-neural conversion occurs in vivo and whether induced neurons could be incorporated into preexisting neural circuits. Liu discusses design of an in vivo expression vector to express Ascl1 in glial cells by using an AAV vector (claims 14,15,17,19) and the GFAP promoter that is specifically active in glial cells (see page 9339, last para). Liu uses the AAV–FLEX–Arch–GFP as the vector, which is an AAV9 vector, as evidenced by Higgs (claim 18, see Liu page 9337, right col., para 2).
It would have been obvious at the time of filing to combine the teachings of Ali and Liu to use the phosphomutant form of Ascl1 in the method of Liu to transdifferentiate glial cells into functional neurons in vivo. One would have been motivated to substitute the wildtype Ascle gene in the vector of Liu with the mutant form of Ali because Ali taught that the mutant form was not inhibited by phosphorylation and thus lead to a higher efficiency of neuron formation and maturation. One would have had a reasonable expectation of success in making the combination/substitution as all of the requisite technologies to exchange the Ascl1 genes in the vector were well known to one of ordinary skill in the art at the time the invention was made.
B) Claim(s) 13,16 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ali (Development (2014) 141, 2216-2224 doi:10.1242/dev.106377; IDS) in view of Xu (Molecular Psychiatry (2016) 21, 62–70) and Addis (PLoS ONE, December 2011 | Volume 6 | Issue 12 | e28719).
Ali meets the limitations of claims 13 and 16 as set forth above. Ali doesn’t teach including a second transcription factor in the vector.
Xu taught a combination of transcription factors, including Ascl1, Foxa2 and Lmx1b can reprogram fibroblasts into more specific serotonergic neurons that are useful for research and drug discovery on serotonin-related mental disorders. Xu taught co-transfection of cells with separate viral vectors encoding the TFs.
Similarly, Addis taught the combination of Ascl1, LMX1B and Nurr1 reprogram astrocytes into dopaminergic neurons. The factors were initially identified from pools of vectors then cloned into a multicistronic vector to increase the efficiency of cells receiving all three factors.
It would have been obvious at the time of filing to include a second neuronal-related transcription factor such as LMX1B in the vector of Ali because both Xu and Addis taught that addition of other neuronal TFs could more specifically guide cells to specific neuronal fates. One would have been motivated to make such a combination to more effectively express multiple TFs in the same cell to control differentiation into neuronal subtypes. One would have had a reasonable expectation of success in making the combination/substitution as the requisite technologies to generate a polycistronic vector including additional coding regions for TFs were well known to one of ordinary skill in the art at the time the invention was made.
Conclusion
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
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