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 with traverse of:
Species: E2F6 and nuclease-based gene editing system as recited in claim 1 in the reply filed 9/12/2024 was previously acknowledged and entered. Examiner previously extended the search to include one additional species from this group to include STAT3, as this addition would not present a search burden.
Claims 2-9 and 13-16 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim.
Oath/Declaration
The AF/D.132 filed on 1/7/2026 has been considered.
Status of the Claims
Claims 1, 11-12, and 17-21 are under consideration.
Amendments & Arguments
This action is in response to papers filed 01/07/2026 in which claims 1 and 21 were amended, and no claims were cancelled or added. All of the amendments have been thoroughly reviewed and entered.
Applicant has amended:
Claims 1 and 21 to overcome the §112(a) rejections; the §112(a) rejections are withdrawn.
Claims 1 and 21 to overcome the §103 rejection; the §103 rejection is withdrawn.
Applicant argues:
The amendment and declaration have overcome the §103 rejection of claims 1, 11-12, 17, and 21. Applicant’s arguments are persuasive.
Various reasonings against the Double Patenting Rejections. Applicant’s arguments are not persuasive.
Arguments are further addressed below. Arguments that are no longer relevant are not addressed.
All of the amendments have been thoroughly reviewed and entered. Rejections not reiterated here are withdrawn.
Response to Applicant’s Remarks:
Applicant's arguments filed 1/07/2026 have been fully considered and they are persuasive because:
Applicant argues, the declaration and amendments overcome the §112a and §103 rejections. The declaration shows CRISPRi-mediated epigenetic knockdown of E2F6 and ZNF274, both alone and in combination, in aged human glial progenitors, sharply suppressed genes associated with senescence, such as p16/CDKN2A and p21/CDKN1A. The results are persuasive; the rejections are withdrawn.
Applicant next argues that the teachings of Wenfeng fail to teach that glial progenitor cells, rather teach neural progenitor cells. They provide an excerpt from the Inventor’s declaration to prove how different the cells used in the primary reference, neural progenitor cells, are from the cells of the invention – adult glial progenitor cells.
Briefly, the declaration states: Neural progenitor cells are multi potent cells that mainly differentiate into neurons and can produce certain glial cells; glial progenitor cells are restricted progenitors that differentiate into glial cells (e.g., astrocytes and oligodendrocytes, but not neurons).
This is persuasive.
Regardless of if discussing NPC or oligodendrocytes themselves, the mechanism of action impacting senescence and the showings by Wenfeng of E2F6’s role in neural stem cell differentiation to oligodendrocyte cells, is different from a showing of senescence, as instant claims require.
Further, the instant claims are directed to a method of administering an inhibitor of E2F6 to a population of glial progenitor cells with the outcome of inhibiting p16/p21. The applied reference teaches inhibiting E2F6 in a population of neural progenitor cells. Instant method further requires that such inhibition be brought about by a gRNA. The office agrees with Applicants that Wenfeng fail to directly teach or suggest gRNA to E2F6.
The §103 rejection is withdrawn.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent
possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed.Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
The rejection below has been rewritten for clarity.
Claims 1, 11-12, and 17-21 remain provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-10 and 14-18 of copending Application No. 18/047,831 (reference application) in view of Jinek (Jinek M. et al., Science. 2012 August 17; 337(6096): 816–821), GenBank (GenBank, Homo sapiens E2F6 mRNA, NM_001278277.2, revision Jun 29 2021, retrieved Aug 28 2025, 7pgs), and Fernandes (US 20240254466 of US-provisional-application US 63246543 filed, 21st Sept, 2021), (all of record, in the non-final OA dated 9/10/2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant application is anticipated by the cited application in view of the suppressing agent claimed in the conflicting patent or application anticipates the claimed agent in the application being examined. Claims 11-13 and 19-20 are not included in the rejection because they are directed to i) different species of suppressing agents (siRNA or miRNAs) than instant and ii) administration of a cell to a patient.
Instant Application
18/047,831 (Reference Application)
Instant claim 1:
A method of …, said method comprising: administering, to the population of adult glial progenitor cells, an effective amount of an agent that suppresses one or more transcription factors selected from the group consisting of
(i) zinc finger protein 274 (ZNF274), (ii) Myc-associated factor X (MAX),
(iii) E2F transcription factor 6 (E2F6), (iv) zinc finger protein Aiolos (IKZF3), and (v) signal
transducer and activator of transcription 3 (STAT3)…
18/047,831 claim 1:
A method of rejuvenating, or enhancing the development potential of, a glial progenitor cell or a progeny thereof, said method comprising suppressing in the glial progenitor cell or the progeny a transcription repressor selected from the group consisting of E2F6, ZNF274, MAX, and IKZF3.
18/047,831 claim 4:
wherein the suppressing step comprises expressing or introducing in the glial progenitor cell or the progeny a suppressor of the transcription repressor.
18/047,831 claim 10:
wherein the suppressor comprises a small molecule compound, an oligonucleotide, a nucleic acid, a peptide, a polypeptide, a CRISPR/Cas system, or an antibody or an antigen-binding portion thereof.
18/047,831 claim 14:
wherein the suppressor comprises a CRISPR-Cas system.
While copending claims 10 and 14 require a CRISPR-Cas system, they do not teach or require a gRNA.
However, before the effective filing date of instant invention, i. the recited accession number for E2F6 gene was known in the prior art in Genbank, and ii. CRISPR-Cas for genome editing is a mature field and one of skill in the art knows the teachings of Jinek (Jinek M. et al., Science. 2012 August 17; 337 (6096): 816–821) with respect to Cas9 mediated genome editing with gRNAs. As per the well-known rules of gRNA design taught by Jinek:
Rational design of gRNAs is robust and allows for targeting of any DNA sequence of interest with few constraints beyond the presence, in the target DNA, of a GG dinucleotide (PAM) adjacent to the targeted sequence (pg. 820 last para before conclusion and conclusion para).
With respect to gRNA, a contiguous stretch of at least 13 base pairs between the gRNA and the target DNA site proximal to the PAM is required for efficient target recognition/cleavage, while up to six contiguous mismatches in the 5’-terminal region of the gRNA are tolerated (pg. 818 last para and Fig. 3E).
The DNA strand that is complementary to the target-binding sequence in the gRNA is cleaved at a site three base pairs upstream of the PAM (Fig. 1D, E and fig. S5B, C). The non-complementary DNA strand is cleaved at one or more sites within 3 to 8 base pairs upstream of the PAM.
Fig. 3D shown below sums up the rules:
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See the FASTA format of NM_001278277.2 with GG highlighted, in the non-final OA Appendix dated 9/10/2025. There are 163 GG dinucleotides. Of these ~40% do not have the required 13-bp stretch free of GG that would serve as potential gRNAs, as required by Jinek. Thus, further eliminating the available choices of sequences for gRNA. Thus, one skilled in the art would know to look for GG dinucleotide, as this is the required PAM for Cas9 and further nucleotides in the 5’-region, such as the GG dinucleotide, are not in the seed region and therefore, inconsequential for CRISPR-Cas9 genome editing/indel activity, and arrive at a gRNA that is targeted to E2F6 and that is 5-100 nucleotides in length.
Neither Genbank nor Jinek teach the use of gRNA in glial cells.
However, before the effective filing date of instant invention, Fernandes taught a method of silencing transcription factors in glial cells using an agent, wherein the agent is a CRISPR system, wherein the CRISPR system comprises a nucleic acid molecule that comprises a first nucleic acid sequence encoding a Cas protein and a second nucleic acid sequence encoding a guide RNA (middle of [0006]: vectors encoding or comprising the components of the dXR:gRNA systems). Fernandes teaches making and using catalytically-dead Class 2 CRISPR proteins linked with one or more transcription repressor domains as a fusion protein and a guide ribonucleic acid (gRNA), which is useful in certain disease indications where gene silencing, or repression, is preferable to gene editing [0004]. Fernandes teaches by example that their system can suppress a protein, PTBP1, expressed in glial cells (repress PTBP1 in primary midbrain astrocyte cultures, [0580]). Thus, Fernandes had reduced to practice, suppression of a target sequence in glial cells using a CRISPR system.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The double patenting rejection of Claims 1, 11-12, and 17-21 on the grounds of nonstatutory double patenting as being unpatentable over claims 2-3, 6, 23-24, 29-35 of 18/467,442 (reference application) is withdrawn.
The double patenting rejection of Claims 1, 11-12, and 17-21 on the grounds of nonstatutory double patenting as being unpatentable over claims 1-13 of US 12565648 (Application No. 17/968,984, reference application) is withdrawn.
Response to Applicant’s Remarks:
Applicant's arguments filed 1/7/2026 have been fully considered but they are not persuasive because:
Regarding the maintained nonstatutory double patenting, applicant did not address the merits of the provisional rejection. It is noted the response states that they will address the rejection at such time as the claims are otherwise considered allowable.
Applicants arguments are not dispositive. The rejections are maintained.
Regarding the withdrawn nonstatutory double patenting rejections, applicant argues, i) amendments and ii) the ref app (now US 12565648) is directed to microRNAs that target MAX, E2F6, or STAT3.
This argument is persuasive. The rejection over 18/467,442 and US 12565648 is therefore withdrawn.
Conclusion
No claim is allowed.
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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHABANA MEYERING, Ph.D. whose telephone number is (703)756-4603. The examiner can normally be reached M - F: 9am to 5pm EST.
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/SHABANA S MEYERING/
Examiner, Art Unit 1635
/SHABANA S MEYERING/Examiner, Art Unit 1635
/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635