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 .
DETAILED ACTION
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 instant application is in response to the papers filed on May 18, 2026. Pursuant to the amendment filed on May 18, 2026, claims 1-4 and 22-33 are currently pending of which claims 1-4 and 22-33 have been amended. No claims have been amended and no claims have been added.
Therefore, claims 1-4, and 22-33 are currently under examination to which the following grounds of rejection are applicable.
Priority
Applicant has filed the English translation of the non-English language provisional application on May 18, 2026. The submitted English translation includes a cover sheet executed by Applicant/client stating that the English translation is accurate. The notice regarding the missing English translation and accuracy statement under 37 C.F.R. § 1.78 has been withdrawn accordingly.
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/JP2022/001814, filed January 19, 2022. Applicant' s claim for the benefit of a prior-filed parent provisional application 63/141,626, filed on January 26, 2021 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. Thus, the earliest possible priority for the instant application is January 26, 2021.
Response to Arguments
Withdrawn Objections/Rejections in response to Applicants’ arguments or amendments:
Drawings
In view of Applicants’ Remarks filed on May 18, 2026 that cite sections of the Specification that support the labels used in Figure 2, the objection to the Drawings have been withdrawn.
Claim Objections
In view of Applicants’ amendment to the claims dated May 18, 2026, in which claims 1-4, and 22-33 have been amended, the objection to claims 1-3, 22, 24-26, and 30 that were objected to for not spelling out abbreviations at first encounter, have now been withdrawn.
Claim Rejections - 35 USC § 102
In view of Applicants’ amendment to the claims dated May 18, 2026, in which claims 1-4, and 22-33 have been amended, the rejection to claims 1, 2, 4, 22-27, 30-31 rejected under 35 U.S.C. 102(a)(1)(2) as being anticipated by Vallier et al . (US 2019/0338309 A1), have been withdrawn.
The withdrawn rejections are in view of the amendment to claim 1 now reciting “a factor that promotes cell proliferation, the factor comprising a p53 dominant-negative mutant, short hairpin RNA (shRNA) or small interfering RNA (siRNA) that interferes with p53 gene or Rb gene, or MYC.”
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Claim Rejections - 35 USC § 103
In view of Applicants’ amendment to the claims dated May 18, 2026, in which claims 1-4, and 22-33 have been amended, the rejection to claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al . (US 2019/0338309 A1) in view of Sugimori et al. (Development 1 April 2008; 135 (7): 1271–1281), have been withdrawn.
In view of Applicants’ amendment to the claims dated May 18, 2026, in which claims 1-4, and 22-33 have been amended, the rejection to claims 22, 24, 28-29, 32-33 rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al . (US 2019/0338309 A1) in view of Yamanaka et al. (US 8,048,999 B2) and Wang et al. (Proceedings of the National Academy of Sciences 111.28 (2014): E2885-E2894), have been withdrawn.
The withdrawn rejections are in view of the amendment to claim 1 now reciting “a factor that promotes cell proliferation, the factor comprising a p53 dominant-negative mutant, short hairpin RNA (shRNA) or small interfering RNA (siRNA) that interferes with p53 gene or Rb gene, or MYC.”
Applicants’ arguments are moot in view of the withdrawn rejection. A response to any argument pertaining to a new or maintained rejection can be found below.
Response to Applicants’ Arguments as they apply to rejection of claims 1-4, 22-33 under 35 USC § 102 and 103
Applicant’s arguments, see Remarks pages 7-10, filed on May 18, 2026, with respect to the rejection(s) of claim(s) 1-4, and 22-33 rejected under 102 and 103 have been fully considered and are persuasive. Vallier did not teach the new limitation of claim 1 that is a factor that promotes cell proliferation, the factor comprising a p53 dominant-negative mutant, short hairpin RNA (shRNA) or small interfering RNA (siRNA) that interferes with p53 gene or Rb gene, or MYC”, and therefore the rejections are withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Okita et al. The remarks are largely directed to this new limitation presented in the claims, and therefore the arguments are moot in view of the grounds of rejection that employ Okita to teach the limitations pertaining to the “factors.”
New Grounds of Rejection:
Claim Rejections - 35 USC § 103
Claims 1-4 are newly rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al . (US 2019/0338309 A1; hereinafter 'Vallier'; of record) in view of Okita et al. (US 9,404,124 B2; hereinafter ‘Okita’).This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on May 18, 2026.
Regarding claim 1, Vallier teaches a method of producing oligodendrocytes from pluripotent stem cells, said method comprising the steps of: a) the targeted insertion of a gene encoding a transcriptional regulator protein into a first genetic safe harbor site of human somatic cells or human pluripotent stem cells; and b) the targeted insertion of any combination of the SOX10, OLIG2, NKX2.2, and NKX6.2 genes that are operably linked to an inducible promoter into a second genetic safe harbor site, wherein said inducible promoter is regulated by a transcription regulatory protein (claims; paragraph par 69-72). Moreover, Example 4 states that an OLIG2 gene and a SOX2 gene in form of a bicistronic expression cassette were inserted into human pluripotent stem cells, and that double-overexpressing cells were induced in oligodendrocytes (figure 12).
Vallier teaches introduction of select genes encoding transcription factors could convert adult cells into pluripotent stem cells, stating, “Additional genes including certain members of the Klf family, the Myc family, Nanog, and LIN28, may increase the induction efficiency. Examples of the genes which may be contained in the reprogramming factors … c-Myc…, and these reprogramming factors may be used singly, or in combination of two or more kinds thereof.” (par 201); “For the treatment of solid tumours , genes encoding toxic peptides … , tumour suppressor genes such as p53 , genes coding for mRNA sequences which are antisense to transforming oncogenes , … may be expressed.” (par 231).
Vallier does not teach the factor comprising a p53 dominant negative mutant, short hairpin RNA (shRNA) or small interfering RNA (siRNA) that interferes with p53 gene or Rb gene, or MYC.
Okita teaches iPS cell establishment efficiency can be improved via suppression of p53 with a dominant negative mutant of p53 and/or the introduction of L-Myc or c-myc (col 3, ln 50-63; Example 1). The dominant negative mutant of p53 is not particularly limited, as far as the mutant is capable of competitively acting against the wild-type p53 protein, and it may consist of p53P275S, p53DD, p53S58A, p53C135Y, p53A135V, p53R172H, p53R270H, and p53D278N, and furthermore siRNAs and shRNAs against p53 (col 21, ln 1-30; col 4, ln 36-39).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the method for producing oligodendrocytes and progenitor cells from induced pluripotent stem (iPS) cells with the introduction of inducers by including suppressors of p53 and/or MYC proteins, e.g. L-Myc, c-myc, because of Okita’s teachings that these compounds improved outcomes for establishing iPS cells. Therefore, there is a reasonable expectation that by using these inducers in the method of producing oligodendrocytes and progenitor cells as taught by Vallier the iPS cells will similarly show improved outcomes related to cell establishment which is a necessary prerequisite for cell proliferation.
Secondly, because the currently recited claim is not stating particular time points at which these inducers are being included with stem cells, and Vallier in view of Okita teaching all the claimed inducers at particular time points during which stems are present, it would be clearly obvious to include these inducers during the claimed process of differentiation at some point based on the combined teachings of Vallier and Okita.
Regarding claim 2, dependent on claim 1, the rejection to claim 1 is applied herein, wherein Vallier teaches inducers comprise OLIG, NKX, and SOX (“the production of oligodendrocytes from pluripotent stem cells, comprising the steps of:…targeted insertion of any combination of the SOX10, OLIG2, NKX2.2, AND NKX6.2 genes” (par 69-71).
Regarding claim 3, Vallier teaches the introduction of master regulators for cellular reprogramming, stating, “Cellular reprogramming strategies can be enhanced by combining master regulator or transcription factor overexpression with extracellular signalling cues” (par 0209); “A master regulator is an expressed gene that influences the lineage of the cell expressing it.” (par 0167), and then listing ASCL1 as a master regulator (par 0168).
Regarding claim 4, dependent on claim 1, the rejection to claim 1 is applied herein as Okita teaches a p53 dominant-negative mutant selected from the group consisting of p53P275S, p53DD, p53S58A, p53Cl35Y, p53Al35V, p53Rl 72H, p53R270H, and p53D278N (col 21, ln 1-30).
Claims 22-33 are newly rejected under 35 U.S.C. 103 as being unpatentable over Vallier et al . (US 2019/0338309 A1) in view of Okita et al. (US 9,404,124 B2) and Sugimori et al. (Development 1 April 2008; 135 (7): 1271–1281; hereinafter ‘Sugimori’; of record). This is a new rejection necessitated by Applicants’ amendments to the claims in the response filed on May 18, 2026.
Regarding claims 22, 24-27, and 30-31, which are similar to claim 1 as seen in the introduction of the inducers: OLIG, SOX, and NKX, and the inducers comprising the aforementioned factors as described in claim 1, these claims are different in that the inducers further include ASCL, and secondly the introduction is in somatic cells as opposed to pluripotent stem cells.
Vallier teaches select enhancers, e.g. SOX10, OLIG2, and NKX2.2, to be overexpressed in pluripotent stem cells for the production of oligodendrocytes (par 0069-71). Vallier teaches the cell types to be modified with enhancers comprise mature somatic cells that further include blood cells (par 0225-0227).
As described in the claim 1 rejection above, Okita teaches wherein the inducers further comprise a factor that promotes cell proliferation, the factor comprising a p53 dominant-negative mutant, short hairpin RNA (shRNA) or small interfering RNA (siRNA) that interferes with p53 gene, or MYC (col 3, ln 50-63; Example 1). Furthermore, the dominant negative mutant of p53 consist of p53P275S, p53DD, p53S58A, p53C135Y, p53A135V, p53R172H, p53R270H, and p53D278N, and furthermore siRNAs and shRNAs against p53 (col 21, ln 1-30; col 4, ln 36-39).
Vallier in view of Okita do not teach the enhancers that are introduced to somatic cells as including ASCL (only teaches it with pluripotent cells).
Sugimori teaches Ascl1 is involved in terminal differentiation of oligodendrocytes late in development, the co-expression of Olig2 and Nkx2-2 in oligodendrocyte progenitors (OLPs) are impaired in Ascl1–/– mutants, and furthermore, gain-of-function studies showed that Ascl1 collaborates with Olig2 and Nkx2-2 in promoting differentiation of OLPs into oligodendrocytes in vitro, in which the overexpression of Ascl1, Olig2 and Nkx2-2 alone stimulated the specification of OLPs, but the combinatorial action of Ascl1 and Olig2 or Nkx2-2 was required for further promoting their differentiation into oligodendrocytes. The studies determined Ascl1 regulates multiple aspects of oligodendrocyte development in the spinal cord (abstract).
It would have been prima facie obvious for one of ordinary skill in the art at the time of the effective filing date to have modified the inducers to promote differentiation to oligodendrocytes as taught by Vallier in view of Okita by incorporating ASCL1 as taught by Sugimori because it would have been obvious to combine prior art elements according to known methods to yield predictable results, wherein the result is successful differentiation to oligodendrocytes . The inclusion of ASCL1 for differentiation of as described Sugimori would have led to predictable results with a reasonable expectation of success because Sugimori clearly describes that the ASCL1 is connected with Olig2 and Nkx2-2 in promoting differentiation of oligodendrocyte progenitor cells into oligodendrocytes, and therefore the use of all the claimed inducers are likely to produce oligodendrocytes.
Regarding claim 23, dependent on claim 22, the rejection to claim 22 is applied herein as Okita teaches the p53 dominant-negative mutant selected from the group consisting of p53P275S, p53DD, p53S58A, p53Cl35Y, p53Al35V, p53Rl 72H, p53R270H, and p53D278N (col 21, ln 1-30).
Regarding claims 28-29, 32-33, that are directed to the reprogramming of somatic cells to oligodendrocytes with the claimed inducers rejected above for claims 22 and 24, Vallier teaches somatic cells can be differentiated oligodendrocytes, but does not teach these somatic cells as including fibroblasts or mononuclear cells.
Okita teaches the reprogramming of somatic cells by the transfection of Oct4, Sox2, Klf4, or c-Myc as a means for inducing reprogramming of a differentiated cell, particularly fibroblast cells to establish iPS cells (col 1, ln 50-65). Okita further teaches the iPS cells were established from fibroblasts cells more efficiently when using suppressors of p53 and/or Myc (col 3, ln 50-62). Okita states peripheral blood mononuclear cells may be used to generate iPS cells, as opposed to just fibroblasts (col 12, par 1).
Conclusion
Claims 1-4, and 22-33 are rejected. No claims are 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.
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/MICHAEL ANGELO RIGA/Examiner, Art Unit 1634
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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