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 papers filed January 21, 2026.
Claims 59-88 are pending in the application.
Applicant’s election of Group I (claims 59-83) in the reply filed on 01/21/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claims 84-88 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/21/2026.
Therefore, claims 59-83 are examined on the merits.
Priority
The present application is a CON of Application 18/852,012 filed 09/27/2024 which is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2023/065140 filed March 30, 2023.
Applicant’s claim for the benefit of a prior-filed provisional applications 63/444,108 filed on 02/08/2023 and 63/326,640 filed on 04/01/2022 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is April 01, 2022.
Claim Objections
Claims 59-61 are objected to because of the following informalities: the first time an acronym is utilized in a claim-set, said acronym should be spelled out in its entirety followed by said acronym in parenthesis (e.g. nuclear receptor subfamily 5 group A member 1 (NR5A1)).
Appropriate correction is required.
Claims 59-62 and 72-75 are objected to because the terms “encoding NR5Al Protein”, “encoding RUNXl protein, “encoding GATA4 protein” and encoding TCF21 protein” should be preceded by the indefinite article “a”, e.g., encoding a GATA4 protein.
Appropriate correction is required.
Claims 64 and 77 in line 2 improperly state their intended Markush groups; the proper format requires the use of the “selected from the group consisting of”. Amending both claims to insert the phrase “the group consisting of” after “selected from” will overcome this aspect of the objection.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 65 and 78 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 65 and 78 recite “and/or” in line 3. It is unclear what the metes and bounds of this term, as “and” could be interpreted to include only one inducible promoter, or a promoter inducible by all of the listed compounds, or, “or” would imply that all the promoters with their inducible compounds are in the alternative. Appropriate correction is required.
Therefore, claims 65 and 78 are rejected as being indefinite.
Claim Rejections - 35 USC § 103
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.
Claims 59-60, 63; 66, 70-73, 76, 79 and 83 are rejected under 35 U.S.C. 103 as being unpatentable over Ishida (Endocrinology, 2021, Vol. 162, No. 12, 1–11) in view of Nicol (NATURE COMMUNICATIONS| (2019) 10:5116; IDS Reference filed 10/27/2025) and LaVoie (Mol Reprod Dev. 2017;84:788–801).
Regarding claims 59 and 72, Ishida teaches human induced pluripotent stem cells (hiPSC) which have been modified by providing an exogenous polynucleotide which encodes an NR5A1 protein with a doxycycline inducible promoter (p. 2, 2nd column). The aim of the study was to determine that Leydig cells could be induced from hiPSCs via the forced expression of NR5A1(p. 3, 1st column).
However, Ishida does not teach exogenous RUNX1 protein within the hiPSCs.
Nicol teaches RUNX1 is “a transcription factor involved in pre-granulosa cell differentiation/maintenance. RUNX1 first delineates the supporting cell lineage and then
becomes pre-granulosa cell-specific during gonad development. RUNX1 plays redundant roles with FOXL2 through binding of common chromatin regions and control of common sets of genes to maintain pre-granulosa cell identity in the fetal ovary. Our findings provide insights into the genomic control of granulosa cell differentiation and pave the way for the identification of
transcription factors and cis-signatures contributing to the fate determination of granulosa cells and the consequent formation of a functional ovary” (p. 12, 1st paragraph).
Moreover, LaVoie teaches that in females, FSHR gene expression is highly restricted to ovarian granulosa cells, and that transcription factors linked to ovarian FSHR promoter regulation in various species include Nuclear receptor subfamily 5 group A member 1 (NR5A1), GATA-binding proteins 4 and 6 (GATA4/6) (p. 792, 1st column). LaVoie further discusses the presence of GATA4 and NR5A1 as regulatory factors in various genes (p. 796, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the hiPSC cell of Ishida which comprises an exogenous polynucleotide encoding a NR5A1 protein to additionally comprise an exogenous polynucleotide encoding RUNX1 with a reasonable expectation of success. An artisan would be motivated to include and additional polynucleotide encoding a RUNX1 protein in the cell differentiation protocol of Ishida in order to differentiate the cells to lead a hiPSCs not only to Leydig cells but potentially to a granulosa cell fate. As shown in LaVoie, GATA4 and NR5A1 (both mentioned in Ishida) are important regulatory factors within granulosa cells.
Regarding claims 60 and 73, the combination of Ishida, Nicol and LaVoie make obvious claims 59 and 72. Moreover, Ishida teaches it is known in the art that GATA4 and NR5A1 are transcriptional factors in the same grouping to differentiate cell fate (p. 2, 1st column) rendering obvious to further include an additional exogenous polynucleotide comprising an open reading frame encoding GATA4 protein.
Regarding claims 63, 66, 76 and 79, the combination of Ishida, Nicol and LaVoie make obvious claims 59 and 72. Moreover, Ishida teaches NR5A1 is operably linked to the TetO promoter (i.e. tetracycline or doxycycline inducible promoter) (Figure 1). Therefore, it would have been obvious to one of ordinary skill in the art to operably link each open reading frame to a heterologous promoter.
Regarding claims 70 and 71, the combination of Ishida, Nicol and LaVoie make obvious claims 59 and 72. Regarding the limitation of every polynucleotides is present within a single nucleic acid molecule or the polynucleotides is present within separate nucleic acid molecules this separation or joining can be at once envisaged within the hiPSC comprising the constructs as made obvious by the above references. See MPEP 2131.02.
Regarding claim 83, the combination of Ishida, Nicol and LaVoie make obvious claims 59 and 72. Moreover, Ishida teaches for EB formation, 3 × 104 NR5A1-iPSCs were allowed to aggregate in maintenance medium (p. 3, 1st column). Therefore, Ishida had 1x102 to 1x107 hiPSCs.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 61-62 and 74-75 are rejected under 35 U.S.C. 103 as being unpatentable over Ishida (supra) in view of Nicol (supra) and LaVoie (supra) as applied to claims 59-60 and 72-73, above, and in further view of Ford (Biology of Reproduction, 2022, 106(3), 503–514; published Oct 2021)
As discussed above, the combined teachings of Ishida, Nicol and LaVoie make obvious a human induced pluripotent stem cells (hiPSC) which have been modified by providing an exogenous polynucleotide which encodes an NR5A1 protein, GATA protein and RUNX1 protein with a doxycycline inducible promoter, as discussed above and incorporated herein in its entirety.
However, these references do not teach an additional exogenous polynucleotide comprising an open reading frame encoding TCF21 protein.
Ford teaches POD1 (TCF21) as a negative regulator of steroidogenic factor-1 (SF-1; NR5A1), an important regulator of granulosa cell regulated ovary development suggesting a possible role in the differentiation of granulosa cells (p. 512, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the hiPSC cell of Ishida, Nicol and LaVoie which comprises an exogenous polynucleotide encoding NR5A1 protein, RUNX1 protein and GATA4 protein to additionally comprise an exogenous polynucleotide encoding TCF21 with a reasonable expectation of success. An artisan would be motivated to include TCF in the cell differentiation protocol in order to differentiate the cells to a granulosa cell fate. As taught in Ford, TCF21 is a negative regulator of steroidogenic factor-1 (SF-1), which has a possible role in the differentiation of granulosa cells.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 64-65 and 77-78 are rejected under 35 U.S.C. 103 as being unpatentable over Ishida (supra) in view of Nicol (supra) and LaVoie (supra) as applied to claims 59, 63, 72 and 76, above, and in further view of Ng (US20210054448A1; Published 02-25-2021).
As discussed above, the combined teachings of Ishida, Nicol and LaVoie make obvious a human induced pluripotent stem cells (hiPSC) which have been modified by providing an exogenous polynucleotide which encodes an NR5A1 protein, GATA protein and RUNX1 protein with a doxycycline inducible promoter, as discussed above and incorporated herein in its entirety.
However, regarding claims 64-65 and 77-78, these references do not teach that the promoter is an alcohol-regulated promoter, a steroid-regulated promoter, a metal-regulated promoter, a pathogenesis-regulated promoter, a temperature-inducible promoter, or a light- responsive promoter.
Ng teaches that vectors which carry transcription factors have inducible promoters known in the art such as “chemically/biochemically-regulated and physically-regulated promoters such as alcohol-regulated promoters, tetracycline-regulated promoters (e.g., anhydrotetracycline (aTc)-responsive promoters and other tetracycline responsive promoter systems, which include a tetracycline repressor protein (tetR), a tetracycline operator sequence (tet0) and a tetracycline transactivator fusion protein (tTA)), steroid-regulated promoters (e.g., promoters based on the rat glucocorticoid receptor, human estrogen receptor, moth ecdysone receptors, and promoters from the steroid/retinoid/thyroid 25 receptor superfamily), metal-regulated promoters (e.g., promoters derived from metallothionein (proteins that bind and sequester metal ions) genes from yeast, mouse and human), pathogenesis-regulated promoters (e.g., induced by salicylic acid, ethylene or benzothiadiazole (BTH)), temperature/heat-inducible promoters (e.g., heat shock promoters), and light-regulated promoters (e.g., light responsive promoters from plant cells)” (para 0044).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize an inducible promoter as described in Ng for the tetO promoter of Ishida, Nicol and LaVoie with a reasonable expectation of success. An artisan would be substituting one known inducible promoter in the art for another for the same purpose of transcription factor expression in iPSCs.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 67 and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Ishida (supra) in view of Nicol (supra) and LaVoie (supra) as applied to claims 59 and 72 above, and in further view of UniProt1 (ABSS Sequence Search, Rup result SEQ ID NO: 1) and Uniprot2 (UniProt1 (ABSS Sequence Search, Rup result SEQ ID NO: 2)
As discussed above, the combined teachings of Ishida, Nicol and LaVoie make obvious a human induced pluripotent stem cells (hiPSC) which have been modified by providing an exogenous polynucleotide which encodes an NR5A1 protein, GATA protein and RUNX1 protein with a doxycycline inducible promoter, as discussed above and incorporated herein in its entirety.
However, NR5A1 and RUNX1 are not taught as SEQ ID NO:1 and SEQ ID NO: 2 respectively.
However, SEQ ID NO: 1 was taught in Uniprot as “STF1_Human” as shown below in the Rup results.
PNG
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762
1453
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And SEQ ID NO: 2 was taught in Uniprot as “RUNX1_HUMAN” as shown below in the Rup results.
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787
1551
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Greyscale
It would have been obvious at the time of filing to use the Uniprot database as a source for the protein sequences known in the art to utilize in the method of Ishida, Nicol and LaVoie with a reasonable expectation of success. An artisan would have been motivated to use these sequences as they are known to be the desired transcription factors rendered obvious by Ishida, Nicol and LaVoie. One would have had a reasonable expectation of success in carrying out the invention as it was well within the skill of the ordinary artisan to substitute one sequence for another.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 68 and 81 are rejected under 35 U.S.C. 103 as being unpatentable over Ishida (supra) in view of Nicol (supra) and LaVoie (supra) as applied to claims 59, 60, 72 and 73 above, and in further view of UniProt5 (ABSS Sequence Search, Rup result SEQ ID NO: 5)
As discussed above, the combined teachings of Ishida, Nicol and LaVoie make obvious a human induced pluripotent stem cells (hiPSC) which have been modified by providing an exogenous polynucleotide which encodes an NR5A1 protein, GATA protein and RUNX1 protein with a doxycycline inducible promoter, as discussed above and incorporated herein in its entirety.
However, GATA4 is not taught as SEQ ID NO: 5.
However, SEQ ID NO: 5 was taught in Uniprot as “GATA4_Human” as shown below in the Rup results.
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757
1512
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Greyscale
It would have been obvious at the time of filing to use the Uniprot database as a source for the protein sequences known in the art to utilize in the method of Ishida, Nicol and LaVoie with a reasonable expectation of success. An artisan would have been motivated to use these sequences as they are known to be the desired transcription factors rendered obvious by Ishida, Nicol and LaVoie. One would have had a reasonable expectation of success in carrying out the invention as it was well within the skill of the ordinary artisan to substitute one sequence for another.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 69 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Ishida (supra) in view of Nicol (supra) and LaVoie (supra) and Ford (supra) as applied to claims 59, 61, 72, and 74 above, and in further view of UniProt4 (ABSS Sequence Search, Rup result SEQ ID NO: 4)
As discussed above, the combined teachings of Ishida, Nicol, LaVoie, and Ford make obvious a human induced pluripotent stem cells (hiPSC) which have been modified by providing an exogenous polynucleotide which encodes an NR5A1 protein, GATA protein, RUNX1 protein and a TCF21 (POD1) protein with a doxycycline inducible promoter, as discussed above and incorporated herein in its entirety.
However, TCF21 is not taught as SEQ ID NO: 4.
However, SEQ ID NO: 4 was taught in Uniprot as “TCF21_Human” as shown below in the Rup results.
PNG
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856
1310
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Greyscale
It would have been obvious at the time of filing to use the Uniprot database as a source for the protein sequences known in the art to utilize in the method of Ishida, Nicol, LaVoie and Ford with a reasonable expectation of success. An artisan would have been motivated to use these sequences as they are known to be the desired transcription factors rendered obvious by Ishida, Nicol, LaVoie and Ford. One would have had a reasonable expectation of success in carrying out the invention as it was well within the skill of the ordinary artisan to substitute one sequence for another.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 59-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 22 of copending Application No. 18/852, 012 as per claims filed on 06/16/2025 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claims 1 and 4 of Application ‘012 read on the independent claims of the present application, claims 59 and 72. Claims 1, 4 and 22 teach a population of pluripotent stem cells (i.e. iPSCs) which comprise an engineered polynucleotide encoding a RUNX family member protein, which can be RUNX1 or RUNX2, and a NR5A1 protein.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
***
Claims 59-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 59-83 of copending Application No. 19/361,182 in view of Nicol (NATURE COMMUNICATIONS| (2019) 10:5116; IDS Reference filed 10/27/2025)
The copending claims are identical to the instant claims with the exception that the copending claims use the RUNX2 transcription factor where the instant claims recite RUNX1.
The use of RUNX1 guide hiPSC differentiation was taught by Nicol. Nicol further stated the “runt gene, critical for ovarian determination, has three orthologs in mammals: RUNX1, RUNX2, and RUNX3. Although all three RUNX transcription factors bind the same DNA motif, they are known to have distinct, tissue-specific functions. In the mouse, Runx1 was the only one with a strong expression in the fetal ovary, whereas Runx2 and Runx3 were expressed weakly in the fetal gonads in a non-sexually dimorphic way (Fig. 1a).”
Nicol demonstrates that RUNX1 and RUNX2 are orthologs which are both present in the XX gonads and the XY gonads of vertebrates (Figure 1a).
Thus, an artisan would have been motivated to make such a substitution to test the differential effect of the RUNX family members on differentiation as it would be obvious to try from the three ortholog options. An artisan would have had a reasonable expectation of success as it would be substituting proteins known in the art for the same purpose of cell differentiation.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634