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 I, claim s59-83, in the reply filed on 02/19/2026 is acknowledged.
Claims 84-88 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Claim Rejections - 35 USC § 112
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 63 and 66 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.
Claim 63 recites “wherein each of the open reading frames is operably linked to a promoter. It is not clear if each open reading frame has it’s own promoter.Because the polynucleotides can be multicistronic, two open reading frames can be linked to the same promoter. Claim 63 is unclear given dependent claim 66 which recites “each heterologous promoter is independently…”. Claim 66 makes it unclear if claim 63 is intended to only encompass the requirement of two separate promoters for each open reading frame. Claim 63 on its own, encompasses both a single promoter as well as two separate promoters. Claim 66 infers that claim 63 is only encompassing two separate promoters.
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.
Claim(s) 59-66,70-79, 83 is/are rejected under 35 U.S.C. 103 as being unpatentable over US2020/0063105 (Ng1; IDS) or 11,788,1331 (Ng2) in view of Liang (eLife 2019;8:e48767. DOI: https://doi.org/10.7554/eLife.48767), LaVoie (MolReprodDev.2017;84:788–801.), Park (Mol Endocrinol, April 2010, 24(4):846–858) and Ford (Biology of Reproduction, 2022, 106(3), 503–514).
Claim 59 is drawn to a hiPSC comprising an exogenous polynucleotide encoding NR5A1 and a polynucleotide encoding Runx2. Claim 72 is drawn to a plurality of said cells. The claims do not recite that expression of these protein occurs nor do they require an effect from their expression.
Ng1 designed a library of human transcription factors to express in human iPSCs for large scale combinatorial screening to discover transcription factors that induce differentiation into a variety of cell types. Ng1 screened 1,578 genes encoding transcription factors. Among those TFs were NR5A2 (not NR5A1, as claimed), RUNX1 (not RUNX2, as claimed), GATA1 (not GATA4, as claimed), and TCF21 (claim 61 and 62). Thus, Ng1 taught generating hiPSCs comprising combinations of nucleic acids encoding TFs, some of which are highly related to those claimed and one of which was the claimed TCF21. Each TF of Ng1 was encoded on a separate polynucleotide in the library (claim 71; para 59). Claims 63 and 76 require a promoter with claims 64 -66 and 77-79 limiting the promoter identity. Ng taught a dox-inducible heterologous promoter in the TFome constructs (claim 66, 79; para 44).
Ng2 taught a differentiation screen of a smaller combination of TFs but teaches that “Any transcription factor from any species (e.g., human, mouse, dog, cat, pig or bird) known in the art and variants thereof may be used” (Col. 8, lines 33-35) and the use of the same inducible promoters recited in claims 63-65 and 76-78,
“…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). (col. 10, li 22-33)
Ng2 also taught the combinations of TFs can be encoded on multicistronic vectors (claim 70, para bridging cols. 8-9). Ng2 taught starting with 500,00-800,000 hiPSCs (claim 83, col. 15, li. 57).
Claim 59 and 72 require the polynucleotides encode NR5A1 and RUNX2. Dependent claims limit the TFs to a variety of combinations as follows:
60,73- NR5A1, RUNX2 and GATA4
61,74- NR5A1, RUNX2 and TCF21
62,75- NR5A1, RUNX2, GATA4 and TCF21. Neither Ng1 nor Ng2 taught these particular combinations.
Liang also taught a smaller, more focused screen using the same concept where transcription factors known to be associated with a particular cell type of interest were used. Liang screened 5 polynucleotides encoding TFs associated with Sertoli calls, which are a male equivalent of female granulosa cells. They were able to narrow the group of 5 down to two, NR5A1 and GATA4 (claim 60), that guided differentiation into Sertoli-like cells.
With regard to the recited combination of TFs (59,72-NR5A1 and RUNX2; 60,73- NR5A1, RUNX2 and GATA4; 61,74- NR5A1, RUNX2 and TCF21; 62,75- NR5A1, RUNX2, GATA4 and TCF21), these TFs were all known to be associated with granulosa cell fate. For example, LaVoie taught that in females, NR5A1 and GATA4 regulate FSHR gene expression in granulosa cells. These are the same genes having a role in Sertoli cells in males. Likewise, Park taught a role for Runx2 in cell differentiation and expression of downstream luteal genes. With regard to Tcf21, this TF was taught by Ng1 as one of the 1500+ TFs. However, with more specific regard to the other claimed TFs and differentiation into Sertoli/granulosa cells, Ford taught transcriptional profiling of granulosa cells and noted Tcf21, GATA4 and Nr5a1 as associated with granulosa cell fate.
Thus, it would have been obvious at the time of filing to screen TFs for their effects on differentiation of hiPSCs as taught by Ng1 and by Ng2, using various combinations of TFs known to be associated with granulosa and/or Sertoli cell fate to induce hiPSCs to generate those cells types, or to find combinations that generate those cell fates, in vitro. One would have been motivated to make such a combination as the use of TF combinatorial libraries to screen for TFs that lead to cell fates was known as taught by Ng1, Ng2 and by Liang, and the claimed TFs were taught in various combinations as associated with Sertoli and granulosa cell type by each of LaVoie, Park and Ford. One would have had a reasonable expectation of success as the claims merely require addition of the polynucleotides to the cell which was achievable with a high level of predictability.
2) Claim(s) 67 and 80 is/are rejected under 35 U.S.C. 103 as being unpatentable over US2020/0063105 (Ng1) or 11,788,1331 (Ng2) in view of Liang (eLife 2019;8:e48767, 27 pages), LaVoie (MolReprodDev.2017;84:788–801.), Park (Mol Endocrinol, April 2010, 24(4):846–858) and Ford (Biology of Reproduction, 2022, 106(3), 503–514) as applied to claims 59-63,66,71-76, 82 above, and further in view of NCBI Genbank Accession Q13285 (IDS) and NCBI Genbank Accession Q13950 (IDS).
Ng1/Ng2, Liang, LaVoie, Park and Ford meet the limitations of claim 59 and 63 as set forth above. While liang and Lavoie teach Nr5A1 and Park teaches RUNX2, they do not provide the amino acid sequences for the proteins and therefore do not meet the limitations of claims 67 or 80.
However, the sequences were taught in Genbank (NR5A1 (Seq Id No: 1)=Genbank Accession Q13285 and RUNX2 (Seq Id No:3)=Genbank Accession Q13950)
It would have been obvious at the time of filing to use the Genbank database as a source for the protein sequences because Ng2 taught screening TFs and looking to Genbank for the sequence information. Ng2 states “The sequences of exemplary transcription factors may be obtained from the National Center for Biotechnology Information (NCBI) GenBank database” (col. 8 lin 34-37). One would have been motivated to use these sequences as they are known to be the desired transcription factors rendered obvious by Liang, LaVoie, Park 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.
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3) Claim(s) 68 and 81 is/are rejected under 35 U.S.C. 103 as being unpatentable over US2020/0063105 (Ng1) or 11,788,1331 (Ng2) in view of Liang (eLife 2019;8:e48767, 27 pages; IDS), LaVoie (MolReprodDev.2017;84:788–801.), Park (Mol Endocrinol, April 2010, 24(4):846–858) and Ford (Biology of Reproduction, 2022, 106(3), 503–514) and as applied to claims 59-63,66,71-76, 82 above, and further in view of NCBI Genbank Accession P43694 (IDS).
Ng1/Ng2, Liang, LaVoie, Park and Ford meet the limitations of claim 60 as set forth above. The references do not provide the amino acid sequence of GATA4 that is required by claims 68 and 81. While Liang and Lavoie teach GATA4 they do not provide the amino acid sequences for the proteins and therefore do not meet the limitations of claims 68 or 81.
However, the sequence was taught in Genbank (GATA4 (Seq Id No: 1)=Genbank Accession P43694.
It would have been obvious at the time of filing to use the Genbank database as a source for the protein sequences because Ng2 taught screening TFs and looking to Genbank for the sequence information. Ng2 states “The sequences of exemplary transcription factors may be obtained from the National Center for Biotechnology Information (NCBI) GenBank database” (col. 8 lin 34-37). One would have been motivated to use these sequences as they are known to be the desired transcription factors rendered obvious by Liang, LaVoie, and Park. 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.
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4) Claim(s) 69 and 82 is/are rejected under 35 U.S.C. 103 as being unpatentable over US2020/0063105 (Ng1) or 11,788,1331 (Ng2) in view of Liang (eLife 2019;8:e48767, 27 pages), LaVoie (MolReprodDev.2017;84:788–801.), Park (Mol Endocrinol, April 2010, 24(4):846–858) and Ford (Biology of Reproduction, 2022, 106(3), 503–514) and as applied to claims 59-63,66,71-76, 82 above, and further in view of NCBI Genbank Accession O43680 (IDS).
Ng1/Ng2, Liang, LaVoie, Park and Ford meet the limitations of claim 59 as set forth above. The references do not provide the amino acid sequence of GATA4 that is required by claims 69 and 82. While Ng1 teaches TCF21, they do not provide the amino acid sequences for the proteins and therefore do not meet the limitations of claims 69 or 82.
However, the sequence was taught in Genbank (TCF21 (Seq Id No: 4)=Genbank Accession O43680.
It would have been obvious at the time of filing to use the Genbank database as a source for the protein sequences because Ng2 taught screening TFs and looking to Genbank for the sequence information. Ng2 states “The sequences of exemplary transcription factors may be obtained from the National Center for Biotechnology Information (NCBI) GenBank database” (col. 8 lin 34-37). One would have been motivated to use these sequence as is known to be a desired transcription factor as taught by Ng1. 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.
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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.
A) Claims 59-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 59-83 of copending Application No. 19/361,681 in view of US2020/0063105 (Ng1; IDS). The copending claims are indentical to the instant claims with the exception that the copending claims use the RUNX1 transcription factor where the instant claims recite RUNX2. The use of RUNX1to guide hiPSC differentiation was taught by Ng1.
Ng1 designed a library of human transcription factors to express in human iPSCs for large scale combinatorial screening to discover transcription factors that induce differentiation into a variety of cell types. Ng1 screened 1,578 genes encoding transcription factors. Among those TFs were RUNX1 (not RUNX2, as claimed), NR5A2 (not NR5A1, as claimed), GATA1 (not GATA4, as claimed), and TCF21. Thus, Ng1 taught generating hiPSCs comprising combinations of nucleic acids encoding TFs, some of which are highly related to those claimed and one of which was the claimed TCF21 and the copending RUNX1.
It would have been obvious to substitute the instant claimed RUNX2 with RUNX1 as taught by Ng1 to arrive at the invention as claimed. One would have been motivated to make such a substitution to test the differential effect of the RUNX family members on differentiation. One would have had a reasonable expectation of success in making such a substitution because for screening effect of RUNX2, one merely needs to substitute the proteins and that was routine and well within the abilities on one of ordinary skill.
This is a provisional nonstatutory double patenting rejection.
B) Claims 59-83 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 59-83 of copending Application No. 18/852,012 in view of Park (Mol Endocrinol, April 2010, 24(4):846–858).
The copending claims are indentical to the instant claims with the exception that the copending claims claim a RUNX transcription factor family member in claim 59 where the instant claims recite RUNX2. Park taught a role for Runx2 in cell differentiation and expression of downstream luteal genes.
It would have been obvious to use the instant claimed RUNX2 as a RUNX family as to arrive at the invention as claimed. One would have been motivated to RUNX2 as Park had taught the RUNX2 is a transcription factor that does, in fact, affect differentiation of iPSCs. One would have had a reasonable expectation of success in making such a substitution because for screening effect of RUNX2, one merely needs to substitute the proteins and that was routine and well within the abilities on one of ordinary skill.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632