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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/21/2026 has been entered.
Claims 1, 3-4, 6-7, 9-21, and 24-28, of record 4/21/2026, are pending and subject to prosecution. Claims 24-28 remain withdrawn per the restriction requirement of 9/20/2021. Claim 1 is amended.
Status of Prior Rejections
RE: Rejection of claims 1, 3, 6-7, 9-11, and 13-21 under 35 U.S.C. 103 over Ginsburg et al. (Nature Protocols, 2015) in view of Nakajima-Takagi et al. (Blood, 2013), Clarke et al. (Nature Cell Biology, 2013), and Lee et al. (Circulation Research, 2014):
Re: Rejection of claims 1, 3-4, 6-7, and 9-21 under 35 U.S.C. 103 over Ginsburg et al. (Nature Protocols, 2015) in view of Nakajima-Takagi et al. (Blood, 2013), Clarke et al. (Nature Cell Biology, 2013), and Lee et al. (Circulation Research, 2014), further in view of Warren et al. (Cell Stem Cell, 2010):
RE: Rejection of claims 1, 3, 6-7, and 9-21 under 35 U.S.C. 103 over Ginsburg et al. (Nature Protocols, 2015) in view of Nakajima-Takagi et al. (Blood, 2013), Clarke et al. (Nature Cell Biology, 2013), and Lee et al. (Circulation Research, 2014), further in view of Cooke et al. (US 20150225699 A1):
The applicant asserts that the prior art references teach the expression of Sox17 in undifferentiated cells and mature endothelial cells, rather than more primitive reprogramming-derived endothelial cells, and do not provide a motivation to constitutively express Sox17 in reprogramming-derived endothelial cells to enhance engraftment with any reasonable expectation of success (Applicant Remarks, page 7-8).
In view of the applicant’s arguments and upon further consideration, the rejections are withdrawn in favor of new rejections.
New Rejections
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.
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 1, 3, 6-7, 9-11, and 13-21 are rejected under 35 U.S.C. 103 as being unpatentable over Ginsburg et al. (Nature Protocols, 2015), of record, in view of Firas et al. (US 20190017032 A1) and Aranguren et al. (Blood, 2013).
Regarding claims 1, 3, 11, and 21: Ginsburg et al. teach a method of generating endothelial cells by reprogramming amniotic cells. The amniotic cells (which read on “non-vascular cells”) are transduced using lentiviral vectors for the expression of ETV2, FLI1, and ERG1 (which reads on “ERG”), with culturing in the presence of SB-431542 (which reads on “a TGF-β signaling inhibitor”) (See fig. 1 legend, lines 1-6). The reprogrammed vascular endothelial cells are termed rAC-VECs (See abstract and Fig. 1A). The rAC-VECs read on “reprogramming-derived endothelial cells”. The rAC-VECs express VE-cadherin, CD31, and VEGFR2 (See fig. 1 legend, lines 7-9). Ginsburg et al. do not teach constitutive expression of Sox17 in the cells for at least 20 days or enhanced engraftment of the cells.
Firas et al. teach methods for the transdifferentiation of cells using transcription factors (See Abstract). The starting cells can be any somatic cell, including stem cells or differentiated cells such as fibroblasts (See ¶0049, 0347-0348, and 0351). The target cell can be an endothelial cell (See ¶0049, 0078, 0115, and 0156-0157). Conversion to endothelial cells can be carried out by increasing expression of any one or more transcription factors such as Sox17 (See ¶0079, 0115, and 0156-0160). Reprogramming vectors can use constitutive promoters, and culturing is performed for a sufficient time for endothelial cell generation, such as at least 1-30 days (See ¶0157, 0162, and 0380).
Aranguren et al. examine differential gene expression in arterial and venous endothelial cells (See Abstract). Sox17 is identified as being associated with arterial specification (See page 3984, col. 1, ¶1 and page 3986, col. 1, ¶1). Venous endothelial cells could be converted to an arterial phenotype by constitutive overexpression of lentivirally-transduced transcription factors including Sox17 (which reads on “an exogenous nucleic acid encoding transcription factor Sox17” and “a vector comprising a nucleic acid encoding Sox17 to achieve expression of Sox17”) for 6-28 days in culture (See page 3983, col. 2, full ¶1 and page 3986, col. 1, ¶1). Aranguren et al. suggest that arterial pre-specification prior to cell transfer may significantly improve arterial engraftment (See page 3991, col. 2, ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Ginsburg et al. to comprise the inclusion of Sox17 as a transcription factor for the conversion of amniotic cells to endothelial cells. One would have been motivated to make this modification because Firas et al. and Aranguren et al. teach Sox17 as being associated with endothelial specification. Aranguren et al. specifically teach Sox17 as being associated with arterial specification, which could significantly enhance arterial engraftment if done prior to cell transplantation (See page 3984, col. 1, ¶1; page 3986, col. 1, ¶1; and page 3991, col. 2, ¶1). One would also be motivated to constitutively express Sox17 for periods of 1-30 or 6-28 days (which read on “for at least 20 days”), as Aranguren et al. teach that the changes induced by transcription factors were stable at day 6 and up to day 28 (See page 3986, col. 1, 1 and page 3987, col. 1, 1) and Firas et al. teach that the cells can be cultured for a duration, such as 1-30 days, sufficient to yield endothelial cell characteristics in the reprogrammed cells (See ¶0157 and 0162). There would be a reasonable expectation of success in making these modifications because Sox17 could be readily included with ETV2, FLI1, and ERG1 as transcription factors for endothelial cell specification in the method of Ginsburg et al.
Regarding claims 6-7: Following the discussion of claims 1, 3, 11, and 21, Ginsburg et al. teach culturing of rECs for 3-4 weeks (which reads on “cultured for a total duration of at least 28 days”) (See page 1976, col. 2, full ¶1). Ginsburg et al. also teach that rECs can be stably cultured through more than 15 passages (which reads on “cultured for a total duration of at least 42 days”, since the conversion protocol takes 21-28 days) (See page 1984, Anticipated Results, ¶3).
Regarding claims 9-10: Following the discussion of claims 1, 3, 11, and 21, Ginsburg et al. teach transient expression of ETV2 for two weeks (which reads on “13-15 days”) and constitutive expression of FLI1 and ERG1 (which reads on “ERG”) (See page 1975, Abstract).
Regarding claim 13: Following the discussion of claims 1, 3, 11, and 21, Ginsburg et al. teach culturing of the cells with a TGF-β inhibitor for three weeks (which reads on “present in the cell culture of the non-vascular cells for 20-24 days”) (See page 1975, Abstract).
Regarding claims 14-17: Following the discussion of claims 1, 3, 11, 13, and 21, Ginsburg et al. teach treatment of the cells with the TGF-β signaling inhibitor SB-431542 (which reads on “specific for type I TGF-β receptors” and “small molecule compound”) (See fig. 1 legend, lines 1-6).
Regarding claim 18: Following the discussion of claims 1, 3, 11, and 21, Ginsburg et al. teach culture of non-vascular cells with transient expression of ETV2 for the first two weeks (which reads on “for the first 13-14 days”), SB-431542 treatment for the first three weeks (which reads on “presence of a TGF-β signaling inhibitor for the first 20-21 days”), and constitutive expression of FLI1 and ERG (which reads on “ERG”) (See page 1975, Abstract).
Claims 1, 3-4, 6-7, and 9-21 are rejected under 35 U.S.C. 103 as being unpatentable over Ginsburg et al. (Nature Protocols, 2015), of record, in view of Firas et al. (US 20190017032 A1) and Aranguren et al. (Blood, 2013), further in view of Warren et al. (Cell Stem Cell, 2010), of record.
The teachings of Ginsburg et al., Firas et al., and Aranguren et al. are set forth above and are incorporated herein in their entirety.
Regarding claims 4 and 12: Following the discussion of claims 1, 3, 6-7, 9-11, and 13-21, Ginsburg et al., modified by Firas et al. and Aranguren et al., render obvious the production of endothelial cells from non-vascular cells but fail to teach the delivery of exogenous mRNA for the expression of Sox17, ETV2, FLI1, and ERG1 (which reads on “ERG”).
Warren et al. teach a method for making mRNA from plasmid DNA and its use in transfection (See page 626, col. 2, full ¶1; page 627, col. 1, ¶1-2; and fig. 1-2 and 5). It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the vector-generating DNA constructs of Ginsburg et al. and Aranguren et al. encoding Sox17, ETV2, FLI1, and ERG1 for mRNA transfection. One would have been motivated to make this modification because Warren et al. teach that the use of mRNA is non-mutagenic, unlike some viral vectors, and is highly controllable for reprogramming cells (See page 619, col. 1, full ¶2). There would have been a reasonable expectation of success in doing so because the mRNAs could be readily used in place of lentiviral vectors and because Warren et al. demonstrate that their methods could be applied to multiple transcription factors and diverse cell types (See page 621, col. 1, full ¶2; page 627, col. 2, full ¶2; and fig. 2D and S2).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/JENNIFER S SPENCE/Examiner, Art Unit 1633
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