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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/10/2025 has been entered.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14, 15, 17-22, 24-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of arterial specification of hemogenic endothelium wherein ETS1 is used, does not reasonably provide enablement for such methods wherein activation of ERK signaling is used, or wherein other types of “pure” cells are created (e.g. T-cells) or. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This rejection is maintained for reasons made of record in the Office Actions dated 8/29/2024, 4/10/2025 and for reasons set forth below.
The test of enablement is whether one skilled in the art could make and use the claimed invention from the disclosures in the application coupled with information known in the art without undue experimentation (United States v. Telectronics, Inc. 8 USPQD2d 1217 (Fed. Cir. 1988)). Whether undue experimentation is required is a conclusion reached by weighing several factors. These factors were outlined in Ex parte Forman, 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and again in In re Wands, 8 USPQQ2d 1400 (Fed. Cir. 1988) and include the following:
State of the prior art and level of predictability in the art: In spite of considerable interest in generating hemogenic endothelium (HE), the prior art of record contains no description of methods of doing so using ERK signaling. In a paper published in 2018, Park et al (Cell Reports) teach that the induction of HE from mesoderm or pluripotent stem cells (hPSCs) requires expression of DLL4 and increased Notch signaling (also a conclusion of the instant specification, ¶[0069] of the USPGPUB 20180142207). Much like the instant specification, Park et al use ETS1 to induce DLL4 expression and subsequent Notch signaling (abstract, Fig. 1D). Park et al also underscores how complex the maze of various transcription factors and signaling molecules can be in such developmental pathways (Fig. 7A and B), the data indicating that no other ETS family transcription factor, or ERK signaling, was known to induce the requisite DLL4/Notch expression. Likewise, Uenishi et al (2018) use DLL4 expression to induce Notch signaling in HE induction, and found that ETS transcription factors were induced downstream of DLL4 and Notch1 (see ERG and ETV6 in Fig. 6), not that such transcription factors could be used to induce DLL4 and Notch1. Further, in a review of ETS family transcription factors (Sizemore et al, 2017) does not mention the induction of DLL4 expression or Notch signaling by these transcription factors. None of the above use a generic activation of ERK or Notch to induce AHE, or produce the cell types recited by the claims, at a level of purity required by the claims (e.g. claim 24) from generic mesoderm cells.
Thus, the use of a general family of factors, or a specific reagent, to activate ERK signaling via a PI3K inhibitor in order to induce arterial specification of hemogenic endothelium from human mesoderm cells is not well understood. This relevant art clearly evidences that such methods were at an early stage of development at the time of filing and that the skilled artisan would not know how to predictably perform the claimed methods without explicit guidance from the specification or significant empirical experimentation.
Amount of direction provided by the inventor and existence of working examples: The working examples use ETS1 to practice the claimed methods and induce arterial HE from mesoderm and hPSCs, further, specific, differentiated mesoderm cells (termed APLNR+PDGFRa+) were induced into T cells via complex scheme involving more than Notch signaling (e.g. Example 2 in the specification). All of the working examples in the specification rely upon an initial induction of AHE from human mesoderm cells using ETS1. None of the working examples demonstrate how to arrive at the required AHE cells by activation of ERK signaling alone, as encompassed by the instant claims. The specification also discloses well-known methods for manipulating, culturing and transfecting mammalian cells.
Although the specification suggests methods by which one might attempt to produce arterial HEs by using any given generic activation of ERK signaling, there is no evidence that the broad methods contemplated would actually produce the claimed cell type(s). Thus, in order to make and use the invention as claimed, the skilled artisan would have to further develop methods of mesoderm or hPSCs induction such that the breadth of “ERK signaling” recited in the claims could be used to produce the claimed cells.
Nature of the invention and Breadth of the claims: The claims are directed to methods of producing arterial HEs or pure T-cells by activation of ERK or Notch signaling from mesoderm or already prepared AHE cells. The claims are not limited to any particular ERK signaling factor, other than claim 17, which recites LY294002 a PI3K inhibitor which does not produce the necessary events for arterial HE production (see above and the instant specification). Thus, the claimed methods encompass a divergent genus of methods that encompasses the use of any PI3K inhibitor along with any other factors that might be necessary to provide the requisite induction of AHE, DLL4 expression and Notch signaling. As the claims encompass a wide variety of species of methods, it is incumbent upon the disclosure to set forth the manner and process of making and using a variety of species that is commensurate with the scope of protection sought.
Relative skill of those in the art and quantity of experimentation needed to make or use the invention: Although the level of skill in the art of culturing and manipulating mesoderm or hPSCs is high, the level of skill in the art of doing so the produce arterial HEs by activation of ERK signaling is low. One would not be able to make or use the claimed methods by the activation of ERK or Notch signaling given no more than the teachings available at the time of filing without undue experimentation. The art of record does not provide a single working example of ERK or Notch signaling, alone and without ETS1, that is operative in mesoderm to induce arterial HEs. Likewise, all of the teachings in the instant application are specifically directed to making said arterial HEs with ETS1, with additional prophetic statements suggesting how the technology might be further developed using activation of ERK or Notch signaling alone. Given the broad scope of the claims, the early developmental stage and the unpredictability of the art at the time of filing, making embodiments of the claimed invention that are operative would clearly require undue experimentation. Therefore, the claims are properly rejected under 35 USC 112, first paragraph, as lacking enablement.
Given the above analysis of the factors which the courts have determined are critical in determining whether a claimed invention is enabled, it must be considered that undue and excessive experimentation would have to be conducted by the skilled artisan in order to practice the claimed invention.
Response to Arguments
Applicant's arguments filed 10/10//2025 have been fully considered but they are not persuasive. Applicants essentially assert that the specification provides examples of using ERK activation via a PI3K inhibitor to induce AHE.
Such is not convincing. The passages in the specification referenced by applicants teach the construction of the ETS1 vector and ETS1 hESC cell lines; “Downstream RNAseq bioinformatics analysis”; or are not part of the specification as filed (the specification contains no ¶’s [0161]-[0164] or [00161]-[00164]). Thus, these passages do not address this rejection directly. Further, a review of the passages that do mention LY294002 use ETS1 upregulation in order to arrive at the claimed methods wherein the starting cells (human mesoderm, hESC’s) differentiate into the claimed arterial hemogenic endothelium (AHE). This would appear to bolster the crux of this rejection rather than argue against it. All of the passages cited by applicants rely upon the initial induction of AHE by ETS1, or do not begin with the claimed mesoderm or AHE cells (regardless of further downstream applications or cell types). Thus, these examples cannot serve to provide support for the claimed methods that do not utilize ETS1.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 D BURKHART/Primary Examiner, Art Unit 1638