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 .
Applicant’s election without traverse of Group I claims 1-13 and 26 in the reply filed on 02/20/2026 is acknowledged.
Claims 14-25 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 02/20/2026.
Status of Claims
Claims 1-13 and 26 are under examination.
Claim 14-25 are cancelled.
Claim Objections
Claims 5, 8, 9, 10, 11, 13, and 26 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Claims 1-2, 4, 6, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over McCracken et al. (Nature, 2015) in view of Natarajan et al. (ACS Omega, 2019) and Peng et al. (Front. Cell Dev. Biol, 2021).
Regarding claim 1, McCracken et al. teach a method of generating cells which comprises :(a) cultivating a first cell culture comprising pluripotent stem cells (PSCs), for at least 3 days, in a first culture medium, comprising:- a WNT pathway-activator, and- FGF (b) replacing the first culture medium by a second culture medium, comprising: a BMP pathway inhibitor (ii) retinoic acid (RA),- a WNT pathway-activator, and FGF and (c) cultivating the cells for at least 3 days (page 5, Methods).
McCracken et al. do not teach the culturing generates a neuro-muscular junction cell culture model. McCracken et al. further do not teach the second culture medium contains a TGFβ pathway inhibitor.
Natarajan et al. teach various methods of developing neuro-muscular junction cell culture models. Natarajan et al. teach the advent of stem cells and human induced pluripotent stem cells (iPSCs) provide attractive opportunities to study the human NMJ using in vitro models (page 12970, right column). Natarajan et al. teach the use of hiPSCs offers an opportunity to test and study drug effects on human tissue (page 12975, left column). Natarajan et al. teach iPSCs have opened new avenues of investigation in different fields including studies on NMJ. Natarajan et al. teach iPSCs from patients with neurodegenerative diseases such as ALS70 and SMA71 can be differentiated into motor neurons (page 12973, right column).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of McCracken et al. for a method of generating cells with the teachings of Natarajan et al. for methods of developing neuro-muscular junction cell culture models. Natarajan et al. provide motivation by teaching that stem cells and human induced pluripotent stem cells (iPSCs) provide attractive opportunities to study the human NMJ using in vitro models. One of skill in the art would have had a reasonable expectation of success at combining McCracken et al. and Natarajan et al. because both teach generation of in vitro models.
McCracken et al. and Natarajan et al. do not teach the second culture medium contains a TGFβ pathway inhibitor.
Peng et al. teach formation of the neural plate, the first step in the genesis of the nervous system, is triggered during gastrulation by signals produced by an organizer region on the dorsal blastophore lip. Peng et al. teach signals act primarily by inhibiting signaling by TGF-β family members (page 1, neural induction).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of McCracken et al. and Natarajan et al. for PSC induction of an NMJ model with the teachings of Peng et al. for neural induction. Peng et al. provide motivation by teaching that Peng et al. teach signals act primarily by inhibiting signaling by TGF-β family members. One of skill in the art would have had a reasonable expectation of success at combining McCracken et al. and Natarajan et al. and Peng et al. because they both teach differentiation of stem cells.
Regarding claim 2, Natarajan et al. teach a 2D cell culture model which is a self-organizing neuro-muscular junction cell culture model (page 12971, 2D in Vitro NMJ Models).
Regarding claim 4, McCracken et al. teach replacing after 2-5 days the second culture medium by a third culture medium comprising retinoic acid and cultivating the cells for 20 days (page 6, methods).
Regarding claim 6, McCracken et al. teach after 3 days, in a first culture medium, the first culture medium by a second culture medium, comprising: a BMP pathway inhibitor, and retinoic acid (RA) (page 5, Methods).
Regarding claim 12, Natarajan et al. teach that iPSCs from patients with neurodegenerative diseases such as ALS70 and SMA71 can be differentiated into motor neurons (page 12973, Right column).
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over McCracken et al. (Nature, 2015) in view of Natarajan et al. (ACS Omega, 2019) and Peng et al. (Front. Cell Dev. Biol, 2021) as applied to claim 1 above and in further view of Meyers et al. (Cold Spring Harbor Perspectives in Biology, 2017).
Regarding claim 3, McCracken et al., Natarajan et al., and Peng et al. make obvious the in vitro method of claim 1. McCracken et al. teach cultivating the cells for at least 4 days, and optionally replacing the culture medium by a medium suitable for maintenance of the cell culture model (page 5, Methods).
McCracken et al., Natarajan et al., and Peng et al. do not teach the addition of FGF.
Meyers et al. teach fibroblast growth factor (FGF) signaling down-regulates the expression of BMP-4 and BMP-7, and FGF together with insulin-like growth factor (IGF) activate the mitogen-activating protein (MAP) kinase cascade that regulates BMP signaling. Meyers et al. teach FGF and IGF obstruct BMP signal transduction by phosphorylating the linker region of Smad1 that blocks translocation of Smad to the nucleus. Meyers et al. teach BMP and FGF are necessary for proper neural development (page 4, Neural Induction).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of McCracken et al., Natarajan et al., and Peng et al. for an in vitro method of generating NMJ cell models with the teachings of Meyers et al. for the addition of FGF for neural development. Meyers et al. provide motivation by teaching FGF is required for proper neural development. One of skill in the art would have had a reasonable expectation of success at combining McCracken et al., Natarajan et al., and Peng et al. and Meyers et al. because they both teach generation of NMJ.
Claims 7 is rejected under 35 U.S.C. 103 as being unpatentable over McCracken et al. (Nature, 2015) in view of Natarajan et al. (ACS Omega, 2019) and Peng et al. (Front. Cell Dev. Biol, 2021) as applied to claim 1 above and in further view of Schafer et al. (Gero Science, 2019).
Regarding claim 7, McCracken et al., Natarajan et al., and Peng et al. make obvious the in vitro method of claim 1. McCracken et al. teach the addition of a BMP pathway inhibitor (page 5, Methods).
McCracken et al., Natarajan et al., and Peng et al. do not teach the addition of GDF11.
Schafer et al. teach growth differentiation factor 11 (GDF11) is a transforming growth factor β (TGFβ) protein that regulates aspects of central nervous system (CNS) formation and health throughout the lifespan. Schafer et al. teach during development, GDF11 influences CNS patterning and the genesis, differentiation, maturation, and activity of new cells, which may be primarily dependent on local production and action (page 1, abstract).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings McCracken et al., Natarajan et al., and Peng et al. for PSC induction of cells with the addition of a BMP pathway inhibitor with the teachings of Schafer et al et al. for the addition of growth differentiation factor 11 (GDF11). Schafer et al. provide motivation by teaching that teach growth differentiation factor 11 (GDF11) is a transforming growth factor β (TGFβ) protein that regulates aspects of central nervous system (CNS) formation. One of skill in the art would have had a reasonable expectation of success at combining McCracken et al., Natarajan et al., Peng et al., and Shafer et al. because both teach the importance of transforming growth factor β (TGFβ) regulation in CNS development.
Conclusion
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/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
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