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 .
Status of the Claims
Claims 1, 3-4, 6, 8, 10, 12, 14, and 16-37 are pending responsive to communications on 05/15/2023 are pending.
Claim 1 is newly amended.
Claims 1, 3-4, 6, 8, 10, 12, 14, and 16-37 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn. Prior objections have been addressed by amendment.
The rejection of claims 1, 3-4, 10, 23-25, and 28 under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023) as evidenced by Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023) and Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023) is withdrawn in order to address the claims as amended.
The rejection of claims 6, 8, 26-27 under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023) as evidenced by Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023) and Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), as applied to claims 1, 3-4, 10, 23-25, and 28 above, and further in view of Oshima et al. (BMC Developmental Biology, 2007, previously cited 11/16/2023) is withdrawn in order to address the claims as amended.
The rejection of claims 12, 14 and 29-30 under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023) as evidenced by Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023) and Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), as applied to claims 1, 3-4, 10, 23-25, and 28 above, and further in view of Semeckhkin et al. (WO2016086052A1, previously cited 11/16/2023), Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023), and Morrison et al. (US20040110288A1, 2004, previously cited 11/16/2023) is withdrawn in order to address the claims as amended.
The rejection of claims 16-17 and 31-32 under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023) as evidenced by Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023) and Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), as applied to claims 1, 3-4, 10, 23-25, and 28 above, and further in view of Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023) and Nikopoulos et al. (Stem Cells, 2007, previously cited 11/16/2023) is withdrawn in order to address the claims as amended.
The rejection of claims 18-19 and 33-34 under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023), and Nikopoulos et al. (Stem Cells, 2007, previously cited 11/16/2023), and as evidenced by Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023) and Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), as applied to claims 1, 3-4, 10, 16-17, 23-25, 28, and 31-32 above, and further in view of Oshima et al. (BMC Developmental Biology, 2007, previously cited 11/16/2023) is withdrawn in order to address the claims as amended.
The rejection of claims 20-22 and 35-37 under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023) and Nikopoulos et al. (Stem Cells, 2007, previously cited 11/16/2023), as evidenced by Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023) and Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), as applied to claims 1, 3-4, 10, 16-17, 23-25, 28, and 31-32 above, and further in view of Semeckhkin et al. (WO2016086052A1, previously cited 11/16/2023) and Morrison et al. (US20040110288A1, 2004, previously cited 11/16/2023) is withdrawn in order to address the claims as amended.
Claim Interpretation
Claim 6 recites a “CNS progenitor cell”. This term is not defined in the disclosure. Typically, in the art, the term used is “neural progenitor cell”, which, as evidence by Graham et al. (Neuron, 2003), neural progenitor cells are found throughout the central nervous system (Summary, p749; Introduction, pp749). Therefore, giving the term its broadest reasonable interpretation in view of the disclosure and the art, the term “CNS progenitor” has been interpreted as being synonymous with “neural progenitor cell”.
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.
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 1, 3-4, 10, 23-25, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023), Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), Zhang et al. (Cell Stem Cell, 2016), and Cairns et al. (Stem Cell Reports, 2016).
In regards to claim 1, see the PTAB decision on 04/24/2026.
Specifically, Schoeler is directed to "a method for producing mammalian neural plate border stem cells ('NPBSCs'), comprising: (a) differentiation of mammalian pluripotent stem cells." Schoeler ¶ 2. Schoeler also teaches that:
[P]luripotent stem cells can be induced pluripotent stem cells. The term "induced pluripotent stem (iPS) cells", as used herein, refers to pluripotent stem cells derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of certain genes. Induced pluripotent stem cells are identical to natural pluripotent stem cells. Id. at ¶ 39.
Schoeler further teaches that "[a]s another example, human [induced pluripotent stem] cells can also be obtained from embryonic fibroblasts without viral integration using adenoviral vectors expressing c- Myc, Klf4, Oct4, and Sox2." Id. at ¶ 40. Schoeler thus teaches that mature (i.e., differentiated) cells can be transformed into induced pluripotent stem cells, and then, in a second phase or step, these induced pluripotent stem cells can be transformed into neural plate border stem cells.
The preamble to independent claim 1 as amended recites “An in vitro method, comprising directly reprogramming mature human cells.”
The Specification provides no express definition of the claim term "direct reprogramming," as Appellant acknowledged during oral argument. See Transcr. 4. Moreover, the preamble's use of the claim term "comprising," does not preclude additional steps not recited in the claims. See Crystal Semiconductor Corp. v. TriTech Microelectronics Int 'l, Inc., 246 F.3d 1336, 1348 (Fed. Cir. 2001) (holding that "[i]n the parlance of patent law, the transition "comprising" creates a presumption that the recited elements are only a part of the device, that the claim does not exclude additional, unrecited elements").
However, Appellant's Specification discloses "in a first aspect, the present invention relates to an in vitro method for the direct reprogramming of mature human cells." Spec. ¶ 15. It further discloses that:
[T]he present invention relates to isolated central nervous system primed neural progenitor cell line of the central nervous system lineage wherein said cell line is characterized by epigenetically corresponding to mature human cells, particularly wherein said cell line has been obtained from said mature human cells in a direct reprogramming method according to the present invention.
Id. at ¶ 23 (emphasis added); see also id. at ¶ ¶ 25, 27, 28, 30. The Specification also discloses that:
Various types of neural stem and progenitor cells (NSPCs) can be derived by directed differentiation from pluripotent stem cells (PSCs) as well as fetal and adult brain tissue. However, NSPCs exhibit large variability with respect to self-renewal and differentiation capacity. The[] variability of NSPC generated by directed differentiation and cell types derived ther[e]of is particularly problematic when future clinical applications are envisaged. Id. at ¶ 2 (internal references omitted).
Merriam-Webster's dictionary defines "direct," as an adjective, is, relevantly, "stemming immediately from a source." Direct, Merriam- Webster Dictionary, available at: https://www.merriam- webster.com/dictionary/direct (last visited April 1, 2026). Therefore, weighing the disclosures of the Specification, and the dictionary definition before us, the broadest reasonable construction of the claim term "direct reprogramming of mature human cells" to obtain induced neural border stem cells is "reprogramming mature cells into neural border stem cells without an intermediate pluripotent stem cell step."
Nevertheless, Ladran expressly teaches that it was known in the art at the time of invention that mature cells could be directly transformed into induced neural stem/progenitor cells ("iNSPCs"). Specifically, Ladran teaches that: The induction of iNSPCs from somatic cells provides a near limitless source of neural cells for cell-replacement therapies in vivo and cell-based in vitro models of neurological disease. iNSPC technology provides a fast and robust protocol to obtain proliferative neural precursors and generates more homogeneous populations than current induced Neuron (iNeuron) methods, while bypassing time-consuming induced pluripotent stem cell (iPSC) generation. Ladran, 706 (emphases added, internal references omitted). Similarly, Liu teaches: Induced neural stem cells (iNSCs) keep the capacity of self- renewing and are easier to terminally differentiate into three cell lineages, that is, neuron, astrocyte, and oligodendrocyte. Thus, iNSCs hold more opportunities than [induced pluripotent stem cells] to treat neural diseases in clinics . . . Recently, several studies have reported that fibroblasts can be reprogrammed into iNSCs by [transcription factors]. Liu, 297.
Ladran continues: "Incomplete sets of the original iPSC reprogramming cocktail (OCT4, SOX2, KLF4, and c-MYC) can reprogram iNSPCs from fibroblasts" and that "[b]oth constitutive expression of SOX2, KLF4, and c-MYC, when paired with transient OCT4 activity, as well as overexpression of OCT4, SOX2, and KLF4 in the presence of another pluripotency gene, ZIC3, are sufficient to generate iNSPCs." Ladran 706. Ladran thus teaches that it was known in the art that mature cells can be directly reprogrammed into neural border stem cells using "a mixture of transcription factors, wherein said mixture comprises the factors BRN2, SOX2, KLF4 and ZIC3," as recited in claim 1.
Ladran does not, however, teach the use of the claimed "GSK-3 inhibitor Chir99021; Alk5 inhibitor II; and Purmorphamine." Liu is directed to the induction of neural stem cells from somatic cells. Liu, Abstr., 297. Liu teaches that "recent studies have showed that small molecules (SMs) can dramatically improve the efficiency of reprogramming and SMs alone can even convert one kind of somatic cells into another, which is much safer and more effective than transcription factor-based methods." Id., Abstr. (emphasis added). Liu continues: "Typically, SMs can increase the efficiency or even manipulate cell fate by playing four separate roles: (1) epigenetic modifiers; (2) signaling pathway regulators; (3) metabolic modulators; and (4) nuclear receptor agonists and antagonists, although the first two mechanisms are more widely used in reprogramming researches." Id. at 297. Liu teaches that, among such SMs are the claimed GSK-3 inhibitor Chir99021, the Alk5 inhibitor RepSox; and purmorphamine. Liu, 307, 306, 298. Specifically, Liu reports, inter alia:
Mirakhori et al. converted human foreskin fibroblasts (HFFs) into induced neural progenitor cells (iNPCs) by using SOX2 protein transduction, human LIF, and a cocktail of SMs composed of LDN193189, SB431542 [an Alk5 inhibitor II, claimed⁴], CHIR99021 [claimed], purmorphamine [claimed], and VPA in 3D culture condition, while using SOX2 protein or SMs alone could only partially convert these cells. Id. at 298.
Schoeler also teaches that activin/TGF-B signaling can be inhibited with SB431542, that WNT signaling can be activated with CHIR99021, and that Hedgehog can be inhibited with purmorphamine. Id. (citing Schoeler 11 79, 90, 94).
Inman teaches that small molecu!e inhibitors have proven extremely useful for investigating signal transduction pathways and have the potential for development into therapeutics for inhibiting signal transduction pathways whose activities contribute to human diseases. Inman, Abstr. Inman teaches that SB431542 is a selective inhibitor for ALK4, ALK5, and ALK7. Id. at 73.
Therefore, it is concluded that a person of ordinary skill in the art would have been motivated to combine the claimed GSK-3 inhibitor Chir99021, an Alk5 inhibitor II such as SB431542, and purmorphamine, as taught by Liu, Schoeler, and Inman, with the claimed transcription factors BRN2, SOX2, KLF4, and ZIC3, as taught by Ladran and Liu, because the addition of the small-molecule inhibitors "can dramatically improve the efficiency of reprogramming" of somatic cells into the claimed induced neural border stem cells. It is also concluded, from the teachings of the cited prior art, that a skilled artisan would have had a reasonable expectation of success in combining these teachings. See, e.g., Liu, 298, supra (combination of small- molecule inhibitors and transcription factors effective in transforming fibroblasts into induced neural progenitor cells).
In regards to reprogramming with tranylcypromine (also called parnate in the art), a person of ordinary skill in the art would have been motivated to reprogram cells with tranylcypromine because Zhang teaches that it enhances neural stem cell markers Sox2+/Nestin+ cells and improves neural induction efficiency from fibroblasts (Identification of Chemically Defined Condition to Reprogram Fibroblasts into Neural Stem Cells, p655). Furthermore, because Zhang demonstrates that fibroblasts can be directly reprogrammed to neural stem cells with tranylcypromine (parnate) (Identification of Chemically Defined Condition to Reprogram Fibroblasts into Neural Stem Cells, p655) and without a pluripotent state (“Remarkably, except for gradual acquisition of neural gene expression . . . we could not detect the transcripts of other lineage-specific master genes such as Nanog, Oct4, and Rex1 (pluripotency)” (p660, left column), a person of ordinary skill in the art could have added tranylcypromine to improve reprogramming efficiency of fibroblasts with predictable results and a reasonable expectation of success.
In regards to performing the reprogramming on inactivated mouse embryonic mouse fibroblast, a person of ordinary skill in the art would have been motivated to perform the reprogramming on an inactivated mouse embryonic fibroblasts (MEF) feeders because Cairns teaches that this allows for indefinite proliferation while maintaining a neurosphere or dome-like shape (Fig. 1, p558; Results, p558-559; Experimental Procedures, p569). Furthermore, because Cairns teaches that adult fibroblasts can be directly converted to induced neural stem cells on inactivated MEF feeders (Fig. 1, p558; Results, p558-559; Experimental Procedures, p569; Results, p558) a person of ordinary skill in the art could have performed the reprogramming on inactivated MEF feeders with predictable results and a reasonable expectation of success.
In regards to claims 3-4 and 25, Schoeler teaches that cells may be further cultured in the presence of conditions (factors) which allow for differentiation (paragraph [0117]; specific example, paragraph [0301]).
In regards to claims 10 and 28, Schoeler teaches that neural plate border cells may be differentiated to neural crest lineage cells such as PNS neurons or neural crest-derived mesenchymal cells (claim 6; paragraphs [0113, 0223, 0300]).
In regards to claim 23-24, as above Schoeler teaches that a method for producing (obtaining) neural plate border stem cells (Abstract, claim 1), and that these cells can be identified by specific marker profiles (paragraph [0034]), indicating that these cells can be specifically isolated. Schoeler also teaches that these cells are a useful source of CNS and PNS neurons that can be used for disease modeling and drug discovery )paragraph [0010]). While Schoeler is silent on whether these cells are a stem cell line specifically, a person of ordinary skill in the art would have been motivated to establish a stem cell line for their use in the different differentiation applications discussed above. Furthermore, because Schoeler teaches that neural border plate stem cells can be expanded and passaged (cultured) (paragraph [0110-0111]), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Schoeler, Ladran, Liu, Inman, Zhang, and Cairns renders the invention unpatentable as claimed.
Claims 6, 8, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023), Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), Zhang et al. (Cell Stem Cell, 2016), and Cairns et al. (Stem Cell Reports, 2016), as applied to claims 1, 4, and 23-25 above, and further in view of Oshima et al. (BMC Developmental Biology, 2007, previously cited 11/16/2023).
In regards to claims 6, 8, and 26-27, Schoeler teaches that neural border plate stem cells can be expanded and passaged (paragraph [0110-0111]), and adopt a table identity of regionally specified neural progenitors (thus “CNS progenitors”) after four passages (paragraph [0256]; Fig. 5). Schoeler teaches that the expansion medium comprises an activator of WNT signaling (such as CHIR99021), and an activator of Hedgehog signaling (such as purmorphamine) (Claim 1). Schoeler also teaches that the neural border plate stem cells can be cultured in a neural medium comprising an activator of FGF (paragraph [0236]), which can be FGF2 (paragraph [0189]), which is the same as bFGF (paragraph (0045]). Schoeler also teaches that neural border plate stem cells can be differentiated to dopaminergic neurons, which would require passage through a neural progenitor, in the presence of an activator of an activator of activin/TGF-β (such as SB431542) (paragraph [0204]).
Schoeler does not explicitly teach that the medium could also comprise LIF. However, a person of ordinary skill in the arts would have been motivated to add LIF because, as taught by Oshima, addition of LIF maintains pools of neural progenitors and is a powerful took to control neural differentiation (Abstract, p1). Furthermore, because Oshima teaches methods for culturing neural progenitors with LIF and that it increased the number of neural progenitors (Figure 3, p5), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Schoeler, Ladran, and Oshima renders the invention unpatentable as claimed.
Claims 12, 14 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023), Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), Zhang et al. (Cell Stem Cell, 2016), and Cairns et al. (Stem Cell Reports, 2016), as applied to claims 1, 10, 23-25, and 28 above, and further in view of Semeckhkin et al. (WO2016086052A1, previously cited 11/16/2023), Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023), and Morrison et al. (US20040110288A1, 2004, previously cited 11/16/2023).
In regards to claims 12, 14, and 29-30, Schoeler teaches that neural plate border cells may be differentiated to neural crest derivatives such as PNS by being cultured with CHIR99021 and BMP4 (paragraph [0279]). Schoeler does not explicitly teach that this media also comprised Alk5 inhibitor II, and was followed by media comprising CHIR99021, FGF8, IGF1, and DAPT.
However, Semeckhkin teaches a method for derivation of neural crest from pluripotent stem cells comprising contacting cells with a GSK-3 inhibitors (which can be CHIR99021) and an ALK5 receptor inhibitor (which can be RepSox, Alk5 inhibitor II, specifically [0062])). Semeckhkin also teaches that the cells can be contacted for 1-10 days (claim 9) which overlaps with the range of 3 days. A person of ordinary skill in the arts would have been motivated to also include Alk5 Inhibitor II because Semeckhkin also teaches that the method robustly induces generation of neural crest cells (paragraph [0007]) which can be used to study defects in neural crest (paragraph [0006]). Furthermore, because Semeckhkin teaches that Alk5 Inhibitor II can be used in combination with CHIR99021, and because Semeckhkin and Schoeler are in the same technical field of deriving neural crest cells, it could have been done with predictable results and a reasonable expectation of success.
Semeckhkin teaches that neural crest cells can either be maintained and subsequently differentiated (claims 22-23, paragraph [0062])). While this media could comprise CHIR99021, Semeckhkin does not explicitly teach that this media also comprised FGF8, IGF1, and DAPT. However, a person of ordinary skill in the arts would have been motivated to add FGF8 and DAPT because Noisa teaches that the combination of FGF8 and DAPT promoted the induction of migratory neural crest cells which were capable of migrating, and that this behavior was not observed if either reagent was used alone (Notch signaling modulates the fate of pNCCs, p2087-2088; Fig. 5, p2089). Furthermore, they would have been motivated to add IGF1 because Morrison teaches that IGF1 promotes survival of neural crest progenitors without influencing their differentiation (paragraph [0104]). Moreover, because Noisa teaches methods for treating neural crest cells with FGF8 and DAPT (Notch signaling modulates the fate of pNCCs, p2087-2088; Fig. 5, p2089), Morrison teaches methods for contacting neural crest cells with IGF1 (paragraph [0104]), and Semeckhkin, Noisa, and Morrison are all in the same field of deriving neural crest cells, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Schoeler, Ladran, Liu, Inman, Zhang, Cairns, Semeckhkin, Noisa, and Morrison renders the invention unpatentable as claimed.
Claims 16-17 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023), Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), Zhang et al. (Cell Stem Cell, 2016), and Cairns et al. (Stem Cell Reports, 2016), as applied to claims 1, 3, and 23-24 above, and further in view of Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023) and Nikopoulos et al. (Stem Cells, 2007, previously cited 11/16/2023).
In regards to claims 16 and 31, the method of Schoeler, as modified by Semeckhkin does not explicitly teach that induced neural border stem cells were cultured in the presence of proliferating-supporting cytokines DLL4 and JAGGED-1. However, Noisa teaches that neural crest cells are specified at the border between the neural plate and ectoderm, and that Notch activity is required for the maintenance of a pre-migratory neural crest state (Abstract, p2083), with Jagged-1 and Delta-4 (DLL4) being canonical Notch ligands (Introduction, p2083). Moreover, Nikopoulos teaches that soluble Jagged-1 allows for clonal expression of neural crest stem cells (Abstract, p3134). Therefore, a person of ordinary skill in the art would have been motivated to include JAGGED-1 and DLL4 because, as taught by Noisa, it would promote Notch activity which is required for maintenance of a pre-migratory neural crest state. Furthermore, because it is known in the art that soluble JAGGED-1, at least can allow for clonal expression of neural crest stem cells, it could have been done with predictable results and a reasonable expectation of success.
In regards to claims 17 and 32, as above, Schoeler teaches that cells may be further cultured in the presence of conditions (factors) which allow for differentiation (paragraph [0117]; specific example, paragraph [0301]).
Therefore, the combined teachings of Schoeler, Schoeler, Ladran, Liu, Inman, Zhang, Cairns, Noisa, and Nikopoulos renders the invention unpatentable as claimed.
Claims 18-19 and 33-34 are rejected under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023), Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), Zhang et al. (Cell Stem Cell, 2016), Cairns et al. (Stem Cell Reports, 2016), Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023), and Nikopoulos et al. (Stem Cells, 2007, previously cited 11/16/2023) as applied to claims 1, 3, and 16-17 above, and further in view of Oshima et al. (BMC Developmental Biology, 2007, previously cited 11/16/2023).
In regards to claims 18-19 and 33-34, as discussed above, Schoeler teaches that neural border plate stem cells can be expanded and passaged (paragraph [0110-0111]), and adopt a table identity of regionally specified neural progenitors (thus “CNS progenitors”) after four passages (paragraph [0256]; Fig. 5). Schoeler teaches that the expansion medium comprises an activator of WNT signaling (such as CHIR99021), and an activator of Hedgehog signaling (such as purmorphamine) (Claim 1). Schoeler also teaches that the neural border plate stem cells can be cultured in a neural medium comprising an activator of FGF (paragraph [0236]), which can be FGF2 (paragraph [0189]), which is the same as bFGF (paragraph (0045]). Schoeler also teaches that neural border plate stem cells can be differentiated to dopaminergic neurons, which would require passage through a neural progenitor, in the presence of an activator of an activator of activin/TGF-β (such as SB431542) (paragraph [0204]).
Schoeler does not explicitly teach that the medium could also comprise LIF. However, as above, a person of ordinary skill in the arts would have been motivated to add LIF because, as taught by Oshima, addition of LIF maintains pools of neural progenitors and is a powerful took to control neural differentiation (Abstract, p1). Furthermore, because Oshima teaches methods for culturing neural progenitors with LIF and that it increased the number of neural progenitors (Figure 3, p5), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Schoeler, Schoeler, Ladran, Liu, Inman, Zhang, Cairns, Noisa, Nikopoulos, and Oshima renders the invention unpatentable as claimed.
Claims 20-22 and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Schoeler et al. (US20170037367A1, 02/09/2017, previously cited 11/16/2023) in view of Ladran et al. (WIREs System Biology and Medicine, 2013, previously cited 11/16/2023), Inman et al. (Molecular Pharmacology, 2002, previously cited 11/16/2023), Liu et al. (Stem Cells and Development, 2018, previously cited 11/16/2023), Zhang et al. (Cell Stem Cell, 2016), Cairns et al. (Stem Cell Reports, 2016), Noisa et al. (Journal of Cell Science, 2014, previously cited 11/16/2023), and Nikopoulos et al. (Stem Cells, 2007, previously cited 11/16/2023) as applied to claims 1, 3, 16-17, and 31-32 above, and further in view of Semeckhkin et al. (WO2016086052A1, previously cited 11/16/2023) and Morrison et al. (US20040110288A1, 2004, previously cited 11/16/2023).
In regards to claims 20-22 and 35-37, as discussed above, Schoeler teaches that neural plate border cells may be differentiated to neural crest derivatives such as PNS by being cultured with CHIR99021 and BMP4 (paragraph [0279]). Schoeler does not explicitly teach that this media also comprised Alk5 inhibitor II, and was followed by media comprising CHIR99021, FGF8, IGF1, and DAPT.
However, Semeckhkin teaches a method for derivation of neural crest from pluripotent stem cells comprising contacting cells with a GSK-3 inhibitors (which can be CHIR99021) and an ALK5 receptor inhibitor (which can be RepSox, Alk5 inhibitor II, specifically [0062])). Semeckhkin also teaches that the cells can be contacted for 1-10 days (claim 9) which overlaps with the range of 3 days. A person of ordinary skill in the arts would have been motivated to also include Alk5 Inhibitor II because Semeckhkin also teaches that the method robustly induces generation of neural crest cells (paragraph [0007]) which can be used to study defects in neural crest (paragraph [0006]). Furthermore, because Semeckhkin teaches that Alk5 Inhibitor II can be used in combination with CHIR99021, and because Semeckhkin and Schoeler are in the same technical field of deriving neural crest cells, it could have been done with predictable results and a reasonable expectation of success.
Semeckhkin teaches that neural crest cells can either be maintained and subsequently differentiated (claims 22-23, paragraph [0062])). While this media could comprise CHIR99021, Semeckhkin does not explicitly teach that this media also comprised FGF8, IGF1, and DAPT. However, a person of ordinary skill in the arts would have been motivated to add FGF8 and DAPT because Noisa teaches that the combination of FGF8 and DAPT promoted the induction of migratory neural crest cells which were capable of migrating, and that this behavior was not observed if either reagent was used alone (Notch signaling modulates the fate of pNCCs, p2087-2088; Fig. 5, p2089). Furthermore, they would have been motivated to add IGF1 because Morrison teaches that IGF1 promotes survival of neural crest progenitors without influencing their differentiation (paragraph [0104]). Moreover, because Noisa teaches methods for treating neural crest cells with FGF8 and DAPT (Notch signaling modulates the fate of pNCCs, p2087-2088; Fig. 5, p2089), Morrison teaches methods for contacting neural crest cells with IGF1 (paragraph [0104]), and Semeckhkin, Noisa, and Morrison are all in the same field of deriving neural crest cells, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Schoeler, Schoeler, Ladran, Liu, Inman, Zhang, Cairns, Noisa, Nikopoulos, Semeckhkin, and Morrison renders the invention unpatentable as claimed.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
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