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. Application Status Claims 40-54 from the claim set listed February 27, 2026 are pending. Examiner acknowledges the cancellation of claims 1-39. Claims 50-54 are withdrawn. Examination on the merits commences on claims 40-49. 35 U.S.C. 371 Restriction Restriction is required under 35 U.S.C. 121 and 372. This application contains the following inventions or groups of inventions which are not so linked as to form a single general inventive concept under PCT Rule 13.1. In accordance with 37 CFR 1.499, applicant is required, in reply to this action, to elect a single invention to which the claims must be restricted. Group I, claims 40-49, drawn to a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell (i.e., a method of making a cerebral organoid). Group II, claims 50-54, drawn to a method for producing a high-purity cerebral cortical cell aggregate from a pluripotent stem cell in the absence of a sustentacular cell. (I.e., a method of using the cerebral organoid obtained via the method of claim 40). The groups of invention listed above do not relate to a single general inventive concept under PCT Rule 13.1. REQUIREMENT FOR UNITY OF INVENTION As provided in 37 CFR 1.475(a) , a national stage application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”). Where a group of inventions is claimed in a national stage application, the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. The expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art. The determination whether a group of inventions is so linked as to form a single general inventive concept shall be made without regard to whether the inventions are claimed in separate claims or as alternatives within a single claim. See 37 CFR 1.475(e). When Claims Are Directed to Multiple Categories of Inventions: As provided in 37 CFR 1.475 (b) , a national stage application containing claims to different categories of invention will be considered to have unity of invention if the claims are drawn only to one of the following combinations of categories: (1) A product and a process specially adapted for the manufacture of said product; or (2) A product and a process of use of said product; or (3) A product, a process specially adapted for the manufacture of the said product, and a use of the said product; or (4) A process and an apparatus or means specifically designed for carrying out the said process; or (5) A product, a process specially adapted for the manufacture of the said product, and an apparatus or means specifically designed for carrying out the said process. Otherwise, unity of invention might not be present. See 37 CFR 1.475 (c). The inventions listed as Groups I-II do not relate to a single general inventive concept under PCT Rule 13.1 because they do not relate to one invention only, or to a group of inventions so linked so as to form a single inventive concept: The inventions listed as Groups I-II do not constitute a combination of categories of inventions in accordance with 37 CFR 1.475(b). In the instant application, the claims are drawn to two methods (Groups I and II), a method of making (i.e., a cerebral organoid) (Group I) and a method of using (i.e., using the cerebral organoid) (Group II). The claims are not drawn only to one of the combinations of categories set forth above and therefore lack inventive unity. Groups I-II lack inventive unity as provided under 37 CFR 1.475(a) which states the requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features. Groups I-II share the technical feature of a cerebral organoid from a pluripotent stem cell, which appears to be an unclaimed product. As is discussed below in the 103 rejection of claim 40, Becker teaches a cerebral organoid from a pluripotent stem cell. (Please see the below discussed rejection of claim 40 for more details.) Thus, Becker teaches of the technical feature of the claimed invention. Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17( i ). Election/Restrictions Applicant was contacted via phone on Feb 19, 2026 to discuss an oral election. Subsequently, Applicant filed a preliminary amendment on February 27, 2026. Per Applicant remarks filed concurrently with the updated claim set, Applicant has elected Group I, claims 40-49, drawn to a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Thus, claims 50-54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Examination on the merits commences on claims 40-49. Priority A claim for benefit of a prior-filed application under 35 U.S.C. 119(a)-(f) or under 35 U.S.C. 120, 121, 365(a)-(c), 386 (a) or 386(c) has been made. The effective filing date of the present application is June 17, 2021. Information Disclosure Statement The information disclosure statements (IDS) submitted on 1/29/2024, 5/27/2025, and 9/4/2025 are in compliance with the provisions of 37 CFR 1.97 . Accordingly, the information disclosure statements are being considered by the examiner. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892 or listed on the submitted IDS(s), they have not been considered. Claim Interpretation The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. In regards to the language of claim 40, and specifically to the phrase “substantially free of bFGF ”, said claim language is being interpreted to mean a culture solution that originally contains no bFGF or has not been exogenously supplemented with bFGF , per the instant specification [0081]. This same interpretation is being applied to claim 41 in regards to “substantially free of TGFß signaling inhibitor and a Wnt signaling inhibitor”. I.e., said claim language is being interpreted to mean a culture solution that originally contains no TGFß signaling inhibitor or Wnt signaling inhibitor, or has not been exogenously supplemented with said inhibitors. Claim Rejections - 35 USC § 112(a) 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. Claims 40-49 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention. Dependent claims 41-49 either depend directly from claim 40 or incorporate the method of claim 40. The method of claim 40 is drawn to producing a cerebral organoid from a pluripotent stem cell comprising the steps of (1) an adhesion/maintenance culture step (i.e., a culturing step) for induced pluripotent stem cells and (2) a suspension culturing step in which the cells cultured in step (1) are induced to differentiate into neural cells (i.e., a differentiation culture step). Further, step (1) is required to be substantially free of bFGF and comprise a TGFß signal inhibitor. Per the instant specification [0081], “substantially free of bFGF ” is a culture solution that originally contains no bFGF or has not been exogenously supplemented with bFGF . To satisfy the written description aspect of 35 U.S.C. 112, first paragraph, Applicants must show that they are in possession of the invention being claimed. Possession of an invention may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings, structural or chemical formulas or sequences that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Elecs., Inc. , 525 U.S. 55, 68, 119 S.Ct . 304, 312, 48 USPQ2d 1641, 1647 (1998). The application is considered to lack written description for the full genus of a method for producing a cerebral organoid from a pluripotent stem cell comprising the steps required by claim 40. Per the instant specification, (p114, [0320]) steps (1) and (2) of claim 40 were performed according to a scheme illustrated in Figure 3 or Figure 5. As stated in the specification, maintenance culture (i.e., step (1)) of human iPS cells was performed in StemFit culture medium [0320]. Examiner respectfully notes Figures 3 and 5 as well as the specification ([0320] -[ 0321]) are unclear as to exactly what is being utilized as the maintenance culture medium of step (1). Per [0321] of the instant specification, the culture medium was exchanged with: (a) a culture medium obtained by adding 5 µM SB431542 (i.e., a TGFß inhibitor) to StemFit culture medium without solution C (i.e., a bFGF -free culture medium) (Figure 3) or (b) Essential 6 culture medium (i.e., a bFGF -free, TGFß free culture medium) (Figure 5), and adhesion culture (i.e., step 1) was performed for 1 day. Examiner respectfully notes when looking at Figure 3, it appears StemFit medium (not noted as being without Solution C and thus comprising bFGF ) plus a coating agent (laminin 511E8, i.e., noted in Fig 5 as LM511-E8) were not exchanged with StemFit without solution C and SB431542 (i.e., a TGFß inhibitor). Rather, it appears when looking at Figure 3, that the initial StemFit medium (i.e., comprising bFGF ) and LM511-E8 were then supplemented with StemFit without solution C and SB431542. Thus, Examiner believes Figure 3 indicates the iPSC maintenance culture is not “substantially free of bFGF ” due to the initial culture medium of StemFit comprising bFGF . Thus, in regards to the culture medium of step (1) being “substantially free of bFGF ”, the specification does not provide adequate written description. In regards to a TGFß inhibitor, the specification does not support the method wherein any amount of a TGFß signal inhibitor is provided, e.g., 0.00001 uM , for the maintenance culture. Claim 1 is broad in scope in that the claim language, as currently written, indicates any amount of TGFß inhibitor is sufficient for the maintenance culture. The specification however indicates 5µM of TGFß inhibitor was added to the culture medium. Examiner respectfully notes when looking at Figure 5, it appears to agree with the specification [0321], in that Figure 5 shows StemFit (i.e., with solution C, i.e., with bFGF ) being exchanged with either: (a) a culture medium obtained by adding 5 µM SB431542 (i.e., a TGFß inhibitor) to StemFit culture medium without solution C (i.e., a bFGF -free culture medium) (Figure 3) or (b) Essential 6 culture medium (i.e., a bFGF -free, TGFß free culture medium) (Figure 5), and adhesion culture (i.e., step 1) was performed for 1 day. Thus, when looking at the limitations required by claim 1 and comparing said limitations to Figure 5, it is unclear if a TGFß signal inhibitor is required or if it is sufficient for the medium to be a TGFß free culture medium (i.e., such as E6). Thus, in regards to the culture medium of step (1) comprising a TGFß signal inhibitor, the specification does not support the method wherein any amount of a TGFß signal inhibitor is provided, e.g., 0.00001 uM . Additionally, Examiner respectfully notes that the specification at Figure 3 supports that a Rock inhibitor (i.e., Y-27632) was initially added to the maintenance culture medium, however step 1 of claim 40 does not recite the required reagent for producing a cerebral organoid. In regards to step (2) of claim 40, i.e., a suspension culture for differentiation of iPSCs, the specification [0322] teaches step 2 is broken into two parts, i.e., step 2(a) and step 2(b). Examiner notes dependent claim 41 addresses 2(a) and 2(b) but respectfully notes independent claim 40 does not require steps 2(a) and 2(b). The specification teaches [0322] step 2(a) was performed via the iPS cells cultured in step (1) being dispersed into single cells by enzymatic treatment. Further, said single cells were seeded and subjected to suspension in Glasgow MEM, i.e., GMEM supplemented with 5µM SB431542 (i.e., TGFß inhibitor) and 3µM IWR1e (i.e., Wnt signaling inhibitor). Further, Y-27632 (i.e., Rock inhibitor) was added to reach 50µM on day 0, and not added in subsequent culture exchanges. Examiner notes Figure 3 teaches of the medium comprising KSR and suspension culture rather than GMEM/KSR as indicated in Figure 5. Thus, it is unclear whether either medium will suffice or if the medium of Fig 5 is preferential to the medium of Fig 3 or vice versa. The specification teaches [0323] step 2(b), i.e., day 18, was performed via the cell aggregates being obtained (i.e., at the end of step 2(a)) and transferred to a 90mm dish and being subjected to shaking culture in DMEM/F12/ GlutaMAX culture medium supplemented with N2. Examiner notes Figure 3 does not indicate DMEM/F12 was the culture medium, making it unclear as to what the required medium need be. Further, Examiner respectfully notes, as taught in [0323] that the culture medium was supplemented with N2, i.e., an additive used to support growth, survival and differentiation of neurons. Thus, Examiner respectfully notes it appears that step (2) requires specific amounts of TGFß inhibitor, WNT inhibitor and Rock Inhibitor in order to obtain cell aggregates and further requires a specific amount of N2 additive, in order to obtain a cerebral organoid. However, the claim language of claim 40, as currently written, does not require a TGFß inhibitor, WNT inhibitor, Rock Inhibitor and N2 additive. Therefore, the specification does not comprise written description for the full scope of a method for producing a cerebral organoid from a pluripotent stem cell comprising the steps required by claim 40. Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph. 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. Claims 40, 44-46, and 48-49 are rejected under 35 U.S.C. 103 as being unpatentable over Becker (CA3129656A1, published 8/20/2020; PTO 892) in view of Lee (Lee, et al., (2017) Journal of Biomedical Science 24:59; PTO 892). Claim 40 of the instant application requires : A method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell comprising: a step of culturing in an adhesion culture the pluripotent stem cell in a culture solution, wherein the culture solution is substantially free of (i.e., is not exogenously supplemented with) bFGF (i.e., FGF2) and comprises a TGFß inhibitor; and a step of subjecting the cell obtained in step (1) to suspension culture to obtain a cerebral organoid in a culture solution wherein the cell obtained in step (1) differentiate into a neural cell. Becker teaches in Example 1 of the generation of PSC derived cerebral organoids (p30). In regards to step (1), Becker teaches for the generation of human brain organoids, human pluripotent stem cells were dissociated into single cells using standard procedures. Cells were seeded into 96 well plates in standard stem cell medium lacking typical cytokines such as activin A, bFGF or TGFß . This reads on being substantially bFGF free as no exogenous bFGF was added to the solution. Within 24 hours cells clustered and the formation of round dense structures was observed (p30, lines 5-11). Becker denotes this step as “M1” and teaches M1 is the precursor step to induction of differentiation, i.e., neural induction, i.e., step “M2” (p30, lines 11-13) (Fig 1). Fig 1, Becker In regards to step (2), Becker teaches roughly 24 hours after seeding, the medium was replaced with neural induction media, i.e., step “M2” (Fig1; p30 lines 11-13). As can be seen in Fig 1, a 96 well plate, noted as being ultra-low attachment, was used for the cell suspension. Becker teaches media exchanges were done every other day until day five. On day 5, early neural tissues were transferred to 24 well plates and medium 3 was added, i.e., step “M3” (p30, lines 13-16). On day 15, the developing neural tissue was transferred to 10 cm dishes which were placed onto a shaker. Depending on the desired developmental stage, the organoids could be cultivated >100 days. From day 15, the cerebral organoids were cultured in cerebral organoid differentiation medium (p30, lines 16-20). Thus, Becker teaches a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell comprising a step of culturing the pluripotent stem cell in a culture solution that is substantially free of bFGF and of subjecting the cell obtained in step (1) to suspension culture to obtain a cerebral organoid wherein the cell obtained in step (1) differentiates into a neural cell. Becker differs from the instant application in that Becker does not teach of an adhesion culture for step (1) and rather than teach the use of a TGFß inhibitor, Becker teaches the culture medium of step (1) is TGFß free. In regards to “a step of culturing in an adhesion culture”, Examiner respectfully notes the specification teaches step 1 may be performed as either a suspension culture or an adhesion culture [0096]. Thus, the instant application teaches either type of culturing is suitable for step (1). Examiner thus respectfully notes the type of culturing, i.e., suspension versus adhesion, is only the routine optimization of culture conditions. Said optimization would have been obvious and well within the purview of the ordinarily skilled artisan at the time of filing. Absent any teaching of criticality or unexpected results by the Applicant, it would be obvious that one of ordinary skill in the art would recognize that culturing as a suspension culture or as an adhesion culture is a result effective variable and Examiner notes that the optimization of culturing as either a suspension or as an adhesion would have been prima facie obvious to one of ordinary skill in the art at the time of filing. Generally, differences in parameters will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such parameter is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller , 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05). In regards to the limitation “comprises a TGFß inhibitor”, as discussed supra , Becker teaches the culture solution of claim 1 is TGFß free. As a POSITA will appreciate, and as is well known in the art and taught by Lee, a TGFß inhibitor (SB431542) is often used to promote a more protracted cortical development in regards to pluripotent stem cell derived brain organoids (p2, 2 nd column, hPSC -derived 3D brain organoids). Thus, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Becker and Lee in order to ensure, via the addition of a TGFß inhibitor (SB431542) as taught by Lee, the culture solution of step (1) was the most beneficial culture solution for cortical, i.e., cerebral, development. A POSITA would have been so motivated and had a reasonable expectation of success due to both Becker and Lee teaching of pluripotent stem cell derived brain organoids and Becker teaching the culture solution of step (1) is TGFß free. Thus, the claim is obvious and is properly rejected. In regards to claims 44 and 45 , Becker and Lee teach the method of claim 40. Further, Becker teaches in Example 1 of the generation of PSC derived cerebral organoids (p30). In regards to step (1), Becker teaches for the generation of human brain organoids, human pluripotent stem cells were dissociated into single cells using standard procedures. Cells were seeded into 96 well plates in standard stem cell medium lacking typical cytokines such as activin A, bFGF or TGFß . This reads on being substantially bFGF free as no exogenous bFGF was added to the solution. Within 24 hours cells clustered and the formation of round dense structures was observed (p30, lines 5-11). Becker denotes this step as “M1” and teaches M1 is the precursor step to induction of differentiation, i.e., neural induction, i.e., step “M2” (p30, lines 11-13) (Fig 1). Thus, Becker teaches a culture period for step (1) of 24 hours. Thus, Becker teaches wherein the culture period in step (1) is less than 3 days (i.e., claim 44) and further teaches wherein the culture period in step (1) is 12 hours or more and 2 days or less (i.e., claim 45). Thus, the claims are obvious and is properly rejected. In regards to claim 46 , Becker and Lee teach the method of claim 40. Further, Lee teaches the TGFß inhibitor (SB431542) (p2, 2 nd column, hPSC -derived 3D brain organoids). Thus, the claim is obvious and is properly rejected. In regards to claim 48 , Becker and Lee teach the method of claim 40. Further Becker teaches of the generation of human brain organoids from human pluripotent stem cells (Example 1, p30, lines 5-11) and further teaches inducing said pluripotent stem cell (p39, lines 25-28). Thus, Becker teaches wherein the pluripotent stem cells is a human induced pluripotent stem cell. Thus, the claim is obvious and is properly rejected. In regards to claim 49 , Becker and Lee teach the method of claim 40. Further Becker teaches of screening a plurality of cell aggregates obtained from step (2) for a cerebral organoid on the basis of shape, size and internal structure (Fig 2; Example 1 p30 lines 21-34). Thus, the claim is obvious and is properly rejected. Claims 41-43 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Becker in view of Lee and further in view of Kanemura (JP2021000024A, published 1/7/2021; PTO 892). Claim 41 of the instant application requires step (2) to consist of 2 parts, i.e., step (2a) and step (2b). Step (2a) requires a step of subjecting the cell obtained in step (1) to suspension culture in a culture solution containing a TGFß inhibitor and a Wnt signaling inhibitor to obtain a cell aggregate and step (2b) requires a step of subjecting the cell aggregate obtained in step (2a) to suspension culture in a culture solution substantially free of a TGFß signaling inhibitor and a Wnt signaling inhibitor to obtain a cerebral organoid. Becker and Lee teach the method according to claim 40. In regards to step (2a) , Becker teaches of step “M2” in which the culture medium from step “M1” (i.e., the culture medium of step 1 of claim 40) is replaced with a neural induction media (p30, lines 10-13). Becker teaches the neural induction medium induces the multicellular aggregation from human pluripotent stem cells to differentiate to artificial neural tissue (p11, lines 11-15) and further teaches said neural induction medium (also known as medium b (p11, line 16), or medium 2 (Fig 1)) comprises a TGFß inhibitor (p11, lines 16-20). Becker does not teach of a Wnt signaling inhibitor. In regards to step (2b), Becker teaches subjecting the differentiated multicellular aggregation obtained via step “M2” (i.e., step (2a) of the instant application) to a suspension in a differentiation medium (p10, lines 15-25) (i.e., mediums 3 and 4; Fig 1). Becker does not per se teach the differentiation medium is free of a TGFß signaling inhibitor. Rather, Becker provides the addition of a TGFß signaling inhibitor to be an option. Becker does teach the differentiation medium comprises a Wnt signaling activator, thus reading on the solution is substantially free of a Wnt signaling inhibitor as no exogenous Wnt signaling inhibitor is added to the solution (p35, claim 7). Thus, Becker and Lee teach of step (2a) minus the addition of a Wnt signaling inhibitor and teach of step (2b) in regards to being substantially free of a Wnt signaling inhibitor. Kanemura teaches of the production of neuronal precursor cells of the forebrain type from pluripotent stem cells (Abstract). Kanemura teaches of the X and XH Method (p4, point (1) Induction of differentiation according to X and XH Method) which teaches: Semi-confluent iPS cells were dissociated into single cells To the dissociated cells, 3 inhibitors were added: SB431542 (i.e., a TGFß inhibitor), LDN193189 (i.e., a BMP inhibitor) and XAV939 (i.e., a Wnt inhibitor) and the cells were suspended in a human pluripotent stem cell medium (i.e., nerve differentiation induction medium) without growth factor FGF2 (i.e., bFGF ) added and with a ROCK inhibitor, cells were plated in a 96 well plate with an ultra-low adhesive surface treatment (i.e., a suspension culture) Embryoid bodies (i.e., cell aggregates) were formed via standing (i.e., static culture) in an incubator at 37 degrees Embryoid bodies were collected on day 10, and a suspension culture was performed in a flask or dish in DMEM/F12 medium (i.e., neural progenitor cell medium) in an incubator (i.e., static culture) (Examiner notes this reads on the suspension culture medium being “substantially free of a TGFß inhibitor and a Wnt signaling inhibitor as said culture was not exogenously supplemented with either.) Step 4 culture was continued for at the minimum 11 days more Kanemura teaches the above method, i.e., the X and XH method, teaches neural progenitor cells induced to differentiate from iPS cells (p5, point (6)). Further, Kanemura teaches the neural progenitor cells differentiated into glial cells (p5, point (8)). Thus, Kanemura teaches a method for producing a neural cell from a pluripotent stem cell. Further, Kanemura teaches a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell. Kanemura teaches pluripotent stem cells induced to differentiate into embryoid bodies that subsequently generate into neural progenitor cells and glial cells. Thus, the method of Kanemura teaches the foundational basis for creating cerebral organoids, i.e., the method of Kanemura replicates human brain development via generating organized neural structures to include glial cells. Thus, Examiner respectfully notes, step (2) of Kanemura is most similar to step “M2” of Becker. Becker teaches the M2 culture solution comprises a TGFß signaling inhibitor (p11, lines 15-20) and Kanemura teaches the step (2) culture solution comprises both SB431542 (i.e., a TGFß inhibitor) and XAV939 (i.e., a Wnt inhibitor) (p4, point (1) Induction of differentiation according to X and XH Method). Further. Examiner respectfully notes the M3 and M4 differentiation mediums of Becker are most similar to step (4) of Kanemura and thus do not comprise a Wnt signaling inhibitor (p35, claim 7). Kanemura teaches the step (4) culture solution is DMEM/F12 and thus this reads on the suspension culture medium being “substantially free of a TGFß inhibitor and a Wnt signaling inhibitor as said culture was not exogenously supplemented with either (p4, point (1) Induction of differentiation according to X and XH Method). Therefore, it would have been obvious to a POSITA, before the effective filing date of the claimed invention, to combine the teachings of Becker/Lee and Kanemura . A POSITA would have been so motivated and would have had a reasonable expectation of success in combining said teachings due to both Kanemura and Becker/Lee teaching of the development of neural cells from pluripotent stem cells. A POSITA would have been motivated to add a Wnt signaling inhibitor to the M2 solution of Becker, thus ending with a solution comprising both a TGFß inhibitor and a Wnt signaling inhibitor (i.e., as is required by step (2a)). Further, a POSITA would have been motivated to use the DMEM/F12 neural differentiation medium (i.e., substantially free of a TGFß and a Wnt signaling inhibitor) as the basis of the differentiation medium of M3 and M4 of Becker (i.e., fulfilling the medium requirements of step (2b)). Thus, the claim is obvious and is properly rejected. In regards to claim 42 , the above cited references teach the method according to claim 41. Further, Becker teaches of static culture conditions for steps M1-M3, i.e., encompassing step (2a) of the instant application which coincides with step M2 of Becker (Fig 1). Thus, the claim is obvious and is properly rejected. In regards to claim 43 , the above cited references teach the method according to claim 41. Further, Becker teaches of shaking culture conditions for step M4, i.e., encompassing step (2b) of the instant application (Fig 1). Thus, the claim is obvious and is properly rejected. In regards to claim 47 , the above cited references teach the method according to claim 41. Further, Kanemura teaches serum-free culture solutions in the subculture step and additionally teaches of serum-free culture solutions for the differentiation medium steps (p3, 3 rd to last paragraph; p4 1 st line). Thus, the claim is obvious and is properly rejected. Conclusion No claims are allowable. 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