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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/05/2026 has been entered.
Status of the Claims
Claims 1-2, 4-16, 18-19, 21-23, and 25 are currently pending.
Claim 18 has been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claim 3, 17, 20, and 24 remain cancelled.
Claims 1-2, 4-16, 19, 21-23, and 25 have been considered on the merits.
Maintained 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.
Claims 1-2, 4-16, 19, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Ashton et al (US20190024046A1) (reference of record), in view of Smirnov et al (Biomaterials, 2014).
With regards to claims 1 and 19, Ashton teaches a method of producing a biomimetic neuroepithelial tissue having a singular rosette structure as required by claim 19 ([0006]). The method is taught to comprise the steps as follows:
Step a comprises seeding the hPSCs with rho kinase inhibitor on a micropatterned substrate that instructs biomimetic neural morphogenesis of the cells as required by claims 1 and 19; ([0006]);
Step b comprises culturing the cells for 1-2 days using a pluripotency maintenance medium which contains a rho kinase inhibitor as required by claims 1 and 19 ([0006]);
Step c comprises a second culture period of 3-6 days under adherent culture conditions in neural differentiation medium as required by claims 1 and 19 ([0006]).
Ashton also teaches wherein the micropatterned substrate is two circular bounded regions, which can have a diameter of 150-800 um as required by claims 1 and 2 ([0008]). Ashton also teaches that the tissue with the desired rosette structure is obtained and comprises polarized neuroepithelial cells and has a microscale cellular organization similar to that of a traverse section of in vivo developing human neural tube as required by claims 17, 20, and 24 ([0006]). Ashton teaches that the hPSCs are seeded at a density of 75 x 103 to 2.5 x 105 cells/cm2 as required by claim 4 ([0007]). The pluripotency medium is taught to contain DMEM/F-12, ascorbic acid, sodium bicarbonate, selenium, insulin, transferrin, FGF2 and TGFB1 as required by claim 5 ([0007]). Ashton also teaches that the pluripotency medium is E8 medium as required by claim 6 ([0054]). The neural differentiation medium is taught to contain DMEM/F-12, ascorbic acid, sodium bicarbonate, selenium, insulin, and transferrin as required by claim 7 ([0007]). The neural differentiation medium is taught to be E6 medium as required by claim 8 ([0054]). Further, the neural differentiation medium contains FGF with or without a beta-catenin activator, which could be FGF2, FGF8a, FGF8b, FGF8f, FGF17 or FGF18 as required by claims 5, 9 and 10 ([0054]). The beta-catenin activator is a GSK3 kinase activator, more specifically CHIR99021 as required by claims 11 and 12 ([0054]). The method also comprises transiently exposing cells on the micropatterned substrate to an activator of wnt/ beta-catenin for about 24-72 hours after plating as required by claim 13 ([0006]). The method further comprises exposing the seeded cells to RA and SHH or an SHH agonist for about 1-5 days, where the rosette structure comprises oligo2+ motor neuron progenitors as required by claim 14 ([0006]). The cells are exposed to RA/SHH/SHH agonist for about 24-72 hours as required by claim 22 ([0006]). The micropatterned substrate comprises a singular or plurality of PEG brushes of peptide-immobilizing PEG brushes arranged in a user defined, bounded geometry as required by claim 15 ([0008]). The method further comprises overlaying the neuroepithelial tissue obtained in step c with a hydrogel layer and culturing the neuroepithelial tissue comprising the hydrogel layer, taught to be Matrigel, where the tissue morphs into a bioengineered neuroepithelial tube and becomes encased in the hydrogel layer as required by claim 16 and 19 ([0131]). The neuroepithelial tissue and the hydrogel layer is cultured for about 24 hours and then removed as required by claim 19 and 23 ([0143]).
Ashton does not teach that the micropatterned substrate comprises at least two circular regions bound through a connection by a cell-adhesive bridge having a length between 25-125 um and a width of about 10-100 um as required by claim 1, 19, and 21.
However, Ashton does describe a micropatterned substrate that comprises regions that promote adherence of cells cultured there on as required by claims 1 and 21 ([0062]). Ashton further teaches that the “bounded geometric shape can be any two-dimensional (2-D) shape (e.g., regular or irregular) having dimensions defined by the shape (e.g., pre-defined diameter, length, width etc.) (e.g., diameter, width, length and the like). In some embodiments, the bounded geometric shapes are circle, triangles, squares, rectangles, or ovals of varying dimensions (e.g., 36 μm, 100 μm, 490 μm, 4.8 mm, and 12.6 mm in diameter; typically about 200-800 μm).” ([0062]). Further, Ashton teaches that both the length and width of the entire shape is between 100-800 um ([0062]).
Additionally, Smirnov teaches the effects of confinement to particular micropatterned substrates on neuron growth cone morphology (abstract). Smirnov teaches a series of bounded/interconnected circular/elliptical geometries which are connected through a channel (i.e. bridge) (Fig. 1). Smirnov teaches that the channel/bridge width range from 1.5 to 12 um as required by claim 1 (pg. 6753, para 2). Smirnov teaches that the channel/bridge width of 12 um resulted in a higher growth cone velocity (Fig, 3). Further, Smirnov teaches that the length of the bridge is at least higher than 25 um as required by claim 1 (Fig. 3a).
Regarding the length of the channel, Smirnov teaches that the length of the bridge is at least longer than 25 um and Ashton teaches that both the length and width of the entire shape is between 100-800 um ([0062]). Additionally, Ashton teaches that the “bounded geometric shape can be any two-dimensional (2-D) shape (e.g., regular or irregular) having dimensions defined by the shape (e.g., pre-defined diameter, length, width etc.) (e.g., diameter, width, length and the like). In some embodiments, the bounded geometric shapes are circle, triangles, squares, rectangles, or ovals of varying dimensions (e.g., 36 μm, 100 μm, 490 μm, 4.8 mm, and 12.6 mm in diameter; typically about 200-800 μm).” ([0062]). Therefore, based on both Ashton and Smirnov a person of ordinary skill in the art would easily arrive at a channel length between 25 and 125 um.
One of ordinary skill in the art would find it obvious before the effective filling date of the instant invention to combine the biomimetic neuroepithelial tissue having a singular rosette structure on a micropatterned substrate as taught by Ashton with the micropatterned substrate containing a connecting bridge taught by Smirnov to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Smirnov teaches that the channel/bridge width of 12 um resulted in a higher growth cone velocity (i.e. faster neurite outgrowth) (Fig. 3). One of ordinary skill in the art would have a reasonable expectation of success when combining Ashton with Smirnov because Ashton teaches all aspects of the growth of the biomimetic neuroepithelial tissue on micropatterned substrate and Smirnov teaches that including a channel/bridge as part of the micropatterned substrate increased speed of neurite growth cone outgrowth (Fig. 3).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Ashton et al (US20190024046A1), in view of Smirnov et al (Biomaterials, 2014) (references of record), as applied to claims 1-2, 4-16, 19, and 21-23 above, and in further view of Mahoney (Biomaterials, 2003).
With regards to claim 25, Ashton and Smirnov teach the limitations of the independent claim 1 above.
Ashton and Smirnov do not teach that the cell-adhesive bridge has a width of about 25 𝜇m.
However, as stated above, Smirnov teaches that the channel/bridge width range from 1.5 to 12 um as required by claim 1 (pg. 6753, para 2). Smirnov teaches that the channel/bridge width of 12 um resulted in a higher growth cone velocity (Fig, 3).
Additionally, Mahoney teaches about the influence of microchannels on neurite growth and architecture. Mahoney discloses the use of microchannels which are 20-60 𝜇m, more specifically Mahoney discloses that “[m]icrochannels 20-30 𝜇m wide maybe most useful in directing growth of unipolar and bipolar neurons… wider microchannels may be useful for directing the growth of cells that extend multiple dendrites…[and that their] data suggest that materials with different microstructural features might be useful in encouraging the development of appropriate neuronal architecture” (pg. 777, col. 2, para 2).
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007)): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A, E, and G are applicable. The claims merely require the combining of known prior art methods of adjusting microchannel width as taught by both Smirnov and Mahoney. Additionally, Mahoney provides a support and motivation for one of ordinary skill in the art to test and refine the microchannel width for the specific desired outcome by stating: “[m]icrochannels 20-30 𝜇m wide maybe most useful in directing growth of unipolar and bipolar neurons… wider microchannels may be useful for directing the growth of cells that extend multiple dendrites…[and that their] data suggest that materials with different microstructural features might be useful in encouraging the development of appropriate neuronal architecture” (pg. 777, col. 2, para 2). The combination of Smirnov and Mahoney would lead to a predictable result absent results to the contrary. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 05/05/2026 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 8, and pg. 11-12) that the cited art, Smirnov is not analogous art because it is not in the same field of endeavor as the present application and because Smirnov is not reasonably pertinent to the problem faced by the inventors.
In response, the argument is not found persuasive. In response to applicant's argument that Smirnov is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
In the case of Smirnov, Smirnov is concerned with the effects of confinement on neuronal growth and velocity. Smirnov examines the growth of neuronal cells on micropatterned surfaces. The instant invention is drawn to a method which includes growth of cells which are differentiated into neurons on micropatterned surfaces. Thus, the argument that Smirnov is a non-analogous art is not found persuasive.
Applicant also states that Smirnov is not reasonably pertinent to the problem faced by the inventors due because Smirnov does not reasonably teach how one could modify an in vitro stem cell culture protocol to provide a result of a 3D neuroepithelial tissue. This is also not found persuasive because Smirnov is not relied upon to teach these limitations, rather Ashton is. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Thus, the argument is not found persuasive.
Applicant argues (Remarks, pg. 8 and pg. 12-13) that Mahoney is not analogous art because it is not in the same field of endeavor as the present application and because Smirnov is not reasonably pertinent to the problem faced by the inventors.
In response, the argument is not found persuasive. In response to applicant's argument that Smirnov is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
In the case of Mahoney, Mahoney is concerned with neural growth and Applicant admits in the remarks at pg. 12 para 3 that Mahoney and Smirnov are in the same field of endeavor. The instant invention is drawn to a method which includes growth of cells which are differentiated into neurons on micropatterned surfaces. Thus, the argument that Mahoney is a non-analogous art is not found persuasive.
Applicant also states that Mahoney is not reasonably pertinent to the problem faced by the inventors due because Mahoney does not reasonably teach how one could modify an in vitro stem cell culture protocol to provide a result of a 3D neuroepithelial tissue. This is also not found persuasive because Mahoney is not relied upon to teach these limitations, rather Ashton is. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Thus, the argument is not found persuasive.
Conclusion
No claims are allowed.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
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