DETAILED ACTION
Claims 40-59 from the claim set filed 8/10/2026 are pending. Claims 1-39 are cancelled. Claims 50-54 are withdrawn. Thus, claims 40-49 and 55-59 are being examined on the merits herein.
Applicant’s response filed 8/10/2026 has been received and entered into the application file. Applicant’s arguments and amendments to the claims have been fully considered.
Upon further consideration, Examiner has deemed new grounds of rejection are necessitated, which are set forth below. Due to the new grounds of rejection not being solely related to Applicant amendment but rather to further consideration on the Examiner’s part, a second non-final is being sent out to address the new grounds of rejection.
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 .
Objection(s)/Rejection(s) Withdrawn
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.
RE: 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).
Applicant remarks have been found persuasive in regards to the prior art not teaching an adhesion culture. Applicant remarks have additionally been found persuasive in regards to there not being a reasonable expectation of success in combining the prior art. As such, the previously filed rejections are withdrawn.
RE: 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).
For the reasons discussed above, the obviousness rejection over Becker in view of Lee is withdrawn, and thus the obviousness rejections that are based on the same basis are likewise withdrawn.
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.
RE: 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.
After further thought and consideration, Examiner has decided to withdraw the previously filed written description rejection.
Interpretation/Objection(s)/Rejection(s) Maintained
Claim Interpretation
RE: The claims in this application are given their broadest reasonable interpretation using the plainest 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.
Applicant remarks filed 8/10/2026 state “Applicant submits that Applicant does not necessarily concede with the Examiner’s interpretations but nonetheless has amended the claims, rendering the Examiner’s interpretation moot.” Examiner respectfully notes amended claims 40 and 41 still utilize the phrases “substantially free of bFGF” (claim 40) and “substantially free of TGFß signaling inhibitor and a Wnt signaling inhibitor” (claim 41). As such, as Applicant did not argue Examiner’s interpretation, said interpretation stands.
Additionally, Examiner notes Applicant amendment to claim 40 has added the phrase “substantially free of a TGFß signal activator”. Examiner is interpreting said claim language to mean “a culture solution that originally contains no TGFß signal activator or has not been exogenously supplemented with TGFß signal activator.
New Ground(s) of Rejection
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 and 55-59 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 and 55-59 either depend directly from claim 40 or incorporate the method of claim 40.
The method of claim 40 is drawn to a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell, comprising culturing or passaging pluripotent stem cells with a culture medium suitable for expansion culture of pluripotent stem cells followed by; (1) culturing in an adhesion culture pluripotent stem cells obtained from the expansion culture medium, wherein the culture solution is substantially free of bFGF, and (i) comprises a TGFß signal inhibitor in a concentration of 100nM to 1mM or (ii) is substantially free of a TGFß signal activator; and (2) subjecting the cells obtained from step (1) to a suspension culture to obtain a cerebral organoid in a culture solution wherein the cells obtained in step (1) differentiate into a neural cell.
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 limitations required by claim 40.
The application contains written description for the single species of a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell, comprising culturing or passaging pluripotent stem cells with a culture medium suitable for expansion culture of pluripotent stem cells followed by; (1) culturing in a defined adhesion culture (such as is shown in Figure 5) a specific concentration of pluripotent stem cells, wherein the culture solution is substantially free of bFGF, and (i) comprises a TGFß signal inhibitor in a concentration of 100nM to 1mM or (ii) is substantially free of a TGFß signal activator for a specified period of time (such as is shown in Figure 5); and (2) subjecting a specific concentration of cells (such as 9,000 cells per well [0322]) obtained from step (1) to a defined suspension culture (such as is shown in Figure 5) for a specified period of time (such as is shown in Figure 5) to obtain a cerebral organoid in a culture solution wherein the cells obtained in step (1) differentiate into a neural cell.
However, regarding the claimed method of claim 40 as currently written, Applicants have not disclosed a representative number of species within the genus to demonstrate that Applicants were in possession of the full genus of a method of producing a cerebral organoid from a pluripotent stem cell as claimed. The specific reagents, concentrations of said reagents, cell concentrations, and time periods provided in Figure 5 and in the Examples are not representative of the broad genus of the method encompassed by the claims as currently written.
Further, Lancaster 2014 (reference citation provided below in Conclusion) teaches cerebral organoids develop through intrinsic self-organizing processes upon timely application of components and culture environments (p1 last paragraph). Lancaster further teaches of the difficulty in producing a protocol for the generation of cerebral organoids and teaches of testing a multitude of combinations of media formulations and further of testing said combinations of media at various time points. Thus, Lancaster teaches of the need for a precise description of time points, reagents, concentration, etc in order to produce a cerebral organoid from pluripotent stem cells.
As no prior art has been applied due to the lack of a reasonable expectation of success in combining the prior art to produce a cerebral organoid, thus the instant specification and claims must clearly describe the claimed invention.
Accordingly, the claims are considered to lack sufficient written description and are properly rejected under 35 USC 112, first paragraph.
Claim 40-49 and 55-59 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 enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification, while being enabling for the single species of a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell, comprising culturing or passaging pluripotent stem cells with a culture medium suitable for expansion culture of pluripotent stem cells followed by; (1) culturing in a defined adhesion culture (such as is shown in Figure 5) a specific concentration of pluripotent stem cells, wherein the culture solution is substantially free of bFGF, and (i) comprises a TGFß signal inhibitor in a concentration of 100nM to 1mM or (ii) is substantially free of a TGFß signal activator for a specified period of time (such as is shown in Figure 5); and (2) subjecting a specific concentration of cells (such as 9,000 cells per well [0322]) obtained from step (1) to a defined suspension culture (such as is shown in Figure 5) for a specified period of time (such as is shown in Figure 5) to obtain a cerebral organoid in a culture solution wherein the cells obtained in step (1) differentiate into a neural cell, does not reasonably provide enablement for the genus of a method for producing a cerebral organoid from a pluripotent stem cell as is currently claimed in claim 40. Dependent claims 41-49 and 55-59 either depend directly from claim 40 or incorporate the method of claim 40.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” See MPEP § 2164. These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill:
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples;
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Breadth of the claims:
With respect to the breadth of the claims, the claims as currently drafted encompass the genus of a method for producing a cerebral organoid from a pluripotent stem cell in which specific concentrations, reagents used, and time periods are not provided. As such, the breadth of the claims is expansive.
Nature of the invention:
The invention is in the field of cerebral organoid development.
The nature of the invention is in a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fec. Cir. 2001).
The state of the prior art and predictability in the art:
With respect to the state of the prior art, and predictability of the art, at the time of filing the instant invention, methods for developing cerebral organoids from pluripotent stem cells were known. Please see the cited art below in the conclusion section. However, Lancaster 2014 (reference citation provided below in Conclusion) teaches cerebral organoids develop through intrinsic self-organizing processes upon timely application of components and culture environments (p1 last paragraph). Lancaster further teaches of the difficulty in producing a protocol for the generation of cerebral organoids and teaches of testing a multitude of combinations of media formulations and further of testing said combinations of media at various time points.
Thus, Lancaster supports there is reason to conclude that there would be a high degree of unpredictability in a method for producing a cerebral organoid from a pluripotent stem cell as is currently claimed in claim 40.
Guidance of the Specification/Workinq Examples:
Applicants have not provided working examples encompassing the genus of a method for producing a cerebral organoid from a pluripotent stem cell as is currently claimed in claim 40 and as is discussed above. Applicants have provided a working example for a method for producing a cerebral organoid from a pluripotent stem cell as shown in Figure 5. Said Figure provides specific reagents used as well as specific time periods for the steps claimed in claim 40. The specification further provides specific concentrations of cells and reagents used in the Examples starting p103 of the instant specification. Examples include concentration of cells placed in the 96-well plates [0311], concentration of TGFß inhibitor [0311], concentration of Wnt inhibitor [0311], etc.
The absence of working examples directed to the claimed method necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to make and use the claimed genus of a method for producing a cerebral organoid from a pluripotent stem cell.
The Quantitation of Experimentation Required:
Undue experimentation would be required to practice the invention as claimed due to the amount of experimentation necessary because of the expansive breadth of the claims, the state of the prior art and its lack of predictability, and the lack of guidance in the form of working examples in the specification.
MPEP §2164.01(a), provides that “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
After applying the Wands factors and analysis to claims 40-49 and 55-59, in view of the Applicant’s entire disclosure, it is concluded that the practice of the invention as claimed in said claims, would not be enabled by the written disclosure. Therefore, said claims are rejected under 35 U.S.C. §112(a) for failing to disclose sufficient information to enable a person of skill in the art to make the invention commensurate in scope with the claims.
CONCLUSION
PRIOR ART MADE OF RECORD BUT NOT APPLIED
Lancaster et al., Nat Protoc (2014) 9(10): 2329-2340; cited in Applicant remarks filed 8/10/2026)
Becker (CA3129656A1, published 8/20/2020; previously cited in OA filed 3/9/2026)
Johns Hopkins (US 2020/0208090 A1, published July 2, 2020; cited in the Incoming Written Opinion of the International Searching Authority filed 12/13/2023; IDS filed 1/29/2024)
Corning Matrigel (retrieved 9/15/2026 from https://www.corning.com/catalog/cls/documents/faqs/CLS-DL-CC-026.pdf; PTO 892)
Amended claim 40 requires a method for producing a cerebral organoid from a pluripotent stem cell in the absence of a sustentacular cell, comprising:
(a) culturing or passaging pluripotent stem cells with a culture medium suitable for expansion culture of pluripotent stem cell; followed by
step (1) culturing in an adhesion culture the pluripotent stem cell obtained in step (a) in a culture solution, wherein the culture solution is substantially free of bFGF, and (i) comprises a TGFß signal inhibitor in a concentration of 100 nM to 1mM or (ii) is substantially free of a TGFß signal activator; and
step (2) 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) differentiates into a neural cell.
In regards to the prior art, Examiner notes there are MANY different protocols for generating cerebral organoids from pluripotent stem cells with the seminal protocol being taught by Lancaster 2014.
As noted in the Fig 1 legend, Lancaster teaches the generation of embryoid bodies (EBs) is outlined in step 1.
Prior to step 1, Lancaster teaches maintaining (i.e., expanding) hESCs in mTeSR1 medium, i.e., a medium suitable for expansion culture of pluripotent stem cells (p8, Feeder-free hESC). Thus, Lancaster teaches point (a) of claim 40.
Step 1 teaches growing hESC or iPSC colonies in one well of a 6-well plate until 70-80% confluent (p10, Procedure Step 1). Lancaster further teaches dissolving low-growth factor Matrigel in DMEM-F12 to coat an entire 6-well plate. As a POSITA will appreciate, growing iPSC or hESC colonies on a low growth factor Matrigel plate is an adhesion culture system.
Lancaster teaches low-growth factor Matrigel in DMEM-F12 and specifically teaches growth factor reduced Matrigel (formerly known as BD Biosciences now known as Corning, cat. No. 356230) (p6, Reagents). As can be seen in the growth factor concentration chart supplied by Corning, there is an extremely low concentration of bFGF present in said Matrigel (retrieved 9/15/2026 from https://www.corning.com/catalog/cls/documents/faqs/CLS-DL-CC-026.pdf).
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Thus, in regards to step (1), Lancaster teaches culturing in an adhesion culture the pluripotent stem cell obtained in step (a) in a culture solution wherein said culture solution is low bFGF.
Lancaster does not teach “wherein the culture solution is substantially free of bFGF, and (i) comprises a TGFß signal inhibitor in a concentration of 100 nM to 1mM or (ii) is substantially free of a TGFß signal activator”.
Lancaster teaches in step 1(v-vi) of resuspending the cells from step 1(i-iv) in low bFGF hESC media with ROCK inhibitor in a 96-well u-bottom plate (p11, From feeder-independent hESCs point (v)). As seen in Figure 1, the product of the Lancaster protocol is brain tissue, i.e., cerebral organoid, i.e., said cells obtained in step 1 have differentiated into neural cells. Thus, Lancaster teaches 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) differentiates into a neural cell. Thus, Lancaster teaches step 2.
Fig 1 Lancaster 2014
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As noted supra, Lancaster does not teach “wherein the culture solution is substantially free of bFGF, and (i) comprises a TGFß signal inhibitor in a concentration of 100 nM to 1mM or (ii) is substantially free of a TGFß signal activator”. When looking to the prior art, Examiner respectfully notes there are protocols for generating a cerebral organoid teaching the limitations of “wherein the culture solution is substantially free of bFGF”, “comprises a TGFß signal inhibitor in a concentration of 100 nM to 1mM”, and/or “is substantially free of a TGFß signal activator”. Examples include the teachings of Becker (discussed in the previously filed OA) as well as the teachings of John Hopkins.
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 and further reads on the newly added limitation of “substantially free of a TGFß signal activator as Becker teaches the medium is TGFß free and thus no exogenous TGFß signal activator was added. 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
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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 substantially free of a TGFß signal activator 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). Becker differs from Lancaster in that Lancaster does not teach of bFGF free and TGFß free. Thus, Becker and Lancaster differ in the method of culture for step 1 both in the type of culture, i.e., adhesion versus suspension, and in the reagents, i.e., no bFGF and no TGFß. Thus, Examiner believes there would not be a reasonable expectation of success in generating a cerebral organoid via combining Becker and Lancaster.
John Hopkins teaches culturing forebrain organoids, i.e., cerebral organoids from human iPSCs. John Hopkins teaches culturing iPSCs without FGF2, i.e., bFGF, and further teaches the addition of 2microM A83-01 (i.e., a TGFß inhibitor per instant claim 46). However, John Hopkins teaches said culture is a suspension culture performed in an ultra-low attachment 6-well plate [0146]. Thus, Examiner believes there would not be a reasonable expectation of success in generating a cerebral organoid via combining John Hopkins and Lancaster due to differing in the method of culture for step 1 both in the type of culture, i.e., adhesion versus suspension, and in the reagents, i.e., no bFGF and no TGFß.
Examiner has discussed the above supplied art to put on the record that while the art does teach the individual limitations required by claim 40, the art does not teach, with a reasonable expectation of success, of combining the individual limitations required by claim 40 into a method for producing a cerebral organoid, as defined by instant claim 40. Support for this is found in Lancaster 2014. Lancaster teaches cerebral organoids develop through intrinsic self-organizing processes upon timely application of components and culture environments (p1 last paragraph). Lancaster further teaches of the difficulty in producing a protocol for the generation of cerebral organoids and teaches of testing a multitude of combinations of media formulations and further of testing said combinations of media at various time points.
Thus, Lancaster supports Examiner’s belief that the prior art does not provide a reasonable expectation of success in combining the required limitations of claim 40. As such, no prior art has been applied.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE R SMALL whose telephone number is (703)756-4783. The examiner can normally be reached Monday - Friday 8:30am-4pm.
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/KATHERINE R SMALL/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
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