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 .
Election/Restrictions
Applicant’s election without traverse of Group II (claim 20 and newly added dependent claims 41-57) in the reply filed on 4/10/2026 is acknowledged. The examiner acknowledges cancelation of claims 1-14, 18-19, and 38-40.
Claims 20 and 41-57 are pending and have been examined herein.
Priority
The instant claims herein are examined utilizing the accepted effective filing date of 8/12/2020 for the basis of any prior art rejections.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 9/6/2023, 4/4/2024, 11/25/2025, and 4/10/2026 are acknowledged. The IDS has been considered except where noted in the IDS. The struck through documents were not considered because a copy was not provided to the Office.
Claim Objections
Claims 53-54 are objected to because of the following informalities:
Claims 53 and 54 recite “OPC-like,” “AC-like,” “NPC-like,” and “MES-like”. The claims should recite the entire phrase (e.g., astrocyte-like) spelled out followed by abbreviations in parentheses.
Appropriate correction is required.
Claim Interpretation
Claim 20 and its dependents are drawn to “a dorsal forebrain organoid.” According to post-dated Zhang et al (Curr Opin Neurobiol. 2022 Jun;74:102536. Epub 2022 Apr 8), cortical organoids are often termed as dorsal forebrain organoids as the cerebral cortex is a major component of the forebrain (“Forebrain organoids”, para 1). As such, the examiner is interpreting dorsal forebrain organoid and cortical organoid to be the same.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 42, 46, 48, 53-54, and 56 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 42, 46, and 48 recite “wherein the organoid has been cultured for at least . . .”. There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of any culture/culturing step in independent claim 20 (of which these claims ultimately depend from). Thus, the claim is indefinite. Claims 43-44 are included in this rejection for being dependent on indefinite claim 42.
Claims 53 and 54 recite “OPC-like,” “AC-like,” “NPC-like,” and “MES-like”. It is unclear what applicant intends to claim as the specification does not define what it means to be “like” these cells. There are no indications of what characteristics are required for the cells to be like “OPC”, “AC”, “NPC” and/or “MES” cells. Thus, the claims are indefinite.
Claim 56 recites the limitation "the brain organoid". There is insufficient antecedent basis for this limitation in the claim as there is no previous recitation of a “brain organoid” in the claims in which 56 depends on.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 56 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 56 recites “the brain organoid”, which is broader than the dorsal forebrain organoid recited in instant claim 20. Thus, claim 56 fails to further limit, and instead broadens, the scope of the subject matter claimed in independent claim 20. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 20 and 41-56 is/are rejected under 35 U.S.C. 102(a)(2) as anticipated by Muotri et al (WO2019023516A1, 7/26/2018; published 1/31/2019).
Muotri teaches functional cortical organoids, wherein the organoids are cultured with cancer cells to form organoids comprising cancerous tumors (abstract and claim 1 and 10 of Muotri) (“wherein the implantation is performed by seeding the brain with tumor cells on a surface of the brain organoid” as in instant claim 56). Progressive human brain tumor growth can be modeled using integration of cancerous cells with organoid disclosed (para 78 of Muotri) (“method of modeling a brain tumor, the method comprising: implanting brain tumor cells into a dorsal forebrain organoid with a core comprising less than 25% apoptotic or hypoxic cells” as in instant claim 20; “wherein the core comprises less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, or less than 0.1% apoptotic or hypoxic cells” as in instant claim 41; please note that the Muotri reference is silent to the presence of either apoptotic or hypoxic cells in the organoid. Thus, absent evidence to the contrary, the organoid of the Muotri reference does not have any apoptotic or hypoxic cells). The functional cortical organoids comprise a proliferative region that is surrounded by intermediate progenitor cells expressing TBR2+ and deep cortical layer markers TBR1+ and CTIP2+ and wherein cortical plate folding is observed in the cortical organoids (para 8 of Muotri) (“wherein the organoid comprises one or more of . . . intermediate progenitor cells” as in instant claim 43 and instant claim 46; “about 3-6% intermediate progenitor cells” as in instant claim 44 and “about 1-7% intermediate progenitor cells” as in instant claim 47 (see MPEP 214.05 regarding concentrations)). The functional cortical organoids are differentiated for at least 60 days, at least 300 days, and up to 2 years (see claims 6 and 8 of Muotri) (overlaps with “wherein the organoid has been cultured for at least 3 months”, “wherein the organoid has been cultured for at least 6 months”, and “wherein the organoid has been cultured for at least 9 months or at least a year” as in instant claims 42, 45, and 48 respectively). The reference teaches that the cancer cells are from cells from a cancer selected from the group consisting of brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, and visual pathway and hypothalamic glioma and that the cancer cells are glioblastoma cells, glioblastoma multiforme cells (See claims 13-14 of Muotri) (“wherein the brain tumor is a glioma” as in instant claim 49; “wherein the brain tumor cells are glioma cells” as in instant claim 50; “wherein the glioma cells comprise glioblastoma cells” as in instant claim 51). Anti-tumor efficacy of ZIKV was interrogated against a panel of brain tumor cells - two pediatric pontine gliomas (i.e., DIPG cells), four medulloblastomas, an ependymoma, and two meningiomas - grown under serum-free conditions to enrich for stem-like populations (para 141 of Muotri) (“wherein the patient-derived glioma cells comprise . . . diffuse intrinsic pontine glioma cells” as in instant claim 55). The cancerous tumors of the functional cortical organoids are generated from the patient's cancer cells, wherein the patient has a brain cancer (See claims 35-36 of Muotri) (“wherein the glioma cells are patient-derived glioma cells” as in instant claim 52).
Regarding claims 53-54, Muotri does not explicitly teach “wherein the patient-derived glioma cells grow to glioma cells comprising one or more of: OPC-like cells, AC-like cells, NPC-like cells, and MES- like cells” and “wherein the patient-derived glioma cells grow to glioma cells comprising two or more, or three or more of OPC-like cells, AC-like cells, NPC-like cells, and MES-like cells” as recited respectively. However, the claims are an intended result of the instantly claimed active method step. Thus, absent evidence to the contrary, the patient-derived tumor cells of Muotri would grow to these types of glioma cells.
Accordingly, the claimed invention was anticipated by the teachings of Muotri.
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.
Claim(s) 20 and 41-56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Muotri et al (WO2019023516A1, 7/26/2018; published 1/31/2019).
Muotri teaches functional cortical organoids, wherein the organoids are cultured with cancer cells to form organoids comprising cancerous tumors (abstract and claim 1 and 10 of Muotri) (“wherein the implantation is performed by seeding the brain with tumor cells on a surface of the brain organoid” as in instant claim 56). Progressive human brain tumor growth can be modeled using integration of cancerous cells with organoid disclosed (para 78 of Muotri) (“method of modeling a brain tumor, the method comprising: implanting brain tumor cells into a dorsal forebrain organoid with a core comprising less than 25% apoptotic or hypoxic cells” as in instant claim 20; “wherein the core comprises less than 20%, less than 15%, less than 10%, less than 5%, less than 1%, or less than 0.1% apoptotic or hypoxic cells” as in instant claim 41; please note that the Muotri reference is silent to the presence of either apoptotic or hypoxic cells in the organoid. Thus, absent evidence to the contrary, the organoid of the Muotri reference does not have any apoptotic or hypoxic cells). The functional cortical organoids comprise a proliferative region that is surrounded by intermediate progenitor cells expressing TBR2+ and deep cortical layer markers TBR1+ and CTIP2+ and wherein cortical plate folding is observed in the cortical organoids (para 8 of Muotri) (“wherein the organoid comprises one or more of . . . intermediate progenitor cells” as in instant claim 43 and instant claim 46; “about 3-6% intermediate progenitor cells” as in instant claim 44 and “about 1-7% intermediate progenitor cells” as in instant claim 47 (see MPEP 214.05 regarding concentrations)). The functional cortical organoids are differentiated for at least 60 days, at least 300 days, and up to 2 years (see claims 6 and 8 of Muotri) (overlaps with “wherein the organoid has been cultured for at least 3 months”, “wherein the organoid has been cultured for at least 6 months”, and “wherein the organoid has been cultured for at least 9 months or at least a year” as in instant claims 42, 45, and 48 respectively). The reference teaches that the cancer cells are from cells from a cancer selected from the group consisting of brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, and visual pathway and hypothalamic glioma and that the cancer cells are glioblastoma cells, glioblastoma multiforme cells (See claims 13-14 of Muotri) (“wherein the brain tumor is a glioma” as in instant claim 49; “wherein the brain tumor cells are glioma cells” as in instant claim 50; “wherein the glioma cells comprise glioblastoma cells” as in instant claim 51). Anti-tumor efficacy of ZIKV was interrogated against a panel of brain tumor cells - two pediatric pontine gliomas (i.e., DIPG cells), four medulloblastomas, an ependymoma, and two meningiomas - grown under serum-free conditions to enrich for stem-like populations (para 141 of Muotri) (“wherein the patient-derived glioma cells comprise . . . diffuse intrinsic pontine glioma cells” as in instant claim 55). The cancerous tumors of the functional cortical organoids are generated from the patient's cancer cells, wherein the patient has a brain cancer (See claims 35-36 of Muotri) (“wherein the glioma cells are patient-derived glioma cells” as in instant claim 52).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to use the method of Muotri with a reasonable expectation of successfully producing a brain tumor model using a cortical organoid and glioblastoma cells. One of ordinary skill would have been motivated to do so because Muotri teaches that cancerous cells, such as glioma cells, can be seeded into cortical organoids and progressive human brain tumor growth can be modeled with the integration of cancerous cells.
Claim(s) 57 is/are rejected under 35 U.S.C. 103 as being unpatentable over Muotri as applied to claims 20 and 41-56 above, and further in view of Quadrato et al (US20190002835 A1, 12/30/2016; published 1/3/2019).
The teachings of Muotri were recited in the above 35 U.S.C. 102/103 rejection as applied to claim 20 of which claim 57 depend. The teachings will not be repeated here.
The difference between the teachings and the invention as instantly claimed is that it does not teach testing growth rates, transcriptional states, cellular lineages and/or hierarchies, cell morphologies, tumor-organoid microenvironmental interactions, invasive potential of tumor cells, intercellular communication, and/or intercellular connectivity of the tumor cells.
Quadrato teaches brain organoids created from human pluripotent stem cells. The reference teaches that methods for screening of molecular, cellular and network-level defects associated with complex mental diseases through use of patient-derived induced pluripotent stem cells (abstract). The reference further teaches that the brain organoids can be used for to generate cells that can be isolated and printed in any desired conformation and/or combination and that the isolated one or more cell types are used for screening for cell-cell interactions and/or neural network properties (para 155) (“further comprising testing . . . microenvironmental interactions, . . ., intercellular communication” as in instant claim 57).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to implant brain tumor cells into a cortical organoid as taught by Muotri, where the organoid is used to test microenvironment interactions and cellular communication as taught by Quadrato, to arrive at the instantly claimed invention. As Quadrato shows that brain organoids can be used to study both normal brain development and complex human diseases that affect multiple cell types, the interactions between them, and the function of neuronal circuits, one of ordinary skill would have been motivated to modify the method as taught by Muotri to include studying interactions between effected cell types in brain diseases as taught by Quadrato with a reasonable expectation of advantageously modeling complex disease interactions and defects as taught by the prior art.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr can be reached at (571) 272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632
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