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 of the screening methods of Group 2 (claims 16-28) and the particular variant gene that is SUV420H1 in the reply filed on 10/16/205 is acknowledged. In light of the Examiner’s search of the elected gene, the requirement as it was applied between the elected gene SUV420H1 and the gene that is CHD8 is withdrawn.
Applicant’s election of the particular combination of genes that is “SLA, GRIK3, MEF2C, ZEB2, SEMA3A, BCL11iB, CACNA1A, and RAB3A”, relevant to claim 27, in the reply of 05/18/2026 is acknowledged.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement(s), the election has been treated as an election without traverse (MPEP § 818.01(a)).
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825 because it does not contain a "Sequence Listing" as a separate part of the disclosure or a CRF of the “Sequence Listing.”.
Required response - Applicant must provide:
A "Sequence Listing" part of the disclosure; together with
An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(a)(2);
A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.821(a)(4); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(a)(3).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
If the "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, applicant must also provide:
A CRF in accordance with 37 CFR 1.821(e)(1) or 1.821(e)(2) as required by 1.825(a)(5); and
A statement according to item 2) a) or b) above.
II. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (see Figure 29 of the Drawings, and the brief description of Figure 29 on p.28 of the specification as filed) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/108,246, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The claims require subject matter that is not provided in the provisional application (63/108,246) as follows: premature expansion of GABAergic neuron lineage (claim 18); a variant ARID1B gene (claim 20); measuring spontaneous neuronal activity and/or delayed neuronal differentiation (claim 25); measuring expression of the particularly recited genes of claim 27.
The effective filing date of claims 18, 20, 25 and 27 is the filing date of the parent PCT application (PCT/US2021/057632) which is 11/01/2021.
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
Claims 16-28 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 16-28 are unclear over recitation of the limitation “having one or more genetic variations”, as recited in claim 16 from which claims 17-28 depend, because the claims does not set forth any standard for comparison to determine that any genomic content is a variation. Where any cell or organoid may have a genomic material, it is unclear what genomic material (e.g.: gene sequence(s) ) is required or encompassed by a requirement for “genetic variations”. Where there is no standard for comparison it is noted that any genome may be considered a variant when compared to any other different genome.
Claims 16-28 are unclear over recitation of the limitation “asynchronous development of a cortical neuronal lineage”, as recited in claim 16 from which claims 17-28 depend. As used in the claim the term “asynchronous” means that something (in this case the “development of a cortical neural lineage”) does not happen at the same time, but there is no indication in the claims as to what that other time that is intended to be (i.e.: there is to standard or reference for the determination of synchrony or asynchrony). It is unclear if the development is “asynchronous” as compared to some other biological sample (a brain organ in a subject animal), or some other different type of neuronal cell, or a synchronous as compared to the same organoid with the same variant that has no been exposed to a candidate agent.
Claims 21-23 are each unclear over recitation of the phrase “after introduction of the genetic variation”, because there is no antecedent basis for, or inherent requirement, for any “introduction” of a genetic variation.
Claim Rejections - 35 USC § 112 – Failure to Limit
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 24 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 24 recites the limitation “the asynchronous development of a cortical neuronal lineage comprises asynchronous development of a cortical neuronal lineage” which is itself internally redundant (i.e.: it recites “asynchronous development of a cortical neuronal lineage” twice), and furthermore the limitation is already presence in claim 16, form which claim 24 depends, where claim 16 recites “testing effects … on asynchronous development of a cortical neuronal lineage”.
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 § 112 – Written Description
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 19 and 20 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 claim(s) contains 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant rejection of claims is relevant to several aspects of the claims that require “genetic variations” (as recited in claim 16) that “causes haploinsufficiency in a gene” (as recited in claim 19). Initially it is noted that the rejected claims generically encompass any genetic variations. The structures of the claims are broad, and encompass any type of variation (e.g.: and single- or multi-nucleotide insertion, deletion or substitution, or any larger genomic rearrangement, translocations, or structural alteration of chromosomes) in any gene from a genome of any subject organism. This generically broad genetic variation is recited in the claims as causing “haploinsufficiency in a gene”, thus requiring a particular functionality associated with the variations. “Haploinsufficiency” is the related art is typically considered to be a genetic condition where having only one functional copy of a gene is not enough to maintain normal cellular function. However, neither the application as filed nor the related art provide the skilled artisan with the ability to pick form the broadly encompassed structures (i.e.: the breadth is detailed above) those particular variants that will provide the required functionality. For example, the substitution of amino acid residues with conversative substitutions, which may have little or no effect on protein function, is known in the art (e.g.: French et al, 1983). But some “silent” mutations may have effects on encoded protein production function by other unpredictable mechanisms (e.g.: Zimmer (2023)). Thus while the application as filed provide some specific genetic alterations of particular gene in the human genome (e.g.: Fig 29) that are asserted to provide haploinsufficiency of those genes, such a particular disclosure is not a description of any other alteration in any other different genes that demonstrates possession of the broadly claimed invention.
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.
Claim(s) 18, 20, 25, 27 and 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Paulsen et al (November 12, 2020) in view of Qian et al (2019).
The citing of Paulsen et al in the instant rejection of claims is appropriate in light of the effective filing date afforded to the claims (as detailed earlier in this Office Action) and the authors listed on the reference that are not included as inventors of the instant application.
Relevant to the instant rejection of claims, Paulsen et al teaches creating organoids with genetic variations that created haploinsufficiency of SUV420H1 (e.g.: p.23 - CRISPR-mediated gene editing of SUV420H1 and PTEN; p.1 – Abstract) (relevant to claim 20, and using scRNA-seq to detect temporal ordering of cortical neuronal lineages (e.g.: p.10 - Developmental trajectories of SUV420H1, PTEN, and CHD8 mutant organoids show accelerated neurogenesis of specific neuronal subtypes; Supp Fig 6). With regard to the rejection of claims 18 and 25, scRNA-seq provides transcriptome-wide data that can provide a test of GABAergic neuron lineage (claim 18) and, neuronal differentiation (claim 25). With regard to claim 27, Paulsen et al teaches measurement of gene expression using scRNA-seq provides transcriptome-wide data, as specifically includes BCL11B (e.g.: Supp Fig 1) which is recited in claim 27.
Paulsen et al does not exemplify contacting the organoid with a candidate agent, but the use of brain organoids for compound screening was known in the prior art and is taught by Qian et al.
Qian et al teaches that brain organoids can be used for high-throughput compound screening and subsequent validation (e.g.: Fig 4; p.7, left col.; p.9, right col).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have performed a screening of compounds, as taught by Qian et al, using brain organoids with genetic variants, as taught by Paulsen et al. Where Paulsen et al teaches that variants in autism related genes lead to an acceleration of the developmental trajectory of specific classes of human cortical neurons (p.12 – left col), the skilled artisan would be motivated to screen for agents which alleviate this pathological effect, identified by testing temporal ordering of cell type development as suggested by Paulsen et al, in an effort to screen for compounds that may find use in treating the pathology, as suggested by Qian et al.
Claim(s) 16-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Velasco et al (2019) in view of Jian et al (2019) in view of and Qian et al.
Velasco et al teaches the development of brain organoids for use as models of the human brain for experimental investigation of developmental abnormalities associated with human neurological disease. Relevant to the instant rejection of claims, Velasco teaches the determination of cortical neuron development at different times during organoid differentiation, including up to six-months (relevant to step b of claim 16, and claims 21, 22, and 23). Relevant to claims 17, 18 and 24, Velasco et al teaches the detection of cell types using single-cell RNA-sequencing (scRNA-seq) analysis of organoid cells at different durations of culturing, and identification of cells from organoids by comparing signatures of differentially expressed genes in the transcriptome (relevant to claims 26 and 27) which is a test that can detect asynchronous development of cortical neurons of any of the required lineage types, and provides a measure of neuronal differentiation (relevant to claim 25) at different time points (e.g.: Fig 1; Fig 2).
Velasco et al does not exemplify organoids with genetic variants, but the introduction, into brain organ cells, of genetic variants in autism related genes for the identification of pathological results of such genetic variants, was known in the prior art and is taught by Jian et al.
Jian et al teaches the use of genome editing for the introduction of mutations in ASD risk genes within progenitor cells of the developing brain (e.g.: p.3 - In vivo Perturb-Seq to assess the function of ASD risk genes) (relevant to the limitations of step a of claim 16). Jian et al teaches a variant in CHD8 that provides haploinsufficiency (relevant to claims 19 and 20) (e.g.: p.7 – “Chd8+/- cortex” ). Jian et al teaches detection of cell types using singe cell RNA sequencing (e.g.: p.32 - In vivo Perturb-Seq experiment; p.35 – Cell type clustering analysis). Further relevant to the claims Jian suggests that the different ASD genes act in developmental events of different cell types and temporal frames (e.g.: p.4).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have introduced genentic variants, as taught by Jian et al, into the brain organoids of Velasco et al. The skilled artisan would have been motivated introduced genentic variants into brain organoids based on the expressed teachings of Velasco et al that brain organoids can be useful as models of the human brain for experimental investigation of human neurological pathology, and the expressed teachings of Jian et al that variants in ASD genes in brain organ affect gene programs and cell states within and across subpopulations of cells (e.g.: p.7 - The ASD risk genes Chd8 and Gatad2b alter gene programs in oligodendrocyte progenitors). The skilled artisan would thus recognize that brain organoids featuring ASD gene variants would provide a model systems for experimental investigation of ASD.
Velasco et al in view of Jian et al does not specifically suggest contacting the organoid having a genetic variation with a candidate agent, but the use of brain organoids for compound screening was known in the prior art and is taught by Qian et al.
Qian et al teaches that brain organoids can be used for high-throughput compound screening and subsequent validation (e.g.: Fig 4; p.7, left col.; p.9, right col).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have performed a screening of compounds, as taught by Qian et al, using brain organoids with genetic variants, as rendered obvious by Velasco et al in view of Jian et al. Where Velasco et al in view of Jian et al renders obvious the analysis of the development of different cell types at different times during organoid development, and the alteration of development of different cell types with in the introduction of ASD-gene variants, the skilled artisan would be motivated to screen for agents which alleviate this pathological effect, identified by testing temporal frames of cell type development as suggested by Jian et al, in an effort to screen for compounds that may find use in treating the pathology, as suggested by Qian et al.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
Prosecution Insights