DETAILED ACTION
Applicant’s response, filed 10 Nov. 2025 has been fully considered. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 .
Status of Claims
Claims 1-38 are cancelled.
Claims 42-59 are newly added.
Claims 39-59 are pending.
Claims 39-59 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application, U.S. Provisional App. No. 62/865,033 filed 21 June 2019, under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Accordingly, the effective filing date of the claimed invention is 21 June 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05 Nov. 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the list of cited references was considered in full by the examiner.
Drawings
The replacement drawing sheet filed 10 Nov. 2025 has been entered.
The objection to the drawings filed 20 Dec. 2021 in the Office action mailed 11 June 2025 has been withdrawn in view of the replacement drawing sheet filed 10 Nov. 2025.
The drawings filed 10 Nov. 2025 and 20 Dec. 2021 are accepted.
Specification
The amendments to the abstract filed 10 Nov. 2025 has been entered.
The objection to the abstract in the Office action mailed 11 June 2025 has been withdrawn in view of the amendments to the abstract filed 10 Nov. 2025.
Claim Interpretation
Claim 39 recites “providing single-cell ribonucleic acid (RNA) sequence data for a plurality of diseased cells and a plurality of normal cells of a cell type…”, which under the broadest reasonable interpretation of the claim, is interpreted to encompass inputting/providing already generated single-cell RNA sequence data (e.g. by a computer), but the claim does not require a step of physically sequencing a sample to generate the sequence data.
Claim Interpretation-35 USC § 112(f)
The following interpretation is newly recited and necessitated by claim amendment:
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
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. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitations are:
a genomic editing unit, used for editing one or more genomic regions in a cell in clam 39.
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
Applicant’s specification at para. [0014] discloses the “genomic editing unit” is a CRISPR system, a CRISPRi system, a CRISPRa system, an RNAi system, or an shRNA system. Therefore the genomic editing unit will be interpreted to be one of these systems, including equivalents thereof.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
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 39-59 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains 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. This rejection is newly recited and necessitated by claim amendment.
In In re Wands (8 USPQ2d 1400 (CAFC 1988)) the CAFC considered the issue of enablement in molecular biology. The CAFC summarized eight factors to be considered in a determination of "undue experimentation." These factors include: (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; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In considering the factors for the instant claims:
(A) The breadth of the claims: Claims 39-59 encompass constructing a trajectory defining a transcriptional transition between a first phenotype state of diseased cells and a second phenotypic state of normal cells, identifying regions along the trajectory, and then editing the one or more genomic regions in a cell to reprogram the cell from the diseased (first) phenotypic state to the normal (second) phenotypic state. The claims are extremely broad in that they encompass identifying any one or more genomic regions along the trajectory using any method, and then reprogramming any type of diseased cell to a normal cell state, thus encompassing the ability to reprogram any diseased cell back to a normal cell state.
(B) The nature of the invention: The invention relates to the construction of a trajectory defining a transcription transition between a diseased and healthy cell state using RNA sequencing data and
(C) The state of the prior art:
Methods of constructing a trajectory defining a transcriptional transition between a first and second phenotypic state by analyzing single cell RNA sequencing data of different cell types in a latent space were known in the art before the effective filing date of the claimed invention:
Gong et al. (TCM visualizes trajectories and cell populations from single cell data, 2018, Nature Communications, pg. 1-8; newly cited) discloses a method of analyzing expression trajectories between cell subpopulations (Abstract), which comprises analyzing high dimensional gene expression in a latent space that preserves global development trajectories and separates subpopulations of cells (i.e. cell types) within each developmental stage (pg. 2, col. 1, para. 1 to col. 2, para. 2; FIG. 1) in addition to identifying specific genes (i.e. regions) specific to certain subpopulations during differentiation (i.e. cell types) (pg. 4, col. 2, para. 1; pg. 5, col. 1, para. 3 to col. 2, para. 1).
Chen et al. (DensityPath: an algorithm to visualize and reconstruct cell state-transition path on density landscape for single-cell RNA (sc-RNA) sequencing data, Bioinformatics, 35(15), 2019, pg. 2593-2601; published 2018; newly cited) similarly discloses an algorithm for reconstructing cell state-transition paths from single-cell RNA sequencing data (Abstract). Chen discloses the algorithm reconstructs an optimal cell state-transition path from scRNA-seq data by embedding the high dimensional expression data into a stable low-dimensional latent space (pg. 2596, col. 2, para. 3; Fig. 1) and further discloses identifying specific genes (i.e. regions) relating to branch points within the cell-state transition path (pg. 2597, col. 2, para. 3).
Qiu et al. (Reversed graph embedding resolves complex single-cell developmental trajectories, 2017, bioRxiv, pg. 1-29; newly cited) also discloses a method of resolving complex single-cell trajectories from single-cell RNA sequencing data (Abstract), which involves performing dimensionality reduction on the sequencing data of different cell types (Figure 1; pg. 2, para. 3 to pg. 3, para. 1), analyzing the resulting latent space to identify a transcription trajectory between cell types (Figure 2; pg. 4, para. 3), and identifying genes (i.e. one or more regions) with significant branch-dependent expression along the trajectories (pg. 6, para. 3; pg. 10, para. 4). Qiu discloses that few experiments probing complex biological trajectories with multiple fates have been performed to date, and experimentally validating the architecture of these trajectories is extremely challenging, and so the accuracy of existing methods remain unclear (pg. 2, para. 2).
Tritschler et al. (Concepts and limitations for learning developmental trajectories from single cell genomics, 2019, Development, 146, pg. 1-12; newly cited) reviews methods of constructing developmental transcriptional trajectories from single cell genomics (Abstract), and discloses that gene expression alone might not completely reflect a cell’s state, and instead, morphogenetic movements and the location of a cell are important for cell fate decisions, which is not usually available in scRNA-seq (pg. 5, col. 2, para. 2). Tritschler further discloses that cell memories, such as chromatin state, metabolic state, or post-translational modifications are also not considered by scRNA-seq data, and that the combination of pseudotime (e.g. the trajectories) with different pieces of information such as chromatin state, protein expression and phosphorylation, spatial arrangement is crucial for the identification and validation of novel cell transitions and lineage relationships (pg. 5, col. 2, para. 1).Tritschler additionally discloses that perturbation experiments can be combined with transcriptomics and play an important role in reconstructing regulatory networks (FIG. 3; pg. 10, col. 1, para. 5).
Specific methods for reprogramming some, but not all cells, from one state to another are also known in the art.
Camp et al. (Single-cell genomics to guide human stem cell and tissue engineering, 2018, Nature Methods, 15, pg. 661-667; newly cited), reviews the application of single-cell genomics, including scRNA-seq, in guiding human stem cell and tissue engineering (Abstract). Camp discloses various strategies used to guide cell and tissue engineering, including transcription factor combinatorics, spatial reconstruction to identify signaling pathways, CRISPR-Cas9 screens, in addition to lineage-coupled transcriptomics (e.g. transcription trajectories) (Fig. 3). Camp explains that single-cell transcriptome measurements are used to dissect cell differentiation trajectories, but these measurements are descriptive and might only provide hypothesis about underlying mechanisms, while CRISPR-Cas9 knockout screens can be used to investigate the effect of genetic perturbations and scRNA-seq coupled genetic screens can be used to elucidate mechanisms controlling cell differentiation (pg. 664, col. 1, para. 3 to col. 2, para. 1). Camp also discloses that the direct differentiation of stem cells to defined cell types or reprogramming one somatic cell type to another is often inefficient due to a lack of precision of protocol and also due to the influence of cell-intrinsic vs environment effects on differentiation (pg. 660, col. 1, para. 2 to pg. 661, col. 1, para. 1). Camp explains that integration of perturbation, lineage tracing, and epigenomic measures in engineered cells will connect the genome with its function and improve models of cell fates in health and disease (pg. 665, col. 2, para. 3 to col. 2, para. 1).
Wang et a. (Direct cell reprogramming: approaches, mechanisms and progress, 2021, Nature Reviews | Molecular Cell Biology, 22, pg. 410-424; newly cited) also reviews direct cell reprogramming approaches (Abstract), and discloses that the number of cell types that can be generated by direct reprogramming has been increasing, and it is a promising strategy to produce functional cells for therapeutic purposes (Abstract). Wang discloses direct reprogramming has been achieved for several cell types in vitro and in vivo and not other somatic cell types, but efficiency of conversion remains low (pg. 410, col. 2, para. 1-2). Wang further discloses that molecular mechanisms of reprogramming include epigenetic modifiers, non-coding RNAs and metabolic repatterning (pg. 421, col. 2, para. 2). Wang also discloses reprogramming some cell types requires identifying epigenetic barriers for cardiac reprogramming (pg. 414, col. 1, para. 2). Wang also discloses that trajectory analysis of single-cell RNA-seq data helps reveal reprogramming trajectories and novel cell states (pg. 420, col. 2, para. 2), and further discloses that integrating single-cell multi-omics datasets is the next challenge in direct reprogramming and for cell types that have not been generated by direct reprogramming, leveraging new technologies such as CRISPR-Cas9 screens and modeling can predict reprogramming factors for a desired lineage followed by experimental validation (pg. 420, col. 2, para. 3; pg. 421, col. 2, para. 2).
However, after a review of the prior art, a method of using these transcription trajectories between cell-states to identify one or more gene regions that can be genetically edited to directly reprogram any type of diseased cell to any type of normal cell state is not generally known in the art.
(D) The level of one of ordinary skill: The level of ordinary skill in the art in the field of bioinformatics and molecular biology is high.
(E) The level of predictability in the art: In view of the prior art, the level of predictability in cell-reprogramming is low. Reprogramming cells is generally inefficient and is affected by multiple factors including chromatin states, metabolic states, post-translational modifications, and expression data. For example, both Camp and Wang explain that the efficiency of conversion is low in reprogramming cells (Wang: pg. 410, col. 2, para. 1-2; and Camp: pg. 660, col. 1, para. 2 to pg. 661, col. 1, para. 1). Camp elaborates that this is often inefficient due to a lack of precision of protocol and also due to the influence of cell-intrinsic vs environment effects on differentiation (pg. 660, col. 1, para. 2 to pg. 661, col. 1, para. 1). Tritschler also explains that that cell memories, such as chromatin state, metabolic state, or post-translational modifications are also not considered by scRNA-seq data, and that the combination of pseudotime (e.g. transcription trajectories) with different pieces of information such as chromatin state, protein expression and phosphorylation, spatial arrangement is crucial for the identification and validation of novel cell transitions and lineage relationships (pg. 5, col. 2, para. 1). Wang discloses an example in which direct reprogramming to a cardiac cell requires identifying epigenetic barriers for cardiac reprogramming (pg. 414, col. 1, para. 2), demonstrating that altering gene expression alone does not predictably result in reprogramming.
(F) The amount of direction provided by the inventor: The specification does not provide detailed direction for the genetic modifications being made to the identified one or more genomic regions, including any additional modifications made to the cells (e.g. epigenetic, signaling, spatial arrangements) to reprogram the cell from any diseased state to a healthy state. Instead, Applicant’s specification at para. [0005] discloses interrogating potential genetic drivers using a pooled CRISPR editing experiment. Applicant’s specification at para. [0038] discloses how genetic interrogation using CRISPR can be used to quantify an ability of a genetic modification to program a diseased cell toward a desired phenotypic state ([0038]). Applicant’s specification at para. [0086] discloses that after genomic regions are identified a genetic editing unit can be used to edit a respective genomic region, and after editing an algorithm may be used to detect a shift in the latent space of the edited cell. Applicant’s specification at para. [0113]-[0118] discloses using CRISPR gene interrogation to quantify the ability of target genes to shift a diseased cell toward a desired state, and ultimately identifying genes with the most extensive re-programming to a target state for further biological validation. Overall, Applicant’s specification provides details for using genetic editing to screen the effect of genetic perturbations in the identified region(s) on a cell’s phenotypic state to identify the best candidate genes for biological validation (as also discussed by Camp above in using scRNA-seq coupled genetic screens), but does not provide a detailed direction on how to successfully reprogram a diseased cell to healthy cell state.
(G) The existence of working examples: The specification does not provide a working example of reprogramming a cell in a diseased state to a healthy cell state. Instead, Applicant’s specification at para. [0112]-[0118] and FIG. 3A-C provides an example of quantifying transitions between cell states by using a genetic screen and detecting shifts in the latent space in order to ultimately identify optimal genetic targets for re-programming. Applicant’s specification at para. [0125]-[0126], Example 6, discloses how re-programming targets are identified in a latent space. Applicant’s specification at para. [0127]-[0134], Example 7, provides a working example of an analysis to reprogram cancer cells toward cells at different stages of cancer progression that involves generating transcriptional trajectories from sequencing data of cancer cells having particular gene mutations and wild-type cells, and how target genes for reprogramming are identified.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure: The skilled practitioner would first turn to the instant specification for guidance in practicing the subject matter of claims 39-59. The specification does not provide a working example regarding how to reprogram a particular diseased cell type to a normal cell type, and instead discloses performing genetic screens on identified genomic regions may to facilitate re-programming, and analyzing shifts in the latent space due to the gene editing to identify target regions for validation. The specification does not provide guidance on how to reprogram a particular diseased cell type successfully to a normal cell state.
Therefore, the skilled practitioner would turn to the prior art for such guidance on how to successfully carry out the reprogramming of the diseased cell state to the normal cell state. First, Gong and Chen do disclose a method of analyzing single-cell RNA-seq data in a latent space to identify a transcriptional trajectory between cell states, and identifying target genes for the transition of a cell from one state to the other. However, Gong, Chen, and Qiu do not provide any guidance on how to translate this information to successfully reprogram a cell from one state to the other. Instead, Qiu discloses that few experiments probing complex biological trajectories with multiple fates have been performed to date, and experimentally validating the architecture of these trajectories is extremely challenging (pg. 2, para. 2), demonstrating that validating, let alone applying the architecture to perform reprogramming, is extremely difficult to one of ordinary skill in the art. Camp, discussed above, also explains that trajectories or linages from scRNA-seq data may be combined with CRISPR based genetic screens to better understand mechanisms controlling differentiation (pg. 664, col. 1, para. 3 to pg. 2, para. 2), similar to the examples provided in the specification, but does not explain how to carry out re-programming only using identified genes in a constructed transcriptional trajectory.
Furthermore, the prior art demonstrates the variety of information and factors that must be considered in order to carry out re-programming. As discussed above, the efficiency of conversion is low in reprogramming cells, and information such as chromatin state, metabolic state, post-translation modifications not considered by scRNA-seq data are crucial for the identification of novel cell transitions (Tritschler: pg. 5, col. 1, para. 1). For example, direct reprogramming to a particular cell may require identifying epigenetic barriers for cardiac reprogramming (Wang: pg. 414, col. 1, para. 2), which is not addressed by RNA-seq data. Wang also states that direct reprogramming of some cells, and not other somatic cell types has been achieved (pg. 410, col. 2, para. 1-2), and further discloses that molecular mechanisms of reprogramming include epigenetic modifiers, non-coding RNAs and metabolic repatterning (pg. 421, col. 2, para. 2). Camp similarly explains that integration of perturbation, lineage tracing, and epigenomic measures in engineered cells will connect the genome with its function and improve models of cell fates in health and disease (pg. 665, col. 2, para. 3 to col. 2, para. 1). Therefore, the successful reprogramming from one cell type to requires consideration and analysis of diverse biological information, and successful re-programming may be dependent on successful consideration of epigenetic blocks, chromatin structure, etc. Camp also discloses various strategies used to guide cell and tissue engineering, including transcription factor combinatorics, spatial reconstruction to identify signaling pathways, CRISPR-Cas9 screens, in addition to lineage-coupled transcriptomics (e.g. transcription trajectories) (Fig. 3). Camp explains that single-cell transcriptome measurements are used to dissect cell differentiation trajectories, but these measurements are descriptive and might only provide hypothesis about underlying mechanisms, while CRISPR-Cas9 knockout screens can be used to investigate the effect of genetic perturbations (pg. 664, col. 1, para. 3 to col. 2, para. 1).
Given the efficiency of re-programming is generally low, editing a single region or multiple regions to affect gene expression alone is often not sufficient to allow for cell reprogramming (e.g. in the presence of epigenetic barriers, other post-translational modifications, issues with chromatin structure, etc.), and the reprogramming of any diseased cell type to any another normal cell type has yet to be discovered (see Wang above), the skilled practitioner would turn to trial and error in order to carry out the reprogramming of any diseased cell state to a normal cell state based simply on identified genes/regions in a transcription trajectory. Such represents undue experimentation.
Examiner comment:
It appears Applicant’s specification at least at FIG. 3 and para. [0017]-[0018], [0078], and [0086] is enabled for using genetic editing to perform genetic screens and interrogate potential genetic drivers in cell types using the identified one or more target regions, and then test whether a cell state has shifted toward a desired cell state by again analyzing RNA-seq data of the edited cell in a latent space. Therefore, it is acknowledged that the identified transcriptional trajectories may be used to inform and carry out genetic screens in facilitating cell-reprogramming. However, the specification is not enabled for re-programming any cell from a first diseased state to a normal state simply by editing (in any way) the identified one or more genomic regions.
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.
Claims 52 and 59 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention. This rejection is newly recited and necessitated by claim amendment.
Claim 52 is indefinite for recitation of “low-frequency genomic regions”. The term “low frequency” is a relative term which renders the claim indefinite. The term “low frequency” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. For purpose of examination, the claim is interpreted to mean any genomic regions are removed from the sequencing data prior to mapping. Clarification is requested.
Claim 59 is indefinite for recitation of “…wherein said editing of said one or more genomic regions in said cell is performed iteratively to evaluate said one or more genomic regions for therapeutic targeting”. Claim 39, from which claim 59 depends, recites “editing…said one or more genomic regions in a cell…to re-program said cell to exhibit said second phenotype”. It is unclear in what way claim 59 intends for the editing of claim 39 to be performed “iteratively”. Specifically, it is not clear what part of the editing process is supposed to be iterated through. For example, it is not clear if claim 59 intends to require multiple genomic regions, and each genomic region is edited “iteratively” or one at a time, or if claim 59 intends to require the editing of the one or more genomic regions to be performed at least twice on the cell. It is further unclear if “to evaluate said one or more genomic regions for therapeutic targeting” is simply an intended use of the iterative editing, or if this limitation is intended to inform the iterating in some way. Clarification is requested. For purpose of examination, the limitation will be interpreted to mean that the editing of genomic regions is performed iteratively, with the intended use of evaluating regions of therapeutic targeting.
Claim Rejections - 35 USC § 101
The rejection of claims 39-41 under 35 U.S.C. 101 in the Office action mailed 11 June 2025 has been withdrawn in view of claim amendments received 10 Nov. 2025. The claims integrate the recited judicial exception into a practical application by reprogramming a cell in a diseased state to exhibit a normal cell state by performing genetic editing on identified genomic regions along the identified transcriptional trajectory between the diseased and normal cell state. Applicant’s specification discloses disentangling which genes are causal versus correlative in a given reprogramming process is challenging, and may require extensive, time-intensive experimental assays ([0002]), such that reprogramming a cell by editing only regions identified along a transcription trajectory represents an improvement in cell reprogramming.
Claim Rejections - 35 USC § 103
The rejection of claims 39-41 under 35 U.S.C. 103 as being unpatentable over Stamatoyannopoulous (2019) in view of Liang (2014) in the Office action mailed 11 June 2025 has been withdrawn. The prior art does not disclose performing genetic editing on one or more genomic regions specifically identified from a transcriptional transition between cells identified in a latent space to reprogram a cell from a first diseased state to a normal cell state as claimed.
The closest prior art of record, Gong et al. (TCM visualizes trajectories and cell populations from single cell data, 2018, Nature Communications, pg. 1-8; newly cited) discloses a method of analyzing expression trajectories between cell subpopulations (Abstract), which comprises analyzing high dimensional gene expression in a latent space that preserves global development trajectories and separates subpopulations of cells (i.e. cell types) within each developmental stage (pg. 2, col. 1, para. 1 to col. 2, para. 2; FIG. 1) in addition to identifying specific genes (i.e. regions) specific to certain subpopulations during differentiation (i.e. cell types) (pg. 4, col. 2, para. 1; pg. 5, col. 1, para. 3 to col. 2, para. 1). However, Gong does not describe how to then utilize these specific genes to directly reprogram a cell from a diseased cell state to a normal cell state. Furthermore, as discussed in the 112(a) rejection above, while constructed transcription trajectories for cell reprogramming can be used to guide CRISPR screenings to assess the effect of genetic perturbations in controlling cell differentiation (Camp: pg. 664, col. 1, para. 3 to col. 2, para. 2, e.g. scRNA-seq-coupled genetic screens), the art does not disclose how to reprogram a diseased cell to a normal cell state from a transcription trajectory as claimed with a reasonable expectation of success.
Terminal Disclaimer
The terminal disclaimer over U.S. Patent App. No. 17/735,494, now U.S. Patent No. 11,710536 B2, filed 23 Feb. 2023 in App. 17/735,494 was approved 23 Feb. 2023.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 39-41 50-54, and 59 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of copending Application No. 18/206,981 (reference application). Any newly recited portion is necessitated by claim amendment.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding instant claim 39, reference claims 1, 10, and 12 anticipates instant claim 39. It is noted that reference claim 1 is narrower than instant claim 39.
Regarding instant claims 40-41, reference claims 5-6 further disclose the limitations of instant claims 40-41.
Regarding instant claim 50, reference claim 10 discloses this limitation.
Regarding instant claim 51, reference claim 13 discloses this limitation.
Regarding instant claim 52, reference claim 11 discloses this limitation.
Regarding instant claim 53, reference claim 14 discloses this limitation.
Regarding instant claim 54, reference claims 1 and 11 disclose using scRNA-seq data, which would require generating the data.
Regarding instant claim 59, reference claim 24 discloses an iterative editing process.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments filed 10 Nov. 2025 have been fully considered regarding the double patenting rejection but they are not persuasive.
Applicant remarks claims 39-41 have been amended to clarify the claimed subject matter and are now distinct from the reference claims, and the rejection should be withdrawn (Applicant’s remarks at pg. 12, para. 4 to pg. 13, para. 1).
This argument is not persuasive. The reference claims also disclose analyzing genomic regions that facilitate reprogramming of one cell type to another by analyzing RNA sequencing data in a latent space, and then carrying out genetic editing to perform reprogramming. Applicant merely asserts the claims are distinct, but does not explain why. And therefore, the rejection is maintained.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685