DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, 18010044, PG Publication US 20230160009, 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 with traverse of the species election in the reply filed on 11/18/2025 is acknowledged. The traversal is on the ground(s) that the prior art publication of Juno, as cited in the requirement for election of species, in the lack of unity restriction, mailed 8/19/2026, does not teach the technical feature linking the claims. This is not found persuasive because applicant alleges that the prior art reference of Juno does not identify pre-treatment predictive response biomarker, i.e. “response-capable” immune cells, does not represent a contribution over the prior art, and so is a special technical feature.
This argument is not persuasive, as this technical feature is taught by the prior art of Hause, US 20200292526, and/ or Faham, US 20180023143, of record, IDS, (see infra, rejection under 35 USC 103. Furthermore, it is noted that species requirement pressed for instant claim 11, is to the method optionally using the gene panel of claim 3. As this is an optional limitation, and in a dependent claim, it is not considered a technical feature that links the claims.
The requirement is still deemed proper and is therefore maintained.
Priority
The filing receipt, mailed 7/3/23, states that this application, filed 12/13/2022, is a 371 of PCT/US2021/037916, filed 06/17/2021 and claims domestic priority benefit of 63/041,440, filed 06/19/2020 and claims benefit of 63/079,507, filed 09/17/2020 and claims benefit of 63/172,904, filed 04/09/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/25/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
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 1-15, are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c),(d).
In the present instance, claims 1, 2, 5, 6, 12, 13, 14, 15, explicitly recite the broad recitations “disease”, “stored” (claim 5), “cytokine” (claim 6), a method of determining, (claim 12, “e.g., sequencing”) and the claims variously also recite: “cancer”, “a frozen”, “IL-2, TNF”, “by CD3 cross-linking”, (CTLA, B7, CD28, etc”, “a single-cell RNA sequencing”, “cell type composition”, “flow cytometry”, which are the narrower statements of the range/limitations, and so are indefinite.
Claim 6 is rejected for using the indefinite term “etc”, on the grounds that it is exemplary language and does not make clear the metes and bounds of the claimed invention. Also “etc” should end in a period.
Claims 4, 9, 11 explicitly use the term “such as”, which is exemplary language, and so are indefinite on the grounds that it is exemplary language and does not make clear the metes and bounds of the claimed invention.
Furthermore, in claim 11, it is not clear whether the various genes that are named specifically, are claimed in the alternative (e.g. a gene for T-cell activation, such as CD25, Ganzyme B, Perforin, . . . ” and therefore members of a Markush group, or claimed in combination. Claim 11 also claim 11 ends with “optionally, the gene panel further comprises CD4, CD8, FOXP3, CD62L, CD44, CD127, CD27, IL33R, and/or PTPRC,” which seems to suggest a possible interpretation choice as claiming a Markush group. These problems with the clarity of Claim 11 as explicitly raised in the requirement for election, mailed 8/19/2025, but have not been adequately addressed by amendment.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. The claims which depend from claims 1, 2, 4-6, 9, 11-15 are rejected under 12(b) over these grounds of rejection of the claims from which they depend, as well.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hause, US 20200292526, and Faham, US 20180023143, of record, IDS.
Hause throughout the publication and abstract discloses a method of identifying a predictive response biomarker (PRB) for treating a disease using a T/B-cell-targeted immunomodulatory therapy. Hause states:
[0003] The present disclosure relates to methods for tracking certain cells associated with a cell therapy, such as from a starting cell composition or a sample prior to administration to a subject and from a sample following administration to a subject. In some aspects, the methods include assessing one or more parameters or attributes of such cells and methods of identifying cellular attributes associated with particular desired cells. The provided methods can be used in connection with cell therapy including adoptive transfer of engineered T cells or T cell precursors.
Hause at para [0003], (emphasis added).
In some aspects, the methods include assessing one or more parameters or attributes of such cells and methods of identifying cellular attributes associated with particular desired cells, para [0003]; In particular embodiments, subjects administered a cell therapy containing engineered cells (e.g. CAR-T cells) are assessed and/or monitored for a period of time to determine if the subjects experience a response, para. [0094]; Antigens targeted by the receptors in some embodiments include antigens associated with a B cell malignancy, such as any of a number of known B cell marker. In some embodiments, the antigen is or includes CD20, CD19, para [0037]).
The reference disclosure relates to methods for tracking certain cells associated with a cell therapy, such as from a starting cell composition or a sample prior to administration to a subject and from a sample following administration to a subject, reference para [0003]; Provided herein are methods for identifying a property or attribute of a cell including (a) identifying the clonotype and/or a TCR sequence of all of a portion of a native TCR alpha and/or beta variable region or pair thereof, of at least one T cell from at least one test biological sample from a subject, said test biological sample obtained from the subject following administration of a cell therapy containing T cells expressing a recombinant receptor, reference para [0006]. In some embodiments, the test biological sample is obtained from a subject at a time after the subject exhibits a response to the cell therapy following the administration, said response selected from a complete response (CR), Para [0013].
In some embodiments, the desired feature may be associated with or related to the expansion. of such cells, reference para [0050]. The provided embodiments offer advantages in identifying and characterizing specific attributes of cells associated with certain cell clones, e.g., T cell clones, that are capable of persisting and expanding in the subject over time, reference para [0056]); and, (b) generating a list of genes upregulated and/or down-regulated in said response-capable T/B cells in the pre-treatment sample, to create the PRB (In some embodiments, the at least one property or parameter is determined by single cell gene expression profiling, reference para [0033].
In some aspects, following manufacturing and ex vivo generation of a therapeutic T cell composition, represented clonotypes, and associated cell phenotypes or molecular signatures, can change compared to the initial T cell composition obtained or selected from a sample from a subject. In some cases, the clonotype repertoire can be different compared to the initial T cell composition or engineered T cell compositions, as certain clones expand and persist better than others, reference para [0058]. In some embodiments, exemplary panel of genes for expression profile analysis includes genes involved in function of immune cells, e.g., T cells, or phenotypic markers of an immune cell, e.g., T cells, reference para [0428]); (c) optionally, each gene in said PRB is weighed using a logistic regression coefficient obtained by fitting said each gene as predictor with expansion status and/or clinical response status as outcome.
Among the antigens targeted by the chimeric receptors are those expressed in the context of a disease, condition, or cell type to be targeted via the adoptive cell therapy. Among the diseases and conditions are leukemias, and/or myelomas, such T leukemias, reference para [0451].
In some embodiments, such starting or initial compositions include any T cell composition containing T cells produced as part of an ex vivo process for producing genetically engineered T cells, reference para [0055]. Hause teaches the T cell composition contains T cells that are, or have been derived from, T cells previously obtained from the subject prior to administering the cell therapy to the subject, reference para [0005]); (In some embodiments, flow cytometry can be used on the population level to sort specific subsets of cells for clonotype analysis. In some embodiments, cell surface phenotype determination and cell sorting based on cell surface markers, can be used to select specific populations of cell of interest. For example, surface expression of markers that are associated with function, activation state, maturity, potential for differentiation, expansion, recirculation, localization, and/or persistence capacities, antigen-specificity, type of antigen receptor, presence in a particular organ or compartment, marker or cytokine secretion profile, and/or degree of differentiation in T cells, can be used to select cells exhibiting particular phenotypes or attributes, Para [0437].
In some aspects, it is contemplated that a particular desirable feature or property of genetically engineered T cells (e.g. CAR-T cells) in vivo in a subject, e.g. persistence of cells in responders, are associated with a unique molecular signature of T cells in such starting (ex vivo) T cell compositions, Para [0055]; One or more single cells can be isolated in one or more emulsions, in the presence of a vessel barcode and molecular barcodes, so that one droplet of the one or more emulsions can contain a maximum of 1 cell or less, Para [0216]; Up to a million cells per hour can be isolated in individual -65 picoliter emulsion droplets, Para [0084]);
Hause discloses methods for identifying a property or attribute of a cell including (a) identifying the clonotype and/or a TCR sequence of all of a portion of a native TCR alpha and/or beta variable region or pair thereof, of at least one T cell from at least one test biological sample from a subject, para [0005]; In some embodiments, the desired feature may be associated with or related to the expansion. of such cells, Para [0050]; Provided herein are methods in which the native TCR sequence of genetically engineered T cells (e.g. CAR-T cells) that are determined to have a desirable property or feature, such as following administration to a subject, e.g. persistent cells of a responder, Para [0054]).
In the present embodiments the lymphocyte pool can be enriched for the desired immune cells by any suitable method, Hause at Para [0133. The droplets range in size from roughly 0.5 micron to 500 micron in diameter, which corresponds to about 1 picoliter, Para [0294]).
Hause discloses the pre-treatment sample is a whole blood sample, Para [0022
Hause discloses clonotype and/or TCR sequence is determined by high-throughput or next- generation RNA sequencing (RNAseq) In some cases, the clonotype and/or TCR sequence is determined by high-throughput single cell immune sequencing of nucleic acid encoding natively paired TCR chains, Paras. [0029]-[0030]).
Hause fails to explicitly disclose wherein each gene in said PRB has a log2-fold change of >0.2, and is expressed in <40% of T cells with TCR clonotypes that are not clonally expanded in the matching post-treatment sample; optionally, wherein said scRNA-seq is carried out using a gene panel specifically designed for a mechanism of action of the compound, or a pre-determined gene panel designed to assess immuno-modulation. It would have been obvious to one of ordinary skill in the art at the time the invention was made to select genes with a log2-fold change of >0.2 and expressed in <40% of T cells with TCR clonotypes that are not clonally expanded in the matching post-treatment sample, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. The motivation for doing so would be to identify genes predictive of response based on clonal expansion of T cells in T cells that are therapeutically effective for treatment of a disease such as cancer to optimize the prediction of an efficacious response to a therapy.
Hause does not teach explicitly a T/B-cell-targeted immunomodulatory therapy. Hause does not teach a microfluidic device. Hause fails to explicitly disclose wherein each gene in said PRB has a log2-fold change of >0.2, and is expressed in <40% of T cells with TCR clonotypes that are not clonally expanded in the matching post-treatment sample.
Faham, US 20180023143, of record, IDS, throughout the publication and abstract, para [0008], [0407]. Faham teaches, at [0008], immune cell profiling in treatment of cancer in evaluation of the response to treatment and recurrence of disease; at [0009], generation of markers for lymphoid neoplasms using immune cell or clonotype profiling; at [0017], determining a clonotype profile from peripheral blood cells, and repeating to monitor the disease or condition in the patient; at [0040], determining a profiled of recombined DNA sequences in T-cells and/or B-cells. Faham teaches, e.g., at [0007], [0041], and [0043], predictive clonotypes, which read on the predictive response biomarkers of the instant claims. Faham teaches, at para [0083], microfluidic chips.
It would have been prima facie obvious for to one of ordinary skill in the art before the application was filed to have combined a T/B-cell-targeted immunomodulatory therapy and a microfluidic device technology with the method of Hause. It would have been obvious e wherein each gene in said PRB has a log2-fold change of >0.2, and is expressed in <40% of T cells with TCR clonotypes that are not clonally expanded in the matching post-treatment sample
It would have been prima facie obvious for to one of ordinary skill in the art before the application was filed to select genes with a log2-fold change of >0.2 and expressed in <40% of T cells with TCR clonotypes that are not clonally expanded in the matching post-treatment sample, since where the general conditions of the claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art.
One of ordinary skill in the art would have motivated to have combined explicitly methods of identifying predictive response biomarkers for treating a disease using B cell-targeted immunomodulatory therapy, because Faham, at para [0003], teaches that the immune response comprises humoral (B cell indicated) and cytotoxic (T cell-mediated) response, so that a complete response to disease would entail B cell biomarkers. Furthermore, as both B cells and T cells are lymphocytes, one of ordinary skill in the art would expect that identifying predictive response disease biomarkers would proceed similarly for both. One of ordinary skill in the art would be motivated to combine and use microfluidic devices in the claimed single cell methods, including nucleic acid amplification, as they are on the same dimensional scale.
One of ordinary skill in the art would have been motivated further to select genes with a log2-fold change of >0.2 and expressed in <40% of T cells with TCR clonotypes that are not clonally expanded in the matching post-treatment sample for doing so would be to identify genes predictive of response based on clonal expansion of T cells in T cells that are therapeutically effective for treatment of a disease such as cancer to optimize the prediction of an efficacious response to a therapy.
Conclusion
2. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mark L Shibuya whose telephone number is (571)272-0806. The examiner can normally be reached M-F, 9AM-4:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Doug) Schultz, can be reached at (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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MARK L. SHIBUYA
Primary Patent Examiner
Art Unit 1631
/MARK L SHIBUYA/Primary Patent Examiner, Art Unit 1631