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 .
Application Status
Claims 77-117 are pending.
Claims 77-97 are withdrawn.
Claims 98-117 are examined on the merits herein.
Grounds of Rejection Withdrawn
Previous rejection of claim 105 under 35 U.S.C. 112(b) is withdrawn in view of claim amendment.
Previous rejection of claims 98, 101-104, 106-108, and 110-117 over claims 109 and 112-114 of copending Application No. 18/007,024 has been withdrawn in view of amendments to the copending claims.
Information Disclosure Statement
Maintained
The information disclosure statement filed September 23, 2022 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed; Foreign patent documents 038 and 039, were not attached. It has been placed in the application file, but the information referred to therein has not been considered.
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:
Sequences appearing in the are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the claim following each sequence 4 or more amino acid residues in length.
Required response – Applicant must provide: Amended claims with requisite SEQ ID NO: X following each sequence 4 or more amino acid residues.
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.
Claim 105 is 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.
Claim 105 recites a series of peptide sequences longer than 3 amino residues in length without corresponding identifiers (SEQ ID NO:X); as such this renders the claim unable to be properly searched and therefore indefinite.
Claim Rejections - 35 USC § 103
New Rejection
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.
Claims 98, 101-104, 106-108, and 110-117 are rejected under 35 U.S.C. 103 as being unpatentable over Slanetz (WO 2018/005712 A1, cited in OA 02/26/2026), Tanaka (The Journal of Immunology, Volume 162, Issue 12, June 1999, Pages 7155–7161; PTO-892) and Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022).
Regarding claims 98, 101-102, 104, 110-111, 113-114, and 116-117, Slanetz teaches a method for making a composition comprising T-cells, the method comprising the steps of: (a) obtaining an initial cell population comprising T-cells; (b) stimulating the T-cells by exposing the cell population to one or more target antigens and to cytokines, (c) culturing the cell population in media comprising cytokines; (d) testing the cell population for antigen- specific reactivity; and (e) harvest the resulting composition comprising T cells (claim 21), wherein the one or more target antigens comprises a plurality of overlapping peptides derived from the one or more target antigens (claim 30), wherein the one or more target antigens comprises polypeptides derived from one or more neoantigens (claim 32), wherein the T cell composition resulting from the method comprises greater than 70% CD3+ T cells with predominantly CD8+ versus CD4+ T cells (claim 37), wherein the T cell composition resulting from the method wherein greater than about 1 % of the total CD3+ cells have reactivity toward the antigen or antigens (claim 20). Slanetz teaches that to create a reactive T cell population, a source of T cells is needed, peripheral blood mononuclear cells (PBMCs) are currently preferred (para 0115) and further that PBMCs are suspended in culture medium, exposed to multiple polypeptides derived from target antigens (which load onto MHC structures on APCs in the cell population) and expanded (paras 0127-0133). Slanetz further teaches that using the method for ex vivo T cell expansion disclosed in the present application, a seeding of culture of about 30- to 100 million PBMCs, typically may yield approximately 10-100 million effective T cells for immunotherapy after about 21 days of culture (para 0172), and further generation of >2 billion CD3+ cells by Day 28 harvest (Figs 2-4). Slanetz further teaches that PepMixes are a pool of peptides (also referred to herein as "polypeptides") derived from a peptide scan of the target antigen of interest (each polypeptide is 15 amino acids with 11 amino acid overlap) that are capable of stimulating CD4+ and CD8+ T cells (para 0187). Slanetz further teaches that a validated neoantigen is described as being associated with a disease state that is amenable to immune therapy, and where the neoantigen is capable of binding to MHC class I and/or class II molecules, and is immunogenic to T cells in that it causes T cell activation, proliferation and/or memory responses in CD4+ and/or CD8+ subpopulations; in one embodiment three or more neoantigens are prepared and validated (para 0101). Slanetz further teaches that T cell assays suitable for measuring the immunogenicity of antigens include: ELISA measuring levels of various activation cytokines, and ELISpot to quantify the frequency of cytokine-producing cells (para 0113). Slanetz further teaches that ex vivo expanded cells are tested for appropriate release criteria to be deemed fit for immunotherapy including (a) an effective cell number required for the adoptive therapy, (b) cell viability, (c) expression of cell surface markers for effective antigen recognition diversity, (d) an effective mix of desired phenotypes, (e) cellular response with respect to cytokine generation and cytotoxicity for the target cells are included in the release criteria (para 0173). Slanetz teaches the Cytotoxicity Assay: LDH Cytotoxicity Detection Kit (para 0223); as well as assaying for cytokines IFN gamma, IL-2 and TNF alpha on days 25-28 (figs 2-4).
Regarding claim 105, Slanetz teaches in accordance with the invention, Ras-based neoantigen candidates are designed and validated as follows (para 0104)
Regarding claim 106, Figs 5C-5D teach HLA alleles including A2*0201.
Regarding claim 107 and 113, Slanetz teaches that the number of antigen specific spots were divided by DMSO alone background counts to determine the relative frequency of total T cells that responded to each antigen (para 0194). Slanetz further teaches that DMSO was also used as control for intracellular cytokine staining (para 0201).
Regarding claim 108, Slanetz teaches cells stimulated with human serum separate from the Pepmix (para 0201) human serum would comprise other peptide epitopes.
Regarding claim 112, Slanetz teaches pepmix generated better than 2 fold higher cytotoxicity in T cell versus DMSO control (Fig 8C).
Regarding claim 115, Slanetz teaches that 33.5% of the 2 billion cells generated were CD4+ (Fig. 8a) as >1% of the >70% CD3 cells are antigen specific and the majority of the CD3 cells were CD8+ (>50%) (claim 20); the ordinary artisan can deduce that this would generate at least 0.1% antigen specific CD4+ T cells especially as Slanetz further teaches one of the specific advantages of the use of IL-7 in T cell culture is that it promotes antigen specific CD4+ T cell expansion (para 0139).
Slanetz does not teach generation of epitope sequence presentation by APC according to mass spectroscopy; or that the peptides are encoded by RNA.
Regarding claim 98, Tanaka teaches a method of testing combinatorial and degenerate peptide libraries derived from a CD4+ T cell reactive to K-RAS using mass spectrometry analysis and testing on T cell proliferation (abstract). Tanaka further teaches that identification of peptide superagonists was based on use of various strategies including single amino acid modifications exert additive effects when combined in one peptide species containing multiple substitutions, unbiased approaches using completely randomized combinatorial peptide libraries led to the identification of peptide superagonists for a particular T cell clone; etc (discussion). Tanaka further teaches that synthetic artificial peptides that carry the best residue substitution at each position of combinatorial peptide libraries do not necessarily result in superagonists; rather, “unexpected” amino acids at other positions play important roles in superagonism (discussion). Tanaka further teaches that Ras is a protooncogene with point mutations known to be involved in the carcinogenesis of many different types of malignancies and that human T cells that recognize Ras protein and/or peptide have been described previously these cells were induced by stimulating a large number of PBMCs or spleen cells with peptides or Ras protein in vitro and further that the superagonists described herein may be useful for stimulating T cells ex vivo, for purposes of cancer immunotherapy (discussion).
Regarding claim 98, Abelin teaches a method comprising (a) expressing affinity acceptor tagged HLA-peptide complexes (b) identifying an HLA-allele specific peptide or complex of the affinity acceptor tagged HLA- peptide complexes; and (c) developing a therapeutic based on one or more sequences of an HLA-allele specific peptide (claim 1), wherein the therapeutic comprises… (c) one or more APCs comprising the one or more peptides… (e) a cell comprising a TCR or a chimeric T cell receptor (CAR) specific for an HLA in complex with the one or more peptides (claim 5), wherein identifying comprises performing mass spectrometry (claim 23). Abelin further teaches that there are different approaches to determine HLA-ligand profiling and that mass spectrometry has become a desired method of HLA-associated peptide sequencing (para 0256) and more specifically that mono- allelic mass spectrometry is high-throughput and therefore provides a rapid, unbiased, and clean approach for defining peptide- binding motifs across diverse MHC alleles (para 0128).
Regarding claim 103, Abelin teaches the one or more nucleic acids encoding the one or more peptides is RNA, optionally wherein the RNA is mRNA (para 0453).
Regarding claim 106, Abelin teaches a schematic of constructs designed for HLA class I and II expression in cultured cell lines. HLA-A*02:0l constructs in Fig. 2, including HLA-A*02:0l constructs represent HLA class I design.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to validate superagonist epitopes as taught by Tanaka, to have utilized mass spectroscopy for the identification of epitope presentation by APC as taught by Abelin, in the method of making antigen specific T cells as taught by Slanetz. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because the method of Slanetz and Abelin are analogous arts with similar methodology and goals, therefore the method of assessment taught by Abelin would meet concept of most informative assay as taught by Slanetz, Tanaka, as Abelin taught that mass spectrometry is high-throughput and therefore provides a rapid, unbiased, and clean approach. Further Tanaka’s method of testing combinatorial and degenerate peptide libraries derived from a CD4+ T cell reactive to K-RAS using mass spectrometry analysis and testing on T cell proliferation allows for library validation prior to use in the method of T cell generation and this would be beneficial for purpose of cancer immunotherapy.
All the claimed elements were known in the prior art and one skill in the art could have combined the elements as claimed by known methods with no change in their respective function and the combination would have yield predictable results to one of ordinary skill in the art at the time of the invention ( see KSR International Co v Teleflex Inc., 550U.S.-, 82 USPQ2d 1385, 2007).
Claim 99 is rejected under 35 U.S.C. 103 as being unpatentable over Slanetz (WO 2018/005712 A1, cited in OA 02/26/2026), Tanaka (The Journal of Immunology, Volume 162, Issue 12, June 1999, Pages 7155–7161; PTO-892) and Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022) as applied to claims 98, 101-104, 106-108, and 110-117 above, and further in view of Kaiser et al. (US 2017/0037370A1, IDS entered September 23, 2022).
The teachings of Slanetz, Tanaka and Abelin are detailed above.
Slanetz, Tanaka and Abelin do not teach wherein the cells are CD25 or CD14 depleted.
Regarding claim 99, Kaiser et al. teaches a method of producing T cells, T cell subsets and/or T cell progenitors from PBMC (abstract, [0087] and Examples). Kaiser et al. teaches that the step of separation of T cells, T cell subsets and/or T cell progenitors may comprise negative enrichment (direct labeling of non-T cells) of T cells or of the depletion of cellular subsets to be removed from the preparation. For example B cells may be removed from lymphoma patient material via the CD19 marker, inhibitory cells such as regulatory T cells (CD25 high), monocyte (CD14) can be removed as well using the markers CD25 and CD14, respectively ([0052]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have obtained CTL precursor cells from PBMC by depleting CD25 expressing cells in view of Kaiser to use in the method of Slanetz, Tanaka, and Abelin to generate antigen specific CTLs. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because the method of Slanetz requires CTL precursor cells with a preferred source of PBMCs and Kaiser teaches that T cells, T cell subsets and/or T cell progenitors can be obtained from PBMCs by depleting other cell types including CD25 regulatory T cells.
All the claimed elements were known in the prior art and one skill in the art could have combined the elements as claimed by known methods with no change in their respective function and the combination would have yield predictable results to one of ordinary skill in the art at the time of the invention ( see KSR International Co v Teleflex Inc., 550U.S.-, 82 USPQ2d 1385, 2007).
Claim 100 is rejected under 35 U.S.C. 103 as being unpatentable over Slanetz (WO 2018/005712 A1, cited in OA 02/26/2026), Tanaka (The Journal of Immunology, Volume 162, Issue 12, June 1999, Pages 7155–7161; PTO-892), Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022), and Kaiser et al. (US 2017/0037370A1, IDS entered September 23, 2022) as applied to claims 98-99, 101-104, 106-108, and 110-117 above, and further in view of Mallone et al (US 2016/0341718A1, cited in OA 09/03/2025).
The teachings of Slanetz, Tanaka, Abelin, and Kaiser are detailed above.
Slanetz, Tanaka, Abelin, and Kaiser do not teach incubation of cells in the presence of FLT3L.
However, Mallone teaches that to boost antigen presenting cells and optimizing T cell priming, the stimulation cocktail incorporated FLT-3 ligand, PGE2 and IL-7 ([0103]). Mallone teaches that FLT3L primed CD8+ T cells displayed a significantly more robust polyfunctional profile than GM-CSF/IL-4 cells ([0105]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a step in the generation of antigen specific CTLs from PBMCs that are CD14 depleted as taught by Slanetz, Tanaka, Abelin, and Kaiser with the stimulation cocktail incorporating FLT-3 ligand in view of Mallone. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Mallone teaches that the stimulation cocktail can boost antigen presenting cells and optimize T cell priming.
All the claimed elements were known in the prior art and one skill in the art could have combined the elements as claimed by known methods with no change in their respective function and the combination would have yield predictable results to one of ordinary skill in the art at the time of the invention ( see KSR International Co v Teleflex Inc., 550U.S.-, 82 USPQ2d 1385, 2007).
Claim 109 is rejected under 35 U.S.C. 103 as being unpatentable over Slanetz (WO 2018/005712 A1, cited in OA 02/26/2026), Tanaka (The Journal of Immunology, Volume 162, Issue 12, June 1999, Pages 7155–7161; PTO-892) and Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022) as applied to claims 98, 101-104, 106-108, and 110-117 above, and further in view of Bozzacco ( J Proteome Res. 2011 Nov 4;10(11):5016-30; cited in OA 02/26/2026).
The teachings of Slanetz, Tanaka and Abelin are detailed above.
Slanetz, Tanaka and Abelin do not teach wherein the mass spectrometry assay comprises detecting the epitope sequence by MS after elution from the APCs with a mass accuracy of the detected peptide to be less than 15 Da or less than 10,000 parts per million.
Bozzacco teaches identification of peptide sequences from in vivo MHC-peptide complexes from dendritic cells (abstract). Bozzacco teaches that the maximum error tolerance for MS scans was 10 ppm for MS and 1.0 Da for MS/MS and that only peptides with mass deviation less than 5ppm were considered for analysis (database search). Bozzacco further teaches that it is feasible to use MS technology to examine peptide presented by DCs and allows for critical interpretation of biological findings based on antigen presentation and T cell responses (page 5028, col 1, para 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added quality control parameters to the mass spectrometry analysis of the peptide as taught by Bozzacco in the method of generating antigen specific CTLs as taught by Slanetz, Tanaka and Abelin. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Bozzacco teaches that it is feasible to use MS technology to examine peptide presented by DCs and allows for critical interpretation of biological findings based on antigen presentation and T cell responses with high accuracy.
All the claimed elements were known in the prior art and one skill in the art could have combined the elements as claimed by known methods with no change in their respective function and the combination would have yield predictable results to one of ordinary skill in the art at the time of the invention ( see KSR International Co v Teleflex Inc., 550U.S.-, 82 USPQ2d 1385, 2007).
Response to Arguments
Applicant's arguments filed 07/13/2026 have been fully considered but they are not persuasive.
Applicant submits: I. The combination of references does not disclose all the elements of claim 98. Applicant submits that this interpretation leads to an unwarranted oversimplification that undermines the instant claimed method. A peptide scan on the target antigen can merely reveal amino acid sequences of possible epitopes on a protein and does not reveal any characteristics of the epitope, particularly, with respect to generating an immune response. Claim 98 recites obtaining epitope sequences from a library of curated epitopes for T cell activation and proliferation in vitro, (the claimed method), wherein each epitope sequence in the library is accompanied with the knowledge of said epitope' s HLA binding characteristics, e.g., HLA binding affinity and capability of stimulating T cells in vitro.
Slanetz, as acknowledged by the Office teaches using polypeptides that are capable of stimulating CD4+ and CD8+ T cells "without the requirement of knowing HLA restriction." (Office Action at p. 6). Thus, Slanetz does not teach a method requiring epitopes from a prevalidated and curated peptide library as claimed herein, because an epitope, according to Slanetz is not required to satisfy criteria (i) of the claim, that the peptide binds to HLA allele concerned. Nowhere does Slanetz teach selecting antigenic peptides based on whether they can bind to a patient's HLA allele for the purpose of T cell stimulation and expanding. Nowhere does Slanetz teach or suggest preparing a prevalidated library of epitopes in advance and preparing T cells responsive to the same. On the contrary, the instant claims require that "the prevalidated, warehouse curated library satisfies each of the following criteria."
The prevalidated, warehouse curated library is different from Slanetz' s peptides as is further evidenced by the instant specification, e.g., at least paragraph [0335], which states: A library of prevalidated epitopes is generated in advance. Such epitopes are collected from prior knowledge in the field, common driver mutations, common drug, mutations, tissue specific antigens, and tumor associated antigens. With the help of an efficient computer-based program for epitope prediction, HLA binding and presentation characteristics, pre-validated peptides are generated for storage and stocking as shown in a diagram in FIG. 2. ( emphasis added)
In response: Slanetz specifically teaches that the epitopes used “are capable of stimulating CD4+ and CD8+ T cells” and further that “a validated neoantigen is described as being associated with a disease state that is amenable to immune therapy, and where the neoantigen is capable of binding to MHC class I and/or class II molecules, and is immunogenic to T cells in that it causes T cell activation, proliferation and/or memory responses in CD4+ and/or CD8+ subpopulations; in one embodiment three or more neoantigens are prepared and validated” as detailed in the rejection above, which means that Slanetz et al. are generating a curated peptide library that has been validated by immunogenicity (ability to stimulate T cell to activation, proliferation and/ or memory response).
In more detail: Slanetz further teaches that “Ras-based neoantigen candidates are designed and validated as follows. A portion of a patient's genome including Ras is sequenced and the patient's tumor is sequenced, or a consensus tumor sequence is derived, and differences between the two are ascertained. The above Ras mutations are typical of expected sequencing results, and provide excellent neoantigen candidates. Peptide sequences of approximately 8-10 amino acids in length are created, spanning the mutation sites (i.e., at the first, second, third etc. up to eighth amino acid position). These candidate peptides are evaluated for potential MHC class I binding fit by computer modeling. Best fit candidates are advanced. These sequences are extended up to 15-24 amino acids in length using the tumor sequence. These longer peptides are modeled for class II binding fit, and optionally their ability to bind MHC class II is validated empirically. Peptide sequences that are able to bind MHC class I and/or class II structures are used to prime T cells or T cells obtained from blood are screened against panels of Ras peptides, and the reactive populations amplified” (para 104). Slanetz further teaches that an antigen is validated by confirming its immunogenicity (para 108).
Therefore the cell population that is being prepared is only being amplified against an epitope mixture that binds MHC, is immunogenic, which requires binding to an HLA allele protein.
The claim does not require knowledge of the HLA binding characteristics but that each epitope does bind a protein encoded by an HLA allele.
Further new art from Tanaka in the updated rejection above teaches a method of testing combinatorial and degenerate peptide libraries derived from a CD4+ T cell reactive to K-RAS using mass spectrometry analysis and testing on T cell proliferation, and that there are other known activating peptides from previous art.
Therefore, the ordinary artisan would know to validate the peptide set (library) before generating an expanded cell population specific to those peptides
Applicant submits: Office further alleges that Slanetz teaches T cell assays for measuring immunogenicity or various release criteria (Office Action at p. 6). As noted therein, these are post-production evaluation of the T cell product: the "release criteria". It does not provide any premonition whether the peptide to be used in PBMC stimulation will generate successful T cell population suitable for therapeutic application.
In response: Slanetz teaches that the peptides are capable of stimulating CD4+ and CD8+ T cells (para 0187). Slanetz further teaches that a validated neoantigen is described as being associated with a disease state that is amenable to immune therapy, and where the neoantigen is capable of binding to MHC class I and/or class II molecules, and is immunogenic to T cells in that it causes T cell activation, proliferation and/or memory responses in CD4+ and/or CD8+ subpopulations; in one embodiment three or more neoantigens are prepared and validated (para 0101).
The teaching of the release criteria for the expanded cell population is separate to the validation test.
Applicant submits: Abelin describes a method of identifying HLA-allele specific peptides. Abelin does not teach the instant claimed method. Abelin does not teach a method of preparing a cell population comprising at least 5 x I OAS total cells, comprising antigen-specific T cells, wherein the antigen specific T cells are prepared ex vivo by using peptides comprising T cell epitopes selected from a prevalidated, warehouse curated library of epitope sequences, wherein each peptide within the prevalidated, warehouse curated library satisfies criteria (i)-(iv) in the claim, of which, identification of epitopes that bind to a certain MHC protein encoded by an HLA allele by mass spectrometry is but one criterion.
In Response: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Abelin does not teach the generation of a high cell density population of antigen specific T cells. This limitation is taught by Slanetz as detailed in the obvious type rejection above.
Applicant submits: The instant claimed invention provides considerable improvement over Applicant's earlier work represented in Abelin, in that the instant claim requires inter alia, the presence of a robust library of prior-validated T cell activating epitope sequences that have not only been identified as capable of binding to a specific HLA allele via mass spectrometry, but also validated for their functionality in successfully activating T cells in vitro; the instant method requires selection of at least one peptide that is HLA-matched to a patient's HLA to stimulate patient PBMC with a peptide; coupled with a rapid method of making the antigen specific T cells. In the method as described in Slanetz, the T cells are exposed to a plurality of peptides without any prior knowledge of their cognate HLA, thus T cells are exposed to peptides with unknown T cell activation efficiency. For examples, Slanetz, FIG. 5B demonstrates that T cells were exposed to a total of 374 viral peptide antigens (Pepmix), and this results in undetectable T cell response against a total of 94 LMPl peptides of the Pepmix in 12 out of 16 healthy human donors; additionally, with 122 LMP2 peptides it was reported to yield undetectable responses in 8 of 16 healthy human donor samples ... etc. In contrast, the claimed method ensures T cell activation specificity by selecting HLA-specific peptides that have been identified by mass.
In Response: The improvement seen in the instant claims is predicted by the combination of the prior arts as detailed in the new 103 rejection above. Tanaka specifically teaches use of patient specific T cells to identify and validate superantigens for RAS as indicated by increased T cell proliferation; which would therefore be a method of validation and library formation prior to use generating an antigen specific T cell population.
Applicant submits: Moreover, the specific advantage of the claimed method is explained in the specification at para [0335]: Provided in this example is a method of bypassing lengthy sequencing, identification and manufacture of subject specific neoantigen peptides and thereafter generating T cells having the subject specific TCRs for cancer immunotherapy, at least for the time when a subject undergoes a process of such evaluation and preparations for the personalized therapy. Advantage of this process is that it is fast, targeted and robust. As shown in FIG. lA, patient identified with a cancer or tumor can be administered T cells that are activated ex vivo with warehouse curated peptides having selected, prevalidated collection of epitopes generated from a library of shared antigens known for the identified cancer. The process from patient selection to the T cell therapy may require less than 6 weeks.
In Response: In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., an advantage of shorter time to generated cell population) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Using a validated antigen set is contemplated to generate immunotherapy specifically as it affects ex vivo T cell proliferation by Tanaka as far back as 1999 in regards to the oncogene RAS and there are numerous peptide antigens that have already been validated and published that could be used as a “library” to generate the antigen specific T cells needed therefore this argument is a benefit that would naturally flow from the combination of the prior arts.
Applicant submits: However, Slanetz does not demonstrate that " ... the CD8+ T cells that are specific to the at least one cancer antigen epitope sequence is at least 1 % of total CD8+ T cells in the cell population." Applicant submits that 1 % of total CD3+ cells is different from a number ( or fraction) represented by at least 1 % of total CD8+ T cells. Additionally, it should be noted that the instant claim recites that at least 1% of total CD8+ T cells are specific to the at least one cancer antigen; hence the total number of antigen specific CD8+ T cells is the sum of all the "at least one cancer antigen[s]" present in the plurality of peptides.
In Response: It is not necessary for a reference to reduce to practice a limitation to be valid prior art please see MPEP § 2121: When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable.
Further Slanetz teaches T cell expansion from normal healthy donor PBMCs was performed at what we consider as process scale. Figure 2 is a schematic outlining important steps for the process. Compared to historical methods for expanding large numbers of EBV-specific T cells, the method described here is straight-forward yet effective. The cell number yield at Day 28 harvest was over 2 billion viable cells with a CD3% of >95%. The product is predominantly CD8+ (63%) with 12.5% of the total CD3 population expressing CCR7 and more than half the CD3 cells expressing the chemokine trafficking receptor CXCR3. (para 0225) Slanetz further shows 10.8% CD107a (marker of degranulation) positive CD3+ cells in response to EBNA (Fig 8B).
Applicant submits: Kaiser does not rectify the deficiencies as Slanetz and Abelin, as Kaiser fails to teach expanding T cells with a composition comprising RNA encoding the plurality of peptides containing the at least one cancer antigen epitope sequence, wherein the at least one cancer antigen epitope sequence is selected from a prevalidated, warehouse curated library of epitope sequences, as recited in instant claim 98.
Applicant discussed non-obviousness of claim 98 over the combination of Slanetz, Abelin and Kaiser in the preceding paragraph. Mallone does not cure the deficiencies of Slanetz, Abelin, and Kaiser. Claim 100 is dependent on claim 98. As such claim 100, being dependent from claim 98 bears all the features of the independent claim. Accordingly, Applicant requests withdrawal of the rejection of the claims and passing the claim to allowance.
Claim 109 is dependent on claim 98. As such claim 100, being dependent from claim 98 bears all the features of the independent claim. Accordingly, Applicant requests withdrawal of the rejection of the claims and passing the claim to allowance.
In Response: These arguments are addressed in detail above and as the 103 rejection is not overcome there is no deficiency seen in the rejection of claim 98 and therefore the rejection of the dependent claims are also not overcome.
Applicant submits: Moreover, Kaiser teaches expanding "genetically modified T cells," (Kaisar, title). Genetically modified T cells (CAR T cells) do not require APC mediated antigen presentation for stimulation. The instant method of claim 98 requires "contacting peripheral blood mononuclear cells (PBMCs) of a subject comprising T cells and antigen presenting cells (APCs) with a composition..." As indicated in prior response, APCs are necessary for antigen presentation and T cell activation, therefore magnetic separation of T cells in the process taught in Kaiser, therefore, eliminates any APCs in the cell culture and defeats the purpose in the instant method. At least for this reason, Kaiser fails to render the claims obvious. Thus, claim 98, and dependent claims 101-104, 106- 108, and 110-117 are not obvious over the combination of Slanetz, Abelin and Kaiser.
In Response: Depletion of CD25 Treg cells as taught by Kaiser would not deplete all of the APC in the PBMC used for expansion, the claim is drawn to depletion of CD25 or CD14 and therefore the rejection using Kaiser. Further depletion of CD14 would also not remove all APCs from the PBMC starting culture; while removing monocytes it would not remove dendritic cells or B cells which are also APCs.
Applicant submits: Erikson fails to disclose any of the specific epitopes recited in amended claim 105, let alone any teaching of HLA-specificity of the mutated epitopes, which is in contrast to the features of claim 98, that requires the selection of the peptide in accordance to its HLA binding specificity. For example, Erikson, at Figure 7 discloses T cell proliferative capability of a peptide mixture comprising G12 and G13 mutated sequences, wherein G12 mutated sequences include as SEQ ID NO: 22 (KLVVVGACGVGKSALTI), SEQ ID NO: 23 (KLVVVGADGVGKSALTI), SEQ ID NO: 24 (KLVVVGARGVGKSALTI), SEQ ID NO: 25 (KLVVVGASGVGKSALTI), SEQ ID NO: 26 (KLVVVGAVGVGKSALTI), therefore failing to disclose any antigens of claim 105; Erikson's method demonstrates proliferation of T cells to a variety of RAS mutations without any regard for HLA specificity of the resulting T cells in the mixed population. Thus, Erikson does not cure the deficiency of Slanetz and Abelin in rendering claim 98 obvious.
In response: Claim 105 is currently rejected under 112(b) for being out of sequence compliance and cannot therefore be searched for an updated 103 rejection.
Double Patenting
New Rejection
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.
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Claims 98-104, 106-108, and 109-117 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,162,072 B2 in view of Slanetz (WO 2018/005712 A1, cited in OA 02/26/2026), Tanaka (The Journal of Immunology, Volume 162, Issue 12, June 1999, Pages 7155–7161; PTO-892), and Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022).
Regarding claim 98-100, the patented claims teach a method of preparing tumor antigen-specific T cells ex vivo suitable for use as an autologous therapy, the method comprising: (a) depleting CD14+ cells and CD25+ cells from a population of immune cells comprising antigen presenting cells (APCs) and T cells, thereby forming a CD14/CD25 depleted population of immune cells comprising a first population of APCs and T cells, wherein the population of immune cells is from a biological sample from a human subject with cancer; and (b) incubating the CD14/CD25 depleted population of immune cells for a first time period in the presence of: (i) FMS-like tyrosine kinase 3 receptor ligand (FLT3L), and (ii) (A) a polypeptide comprising at least two tumor antigen epitope sequences expressed by cancer cells of a human subject, wherein each of the at least two tumor antigen epitope sequences contains a mutation and binds to an MHC protein expressed by the subject or (B) a polynucleotide encoding the polypeptide; thereby forming a population of stimulated T cells (claim 1).
The patented claims do not teach use of a curated prevalidated warehouse library; a specific number of cells generated, that the population of cells is PBMCs or specific validation assays.
Regarding claims 98, 101-102, 104, 110-111, 113-114, and 116-117, Slanetz teaches a method for making a composition comprising T-cells, the method comprising the steps of: (a) obtaining an initial cell population comprising T-cells; (b) stimulating the T-cells by exposing the cell population to one or more target antigens and to cytokines, (c) culturing the cell population in media comprising cytokines; (d) testing the cell population for antigen- specific reactivity; and (e) harvest the resulting composition comprising T cells (claim 21), wherein the one or more target antigens comprises a plurality of overlapping peptides derived from the one or more target antigens (claim 30), wherein the one or more target antigens comprises polypeptides derived from one or more neoantigens (claim 32), wherein the T cell composition resulting from the method comprises greater than 70% CD3+ T cells with predominantly CD8+ versus CD4+ T cells (claim 37), wherein the T cell composition resulting from the method wherein greater than about 1 % of the total CD3+ cells have reactivity toward the antigen or antigens (claim 20). Slanetz teaches that to create a reactive T cell population, a source of T cells is needed, peripheral blood mononuclear cells (PBMCs) are currently preferred (para 0115) and further that PBMCs are suspended in culture medium, exposed to multiple polypeptides derived from target antigens (which load onto MHC structures on APCs in the cell population) and expanded (paras 0127-0133). Slanetz further teaches that using the method for ex vivo T cell expansion disclosed in the present application, a seeding of culture of about 30- to 100 million PBMCs, typically may yield approximately 10-100 million effective T cells for immunotherapy after about 21 days of culture (para 0172), and further generation of >2 billion CD3+ cells by Day 28 harvest (Figs 2-4). Slanetz further teaches that PepMixes are a pool of peptides (also referred to herein as "polypeptides") derived from a peptide scan of the target antigen of interest (each polypeptide is 15 amino acids with 11 amino acid overlap) that are capable of stimulating CD4+ and CD8+ T cells without the requirement of knowing HLA restriction (para 0187), which are interpreted to represent a prevalidated, curated library. Slanetz further teaches that a validated neoantigen is described as being associated with a disease state that is amenable to immune therapy, and where the neoantigen is capable of binding to MHC class I and/or class II molecules, and is immunogenic to T cells in that it causes T cell activation, proliferation and/or memory responses in CD4+ and/or CD8+ subpopulations; in one embodiment three or more neoantigens are prepared and validated and further that the number of neoantigens in the preparation used to immunize T cells may include ten, fifteen or twenty or more individual neoantigens (para 0101). Slanetz further teaches that T cell assays suitable for measuring the immunogenicity of antigens include: ELISA measuring levels of various activation cytokines, and ELISpot to quantify the frequency of cytokine-producing cells (para 0113). Slanetz further teaches that ex vivo expanded cells are tested for appropriate release criteria to be deemed fit for immunotherapy including (a) an effective cell number required for the adoptive therapy, (b) cell viability, (c) expression of cell surface markers for effective antigen recognition diversity, (d) an effective mix of desired phenotypes, (e) cellular response with respect to cytokine generation and cytotoxicity for the target cells are included in the release criteria (para 0173). Slanetz teaches the Cytotoxicity Assay: LDH Cytotoxicity Detection Kit (para 0223); as well as assaying for cytokines IFN gamma, IL-2 and TNF alpha on days 25-28 (figs 2-4).
Regarding claim 105, Slanetz teaches in accordance with the invention, Ras-based neoantigen candidates are designed and validated as follows (para 0104)
Regarding claim 106, Figs 5C-5D teach HLA alleles including A2*0201.
Regarding claim 107 and 113, Slanetz teaches that the number of antigen specific spots were divided by DMSO alone background counts to determine the relative frequency of total T cells that responded to each antigen (para 0194). Slanetz further teaches that DMSO was also used as control for intracellular cytokine staining (para 0201).
Regarding claim 108, Slanetz teaches cells stimulated with human serum separate from the Pepmix (para 0201) human serum would comprise other peptide epitopes.
Regarding claim 112, Slanetz teaches pepmix generated better than 2 fold higher cytotoxicity in T cell versus DMSO control (Fig 8C).
Regarding claim 115, Slanetz teaches that 33.5% of the 2 billion cells generated were CD4+ (Fig. 8a) as >1% of the >70% CD3 cells are antigen specific and the majority of the CD3 cells were CD8+ (>50%) (claim 20); the ordinary artisan can deduce that this would generate at least 0.1% antigen specific CD4+ T cells especially as Slanetz further teaches one of the specific advantages of the use of IL-7 in T cell culture is that it promotes antigen specific CD4+ T cell expansion (para 0139).
Regarding claim 98, Abelin teaches a method comprising (a) expressing affinity acceptor tagged HLA-peptide complexes (b) identifying an HLA-allele specific peptide or complex of the affinity acceptor tagged HLA- peptide complexes; and (c) developing a therapeutic based on one or more sequences of an HLA-allele specific peptide (claim 1), wherein the therapeutic comprises… (c) one or more APCs comprising the one or more peptides… (e) a cell comprising a TCR or a chimeric T cell receptor (CAR) specific for an HLA in complex with the one or more peptides (claim 5), wherein identifying comprises performing mass spectrometry (claim 23). Abelin further teaches that there are different approaches to determine HLA-ligand profiling and that mass spectrometry has become a desired method of HLA-associated peptide sequencing (para 0256) and more specifically that mono- allelic mass spectrometry is high-throughput and therefore provides a rapid, unbiased, and clean approach for defining peptide- binding motifs across diverse MHC alleles (para 0128).
Regarding claim 103, Abelin teaches the one or more nucleic acids encoding the one or more peptides is RNA, optionally wherein the RNA is mRNA (para 0453).
Regarding claim 106, Abelin teaches a schematic of constructs designed for HLA class I and II expression in cultured cell lines. HLA-A*02:0l constructs in Fig. 2, including HLA-A*02:0l constructs represent HLA class I design.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to validate superagonist epitopes as taught by Tanaka, to have utilized mass spectroscopy for the identification of epitope presentation by APC as taught by Abelin and to add use of a curated peptide library to generate a specific cell number as taught by Slanetz, in the method of making antigen specific T cells as taught by the patented claims. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because the method of the patented claims, Slanetz and Abelin are analogous arts with similar methodology and goals. Further Tanaka’s method of testing combinatorial and degenerate peptide libraries derived from a CD4+ T cell reactive to K-RAS using mass spectrometry analysis and testing on T cell proliferation allows for library validation prior to use in the method of T cell generation and this would be beneficial for purpose of cancer immunotherapy.
All the claimed elements were known in the prior art and one skill in the art could have combined the elements as claimed by known methods with no change in their respective function and the combination would have yield predictable results to one of ordinary skill in the art at the time of the invention ( see KSR International Co v Teleflex Inc., 550U.S.-, 82 USPQ2d 1385, 2007).
Claim 98, 101-104, 106-108, and 110-117 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 9, and 13 of U.S. Patent No. 12,246,067 B2 in view of Slanetz (WO 2018/005712 A1, PTO-892), Tanaka (The Journal of Immunology, Volume 162, Issue 12, June 1999, Pages 7155–7161; PTO-892) and Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022).
Regarding claim 98, the patented claims teach a composition comprising T cells specific to an HLA-peptide complex comprising at least one mutant RAS peptide sequence, wherein the HLA-peptide complex comprises a protein encoded by an HLA-C03:04 allele, and the at least one mutant RAS peptide sequence consists of (SEQ ID NO: 2064) GAVGVGKSA (claim 1), and a method of preparing the composition of claim 1, comprising priming T cells with antigen presenting cells (APCs) comprising (i) a polypeptide comprising the at least one mutant RAS peptide sequence (claim 3), further comprising priming the T cells with APCs in the presence of one or more additional mutant RAS peptide sequences (claim 9), wherein the T cells comprise CD4+ and CD8+ T cells (claim 13).
The patented claims do not teach use of a curated prevalidated warehouse library; a specific number of cells generated, that the population of cells is PBMCs or specific validation assays.
Regarding claims 98, 101-102, 104, 110-111, 113-114, and 116-117, Slanetz teaches a method for making a composition comprising T-cells, the method comprising the steps of: (a) obtaining an initial cell population comprising T-cells; (b) stimulating the T-cells by exposing the cell population to one or more target antigens and to cytokines, (c) culturing the cell population in media comprising cytokines; (d) testing the cell population for antigen- specific reactivity; and (e) harvest the resulting composition comprising T cells (claim 21), wherein the one or more target antigens comprises a plurality of overlapping peptides derived from the one or more target antigens (claim 30), wherein the one or more target antigens comprises polypeptides derived from one or more neoantigens (claim 32), wherein the T cell composition resulting from the method comprises greater than 70% CD3+ T cells with predominantly CD8+ versus CD4+ T cells (claim 37), wherein the T cell composition resulting from the method wherein greater than about 1 % of the total CD3+ cells have reactivity toward the antigen or antigens (claim 20). Slanetz teaches that to create a reactive T cell population, a source of T cells is needed, peripheral blood mononuclear cells (PBMCs) are currently preferred (para 0115) and further that PBMCs are suspended in culture medium, exposed to multiple polypeptides derived from target antigens (which load onto MHC structures on APCs in the cell population) and expanded (paras 0127-0133). Slanetz further teaches that using the method for ex vivo T cell expansion disclosed in the present application, a seeding of culture of about 30- to 100 million PBMCs, typically may yield approximately 10-100 million effective T cells for immunotherapy after about 21 days of culture (para 0172), and further generation of >2 billion CD3+ cells by Day 28 harvest (Figs 2-4). Slanetz further teaches that PepMixes are a pool of peptides (also referred to herein as "polypeptides") derived from a peptide scan of the target antigen of interest (each polypeptide is 15 amino acids with 11 amino acid overlap) that are capable of stimulating CD4+ and CD8+ T cells without the requirement of knowing HLA restriction (para 0187), which are interpreted to represent a prevalidated, curated library. Slanetz further teaches that a validated neoantigen is described as being associated with a disease state that is amenable to immune therapy, and where the neoantigen is capable of binding to MHC class I and/or class II molecules, and is immunogenic to T cells in that it causes T cell activation, proliferation and/or memory responses in CD4+ and/or CD8+ subpopulations; in one embodiment three or more neoantigens are prepared and validated and further that the number of neoantigens in the preparation used to immunize T cells may include ten, fifteen or twenty or more individual neoantigens (para 0101). Slanetz further teaches that T cell assays suitable for measuring the immunogenicity of antigens include: ELISA measuring levels of various activation cytokines, and ELISpot to quantify the frequency of cytokine-producing cells (para 0113). Slanetz further teaches that ex vivo expanded cells are tested for appropriate release criteria to be deemed fit for immunotherapy including (a) an effective cell number required for the adoptive therapy, (b) cell viability, (c) expression of cell surface markers for effective antigen recognition diversity, (d) an effective mix of desired phenotypes, (e) cellular response with respect to cytokine generation and cytotoxicity for the target cells are included in the release criteria (para 0173). Slanetz teaches the Cytotoxicity Assay: LDH Cytotoxicity Detection Kit (para 0223); as well as assaying for cytokines IFN gamma, IL-2 and TNF alpha on days 25-28 (figs 2-4).
Regarding claim 105, Slanetz teaches in accordance with the invention, Ras-based neoantigen candidates are designed and validated as follows (para 0104)
Regarding claim 106, Figs 5C-5D teach HLA alleles including A2*0201.
Regarding claim 107 and 113, Slanetz teaches that the number of antigen specific spots were divided by DMSO alone background counts to determine the relative frequency of total T cells that responded to each antigen (para 0194). Slanetz further teaches that DMSO was also used as control for intracellular cytokine staining (para 0201).
Regarding claim 108, Slanetz teaches cells stimulated with human serum separate from the Pepmix (para 0201) human serum would comprise other peptide epitopes.
Regarding claim 112, Slanetz teaches pepmix generated better than 2 fold higher cytotoxicity in T cell versus DMSO control (Fig 8C).
Regarding claim 115, Slanetz teaches that 33.5% of the 2 billion cells generated were CD4+ (Fig. 8a) as >1% of the >70% CD3 cells are antigen specific and the majority of the CD3 cells were CD8+ (>50%) (claim 20); the ordinary artisan can deduce that this would generate at least 0.1% antigen specific CD4+ T cells especially as Slanetz further teaches one of the specific advantages of the use of IL-7 in T cell culture is that it promotes antigen specific CD4+ T cell expansion (para 0139).
Regarding claim 98, Abelin teaches a method comprising (a) expressing affinity acceptor tagged HLA-peptide complexes (b) identifying an HLA-allele specific peptide or complex of the affinity acceptor tagged HLA- peptide complexes; and (c) developing a therapeutic based on one or more sequences of an HLA-allele specific peptide (claim 1), wherein the therapeutic comprises… (c) one or more APCs comprising the one or more peptides… (e) a cell comprising a TCR or a chimeric T cell receptor (CAR) specific for an HLA in complex with the one or more peptides (claim 5), wherein identifying comprises performing mass spectrometry (claim 23). Abelin further teaches that there are different approaches to determine HLA-ligand profiling and that mass spectrometry has become a desired method of HLA-associated peptide sequencing (para 0256) and more specifically that mono- allelic mass spectrometry is high-throughput and therefore provides a rapid, unbiased, and clean approach for defining peptide- binding motifs across diverse MHC alleles (para 0128).
Regarding claim 103, Abelin teaches the one or more nucleic acids encoding the one or more peptides is RNA, optionally wherein the RNA is mRNA (para 0453).
Regarding claim 106, Abelin teaches a schematic of constructs designed for HLA class I and II expression in cultured cell lines. HLA-A*02:0l constructs in Fig. 2, including HLA-A*02:0l constructs represent HLA class I design.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized mass spectroscopy for the identification of epitope presentation by APC as taught by Abelin and to add use of a curated peptide library to generate a specific cell number as taught by Slanetz, in the method of making antigen specific T cells as taught by the patented claims. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because the method of the patented claims, Slanetz and Abelin are analogous arts with similar methodology and goals.
All the claimed elements were known in the prior art and one skill in the art could have combined the elements as claimed by known methods with no change in their respective function and the combination would have yield predictable results to one of ordinary skill in the art at the time of the invention ( see KSR International Co v Teleflex Inc., 550U.S.-, 82 USPQ2d 1385, 2007).
Response to Arguments
Applicant's arguments filed 07/13/2026 have been fully considered but they are not persuasive.
Applicant submits: The claims in '072 patent do not disclose a method comprising contacting PBMCs of a subject comprising T cells and antigen presenting cells (APCs) with a composition comprising RNA a plurality of peptides containing the at least one cancer antigen epitope sequence, wherein the at least one cancer antigen epitope sequence is selected from a prevalidated, warehouse curated library of epitope sequences. Slanetz and Abelin fail to cure the deficiencies as discussed above.
In response: The alleged deficiencies of Slanetz and Abelin are discussed in detail in the response to arguments for the 103 rejection above.
Applicant submits: Additionally, the patented claims (‘067) are drawn to a method involving contacting the cells comprising APCs and T cells with tumor antigen epitope sequences expressed by cancer cells of a human subject, wherein each of the tumor antigen epitope sequences contains a mutation and binds to an MHC protein expressed by the subject with a stronger affinity than a corresponding wild-type epitope sequence in the subject.
In Response: The epitopes described in the patent anticipates limitations of the instant claims in that they are prevalidated cancer epitopes; contacting cells with APC and T cells using these cancer epitopes also anticipates limitations of the instant claims. The deficiencies in the patent are covered by Slanetz, Tanaka and Abelin in the obvious type rejection in detail above.
Applicant submits: The Office opines "the methods of determining immunogenicity, presentation by APCs and cytotoxicity do not structurally change the composition itself and therefore the patented claims are not distinct from the instant claims." (Office Action at p. 14, second para.). Applicant disagrees, for the reason that instant claim 98 recites features that are not recited in the claims of the '067 patent, e.g., a selection step for the at least one cancer antigen epitope sequence from a prevalidated, warehouse curated library. Slanetz and Abelin fail to cure the deficiencies as discussed above.
In Response: The alleged deficiencies of Slanetz and Abelin are discussed in detail in the response to arguments for the updated 103 rejection above.
Conclusion
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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