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Claims 77-97 are withdrawn.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Grounds of Rejection Withdrawn
Previous rejection of claims 98-100 under 35 U.S.C. 102 in view of van Buuren are withdrawn in view of the 102(b)(2)(C) exception statement filed 12/03/2025.
Previous rejection of claim 98 under 35 U.S.C. 102 in view of Juneja are withdrawn in view of the 102(b)(2)(C) exception statement filed 12/03/2025.
Previous rejection of claims 98-100 under NSDP over copending Application No. 17/253,922 is withdrawn in view claim amendments.
Previous rejection of claims 98 under NSDP over copending Application No. 17/618,067 is withdrawn in view claim amendments.
Previous rejection of claims 98 under NSDP over copending Application No. 19/046,067 is withdrawn in view claim amendments.
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, non-patent literature documents 110, 113, 186, and 331 were not attached. It has been placed in the application file, but the information referred to therein has not been considered.
The information disclosure statement filed August 28, 2024 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; non patent literature documents 014, 015 and 031 were not attached. It has been placed in the application file, but the information referred to therein has not been considered.
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.
The instant claim attempts to incorporate by reference to a specific table; however, such incorporation is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. In the instant case, there is a practical way to define the invention in words. Incorporation by reference is a necessity doctrine, not for applicant' s convenience. See MPEP 2173.05(s).
Claim Rejections - 35 USC § 103
New Rejection Necessitated by Amendment
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, 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 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).
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, 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 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, as Abelin taught that mass spectrometry is high-throughput and therefore provides a rapid, unbiased, and clean approach.
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, 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 and Abelin are detailed above.
Slanetz 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 CD14 expressing cells in view of Kaiser to use in the method of Slanetz 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 CD14 high monocytes.
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, 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, Abelin, and Kaiser are detailed above.
Slanetz, 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, 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 105 is rejected under 35 U.S.C. 103 as being unpatentable over Slanetz (WO 2018/005712 A1, 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 Eriksen (WO 2015/086590 A2; PTO-892).
The teachings of Slanetz and Abelin are detailed above.
Slanetz teaches there are specific genomic loci known to be mutated frequently in various cancers, such as the KRAS gene mutations (para 0094) and further that constitutively activated Ras can contain one or more mutations that eliminate or reduce GTP hydrolysis, which results in the protein being rendered permanently active, including the most common found at glycine residue G12 within the P-loop, as well as the catalytic residue Q61 (para 0102). Slanetz further teaches that in accordance with the invention Ras-based neoantigen candidates are designed and validated (para0104).
Slanetz and Abelin do not teach wherein at least one cancer antigen epitope sequences is a mutated RAS sequence selected from sequences listed in table 4A-4M.
Eriksen teaches a peptide mixture suitable for eliciting an immune response comprising 2 peptides wherein each comprise at least 8 amino acids that include position 13 of the RAS protein, each of the peptides has a point mutation at position 13 (claim 1), wherein the peptide mixture further comprises: at least one further peptide corresponding to a fragment of the RAS protein comprising a region of a least 8 amino acids which includes position 12 of the RAS protein, has at least 6 amino acid residues and wherein there is a point mutation at the amino acid corresponding to position 12 of the RAS protein and/ or at least one further peptide corresponding to a fragment of the RAS protein comprising a region of a least 8 amino acids which includes position 61 of the RAS protein (claim 3), wherein the point mutation at the amino acid corresponding to position 12 of the RAS protein is selected from a G12A, G12C, G12D, G12R, G12S or a G12V mutation and/or wherein the point mutation at the amino acid corresponding to position 61 of the RAS protein is selected from a Q61 E, Q61 H, Q61 K, Q61 L, a Q61 P or a Q61 R mutation (claim 4). Erikson further teaches SEQ ID NO: 16 comprising DGETCLLDILDTAGLEEYSAMRDQYMRTGE including a Q61L mutation and SEQ ID NO: 22 comprising KLVVVGACGVGKSALTI including a G12C mutation. At least 8 amino acids of SEQ ID NO 16 including the mutation Q61L would include peptides from Table 4E including the first 4 peptides listed. At least 6 amino acids of SEQ ID NO: 22 including the mutation G12C includes the first peptide listed in Table 4A.
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 used specific immunogen Ras sequences as taught by Eriksen in the method of generating antigen specific CTLs as taught by Slanetz and Abelin. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Eriksen teaches these peptides are suitable for eliciting an immune response as well as giving the specific peptide size limitations required and Slanetz also incorporates the use of Ras mutated proteins in the peptides to be used for generation of antigen specific CTLs.
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, 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; PTO-892).
The teachings of Slanetz and Abelin are detailed above.
Slanetz 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 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 12/03/2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to claim(s) 98-100 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant submits: In contrast, the claimed method yielded surprising and unexpected results. As recited in the claim, the method resulted in high yield of expanded cells e.g., comprising at least 5 x 10^8 total cells, comprising antigen-specific T cells, in combination with expanding the antigenspecific T cells ex vivo, thereby generating CD8+ T and CD4+ T cells specific to the one or more peptides containing the at least one cancer antigen epitope sequence by the process, wherein "the CD8+ T cells that are specific to the at least one cancer antigen epitope sequence is at least 1% of total CDS+ T cells in the cell population" as recited in claim 98.
In response: In view of the nearly cited art Slanetz as detailed above these results are not surprising as Slanetz generated 2 x 10^9 cells comprising antigen specific CD8+ and CD4+ with more than 70% being CD3+ with the majority being CD8+ and at least 1% of all of the CD3+ cells being antigen specific.
Applicant submits: Furthermore, Kaiser teaches isolation or enrichment of T cells from peripheral blood cells, followed by genetic modification of the isolated T cells. See for example, Kaiser at paragraphs [0018]-[0026] or paragraph [0037]. 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 ... " 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.
In response: While Kaiser is directed to isolation of the T cells before genetic manipulation, the goal of Slanetz to acquire a minimum of 70% of CD3+ cells in combination with in process monitoring of cell population composition would render it obvious to the ordinary artisan that the depletion of the monocytes could occur after APC presentation of the neoantigens in the mixed PBMC culture as taught by Slanetz to further purify the population.
Double Patenting
New Rejection Necessitated by Amendment
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 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, 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 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).
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) 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).
Claims 98, 101-104, 106-108, and 110-117 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 109 and 112-114 of copending Application No. 18/007,024 (reference application) in view of Slanetz (WO 2018/005712 A1, PTO-892) and Abelin et al. (WO 2018/148671 A1; IDS entered September 23, 2022).
Regarding claim 98, the copending claims teach a method of producing an ex vivo population of expanded antigen specific T cells, the method comprising: a) culturing T cells from a biological sample from a subject in a first cell culture medium comprising antigen presenting cells (APCs) to produce a first population of T cells, wherein the APCs present an epitope of a peptide antigen in complex with an MHC protein; b) culturing the first population of T cells in a second cell culture medium to produce a second population of T cells; c) enriching CD137 (4-lBB)-expressing T cells from the second population of T cells to produce a third population of T cells; and d) expanding the third population of T cells in a third cell culture medium to obtain ex vivo population of expanded antigen specific T cells (claim 109), wherein the first cell culture medium comprises one or more peptide antigens comprising the peptide antigen (claim 114).
Regarding claim 99, wherein the biological sample is a sample of peripheral blood mononuclear cells (PBMCs) from the subject; and wherein the method further comprises depleting CD14+ cells from the PBMC prior to culturing (claim 112) and wherein the method further comprises depleting CD25+ cells from the PBMC prior to culturing (claim 113).
The copending 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 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 copending 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 copending 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).
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 12/03/2025 have been fully considered but they are not persuasive.
Applicant’s arguments with respect to claim(s) 98-100 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant submits: but none of the claims in '072 recite contacting PBMCs with "at least one cancer antigen epitope sequence is selected from a prevalidated, warehouse curated library of epitope sequences .... "
In response: The new obviousness rejection in view of Slanetz addresses this as detailed above.
Applicant submits: Regarding U.S. Patent No. 12,246,067 B2…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.
In response: The new obviousness rejection in view of Slanetz addresses this as detailed above.
Conclusion
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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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643