DETAILED ACTION
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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4 and 7-16 in the reply filed on 2/27/2025 is acknowledged.
Claims 17-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/27/2025.
Claims 5-6 are cancelled.
Claims 1-4 and 7-16 are examined herein.
Priority
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2020/035307, filed 05/29/2020, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 62/855,718, filed 05/31/2019.
Information Disclosure Statement
The information disclosure statement filed on 6/14/2022, and the information disclosure statement filed on 2/27/2025 are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
In page 44 paragraph 2, "ELIPOT" appears to be a typographical error, namely it is suggested that "ELIPOT" read as "ELISPOT" as per Fig. 1 and page 4 paragraphs 2 and 5 of the specification.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 9-10 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Nielsen et al. Clin Cancer Res (2016) 22 (9): 2226–2236 https://doi.org/10.1158/1078-0432.CCR-15-2023 (Cited on sheet 10 of IDS filed 6/14/2022) ("Nielsen") as evidenced by JS Nielsen et al. Supplemental Materials Clin Cancer Res (2016) 22 (9): 2226–2236 https://doi.org/10.1158/1078-0432.CCR-15-2023 (retrieved online https://aacrjournals.org/clincancerres/article/22/9/2226/79648/Toward-Personalized-Lymphoma-Immunotherapy on 3/31/2025)..
Regarding claims 1-2, Nielsen teaches a method for detecting antigen specific T cell activation in a population of T cells (“In vitro T-cell priming Monocyte-derived dendritic cells were pulsed with peptides and cultured with autologous PBMC to activate peptide-specific CD8+ T cells (Supplementary Methods)… The frequency of responding T cells was determined by counting the number of positive wells and dividing by the number of input cells” page 2227 column 2 paragraph 4), comprising: in vitro stimulation (IVS) of a population of T cells (“Stimulations were performed in 96-well plates” page 2227 column 2 paragraph 4), wherein the IVS involves culturing the T cells in an enriched media (“Cells were cultured in 96-well plates (15,000 APC plus 150,000 PBMC/well) in 0.22 µm-filtered CTL media: RPMI-1640 (Hyclone) supplemented with 10% heat-inactivated human AB serum (Sigma-Aldrich), 12.5 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin/100 µg/ml streptomycin (Hyclone), and 50 µM β-mercaptoethanol (Sigma-Aldrich)” Supplemental Materials page 2). Note that while the specification page 1 paragraph 4 discloses that “[i]n some embodiments the enriched media includes IL-2, IL-7, or IL-2 and IL-7”, the use of the language “[i]n some embodiments” is interpreted as exemplary and does not limit the claimed method to an enriched media that must contain IL-2, IL-7, or IL-2 and IL-7. Therefore, using the broadest reasonable interpretation of “enriched media” the teaching of Nielsen of RPMI-1640 (Hyclone) media supplemented with 10% heat-inactivated human AB serum (Sigma-Aldrich), 12.5 mM HEPES, 2 mM L-glutamine, 100 U/ml penicillin/100 µg/ml streptomycin (Hyclone), and 50 µM β-mercaptoethanol (Sigma-Aldrich) anticipates “enriched media”. Nielsen further teaches stimulation of the cultured T cells with neoantigen matured autologous dendritic cells (DCs) (“Monocyte-derived dendritic cells were generated by culturing the adherent fraction of PBMC in AIM-V serum-free media (Gibco, Life Technologies) supplemented with 20 mM HEPES (Hyclone), 2 mM L-glutamine (Hyclone), 800 IU/ml GM-CSF (PeproTech), and 800 IU/ml IL-4 (PeproTech). Media was partially replaced on days 3 and 5 with media containing 600 IU/ml GM-CSF and 600 IU/ml IL-4. On day 6, 50 µg/ml poly(I:C) (Sigma-Aldrich) was added to mature the dendritic cells for use 18 hours later as antigen presenting cells (APC) (4). Dendritic cells were harvested, pulsed with patient-specific peptide libraries (1 µM/peptide), irradiated (32 Gy), and cultured for 10 days with autologous PBMC to activate antigen-specific CD8+ T cells” Supplemental Materials page 1 paragraph 2 and page 2), and expanding the stimulated T cells to produce a population of expanded T cells (“[c]ells were cultured” Supplemental Materials page 2); restimulation of the expanded T cells (“After 10-11 days, a second round of stimulation was performed” Supplemental Materials page 2) with neoantigen matured autologous DCs (“peptide-pulsed autologous PBMC (50,000 cells/well) as APC, along with 50 µg/ml poly(I:C)” Supplemental Materials page 2, “patient PBMCs from all available time points were subjected to two rounds of in vitro stimulation with autologous APC pulsed with a pool of purified, synthetic peptides corresponding to each patient's predicted epitopes” page 2228 column 1 last paragraph and column 2 paragraph 1); and analyzing the restimulated T cells to detect antigen specific T cell activation (“T cells were screened for reactivity by IFNγ ELISPOT (Supplementary Methods). The frequency of responding T cells was determined by counting the number of positive wells and dividing by the number of input cells” page 2227 column 2 paragraph 4). Nielsen further suggests wherein the analysis of T cell activation is performed on a patient receiving a personalized cancer vaccine and wherein the personalized cancer vaccine is reformulated based on the analysis and the patient is administered the reformulated personalized cancer vaccine, wherein the reformulated personalized cancer vaccine includes at least one neoantigen that is not in the personalized cancer vaccine initially administered to the patient (“A fundamental challenge in cancer genomics is to design effective treatments that exploit the mutational profile of tumors” page 2226 column 2 paragraph 1, “Indeed, T cells that recognize the common drivers BCR-ABL and mutant KRAS have been identified in patient blood samples, and peptide-based vaccines against these mutations have shown promise in the clinic (3–6). With the advent of NGS, it is now feasible to extend this concept to additional driver mutations, even those that are unique to individual patients. Indeed, many cancer clinics are now using "panel" approaches wherein commonly mutated genes are sequenced to guide the design of individualized therapies” page 2227 column 1 paragraph 1, “NGS data are currently being used to design personalized mutation-specific vaccines” page 2234 column 1 paragraph 3). Nielsen further teaches that “[e]ncouragingly, our findings suggest that a higher proportion of mutations can be recognized by autologous T cells than previously thought based on analyses of pre-existing T-cell responses alone” (page 2233 column 1 last paragraph).
Nielsen teaches all of the limitations of claim 1 in separate embodiments. Nielsen teaches the restimulation of the expanded T cells with autologous PBMCs, which is interpreted as a genus of the dendritic cells claimed. However, Nielsen teaches the neoantigen matured autologous DCs in the first stimulation of the T cells (Supplemental Materials page 2).
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 combine the teachings of Nielsen from separate embodiments, i.e., using dendritic cells, taught in the first stimulation of T cells, from the APC-PBMCs taught in the restimulation of the expanded T cells because it would have been obvious to try from a finite list of possible predictable solutions. In this case, there was the recognized problem of designing effective treatments that exploit the mutational profile of tumors. Given that Nielsen identified dendritic cells as PBMCs, it would have been obvious for a person having ordinary skill in the art to use dendritic cells from the genus APC-PBMCs. One would have been motivated to make such a modification because known work in one field of endeavor may prompt variations. The design incentive to produce effective treatments that exploit the mutational profile of tumors would have prompted a person having ordinary skill in the art to use dendritic cells from the APC-PBMC taught by Nielsen, especially since Nielsen teaches that the method taught is more efficient than other methods for detecting antigen specific T cell activation. A person having ordinary skill in the art would have had a reasonable expectation of success given that Nielsen teaches the protocol to generate neoantigen matured autologous dendritic cells from PBMCs.
Regarding claim 3, Nielsen suggests wherein the analysis of T cell activation is performed on a patient receiving a therapeutic treatment with a cancer vaccine and wherein the therapeutic treatment is modified based on the analysis (“Adoptive T-cell therapy (10, 48) allows one to circumvent issues of low precursor frequency, cross-reactivity, and immune suppression by isolating and expanding T cells from peripheral blood to produce defined T-cell products with high specificity for target mutations. Recent adoptive cell therapy trials using TIL specifically selected for mutation reactivity (or retrospectively shown to be mutation-reactive) underscore the clinical feasibility and efficacy of this strategy (8–10)” page 2234 column 1 last paragraph).
Regarding claim 9, Nielsen suggests wherein the restimulated T cells are analyzed using flow cytometry (“By flow cytometry, we confirmed that 2 of 2 tested bona fide mutation-specific responses were mediated by CD8+ rather than CD4+ T cells (Supplementary Fig. S3)” page 2231 column 1 paragraph 1).
Regarding claim 10, Nielsen teaches wherein the population of T cells is a sample of pan T cells purified from a patient's PBMCs (“and cultured for 10 days with autologous PBMC to activate antigen-specific CD8+ T cells” Supplemental Materials page 1 paragraph 2 and page 2).
Regarding claim 15, Nielsen teaches wherein the antigen specific T cell activation is measured as a percent frequency (% freq) of CD8+IFNy+ cells (“CD8+ T cells… T cells were screened for reactivity by IFNγ ELISPOT (Supplementary Methods). The frequency of responding T cells was determined by counting the number of positive wells and dividing by the number of input cells” page 2227 column 2 paragraph 4).
Regarding claim 16, Nielsen teaches wherein a % freq of CD8+IFNy+ cells greater than or equal to 3x over baseline indicates that a T cell population exceeds a threshold level of T cell activation (“Table 1. Summary of T-cell responses against pools of peptides corresponding to patient-specific mutations…aFrequency of … CD8+ T-cell fraction was approximately 10-fold higher” page 2229 Table 1).
Claims 4 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Nielsen as applied to claims 1 and 3 above, and further in view of Chiriva-Internati (WO 2016168264) and Rajasagi et al. Blood (2014) 124 (3): 453–462 https://doi.org/10.1182/blood-2014-04-567933 (Cited on sheet 12 of IDS filed 6/14/2022) ("Rajasagi").
Regarding claim 4, Nielsen suggests the method of claim 3 as discussed above.
Nielsen fails to teach wherein a dose of the therapeutic treatment is modified, the administration schedule of the treatment is modified, a co-therapy is administered, or any combination thereof.
Chiriva-Internati teaches “methods and compositions for the treatment and/or prevention of cancer” (Abstract). Chiriva-Internati further teaches a method for detecting antigen specific T cell activation in a population of T cells (“The ability to induce lymphocytes to exhibit an immune response can be determined by any method including, but not limited to, determining T lymphocyte cytolytic activity in vitro using for example tumor-associated antigen-specific antigen-presenting cells as targets of tumor associated antigen-specific cytolytic T lymphocytes (CTL); assaying tumor-associated antigen specific T lymphocyte proliferation; …. T lymphocytes can be obtained from any suitable source such as peripheral blood” page 34 paragraphs 3-4). Chiriva-Internati further teaches wherein the analysis of T cell activation is performed on a patient receiving a therapeutic treatment with a cancer vaccine (“the tumor-associated antigen(s) or peptide(s) of the present invention also may be administered to the subject, or in vitro to T cells, in the form of a nucleic acid vaccine” page 35 paragraph 2). Chiriva-Internati further suggests wherein a co-therapy is administered to the patient (“Accordingly, the antigen-primed antigen-presenting cells of the present invention and the antigen-specific T lymphocytes generated with these antigen-presenting cells can be used as immunomodulating compositions for prophylactic or therapeutic applications for cancer. In some embodiments, the tumor-associated antigen-primed antigen-presenting cells of the invention can be used for generating CD8+ CTL, CD4+ CTL, and/or B lymphocytes for adoptive transfer to the subject” page 35 paragraph 4). Chiriva-Internati further teaches that “[t]he present compositions or methods may function to provide or enhance an immune response” (page 35 last paragraph). Chiriva-Internati further teaches that “[t]he immune response that is elicited or enhanced may be sufficient for prophylactic or therapeutic treatment of a neoplastic disease, or a symptom associated therewith, particularly cancer” (page 36 paragraph 2). Chiriva-Internati further teaches that “[t]he immunological efficacy of the present methods and compositions may be determined based on the Distribution Free Resampling (DFR) method proposed and described by Moodie et al [66]. The release of cytokines (e.g., IFN-y, TNF-a, and/or IL-17) may be assayed by, e.g., ELISpot assay, to determine immune responses” (page 36 paragraphs 3-4).
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 modify the teachings of Nielsen to rely on administering a co-therapy to the patient taught by Chiriva-Internati because Chiriva-Internati teaches that the co-therapy treats cancer symptoms by enhancing an immune response. A person having ordinary skill in the art would have had a reasonable expectation of success because Chiriva-Internati teaches methods to determine the immunological efficacy of the co-therapy and both Chiriva-Internati and Nielsen teach a method for detecting antigen specific T cell activation.
Regarding claim 7, Nielsen teaches the method of claim 1 as discussed above.
Nielsen fails to teach wherein the enriched media includes IL-2, IL-7, or IL-2 and IL-7, and optionally wherein the T cells are cultured in the enriched media for about 24 hours before stimulation with neoantigen matured autologous DCs.
Rajasagi teaches “[s]ystematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia [CLL]” (Title). Rajasagi further suggests a method for detecting antigen specific T cell activation in a population of T cells (“To generate peptide-reactive T cells from CLL patients…T-cell specificity against peptide pools or autologous tumor was tested” page 454 column 2 paragraph 1, “we report herein a comprehensive strategy to systematically identify potential immunogenic neoantigens across cancers” page 459 column 1 paragraph 1), comprising: in vitro stimulation (IVS) of a population of T cells, wherein the IVS involves culturing the T cells in an enriched media, stimulation of the cultured T cells with neoantigen matured autologous dendritic cells (DCs), and expanding the stimulated T cells to produce a population of expanded T cells (“CD8+ T cells (10 million) from pre- and posttransplant PBMCs (CD81 Microbeads; Miltenyi, Auburn, CA) were cultured with autologous peptide pool-pulsed DCs (at a 40:1 ratio)… All stimulations were conducted in complete medium supplemented with 10% fetal bovine serum and 5 to 10 ng/mL interleukin (IL)-7, IL-12, and IL-15 (R&D Systems, Minneapolis, MN). APCs were pulsed with peptide pools (10 mM/peptide/pool for 3 hours)” page 454 column 2 paragraph 1); restimulation of the expanded T cells (“Subsequently, T cells were restimulated weekly (starting on day 7)” page 454 column 2 paragraph 1); and analyzing the restimulated T cells to detect antigen specific T cell activation (“T-cell specificity against peptide pools or autologous tumor was tested by interferon (IFN)-g ELISPOT” page 454 column 2 paragraph 1), wherein the analysis of T cell activation is performed on a patient receiving a personalized cancer vaccine (“Past cancer vaccine efforts have lacked efficacy” page 453 column 1 paragraph 1, “Herein, we report that putative neoantigens identified… are immunogenic in humans and can target malignant cells in a tumor-specific fashion” page 454 column 1 paragraph 3) and wherein the personalized cancer vaccine is reformulated based on the analysis and the patient is administered the reformulated personalized cancer vaccine (“Our approach provides a basis for designing truly personalized immunotherapeutic vaccines in humans” page 454 column 1 paragraph 3). Rajasagi further teaches wherein the enriched media includes IL-7 (“All stimulations were conducted in complete medium supplemented with 10% fetal bovine serum and 5 to 10 ng/mL interleukin (IL)-7… (R&D Systems, Minneapolis, MN)” page 454 column 2 paragraph 1). Rajasagi further suggest that the method for detecting antigen specific T cell activation “provide[s] a method for selecting neoantigens for future personalized vaccines broadly applicable across tumors” (page 459 column 2 paragraph 1).
Chiriva-Internati teaches that IL-7 is an immunostimulatory agent designed to enhance the immunologic response.
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 modify the teachings of Nielsen to rely on wherein the enriched media includes IL-7 taught by Rajasagi because it would have been a simple matter of applying a known technique to a known method. In this case, both Nielsen and Rajasagi teach a method for detecting antigen specific T cell activation in a population of T cells, comprising: in vitro stimulation (IVS) of a population of T cells, wherein the IVS involves culturing the T cells in an enriched media, stimulation of the cultured T cells with neoantigen matured autologous dendritic cells (DCs), and expanding the stimulated T cells to produce a population of expanded T cells; restimulation of the expanded T cells; and analyzing the restimulated T cells to detect antigen specific T cell activation. Rajasagi simply applies the art-recognized technique of wherein the enriched media includes IL-7. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Rajasagi to the base method taught by both references. One would have been motivated to make such a modification because Rajasagi suggest that this method enables future personalized vaccines broadly applicable across tumors. One would have been further motivated to make such a modification because Chiriva-Internati teaches that IL-7 is an immunostimulatory agent designed to enhance the immunologic response. A person having ordinary skill in the art would have had a reasonable expectation of success because Rajasagi teaches the commercial company where the enriched media was sourced from.
Claims 8 is rejected under 35 U.S.C. 103 as being unpatentable over Nielsen et al. Clin Cancer Res (2016) 22 (9): 2226–2236 https://doi.org/10.1158/1078-0432.CCR-15-2023 (Cited on sheet 10 of IDS filed 6/14/2022) ("Nielsen") as applied to claim 1 above and further in view of Rajasagi et al. Blood (2014) 124 (3): 453–462 https://doi.org/10.1182/blood-2014-04-567933 (Cited on sheet 12 of IDS filed 6/14/2022) ("Rajasagi").
Regarding claim 8, Nielsen teaches the method of claim 1 as discussed above.
Nielsen teaches wherein the stimulated T cells are expanded for 11 days (“After 10-11 days, a second round of stimulation was performed” Supplemental Materials page 2).
Nielsen fails to teach wherein the stimulated T cells are expanded for 12-16 days.
Rajasagi teaches wherein the stimulated T cells are expanded for 12-16 days (“For 1 of these neoepitopes (mutated FNDC3B), identified following only 2 weeks of in vitro stimulation” page 459 column 1 paragraph 2). Rajasagi further teaches that “these T cells are (1) stimulated by the mutated but not by the cognate native peptide (Figure 5D), (2) recognize autologous APCs transfected with a minigene encoding a portion of the FNDC3B gene including the mutation (Figure 5E), and (3) recognize autologous tumor cells and peptide-pulsed autologous B cells (Figure 5F). Clinically, the level of this T-cell population correlated with disease remission as measured both by ELISPOT analysis and qPCR of the TCR associated with this target (Figure 6A), and these T cells were induced to express CD107a, a marker of cytotoxic potential, following exposure to patient CLL cells (Figure 6B). All these features are consistent with the role of neoantigens in protective immunity in solid tumors as discussed above, but now are extended to a hematological malignancy with a low mutation rate. Our results and the results of others, together with our pipeline, provide a method for selecting neoantigens for future personalized vaccines broadly applicable across tumors” (page 459 column 1 paragraph 2).
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 modify the teachings of Nielsen to rely on wherein the stimulated T cells are expanded for 12-16 days taught by Rajasagi because it would have been a simple matter of applying a known technique to a known method. In this case, both Nielsen and Rajasagi teach a method for detecting antigen specific T cell activation in a population of T cells, comprising: in vitro stimulation (IVS) of a population of T cells, wherein the IVS involves culturing the T cells in an enriched media, stimulation of the cultured T cells with neoantigen matured autologous dendritic cells (DCs), and expanding the stimulated T cells for at least 11 days to produce a population of expanded T cells; restimulation of the expanded T cells; and analyzing the restimulated T cells to detect antigen specific T cell activation. Rajasagi simply applies the art-recognized technique of wherein the stimulated T cells are expanded for 12-16 days. Therefore, a person having ordinary skill in the art would have found it obvious to apply the technique taught by Rajasagi to the base method taught by both references. One would have been motivated to make such a modification because Rajasagi suggest that this is an efficient amount of time that enables accurate detection of antigen specific T cell activation, validated by its correlation with disease remission and the role of neoantigens in protective immunity in solid tumors. A person having ordinary skill in the art would have had a reasonable expectation of success because both Nielsen and Rajasagi teach a method for detecting antigen specific T cell activation involving expanding the T cells for at least 11 days.
Claims 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Nielsen as applied to claim 10 above, and further in view of Johanns et al. (2019) OncoImmunology, 8:4, e1561106, DOI:10.1080/2162402X.2018.1561106 (“Johanns”) and Cafri et al. NATURE COMMUNICATIONS | (2019) 10:449 | https://doi.org/10.1038/s41467-019-08304-z (“Cafri”).
Regarding claims 11 and 13, Nielsen teaches the method of claim 10 as discussed above.
Nielsen fails to teach wherein the patient’s PBMCs are obtained from patient apheresis at baseline of a putative therapeutic treatment, i.e., a personalized cancer vaccine.
Johanns teaches “[d]etection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma” (Title). Johanns further teaches detecting antigen specific T cell activation from patient’s PBMCs, wherein the patient’s PBMCs are obtained at baseline of a putative therapeutic treatment, i.e., a personalized cancer vaccine (“Here, we report the application of the same immunogenomics pipeline to identify candidate neoantigens and guide screening for neoantigen-specific T cell responses in a patient with GBM treated with a personalized synthetic long peptide vaccine following autologous tumor lysate DC vaccination. Following vaccination, reactivity to three HLA class I- and five HLA class II-restricted candidate neoantigens were detected by IFN-γ ELISPOT in peripheral blood” Abstract, “reactivity was also measured in a PBMC sample obtained immediately prior to GBM.PVax” page 2 column 2 paragraph 2). Johanns further teaches that this method enables the determination of “whether these neoantigen-specific responses were induced or augmented by vaccination rather than as a result of prior therapies” (page 2 column 2 paragraph 2). Johanns further teaches that “we were able to demonstrate an augmentation of neoantigen-specific T cell responses following vaccination… these results support the rationale for targeting neoantigens even in lower mutational burden tumors like GBM, where the number of potentially immunogenic candidates is perhaps more limited than higher mutational tumors, such as melanoma” (page 7 column 2 paragraph 1). Johanns further shows “Figure 1. Schematic representation of treatment course” (page 2). Johanns further teaches that “Heparinized blood was collected by venipuncture prior to GBM.PVax initiation and by leukapheresis after GBM.PVax cycle 4” (page 9 column 1 paragraph 5).
Cafri teaches “Memory T cells targeting oncogenic mutations detected in peripheral blood” (Title). Cafri further teaches wherein the patient’s PBMCs are obtained from patient apheresis (“IVS of naive and memory T cells. Apheresis samples were thawed, washed, set to 5–10e6 cells/ml with AIM-V media (Life Technologies) and 1.75–2 × 108 viable cells were incubated” (page 5 column 2 paragraph 2 and page 6 column 1 paragraph 1). Cafri further teaches that “[e]mploying this novel approach enabled us to identify and isolate neoantigen-reactive T cells that were present at very low frequencies in the circulation of metastatic cancer patients” (page 5 column1 paragraph 2).
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 modify the teachings of Nielsen to rely on detecting antigen specific T cell activation from patient’s PBMCs, wherein the patient’s PBMCs are obtained at baseline of a putative therapeutic treatment, i.e., a personalized cancer vaccine taught by Johanns because Johanns teaches that this method enables the determination of whether these neoantigen-specific responses were induced or augmented by vaccination rather than as a result of prior therapies. A person having ordinary skill in the art would have had a reasonable expectation of success because both Nielsen and Johanns teach a method for detecting antigen specific T cell activation in PBMCs wherein the PBMCs are obtained from a patient receiving a personalized cancer vaccine and Johanns also shows a schematic representation of the treatment course.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nielsen in view of Johanns to rely on obtaining the PBMCs from patient apheresis taught by Cafri because Cafri teaches that this method can identify neoantigen-reactive T cells that are present at very low frequencies in the circulation. A person having ordinary skill in the art would have had a reasonable expectation of success because Johanns teaches obtaining PBMCs using patient leukapheresis but on a method drawn to post therapeutic treatment, and Nielsen, Johanns, and Cafri teach detecting antigen specific T cell activation in PBMCs.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Nielsen as applied to claim 10 above, and further in view of Carreno et al. Science, 2 Apr 2015, Vol 348, Issue 6236, pp. 803-808 DOI: 10.1126/science.aaa38 (“Carreno”) and Cafri et al. NATURE COMMUNICATIONS | (2019) 10:449 | https://doi.org/10.1038/s41467-019-08304-z (“Cafri”)..
Regarding claim 12, Nielsen teaches the method of claim 10 as discussed above.
Nielsen fails to teach wherein the patient’s PBMCs are obtained from patient apheresis at 7 days post-dose of a putative therapeutic treatment.
Carreno teaches that “[a] dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells” (Title). Carreno further teaches a method of detecting antigen specific T cell activation from patient’s PBMCs obtained 7 days post dose of a putative therapeutic treatment (“To examine the kinetics and magnitude of T cell immunity to AAS peptides upon vaccination, we collected peripheral blood mononuclear cells (PBMCs) prior to vaccination and weekly thereafter. The CD8+ T cell response to each peptide was analyzed using a HLA-A*02:01/AAS-peptide dextramer assay after a single round of in vitro stimulation (fig. S4A) (7)” page 804 column 2 paragraph 2 and column 3 paragraph 1). Carreno further teaches that this method enables the examination of the kinetics and magnitude of T cell immunity due to the therapeutic treatment (page 804 column 2 paragraph 2).
Cafri teaches “Memory T cells targeting oncogenic mutations detected in peripheral blood” (Title). Cafri further teaches wherein the patient’s PBMCs are obtained from patient apheresis (“IVS of naive and memory T cells. Apheresis samples were thawed, washed, set to 5–10e6 cells/ml with AIM-V media (Life Technologies) and 1.75–2 × 108 viable cells were incubated” (page 5 column 2 paragraph 2 and page 6 column 1 paragraph 1). Cafri further teaches that “[e]mploying this novel approach enabled us to identify and isolate neoantigen-reactive T cells that were present at very low frequencies in the circulation of metastatic cancer patients” (page 5 column1 paragraph 2).
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 modify the teachings of Nielsen to rely on detecting antigen specific T cell activation from patient’s PBMCs, wherein the patient’s PBMCs are obtained 7 days post-dose of a putative therapeutic treatment, taught by Carreno because Carreno teaches that this method enables the examination of the kinetics and magnitude of T cell immunity due to the therapeutic treatment. A person having ordinary skill in the art would have had a reasonable expectation of success because both Nielsen and Carreno teach a method for detecting antigen specific T cell activation in PBMCs.
It would have been further prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Nielsen in view of Carreno to rely on obtaining the PBMCs from patient apheresis taught by Cafri because Cafri teaches that this method can identify neoantigen-reactive T cells that are present at very low frequencies in the circulation. A person having ordinary skill in the art would have had a reasonable expectation of success because Nielsen, Carreno, and Cafri teach detecting antigen specific T cell activation in PBMCs.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Nielsen, Johanns and Cafri as applied to claim 13 above, and further in view of Kreiter et al. Nature 520, 692–696 (2015). https://doi.org/10.1038/nature14426 (Cited in sheet 10 of IDS filed 6/14/2022) ( (“Kreiter”) and Diken et al. Current Issues in Molecular Biology, 22(1), 113-128. https://doi.org/10.21775/cimb.022.113 ("Dicken"). Regarding claim 14, Nielsen in view of Johanns and Cafri address the method of claim 11 as discussed above.
Nielsen in view of Johanns and Cafri fail to teach wherein the personalized cancer vaccine is an mRNA having one or more open reading frames encoding 3-50 peptide epitopes, wherein each of the peptide epitopes are personalized cancer antigens, formulated in a lipid nanoparticle formulation
Kreiter teaches that “Mutant MHC class II epitopes drive therapeutic immune responses to cancer” (Title). Kreiter further teaches a personalized mRNA cancer vaccine having one or more open reading frames encoding 3-50 peptide epitope, wherein each of the peptide epitopes are personalized cancer antigens, formulated in a lipid formulation (“a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines” Abstract, “synthetic RNA pentatope encoding all five neo-epitopes connected by 10mer non-immunogenic glycine/serine linkers (Fig. 3a)” page 693 column 2 paragraph 2, see Figure 3a showing the mRNA having an open reading frame encoding five personalized peptide epitopes “Engineering of a poly-neo-epitope RNA”, “Vaccination…RNA complexed with cationic lipids” page 697 column 1 last paragraph and column 2 paragraph 1). Kreiter further teaches a method for detecting antigen specific T cell activation in PBMCs wherein the analysis is performed on a patient receiving a personalized cancer vaccine (“In naive BALB/c mice the quantity of IFN-γ-producing T cells elicited by the pentatope was comparable (3 of 5) or even higher than that evoked by the respective monotope (Extended Data Fig. 3a)” page 693 column 2 paragraph 2, “Enzyme-linked ImmunoSpot (ELISpot)… For analysis of T-cell responses in peripheral blood, PBMC were isolated via density gradient centrifugation, counted and restimulated by addition of peptide and syngeneic BMDC... All samples were tested in duplicates or triplicates” page 697 column 2 paragraph 3). Kreiter further teaches that “[t]he vast majority of mutations are unique to the individual patient. Hence, mutanome vaccines need to be individually tailored9 and rapidly manufactured on-demand. This challenge can be viably addressed by RNA vaccine technology (Fig. 3a)” (page 693 column 2 paragraph 1).
Dicken teaches “mRNA: A Versatile Molecule for Cancer Vaccines” (Title). Dicken further teaches a personalized mRNA cancer vaccine encoding peptide epitopes (“[a]ccompanied by the advances in next generation sequencing systems, use of tumor specimens for identification of patient-specific mutations and vaccination with neoantigens holds the promise for new generation cancer immunotherapy (Castle et al., 2012; Kreiter et al., 2012). mRNA can also serve as a powerful format for this type of vaccines such that several identified immunogenic epitopes which possess patient-specific mutations can be incorporated into a personalized mRNA vaccine for induction of immune responses. Kreiter et al. showed the feasibility of this approach in different preclinical tumor models with such a poly-epitope mRNA (Kreiter et al., 2015), providing the proof of feasibility for mRNA vaccines” page 121 column 2 paragraph 2). Dicken further suggests wherein the personalized cancer vaccine is formulated in a lipid nanoparticle formulation (“Quite recently, lipid carrier systems such as liposomes and lipid nanoparticles have been revisited as an attractive delivery option also for mRNA (reviewed in Phua, 2015; Phua et al., 2014a)… Regarding cancer immunotherapy, liposome-complexed chicken ovalbumin (OVA)-encoding mRNA generated antigen-specific CTLs and delayed the growth of established OVA-expressing tumors after i.d.” page 120 column 2 paragraph 2). Dicken further teaches that “Profiting from the extensive research on liposomal DNA-based gene transfer, the possibility to transfer this approach to mRNA based vaccines was demonstrated early by Martinon et al. by the induction of influenza nucleoprotein (NP)-specific cytotoxic T cells after s.c. injection of liposomal NP mRNA (Martinon et al., 1993)” (page 120 column 2 paragraph 2).
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 modify the teachings of Nielsen in view of Johanns and Cafri to rely on the personalized mRNA cancer vaccine having one or more open reading frames encoding 3-50 peptide epitope, wherein each of the peptide epitopes are personalized cancer antigens, formulated in a lipid formulation taught by Kreiter because Kreiter teaches that these can be rapidly manufactured on-demand and elicit an efficient immunogenic response. A person having ordinary skill in the art would have had a reasonable expectation of success because Kreiter shows the engineering of the poly-neo-epitope RNA and both Kreiter Nielsen, Johanns and Cafri teach detecting antigen specific T cell activation in PBMCs.
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 modify the teachings of Nielsen in view of Johanns, Cafri and Kreiter to rely on the lipid nanoparticle taught by Dicken because Dicken teaches that a lipid nanoparticle is an attractive delivery option for mRNA. A person having ordinary skill in the art would have had a reasonable expectation of success because Dicken teaches that lipid nanoparticles for mRNA vaccines has been demonstrated early (1993) and both Kreiter and Dicken teach personalized lipid-containing mRNA cancer vaccines.
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678