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 .
Response to Amendment
Claims 2-3, 5, 7-11, 13-20, and 31-40 have been cancelled and claim 1 has been amended, as requested in the amendment filed on October 16, 2024. Following the amendment, claims 1, 4, 6, 12, and 21-30 are pending in the instant application.
Claims 6 and 21-30 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions in the Response filed July 27, 2021, there being no allowable generic or linking claim.
Claims 1, 4, and 12 are under examination in the instant office action.
Claim Rejections - 35 USC § 112
Claim 13 was rejected under 35 USC § 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 for the recitation of the phrases "preferably", “more preferably”, and “most preferably”. Claim 13 has been cancelled, rendering the rejection moot. As such, the rejection of claim 13 under 35 U.S.C. 112(b) is withdrawn.
Claim Rejections - 35 USC § 112 - New
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 4, and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim recites quantifying “at least five chemokines and cytokines” in a blood sample, wherein quantities above a reference range for normal indicate a “hot” immune system. The claim language is ambiguous. It is unclear as to if quantifying five chemokines, five cytokines, a combination of chemokines and cytokines totaling up to five, or five of each (ten total) satisfies the claim limitation. For the purposes of this office action, the claim limitation is being interpreted to mean: (i) five chemokines, (ii) five cytokines, (iii) or a combination of chemokines and cytokines totaling up to five.
Claim Rejections - 35 USC § 103 - Updated
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 4, and 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Kreiter et. al. published in 2015 (herein after referred to as "Kreiter") in view of non-patent literature by Saletti et. al. published in 2013 (herein after referred to as "Saletti") and non-patent literature by Lee and Margolin published in 2011 (herein after referred to as “Lee”).
With regard to claim 1, Kreiter teaches methods for treating cancer comprising assessing a “patient’s individual tumor-specific mutations” (Abstract). Kreiter unexpectedly discovers “the majority of the immunogenic mutanome is recognized by CD4+ T cells” (Id) and develops “a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of the expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines” (Id). Kreiter further teaches that over 1,680 non-synonymous mutations in the colon carcinoma model CT26 in BALB/c mice had previously been identified, and 48 of those mutations were selected in analogy to the Bl6F10 study based on good MHC class I binding ('low score' 0.1-2.1) while the other half was deliberately chosen for poor binding ('high score' >3.9) and in total about 20% of mutated epitopes were found to be immunogenic in mice immunized with the respective RNA monotopes (Page 2, Fourth Paragraph, Figure lc, Extended Data Table 2). In the 'low' MHC I score subgroup, but not in the 'high' score subgroup, several epitopes inducing CD8+ T cells were identified and the MHC class II-restricted epitopes were represented in similar frequency in both subgroups, constituting the majority CT26 immunogenic mutations (16/21, 80%) (Page 2, Fourth Paragraph, Figure 1c). Kreiter also teaches “the vast majority of mutations are unique to the individual patient” and that “mutanome vaccines need to be individually tailored” which “can be viably addressed by RNA vaccine technology” (Page 3, Paragraph 3). The Kreiter prior art further teaches “though we achieved tumour eradication in mice with a single mutation, to combine several mutations would be preferable to address tumour heterogeneity and immune editing” (Page 3, Paragraph 3). The Kreiter prior art then discloses engineered RNA monotopes encoding four MHC class II (CT26-M03, CT26-M20, CT26-M27, CT26-M6S) and one MHC class I (CT26-M19) restricted mutation from the CT26 model (Page 3, Last Paragraph, Extended Data Table 2) and a synthetic RNA pentatope encoding all five neo-epitopes connected by 10mer non-immunogenic glycine/serine linkers (Page 3, Last Paragraph, Figure 3a) wherein 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 (Page 3, Last Paragraph, Extended Data Figure 3a). Kreiter further teaches that in BALB/c mice with CT26 luciferase-transfected (CT26-Luc) lung metastases vaccinated repeatedly with a mixture of two RNA pentatopes (3 MHC class I- and 7 class II-restricted epitopes) (Page 4, First Paragraph, Extended Data Table 4) including the mutations tested in the previous experiment, tumour growth was significantly inhibited (Page 4, First Paragraph, Figure 3b). Therefore, the Kreiter reference teaches both tumor-specific and patient-specific neoepitopes, and the treatment comprising administering such epitopes to patients who have both the patient-specific MHC class-II restricted epitopes (80% of mice having those immunogenic mutations, such that approximately 31 of the 39 mice treated have the patient-specific mutations) and the tumor-specific mutations. Kreiter also teaches engineering “pharmacologically optimized RNA (stabilizing elements in RNA sequence and liposomal formulation) 3-5 encoding B16-M30, one of the epitopes that elicited strong CD4 T-cell responses in the B16F10 tumour model” wherein “the mutated amino acid was essential for T-cell recognition, hence the wild type peptide was not recognized (Extended Data Fig. 2a)” and discloses that “when B16F10 tumour-bearing C57BL/6 mice were repeatedly vaccinated with the B16-M30 RNA monotope, tumour growth was profoundly retarded (Fig. 2a)" (Page 1). As such, Kreiter contemplated administration of the neoepitopes after determining the immune system to be hot, as an epitope was demonstrated to elicit a T-cell response prior to optimization/engineering and vaccination of tumor-bearing C57BL/6 mice with said epitope. Kreiter discloses that “tumour-bearing C57BL/6 mice were immunized with synthetic 27mer peptides encoding the mutated epitope (mutation in position 14), resulting in T-cell responses which conferred in vivo tumour control” and characterization of “T-cell responses against the neoepitopes, starting with those with a high likelihood of MHC I binding” (Page 2, Paragraph 2). Kreiter focuses heavily on cytokine release, but T-cell response was also measured by an ELISpot assay; the ELISpot assay is a specific type of ELISA assay, wherein wells of a plate are pre-coated, wherein antibodies against a target antigen (e.g., INF-γ or MHC class II antibodies) are immobilized in a well and a target cell population, such as PMBCs, stimulated to express said antigen is added to the wells, washed, and bound antigen is detected via a secondary antibody (Page 8-9). Kreiter teaches exome capture from mouse tumour cells and control tissue samples were sequenced in triplicate (pg. 6, Next-generation sequencing and data processing), which teaches obtaining a tumor biopsy tissue sample and a control sample from the subject as claimed. The authors state: “mutations were selected based on following criteria: (1) present in the respective tumour cell line sequencing triplicates and absent in the corresponding healthy tissue sample triplicates”. The authors utilize omics analysis in which “mutated epitopes were prioritized according to their MHC class I binding predicted by the consensus method (version 2.5) of the Immune Epitope Database (http://www.iedb.org). Mutations shown in Fig. 4b–e were selected based on either their expression (NVRC) alone or together with their predicted MHC class II peptide binding capability (IEDB consensus method version 2.5).” Therefore, the reference teaches using omics to determine a plurality of tumor-specific (“genomic non-synonymous point mutations (nsSNVs)” and patient-specific neoepitopes (“seq2HLA29 was employed to identify the patients’ 4-digit HLA class II (HLA-DQA1, HLA-DQB1, HLA-DRB1) type. Such an omics-based approach is an in vitro method utilized to identify tumor-specific and patient-specific mutations of interest and falls within the scope of the claimed method. However, Kreiter does not teach steps (a)-(b) of claim 1. This deficiency is remedied by Saletti.
Saletti teaches that the enzyme-linked immunospot (ELISPOT) assay was originally developed to enumerate antigen-specific antibody-secreting cells (ASCs), and has subsequently been adapted for various applications, including the detection cytokine-secreting cells and has proven to be especially useful for detecting discrete populations of active cells (e.g., antigen-specific cells); because of its versatility, the ELISPOT assay is used for a wide range of applications, including clonal analyses of immune responses after vaccination or after immunotherapy (Abstract). The authors describe standard protocols for the detection of human ASCs specific to virtually any vaccine antigen after enrichment of circulating plasmablasts and a protocol is described for the measurement of mucosal ASC responses after prior immunomagnetic enrichment of mucosally derived blood lymphocytes wherein the protocols described allow rapid (~6–8 h) detection of specific ASCs in small (1–2 ml) samples of blood (Id.). The occurrence, frequency and characteristics (Ig isotype distribution) of blood ASCs not only provide a very early estimate of the nature and intensity of a humoral immune response to any given vaccine (i.e., predicts immune response/vaccine efficacy) but can also be of diagnostic value for detecting an active or very recent infection (Page 1073, Column 2, Paragraph 2). A schematic of the one-step and two-step ASC ELISPOT assays described in the reference is provided in Figure 2, as shown below:
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Generally, plates are coated with antigen (or with anti-IgG) wherein it is recommended that blocking agents are used to prevent nonspecific binding of secreted antibodies and prevent the formation of artifactual spots and/or background staining (Page 1076, Column 1, Paragraph 3). Cell isolation and preparation of blood samples, wherein the time between blood collection and preparation of cell suspensions should never exceed 6 h for specimens stored at 4–10 °C and 2 h for specimens transported at 20–25 °C, is also described (Page 1076, “Cell Isolation: Preparation of Blood Samples”). The samples are then incubated based on either a two-step or one-step procedure (Page 1077, “Cell Incubation Stage”). After incubation, ESLISPOT wells must be thoroughly washed and zones of antibodies formed by individual ASCs and bound to the antigen-coated surface can be visualized after stepwise incubation with enzyme-conjugated anti-Ig antibodies and pertinent enzyme substrates wherein after the addition of enzyme substrate, macroscopic spots appear at the former location of ASCs (or ISCs) and can be visually/digitally counted (Page 1078). Thus, Saletti teaches ELISPOT assays for direct ex-vivo measurement of humoral immune responses in blood samples, wherein wells of the ELISPOT assay plate are coated with antigen (i.e., immobilized antigen) which immune competent cells “hot” for said antigen will bind to and produce antibodies. Said antibodies subsequently bind the immobilized antigen and can be detected with anti-Ig antibodies conjugated to enzymes that react with substrate and produce spots that can be visualized. As such, Saletti teaches/suggests the active steps of: (i) immobilizing antigens on a solid substrate; (ii) contacting ex-vivo a patient’s blood sample with the immobilized antigens; and (iii) predict effectiveness of vaccination (i.e., treatment) by determining if a patient’s immune system is “hot” for the immobilized antigens based on the binding of immune competent cells to the immobilized antigens and measuring/visualizing the subsequent response. The use of hydrophobic membranes in the ELSIPOT assays as described in a miniaturized 96-well format, reduces antigen (and antibody)-coating concentrations and allows the detection of ASCs (and other cell types, including cytokine-producing cells) (Page 1074, Column 2, Paragraph 4). The use of fluorophore-conjugated secondary antibodies allow for direct visualization of spots and eliminating the final development step of traditional enzyme-based ELISPOT assays, and thus shortening the overall assay time wherein this variant, often referred to as FLUOROSPOT, allows the detection of human ASCs and has proven to be especially useful for simultaneous visualization of individual T cells producing several cytokines (Page 1075, Column 1, Paragraph 1). Furthermore, it is noted that Saletti also specifically suggests cytokine-based T cell ELISPOT assays, which can be performed on frozen and fresh whole PMBCs (Page 1076, Column 1, Paragraph 5). Thus, Saletti also suggests variations for the detection of cytokine-producing cells. However, it is noted that neither Kreiter nor Saletti explicitly teach the quantification of five or more cytokines/chemokines. This deficiency is remedied by Lee.
Lee teaches that cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited
response to a target antigen and the reference reviews the major cytokines involved in cancer
immunotherapy and discusses their basic biology and clinical applications (Abstract). Cytokines directly stimulate immune effector cells and stromal cells at the tumor site and enhance tumor cell recognition by cytotoxic effector cells, and numerous animal tumor model studies have demonstrated that cytokines have broad anti-tumor activity and this has been translated into a number of cytokine-based approaches for cancer therapy; recent years have seen a number of cytokines, including GM-CSF, IL-7, IL-12, IL-15, IL-18 and IL-21, enter clinical trials for patients with advanced cancer (Page 3857, Paragraph 1). Table 1 of Lee lists various cytokines, their sources, their targets, and their biological activities; IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and TNF-α, for example, are all secreted by T cells and/or NK cells and act on the immune system through B cells, T cells, and/or NK cells with roles including cell growth, activation, and/or differentiation (See Table 1). The roles of some of these cytokines as pertain to cancer and immunotherapy are also disclosed by Lee (See Section 4: Current Cytokines in Immunotherapy; Pages 3862-3873). Thus, Lee discloses various cytokines implicated in immune response, wherein one of ordinary skill in the art would recognize that an increase in these secreted cytokines (compared to a baseline) indicates an immune response and/or a “hot” immune system.
Kreiter, Saletti, and Lee are considered to be analogous to the present invention as they are both in the same field of immune responses. Thus, it would have been obvious to one of ordinary skill in the art to modify the method of treatment taught by Kreiter to include an ELISPOT assay which could include a T cell/cytokine based assay, as taught by Saletti, wherein the antigens of Saletti are substituted with cancer-specific and patient-specific neoepitopes and cytokines themselves are detected, as taught by Kreiter, because the references provide some teaching, suggestion, or motivation that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention; Saletti teaches that the occurrence, frequency and characteristics (Ig isotype distribution) of blood ASCs provide a very early estimate of the nature and intensity of a humoral immune response to any given vaccine (i.e., antigens/neoepitopes), which suggests that the ESLISPOT assay can be used to predict immune response (e.g., to vaccines/treatments) and further suggests variants wherein PMBCs can be analyzed for cytokine-secreting cells (e.g., T cells). Lee further discloses various cytokines that contribute to immune responses; thus, it would have been obvious to one of ordinary skill in the art to further modify the method such that the quantification of five or more cytokines can be used to indicate a “hot” immune system; as Kreiter indicates cytokine detection being indicative of immune response and Saletti suggesting the same. Combining prior art elements according to known methods would be expected to yield predictable results.
With regard to claim 4, Kreiter teaches “the vast majority of mutations are unique to the individual patient” and that “mutanome vaccines need to be individually tailored” which “can be viably addressed by RNA vaccine technology” (Page 3, Paragraph 3). The Kreiter prior art further teaches “though we achieved tumour eradication in mice with a single mutation, to combine several mutations would be preferable to address tumour heterogeneity and immune editing” (Page 3, Paragraph 3). The Kreiter prior art then discloses engineered RNA monotopes encoding four MHC class II (CT26-M03, CT26-M20, CT26-M27, CT26-M6S) and one MHC class I (CT26-M19) restricted mutation from the CT26 model (Page 3, Last Paragraph, Extended Data Table 2) and a synthetic RNA pentatope encoding all five neo-epitopes connected by 10mer non-immunogenic glycine/serine linkers (Page 3, Last Paragraph, Figure 3a) wherein 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 (Page 3, Last Paragraph, Extended Data Figure 3a). Kreiter further teaches that in BALB/c mice with CT26 luciferase-transfected (CT26-Luc) lung metastases vaccinated repeatedly with a mixture of two RNA pentatopes (3 MHC class I- and 7 class II-restricted epitopes) (Page 4, First Paragraph, Extended Data Table 4) including the mutations tested in the previous experiment, tumour growth was significantly inhibited (Page 4, First Paragraph, Figure 3b). Therefore, the Kreiter reference teaches both tumor-specific and patient-specific neoepitopes, and treatment comprising administering such epitopes to patients who have both the patient-specific MHC class-II restricted epitopes (80% of mice having those immunogenic mutations, such that approximately 31 of the 39 mice treated have the patient-specific mutations) and the tumor-specific mutations. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 12, Kreiter teaches “[a]s previously described…splenocytes were cultured … and cytokine secretion was detected with an anti-IFN-γ antibody ... For stimulation either 2 μg ml−1 peptide was added or spleen cells were coincubated with 5 × 104 syngeneic bone-marrow-derived dendritic cells (BMDC) transfected with RNA. For analysis of tumour infiltrating lymphocytes, single-cell suspensions of lung metastasis were rested overnight to get rid of living tumour cells via plastic adherence. Viable cells were separated via density gradient centrifugation and added to the ELISpot plate” (pg. 8, section titled ‘Enzyme-linked ImmunoSpot (ELISpot)’). Splenocytes were stimulated RNA-transfected BMDC or 2 μg ml−1 peptide. The authors teach that cells were “stained for CD4+ and CD8+ cell surface markers, permeabilized and fixed using BD Cytofix/Cytoperm according to the manufacturer’s protocol. Thereafter cells were stained for INF-γ, TNF-α and IL-2 cytokines (BD Biosciences). Cytokine secretion among CD4+ or CD8+ T cells in stimulated samples was compared to control samples (medium, irrelevant RNA or irrelevant peptide) in order to determine the responding T-cell subtype (n = 5)” (pg. 9, section titled ‘Flow cytometric analysis”). Thus, Kreiter analyzes a leukocyte profile and the quantities of “preferably at least two, more preferably at least three” cytokines: INF-γ, TNF-α and IL-2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Double Patenting - Updated
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 1, 4, and 12 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-7 of U.S. Patent No. 12,053,512 (herein after referred to as "'512") in view of Kreiter, and Lee.
With regard to instant claim 1, ‘512 claims 1 and 7 are drawn to methods of validating a therapeutic composition generally comprising a neoepitope of a first subject’s tumor by confirming ex vivo a triggering of an immune response to the neoepitope of the first subjects tumor further comprising: (i) obtaining neoepitope sequence data from the first subject’s tumor; (ii) obtaining immune competent cells from peripheral blood of the first subject or a second subject; (iii) generating a neoepitope presentation system; (iv) triggering ex vivo and immune response in the first subject’s tumor by contacting the immune competent cells with the neoepitope presentation system; and (v) confirming the triggering of the immune response in the first subject’s tumor from the contacted immune competent cells. ‘512 claim 6 further limits the method of claim 1 such that the neoepitope in the neoepitope presentation system comprises a subject- and tumor-specific neoepitope or an HLA-matched neoepitope. However, ‘512 does not disclose a method of treating a patient, obtaining a tumor biopsy and blood sample from the patient and determining a plurality of tumor- and patient-specific neoepitopes via omics analysis, the specific active steps (a)-(b) of instant claim 1, nor administering a treatment to the patient. These deficiencies are remedied by Kreiter, Saletti, and Lee.
Kreiter teaches methods for treating cancer comprising assessing a “patient’s individual tumor-specific mutations” (Abstract). Kreiter unexpectedly discovers “the majority of the immunogenic mutanome is recognized by CD4+ T cells” (Id) and develops “a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of the expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines” (Id). Kreiter further teaches that over 1,680 non-synonymous mutations in the colon carcinoma model CT26 in BALB/c mice had previously been identified, and 48 of those mutations were selected in analogy to the Bl6F10 study based on good MHC class I binding ('low score' 0.1-2.1) while the other half was deliberately chosen for poor binding ('high score' >3.9) and in total about 20% of mutated epitopes were found to be immunogenic in mice immunized with the respective RNA monotopes (Page 2, Fourth Paragraph, Figure lc, Extended Data Table 2). In the 'low' MHC I score subgroup, but not in the 'high' score subgroup, several epitopes inducing CD8+ T cells were identified and the MHC class II-restricted epitopes were represented in similar frequency in both subgroups, constituting the majority CT26 immunogenic mutations (16/21, 80%) (Page 2, Fourth Paragraph, Figure 1c). Kreiter also teaches “the vast majority of mutations are unique to the individual patient” and that “mutanome vaccines need to be individually tailored” which “can be viably addressed by RNA vaccine technology” (Page 3, Paragraph 3). The Kreiter prior art further teaches “though we achieved tumour eradication in mice with a single mutation, to combine several mutations would be preferable to address tumour heterogeneity and immune editing” (Page 3, Paragraph 3). The Kreiter prior art then discloses engineered RNA monotopes encoding four MHC class II (CT26-M03, CT26-M20, CT26-M27, CT26-M6S) and one MHC class I (CT26-M19) restricted mutation from the CT26 model (Page 3, Last Paragraph, Extended Data Table 2) and a synthetic RNA pentatope encoding all five neo-epitopes connected by 10mer non-immunogenic glycine/serine linkers (Page 3, Last Paragraph, Figure 3a) wherein 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 (Page 3, Last Paragraph, Extended Data Figure 3a). Kreiter further teaches that in BALB/c mice with CT26 luciferase-transfected (CT26-Luc) lung metastases vaccinated repeatedly with a mixture of two RNA pentatopes (3 MHC class I- and 7 class II-restricted epitopes) (Page 4, First Paragraph, Extended Data Table 4) including the mutations tested in the previous experiment, tumour growth was significantly inhibited (Page 4, First Paragraph, Figure 3b). Therefore, the Kreiter reference teaches both tumor-specific and patient-specific neoepitopes, and treatment comprising administering such epitopes to patients who have both the patient-specific MHC class-II restricted epitopes (80% of mice having those immunogenic mutations, such that approximately 31 of the 39 mice treated have the patient-specific mutations) and the tumor-specific mutations. Kreiter also teaches engineering “pharmacologically optimized RNA (stabilizing elements in RNA sequence and liposomal formulation) 3-5 encoding B16-M30, one of the epitopes that elicited strong CD4 T-cell responses in the B16F10 tumour model” wherein “the mutated amino acid was essential for T-cell recognition, hence the wild type peptide was not recognized (Extended Data Fig. 2a)” and discloses that “when B16F10 tumour-bearing C57BL/6 mice were repeatedly vaccinated with the B16-M30 RNA monotope, tumour growth was profoundly retarded (Fig. 2a)" (Page 1). As such, Kreiter contemplated administration of the neoepitopes after determining the immune system to be hot, as an epitope was demonstrated to elicit a T-cell response prior to optimization/engineering and vaccination of tumor-bearing C57BL/6 mice with said epitope. Kreiter discloses that “tumour-bearing C57BL/6 mice were immunized with synthetic 27mer peptides encoding the mutated epitope (mutation in position 14), resulting in T-cell responses which conferred in vivo tumour control” and characterization of “T-cell responses against the neoepitopes, starting with those with a high likelihood of MHC I binding” (Page 2, Paragraph 2). Kreiter focuses heavily on cytokine release, but T-cell response was also measured by an ELISpot assay; the ELISpot assay is a specific type of ELISA assay, wherein wells of a plate are pre-coated, wherein antibodies against a target antigen (e.g., INF-γ or MHC class II antibodies) are immobilized in a well and a target cell population, such as PMBCs, stimulated to express said antigen is added to the wells, washed, and bound antigen is detected via a secondary antibody (Page 8-9). Kreiter teaches exome capture from mouse tumour cells and control tissue samples were sequenced in triplicate (pg. 6, Next-generation sequencing and data processing), which teaches obtaining a tumor biopsy tissue sample and a control sample from the subject as claimed. The authors state: “mutations were selected based on following criteria: (1) present in the respective tumour cell line sequencing triplicates and absent in the corresponding healthy tissue sample triplicates”. The authors utilize omics analysis in which “mutated epitopes were prioritized according to their MHC class I binding predicted by the consensus method (version 2.5) of the Immune Epitope Database (http://www.iedb.org). Mutations shown in Fig. 4b–e were selected based on either their expression (NVRC) alone or together with their predicted MHC class II peptide binding capability (IEDB consensus method version 2.5)” Therefore, the reference teaches using omics to determine a plurality of tumor-specific (“genomic non-synonymous point mutations (nsSNVs)” and patient-specific neoepitopes (“seq2HLA29 was employed to identify the patients’ 4-digit HLA class II (HLA-DQA1, HLA-DQB1, HLA-DRB1) type. Such an omics-based approach is an in vitro method utilized to identify tumor-specific and patient-specific mutations of interest and falls within the scope of the claimed method. However, Kreiter does not teach steps (a)-(c) of claim 1. This deficiency is remedied by Saletti.
Saletti teaches that the enzyme-linked immunospot (ELISPOT) assay was originally developed to enumerate antigen-specific antibody-secreting cells (ASCs), and has subsequently been adapted for various applications, including the detection cytokine-secreting cells and has proven to be especially useful for detecting discrete populations of active cells (e.g., antigen-specific cells); because of its versatility, the ELISPOT assay is used for a wide range of applications, including clonal analyses of immune responses after vaccination or after immunotherapy (Abstract). The authors describe standard protocols for the detection of human ASCs specific to virtually any vaccine antigen after enrichment of circulating plasmablasts and a protocol is described for the measurement of mucosal ASC responses after prior immunomagnetic enrichment of mucosally derived blood lymphocytes wherein the protocols described allow rapid (~6–8 h) detection of specific ASCs in small (1–2 ml) samples of blood (Id.). The occurrence, frequency and characteristics (Ig isotype distribution) of blood ASCs not only provide a very early estimate of the nature and intensity of a humoral immune response to any given vaccine (i.e., predicts immune response/vaccine efficacy) but can also be of diagnostic value for detecting an active or very recent infection (Page 1073, Column 2, Paragraph 2). A schematic of the one-step and two-step ASC ELISPOT assays described in the reference is provided in Figure 2 of Saletti, as shown previously above. Generally, plates are coated with antigen (or with anti-IgG) wherein it is recommended that blocking agents are used to prevent nonspecific binding of secreted antibodies and prevent the formation of artifactual spots and/or background staining (Page 1076, Column 1, Paragraph 3). Cell isolation and preparation of blood samples, wherein the time between blood collection and preparation of cell suspensions should never exceed 6 h for specimens stored at 4–10 °C and 2 h for specimens transported at 20–25 °C, is also described (Page 1076, “Cell Isolation: Preparation of Blood Samples”). The samples are then incubated based on either a two-step or one-step procedure (Page 1077, “Cell Incubation Stage”). After incubation, ESLISPOT wells must be thoroughly washed and zones of antibodies formed by individual ASCs and bound to the antigen-coated surface can be visualized after stepwise incubation with enzyme-conjugated anti-Ig antibodies and pertinent enzyme substrates wherein after the addition of enzyme substrate, macroscopic spots appear at the former location of ASCs (or ISCs) and can be visually/digitally counted (Page 1078). Thus, Saletti teaches ELISPOT assays for direct ex-vivo measurement of humoral immune responses in blood samples, wherein wells of the ELISPOT assay plate are coated with antigen (i.e., immobilized antigen) which immune competent cells “hot” for said antigen will bind to and produce antibodies. Said antibodies subsequently bind the immobilized antigen and can be detected with anti-Ig antibodies conjugated to enzymes that react with substrate and produce spots that can be visualized. As such, Saletti teaches/suggests the active steps of: (i) immobilizing antigens on a solid substrate; (ii) contacting ex-vivo a patient’s blood sample with the immobilized antigens; and (iii) predict effectiveness of vaccination (i.e., treatment) by determining if a patient’s immune system is “hot” for the immobilized antigens based on the binding of immune competent cells to the immobilized antigens and measuring/visualizing the subsequent response.
Lee teaches that cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited
response to a target antigen and the reference reviews the major cytokines involved in cancer
immunotherapy and discusses their basic biology and clinical applications (Abstract). Cytokines directly stimulate immune effector cells and stromal cells at the tumor site and enhance tumor cell recognition by cytotoxic effector cells, and numerous animal tumor model studies have demonstrated that cytokines have broad anti-tumor activity and this has been translated into a number of cytokine-based approaches for cancer therapy; recent years have seen a number of cytokines, including GM-CSF, IL-7, IL-12, IL-15, IL-18 and IL-21, enter clinical trials for patients with advanced cancer (Page 3857, Paragraph 1). Table 1 of Lee lists various cytokines, their sources, their targets, and their biological activities; IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and TNF-α, for example, are all secreted by T cells and/or NK cells and act on the immune system through B cells, T cells, and/or NK cells with roles including cell growth, activation, and/or differentiation (See Table 1). The roles of some of these cytokines as pertain to cancer and immunotherapy are also disclosed by Lee (See Section 4: Current Cytokines in Immunotherapy; Pages 3862-3873). Thus, Lee discloses various cytokines implicated in immune response, wherein one of ordinary skill in the art would recognize that an increase in these secreted cytokines (compared to a baseline) indicates an immune response and/or a “hot” immune system.
‘512, Kreiter, Saletti, and Lee are considered to be analogous to the present invention as they are in the same field of immune responses. Thus, it would have been obvious to one of ordinary skill in the art to combine the method of validating a treatment composition taught by ‘512 with the method of treatment taught by Kreiter, to obtain a method of treatment that includes validation, wherein the active validation steps include an ELISPOT assay which could include a T cell/cytokine based assay, as taught by Saletti, wherein the antigens of Saletti are substituted with cancer-specific and patient-specific neoepitopes, as taught by ‘512 and Kreiter, because the references provide some teaching, suggestion, or motivation that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention; Saletti teaches that the occurrence, frequency and characteristics (Ig isotype distribution) of blood ASCs provide a very early estimate of the nature and intensity of a humoral immune response to any given vaccine (i.e., antigens/neoepitopes), which suggests that the ESLISPOT assay can be used to predict immune response (e.g., to vaccines/treatments). Lee further discloses various cytokines that contribute to immune responses; thus, it would have been obvious to one of ordinary skill in the art to further modify the method such that the quantification of five or more cytokines can be used to indicate a “hot” immune system; as Kreiter indicates cytokine detection being indicative of immune response and Saletti suggesting the same. Combining prior art elements according to known methods would be expected to yield predictable results.
With regard to claim 4, Kreiter teaches “the vast majority of mutations are unique to the individual patient” and that “mutanome vaccines need to be individually tailored” which “can be viably addressed by RNA vaccine technology” (Page 3, Paragraph 3). The Kreiter prior art further teaches “though we achieved tumour eradication in mice with a single mutation, to combine several mutations would be preferable to address tumour heterogeneity and immune editing” (Page 3, Paragraph 3). The Kreiter prior art then discloses engineered RNA monotopes encoding four MHC class II (CT26-M03, CT26-M20, CT26-M27, CT26-M6S) and one MHC class I (CT26-M19) restricted mutation from the CT26 model (Page 3, Last Paragraph, Extended Data Table 2) and a synthetic RNA pentatope encoding all five neo-epitopes connected by 10mer non-immunogenic glycine/serine linkers (Page 3, Last Paragraph, Figure 3a) wherein 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 (Page 3, Last Paragraph, Extended Data Figure 3a). Kreiter further teaches that in BALB/c mice with CT26 luciferase-transfected (CT26-Luc) lung metastases vaccinated repeatedly with a mixture of two RNA pentatopes (3 MHC class I- and 7 class II-restricted epitopes) (Page 4, First Paragraph, Extended Data Table 4) including the mutations tested in the previous experiment, tumour growth was significantly inhibited (Page 4, First Paragraph, Figure 3b). Therefore, the Kreiter reference teaches both tumor-specific and patient-specific neoepitopes, and treatment comprising administering such epitopes to patients who have both the patient-specific MHC class-II restricted epitopes (80% of mice having those immunogenic mutations, such that approximately 31 of the 39 mice treated have the patient-specific mutations) and the tumor-specific mutations and further suggests variants wherein PMBCs can be analyzed for cytokine-secreting cells (e.g., T cells). It is further noted that ‘512 claim 6 further limits the method of claim 1 such that the neoepitope in the neoepitope presentation system comprises a subject- and tumor-specific neoepitope or an HLA-matched neoepitope. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 12, Kreiter teaches “[a]s previously described…splenocytes were cultured … and cytokine secretion was detected with an anti-IFN-γ antibody ... For stimulation either 2 μg ml−1 peptide was added or spleen cells were coincubated with 5 × 104 syngeneic bone-marrow-derived dendritic cells (BMDC) transfected with RNA. For analysis of tumour infiltrating lymphocytes, single-cell suspensions of lung metastasis were rested overnight to get rid of living tumour cells via plastic adherence. Viable cells were separated via density gradient centrifugation and added to the ELISpot plate” (pg. 8, section titled ‘Enzyme-linked ImmunoSpot (ELISpot)’). Splenocytes were stimulated RNA-transfected BMDC or 2 μg ml−1 peptide. The authors teach that cells were “stained for CD4+ and CD8+ cell surface markers, permeabilized and fixed using BD Cytofix/Cytoperm according to the manufacturer’s protocol. Thereafter cells were stained for INF-γ, TNF-α and IL-2 cytokines (BD Biosciences). Cytokine secretion among CD4+ or CD8+ T cells in stimulated samples was compared to control samples (medium, irrelevant RNA or irrelevant peptide) in order to determine the responding T-cell subtype (n = 5)” (pg. 9, section titled ‘Flow cytometric analysis”). Thus, Kreiter analyzes a leukocyte profile and the quantities of “preferably at least two, more preferably at least three” cytokines: INF-γ, TNF-α and IL-2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claims 1, 4, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-7 of copending Application No. 18/761,799 (herein after referred to as "'799") in view of Kreiter, and Lee.
With regard to instant claim 1, ‘799 claims 1 and 7 are drawn to methods of validating a therapeutic composition generally comprising a neoepitope of a first subject’s tumor by confirming ex vivo a triggering of an immune response to the neoepitope of the first subjects tumor further comprising: (i) obtaining neoepitope sequence data from the first subject’s tumor; (ii) obtaining immune competent cells from peripheral blood of the first subject or a second subject; (iii) generating a neoepitope presentation system; (iv) triggering ex vivo and immune response in the first subject’s tumor by contacting the immune competent cells with the neoepitope presentation system; and (v) confirming the triggering of the immune response in the first subject’s tumor from the contacted immune competent cells. ‘799 claim 6 further limits the method of claim 1 such that the neoepitope in the neoepitope presentation system comprises a subject- and tumor-specific neoepitope or an HLA-matched neoepitope. However, ‘512 does not disclose a method of treating a patient, obtaining a tumor biopsy and blood sample from the patient and determining a plurality of tumor- and patient-specific neoepitopes via omics analysis, the specific active steps (a)-(c) of instant claim 1, nor administering a treatment to the patient. These deficiencies are remedied by Kreiter, Saletti, and Lee, whose teachings are detailed above.
‘799, Kreiter, Saletti, and Lee are considered to be analogous to the present invention as they are both in the same field of immune response. Thus, it would have been obvious to one of ordinary skill in the art to combine the method of validating a treatment composition taught by ‘799 with the method of treatment taught by Kreiter, to obtain a method of treatment that includes validation, wherein the active validation steps include an ELISPOT assay which could include a T cell/cytokine based assay, as taught by Saletti, wherein the antigens of Saletti are substituted with cancer-specific and patient-specific neoepitopes, as taught by ‘799 and Kreiter, because the references provide some teaching, suggestion, or motivation that would have led one of ordinary skill to combine prior art reference teachings to arrive at the claimed invention; Saletti teaches that the occurrence, frequency and characteristics (Ig isotype distribution) of blood ASCs provide a very early estimate of the nature and intensity of a humoral immune response to any given vaccine (i.e., antigens/neoepitopes), which suggests that the ESLISPOT assay can be used to predict immune response (e.g., to vaccines/treatments). Lee further discloses various cytokines that contribute to immune responses; thus, it would have been obvious to one of ordinary skill in the art to further modify the method such that the quantification of five or more cytokines can be used to indicate a “hot” immune system; as Kreiter indicates cytokine detection being indicative of immune response and Saletti suggesting the same. Combining prior art elements according to known methods would be expected to yield predictable results.
With regard to claim 4, Kreiter teaches “the vast majority of mutations are unique to the individual patient” and that “mutanome vaccines need to be individually tailored” which “can be viably addressed by RNA vaccine technology” (Page 3, Paragraph 3). The Kreiter prior art further teaches “though we achieved tumour eradication in mice with a single mutation, to combine several mutations would be preferable to address tumour heterogeneity and immune editing” (Page 3, Paragraph 3). The Kreiter prior art then discloses engineered RNA monotopes encoding four MHC class II (CT26-M03, CT26-M20, CT26-M27, CT26-M6S) and one MHC class I (CT26-M19) restricted mutation from the CT26 model (Page 3, Last Paragraph, Extended Data Table 2) and a synthetic RNA pentatope encoding all five neo-epitopes connected by 10mer non-immunogenic glycine/serine linkers (Page 3, Last Paragraph, Figure 3a) wherein 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 (Page 3, Last Paragraph, Extended Data Figure 3a). Kreiter further teaches that in BALB/c mice with CT26 luciferase-transfected (CT26-Luc) lung metastases vaccinated repeatedly with a mixture of two RNA pentatopes (3 MHC class I- and 7 class II-restricted epitopes) (Page 4, First Paragraph, Extended Data Table 4) including the mutations tested in the previous experiment, tumour growth was significantly inhibited (Page 4, First Paragraph, Figure 3b). Therefore, the Kreiter reference teaches both tumor-specific and patient-specific neoepitopes, and treatment comprising administering such epitopes to patients who have both the patient-specific MHC class-II restricted epitopes (80% of mice having those immunogenic mutations, such that approximately 31 of the 39 mice treated have the patient-specific mutations) and the tumor-specific mutations. It is further noted that ‘799 claim 6 further limits the method of claim 1 such that the neoepitope in the neoepitope presentation system comprises a subject- and tumor-specific neoepitope or an HLA-matched neoepitope. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 12, Kreiter teaches “[a]s previously described…splenocytes were cultured … and cytokine secretion was detected with an anti-IFN-γ antibody ... For stimulation either 2 μg ml−1 peptide was added or spleen cells were coincubated with 5 × 104 syngeneic bone-marrow-derived dendritic cells (BMDC) transfected with RNA. For analysis of tumour infiltrating lymphocytes, single-cell suspensions of lung metastasis were rested overnight to get rid of living tumour cells via plastic adherence. Viable cells were separated via density gradient centrifugation and added to the ELISpot plate” (pg. 8, section titled ‘Enzyme-linked ImmunoSpot (ELISpot)’). Splenocytes were stimulated RNA-transfected BMDC or 2 μg ml−1 peptide. The authors teach that cells were “stained for CD4+ and CD8+ cell surface markers, permeabilized and fixed using BD Cytofix/Cytoperm according to the manufacturer’s protocol. Thereafter cells were stained for INF-γ, TNF-α and IL-2 cytokines (BD Biosciences). Cytokine secretion among CD4+ or CD8+ T cells in stimulated samples was compared to control samples (medium, irrelevant RNA or irrelevant peptide) in order to determine the responding T-cell subtype (n = 5)” (pg. 9, section titled ‘Flow cytometric analysis”). Thus, Kreiter analyzes a leukocyte profile and the quantities of “preferably at least two, more preferably at least three” cytokines: INF-γ, TNF-α and IL-2. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
On Pages 6-10 of Remarks (10/16/2024), with regard to the rejection of claims 1, 4, and 12 under 35 USC § 103 and the double patenting rejections, Applicant argues that neither Kreiter nor Saletti, alone or in combination, teach or suggest a method of treating a patient diagnosed with cancer comprising, among other steps, determining the patient’s immune system to be hot with respect to the tumor when the immune competent cells are bound to the immobilized tumor-specific and patient-specific neoepitopes and when the quantities of at leas five chemokines in the blood sample are above clinical reference range for normal. More specifically, Applicant argues that Kreiter analyzes quantities of three cytokines: IFN-γ, TNF-α, and IL-2 and therefore does not disclose the quantities of at least five chemokines and cytokines in the blood sample as being above clinical reference range for normal. Applicant further argues that the rejection of said claims relies on hindsight to reach the claimed invention; Applicant argues that the rejection contends that Kreiter suggests the use of omics analysis, but Kreiter is silent as to quantification of these neoepitopes, i.e., the measuring response of the patient's immune system to each of the plurality of tumor-specific and patient-specific neoepitopes upon which the claimed method is predicated. The claimed method, comprising an antigen selection model, requires a measurement of a response of the patient's immune system in which binding of immune competent cells from blood of the patient to neoantigens is quantified. Such binding events are then used to (a) proceed to immune therapy treatment using (b) antigens selected for binding the immune competent cells and thus Applicant argues that in the presently claimed method antigens are selected in a manner that is entirely agnostic to MHC class I/II binding, but rather selected on the basis of biological properties of the patient's immune competent cells and more particularly determining the patient's immune system to be hot with respect to the tumor when, among other things, the quantities of at least five chemokines and cytokines in the blood sample are above clinical reference range for normal. This limitation is not taught nor suggested by Kreiter nor found in the additional cited art, and one of skill in the art would not reach the claimed invention of immobilizing and contacting a patient blood sample with a plurality of immobilized tumor-specific and patient-specific neoepitopes wherein the blood sample comprises immune competent cells; determining the patient's immune system to be hot with respect to the tumor when, among other things, the quantities of at least five chemokines and cytokines in the blood sample are above clinical reference range for normal; and administering treatment that comprises at least one of the plurality of tumor-specific and patient-specific neoepitopes, and/or T-cells or NK cells that are predicted to target at least one of the plurality of tumor-specific and patient-specific neoepitopes except through impermissible hindsight. Applicant further argues that the rejection does not adequately explain why one would look to Saletti, which is directed to an ELISPOT assay, to provide the remaining steps of the method, especially when Kreiter already supplies an assay better suited to its self-contained method, and when Saletti fails to supply all of the requisite steps to carry out the method of amended claim 1 (namely, determination of the system as "hot" based on the quantities of at least five chemokines and cytokines). As such, it is not clear, but for the teachings of Applicant, why one would look beyond the given functional ELISPOT assay of Kreiter, which involves immobilized target cells, and rework the entire experiment to reach the claimed invention; the rejection relies on the teachings of the present application to make its case, which is impermissible hindsight.
Applicant’s arguments have been fully considered, but are deemed not persuasive. With regard to the argument that Kreiter and Saletti do not teach all of the limitations of claim 1 as amended, the rejection of claims 1, 4, and 12 under 35 USC § 103 and double patenting have been updated, as detailed above, to include an additional reference for support with regard to measuring at least five cytokines and/or chemokines to determine the patient’s immune system as being “hot”. With regard to the arguments of impermissible hindsight, it is noted that the MPEP states "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Additionally, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness." Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See MPEP 2145(X)(A). The method of Kreiter and the method of Saletti were both known in the prior art before the effective filing date of the instant application. The substitution of one set of assay steps for another, which would arrive at the same conclusion of a “hot” immune system, involves the simple substitution of one known element for another according to known methods, which would be expected to yield predictable results. With regard to the argument that while Kreiter suggests the use of omics analysis, Kreiter is silent as to quantification of these neoepitopes, i.e., the measuring response of the patient's immune system to each of the plurality of tumor-specific and patient-specific neoepitopes, upon which the claimed method is predicated, and that the presently claimed method antigens are selected in a manner that is entirely agnostic to MHC class I/II binding, but rather selected on the basis of biological properties of the patient's immune competent cells and more particularly determining the patient's immune system to be hot with respect to the tumor when, among other things, the quantities of at least five chemokines and cytokines in the blood sample are above clinical reference range for normal, it is noted that, as detailed above, the combination of Kreiter, Saletti, and Lee render all of the limitations of the present claims obvious. The method of selecting neoepitopes via omics analysis is taught by Kreiter, and the argument that the presently claimed method antigens are selected in a manner that is entirely agnostic to MHC class I/II binding is not commensurate in scope with the claims. Kreiter teaches assessing a “patient’s individual tumor-specific mutations” (Abstract). Kreiter unexpectedly discovers “the majority of the immunogenic mutanome is recognized by CD4+ T cells” (Id) and develops “a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of the expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines” (Id). Thus, Kreiter identifies neoepitopes via omics analysis then subsequently evaluates such neoepitopes based on MHC class I/II binding; Kreiter then also evaluates immune response based on quantifying cytokines produced by cytokine secreting T cells in response to vaccination with said epitopes. The present claims are drawn to using omics analysis (of a tissue sample) to identify neoepitopes, as taught by Kreiter, then subsequently determining if an immune system is “hot” with respect to said neoepitopes through the measurement of cytokines secreted by responsive immune-competent cells, also taught by Kreiter wherein the method steps of quantifying said cytokines are steps (a)-(b) of amended claim 1, which are taught by Saletti. Thus, all limitations, in view of additional reference Lee which teaches multiple cytokines/chemokines implicated in immune response, are taught by the cited references.
Conclusion
Claims 1, 4, 6, 12, and 21-30 are pending. Claims 6 and 21-30 are withdrawn. Claims 1, 4, and 12 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee 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 date of this final action.
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/A.R.S./Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642
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