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 .
Claim Status
Claims 2-3, 5, 7-11, 13-20, and 31-40 have been cancelled and claims 1 and 4 have been amended, as requested in the amendment filed on 05/29/2026. 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Claims 6 and 21-30 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions in the Response filed 07/27/2021, there being no allowable generic or linking claim.
Claims 1, 4, and 12 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1, 4, and 12 have an effective filing date of January 13, 2017 corresponding to PRO 62/446,191.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 1, 4, and 12 were 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 in the Patent Board Decision (04/08/2026) due to the recitation of (i) “a plurality of tumor-specific and patient-specific neoepitopes” and (ii) “administering to the patient … 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”.
Applicant has amended instant claim 1 such that the claim now recites (i) “a plurality of neoepitopes, wherein each neoepitope is tumor-specific and patient-specific” and (ii) “administering to the patient … a treatment comprising: (a) at least one neoepitope of the plurality of neoepitopes; (b) T cells that are predicted to target at least one neoepitope of the plurality of neoepitopes; (c) NK cells that are predicted to target at least one neoepitope of the plurality of neoepitopes; or (d) a combination thereof”. In view of the claim amendments, claim 1 and subsequently dependent claims 4 and 12 are deemed to be clear and definite. As such, the rejection of claims 1, 4, and 12 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1, 4, and 12 were rejected under 35 U.S.C. 103 as being unpatentable over non-patent literature by Kreiter et. al. (Nature, 2015, 520(7549), 1-24; previously cited on PTO-892; herein after referred to as "Kreiter") in view of non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
The rejection of claims 1, 4, and 12 was reversed pro forma in the Patent Board Decision (04/08/2026). The rejection of claims 1, 4, and 12 under 35 U.S.C. 103 as being unpatentable over Kreiter, Saletti, and Lee is withdrawn.
Double Patenting - Withdrawn
Claims 1, 4, and 12 were 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 in view of non-patent literature by Kreiter et. al. (Nature, 2015, 520(7549), 1-24; previously cited on PTO-892; herein after referred to as "Kreiter") in view of non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
The rejection of claims 1, 4, and 12 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-7 of U.S. Patent No. 12,053,512 was reversed pro forma in the Patent Board Decision (04/08/2026). The rejection of claims 1, 4, and 12 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-7 of U.S. Patent No. 12,053,512 in view of Kreiter, Saletti, and Lee is withdrawn.
Claims 1, 4, and 12 were 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 in view of in view of non-patent literature by Kreiter et. al. (Nature, 2015, 520(7549), 1-24; previously cited on PTO-892; herein after referred to as "Kreiter") in view of non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
The provisional rejection of claims 1, 4, and 12 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 was reversed pro forma in the Patent Board Decision (04/08/2026). The provisional rejection of claims 1, 4, and 12 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 6-7 of copending Application No. 18/761,799 in view of in view of Kreiter, Saletti, and Lee is withdrawn.
Claim Rejections - 35 USC § 112 - New
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 4, and 12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn a method of treating a patient diagnosed with cancer, generally comprising (1) determining a plurality of neoepitopes and (2) administering to the patient a treatment comprising (a) at least one neoepitope of the plurality of neoepitopes, (b) T cells that are predicted to target at least one neoepitope of the plurality of neoepitopes, (c) NK cells that are predicted to target at least one neoepitope of the plurality of neoepitopes, or (d) a combination thereof. Thus, the claims identify the T cells and NK cells by function only, where the function is to target at least one neoepitope of the plurality of neoepitopes. No T cell or NK cell structure (e.g., T cell receptor structure) is recited.
The instant specification discloses that neoepitope-based treatment may include cell-based treatments such as genetically-modified antigen presenting cells or other cytotoxic or cytolytic immune competent cells (Paragraph 0051). In one embodiment, antigen presenting cells (e.g., dendritic cells) can be modified by recombinant peptide including neoepitope such that the antigen presenting cells can present the neoepitope on their surface; the modified antigen presenting cells can be directly administered to the patient to elicit patient's immune response against the neoepitope or, alternatively, the modified antigen presenting cells can be used to activate immune-competent cells including T cell, NK cell, NKT cells (derived preferably from the patient's blood), and then the activated immune-competent cells can be administered to the patient to boost patient's immune response against the neoepitope (Id.). In another example, at least one or more T cells, NK cells, or NKT cells can be genetically engineered to express recombinant neoepitope-specific receptors; generally, the recombinant protein is a CAR and includes an extracellular single-chain variant fragment, an intracellular activation domain, and a transmembrane linker coupling the extracellular single-chain variant fragment to the intracellular activation domain (Paragraph 0052). A patient's immune cells (e.g., NK cells, NKT cells, etc.) can be genetically engineered to express such a chimeric T cell receptor or a chimeric antigen receptor (CAR) and further administered to the patient, especially to the tumor, to boost the immune response against the tumor in the tumor microenvironment; the ex vivo expanded immune competent cells and/or genetically engineered immune competent cells with a chimeric T cell receptor or a chimeric antigen receptor (CAR) can be further activated ex vivo before being administered to the patient (Paragraph 0064-0065). The instant specification does not disclose any representative structures (e.g., T cell receptor or chimeric antigen receptor sequences or structures) that target the neoepitope(s).
Gupta et. al. (Adv. Exp. Med. Biol. 2020, 1255, 29-50) teach T cell Receptors (TCRs) are restricted to recognizing short peptides of protein antigens processed and presented by major histocompatibility complexes (MHCs) on the body’s own antigen presenting cells (APCs) (p. 30, col. 1). TCRs are composed of two heterodimeric polypeptide chains linked by a disulfide bond. Each chain of the TCR consists of two extracellular immunoglobulin domains, a transmembrane region and a short cytoplasmic tail. The two extracellular domains are made up of the variable (V) region and constant (C) region. The heterodimeric structure of the TCR is analogous to the heavy and light chain heterodimers of B cell receptors (BCRs) or antibodies. However, the forked structure of the BCR consists of two antigen binding sites, whereas each TCR possesses a single antigen binding site. The majority of TCRs possess an α chain and a β chain and are referred to as αβ TCRs. A subset of T cells possesses a γ chain and δ chain and are referred to as γδ TCRs. γδ TCRs are capable of directly recognizing antigens outside the context of MHC and are even capable of recognizing non-peptide antigens. T cells possess the ability to bind to a vast array of peptide antigens through their TCRs; it has been estimated that humans can produce between 1015 and 1020 possible unique TCR chains. This enormous variety is imparted by an unusual genetic mechanism, largely shared with BCR generation, that provides diversity concentrated in the antigen binding regions of the TCR. The V region is the portion of the TCR that participates in antigen binding. The V region is not encoded by a single segment of DNA, but rather is composed of multiple gene segments that are rearranged through somatic DNA recombination. Combinatorial diversity afforded through recombination of the gene segments is further augmented by junctional diversity through the random addition of nucleotides at the interface between segments, thus allowing for the generation of a nearly limitless array of TCRs. The DNA encoding the α chain of the TCR possesses multiple variable (V) and joining (J) segments, whereas the β chain possesses multiple V, diversity (D), and segments as represented in Fig. 3.1 (p. 30, col. 1-2). Fig. 3.1 of Gupta et. al. displays the mRNAs somatic VDJ recombination to form the alpha and beta chains of TCRs. As indicated, there is an arrangement step that recombines the VDJ segment for TCR β and V and J segments for the TCR α chain. The mRNAs formed have addition and deletion of nucleotides at the junctions of these segments leading to junctional diversity that leads to variability for assessing specific antigens. There may be different combinations of genes leading to the final formation of the TCR that consists of the TCR α and β subunit organized in a constant and variable region wherein the variable region is responsible for antigen recognition (p. 30). Gupta et. al. teach: Antigen binding within the TCR V region involves the three complementarity determining regions (CDRs) that contact the antigen MHC complex. CDR1 and CDR2 are primarily encoded in the V germline segments and therefore experience less diversity. CDR3 however includes the junctional regions and is the primary region in contact with the antigen (p. 31, col. 1). Part of Figure 3.1 showing structure of TCR comprising 3 CDRs in each of TCR α and β chains:
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Gupta et. al. teach (p. 31, col. 2): TCRs recognize processed peptide antigen presented on MHC on the surface of the body’s own cells. The two conventional MHCs, MHC I and MHC II are both polygenic and polymorphic noncovalent protein complexes composed of two polypeptide chains. TCRs are specific to both peptide antigen and the MHC to which it is bound, a phenomenon known as MHC restriction. MHC I is on the surface of virtually all nucleated cells in the body. Peptides presented on MHC I are generally 8–10 amino acids in length and result from the processing of foreign intracellular proteins. For this reason, MHC I is frequently used to signal viral infection to cytotoxic CD8 T cells. MHC II is only present on the surface of antigen presenting cells of the immune system including B cells, macrophages, and dendritic cells. MHC II presents peptides of 13–17, amino acids in length that have been collected from the extracellular environment. Figure 3.2 displays both TCR chains binding to the antigenic peptide displayed by MHC II of the APC:
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Thus, the state of the art recognizes that the six CDRs of the TCR chains in a T cell are critical to recognizing and binding the peptide antigen presented by an APC, and the sequences of these CDRs are highly variable and cannot be predicted based on the sequence of the peptide to which they are binding. Much like the six CDRs of antibodies, the sequences of the six CDRs of TCRs critical to antigen binding function cannot be predicted or determined based on the antigen they are binding. The genus of TCR sequences capable of binding an antigen presented by an APC is vast, making the genus of T cells stimulated by an APC comprising even a single defined amino acid sequence vast.
Domogala et. al. (Frontiers in Immunology, 2015, 6(264), 1-9) teach that the potential of natural killer (NK) cells to target numerous malignancies in vitro has been well documented, but only limited success has been seen in the clinic; although NK cells prove non-toxic and safe regardless of the cell numbers injected, there is often little persistence and expansion observed in a patient, which is vital for mounting an effective cellular response (Abstract). As reviewed in Table 1, there have been many studies that well document the expansion of NK cells in vitro, however, there has not yet been a clinically successful product, which proliferates and persists in vivo inducing consistent efficacy; this could be because the optimum activation method and status of the cells before infusion has not yet been identified (Page 3, NK Cell Activation, First Paragraph). As seen in Figure 1, whether the cells should be incubated with cytokines, genetically engineered, differentiated into a “memory-like” phenotype, or primed using NK non-susceptible cell lines are all options that need to be considered (Id.). Cytokine activation has always been a popular method of stimulating NK cells as it is a well-documented pathway of activation in vivo and different cytokines can give rise to the same signaling patterns while differing in their effects on development, activation, and proliferation; IL-2 stimulates cellular proliferation and enhances cytotoxicity, however, it has been noted that this only affects a small sub-population for an extended period and IL-15 significantly improves NK cell survival although it only stimulates minimal expansion (Page 3, NK Cell Activation, Second Paragraph). The use of chimeric antigen receptor (CAR)-expressing NK cells has the potential to offer enhanced effector cell function of increased specificity, wherein allogeneic CAR-engineered NK cells are expected to induce anti-tumor effects and dissipate after a few days (Pages 6-7, Genetic Engineering). Not all tumors are susceptible to NK cell mediated killing, as some cancer cells have developed the ability to escape detection by the immune system, wherein mechanisms that regulate the evasion of tumor cells by NK cells extends to the down-regulation of activating receptor ligands for NKG2D, the production of soluble stress-induced ligands, such as MICA, which degrades NKG2D leading to NK cell inhibition and the release of suppressive cytokines such as IL-10 and TGF-β; some success has been seen by NK cell immunotherapy targeting hematological malignancies, however this has not been transferred to solid tumors (Page 7, Immune Escape Mechanisms). Domogala et. al. indicate that a standard clinical regimen is still to be elucidated and obstacles such as cell dose, activation status, method of expansion, drug complement, and source are still to be determined (Page 7, Concluding Remarks, First Paragraph). Thus, Domogala et. al. discloses complexities associated with NK cell-based immunotherapies and their clinical applicability and success, specifically regarding dose, activation status, method of expansion, drug complement, source, and genetic engineering.
To provide adequate written description and evidence of possession of the claimed T cell genus, and the claimed NK cell genus, the instant specification can structurally describe representative TCRs/structures that function to bind the claimed neoepitopes, or describe structural features common to the members of the genera, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
In this case, the only factor present in the claims is a recitation of the T cell and NK cell function: “predicted to target at least one neoepitope of the plurality of neoepitopes”. The instant specification fails to describe structural features common to the members of the genera, which features constitute a substantial portion of the genus because the instant specification fails to disclose a single exemplary TCR sequence and/or structures that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the T cell and/or NK cell does, rather than what it is. The specification fails to provide any structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of TCR sequences and/or structures for the genera of T cells and/or NK cells that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Applicants have not established any reasonable structure-function correlation with regards to the sequences in the TCR (or CAR) CDRs that result from being stimulated with APCs presenting the neoepitope(s). The instant claims attempt to claim every T cell that resulting from being stimulated with APCs presenting the neoepitope(s), wherein the instant specification does not describe representative examples to support the full scope of the claims because the instant specification fails to disclose a single exemplary TCR (or CAR) of a T cell that functions as claimed. Given the known high level of polymorphism of T cell CDR sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of T cells encompassed by the claimed invention. One could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for T cells and/or NK cells that target a neoepitope as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future T cells and/or NK cells yet to be discovered that may function as claimed. The antigen (i.e., neoepitope) presented by the APC provides no information about the structure of a T cell and/or NK cells that is stimulated and targets it.
Given the lack of representative examples to support the full scope of the claimed T cells and/or NK cells, and lack of reasonable structure-function correlation with regards to the unknown sequences in the TCR (or CAR) CDRs and/or other structures that provide the critical targeting function resulting from stimulation with a neoepitope presented by an APC, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of T cells and/or NK cells resulting from being stimulated with APCs that display the neoepitope(s) that is required to practice the claimed invention.
Claim Rejections - 35 USC § 103 - New
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 2016/0101170 A1 (herein after referred to as "Hacohen") in view of non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
Hacohen discloses a strategy for the personalized treatment of neoplasia, and more particularly to the identification and use of a personalized cancer vaccine consisting essentially of a pool of tumor-specific and patient-specific neo-antigens for the treatment of tumors in a subject. (Paragraph 0008). The invention is based, at least in part, on the discovery that whole genome/exome sequencing may be used to identify all, or nearly all, mutated neo-antigens that are uniquely present in a neoplasia/tumor of an individual patient, and that this collection of mutated neoantigens may be analyzed to identify a specific, optimized subset of neo-antigens for use as a personalized neoplasia vaccine for treatment of the patient's neoplasia/tumor (Id.). It is specifically noted that "neoplasia" is any disease that is caused by or results in inappropriately high levels of cell division, inappropriately low levels of apoptosis, or both, wherein cancer is an example of a neoplasia and examples of cancers are further provided (Paragraph 0052). The invention provides a method of making a personalized neoplasia vaccine for a subject diagnosed as having a neoplasia, which includes identifying a plurality of mutations in the neoplasia, analyzing the plurality of mutations to identify a subset of at least five neo-antigenic mutations predicted to encode neo-antigenic peptides, the neo-antigenic mutations selected from the group consisting of missense mutations, neoORF mutations, and any combination thereof, and producing, based on the identified subset, a personalized neoplasia vaccine (Paragraph 0009). In another aspect, the invention includes a method of treating a subject diagnosed as having a neoplasia with a personalized neoplasia vaccine, which includes identifying a plurality of mutations in the neoplasia; analyzing the plurality of mutations to identify a subset of at least five neo-antigenic mutations predicted to encode expressed neo-antigenic peptides, the neo-antigenic mutations selected from the group consisting of missense mutations, neoORF mutations, and any combination thereof; producing, based on the identified subset, a personalized neoplasia vaccine; and administering the personalized neoplasia vaccine to the subject, thereby treating the neoplasia (Paragraph 0018). In one embodiment, the identifying step may further include sequencing the genome, transcriptome, or proteome of the neoplasia (i.e., genomics, transcriptomics, or proteomics, respectively) (Paragraph 0019). In one embodiment, the personalized neoplasia vaccine comprises: (i) at least 20 neo-antigenic peptides corresponding to the neo-antigenic mutations; (ii) one or more DNA molecules capable of expressing at least 20 neo-antigenic peptides corresponding to the neo-antigenic mutations; or (iii) one or more RNA molecules capable of expressing at least 20 neo-antigenic peptides corresponding to the neo-antigenic mutations (Paragraphs 0022-0024). Figure 10 shows a schematic representation of a strategy to systematically discover tumor neoantigens according to an exemplary embodiment of the invention: (i) tumor specific mutations in cancer samples may be detected using whole-exome (WES) or whole-genome sequencing (WGS) and identified through the application of mutation calling algorithms (e.g., Mutect); (ii) subsequently, candidate neoepitopes may be predicted using well-validated algorithms ( e.g., NetMHCpan) and their identification may be refined by experimental validation for peptide-HLA binding and by confirmation of gene expression at the RNA level; and (ii) these candidate neoantigens may be subsequently tested for their ability to stimulate tumor-specific T cell responses (Paragraph 0093; Figure 10). It is specifically noted that methods suitable for identifying tumor specific neo-antigen mutations are described in Paragraphs 0120- 0134, wherein such methods include sequencing-by-synthesis technologies and direct protein sequencing (i.e., proteomics); it is further noted that any cell type or tissue may be utilized to obtain nucleic acid samples for use in the sequencing methods described by the invention, wherein in a preferred embodiment a DNA or RNA sample is obtained from a neoplasia/tumor or a bodily fluid, e.g., blood, obtained by known techniques or, alternatively, nucleic acid tests can be performed on dry samples such as hair or skin (Paragraph 0125). It would therefore be within the purview of one of ordinary skill in the art that a tissue sample from a neoplasia/tumor could be obtained via biopsy as is routine in the art. Example 9 discloses the assessment of immunological endpoint, which comprises the assessment of T cell response measured by ex vivo IFN-γ ELISPOT (Page 41, Example 9, Paragraphs 0421-0426). T cell responses are detectable ex vivo, i.e. without the need for in vitro expansion of epitope specific T cells through short-term culture, and patients are initially evaluated using the total pool of peptide immunogens as stimulant in the ELISPOT assay and, for patients demonstrating a robust positive response, the precise immunogenic peptide(s) will be determined in follow-up analysis (Paragraph 0421). The IFN-γ ELISPOT is generally accepted as a robust and reproducible assay to detect ex vivo T cell activity and determine specificity, and in addition to the analysis of the magnitude and determinant mapping of the T cell response in peripheral blood monocytes (i.e., a blood sample), other aspects of the immune response induced by the vaccine are critical and will be assessed; these evaluations will be performed in patients who exhibit an ex vivo IFN-γ ELISPOT response in the screening assay and include the evaluation of T cell subsets (Th1 versus Th2, T effector versus memory cells), analysis of the presence and abundance of regulatory cells such as T regulatory cells or myeloid derived suppressor cells, and cytotoxicity assays if patient-specific melanoma cells lines are successfully established (Id.); it is specifically noted that the analysis/evaluation of T cell subsets and the presence/abundance of regulatory cells (e.g., Tregs and/or myeloid derived suppressor cells) generally read on leukocyte profiling (i.e., the analysis of the different types of white blood cells present in a biological sample including abundance, proportions, activation states, and functional characteristics). Example 14 further discloses the deconvolution of epitopes in follow-up ex vivo IFN-γ ELSIPOT assays wherein once an ex vivo IFN-γ ELISPOT response elicited by an overlapping peptide pool is observed (defined as at least 55 spot forming units/I 06 PBMC or increased at least 3 times over baseline), the particular immunogenic peptide eliciting this response will be identified by de-convoluting the peptide pool based into sub-pools based on the immunizing peptides and repeating the ex vivo IFN-γ ELISPOT assays (Page 43, Paragraphs 0437-0444). Additional assays may be conducted on a case-by case basis for appropriate samples, including, for example: (i) the entire 15mer pool or sub-pools will be used as stimulating peptides for intracellular cytokine staining assays to identify and quantify antigen-specific CD4+, CD8+, central memory and effector memory populations; (ii) these pools will be used to evaluate the pattern of cytokines secreted by these cells to determine the TH1 vs TH2 phenotype; (iii) extracellular cytokine staining and flow cytometry of unstimulated cells will be used to quantify Treg and myeloid-derived suppressor cells (MDSC); (iv) if a melanoma cell line is successfully established from a responding patient and the activating epitope can be identified, T-cell cytotoxicity assays will be conducted using the mutant and corresponding wild type peptide; (v) PBMC from the primary immunological endpoint will be evaluated for "epitope spreading" by using known melanoma tumor associated antigens as stimulants and by using several additional identified mutated epitopes that were not selected to be among the immunogens; and /or (vi) immuno-histochemistry of tumor samples will be conducted to quantify CD4+, CD8+, MDSC, and Treg infiltrating populations (Id.). In Example 20, a CLL patient exhibited immunity against a mutated FNDC3B peptide (i.e., neoantigen), wherein T cell reactivity against mut-FNDC3B was polyfunctional (secreting GM-CSF, IFN-γ and IL-2), and specific to the mut-FNDC3B peptide but not its wildtype counterpart (Paragraphs 0460-0462). Thus, Hacohen generally reads on a method of treating a patient diagnosed with cancer, comprising: (i) determining, via omics analysis of a neoplasia/tumor biopsy tissue sample, a plurality of tumor- specific and patient-specific neoepitopes; (ii) measuring response of the patient's immune system (i.e., T cell response) to each of the plurality of tumor- specific and patient-specific neoepitopes by ex vivo IFN-γ ELISPOT assay; (iii) identifying the particular immunogenic peptide eliciting immune response by de-convoluting the peptide pool into sub-pools based on the immunizing peptides and repeating the ex vivo IFN-γ ELISPOT assays; and (iv) treating the patient comprising administering a vaccine comprising at least one of the identified plurality of tumor-specific and patient- specific neoepitopes to which a patient’s immune system responds to (i.e., administering a neoepitope for which the patient’s immune system is “hot”). Hacohen also generally reads on analyzing a leukocyte profile, wherein in patients who exhibit an ex vivo IFN-γ ELISPOT response in the neoepitope screening assay, additional analysis includes the evaluation of T cell subsets (Th1 versus Th2, T effector versus memory cells) and analysis of the presence and abundance of regulatory cells such as T regulatory cells or myeloid derived suppressor cells.
However, Hacohen does not explicitly disclose and/or suggest that when measuring a patient’s immune response, (i) each of a plurality of neoepitopes is immobilized on a solid substrate, (ii) contacting ex vivo the patient’s blood sample, which comprises immune competent cells, with each of the immobilized neoepitopes, and (iii) determining the patient’s immune system to be “hot” when immune competent cells of the blood sample are bound to the immobilized neoepitopes and when the quantities of at least five chemokines and cytokines in the blood sample are above clinical reference range for normal. These deficiencies are remedied by Saletti and Lee.
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 reproduced 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.
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, including multiple cytokines specifically implicated in T cell responses.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the methods of Hacohen such that the ex vivo ELISPOT assay is a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the methods of Hacohen such that the ex vivo ELISPOT assay is a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
Claims 1, 4, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 12,053,512 (herein after referred to as “512”) in view of US 2016/0101170 A1 (herein after referred to as "Hacohen"), non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
The applied primary reference has a common Applicant and Inventor(s) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
512 teaches methods for validating the anticipated effectiveness of one or more cancer neoepitopes to provoke an effective anticancer immune response against an individual subject's tumor or cancer by the steps including: a) obtaining neoepitope sequence data from the tumor of the subject, i.e., a first subject; b) obtaining immune competent cells from the subject, or allogenic cells, or from a second subject that is haploidentical to the first subject; c) using the neoepitope sequence data to generate a neoepitope presentation system; d) triggering an immune response by contacting the immune competent cells with the neoepitope presentation system; and e) quantifying the triggering of the immune response from the contacted immune-competent cells (Column 4, Lines 15-30). It is specifically noted that the inventive methods may be practiced prior to any treatment (and particularly immune therapy), or after surgery but prior to immune therapy, or prior to a second round of treatment ( and particularly immune therapy) (Column 4, Lines 31-35). Neoepitope presentation can be identified using a number of techniques: the neoepitope can be linked to another protein such as albumin or keyhole limpet hemocyanin, a bead such as a microbead or a paramagnetic bead, or a synthetic polymer; T-cell responses can then be assessed by direct binding to the protein-linked neoepitope, the bead-linked neoepitope, or synthetic polymer-linked neoepitope or T-cell responses can also be assessed by exposing an antigen-presenting cell to the protein-linked neoepitope, the bead-linked neoepitope, or synthetic polymer-linked neoepitope, and allowing the antigen-presenting cell to present the neoepitope on the surface of the antigen-presenting cell (Column 15, Lines 8-20). Quantifying the triggering of an immune response can be achieved by selecting an assay for triggering with an objective output; an objective outcome can be the incorporation of tritiated thymidine, the increase in number of immune competent cells, an ELISA or cell-proliferation assay for the presence of an immune reactive molecule, or flow cytometry (Column 15, Lines 27-33). In another alternative, the step of quantifying the triggering of the immune response includes: measuring at least one of a phosphorylation and a Ca2+ flux and/or measuring a cell-killing metric, measuring a T-cell proliferation metric, measuring cytokine secretion, processing the contacted immune competent cells to thereby enhance a measurement, generating a validation measure as a function of a validation criterion, and/or calibrating a validation criterion, that is optionally subject- specific (Column 15, Lines 56-67). Thus, 512 generally reads on a method of validating the anticipated effectiveness of one or more cancer neoepitopes to provoke an effective anticancer immune response against an individual subject's tumor or cancer by the steps including: a) obtaining neoepitope sequence data from the tumor of the subject, i.e., a first subject; b) obtaining immune competent cells from the subject, or allogenic cells, or from a second subject that is haploidentical to the first subject; c) using the neoepitope sequence data to generate a neoepitope presentation system; d) triggering an immune response by contacting the immune competent cells with the neoepitope presentation system; and e) quantifying the triggering of the immune response from the contacted immune-competent cells, wherein such a method may be performed prior any particular treatment.
However, 512 does not teach/suggest 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, administering a treatment to the patient, nor analyzing a leukocyte profile. These deficiencies are remedied by Hacohen, Saletti, and Lee, whose teachings are detailed above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of validating a therapeutic composition of 512 such that, as suggested by Hacohen, a leukocyte profile and ex vivo ELISPOT assay are utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein said ex vivo ELISPOT assay may specifically be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, such as those validated/identified in the methods of both 512 and Hacohen, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the therapeutic validation method of 512 such that, as suggested by Hacohen, an ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein the ex vivo ELISPOT assay may be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 1, 4, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 2024/0350603 A1 (divisional application of US 12,053,512; herein after referred to as “603”) in view of US 2016/0101170 A1 (herein after referred to as "Hacohen"), non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
The applied primary reference has a common Applicant and Inventor(s) with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
It is noted that 603 is a divisional application of US 12,053,512. As such, the disclosure of 603 is the same as that of US 12,053,512, wherein the pertinent teachings of the disclosure are detailed above for US 12,053,512; it is noted that 603 generally reads on a method of validating the anticipated effectiveness of one or more cancer neoepitopes to provoke an effective anticancer immune response against an individual subject's tumor or cancer by the steps including: a) obtaining neoepitope sequence data from the tumor of the subject, i.e., a first subject; b) obtaining immune competent cells from the subject, or allogenic cells, or from a second subject that is haploidentical to the first subject; c) using the neoepitope sequence data to generate a neoepitope presentation system; d) triggering an immune response by contacting the immune competent cells with the neoepitope presentation system; and e) quantifying the triggering of the immune response from the contacted immune-competent cells, wherein such a method may be performed prior any particular treatment.
603 does not teach/suggest 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, administering a treatment to the patient, nor analyzing a leukocyte profile.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of validating a therapeutic composition of 603 such that, as suggested by Hacohen, an ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein said ex vivo ELISPOT assay may specifically be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, such as those validated/identified in the methods of both 603 and Hacohen, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the therapeutic validation method of 603 such that, as suggested by Hacohen, a leukocyte profile and ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein the ex vivo ELISPOT assay may be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Claims 1, 4, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over US 10,532,089 (herein after referred to as “089”) in view of US 2016/0101170 A1 (herein after referred to as "Hacohen"), non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti") and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
The applied primary reference has a common Inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
089 teaches that treatment of various cancers can be significantly improved using recursive identification of patient-, tumor-, and location-specific neoepitopes after immunotherapy and/or chemotherapy and that such subsequently identified neoepitopes can be used as new therapeutic targets to refine or adjust immunotherapy; most notably, such approach also allows targeting specific subpopulations of tumors and/or metastases that may otherwise not be treated using conventional treatment (Column 4, Lines 22-30). The invention is drawn to a method of guided immunotherapy for a patient diagnosed with a tumor that includes the steps of (a) receiving omics data for tumor cells in a first location in a patient, and receiving omics data for tumor cells in a second location in a patient; (b) using the omics data to determine respective neoepitopes in the tumor cells of the first and second locations; (c) identifying treatment relevant neoepitopes in the tumor cells of the first and second locations using at least one of a group attribute, a location attribute, and a function attribute; (d) and creating an immunotherapeutic composition using the treatment relevant neoepitopes, and administering the immunotherapeutic composition to the patient (Column 5, Lines 7-20). Depending on the type and stage of the cancer, it was observed that only a fraction of neoepitopes will generate an immune response; to increase likelihood of a therapeutically effective response, the neoepitopes can be further filtered (Column 8, Lines 29-32). An immunotherapeutic composition may be directly created by producing a vaccine, an antibody or other neoepitope-specific affinity reagent, or a neoepitope-specific cell based composition, or indirectly, by providing information about selected neoepitopes to a manufacturer that generates the immunotherapeutic composition; suitable immunotherapeutic compositions include recombinant (e.g., naked DNA, RNA, viral, bacterial) expression system that encode the treatment relevant neoepitopes, a recombinant immune-competent cell (e.g., NK cell, T cell, dendritic cell) expressing the treatment relevant neoepitopes, a recombinant immune-competent cell expressing a (chimeric) receptor for the treatment relevant neoepitopes (e.g., T cell expressing CAR), a synthetic antibody for binding the treatment relevant neoepitopes, and a population of white blood cells ex vivo activated with the treatment relevant neoepitopes (Column 15, Lines 35-52). Thus, 089 generally reads on a method for guided immunotherapy for a patient diagnosed with a tumor that includes the steps of (a) receiving omics data for tumor cells in a first location in a patient, and receiving omics data for tumor cells in a second location in a patient; (b) using the omics data to determine respective neoepitopes in the tumor cells of the first and second locations; (c) identifying treatment relevant neoepitopes in the tumor cells of the first and second locations using at least one of a group attribute, a location attribute, and a function attribute; (d) and creating an immunotherapeutic composition using the treatment relevant neoepitopes, and administering the immunotherapeutic composition to the patient.
However, 089 does not teach/suggest 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, determining a patient’s immune system to be “hot”, nor analyzing a leukocyte profile. These deficiencies are remedied by Hacohen, Saletti, and Lee, whose teachings are detailed above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of treatment of 089 such that, as suggested by Hacohen, an ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient, wherein said ex vivo ELISPOT assay may specifically be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, such as those identified in the methods of both 089 and Hacohen, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the method of treatment of 089 such that, as suggested by Hacohen, a leukocyte profile and ex vivo ELISPOT assay could be used with a patient’s blood sample to determine immune response to the identified neoepitopes, wherein the ex vivo ELISPOT assay may be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Double Patenting - New
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, 6, 8, and 10 of U.S. Patent No. 10,532,089 (herein after referred to as "089") in view of US 2016/0101170 A1 (herein after referred to as "Hacohen"), non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti"), and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
089 claim 1 is drawn to a method of treating a patient diagnosed with a tumor using guided immunotherapy, comprising: (a) receiving omics data for tumor cells in a first location in the patient and receiving omics data for tumor cells in a second location in the patient, wherein the omics data comprise whole genome DNA sequencing data or exome DNA sequencing data, wherein the first and second locations are anatomically different locations; (b) comparing the omics data for the tumor cells in the first location with matched normal omics data from the patient and comparing the omics data for the tumor cells in the second location with matched normal omics data from the patient to so identify respective DNA sequences that encode neoepitopes in the tumor cells of the first and second locations; wherein the neoepitopes are peptide sequences having a length of between 5 and 30 amino acids and include a mutation in the peptide sequences relative to an amino acid sequence in the matched normal omics data; (c) determining from a patient sample or the matched normal data, an HLA type of the patient; (d) calculating for the neoepitopes respective binding affinities with respect to the determined HLA type of the patient; (e) selecting high-affinity neoepitopes for the first and second locations that have a binding affinity to the determined HLA type of the patient of less than 500 nM; (f) selecting, from the high-affinity neoepitopes, target neoepitopes for the first and second locations such that the target neoepitopes for the first and second locations have the same attribute, wherein the attribute is selected from the group consisting of a group attribute, a location attribute, a function attribute, a metabolic attribute, and a pathway attribute; (g) creating an immunotherapeutic composition comprising a neoepitope-specific cell based composition, wherein the neoepitope-specific cell based composition comprises an immune competent cell that is genetically modified to express a chimeric antigen receptor that specifically recognizes or binds to the at least one of the target neoepitopes to target tumor cells in the first and second locations that express the target neoepitopes; and (h) administering the immunotherapeutic composition to treat the tumor of the patient. 089 claim 6 further limits the method of claim 1 wherein the neoepitope-specific cell based composition is selected from a group consisting of: a recombinant immune competent cell expressing the treatment-relevant neoepitopes, a recombinant immune competent cell expressing a receptor for the treatment-relevant neoepitopes, and a population of white blood cells ex vivo activated with the treatment-relevant neoepitopes. Claim 8 of 089 further limits the method of claim 1, wherein the immunotherapeutic composition further comprises at least one of a vaccine and a neoepitope-specific affinity reagent, wherein the vaccine comprises at least one of the target neoepitopes as an immunogen, wherein the neoepitope-specific affinity reagent is an antibody or fragment thereof that specifically binds to the at least one of the target neoepitopes. 089 claim 10 further limits the method of claim 1, wherein the immune competent cell is selected from a group consisting of: NK cells, T cells, and dendritic cells.
However, 089 does not claim 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, determining a patient’s immune system to be “hot”, nor analyzing a leukocyte profile. These deficiencies are remedied by Hacohen, Saletti, and Lee, whose teachings are detailed above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of treatment claimed by 089 such that, as suggested by Hacohen, an ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient, wherein said ex vivo ELISPOT assay may specifically be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, such as those identified in the methods of both 089 and Hacohen, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the method of treatment of 089 such that, as suggested by Hacohen, a leukocyte profile and ex vivo ELISPOT assay could be used with a patient’s blood sample to determine immune response to the identified neoepitopes, wherein the ex vivo ELISPOT assay may be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
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 US 2016/0101170 A1 (herein after referred to as "Hacohen"), non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti"), and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
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 claim 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, administering a treatment to the patient, nor analyzing a leukocyte profile. These deficiencies are remedied by Hacohen, Saletti, and Lee, whose teaching are detailed above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of validating a therapeutic composition claimed by 512 such that, as suggested by Hacohen, an ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein said ex vivo ELISPOT assay may specifically be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, such as those validated/identified in the methods of both 512 and Hacohen, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the therapeutic validation method of 512 such that, as suggested by Hacohen, a leukocyte profile and ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein the ex vivo ELISPOT assay may be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
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 US 2016/0101170 A1 (herein after referred to as "Hacohen"), non-patent literature by Saletti et. al. (Nature Protocols, 2013, 8(6), 1073-1087; previously cited on PTO-892; herein after referred to as "Saletti"), and non-patent literature by Lee and Morgolin (Cancers, 2011, 3, 3856-3893; previously cited on PTO-892; herein after referred to as "Lee").
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, 799 does not claim 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, determining a patient’s immune system to be “hot”, administering a treatment to the patient, nor analyzing a leukocyte profile. These deficiencies are remedied by Hacohen, Saletti, and Lee, whose teachings are detailed above.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the method of validating a therapeutic composition claimed by 799 such that, as suggested by Hacohen, an ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein said ex vivo ELISPOT assay may specifically be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, wherein one of ordinary skill in the art would recognize that an increase in the detection of T-cell specific cytokines indicates that a patient’s immune system is responsive (i.e., “hot”) to the immobilized neoepitope(s) as taught by Saletti. One would have been motivated to make such modifications in order to, as suggested by Saletti, estimate of the nature and intensity of a humoral immune response to a vaccine (e.g., a vaccine comprising patient- and tumor-specific neoepitope(s) as suggested by Hacohen). One of ordinary skill in the art would have a reasonable expectation of success because cytokines associated with T cell responses are established in the art, as taught by Lee, ELISPOT assays allow for the detection of several cytokines simultaneously, as taught by Saletti, and cytokine-based ELISPOT assays are utilized by Hacohen to evaluate identified patient- and tumor-specific neoepitopes for use in a therapeutic vaccine.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, Hacohen recognizes the need/importance of assessing immune response to identified patient- and tumor-specific neoepitopes, such as those validated/identified in the methods of both 799 and Hacohen, and Saletti further indicates the utility of ELISPOT assays in predicting the effectiveness of a vaccine based on immune response. Given the recognized need/utility of ELISPOT assays in evaluating immune response to evaluate vaccines, and given (i) the known modes of conducting an ELISPOT assay including cytokine-based T cell ELISPOT assays for the visualization of several cytokines simultaneously and (ii) cytokines established/know to be correlated to T cell response, one of skill in the art could have pursued modifying the therapeutic validation method of 799 such that, as suggested by Hacohen, a leukocyte profile and ex vivo ELISPOT assay is utilized to determine the patient’s immune response to the identified neoepitope(s) using a blood sample from the patient and neoepitopes that the patient’s immune system is responsive to is made into a therapeutic composition (i.e., a vaccine) that is subsequently administered to said patient for treatment, wherein the ex vivo ELISPOT assay may be a cytokine-based T cell ELISPOT assay wherein the identified neoepitope(s) is/are immobilized on a solid substrate and contacted ex vivo with a blood sample (wherein said blood sample comprises immune competent T cells) and several released cytokines are detected/visualized, as suggested by Saletti, and wherein said several cytokines that could be detected include, for example, T-cell specific cytokines IL-2, IL-12, IL-15, IL-18, IL-21, IFN-γ, and/or TNF-α, as suggested by Lee, with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
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.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
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