DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendment filed 14 May 2026 is acknowledged. Claims 1, 3, 12, and 13 are amended. Claims 2 and 20 are cancelled.
Claim Status
Claims 1, and 3-19 are pending and under examination in the instant office action.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Withdrawal of Objections
The objection to the specification for missing a sequence identifier in Fig. 28 top (sheet 33/35) has an enumerated sequence not properly identified by SEQ ID NO because there is no Fig. 28 or sheet 33/35; the objection was made in error by the Examiner.
The objection to the specification for improperly demarcated trade names or trademarks is withdrawn in view of the amendments to the specification.
Withdrawal of Rejections
The rejection of claims 1-20 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendments to the claims.
The rejection of claims 1-3 and 7-13 under 35 U.S.C. 102(a)(1) as being anticipated by US 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) as evidenced by Tsukamoto et. al. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82. doi: 10.1002/path.2424. PMID: 18798223 is withdrawn in view of the amendments to the claims.
The rejection of claims 4-6, 18, and 20 under 35 U.S.C. 103 as being unpatentable over U.S. 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) as applied to claim 1 above, and further in view of Tsukamoto et. al. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82. doi: 10.1002/path.2424. PMID: 18798223 is withdrawn in view of the amendments to the claims.
The rejection of claims 14-17 under 35 U.S.C. 103 as being unpatentable over U.S. 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) as applied to claim 1 above, and further in view of U.S. 20160101170 to Hacohen et. al. published 14 April 2016 (Of record, IDS dated 9/25/2025 US 044) is withdrawn in view of the amendments to the claims.
The rejection of claims 18 and 19 under 35 U.S.C. 103 as being unpatentable over U.S. 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) as applied to claim 1 above, and further in view of Lu et. al. Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress. Cancer Res. 2009 Dec 1;69(23):9105-11. doi: 10.1158/0008-5472.CAN-09-2775. Epub 2009 Nov 17. PMID: 19920201; PMCID: PMC2789175 (Hereinafter Lu 2009, Of record, IDS dated 9/25/2025 NPL 096) is withdrawn in view of the amendments to the claims.
Drawings- Pending Petition Review
The drawings are objected to because the brief description of the drawings contains references to color for Fig. 8, 9, 10, and 11 that do not appear in the greyscale images. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The examiner suggests obviating the objection by either filing a petition for color drawings (as described in the Drawings section) or by amending the specification to remove the references to color in the drawings (as described in the Specification section, below). In the Description of the Figures see: p. 10 lines 26, 28, 30; p. 11 lines 2, 4, 5, 6, 8, 10, 15, 16, 17, 20, 22, 24, 27, 28, 29; p. 12 lines 1, 3, 5, 8, 9, 10.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification- Pending Petition Review
The disclosure is objected to because of the following informalities: the brief description of the drawings contains references to color for 8, 9, 10, and 11 that do not appear in the greyscale images.
The examiner suggests obviating the objection by either filing a petition for color drawings (as described in the Drawings section, above) or by amending the specification to remove the references to color in the drawings. In the Description of the Figures see: p. 10 lines 26, 28, 30; p. 11 lines 2, 4, 5, 6, 8, 10, 15, 16, 17, 20, 22, 24, 27, 28, 29; p. 12 lines 1, 3, 5, 8, 9, 10.
Response to Arguments
Applicant has filed a petition for color drawings as requested on 14 May 2026; however, that petition has not yet been reviewed by the Office. Therefore, the objections are held in abeyance and will be withdrawn when the petition for color drawings is approved.
Claim Rejections - 35 USC § 112(a)- Written Description- Maintained, changes necessitated by amendment
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 and 3-19 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.
Scope of the claimed genus
Claim 1 recites for treating cancer in a subject, comprising designing a group of one or more T-cell stimulating peptides, or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject, comprising the following steps:
Obtaining a biopsy of the subject’s tumor;
Obtaining the sequences for nucleic acids and proteins in the biopsy;
Comparing the copy number differential of genes encoding each protein between tumor and normal tissue;
Identifying amplification of EGFR in the biopsy
Identifying bystander proteins that are transcribed in the biopsy, wherein the bystander proteins are selected from the group consisting of SEC61G, VOPP1, LANCL2, SEPT14, and combinations thereof, said bystander proteins being co-amplified with EGFR and encoded on chromosome 7 adjacent to EGFR;
Determining T cell exposed motifs in each of the bystander proteins;
Determining the predicted binding affinity to the subject’s MHC alleles of peptides which comprise each of the T cell exposed motifs, or a subset thereof;
Selecting a group of one or more of the peptides which have a desired predicted binding affinity for one or more of the subject’s MHC alleles;
Generating one or more alternative peptides not present in the tumor biopsy, wherein each alternative peptide comprises a T cell exposed motif identified in the bystander proteins, and in which the amino acids not within the T cell exposed motif are substituted to change the predicted binding affinity to the MHC alleles;
Synthesizing a group of one or more selected peptides comprising the one or more alternative peptides, or nucleic acids encoding the selected peptides from the bystander proteins; and
Administering the selected peptides or nucleic acids to the subject.
Thus, the scope of the claims at the broadest includes a method of treating any cancer comprising an amplified EGFR gene and bystander selected from SEC61G, VOPP1, LANCL2, SEPT14, and combinations thereof by administering any peptide or nucleic acid encoding a peptide that is predicted to bind to MHC and comprise a T cell exposed motif wherein the peptide has an alteration not present in the tumor biopsy to change the amino acids that are not in the T cell exposed motif. The examiner notes that the limitation “said bystander proteins being co-amplified with EGFR and encoded on chromosome 7 adjacent to EGFR” does not limit the bystander proteins to those that are co-amplified with EGFR in the biopsy and therefore does not require identifying anything other than a protein selected from the group consisting of SEC61G, VOPP1, LANCL2, and SEPT14, because as evidenced by Tsukamoto et. al. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82. doi: 10.1002/path.2424. PMID: 18798223, it is a characteristic of each of these genes that they are 1) co-amplified with EGFR and 2) encoded on chromosome 7 adjacent to EGFR.
Claim 3 recites wherein the oncogene EGFR is mutated in the tumor biopsy related to the normal tissue.
Claim 4 recites wherein the genes encoding the bystander proteins are present in increased copy number in the tumor biopsy. Although this somewhat limits the scope and narrows the written description issues as described, it does not fully resolve the written description issues because the scope of a bystander protein still applies to any protein with 1 megabase of an oncogene or tumor suppressor gene in any context.
Claims 5-6 recite wherein the oncogene copy number is increased by a particular amount.
Claim 7 recited wherein the MHC allele is an MHC I allele.
Claim 8 recites wherein the MHC allele is an MHC II allele.
Claims 9-11 recite particular lengths of selected peptides.
Claims 12-13 recite wherein the predicted binding affinity is to MHC I and MHC II alleles carried by the subject, respectively.
Claims 14-17 recite a range of desired predicted binding affinities from less than 20 nanomolar to less than 500 nanomolar.
Claims 18-19 recite particular cancer subtypes, in particular brain cancer subtypes.
State of the Relevant Art
Regarding bystander proteins, the Examiner notes that this is not a term known or used in the art. Because many genomes are fully mapped, genes that are within 1 megabase of an oncogene or tumor suppressor in a reference human genome may be determined. For example, Thomassen, Mads, et. al. "Gene expression meta-analysis identifies chromosomal regions and candidate genes involved in breast cancer metastasis." Breast cancer research and treatment 113.2 (2009): 239-249 (PTO-892 2/18/2026) teaches “We have investigated the relation of gene expression and chromosomal position, using eight datasets including more than 1200 breast tumors, to identify chromosomal regions and candidate genes possibly causal for breast cancer metastasis. By use of “Gene Set Enrichment Analysis” we have ranked chromosomal regions according to their relation to metastasis” (Abstract). However, many tumors have chromosomal instability, aneuploidy, or polyploidy which may contribute to driving the cancer (Baudoin, Nicolaas C et. al. "Karyotype aberrations in action: the evolution of cancer genomes and the tumor microenvironment." Genes 12.4 (2021): 558; see p. 2 ¶1-2; PTO-892 2/18/2026). Baudoin et. al. further teaches that lagging chromosomes can lead to the formation of micronuclei, and that chromosomes in micronuclei undergo DNA that leads to complex structural rearrangements, missegregation of chromosome fragments, unbalanced chromosomal translocations, and other partial chromosomal copy number changes (p. 3 ¶3- p. 4 ¶1). However, as described above, the scope of the amended claims is now limited to four particular bystander proteins of EGFR. The question, therefore, is whether a person of skill in the art would have reasonably believed the applicant to be in possession of a method of treating cancer, wherein the cancer comprises co-amplification of SEC61G, VOPP1, LANCL2, and SEPT14, comprising administering a predicted MHC-binding peptide with a T cell exposed motif from one of these 4 genes wherein the peptide has a desired predicted binding to the subjects MHC allele.
Regarding methods of administering peptides and nucleic acids encoding peptides predicted to bind to a subject’s MHC alleles, some of these methods of cancer vaccination against MHC-presented peptides are described in the art. Liu W, et. al. Peptide-based therapeutic cancer vaccine: Current trends in clinical application. Cell Prolif. 2021 May;54(5):e13025. doi: 10.1111/cpr.13025. Epub 2021 Mar 22. PMID: 33754407; PMCID: PMC8088465 (PTO-892 2/18/2026) reviews peptide-based cancer vaccinations based on epitope peptides stimulating CD8+ or CD4+ T-cells to target tumor-associated antigens or tumor-specific antigens. Regarding selection of target choice, Liu et. al. teaches that “the critical factor is the selection of proper TA for therapeutic cancer vaccines to exert specific toxicity against tumour cells”. Liu et. al. teach that tumor antigens (TAs) are sorted into two classes, tumor associated antigens (TAAs) and tumor specific antigens (TSAs). TAAs overexpress in tumour cells but at a low level in normal cells while TSAs, while TSAs are only expressed in tumor cells (such as mutations, neoantigens, and virus-related antigens). Regarding TAAs, Liu et. al. teach that “the characteristic of proper TAA should be the following: i) differential expression between normal cells and tumour cells; ii) involvement in cell cycle; and iii) association with cell survival. Although the amended claims require gene amplification of the bystander proteins in the tumor, the instant claims and specification do not show that the predicted peptides are 1) expressed by the tumor as peptide-MHC and 2) immunogenic. Additionally, Tran T, et. al. Therapeutic cancer vaccine: building the future from lessons of the past. Semin Immunopathol. 2019 Jan;41(1):69-85. doi: 10.1007/s00281-018-0691-z. Epub 2018 Jul 5. PMID: 29978248 (PTO-892 2/18/2026) teaches that although TAAs are attractive antigens because of their expression across many tumor types “as TAA are expressed in normal cells, specific mechanisms of tolerance may have occurred for some of them. In some cases, secondary to the negative thymic selection of self-antigen, these TAA elicit low avidity rather than high-avidity T cells” (p. 71 left column ¶1). There is reason to believe, then, it would not be predictable which bystander proteins would produce suitable MHC peptides a priori because they would necessarily include self peptides for which self-tolerance must be broken.
In regards to TSAs and neoantigens, some methods of treating cancer using these are known in the art. For example, Lu, Sydney X., et al. "Pharmacologic modulation of RNA splicing enhances anti-tumor immunity." Cell 184.15 (2021): 4032-4047 (PTO-892 2/18/2026) teaches a method of predicting neoepitopes caused by administration of splicing modulators indisulam or MS-023 (p. 4038 right column ¶5-left column). Lu et. al. teaches that using MHC I-bound peptide identification from mass spectrometry compared to four proteomes: the full-length proteome, predicted MHC-I binders, predicted MHC-I binders spiked with non-binders, and filtered predicted binder restricted to predicted binders from differentially expressed or spliced genes (p. 4038 right column ¶2). Lu et. al. teaches “Approximately 80% and 86% of identified peptides were predicted binder for H-2Db and H-2Kb versus 0.6% and 0.9% for peptides randomly sampled from the proteome” (p. 4038 right column ¶3, Fig. 5C). Lu et. al. additionally teaches Selection of a small number of candidates (109) was followed by screening for ability to stabilize H-2 molecules; of the 109 peptide candidates, immunization by hock injection in mice resulted in reactive CD8+ T cells in only 43% of cases (p. 4041 left column ¶2). Lu et. al. teaches that “All 39 candidates based solely on RNA-seq analysis and MHC I binding predictions exhibited some H-2 binding (Figure S7F), and 28% (11/39) were immunogenic in vivo (Figure S7G). An artisan would thus conclude that, even in the case where bystander protein comprised a neoepitope predicted to be expressed in the cancer, screening of each peptide for immunogenicity would be required in order to determine which epitopes would be suitable for the treatment of vaccine. Garcia-Garijo A et al. (Frontiers in Immunology 2019 10 1-19) teaches: “Thus far, clinical trials testing vaccines targeting neoantigens have demonstrated they are safe and well tolerated, and personalized T-cell based therapies targeting neoantigens have shown antitumor responses in selected cases. However, whether individualized immunotherapies targeting neoantigens can mediate effective antitumor responses in a broader patient population, remains an open question. Despite all the technological innovation and development of novel screening assays, the rapid and precise identification of the bona fide neoantigens in any given patient remains a major hurdle that will need to be overcome to translate the potential of neoantigen targeting into effective therapies for patients with cancer” (emphasis is the examiner’s). This is further supported by Guo Y, Lei K, Tang L. Neoantigen Vaccine Delivery for Personalized Anticancer Immunotherapy. Front Immunol. 2018 Jul 2;9:1499. doi: 10.3389/fimmu.2018.01499. PMID: 30013560; PMCID: PMC6036114 (PTO-892 2/18/2026). Guo et. al. teaches that cancer neoantigens are an attractive target for cancer immunotherapies (Abstract). However, Guo et. al. teaches “Many efforts are currently focused on addressing two key challenges in the development of neoantigen-based cancer vaccines for wide clinical applications. First, immunogenic neoantigens are rare and difficult to predict. Current predictive algorithm and validation tools need to be optimized for accurate prediction of major histocompatibility complex (MHC)-binding peptides and reliable selection of highly immunogenic neoepitopes (18)” (Introduction, p. 2 Col. 1 para. 2). Guo et. al. teaches that the reliability of predictive algorithms needs to been improves and that they are not able to account for every factor such as peptide processing and MHC binding stability (“Identification and Selection of Neoantigens” section, p. 2 Col 1 para. 3-Col. 2 para. 2).
Additionally, the instant claims encompass administering a nucleic acid encoding the peptide. These include both RNA and DNA vaccines, some of which are known in the art. Kreiter et al (Nature (2015) 520(7549): 692-696 (PTO-892 2/18/2026)) teaches a subpopulation of known cancer antigen epitopes but also teaches that less than half of the cancer-associated mutations tested are immunogenic. Specifically, 66% of 50 B16F10 mutations immunized with peptide were non-immunogenic (see Figure 1b), 79% of 96 CT26 mutations immunized with RNA were non-immunogenic (see Figure 1c), and 55% of 38 4T1 mutations immunized with RNA were non-immunogenic (see Figure 1d). Therefore, merely identifying cancer-associated gene mutations does not mean the mutation will be an effective immunogenic antigen for a claimed nucleic acid vaccine encoding such peptides. Tran et. al. (supra) further teaches that vaccine formulations include DNA, RNA, or dendritic-cell based vaccines that have been shown to elicit CD8+ T cells in mice and humans, however, “in the last setting, the induction of CD8+ T cells is low and required in vitro stimulation. Some discrepancies between results obtained in mice and humans especially for DNA vaccine have to be more explored” (p. 73 right column). Jahanafrooz, Zohreh, et al. "Comparison of DNA and mRNA vaccines against cancer." Drug discovery today 25.3 (2020): 552-560 (PTO-892 2/18/2026) teaches that “Despite many ongoing efforts to optimize cancer NAVs, researchers still need to deal with many challenges to provide fully effective NAVs for cancer immunotherapy; however, with sufficient time, they might be able to solve all of them. Suggested reasons for the lack of convincing evidence of benefit gained by using current NAVs are as follows. First, unclear understanding of the biology of cancer cells makes it difficult to identify TAs that can engender a powerful immune response, and deeper investigations remain required in this direction [7] […] Second, the immunosuppressive nature of tumors is regarded as a powerful obstacle to the success of NAVs, especially in patients with advanced stages of cancer […] The third reason for the unsuccessful clinical outcome of NAVs might be that human responses to NAVs can induce unnecessary inflammatory signaling and systemic reactions, such as fever and cytokine release syndrome [40]. The fourth reason is the susceptibility of some individuals to autoimmune reactions triggered by the type I INF response caused by NAVs, and this is among potential safety concerns [45]. The fifth reason is unclear understanding of the immune signaling pathways responding to NAVs, because, in some cases, these signaling mechanisms are regarded as boosting adjuvanticity, whereas they might be considered as unnecessary inflammatory signaling 46, 47” (“Future directions and conclusions” section p. 557 left column to right column ¶2).
Summary of Species disclosed in the original specification
The instant specification teaches that the oncogene EGFR is commonly upregulated in glioblastoma including increased copy number on extrachromosomal DNA (p. 37). The specification teaches that “the bystander genes encoded on chromosome 7 close to EGFR include VOPP, SEC61, LANCL2, and SEPT14 (p. 38 lines 1-22). The specification states “We identify T cells epitopes in SEC61G, LANCL2, SEPT14 and VOPP1 and provide synthetic peptides, which when applied to a subject in which these proteins are upregulated, provides a means of targeting an immune response to tumor cells bearing the proteins. In preferred embodiments the immune response is a CD8+ T cell cytotoxic response and in further preferred embodiments a CD8+ response is accompanied by a CD4+ driven T helper response” (p. 38 lines 16-21). The inventors perform an example copy number variation analysis from tumor biopsies and normal tissue of the subject (p. 38 lines 23-p. 39 line 23). Next, the inventors used computational analysis to identify peptide epitopes for binding the subjects HLA alleles and predict MHC I and MHC II binding of the subject. The specification states “While the examples that follow apply to epitopes carried by those proteins encoded and upregulated as co-amplified companions to EGFR, either intra or extra-chromosomally, the examples also provide a road-map for how to approach design of a synthetic peptide vaccine to stimulate T cells directed to epitopes on other proteins, which may be upregulated and coamplified as bystanders or companions to other oncogenes amplified in cancers” (p. 40 lines 15-22). Specifically, the specification discloses a series of peptides from SEC61G with the highest predicted binding affinity for representative MHC I and MHC II alleles which comprise desirable peptides for inclusion in a vaccine composition (p. 48 lines 8-22, Tables 1 and 2); VOPP (p. 49 lines 16-27, Tables 4 and 5); LANC2 (p. 50 lines 15-30, Tables 7 and 8); SEPT14 (p. 51 lines 5-14, Tables 10 and 11). There is no exemplary mass spectrometry showing expression of any of these peptides in any tumor. There is no experimental validation of the binding affinity of any of the recited peptides for any of the representative MHC I and II alleles. There is are no in vitro or in vivo experiments to determine the relative immunogenicity of the prophetically recited peptides. There are no methods of treating cancer comprising administering the recited peptides in the specification.
Are the species representative of a genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
A person of ordinary skill in the art based on the specification and the state of the art, therefore, would not have believed the applicant to be in possession of the entire genus of methods of treatment of cancer comprising administering to a subject any peptide or nucleic acid encoding the peptide with a desired predicted binding to an MHC I or an MHC II in a cancer with EGFR co-amplified with at least one of SEC61G, VOPP1, LANCL2, and SEPT14 peptide that 1) binds to MHC I or II and 2) is modified for stronger binding to MHC I or II. It would not have been predictable which of the MHC-binding peptides would be sufficiently expressed as peptide-MHC on the surface of the tumor and be sufficiently immunogenic to treat the cancer.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed spacer.
In the instant specification, the disclosed correlation between structure and function of the peptides is the algorithm used to predict the affinity of a particular peptide comprised by a bystander protein in silico. As described in the state of the art section above, there are known ways to predict this binding, but it requires experimental validation and the results of whether or not the peptides or nucleic acids encoding the peptides are immunogenic remains unpredictable even with good prediction of binding. Therefore, the structure/function relationship disclosed in the specification is insufficient for an artisan to believe that, at the time of filing, the inventors had possession of the genus of methods comprising a genus of bystander proteins and MHC-binding peptides as claimed.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for bystander proteins SEC61G, VOPP1, LANCL2, and SEPT14, and peptides therefrom binding to MHC and eliciting an immune response in order to describe the genus of methods of treating cancer as claimed. There is a lack of an appropriate number of species of administering the peptides or nucleic acids encoding the peptides and of pMHC show to have immunogenicity. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of methods of claim 1 at the time of filing. Regarding 3-19 the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Response to Arguments
Applicant argues that the amended scope of claim 1 is to the species disclosed and exemplified in the specification; that the specification provides complete peptide tables with predicted MHC I and MHC II binding affinities across dozens of HLA alleles (Tables 1-11); that the specification provide T cell exposed motifs by particular sequence identifiers; that there are examples of alternative peptide generated by GEM substitution; and that the specification provides copy number analysis for EGFR and SEC61G co-amplification (Remarks p. 9-10 5/14/2026). As described in the written description rejection, modifications necessitated by amendment, above, the scope of the instant claims is still insufficient to provide written description to the method of treatment as claimed because although applicant had possession of the predicted MHC-binding peptides of the bystander proteins, it was not predictable at the time of filing whether the tumors comprising the amplified SEC61G, VOPP1, LANCL2, or SEPT14 could be treated with any of the disclosed MHC-binding peptides as claimed. For example, as described above, Kreiter et. al. teaches that for each of the subsets of the predicted MHC binding-peptides, the majority were non-immunogenic. Thus, the scope of the method of treatment of the instant claims includes majority non-immunogenic peptides and nucleic acids encoding them, which could not be predictably used to treat cancer.
Additionally, Applicant argues that “The structure/function correlation supporting the narrowed claims is the TCEM/GEM framework: the TCEM (positions 4, 5, 6, 7, 8 of a 9-mer bound to MHC-I) determines T cell receptor specificity, while the GEM (positions 1, 2, 3, 9) determines MHC binding affinity (specification pp. 24-25). The amino acids which comprise the TCEM in an MHC-II binding peptide typically comprise 2, 3, 5, 7, 8 or -1, 3, 5, 7, 8 based on a 15-mer peptide with a central core of 9 amino acids numbered 1-9 and positions outside the core numbered as negative (N terminal) or positive (C terminal). Id. The specification demonstrates that GEM residues can be substituted while preserving the TCEM to tune predicted MHC binding affinity to a desired level for specific alleles (Tables 3, 6, 9). This is a defined structural framework providing the correlation between structure and function that the Examiner found lacking in the claims as originally presented”. This is not persuasive because, as described above, there is not a predictable relationship between a method of treating and the in silico prediction of the TCEM or GEM. Thus, although the Applicant has described a method of generating HLA-binding proteins from the bystander proteins SEC61G, VOPP1, LANCL2, and SEPT14, there is still not a sufficient structure/function correlation between the 1) predicted MHC binding and the expression of the MHC-binding peptide in the tumor which has amplification of EGFR and SEC61G, VOPP1, LANCL2, or SEPT14 and 2) the ability of the peptides to generate an immune response against the tumor, such that a person of ordinary skill in the art would understand the Applicant to have been possession of a genus of methods of treating such tumors at the time of filing.
Claim Rejections - 35 USC § 103- New, necessitated by amendment
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.
Claims 1, 3-13, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) in view of Tsukamoto et. al. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82. doi: 10.1002/path.2424. PMID: 18798223 (PTO-892 2/18/2026).
Regarding claim 1, Mahr et. al. teaches a method for treating cancer in a subject in particular cancer immunotherapy (Abstract) wherein the method comprising designing a group of one or more T-cell stimulating peptides or nucleic acids encoding T cell stimulating peptides, which have a desired predicted binding affinity for the MHC alleles of the subject SEQ ID NOs: 1-640 or a variant thereof binds to MHC and/or induces T cells cross-reacting with said peptide [0037]. Mahr et. al. teaches that the method comprises the following steps: identifying tumor-associated peptides (TUMAPs) present by a tumor sample from the individual patient (tumor sample reads on instant biopsy); obtaining sequences of the TUMAPs (“the total peptide amount for a TUMAP in a tissue sample was measured by nanoLC-MS/MS as the ratio of the natural TUMAP and a known amount of isotope-labelled version of the TUMAP […] In addition to an over-presentation of the peptide, the mRNA expression of the underlying gene was analyzed. mRNA data were obtained via RNASeq analyses of normal tissues and cancer tissues” [0706-0707]; comparing the copy number differential of genes encoding each protein between tumor and normal tissue and identifying upregulated genes (“It is furthermore desirable that the respective antigen is not only present in a type of tumor, but also in high concentrations (i.e. copy numbers of the respective peptide per cell)” [0033] “The immune response originating from such a therapeutic vaccination can be expected to be highly specific against tumor cells because the target peptides of the present invention are not presented on normal tissue in comparable copy numbers” [0711]; “SEC61G was shown to be up-regulated in gastric cancer (Tsukamoto et. al., 2008). SEC61G is associated with gliomas (Neidert et. al. 2013)” [0509] , (also see [0033], [0091], [0125], [0235], [0313], [0366], Table 12). Mahr et. al. teaches “certain positions of HLA binding peptides are typically anchor residues forming a core sequence fitting to the binding motif of the HLA receptor, which is defined by polar, electrophysical, hydrophobic and spatial properties of the polypeptide chains constituting the binding groove. Thus, one skilled in the art would be able to modify the amino acid sequences set forth in SEQ ID NO: 1 to SEQ ID NO 640, by maintaining the known anchor residues, and would be able to determine whether such variants maintain the ability to bind MHC class I or II molecules. The variants of the present invention retain the ability to bind to the TCR of activated T cells, which can subsequently cross-react with and kill cells that express a polypeptide containing the natural amino acid sequence of the cognate peptide as defined in the aspects of the invention” [0666], (also see [0031], Table 7) (reads on determining T cell exposed motifs in each of the bystander proteins and determining the predicted binding affinity to the subject’s MHC alleles of peptides which comprises each of the T cell exposed motifs; SEQ ID NO: 650 residues 2-10 are 100% identical to instant SEQ ID NO: 1). “Candidate peptides for T cell based therapies according to the present invention were further tested for their MHC binding capacity (affinity) [0899]; “selecting at least one peptide from the warehouse (database) that correlates with a tumor-associated peptide identified in the patient” [0664] (reads on selecting one or more of the peptides which have a desired predicted binding affinity for one or more of the subject’s MHC alleles). Mahr et. al. teaches the peptides were synthesized and subsequently administered to the subject [0898]. Mahr et. al. teaches “ A peptide consisting essentially of the amino acid sequence as indicated herein can have one or two non-anchor amino acids (see below regarding the anchor motif) exchanged without that the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II is substantially changed or is negatively affected, when compared to the non-modified peptide. In another embodiment, in a peptide consisting essentially of the amino acid sequence as indicated herein, one or two amino acids can be exchanged with their conservative exchange partners (see herein below) without that the ability to bind to a molecule of the human major histocompatibility complex (MHC) class-I or -II is substantially changed, or is negatively affected, when compared to the non-modified peptide” and “the amino acid residues that do not substantially contribute to interactions with the T-cell receptor can be modified by replacement with other amino acids whose incorporation does not substantially affect T-cell reactivity and does not eliminate binding to the relevant MHC. Thus, apart from the proviso given, the peptide of the invention may be any peptide (by which term the inventors include oligopeptide or polypeptide), which includes the amino acid sequences or a portion or variant thereof as given” ([0672-0673], also see [0666], [0031], Table 7).
Regarding claim 3, Mahr et. al. teaches the method wherein the oncogene is mutated in the tumor biopsy relative to the normal tissue ([0020], e.g. [0118], [0429]).
Regarding claim 4, Mahr et. al. teaches that T-cell based immunotherapy targets peptide epitopes derived from tumor associated or tumor-specific proteins which are presented by MHC. The antigens are derived from all protein classes which are expressed and are upregulated in tumor cells compared to cells of the same origin [0021].
Regarding claim 7 and 12, Mahr et. al. teaches the peptides of the invention bind preferably to HLA-A*02 (reads on MHC class I) [0643-0644]. Mahr et. al. teaches the peptide or variant of the invention will have the ability to bind to a molecule of MHC class I or II, tested by methods known in the art [0680]. The predicted binding is to MHC alleles based on the expression data of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample obtained from the subject [0864] (reads on the MHC allele carried by the subject).
Regarding claims 8 and 13, Mahr et. al. teaches embodiments of the peptide that are elongated on either or both side in order to lead to MHC class II binding peptides [0678]. Mahr et. al. teaches that by maintaining known anchor residues an artisan would be able to determine which peptides bind MHC class I or class II [0666]. Mahr et. al. teaches an embodiment wherein the MHC class II is the antigen-binding fragment of HLA-DR [0684]. The predicted binding is to MHC alleles based on the expression data of MHC ligands bound to MHC class I and/or class II molecules in the tumor sample obtained from the subject [0864].
Regarding claims 9 and 11, SEQ ID NO: 650 is 10 amino acids long.
Regarding claim 10, Mahr et. al. teaches embodiments the peptides binding the MHC class epitopes of between 13 and 14 for MHC class I and 15, 16, 17, 18, 19, and 20 for MHC class II.
Mahr et. al. does not explicitly teach the method of treating cancer of claim 1 comprising 1) comparing the copy number differential of genes encoding each protein between tumor and normal tissue; 2) identifying amplification of EGFR in the biopsy; and 3) identifying bystander proteins that are transcribed in the biopsy, wherein the bystander proteins are selected from the group of SEC61G, VOPP1, LANCL2, and SEPT14, and combinations thereof, said bystander proteins being co-amplified with EGFR and encoded on chromosome 7 adjacent to EGFR.
This deficiency is resolved by Tsukamoto et. al.
Tsukamoto et. al. teaches that analysis of genetic copy number aberrations (CNAs) in gastric cancer caused upregulation and identified several candidate genes including SEC61G (Abstract). Tsukamoto et. al. teaches that “Interestingly, some candidate genes were localized at genomic loci adjacent to well-known genes such as EGFR, ERBB2, and SMAD4 (Abstract). Tsukamoto et. al. teaches that SEC61G is present in increased copy number in 14/30 of the patients (Table 2, 7p11; Figure 5 second row). Tsukamoto teaches that increased copy number was associated with increased tumor expression (“Overexpression of FDFT1, CDC6, ANP32E, SEC61G, and BYSL in cases with gene amplification” section p. 749). Tsukamoto et. al. further teaches that the expression of EGFR is concordant with the other three genes (EGFR, SEC61G, LANCL2, and ECOP) in the 7p11 locus in three of the four cases with amplification at 7p11, but in none of the cases without amplifications (p. 479 right column).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method comprising 1) comparing the copy number differential of genes in the biopsy; 2) identifying amplification of EGFR; and 3) identifying co-amplification of SEC61G, LANCL2, and ECOP (synonymous with VOPP1) have are present in increased copy number (co-amplified) in the biopsy as taught by Tsukamoto prior in combination with the method of making a TUMAP vaccine as taught by Mahr in order to benefit from an improved method of treating cancer where the tumor-associated antigen SEC61G is expressed at higher levels caused by the increased number and co-amplification with EGFR as taught by Tsukamoto et. al. because an artisan would understand that the method of vaccinating with a TAA that is expressed in normal tissue would require increased expression in the tumor as compared to normal tissue as taught by Mahr et. al. This would have a reasonable expectation of success because an artisan would expect a higher copy number would correlate with increased expression and therefore improved treatment success when administering the SEC61G peptide of Mahr et. al.
Regarding claims 5 and 6, Mahr et. al. as evidenced by Tsukamoto et. al. does not explicitly teach the method wherein the copy number in the tumor biopsy of the oncogene is increased more than five-fold over that in normal tissue or more than ten-fold over that in normal tissue.
This deficiency is resolved by Tsukamoto et. al.
As described above, Tsukamoto et. al. teach gastric cancers wherein the 7p11 region comprising EGFR and SEC61G is amplified. Tsukamoto et. al. teach that under this circumstance, expression of EGFR and SEC61G were concordant (see above). Regarding claims 4 and 5, Tsukamoto et. al. teach a few patients with very high SEC61G expression correlating with 7p11 (reads on oncogene) amplification; see in particular Fig. 5 second row; a log2(ratio) value of >1.3 correspond to copy number greater than 5 (3 patients) and a log2(ratio) value of >2.3 corresponds to copy number greater than 10 (2 or 3 patients).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform the method comprising identifying a protein from the biopsy comprising an oncogene which is upregulated (EGFR) and to administer the MHC-binding SEC61G peptides of Mahr et. al. to treat cancer in order to benefit from an improved treatment of cancer wherein EGFR and SEC61G expression are both increased at the highest levels due to amplification of 7p11 as taught by Tsukamoto. An artisan would expect to benefit because Mahr et. al. teaches that differential expression between normal and cancer tissue is essential for the MHC-binding peptide immunotherapies of Mahr et. al. This would have a predictable effect because an artisan assessing the copy number and expression level of the tumor genes in the method as taught by Mahr et. al. would expect to detect patients with this 7p11 amplification and that it would correlate with SEC61G overexpression as taught by Tsukamoto.
Regarding claim 18, Mahr et. al. in view of Tsukamoto et. al. as described above teaches the method wherein the subjects are afflicted with gastric cancer comprising the 7p11 amplification (reads on gastrointestinal tract cancer).
Regarding claim 20, Mahr et. al. in view of Tsukamoto et. al. as described above teaches identifying EGFR upregulation from the biopsy.
Claims 14-17 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) in view of Tsukamoto et. al. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82. doi: 10.1002/path.2424. PMID: 18798223 (PTO-892 2/18/2026) as applied to claim 1 above, and further in view of U.S. 20160101170 to Hacohen et. al. published 14 April 2016 (Of record, IDS dated 9/25/2025 US 044).
The teachings of Mahr et. al. in view of Tsukamoto et. al. in regard to claim 1 are in the 103 rejection above.
Mahr teaches that candidate peptides for the T-cell based therapies were tested for their MHC binding capacity and that “Only peptide candidates that can effectively bind and stabilize the peptide-receptive MHC molecules prevent dissociation of the MHC complexes” and that low peptide exchange yield, which would be considered high binding affinity, is desirable (Example 5, [0899]).
Mahr et. al. does not explicitly teach the method wherein the desired predicted binding affinity of the peptides for MHC is less than 20 nM, less than 50 nM, less than 100 nM, or less than 500 nM.
This deficiency is resolved by Hacohen et. al.
Hacohen et. al. teaches methods of designing peptides of tumor-specific neoantigens by predicting HLA-binding regions [0137]. Hacohen et. al. teaches that the neo-antigenic peptides may bind an HLA protein (reads on MHC binding) with a greater affinity than the corresponding wildtype peptide wherein the peptide may have an IC50 of about less than 1000 nM, about less than 500 nM, about less than 250 nM, about less than 200 nM, about less than 150 nM, about less than 100 nM, or about less than 50 nM [0138].
Regarding claim 14, Hacohen et. al. teaches one embodiment where the wildtype peptide has a predicted IC50 of 2.57 nM (Fig. 14C).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to design modified peptides as taught by Mahr et. al. with binding affinity of less than 50 nM, less than 100 nM, and less than 500 nM as taught by Hacohen et. al. in order to benefit from peptides with desired predicted binding affinity for MHC as taught by Hacohen et. al. This would have a reasonable expectation of success because Mahr et. al. teaches that artisan can determine the desired binding of MHC and Hacohen et. al. teaches predicted desired binding affinity for immunotherapy of cancer.
Regarding claim 14, although Mahr et. al. in view of Hacohen et. al. does not explicitly teach a range of less than 20nM, Mahr et. al. in view of Hacohen et. al. teaches designing peptides of tumor-specific neoantigens and teaches a particular embodiment with a predicted binding affinity less than 20nM. It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to design a peptide with a predicted binding affinity of less than 20nM because an artisan would be able to determine the desired predicted binding for the particular peptide an application. This would have a reasonable expectation of success because Mahr et. al. teaches known methods to modify the affinity by changing residues of the peptide.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 20170037111 A1 to Mahr et. al. published 9 February 2017 (Of record, IDS dated 9/25/2025 US 047) in view of Tsukamoto et. al. Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. J Pathol. 2008 Dec;216(4):471-82. doi: 10.1002/path.2424. PMID: 18798223 (PTO-892 2/18/2026) as applied to claim 1 above, and further in view of Lu et. al. Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress. Cancer Res. 2009 Dec 1;69(23):9105-11. doi: 10.1158/0008-5472.CAN-09-2775. Epub 2009 Nov 17. PMID: 19920201; PMCID: PMC2789175 (Hereinafter Lu 2009, Of record, IDS dated 9/25/2025 NPL 096).
The teachings of Mahr et. al. in regard to claim 1 are in the 103 rejections above.
As described in the 103 rejection above, Mahr et. al. teaches that SEC61G overexpression is associated with gliomas.
Mahr et. al. does not explicitly teach the method wherein the patient is afflicted with brain cancer, wherein the brain cancer is selected from a group of brain cancers including glioblastoma.
This deficiency is resolved by Lu 2009.
Lu 2009 teaches that in a screen for copy number changes, the most frequently amplified region is at chromosome 7p11.2 and that the minimal region of amplification contains two genes, EGFR and SEC61γ (synonymous with SEC61G) (Abstract, Fig. 1A). Lu 2009 teaches that SEC61γ is always co-amplified with EGFR in 47% of GBMs and overexpressed in 77% of GBMs (p. 2 ¶3). Lu 2009 teaches that of 43 tumor samples from GBM patients, 47% displayed high copy-number gain of SEC61γ (>4-fold) and 17 samples displayed coincident EGFR high copy number gain (>4 fold) (p. 4 ¶3). Lu 2009 teaches that SEC61γ is overexpressed in GBM using q-PCR and that SEC61γ is overexpressed in every sample with SEC61γ amplification (p. 4 ¶5, Fig. 2). Lu 2009 further teaches that SEC61γ is required for tumor cell growth (p. 5 ¶2, Fig. 3).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to use the method of Mahr et. al. in view of Tsukamoto et. al. to treat the glioblastoma patients of Lu 2009 and to administer the MHC-binding SEC61G peptides of Mahr et. al. to treat cancer in order to benefit from an improved treatment of GBM wherein EGFR and SEC61G expression are both increased at the highest levels due to amplification of 7p11 as taught by Lu 2009. An artisan would expect to benefit because Mahr et. al. teaches that differential expression between normal and cancer tissue is essential for the MHC-binding peptide immunotherapies of Mahr et. al. This would have a predictable effect because an artisan assessing the copy number and expression level of the tumor genes in the method as taught by Mahr et. al. would expect to detect patients with this 7p11 amplification and that it would correlate with SEC61G overexpression in glioblastoma as taught by Lu 2009.
Response to Arguments
The Applicants arguments filed 14 May 2026 have been fully considered but are not persuasive.
First, Applicant argues that the amended claims recite multiple limitations that are absent from Mahr, individually and in combination (Remarks 5/14/2026 p. 10 bottom ¶-p. 11). This argument is moot in view of the new 103 rejection, necessitated by amendment, above. However, to the extent the arguments about Mahr apply to the new 103 rejection, they have been considered below:
First, applicant argues that “Amended claim 1 requires "identifying bystander proteins, wherein the bystander proteins are selected from the group consisting of SEC61G, VOPP1, LANCL2, SEPT14, and combinations thereof, said bystander proteins being co-amplified with EGFR and encoded on chromosome 7 adjacent to EGFR." This step requires the active analytical step of recognizing the chromosomal adjacency relationship between EGFR and the specified bystander proteins, and selecting the bystander proteins because of that relationship. The Examiner disagrees with this interpretation of the requirement of “identifying bystander proteins, wherein the bystander proteins are selected from the group consisting of SEC61G, VOPP1, LANCL2, SEPT14, and combinations thereof, said bystander proteins being co-amplified with EGFR and encoded on chromosome 7 adjacent to EGFR”. The broadest reasonable interpretation of this step does not require recognition of SEC61G as a bystander protein because this limitation is not recited in the claim; it merely requires 1) identifying EGFR amplification in the biopsy and 2) identification of a bystander protein, wherein the bystander protein is selected from the group of SEC61G, VOPP1, LANCL2, SEPT14, which are genes that are 1) co-amplified with EGFR and are 2) adjacent to EGFR on chromosome 7; as described in the 112a, above, it is not required that SEC61G be co-amplified in the biopsy with EGFR. However, even if co-amplification were required as in claim 4, as described in the 103 rejection above, it would be obvious from Mahr in view of Tsukamoto to 1) use the TUMAP vaccine of Mahr to treat a cancer where the TAA Sec61G is overexpressed as taught by Mahr and 2) perform the method of treating of Mahr comprising the steps of identifying co-amplification of EGFR and Sec61G as taught by Tsukamoto in order to benefit from the correlation of overexpression of Sec61G and EGFR as taught by Tsukamoto. A person of ordinary skill in the art would understand that there was a reasonable expectation of success to combine these methods because Mahr teaches that TAA vaccines require overexpression of the target gene, and Tsukamoto teaches that EGFR and Sec61G overexpression are highly correlated.
Applicant also argues that VOPP1, LANCL2, or SEPT14 are not taught by Mahr. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As described in the 103 rejection above, Tsukamoto teaches identification of co-amplification of SEC61G, VOPP1, and LANCL2. Additionally, this is not persuasive because the claim requires “identifying bystander proteins that are transcribed in the biopsy, wherein the bystander proteins are selected from the group consisting of SEC61G, VOPP1, LANCL2, SEPT14, and combinations thereof”; as described above it doesn’t require that the proteins be named or recognized as bystander proteins, and further it requires only identification of those transcribed in the biopsy; thus, if only SEC61G were transcribed in the biopsy, identification of the others would not be required.
Applicant argues that Mahr does not teach gene copy number differentials (Remarks p. 12). This is moot in view of the new 103 rejection above of Mahr in view of Tsukamoto, necessitated by amendment. As described Tsukamoto teaches increased copy number of SEC61G in gastric cancer leading to overexpression; Mahr teaches overexpression of SEC61G and that increased copy number of the MHC peptides in the cancer cell is required to target the immune response to the cancer cell. As described, this makes obvious the instant method because a person of ordinary skill in the art would apply the method of Mahr to cancer with increased copy number and expression of SEC61G as taught by Tsukamoto in order to have increased SEC61G expression as taught by Mahr and increased immune response the tumor as required for a TAA vaccine as taught by Mahr.
Applicant argues that Mahr does not teach “determining T cell exposed motifs in each of the bystander proteins” because Mahr does not specifically recite the phrase “T cell exposed motif” and because Mahr describes anchor residues, which “anchor residues are the opposite of the TCEM. As defined in the instant specification, the groove exposed motif (GEM) comprises positions 1, 2, 3, 9 of a 9-mer for MHCI binders (specification p. 24). These are the anchor residues that face into the MHC binding groove. The TCEM comprises positions 4, 5, 6, 7, 8, i.e., the residues that face outward toward the T cell receptor. Likewise, for MHC II binders, two formats of GEM are most common comprising amino acids (-3,2,-1,1,4,6,9,+1,+2,+3) and (-3,2,1,2,4,6,9,+1,+2,+3) based on a 15-mer peptide with a central core of 9 amino acids numbered 1-9 and positions outside the core numbered as negative (N terminal) or positive (C terminal) (specification p. 24). These are structurally defined, positionally distinct, and non-overlapping subsets of the peptide. Mahr's disclosure of MHC binding motifs and anchor residues does not teach or suggest the TCEM concept” (Remarks p. 12). This is not persuasive because, as described in the 103 rejection above, Mahr teaches the identification of residues in the MHC-binding peptides “that do not substantially contribute to interactions with the T-cell receptor”; this also, therefore, requires identification of the residues that do substantially interact with the TCR in order to avoid alteration of these residues, and therefore reads on determining of T cell exposed motifs.
Applicant argues the limitation “generating one or more alternative peptides not present in the tumor biopsy, wherein each alternative peptide comprises a T cell exposed motif identified in the bystander proteins, and in which the amino acids not within the T cell exposed motif are substituted to change the predicted binding affinity to the MHC alleles” is not taught by Mahr because Mahr teaches “maintaining the known anchor residues” which are the groove-exposed motif positions, and therefore would require changing the T cell exposed motif. This is not persuasive because Mahr teaches that the anchor residues are very particular conserved residues that interact with the binding groove of the MHC molecule (e.g., see [0031]), not the instant definition of a groove-exposed motif, which is e.g. 4 positions particular in MHC I; additionally, as described above, Mahr teaches “The amino acid residues that do not substantially contribute to interactions with the T-cell receptor can be modified by replacement with other amino acids whose incorporation does not substantially affect T-cell reactivity and does not eliminate binding to the relevant MHC. Thus, apart from the proviso given, the peptide of the invention may be any peptide (by which term the inventors include oligopeptide or polypeptide), which includes the amino acid sequences or a portion or variant thereof as given” [0073], which teaches that the changes to the peptides would be in GEM residues that are not anchor residues or T-cell exposed motif residues, because those changes would be in residues that contribute to interactions with the TCR.
Applicant further argues that Mahr’s pipeline is fundamentally different than the steps disclosed in the instantly amended claims (Remarks p. 14 ¶1-3). This argument is moot in view of the withdrawal of the 102 rejection and the new 103 rejection, necessitated by amendment, above.
Additionally, Applicant argues in regards to the prior 103 rejection of claims 4-6, 18, and 20 over Mahr in view of Tsukamoto that Mahr dose not teach or disclose the method of amended claim 1 and that Tsukamoto does not cure these deficiencies because Tsukamoto does not teach “(a) identifying bystander proteins of an oncogene as a method step in a vaccine design pipeline; (b) comparing gene copy number differentials between tumor and normal tissue; (c) determining T cell exposed motifs; (d) generating alternative peptides by GEM substitution while preserving TCEM; or (e) the overall analytical arrangement”. This is not persuasive for the reasons described for Mahr individually, above, and in view of the new 103 rejection, necessitated by amendment, above. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As described in the new 103 rejection, Tsukamoto cures the deficiencies of Mahr and makes obvious the instant methods because Tsukamoto teaches a method of identifying 1) copy number variations in EGFR and 2) correlation of EGFR amplification with the genes SEC61G, VOPP1, and LANCL2; it would be obvious to combine the missing steps of comparing copy number differential, identifying amplification of EGFR in the biopsy, and identifying the bystander proteins that are transcribed in the biopsy consisting of SEC61G, VOPP1 (ECOP), and LANCL2 as taught by Tsukamoto prior to a method of administering the SEC61G HLA-binding peptide expressed by the tumor as taught by Mahr in order to benefit from a subset of cancer with increased SEC61G expression required for a TAA vaccine as taught by Mahr; with a reasonable expectation of success because a person of ordinary skill in the art would expect to be able to treat a cancer with EGFR amplification and SEC61G amplification with the SEC61G TAA vaccine taught by Mahr.
Regarding the rejection of claims 14-17 in view of Hacohen, Applicant argues that Hacohen teaches away from the claimed combination because Hacohen is directed exclusively to neo-antigenic peptides and that the claimed bystander proteins are non-mutated; and that a person of ordinary skill in the art would understand that the neo-antigen specific binding activity is not predictably applicable to self-protein peptides that must overcome central and peripheral tolerance. This is not persuasive. First, Applicant does not provide any evidence for the factual statement that the binding of pMHC as taught by Hacohen is neoantigen-specific and that different pMHC affinities would be required to overcome self tolerance.
Second, MPEP §2123 states “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments”. Both the teachings of Hacohen and Mahr are directed towards pMHC vaccines in cancer; Mahr teaches alternatives of both neoantigens and TAAs, which are not mutated and Hacohen teaches that preferred pMHC binding affinities are less than the listed affinities (e.g. 20 nM). The state of the art at the time would have allowed a person of ordinary skill in the art to understand that the ranges of affinities were reasonable pMHC binding affinities and that although Hacohen is directed towards neoantigens, that would not discourage a person of ordinary skill in the art from using the binding affinities of Hacohen for a TAA vaccine preferred by Mahr. For example, Keogh, Elissa, et al. "Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A∗ 0201-binding affinity." The Journal of Immunology 167.2 (2001): 787-796 teaches many TAA peptides with HLA binding affinities less than 500nM through less than 20nM and that 20/22 of the peptides induced CTLs for at least one HLA allele (See Table 1). Thus, it would have been obvious to a person of ordinary skill in the art reading to use the desired predicted binding affinities (e.g. less than 20 nM) of Hacohen as described in the 103 rejection above.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., the non-mutation of SEC61G, VOPP1, LANCL2, and SEPT14) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Therefore, the claims may read on instances in which there is a neoantigenic mutation in one of the instant bystander proteins. Applicant further argues that the IC50 binding affinity thresholds developed for neoantigens, which face no self tolerance barrier, are not predictably applicable to self-protein peptides that must overcome central and peripheral tolerance. MPEP §2145 states that “arguments presented by applicant cannot take the place of factually supported objective evidence. See, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984)”. This is not persuasive because there is no clear scientific basis for this assertion. The claims of applicant are broad and include desired peptide-MHC binding affinities of less than 500 nM, 100 nM, 50 nM, and 20 nM. A person of ordinary skill in the art reading Hacohen would understand that, although Hacohen recites the desired predicted binding affinities for a neoantigen epitope for a cancer vaccine, that these binding affinities between the peptide and MHC have to do with the presentation and stability of the pMHC and would therefore be applicable to any pMHC vaccine. A commonly used threshold for this stability at the time of filing for pMHC was at least less than 500 nM (See e.g. Jurtz, Vanessa, et al. "NetMHCpan-4.0: improved peptide–MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data." The Journal of Immunology 199.9 (2017): 3360-3368, Fig. 6 caption). There is no evidence of record in the instant claims or the specification that there is any effect on self-tolerance for the peptides of the described binding affinities, or that the wild-type peptides as described in the specification are effective at breaking self-tolerance, apart from the requirement that a pMHC complex be stably expressed as taught by Mahr. Although Mahr teaches this with percent exchange yield, a person of ordinary skill in the art would understand that the desired binding affinities for neoantigen epitopes as taught by Mahr would be in the range of those that would result in strong enough binding for desirable exchange yield, and therefore would have a reasonable expectation of success that those nanomolar values as taught by Hacohen represent binding affinities that yield stable pMHC complexes as taught by Mahr.
Regarding the rejection of Mahr in view of Lu 2009, applicant argues that Lu 2009 does not teach or suggest the deficiencies of Mahr as argued (Remarks 7/22/2026 p. 16). This is not persuasive for the reasons described above for the new 103 rejection, necessitated by amendment, of Mahr in view of Tsukamoto and Lu 2009 and in the response to arguments above.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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