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 1-20 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.
Drawings
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
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.
Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Specifically, Fig. 28 top (sheet 33/35) has an enumerated sequence not properly identified by SEQ ID NO.
Appropriate correction is required.
The use of the term HeliScope by Heliso BioSciences (p. 45 line 13); Ion Torrent (p. 45 line 26); Xpandomer (p. 46 line 12), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Instant claim 1 recites a method of treating cancer in a subject comprising designing T-cell stimulating peptides which have a desired predicted binding affinity for the MHC alleles of the subject comprising: obtaining a biopsy of the subject’s tumor; obtaining 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 proteins from the biopsy comprising an oncogene which is upregulated; identifying bystander proteins of the proteins that are transcribed; 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 comprises each of the T cell exposed motifs, or a subset thereof; selecting a group of one or more the peptides which have a desired predicted binding affinity for one or more of the subject’s MHC alleles; synthesizing the group of one or more selected peptides, or nucleic acids encoding the selected peptides from the bystander proteins; and administering the selected peptides or nucleic acids to the subject. The phrase “identifying bystander proteins of the proteins that are transcribed” does not have a clear meaning or any clear link to the other comparing and identifying steps recited. The instant specification defines a bystander protein as “As used herein "bystander protein" refers to a protein encoded in DNA adjacent to an oncogene, on either strand of DNA within about 1 megabase of the start or termination of the oncogene coding region. "co-amplified bystander protein" is used to describe a bystander protein which is overexpressed in conjunction with the over expression of the oncogene protein” (p. 34 lines 8-11). The phrase “the proteins that are transcribed” does not have antecedent basis in the claim. An artisan would not be able to determine whether “the proteins that are transcribed” is limited to bystander proteins of an oncogene as specified in the definition, or if it redefines bystander protein to adjacent to any protein that are transcribed. Are the proteins transcribed in the biopsy, in normal cells, in the subject, or in any subject? It is not clear. Additionally, the specification defines an oncogene as “a gene which in certain circumstances can transform a cell into a tumor cell. A gene that, when activated by a mutation, increases the selective growth advantage of the cell in which it resides [1]. Oncogenes may include both drivers, and also tumor suppressors which when activated by mutation increase the selective advantage of a tumor cell” (p. 33 line 28-p. 34 line 5). This definition is unclear because it expands the definition of oncogene to include tumor suppressors, but also requires that “when activated by a mutation increases the selective growth advantage of the cell in which it resides”. It is well understood in the art that tumor suppressor mutations typically confer a selective growth advantage to cancer when inactivated by a mutation. Thus, the metes and bounds of which proteins may even be considered bystander proteins is unclear. Is a bystander protein a protein a protein that is within one megabase of any oncogene or tumor suppressor in any context? Need the oncogene or tumor suppressor be relevant to the biopsy sample? How must it be related? Does the bystander protein need to be a bystander of an oncogene that is transcribed in the sample? Is it relevant if an oncogene is transcribed in the tumor but does not appear to be relevant to the pathogenesis of that particular tumor? If the tumor has a P53 mutation such that P53 is not transcribed in the cancer, would genes within 1 megabase of P53 be considered bystander proteins? Because the meaning and scope of the bystander proteins that are transcribed cannot be discerned, the claim is indefinite.
Additionally, claim 1 recites “selecting a group of one or more the peptides which have a desired predicted binding affinity for one or more of the subject's MHC alleles; synthesizing the group of one or more selected peptides, or nucleic acids encoding the selected peptides from the bystander proteins; and administering the selected peptides or nucleic acids to the subject”. This is indefinite because the claim recites “selecting a group of one or more the peptides” followed by “administering the selected peptides”. It is unclear if the claim requires more than one peptide to be selected because the word “group” as well as “administering the selected peptides” both imply more than one but the claim also recites that the group may be “one or more”. Thus, the metes and bounds of the claim are unclear because an artisan would not be able to determine whether administering one selected peptide or nucleic acid meets the limitations of the claim.
Claims 2-20 are rejected for dependency on claim 1 while failing to resolve the indefiniteness as described.
Claim Rejections - 35 USC § 112(a)- Written Description
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 1-20 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.
Regarding claim 1, the claim recites a method for treating cancer comprising identifying bystander proteins of a protein that is transcribed (see 112(b) rejection above); 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, synthesizing the group of one or more selected peptides or nucleic acids encoding the selected peptides from the bystander proteins; and administering the selected peptides or nucleic acids to the subject. As described in the 112(b) above, the steps of obtaining a biopsy and sequencing the biopsy, as well as the mental process steps of identifying and comparing various features of the nucleic acids and proteins of the tumor are not connected to the identification of the bystander protein. As claimed, the claim appears to be directed towards administering a peptide comprising a T cell exposed motif of any protein within 1 megabase of any tumor suppressor or any oncogene regardless of the status of that oncogene or tumor suppressor within the tumor biopsy and regardless of the expression status or mutational status of the bystander protein within the instant tumor.
Scope of the claimed genus
As described in the 112(b) rejection above, the scope of claim 1 is indefinite. Claim 1 recites a method of treating cancer in a subject comprising designing T-cell stimulating peptides which have a desired predicted binding affinity for the MHC alleles of the subject comprising: obtaining a biopsy of the subject’s tumor; obtaining 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 proteins from the biopsy comprising an oncogene which is upregulated; identifying bystander proteins of the proteins that are transcribed; 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 comprises 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; synthesizing the group of one or more selected peptides, or nucleic acids encoding the selected peptides from the bystander proteins; and administering the selected peptides or nucleic acids to the subject. Thus, as described in the 112(b) above, the claim is directed to a method comprising identifying a protein within 1 megabase of any oncogene or tumor suppressor gene in any context; determining T cell exposed motifs in each of the bystander proteins; 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; synthesizing the group of one or more selected peptides or nucleic acids encoding the selected peptides from the bystander proteins; and administering the selected peptide(s) or nucleic acid(s) to the subject.
Claim 2 recites the method further comprising 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.
Claim 3 recites wherein the oncogene is mutated in the tumor biopsy related to the normal tissue. The examiner notes that this does not limit the scope of the active methods steps because the instantly claimed bystander protein is not linked to the oncogene. Further, this does not clarify the scope of the oncogenes because it encompasses any mutation which could include deletion or loss of function of a tumor suppressor as discussed in the 112(b) above.
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. As for claim 3, this does not limit the scope of the active methods steps because the instantly claimed bystander protein is not linked to the oncogene.
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 recited particular cancer subtypes, in particular brain cancer subtypes.
Claim 20 recites wherein the oncogene is selected from the group of EGFR, PDGFA, ERBB2, MDM2, MYC, MYCN, and CDK4 and combinations thereof. The examiner notes that, as above, because the oncogene is not linked to the bystander protein in the active methods steps, this claim does not limit the scope of the active methods steps.
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 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 tumor 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). 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). It therefore would not be predictable in the absence of contextually linking the instant bystander protein to the particular tumor genome what coding regions are within 1 megabase of any tumor suppressor or oncogene. 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 comprising administering nearly any peptide from nearly any coding gene comprising a T-cell exposed motif 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 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. Given such a broad genus of proteins within 1 megabase of any oncogene or tumor suppressor in any context regardless of the mutation status of the cancer, an artisan would not be able to discern which of the recited genus of bystander proteins would or would not fit as a candidate TAA target. In some cases, bystander genes of the transcribed genes may not be expressed at all in a particular cancer because some cancers have deletions, and some of these locations could be next to oncogenes. The scope of the claims does not require the bystander protein be expressed in the tumor whatsoever, much less require differential expression between the tumor and normal cells as taught by Liu et. al. An artisan would also not be able to identify from the literature and the instant specification whether any bystander protein of any oncogene or tumor suppressor gene in any context was involved in the cell cycle or associated with cell survival in any context because the art has not determined all functions of every coding gene in all contexts. 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 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 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. 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) 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 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.
Regarding other examples of bystander proteins, the specification prophetically recites CHIC2 and GSX2 as bystander proteins of PDGFA (Fig. 12); STARD3, TCAP, PMNT, PGAP3, GRB7, MIEN1, and IKZF3 as bystander proteins of ERBB2 (Fig. 13); RAP1B, NUP107, SLC35E3, and CPM as bystander proteins of MDM2 (Fig. 14); AGAP2, TSPAN31, MARCHF9, AND CYP27B1 as bystander proteins of CDK4 (Fig. 15); CASC11 as a bystander protein of MYC (Fig. 16). The selected peptides from these bystander proteins are also prophetically recited.
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 from the subject wherein the peptide is from any protein within 1 megabase of an oncogene (including tumor suppressor genes), wherein the cancer need not express the bystander protein at all or differentially from normal tissue.
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 is 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 and peptides therefrom binding to MHC and eliciting an immune response in order to described 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; of pMHC show to have immunogenicity; of methods of treatment of cancer wherein the bystander protein itself is not overexpressed or differentially expressed compared to normal tissue; and of methods of treatment wherein the bystander protein is within 1 megabase of any oncogene or tumor suppressor regardless of the status of that particular oncogene or tumor suppressor within the tumor. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1 at the time of filing. Regarding 2-20 the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 and 7-13 are rejected 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.
Claim interpretation: As described in the 112(b) rejection above, the scope of the instant method is indefinite. Solely for the purposes of expedited prosecution, the method comprising “identifying bystander proteins of the proteins that are transcribed” will be interpreted as “identifying a bystander protein overexpressed by the tumor”; and further “bystander protein” will be understood as referring to a protein selected from the group of bystander proteins explicitly listed in the specification: SEC61G, VOPP, LANC2, and SEPT14 as bystander proteins of EGFR (Fig. 1); CHIC2 and GSX2 as bystander proteins of PDGFA (Fig. 12); STARD3, TCAP, PMNT, PGAP3, GRB7, MIEN1, and IKZF3 as bystander proteins of ERBB2 (Fig. 13); RAP1B, NUP107, SLC35E3, and CPM as bystander proteins of MDM2 (Fig. 14); AGAP2, TSPAN31, MARCHF9, AND CYP27B1 as bystander proteins of CDK4 (Fig. 15); CASC11 as a bystander protein of MYC (Fig. 16).
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 (“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). The method further comprises identifying a bystander protein of the proteins that are transcribed because, as evidenced by Tsukamoto et. al., SEC61G is a bystander protein of EGFR (see Table 5). 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].
Regarding claim 2, 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” ([0672], 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 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. teach 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.
Claim Rejections - 35 USC § 103
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 4-6, 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) 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.
The teachings of Mahr et. al. as evidenced by Tsukamoto et. al. in regards to claims 1-3 and 7-13 are in the 102 rejection above and are incorporated by reference to the instant rejection under 35 U.S.C. 103.
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].
Mahr et. al. as evidenced by Tsukamoto et. al. does not explicitly teach the method of treating cancer of claim 1 wherein the genes encoding the bystander proteins are present in increased copy number in the tumor biopsy.
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 wherein the copy number of the bystander protein SEC61G are present in increased copy number in the biopsy 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 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) 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 regards to claim 1 are in the 102 rejection above.
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) 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 regards to claim 1 are in the 102 and 103 rejections above.
As described in the 102 rejection, 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. 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 cancer 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.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678