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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/17/2026 has been entered.
The amendment filed on 03/17/2026 has been entered.
Applicant’s election without traverse of Group I, claims 12-15, 18, 19, 24-27, 31, 36-38, 43, 45, 47, 52, 74, 75, 92, 120, and 121, in the reply filed on 03/25/2025 is acknowledged.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Claims 24 (elected invention), 43 and 45 (non-elected invention) are canceled in the claim set filed on 03/17/2026.
Claim 172 is newly added.
Claims 12-15, 18-19, 25-27, 31, 36-38, 47, 52, 92, 120-121 and 172 are currently pending and under examination.
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2020/059887, filed internationally on November 10, 2020, which
claims the priority benefit of U.S. Provisional Application Nos. 62/934,445, filed November 12, 2019, and 63/064,728, filed August 12, 2020. Accordingly, the priority date of the instant claim set is determined to be November 12, 2019.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 172 is rejected under 35 U.S.C. 101 because the claimed invention is directed towards an abstract idea of generating a report and routine and conventional methods of detecting EWSR1-WT1 and administering a treatment, without significantly more. The claim recite a(n) abstract idea/mental process relating to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and routine and conventional methods. This judicial exception is not integrated into a practical application because no additional elements integrate the judicial exceptions into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are considered significantly more than the judicial exceptions.
Claim analysis
The instant claim 172 is directed towards: The method of claim 12, further comprising generating a report, wherein the report comprises one or more treatment options identified for the individual based at least in part on the detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, wherein the one or more treatment options comprise the immune checkpoint inhibitor.
The generating a report is considered an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work and is considered to be active steps requiring the analysis of a sample.
The active step is routine and conventional as demonstrated by the 35 USC § 103 rejections stated below.
Although the independent claim 12 recited, “administering to the individual an effective amount of an immune checkpoint inhibitor” and dependent claim 172 recited, “wherein the report comprises one or more treatment options identified for the individual based at least in part on the detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, wherein the one or more treatment options comprise the immune checkpoint inhibitor” which is of great generality being routine and conventional as demonstrated in the prior art rejections documented below. Furthermore, there is an absence of a verified indication of a particular disease or medical condition in a population and the treatment claimed in claim 12 is not a particular treatment and is a merely instructions to "apply" the exception in a generic way. The treatment options of claim 172 are considered as intended use of the invention.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case, the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea.
With regard to claim 172, the claim recites “The method of claim 12, further comprising generating a report, wherein the report comprises one or more treatment options identified for the individual based at least in part on the detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, wherein the one or more treatment options comprise the immune checkpoint inhibitor.” The generating a report is considered an abstract idea (mental process) related to organizing or analyzing information in a way that can be performed mentally or is analogous to human mental work.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? No, there are no additional steps that integrate the claims into a practical application.
Although the independent claim 12 recited, “administering to the individual an effective amount of an immune checkpoint inhibitor” and dependent claim 172 recited, “wherein the report comprises one or more treatment options identified for the individual based at least in part on the detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, wherein the one or more treatment options comprise the immune checkpoint inhibitor” which is of great generality being routine and conventional as demonstrated in the prior art rejections documented below. Furthermore, there is an absence of a verified indication of a particular disease or medical condition in a population and the treatment claimed in claim 12 is not a particular treatment and is a merely instructions to "apply" the exception in a generic way. The treatment options of claim 172 are considered as intended use of the invention.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No, there are no additional elements that are significantly more than the judicial exceptions.
Regarding claim 172, the claim requires the routine and conventional active steps of detecting EWSR1-WT1 fusion gene encoding a neoantigen, based on detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, administering to the individual an effective amount of an immune checkpoint inhibitor, and generating a report for treatment options which are all routine and conventional based on Ladanyi et al. (“Ladanyi”, U.S. Patent No. 5,670,317, Sep. 23, 1997) in view of Artomov et al. (“Artomov” U.S. Patent App. Pub. No. US 2019/0030147 A1, Jan. 31, 2019) and van Erp et al. (“van Erp”; (2017). Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent. Oncotarget, 8(41), 71371–71384.) as discussed below in the 35 U.S.C. 103 section below. Thus, the claim does not provide additional steps which are significantly more.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 12-15,18-19, 25-27, 37, 47, 52, 92, 120-121 and 172 are/remain rejected under 35 U.S.C. 103 as being obvious over Ladanyi et al. (“Ladanyi”, U.S. Patent No. 5,670,317, Sep. 23, 1997) in view of Artomov et al. (“Artomov” U.S. Patent App. Pub. No. US 2019/0030147 A1, Jan. 31, 2019) and van Erp et al. (“van Erp”; (2017). Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent. Oncotarget, 8(41), 71371–71384.).
Ladanyi discloses a method comprising an isolated nucleic acid molecule encoding a chimeric EWS-WT1 protein. This invention also provides an isolated protein which is a chimeric EWS-WT1 protein. This invention further provides method of diagnosing a desmoplastic small round cell tumor in a subject which comprises detecting in a sample from the subject a nucleic acid molecule encoding a chimeric EWS-WT1 protein positive detection indicating the presence of desmoplastic small round cell tumor. This invention also provides a method of inhibiting the growth of a neoplastic cell, wherein the cell is characterized by the presence of a chimeric EWS-WT1 protein which comprises contacting an antibody which specifically recognizes the chimeric EWS-WT1 fusion protein under suitable conditions so that an antibody-antigen complex is formed, thereby inhibiting the growth of the neoplastic cell (Abstract).
Regarding claims 12, Ladanyi teaches a method of diagnosing a desmoplastic small round cell tumor in a subject which comprises detecting in a sample from the subject a nucleic acid molecule encoding a chimeric EWS-WT1 protein (Pg. 15 col. 2 ln 52-55). Ladanyi teaches a method of inhibiting the growth of a neoplastic cell wherein the cell is characterized by the presence of a chimeric EWS-WT1 protein which comprises contacting an antibody conjugated to a therapeutic agent, wherein the antibody recognizes the chimeric EWS-WT1 protein under suitable conditions so that an antibody-antigen complex is formed, thereby inhibiting the growth of the neoplastic cell. (Pg. 17 col. 8 ln 25-32; Pg. 15 col. 2 ln 57-61).
Thus, Ladanyi suggests a method of treating or delaying progression of cancer, comprising:(a) detecting an Ewing sarcoma breakpoint region I- Wilms tumor protein (EWSR1-WT1) fusion gene encoding a neoantigen in a sample from an individual; and (b) based on detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, administering to the individual an effective amount of a treatment.
Ladanyi does not explicitly teach a method comprising: (a) wherein the neoantigen binds, or is predicted to bind, a major histocompatibility complex (MHC) class I molecule of the individual and (b) administering to the individual an effective amount of checkpoint inhibitor.
Artomov discloses methods that relate to constructing therapeutic fusion-specific vaccine libraries, selecting a therapeutic fusion-specific vaccine for a cancer patient, and/or constructing a de nova therapeutic fusion-specific vaccine for patients having a gene fusion that is absent from a fusion specific vaccine library (Abstract).
Regarding claim 12, Artomov teaches a method comprising “identifying one or more fusion junction sequences, wherein the fusion junction sequences comprise nucleic acid sequences and/or amino acid sequences corresponding to one or more tumor-specific gene
fusions, (c) obtaining information relating to interaction between fusion junction sequences with one or more HLA alleles” (Para. 6). Artomov teaches a method comprising “In some embodiments, the fusion-specific vaccine comprises one or more peptides having amino acid sequences corresponding to one or more tumor-specific gene fusions. In some embodiments, the fusion-specific vaccine comprises one or more peptides selected from Table A” (Para. 11). Table A reads on EWSR1-WT1 fusion. Artomov teaches a method comprising identifying long peptides at fusion breakpoints and predicting peptide binding affinity to MHC class I proteins (Para. 46; Figure 1). Thus, Ladanyi and Artomov suggest a method comprising detecting an Ewing sarcoma breakpoint region I- Wilms tumor protein (EWSR1-WT1) fusion gene encoding a neoantigen in a sample from an individual, wherein the neoantigen binds, or is predicted to bind, a major histocompatibility complex (MHC) class I molecule of the individual.
Regarding claim 12, Artomov teaches a method comprising “treatment for a patient with cancer”. (Para. 87). Artomov teaches a method comprising “suitable therapies… include but are not limited to immunotherapies, for example checkpoint blockade therapies, for example, but not limited to, anti-PD1 (nivolumab (Opdivo®), pembrolizumab (Keytruda®), pidilizumab etc.), anti-CTLA4 ( ipilimumab (Yervoy®), tremelimumab), or other checkpoint inhibitors such as BMS-936559, MPDL3280A, MEDI4736, MSB0010718C, IMP321, MGA271” (Para. 91). Thus, Ladanyi and Artomov suggest a method comprising (b) administering to the individual an effective amount of checkpoint inhibitor.
Furthermore, van Erp discloses “In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively). In the alveolar subtype PD-L1 expression was associated with better overall, event-free and metastases-free survival. PD-1 expression on lymphocytes was predominantly seen in synovial sarcomas (18%). High levels of CD8+ lymphocytes were predominantly detected in osteosarcomas (35%) and associated with worse event-free survival in synovial sarcomas. Ewing sarcoma and DSRCTs showed PD-1 on tumor cells instead of on tumor infiltrating lymphocytes. Overall, expression and clinical associations were found to be subtype dependent. For the first time PD-1 expression on Ewing sarcoma (19%) and DSRCT (82%) tumor cells was described.” (Abstract)
Regarding claims 12, van Erp teaches "Desmoplastic small round cell tumors (DSRCTs) are a very rare subtype with an incidence peak in young adult patients and a male predominance. Survival rates are limited to a 5-year survival of 15%, limited treatment options exist and tumors respond poorly to chemotherapy" (Pg. 71372, Introduction, Col. 1, Para. 2) and "DSRCTs present with an EWSR1 translocation that in DSRCTs fuses with the WT1 gene. Despite the use of multimodality treatment the survival rates have stagnated and the need for new therapeutic options is high"(Pg. 71372, Introduction, Col. 1, Para. 2). van Erp teaches a method comprising "All cell lines were authenticated by determining the disease-specific genetic translocation… Ewing sarcoma and EWSR1-WT1 for DSRCT)" (Pg. 71382, Methods, Col. 1, Para. 1). van Erp teaches a method comprising "Treatment effects of nivolumab (Opdivo® 10 mg/ml) were assessed" (Pg. 71382, Methods, Col. 1, Para. 3). van Erp also suggests “further research into the specific mechanistic aspects of immune evasion per subtype in order to determine whether PD-1 blockade is of therapeutic interest. In addition, for the first time, PD-1 expression was found to be present on Ewing sarcoma and DSRCT tumor cells… Given the tremendous need for new therapeutic approaches, in particular for DSRCTs, these observations will be further explored" (Pg. 71381, Discussion, Col. 1, Para. 2)
Thus, Ladanyi, Artomov and van Erp suggest a method comprising:(a) detecting an Ewing sarcoma breakpoint region 1 - Wilms tumor protein (EWSR1-WT1) fusion gene encoding a neoantigen in a sample from an individual, wherein the neoantigen binds, or is predicted to bind, a major histocompatibility complex (MHC) class I molecule of the individual; and (b) based on detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, administering to the individual an effective amount of an immune checkpoint inhibitor.
Ladanyi, Artomov and van Erp are considered to be analogous to the claimed invention because they are in the same field of treating or delaying cancer characterized with EWSR1-WT1 gene fusion. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method comprising detecting Ewing sarcoma breakpoint region 1 - Wilms tumor protein (EWSR1-WT1) fusion gene encoding a neoantigen in a sample from an individual as taught by Ladanyi and incorporating the method wherein the neoantigen binds, or is predicted to bind, a major histocompatibility complex (MHC) class I molecule of the individual and treating cancer cells comprising gene fusions (e.g. EWSR1/WT1-Table A) with a therapy comprising immune checkpoint inhibitors as taught by Artomov to incorporate the method comprising treating cancer cells comprising EWSR1-WT1 with a immune checkpoint inhibitor as taught by van Erp to have yielded the predictable result of treating or delaying progression of cancer in which EWSR1-WT1 fusion gene is detected with a immune checkpoint inhibitor. These claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome according to the limitations of claim 12. Furthermore, one of skill in the art would be motivated to substitute the therapeutic agent/inhibitor administered in the treatment methods of Ladanyi and Artomov, as van Erp highlights the need for new therapeutic options and discloses the checkpoint gene expression markers that may benefit from an immune checkpoint inhibitor. Doing so would allow for a targeted therapeutic approach for treating immuno-responsive cancer patients characterized by EWSR1-WT gene fusions response.
The teachings of Ladanyi, Artomov and van Erp are documented above in the rejection of claim 12 under 35 U.S.C. 103. Claims 14-15,18-19, 25-27, 37, 47, 52, 92 and 172 depend on claim 12. Claims 13 and 120-121 are independent claims.
Regarding claim 13, Ladanyi teaches a method of diagnosing a desmoplastic small round cell tumor in a subject which comprises detecting in a sample from the subject a nucleic acid molecule encoding a chimeric EWS-WT1 protein (Pg. 15 col. 2 ln 52-55). Ladanyi teaches a method of inhibiting the growth of a neoplastic cell wherein the cell is characterized by the presence of a chimeric EWS-WT1 protein which comprises contacting an antibody conjugated to a therapeutic agent, wherein the antibody recognizes the chimeric EWS-WT1 protein under suitable conditions so that an antibody-antigen complex is formed, thereby inhibiting the growth of the neoplastic cell. (Pg. 17 col. 8 ln 25-32; Pg. 15 col. 2 ln 57-61). Thus, Ladanyi, Artomov and van Erp suggest a method of treating or delaying progression of cancer, comprising:(a) acquiring knowledge of an Ewing sarcoma breakpoint region 1 - Wilms tumor protein (EWSRI-WT1) fusion gene encoding a neoantigen in a sample from an individual; and (b) responsive to said knowledge, administering to the individual an effective amount of a treatment comprising a checkpoint inhibitor.
Regarding claim 14, Ladanyi teaches a method wherein diagnosing a desmoplastic small round cell tumor in a subject which comprises detecting in a sample from the subject a nucleic acid molecule encoding a chimeric EWS-WT1 protein (Pg. 14, col. 2, ln 52-55). Ladanyi teaches a method wherein tumor and normal tissue samples were collected (Pg. 20, col. 13, ln 55). Thus, Ladanyi, Artomov and van Erp suggest a method comprising, prior to detecting the presence of an EWSRI-WTI1 fusion gene encoding a neoantigen in the sample, obtaining the sample from the individual.
Regarding claim 15, Ladanyi teaches a method wherein tumor and normal tissue samples were collected (Pg. 20, col. 13, ln 55). Thus, Ladanyi, Artomov and van Erp suggest a method wherein the sample is: (a) a blood, bone marrow, tumor, or tissue sample; (b) from amniotic fluid, blood, plasma, serum, semen, lymphatic fluid, cerebral spinal fluid, ocular fluid, urine, saliva, stool, mucus, sweat, blood, skin, hair, hair follicles, saliva, oral mucous, vaginal mucus, sweat, tears, epithelial tissues, urine, semen, seminal fluid, seminal plasma, prostatic fluid, Cowper's fluid, excreta, biopsy, ascites, cerebrospinal fluid, or lymph; or (c) a biopsy or formalin-fixed paraffin-embedded (FFPE) sample.
Regarding claim 18, Ladanyi teaches a method wherein DNA isolated from frozen tumor (Pg. 19, col. 12, ln 9-10). Thus, Ladanyi, Artomov and van Erp suggest a method wherein the presence of an EWSR1-WT1 fusion gene is detected in DNA or RNA from the sample.
Regarding claim 19, Ladanyi teaches a method wherein Direct sequencing of purified recombinant plasmid DNA was carried out by PCR (Pg. 20, col. 13, ln 12-13). Direct sequencing is interpreted as Sanger sequencing. Thus, Ladanyi, Artomov and van Erp suggest a method wherein the presence of an EWSR1-WT1 fusion gene is detected: (a) in cell-free DNA (cfDNA), (b) in DNA by next-generation sequencing (NGS), polymerase chain reaction (PCR), Sanger sequencing, or fluorescence in situ hybridization (FISH); or (c) in RNA by RNA-sequencing (RNA-seq), polymerase chain reaction (PCR), Sanger sequencing, or fluorescence in situ hybridization (FISH).
Regarding claim 25, Artomov teaches a method comprising determining peptide binding affinity to MHC proteins using biochemical techniques in vitro (Pg. 13, para. 46). Artomov teaches a method wherein peptides with predicted IC50 <500 nM are considered to bind to HLA proteins. In some embodiments, peptides with predicted IC50<50 nM are considered as strong binders to HLA proteins (Pg. 26, para. 201). Both KD and IC50 are interpreted to describe binding affinity. Thus, Ladanyi, Artomov and van Erp suggest a method wherein the neoantigen binds, or is predicted to bind, an MHC class I molecule of the individual with a dissociation constant (KD) of 50 nM or less.
Regarding claim 26, Artomov teaches method wherein information relating to one or more HLA alleles of the cancer patient are obtained by analysis (Pg. 10, para. 10). Artomov teaches method comprising determining a binding affinity of peptide-HLA class I major genes comprising HLA-A, HLA-B, and/or HLA-C. (Pg. 22, para. 48). Thus, Ladanyi, Artomov and van Erp suggest a method comprising: genotyping one or more human leukocyte antigen (HLA)-A, HLA-B, and HLA-C alleles from the sample from the individual.
Regarding claim 27, Artomov teaches a method wherein a patient is selected for vaccination with a therapeutic fusion-specific vaccine from the fusion-specific vaccine library if the patient has one or more HLA proteins that can effectively bind and present to the immune system one or more fusion-derived neoantigens that are present in the library. (Pg.15 para. 68). Thus, Ladanyi, Artomov and van Erp suggest a method wherein:(a) the cancer does not comprise a loss-of-heterozygosity at an HLA-A, HLA-B, or HLA- C allele that encodes an MHC class I molecule to which the neoantigen binds, or is predicted to bind; or(b) the cancer comprises a loss-of-heterozygosity at one or more, but not all, of HLA-A, HLA-B, or HLA-C allele(s) that encode an MHC class I molecule to which the neoantigen binds, or is predicted to bind; or(c) the cancer does not comprise a loss-of-function mutation in a CIITA or B2M gene.
Regarding claim 37, Ladanyi teaches a method wherein EWS and the WT1 genes in DSRCT were initially examined in five DSRCT tissue samples. Ladanyi teaches the results confirmed the presence of a consistent fusion of the EWS and WT1 genes in DSRCT (Pg. 14, col. 2, ln 18-21). Thus, Ladanyi, Artomov and van Erp suggest a method wherein the cancer is a desmoplastic small round cell tumor (DSRCT).
Regarding claim 47, Ladanyi teaches a method wherein EWS and WT1 specific probes and comparison of restriction map data indicated a fusion of the two genes with expected breakpoints within the intron between exons 7 and 8 of EWS and the intron between exons 7 and 8 of WT1 (FIG. 5B) (Pg. 22, col. 17, ln 29-33; Figure 5 B). Thus, Ladanyi, Artomov and van Erp suggest a method wherein EWSR1-WT1 fusion gene:(a) comprises a coding sequence of EWSR1 at the 5' end and a coding sequence of WT1 at the 3' end or (c) is formed via breakpoints in intron 7 of EWSR1 and intron 7 of WT1.
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Regarding claim 52, Ladanyi teaches a method comprising a 100% query match to the 9 aa of SEQ ID No. 1 (instant case) to SEQ ID No. 19 of U.S. Patent 5670317 (Sequence search result 1, see image below). Thus, Ladanyi, Artomov and van Erp suggest a method wherein: (a) the neoantigen comprises at least 5 contiguous amino acids from the sequence SSYGQQSEK (SEQ ID NO:1).
Regarding claim 92, Artomov teaches a method wherein treatment comprises treating a patient with a fusion-derived peptide or vaccine composition in combination with one or more additional therapies. Artomov teaches a method wherein vaccination of a patient is combined with one or more targeted therapies, chemotherapies, radiation, immunotherapy, or with hematopoietic stem cell transplantation. Artomov teaches a method wherein suitable therapies that can be combined with vaccination include but are not limited to immunotherapies, for example checkpoint blockade therapies (Pg. 16. para. 91). Thus, Ladanyi, Artomov and van Erp suggest a method further comprising administering an additional anti-cancer therapy to the individual.
Regarding claims 120, Ladanyi teaches a method of diagnosing a desmoplastic small round cell tumor in a subject which comprises detecting in a sample from the subject a nucleic acid molecule encoding a chimeric EWS-WT1 protein (Pg. 15 col. 2 ln 52-55). Ladanyi teaches a method of inhibiting the growth of a neoplastic cell wherein the cell is characterized by the presence of a chimeric EWS-WT1 protein which comprises contacting an antibody conjugated to a therapeutic agent, wherein the antibody recognizes the chimeric EWS-WT1 protein under suitable conditions so that an antibody-antigen complex is formed, thereby inhibiting the growth of the neoplastic cell. (Pg. 17 col. 8 ln 25-32; Pg. 15 col. 2 ln 57-61). Thus, Ladanyi, Artomov and van Erp suggest a method of treating or delaying progression of cancer, comprising:(a) detecting a Ewing sarcoma breakpoint region 1 (EWSR1) fusion gene encoding a neoantigen in a sample from an individual; and (b) administering to the individual an effective amount of a treatment comprising a cancer checkpoint inhibitor.
Regarding claim 121, Ladanyi teaches a method of diagnosing a desmoplastic small round cell tumor in a subject which comprises detecting in a sample from the subject a nucleic acid molecule encoding a chimeric EWS-WT1 protein (Pg. 15 col. 2 ln 52-55). Ladanyi teaches a method of inhibiting the growth of a neoplastic cell wherein the cell is characterized by the presence of a chimeric EWS-WT1 protein which comprises contacting an antibody conjugated to a therapeutic agent, wherein the antibody recognizes the chimeric EWS-WT1 protein under suitable conditions so that an antibody-antigen complex is formed, thereby inhibiting the growth of the neoplastic cell. (Pg. 17 col. 8 ln 25-32; Pg. 15 col. 2 ln 57-61). Thus, Ladanyi, Artomov and van Erp suggest a method of treating or delaying progression of cancer, comprising:(a) acquiring knowledge of a Ewing sarcoma breakpoint region 1 (EWSR1) fusion gene encoding a neoantigen in a sample from an individual; and (b) responsive to said knowledge, administering to the individual an effective amount of a treatment comprising a cancer checkpoint inhibitor.
Regarding claim 172, Artomov teaches a method further comprising “After the library information is obtained… proceeds to decision block … where it is determined whether patient information obtained … matches library information… For example, it may be determined, in decision block… whether the patient is a candidate for treatment … As disclosed herein, such data may include patient allele data, peptide sequence information, and/or any of the other types of data described herein… patient may be identified as a candidate for de novo vaccine generation and treatment or a candidate for alternative treatment” (Para.183-184). Thus, Ladanyi, Artomov and van Erp suggest a method further comprising generating a report, wherein the report comprises one or more treatment options identified for the individual based at least in part on the detection of the EWSR1-WT1 fusion gene encoding the neoantigen in the sample, wherein the one or more treatment options comprise the immune checkpoint inhibitor.
Response to Arguments
Applicant' s arguments filed on 03/17/2026 (Pg. 9-12) with respect to claims 12-15,18-19, 25-27, 37, 47, 52, 92 120-121 and 172 have been considered but do not apply to the new grounds of rejections, which is revised and updated from the rejection documented in the Final mailed on 10/17/2025 as necessitated by claim amendments filed on 03/17/2026.
Claims 31, 36 and 38 are/remain rejected under 35 U.S.C. 103 as being unpatentable over Ladanyi et al. (“Ladanyi”, U.S. Patent No. 5,670,317, Sep. 23, 1997) in view of Artomov et al. (“Artomov” U.S. Patent App. Pub. No. US 2019/0030147 A1, Jan. 31, 2019) and van Erp et al. (“van Erp”; (2017). Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8+ lymphocytes in primary sarcomas is subtype dependent. Oncotarget, 8(41), 71371–71384.), as applied to claims 12 and 37, and further in view of Cote et al. (“Cote”, (2018). Next‐generation sequencing for patients with sarcoma: A single center experience. The oncologist, 23(2), 234-242.).
The teachings of Ladanyi, Artomov and van Erp are documented above in the rejection of claims 12-15,18-19, 25-27, 37, 47, 52, 92 120-121 and 172 under 35 U.S.C. 103. Claims 31 and 36 depend on claim 12. Claim 38 depends on claim clam 37, which depends on claim 12.
Ladanyi, Artomov and van Erp do not explicitly teach a method further comprising “determining a tumor mutational burden (TMB) from the sample from the individual” and/or “determining microsatellite instability (MSI) from the sample from the individual”.
Cote discloses a method comprising targeted NGS for patients with sarcoma. Mutations were readily detected and 75 (representing 40% of patients) were testable for therapeutic effect using existing drugs within the confines of a clinical trial. These data indicate that targeted NGS is a useful tool in potentially routing patients to mutation specific clinical trials (Abstract- Conclusion).
Regarding claim 31, Cote teaches a method wherein tumor mutational burden (TMB) was calculated (Pg. 235, Tumor Mutational Burden and Microsatellite Status, para. 1). Thus, Ladanyi, Artomov and Cote teach a method comprising determining a tumor mutational burden (TMB) from the sample from the individual.
Regarding claim 36, Cote teaches a method wherein tumors were classified as microsatellite unstable high (MSI-H) or microsatellite stable (MSS) (Pg. 236, Tumor Mutational Burden and Microsatellite Status, para. 1). Thus, Ladanyi, Artomov and Cote teach a method comprising determining microsatellite instability (MSI) from the sample from the individual.
Regarding claim 38, Cote teaches a method wherein microsatellite instability data were available on 50 of the patient samples. Microsatellite instability was stable for all tested samples. Stable is interpreted as not instable, therefore DSRCT was not characterized by MSI. (Pg. 241, para. 2). Thus, Ladanyi, Artomov and Cote teach a method wherein the cancer is a DSRCT, and wherein the DSRCT is characterized by a low TMB and/or is not characterized by microsatellite instability (MSI).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention modify the method of treating and/or delaying progression of a cancer comprising EWSR1-WT1 as taught by Ladanyi, Artomov and van Erp to incorporate the method comprising TMB and MSI determination as taught by Cote to have yielded the predictable result of adding to the parameters used to assess an effective and targeted therapeutic for the cancer. Doing so would allow for the predictable outcome of determining the specificity of a therapeutic for a particular cancer patient.
Response to Arguments
Applicant' s arguments filed on 03/17/2026 (Pg.12) with respect to claims 31, 36 and 38 have been considered but do not apply to the new grounds of rejections, which is revised and updated from the rejection documented in the Final mailed on 10/17/2025 as necessitated by claim amendments filed on 03/17/2026.
Conclusion of Response to Arguments
In view of the amendments, new grounds of rejections and above responses to arguments, no claims are in condition for allowance.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's
disclosure: Patent App. Pub. No: US 20140222443 A1 (Para. 536-538) claim 1-EWS-WT1 and cancer; (Para. 28) claim 172.
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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, Winston Shen can be reached at (571)272-3157. 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.
/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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