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 .
Election/Restrictions
Applicant’s election without traverse of Species I, directed to an in vitro method of selecting a subject suffering from a cancer expressing the O-acetylated-GD2 ganglioside for treatment targeting said cancer according to pending claim 15. In addition, in response to the request of the election of a specific gene or a specific combination of genes in the claim elected, the Applicant provisionally elects, without traverse, the CADS1/CERK gene combination in the reply filed on 06/30/2026 is acknowledged.
Claims 16-17 and 26-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/30/2026.
Claims Status
Claims 15-27 are pending.
Claims 16-17 and 26-27 are withdrawn.
Claims 1-14 are canceled.
Claims 15, 18-25 are currently under examination.
Priority
This application is a 371 of PCT/EP2022/065896, filed on 06/10/2022, which claims foreign priority to EP 21305797.9, filed on 06/10/2021. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. EP2022065896, filed on 06/10/2022. Accordingly, the priority date of the instant claim set is determined to be 06/10/2021.
Claim Rejections - 35 USC § 112
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 15 and 18-25 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 is indefinite over the limitations “subject” (ln 5), It is unclear whether the subject is healthy or comprises a cancer. The preamble is not sufficient for active limitation of the subject population. Claims 18-25 depend on claim 15.
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 15 and 18-25 are rejected under 35 U.S.C. 103 as being unpatentable over Cavdarli et al. (“Cavdarli 2020”; (2020). O-acetylated Gangliosides as Targets for Cancer Immunotherapy. Cells, 9(3), 741.) in view of Cavdarli et al. (“Cavdarli 2019”; (2019). Identification of 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac2) as main O-acetylated sialic acid species of GD2 in breast cancer cells. Glycoconjugate journal, 36(1), 79–90.).
Claim interpretations: The limitation(s) reciting “optionally” in claims 15, 18-19 and 21-22, is interpreted as rendering the phrase thereafter as an optional limitation to the claim. Regarding claim 15, “al') optionally, measuring the expression level of at least one biomarker selected from the group consisting of GD2S, GD3S, OAcGD2, GD2, CERK, PIK3C2A, PDK3, MERTK and NME3, in a biological sample of the subject” is interpreted as optional. Furthermore, the Applicant provisionally elected, without traverse, the CASD1/CERK gene combination, yet CERK is optional. Thus, the election would read on CASD1 and optionally CERK as recited in the claim set filed 12/08/2023.
Cavdarli 2020 discloses “O-acetylation of sialic acid residues is one of the main modifications of gangliosides, and modulates ganglioside functions. O-acetylation of gangliosides is dependent on sialyl-O-acetyltransferases and sialyl-O-acetyl-esterase activities. CAS1 Domain-Containing Protein 1 (CASD1) is the only human sialyl-O-acetyltransferases (SOAT) described until now. O-acetylated ganglioside species are mainly expressed during embryonic development and in the central nervous system in healthy adults, but are re-expressed during cancer development and are considered as markers of cancers of neuroectodermal origin. However, the specific biological roles of O-acetylated gangliosides in developing and malignant tissues have not been extensively studied, mostly because of the requirement of specific approaches and tools for sample preparation and analysis. In this review, we summarize our current knowledge of ganglioside biosynthesis and expression in normal and pathological conditions, of ganglioside O-acetylation analysis and expression in cancers, and of the possible use of O-acetylated gangliosides as targets for cancer immunotherapy.” (Abstract).
Regarding claim 15, Cavdarli teaches a method wherein “The O-acetylation of gangliosides results from highly regulated mechanisms dependent on substrate availability and glycosyltransferase expression, giving a cell-type expression pattern. O-acetylated ganglioside expression is mainly associated with the pro-survival function of neuroectoderm-derived tumors. OAcGD2 seems to be a safer target than its non O-acetylated form, and an anti-OAcGD2 antibody has been developed for cancer therapy” (Conclusions, Para.1). Thus, Cavdarli suggests an in vitro method of selecting a subject suffering from a cancer expressing the O-acetylated-GD2 ganglioside for treatment targeting said cancer.
Regarding claim 15, Cavdarli 2020 teaches a method wherein “O-acetylated GD2 has recently become a target of interest for the treatment of GD2-positive cancers” (Pg. 5). Cavdarli 2020 teaches a method wherein “The biosynthesis and degradation of O-acetylated gangliosides are finely regulated processes, which depend… mostly on the balance between the sialyl-O-acetyltransferases (SOAT) and the sialyl-O-acetylesterase (SOAE) activities. These finely regulated processes give rise to a tissue/cell-type specific pattern of O-acetylated ganglioside expression” (Pg. 5). Cavdarli 2020 teaches a method wherein “Regarding ganglioside O-acetylation, CASD1 has been described as encoding the only human SOAT up-to-now.” (Pg. 5). Cavdarli 2020 teaches a method wherein “the detection and the analysis of O-acetylated gangliosides remain challenging due to the lability of the O-acetyl group using classical procedures, immunological methods or the combination of both” (Pg. 7). Cavdarli 2020 teaches a method wherein “OAcGD2 as an alternative therapeutic target to GD2 in neuroectoderm-derived tumors” (Pg. 8).
Thus, Cavdarli 2020 suggests a method comprising b) based on the level measured at step al), and optionally at step al'), selecting said subject to undergo treatment targeting said cancer expressing the O-acetylated-GD2 ganglioside.
However, Cavdarli 2020 does not explicitly teach limitation comprising a) measuring CASD1 expression level.
Cavdarli 2019 discloses “Mainly restricted to the nervous system in healthy adults, complex gangliosides such as GD3 and GD2 have been shown to be involved in aggressiveness and metastasis of neuro-ectoderm derived tumors such as melanoma and neuroblastoma. Interestingly, O-acetylated forms of GD2, not expressed in human peripheral nerve fibers, are highly expressed in GD2+ tumor cells. Very little information is known regarding the expression of O-acetylated disialogangliosides in breast cancer (BC) cell lines. Here, we analyzed the expression of GD2, GD3 and their O-acetylated forms O-acetyl-GD2 (OAcGD2) and O-acetyl-GD3 (OAcGD3) in BC cells. We used Hs 578T and SUM159PT cell lines, as well as cell clones over-expressing GD3 synthase derived from MDA-MB-231 and MCF-7. Using flow cytometry and immunocytochemistry/confocal microscopy, we report that BC cells express b-series gangliosides GD3 and GD2, as well as significant amounts of OAcGD2. However, OAcGD3 expression was not detected in these cells. O-acetylation of gangliosides isolated from BC cells was examined by LC-MS analysis of sialic acid DMB-derivatives. We report that the main acetylated form of sialic acid expressed in BC gangliosides is 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac2). These results highlight a close interrelationship between Neu5,9Ac2 and OAcGD2 expression, and suggest that OAcGD2 is synthetized from GD2 and not from OAcGD3 in BC cells.” (Abstract).
Regarding claim 15, Cavdarli 2019 teaches a method wherein “The oligonucleotide sequences used as primers for the PCR reactions are given in Table 1. qPCR and subsequent data analysis were performed” (Pg. 81, RNA extraction, cDNA synthesis and quantitative real-time polymerase chain reaction (qPCR)). Cavdarli 2019 recites primers to Casd1 in Table 1. (Pg. 81, CASD1-Table 1 Primer pairs used for qPCR experiments). Cavdarli 2019 teaches a method wherein “We performed qPCR experiments in order to determine the expression of the glycosyltransferase genes involved in GD3 and GD2 biosynthesis’ (Pg. 82). Thus, Cavdarli 2020 and Cavdarli 2019 suggests a method comprising a) measuring CASD1 expression level as a biomarker in a biological sample of the subject.
Thus, Cavdarli 2020 and Cavdarli 2019 suggest the limitations of claim 15.
Cavdarli 2020 and Cavdarli 2019 are both considered to be analogous to the claimed invention because they are in the same field of O-acetylated Gangliosides in cancer. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of selecting said subject to undergo treatment targeting said cancer expressing the O-acetylated-GD2 ganglioside as suggested by Cavdarli 2020 to incorporate the method of measuring CASD1 expression level as a biomarker in a biological sample as suggested by Cavdarli 2019 and provide a method for according to the limitations of claim 15. 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 15. Doing so would improve the method of measuring levels of expression in relation to the O-acetylated-GD2 biomarker.
The teachings of Cavdarli 2020 and Cavdarli 2019 are documented above in the rejection of claim 15 under 35 U.S.C. 103. Claims 18 and 20-25 depends on claim 15. Claim 19 depends on claim 18, which depends on claim 15.
Regarding claim 18, Cavdarli 2019 teaches a method wherein “Hypoxanthine-guanine PhosphoRibosylTransferase (HPRT) gene was used to normalize the expression of genes of interest… For each primer pair, the specificity of the amplification was checked …The quantification was performed by the method described by Pfaffl ” (Pg. 81). “normalize” reads on comparing the expression level measured with a threshold value. Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method further comprising a step a2) of comparing the expression level measured at step al), and/or optionally at step al'), with a threshold value.
Regarding claim 19, Cavdarli 2020 teaches a method wherein “O-acetylated ganglioside expression is mainly associated with the pro-survival function of neuroectoderm-derived tumors. OAcGD2 seems to be a safer target than its non O-acetylated form, and an anti-OAcGD2 antibody has been developed for cancer therapy.” (Pg. 9). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein the subject is selected to undergo a treatment targeting said cancer expressing the O-acetylated-GD2 ganglioside, or is diagnosed as suffering from a cancer expressing the O-acetylated-GD2 ganglioside, if the expression level measured at step al), and/or optionally at step al'), is higher than the threshold value.
Regarding claim 20, Cavdarli 2020 teaches a method wherein “expression in biological samples such as blood, serum, tissues or cells, in order to identify diagnostic tools or biomarkers for diseases.” (Pg. 8). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein the biological sample is selected from the group consisting of a blood sample, a serum sample, a plasma sample, a urine sample, a tissue sample from a biopsy and a cell sample from a biopsy.
Regarding claim 21, Cavdarli 2019 teaches a method wherein “The oligonucleotide sequences used as primers for the PCR reactions are given in Table 1. qPCR and subsequent data analysis were performed” (Pg. 81, RNA extraction, cDNA synthesis and quantitative real-time polymerase chain reaction (qPCR)). Cavdarli 2019 recites primers to Casd1 in Table 1. (Pg. 81, Table 1) Cavdarli 2019 teaches a method wherein “We performed qPCR experiments in order to determine the expression of the glycosyltransferase genes involved in GD3 and GD2 biosynthesis’ (Pg. 82). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein the expression level measured at step al), and/or optionally at step al'), is measured at the DNA or RNA level, preferably by RT-PCR, RT-qPCR, Northern Blot, hybridization techniques, microarrays or sequencing.
Regarding claim 22, Cavdarli 2019 teaches a method wherein “analyzed by immunohistochemistry” (Pg. 87). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein the expression level measured at step al), and/or optionally at step al'), is measured at the protein level, preferably by FACS, immunohistochemistry, mass spectrometry, western blot associated with cell fractionation, enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, fluorescent- linked immunosorbent assay (FLISA), enzyme immunoassay (EIA), radioimmunoassay (RIA) or image analysis.
Regarding claim 23, Cavdarli 2020 teaches a method wherein “a therapeutic antibody against OAcGD2 has been developed” (Pg. 8). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein said treatment comprises an antibody that binds to the O-acetylated-GD2 ganglioside.
Regarding claim 24, Cavdarli 2019 teaches a method wherein “OAcGD2 were detected at the cell surface and in punctuated structures in the different BC cells” (Pg. 83). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein said cancer expressing the O-acetylated-GD2 ganglioside is characterized by the presence of cells expressing the 0- acetylated-GD2 ganglioside at their cell surface in the subject.
Regarding claim 25, Cavdarli 2020 teaches a method wherein “OAcGD2 expression has been established in many neuroectoderm-derived tumor types such as neuroblastoma (NB), glioblastoma, SCLC and BC” (Pg. 7-8). Thus, Cavdarli 2020 and Cavdarli 2019 suggest a method wherein said cancer expressing the O-acetylated-GD2 ganglioside is selected from the group consisting of neuroblastoma, glioma (including glioblastoma), retinoblastoma, Ewing's family of tumors, sarcoma (including rhabdomyosarcoma, osteosarcoma, leiomyosarcoma, liposarcoma, and fibrosarcoma), lung cancer (including small cell lung cancer), breast cancer, melanoma (including uveal melanoma), metastatic renal carcinoma, head and neck cancer, hematological cancers (including leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and myeloma), colorectal cancer, pancreatic cancer, prostate cancer, liver cancer, bladder cancer, gastric/stomach cancer, cervical cancer, endometrial cancer, neuroendocrine cancer, esophageal cancer, ovarian cancer, skin cancer, kidney cancer, soft tissue sarcoma, adrenal cancer, testicular cancer, thymic cancer (including thymoma) and thyroid cancer.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's
disclosure: Human Protein ATLAS. (n.d.). CASD1. Expression of CASD1 in cancer - summary - the human protein atlas. https://web.archive.org/web/20150923102723/http://www.proteinatlas.org/ENSG00000127995-CASD1/cancer Accessed through Wayback's calendar entry of 23 September 2015. (CASD1 expression in cancer) claim 1
Patent App. Pub. No: US 20190023808 A1 (therapeutic antibody targeting GD2-O-acetylated ganglioside can be administrated (Para. 9); treat with antibody (Para. 161) Claim 1-
No claims are in condition for allowance.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
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