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 .
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.
Claims Status
Claims 1-20 are pending.
Claims 4-20 are objected to for being in improper form because the claims are dependent on multiple claims and have not been further treated on the merits. See MPEP § 608.01(n).
Claims 1-3 are examined on the merits.
Priority
The instant application is a national stage application of PCT/CN2019/104946, filed 09/09/2019 that claims priority to application CHINA 201811052794.0, filed 09/10/2018. It is noted that the English translation of the certified foreign priority document has not yet been provided.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The Information Disclosure Statements filed 10/19/2022 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS document is included with this Office Action.
Drawings
The drawings filed 02/09/2022 are accepted.
Claim Objections
Claims 4-20 are objected to under 37 CFR 1.75(c) as being in improper dependent form because dependent claims cannot depend from any other multiple dependent claims. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
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 2-3 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.
Claims 2 and 3 recite the phrase “…preferably any one…”. The term “preferably” renders the claims indefinite because the intended scope of the claim is unclear. It is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 2 recites: “…calculating any one of Z1, Z8, Z11 and Z16, preferably any one of Z1, Z8 and Z11, and further preferably any one of Z1 and Z8.” The limitation is rendered indefinite because the metes and bounds of the claim are not clearly defined. It is not clear whether the term “calculating” is referring to calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes or a total expression of the imprinted genes in skin tumors. For compact prosecution, calculating is interpreted as referring to determining expression levels of the imprinted genes.
Claim 3 recites: “…calculating the combination of any two of the imprinted genes Z1, Z8, Z11 and Z16, and preferably the combination of Z1 and Z8 or the combination of Z8 and Z11.” The limitation is rendered indefinite because the metes and bounds of the claim are not clearly defined. It is not clear whether the term “calculating” is referring to calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes or a total expression of the imprinted genes in skin tumors. For compact prosecution, calculating is interpreted as referring to determining expression levels of the imprinted genes.
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.
Claims 1-3 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. (See MPEP 2106.03) The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because claim 1 recites a grading model for detecting the benign and malignant degree of skin tumors, grading expression states of imprinted genes by calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes in skin tumors... Therefore, the grading model is not a process, machine, manufacture, or composition of matter, but is directed towards an algorithm for calculating imprinted genes expression levels. As such, claims 1-3 are not patent eligible.
Claim Rejections - 35 USC § 102
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)(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.
Claim(s) 1-3 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Fan (US 20070231797 A1, published October 2007; cited on the attached 892 form).
Regarding claim 1, Fan teaches A grading model for detecting the benign and malignant degree of skin tumors, grading expression states of imprinted genes by calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes in skin tumors with “The present invention provides a method for identification of differentially methylated genomic CpG dinucleotide sequences associated with cancer in an individual by obtaining a biological sample comprising genomic DNA from the individual measuring the level or pattern of one or more methylated genomic CpG dinucleotide sequences in two or more of the genomic targets in the sample, and comparing the level of said one or more methylated genomic CpG dinucleotide sequences in the sample to a reference level of methylated genomic CpG dinucleotide sequences, wherein a difference in the level or pattern of methylation of the genomic CpG dinucleotide sequences in the sample compared to the reference level identifies differentially methylated genomic CpG dinucleotide sequences associated with cancer.” (para. [0011]).
Fan teaches grading expression states of imprinted genes with “The method of claim 1, wherein the level of methylation of said differentially methylated genomic CpG dinucleotide sequences is used to stage the progression of the cancer in the individual.” (Claim 5 of Fan).
Fan teaches calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes with “The method of claim 1, wherein said level of methylation in the biological sample is decreased in comparison to the reference level.” (claim 10 of Fan). This corresponds to the claim limitation of loss of imprinting.; “The present invention relates to conditions characterized by differentially methylated genomic CpG dinucleotide sequences and, in particular, to diagnostic and prognostic methods that exploit the presence of such genomic DNA sequences that exhibit altered CpG methylation patterns.” (para. [0003]). This corresponds to the claim limitation of expression of the copy number variation of the imprinted genes; “The genomic targets and nucleic acid probes provided by the present invention are set forth in Table 1, below, and provide diagnostic and prognostic tools based on their ability to detect differential methylation of selected genomic CpG dinucleotide sequences associated with cancer. In the methods provided by the invention, the genomic targets and nucleic acid probes capable of detecting markers located within the genomic targets can be employed to detect altered levels of methylation of genomic CpG dinucleotide sequences in a biological sample compared to a reference level. Furthermore, the methods of the invention allow for use of the genomic markers and nucleic acid probes for the determination of methylation patterns, which are represented by differential methylation of selected genomic CpG dinucleotide sequences that serve as markers in particular sets or subsets of genomic targets. In embodiments directed to the detection of methylation patterns, it is possible to diagnose or predict the susceptibility of an individual to a specific tumor-type based on the correlation between the pattern and the tumor type.” (para. [0055]) and with “After PCR, a thermal melt profile was performed to examine the homogeneity of PCR amplicons. Each DNA sample was analyzed in duplicate and the mean was used for further analysis. The difference of the threshold cycle number (the Ct-values) between the methylated and unmethylated alleles, ΔCt=Ct (unmethylated)−Ct (methylated), was first determined. The percentage of methylated DNA, designated as the methylation level “c”, can be correlated to the ΔCt value through the equation: ΔCt=Log2[c/(1−c)] ((Martens et al., Cancer Res 65: 4101-4117 (20055); Zeschnigk et al.Nucleic Acids Res 32: el25 (2004)). The resulting methylation level thereby equals 2ˆΔCt/(1+2ˆCt). (Para. [0231]).
Fan teaches skin tumour with “…as the list in Table I is exemplary, the methylation state of other genes or genomic sequences can also be used in a method of the invention to determine the presence or severity of cancer. Exemplary cancers that can be evaluated using a method of the invention include, but are not limited to … head & neck cancers, Basal Cell Carcinoma, Mycosis fungoids and sezary syndrome, Squamous Cell Carcinoma, Ceruminoma, Peripheral T-cell lymphoma, Osteoma, Nonchromaffin Paraganglioma, Angioimmunoblastic T-cell lymphoma, Acoustic Neurinoma, Adenoid Cystic Carcinoma, Angiocentric lymphoma, Mucoepidermoid Carcinoma, NK/T-cell lymphoma, Malignant Mixed Tumors, Intestinal T-cell lymphoma, Adenocarcinoma, Malignant Mesothelioma, Fibrosarcoma, Sarcomotoid Type lung cancer, Osteosarcoma, Epithelial Type lung cancer, Chondrosarcoma, Melanoma, cancer of the gastrointestinal tract, olfactory Neuroblastoma, Squamous Cell Carcinoma, Isolated Plasmocytoma, Adenocarcinoma, Inverted Papillomas, Carcinoid, Undifferentiated Carcinoma, Malignant Melanoma, Mucoepidermoid Carcinoma, Adenocarcinoma, Acinic Cell Carcinoma, Gastric Carcinoma, Malignant Mixed Tumor, Gastric Lymphoma, Gastric Stromal Cell Tumors, Amenoblastoma, Lymphoma, Odontoma, Intestinal Stromal Cell tumors, thymus cancers, Malignant Thymoma, Carcinids, Type I (Invasive thymoma), Malignant Mesethelioma, Type II (Thymic carcinoma), Non-mucin producing adenocarcinoma, Squamous cell carcinoma, Lymph epithelioma, cancers of the liver and biliary tract, Squamous Cell Carcinoma, Hepatocellular Carcinoma, Adenocarcinoma, Cholangiocarcinoma, Hepatoblastoma, papillary cancer, Angiosarcoma, solid Bronchioalveolar cancer, Fibrolameller Carcinoma, Small Cell Carcinoma, Carcinoma of the Gallbladder, Intermediate Cell carcinaoma, Large Cell Carcinoma, Squamous Cell Carcinoma, Undifferentiated cancer, cancer of the pancreas, cancer of the female genital tract, Squamous Cell Carcinoma, Cystadenocarcinoma, Basal Cell Carcinoma, Insulinoma, Melanoma, Gastrinoma, Fibrosarcoma, Glucagonamoa, Intaepithelial Carcinoma, Adenocarcinoma Embryonal, cancer of the kidney, Rhabdomysarcoma, Renal Cell Carcinoma, Large Cell Carcinoma, Nephroblastoma (Wilm's tumor), Neuroendocrine or Oat Cell carcinoma, cancer of the lower urinary tract, Adenosquamous Carcinoma, Urothelial Tumors, Undifferentiated Carcinoma, Squamous Cell Carcinoma, Carcinoma of the female genital tract, Mixed Carcinoma, Adenoacanthoma, Sarcoma, Small Cell Carcinoma, Carcinosarcoma, Leiomyosarcoma, Endometrial Stromal Sarcoma, cancer of the male genital tract, Serous Cystadenocarcinoma, Mucinous Cystadenocarcinoma, Sarcinoma, Endometrioid Tumors, Speretocytic Sarcinoma, Embyonal Carcinoma, Celioblastoma, Choriocarcinoma, Teratoma, Clear Cell Carcinoma, Leydig Cell Tumor, Unclassified Carcinoma, Sertoli Cell Tumor, Granulosa-Theca Cell Tumor, Sertoli-Leydig Cell Tumor, Disgerminoma, Undifferentiated Prostatic Carcinoma, Teratoma, Ductal Transitional carcinoma, breast cancer, Phyllodes Tumor, cancer of the bones joints and soft tissue, Paget's Disease, Multiple Myeloma, Insitu Carcinoma, Malignant Lymphoma, Invasive Carcinoma, Chondrosacrcoma, Mesenchymal Chondrosarcoma, cancer of the endocrine system, Osteosarcoma, Adenoma, Ewing Tumor, endocrine Carcinoma, Malignant Giant Cell Tumor, Meningnoma, Adamantinoma, Cramiopharlingioma, Malignant Fibrous Histiocytoma, Papillary Carcinoma, Histiocytoma, Follicular Carcinoma, Desmoplastic Fibroma, Medullary Carcinoma, Fibrosarcoma, Anoplastic Carcinoma, Chordoma, Adenoma, Hemangioendothelioma, Memangispericytoma, Pheochromocytoma, Liposarcoma, Neuroblastoma, Paraganglioma, Histiocytoma, Pineal cancer, Rhabdomysarcoms, Pineoblastoma, Leiomyosarcoma, Pineocytoma, Angiosarcoma, skin cancer, cancer of the nervous system, Melanoma, Schwannoma, Squamous cell carcinoma, Neurofibroma, Basal cell carcinoma, Malignant Periferal Nerve Sheath Tumor, Merkel cell carcinoma, Sheath Tumor, Extramamary Paget's Disease, Astrocytoma, Paget's Disease of the nipple, Fibrillary Astrocytoma, Glioblastoma Multiforme, Brain Stem Glioma, Cutaneous T-cell lymphoma, Pilocytic Astrocytoma, Xanthorstrocytoma, Histiocytosis, Oligodendroglioma, Ependymoma, Gangliocytoma, Cerebral Neuroblastoma, Central Neurocytoma, Dysembryoplastic Neuroepithelial Tumo,r Medulloblastoma, Malignant Meningioma, Primary Brain Lymphoma, Primary Brain Germ Cell Tumor, cancers of the eye, Squamous Cell Carcinoma, Mucoepidermoid Carcinoma, Melanoma, Retinoblastoma, Glioma, Meningioma, cancer of the heart, Myxoma, Fibroma, Lipoma, Papillary Fibroelastoma, Rhasdoyoma, or Angiosarcoma among others.” (para. [0090]).
Fan teaches wherein, the imprinted genes are any one or the combination of at least two of Z1, Z8, Z11 and Z16, the imprinted gene Z1 is Gnas, the imprinted gene Z8 is Dcn, the imprinted gene Z11 is Grb10, and the imprinted gene Z16 is Snrpn/Snurf with Table 5. Fan teaches GNAS, GRB10, Snrpn/Snurf in Table 5 (Table 5 of Fan).
Regarding claim 2, Fan teaches wherein an imprinted gene calculation method of the model comprises: calculating any one of Z1, Z8, Z11 and Z16, preferably any one of Z1, Z8 and Z11, and further preferably any one of Z1 and Z8 with Table 5. Fan teaches GNAS, GRB10, Snrpn/Snurf in Table 5 (Table 5 of Fan). and with “Gene-specific as well as allele-specific probes are designed to measure expression levels of specific transcripts and their isoforms. Cross-referencing gene expression results to DNA methylation data confirms not only the gene silencing caused by DNA methylation, but also helps interpret the association study results. Once specific methylation patterns are derived from this preliminary study, they are validated in (larger) independent sample sets.” (para. [0177]) and with “After PCR, a thermal melt profile was performed to examine the homogeneity of PCR amplicons. Each DNA sample was analyzed in duplicate and the mean was used for further analysis. The difference of the threshold cycle number (the Ct-values) between the methylated and unmethylated alleles, ΔCt=Ct (unmethylated)−Ct (methylated), was first determined. The percentage of methylated DNA, designated as the methylation level “c”, can be correlated to the ΔCt value through the equation: ΔCt=Log2[c/(1−c)] ((Martens et al., Cancer Res 65: 4101-4117 (20055); Zeschnigk et al.Nucleic Acids Res 32: el25 (2004)). The resulting methylation level thereby equals 2ˆΔCt/(1+2ˆCt). (Para. [0231]).
Regarding claim 3, Fan teaches wherein the imprinted gene calculation method of the model comprises: calculating the combination of any two of the imprinted genes Z1, Z8, Z11 and Z16, and preferably the combination of Z1 and Z8 or the combination of Z8 and Z11 with Table 5. Fan teaches GNAS, GRB10, Snrpn/Snurf in Table 5 (Table 5 of Fan) and with “Gene-specific as well as allele-specific probes are designed to measure expression levels of specific transcripts and their isoforms. Cross-referencing gene expression results to DNA methylation data confirms not only the gene silencing caused by DNA methylation, but also helps interpret the association study results. Once specific methylation patterns are derived from this preliminary study, they are validated in (larger) independent sample sets.” (para. [0177]) and with “After PCR, a thermal melt profile was performed to examine the homogeneity of PCR amplicons. Each DNA sample was analyzed in duplicate and the mean was used for further analysis. The difference of the threshold cycle number (the Ct-values) between the methylated and unmethylated alleles, ΔCt=Ct (unmethylated)−Ct (methylated), was first determined. The percentage of methylated DNA, designated as the methylation level “c”, can be correlated to the ΔCt value through the equation: ΔCt=Log2[c/(1−c)] ((Martens et al., Cancer Res 65: 4101-4117 (20055); Zeschnigk et al.Nucleic Acids Res 32: el25 (2004)). The resulting methylation level thereby equals 2ˆΔCt/(1+2ˆCt). (Para. [0231]).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 17295629 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite calculating expression levels of imprinted genes. Overall, the difference is that the claims of the instant application are broader in scope than the claims of the reference application and thus the instant claims are anticipated by the reference application (see MPEP 804.II.B.2). See table below for a mapping of the claims of the reference application that anticipate the claims of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant app# 17274864, 05/10/2021
Reference app# 17295629, 11/30/2021
1. A grading model for detecting the benign and malignant degree of skin tumors, grading expression states of imprinted genes by calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes in skin tumors; wherein, the imprinted genes are any one or the combination of at least two of Z1, Z8, Z11 and Z16, the imprinted gene Z1 is Gnas, the imprinted gene Z8 is Dcn, the imprinted gene Z11 is Grb10, and the imprinted gene Z16 is Snrpn/Snurf.
2. The model according to Claim 1, wherein an imprinted gene calculation method of the model comprises: calculating any one of Z1, Z8, Z11 and Z16, preferably any one of Z1, Z8 and Z11, and further preferably any one of Z1 and Z8.
3. The model according to Claim 1 or 2, wherein the imprinted gene calculation method of the model comprises: calculating the combination of any two of the imprinted genes Z1, Z8, Z11 and Z16, and preferably the combination of Z1 and Z8 or the combination of Z8 and Z11.
1. (Original) A marker used to detect invasive bladder cancer, wherein the marker is imprinted gene Grb10 and/or imprinted gene Diras3.
2. (Original) The marker of claim 1, wherein a total expressed quantity of each said imprinted gene, an expressed quantity of each said imprinted gene being normal, an expressed quantity of each said imprinted gene with a loss of imprinting, and an expressed quantity of each said imprinted gene with a copy number variation are calculated using the following formulas: the total expressed quantity of a said imprinted gene = (b+c+d)/(a+b+c+d)x100%;the expressed quantity of the imprinted gene being normal = b/(b+c+d) x100%;the expressed quantity of the imprinted gene with a loss of imprinting = c/(b+c+d) x100%;and the expressed quantity of the imprinted gene with a copy number variation = d/(b+c+d) x100%;where a is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show no mark in each said cell nucleus, meaning the imprinted gene is not expressed in each said cell nucleus; b is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show one red/brown mark in each said cell nucleus, meaning the imprinted gene is present in each said cell nucleus; c is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show two red/brown marks in each said cell nucleus, meaning the imprinted gene is affected by a loss of imprinting in each said cell nucleus; and d is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show more than two red/brown marks in each said cell nucleus, meaning the imprinted gene shows a copy number variation in each said cell nucleus.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 18509538 (reference application) in view of Fan (US 20070231797 A1, published October 2007; cited on the attached 892 form). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite calculating expression levels of imprinted genes. Overall, the difference is that the claims of the instant application are broader in scope than the claims of the reference application and thus the instant claims are anticipated by the reference application (see MPEP 804.II.B.2). See table below for a mapping of the claims of the reference application that anticipate the claims of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant app# 17274864, 05/10/2021
Reference app# 18509538, 02/04/2024
1. A grading model for detecting the benign and malignant degree of skin tumors, grading expression states of imprinted genes by calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes in skin tumors; wherein, the imprinted genes are any one or the combination of at least two of Z1, Z8, Z11 and Z16, the imprinted gene Z1 is Gnas, the imprinted gene Z8 is Dcn, the imprinted gene Z11 is Grb10, and the imprinted gene Z16 is Snrpn/Snurf.
2. The model according to Claim 1, wherein an imprinted gene calculation method of the model comprises: calculating any one of Z1, Z8, Z11 and Z16, preferably any one of Z1, Z8 and Z11, and further preferably any one of Z1 and Z8.
3. The model according to Claim 1 or 2, wherein the imprinted gene calculation method of the model comprises: calculating the combination of any two of the imprinted genes Z1, Z8, Z11 and Z16, and preferably the combination of Z1 and Z8 or the combination of Z8 and Z11.
1. A method for determining a level of malignancy of a thyroid tumor in a subject and treating the subject, comprising: obtaining a test sample from the subject; performing in situ hybridization of a first probe designed based on the sequence of an intron of imprinted gene HM13 with a first plurality of cells of the test sample, and performing in situ hybridization of a second probe designed based on the sequence of an intron of imprinted gene SNRPN with a second plurality of cells of the test sample; staining the first plurality of cells and the second plurality of cells having been subject to the hybridization with a staining chemical, calculating a total expression, a biallelic expression, and a multiallelic expression for imprinted genes HM13 based on microscopic images of the stained first plurality of cells, and calculating a total expression, a biallelic expression, and a multiallelic expression for imprinted genes SNRPN based on microscopic images of the stained second plurality of cells, respectively; grading the biallelic expression and multiallelic expression of each of the imprinted genes HM13 and SNRPN, deriving an overall gene score for each of the imprinted genes HM13 and SNRPN, and determining the level of malignancy of a thyroid tumor based on a combination of the overall gene score for imprinted gene HM13 and imprinted gene SNRPN; and treating the subject by administration of medication or other treatment in accordance with the determined level of malignancy of said thyroid tumor; wherein the total expression (TE) of each of the imprinted genes HM13 and SNRPN, the biallelic expression (BAE) of each of the imprinted genes HM13 and SNRPN, and the multiallelic expression (MAE) of each of the imprinted genes HM13 and SNRPN are calculated by the following formula:TE = (b+c+d)/(a+b+c+d)x 100%;BAE=c/(b+c+d)x100%;MAE =d/(b+c+d)x100%;wherein, a represents the number of microscopically observed cells each of which has no mark in the nucleus of the cell after the staining, b represents the number of microscopically observed cells for each of which there is one red/brown mark in the nucleus of the cell after the staining, c represents the number of microscopically observed cells for each of which there are two red/brown marks in the nucleus of the cell after the staining, and d represents the number of microscopically observed cells for each of which there are more than two red/brown markers in the nucleus of the cell after the staining.
3. The method according to claim 1, wherein the biallelic expression of each of the imprinted genes and the multiallelic expression of each of the imprinted genes is classified into 5 grades.
Reference app# 18509538 does not teach calculating changes of an expression of the loss of imprinting of the imprinted genes and an expression of the copy number variation of the imprinted genes of claim 1. However, this limitation is taught by Fan.
Fan teaches calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes with “The method of claim 1, wherein said level of methylation in the biological sample is decreased in comparison to the reference level.” (claim 10 of Fan). This corresponds to the claim limitation of loss of imprinting.; “The present invention relates to conditions characterized by differentially methylated genomic CpG dinucleotide sequences and, in particular, to diagnostic and prognostic methods that exploit the presence of such genomic DNA sequences that exhibit altered CpG methylation patterns.” (para. [0003]). This corresponds to the claim limitation of expression of the copy number variation of the imprinted genes; “The genomic targets and nucleic acid probes provided by the present invention are set forth in Table 1, below, and provide diagnostic and prognostic tools based on their ability to detect differential methylation of selected genomic CpG dinucleotide sequences associated with cancer. In the methods provided by the invention, the genomic targets and nucleic acid probes capable of detecting markers located within the genomic targets can be employed to detect altered levels of methylation of genomic CpG dinucleotide sequences in a biological sample compared to a reference level. Furthermore, the methods of the invention allow for use of the genomic markers and nucleic acid probes for the determination of methylation patterns, which are represented by differential methylation of selected genomic CpG dinucleotide sequences that serve as markers in particular sets or subsets of genomic targets. In embodiments directed to the detection of methylation patterns, it is possible to diagnose or predict the susceptibility of an individual to a specific tumor-type based on the correlation between the pattern and the tumor type.” (para. [0055]) and with “After PCR, a thermal melt profile was performed to examine the homogeneity of PCR amplicons. Each DNA sample was analyzed in duplicate and the mean was used for further analysis. The difference of the threshold cycle number (the Ct-values) between the methylated and unmethylated alleles, ΔCt=Ct (unmethylated)−Ct (methylated), was first determined. The percentage of methylated DNA, designated as the methylation level “c”, can be correlated to the ΔCt value through the equation: ΔCt=Log2[c/(1−c)] ((Martens et al., Cancer Res 65: 4101-4117 (20055); Zeschnigk et al.Nucleic Acids Res 32: el25 (2004)). The resulting methylation level thereby equals 2ˆΔCt/(1+2ˆCt). (Para. [0231]).
It would have been prima facia obvious to combine the teachings of copending Application No. 18509538 (reference application) with Fan to arrive at the claimed invention. A person of ordinary skill in the art would have been motivated to modify the method of Copending Application No. 18509538 (reference application) to include calculating changes of an expression of the loss of imprinting of the imprinted genes and an expression of the copy number variation of the imprinted genes as taught by Fan to determine the degree of loss of imprinting and copy number variation. Furthermore, there would have been a reasonable expectation of success, since both Copending Application No. 18509538 (reference application) and Fan teach methods that pertain to the analysis of genomic imprinting.
Claims 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-7 of copending Application No. 17295644 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite calculating expression levels of imprinted genes. Overall, the difference is that the claims of the instant application are broader in scope than the claims of the reference application and thus the instant claims are anticipated by the reference application (see MPEP 804.II.B.2). See table below for a mapping of the claims of the reference application that anticipate the claims of the instant application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Instant app# 17274864, 05/10/2021
Reference app# 17295644, 11/30/2021
1. A grading model for detecting the benign and malignant degree of skin tumors, grading expression states of imprinted genes by calculating changes of an expression of the loss of imprinting of the imprinted genes, an expression of the copy number variation of the imprinted genes and a total expression of the imprinted genes in skin tumors; wherein, the imprinted genes are any one or the combination of at least two of Z1, Z8, Z11 and Z16, the imprinted gene Z1 is Gnas, the imprinted gene Z8 is Dcn, the imprinted gene Z11 is Grb10, and the imprinted gene Z16 is Snrpn/Snurf.
2. The model according to Claim 1, wherein an imprinted gene calculation method of the model comprises: calculating any one of Z1, Z8, Z11 and Z16, preferably any one of Z1, Z8 and Z11, and further preferably any one of Z1 and Z8.
3. The model according to Claim 1 or 2, wherein the imprinted gene calculation method of the model comprises: calculating the combination of any two of the imprinted genes Z1, Z8, Z11 and Z16, and preferably the combination of Z1 and Z8 or the combination of Z8 and Z11.
6. (Currently amended) The typing model of claim 4, wherein the total expressed quantity of each said imprinted gene and the expressed quantity of each said imprinted gene with a copy number variation are calculated using the following formulas: the total expressed quantity of a said imprinted gene = (b+c+d)/(a+b+c+d)x100%; and the expressed quantity of the imprinted gene with a copy number variation = d/(b+c+d) x100%;where a is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show no mark in each said cell nucleus, meaning the imprinted gene is not expressed in those cell nuclei; b is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show one red/brown mark in each said cell nucleus, meaning the imprinted gene is present in those cell nuclei; c is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show two red/brown marks in each said cell nucleus, meaning the imprinted gene is affected by a loss of imprinting in those cell nuclei; and d is the number of cell nuclei that, after corresponding cells are stained with hematoxylin, show more than two red/brown marks in each said cell nucleus, meaning the imprinted gene shows a copy number variation in those cell nuclei.
7. (Currently amended) A method for creating the typing model of claim 4, comprising the steps of: (1) performing in-situ hybridization on samples with known five-year survival rate information, using a probe for the imprinted gene Dcn, of the imprinted gene Peg 10, of (the) imprinted gene Snrpn/Snurf, or of the imprinted gene Trappc9; (2) counting a, b, c, and d under a microscope; calculating a total expressed quantity of the imprinted gene Peg10, Dcn, Snrpn/Snurf, or Trappc9 in each said sample and an expressed quantity of the imprinted gene Peg10, Dcn, Snrpn/Snurf, or Trappc9 with a copy number variation in each said sample according to formulas with which to calculate said expressed quantities; and calculating a product of each said total expressed quantity and a corresponding said expressed quantity corresponding to a copy number variation; and (3) performing a difference analysis, by way of Student's t-test, on the products of the total expressed quantities of the imprinted gene and the expressed quantities of the imprinted gene with a copy number variation so as to create the typing model.
Conclusion
No claims are allowed.
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/K.K./Examiner, Art Unit 1686
/LARRY D RIGGS II/Supervisory Patent Examiner, Art Unit 1686