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 Group I, claims 25-33 & 42, and the species elections of MROH6 gene in claims 25, 27, & 28, of MROH6 gene by using the primers of SEQ ID NO: 10 and SEQ ID NO: 11 and the probe sequence of SEQ ID NO: 28 in claim 29, and of blood sample in claim 31 in the reply filed on 09/25/2025 is acknowledged. The species of HOXB4 gene is rejoined with MROH6 gene in claims 25, 27, & 28 and the species of HOXB4 gene by using primers of SEQ ID NO: 12 and SEQ ID NO: 13 and the probe sequence of SEQ ID NO: 29 is rejoined with MROH6 primers and probe in claim 29. Group II, claims 34-41, 43, & 44, and claim 33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
A first office action on the merits of claims 25-32 & 42 is set forth herein and claims 33-41, 43, & 44 are withdrawn from consideration.
Information Disclosure Statement
Only the abstract of the reference in the IDS submitted on 01/26/2023 that is lined through, under the foreign patent documents section, was considered because an English copy of the full documents were not provided.
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 25-32 & 42 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.
Regarding claim 25, the claim recites the limitation “by determination of the level of methylation of at least one gene” in lines 2-3 of the claim and there is insufficient antecedent basis for this limitation in the claim. (In addition, although directed to non-elected species, applicant is made aware that the recitation of “chr7: 129425301 gene and chr20: 1784267 gene” in line 4 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific gene. A gene refers to a segment of DNA and yet the recitation of “chr7: 129425301” and “chr20: 1784267” refer to singular positions in the genome).
Regarding claim 26, the recitation of “consisting in an hypermethylation is indicative of lung cancer” in line 2 of the claim is unclear how the level of methylation can consist in hypermethylation and how this relates to indication of lung cancer. Does this recitation refer to a level of methylation that is hypermethylated indicates a presence of lung cancer?
Regarding claim 27, the term “superior” in line 8 of the claim is a relative term which renders the claim indefinite. The term “superior” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, it is unclear how to determine that a level of methylation of a gene that is superior a level of methylation in a control sample. (In addition, although not elected, applicant is made aware of the recitation of “chr7: 129425301 gene and chr20: 1784267 gene” in line 5 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific gene. A gene refers to a segment of DNA and yet the recitation of “chr7: 129425301” and “chr20: 1784267” refer to singular positions in the genome).
Regarding claim 28, the recitation of “the nucleotide region of SEQ ID NO: 1 in the MROH6 gene, the nucleotide region of SEQ ID NO: 2 in the HOXB4 gene… the nucleotide region of SEQ ID NO: 9 in the MPR3 gene” in lines 2-8 of the claim is unclear. Does it refer to only that particular SEQ ID NO:, to particular positions within that SEQ ID NO:, or does it include nucleotides within the genome that exist on either end of the SEQ ID NO:? (In addition, although directed to non-elected species, applicant is made aware that the recitation of “chr7: 129425301 gene and chr20: 1784267 gene” in line 4 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific gene. A gene refers to a segment of DNA and yet the recitation of “chr7: 129425301” and “chr20: 1784267” refer to singular positions in the genome).
Regarding claim 29, the recitation of “the level of methylation is determined in at least one the gene selected from” in lines 1-2 of the claim is unclear what “the gene” is referring to. Is “the gene” referring to determining a level of methylation in a specific gene? Is “the gene” a typo and meant to recite “…determined in at least one gene selected from”? (In addition, although directed to non-elected species, applicant is made aware that the recitation of “chr7: 129425301 gene and chr20: 1784267 gene” in line 4 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific gene. A gene refers to a segment of DNA and yet the recitation of “chr7: 129425301” and “chr20: 1784267” refer to singular positions in the genome).
Regarding claim 30, the recitation of “Next Generation Sequencing (NGS), quantitative PCR (qPCR) or digital PCR (dPCR)” in lines 2-3 of the claim is unclear if qPCR and dPCR are part of the same method to determine the level of methylation or if this is the result of a typo and should read “Next Generation Sequencing (NGS), quantitative PCR (qPCR), or digital PCR (dPCR)”.
Regarding claim 31, the recitation of “…stools, plasma or blood sample” in line 2 of the claim is unclear if plasma and blood sample is a part of the same biological sample type or if this is the result of a typo and should read “…stools, plasma, or blood sample”.
Regarding claim 42, the recitation of “A method for predicting the clinical outcome of a patient suffering of lung cancer comprising the step of” in lines 1-2 of the claim is unclear as multiple steps, steps a)-(c), are recited in the claim and not just a step. (In addition, although directed to non-elected species, applicant is made aware that the recitation of “chr7: 129425301 gene and chr20: 1784267 gene” in line 4 of the claim is unclear as to how “chr7: 129425301” and “chr20: 1784267” refer to a specific gene. A gene refers to a segment of DNA and yet the recitation of “chr7: 129425301” and “chr20: 1784267” refer to singular positions in the genome).
Claim 32 is rejected due to its dependence on claim 25.
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 25-28, 30-32, & 42 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation/law of nature and an abstract idea without significantly more. This judicial exception is not integrated into a practical application and the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons set forth below.
35 U.S.C. § 101 requires that to be patent-eligible, an invention (1) must be directed to one of the four statutory categories, and (2) must not be wholly directed to subject matter encompassing a judicially recognized exception. M.P.E.P. § 2106. Regarding judicial exceptions, “[p]henomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972); see also M.P.E.P. § 2106. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, 561 U.S. 593, 601 (June 28, 2010) and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 2354 (2014). See also Myriad v Ambry, CAFC 2014-1361, -1366, December 17, 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66, 71 (2012). “[L]aws of nature, natural phenomena, and abstract ideas” are not patentable. Dia-mond v. Diehr, 450 U. S. 175, 185 (1981); see also Bilski v. Kappos, 561 U. S. at 601 (2010).
Claims Analysis:
As set forth in MPEP 2106, the claims have been analyzed to determine whether they are directed to one of the four statutory categories (STEP 1).
The instant claims are directed to [methods/products] and therefore are directed to one of the four statutory categories of invention.
The claims are then analyzed to determine if they recite a judicial exception (JE) (STEP 2A, prong 1) [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)].
The claimed invention recites a method for diagnosing lung cancer or relapse of lung cancer and a method for predicting the clinical outcome of a patient suffering of lung cancer through determination of the level of methylation of at least one gene selected from a group and indicating lung cancer if level of methylation is hypermethylated or predicting the clinical outcome. This recitation is a natural correlation between level of methylation and indication of lung cancer. With regard to the natural correlation, as in Mayo, the relationship is itself a natural process that exists apart from any human action. The claimed invention also recites “determination of the level of methylation”, “indicative of lung cancer”, “comparing the level of methylation in (a) with the level of methylation for the same gene(s) in a control sample”, and “comparing the level of methylation of the selected gene(s) to a reference value” which is a recitation of an abstract idea because it encompasses conclusions and determinations which can occur entirely within the mind. It is therefore determined that the claims are directed to judicial exceptions.
The claims are then analyzed to determine whether they recite an element or step that integrates the JE into a practical application (STEP 2A, prong 2) [Vanda Pharmaceuticals Inc., v. West-Ward Pharmaceuticals, 887 F.3d 1117 (Fed. Cir. 2018)].
The claims recite steps of determining/assessing the level of methylation of at least one gene from a group through NGS or PCR and comparing the level of methylation of the selected at least one gene to a control, however, this does not integrate the JE into a practical application because it is a mere data gathering step to use the correlation and does not add a meaningful limitation to the method.
In the absence of steps or elements that integrate the JE into a practical application, the additional elements/steps are considered to determine whether they add significantly more to the JE either individually or as an ordered combination, to “’transform the nature of the claim’ into a patent eligible application” [Mayo Collaborative Services v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1293 (2012), Alice Corp. Pry. Ltd. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014)] (STEP 2B).
In the instant situation, the steps of detecting the level of methylation in at least one gene are generally recited and do not provide any particular reagents that might be considered elements that transform the nature of the claims into a patent eligible application because no specific elements/steps are recited. This step is not only a mere data gathering step, but the general recitation of detection of known nucleic acids is well understood, routine, and conventional activity (See MPEP 2106.05(d)(II)). Applicant is reminded that in Mayo, the Court found that “[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself." Further "conventional or obvious" "[pre]solution activity" is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law”. Flook, 437 U. S., at 590; see also Bilski, 561 U. S., at ___ (slip op., at 14) (“[T]he prohibition against patenting abstract ideas ‘cannot be circumvented by’ . . . adding ‘insignificant post-solution activity’” (quoting Diehr, supra, at 191–192)). The Court also summarized their holding by stating “[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.” Therefore these limitations/steps do not “‘transform the nature of the claim’ into a patent-eligible application.’” Alice, 134 S. Ct. at 2355 (quoting Mayo, 132 S. Ct. at 1297).
When viewed as an ordered combination, the claimed limitations are directed to nothing more than the determination that a natural correlation/phenomena exists. Any additional element consists of using well understood, routine and conventional activity, and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.
Accordingly, it is determined that the instant claims are not directed to patent eligible subject matter.
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)(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.
Claim(s) 25, 28, & 30-32 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim (WO 2019/103421 A2, May 2019), machine translation obtained from Science & Technical Information Center (STIC).
Regarding claim 25, it is noted that claim 25 recites a method for diagnosing lung cancer or diagnosing relapse of lung cancer in a biological sample of a patient in the preamble of the claim with one active step comprising determining the level of methylation of at least one gene selected from a group. Therefore, for the purposes of this rejection, it is interpreted that the claim require the limitations of detecting a level of methylation of at least one gene selected from a group, including the MROH6 gene, as the preamble of a method for diagnosing lung cancer or diagnosing relapse of lung cancer is an intended use and not a limitation of the claim (see MPEP §2111.02(II)).
Kim teaches a method for assessing the prognosis or risk stratification of liver cancer through measuring the methylation level of at least one CpG site including the CpG site(s) of SEQ ID NO: 4 located from 144649774 to 144651774 on chromosome 8, comprising SEQ ID NO: 1 of the instant application (MROH6 gene) from positions 821-1060 on SEQ ID NO: 4 of Kim (determination of the methylation level of at least one gene selected from MROH6) (abstract lines 1-3; paragraph [49] lines 1-3; paragraph [50] lines 1-5; paragraph [55] lines 1-4; paragraph [56] lines 1-6; paragraph [74] lines 1-5; Table 1; Table 2).
Regarding claim 28, Kim teaches a method for assessing the prognosis or risk stratification of liver cancer through measuring the methylation level of at least one CpG site including the CpG site(s) of SEQ ID NO: 4 located from 144649774 to 144651774 on chromosome 8, comprising SEQ ID NO: 1 of the instant application (MROH6 gene) from positions 821-1060 on SEQ ID NO: 4 of Kim (level of methylation is determined in at least one nucleotide region selected from the nucleotide region of SEQ ID NO: 1 in the MROH6 gene) (abstract lines 1-3; paragraph [49] lines 1-3; paragraph [50] lines 1-5; paragraph [55] lines 1-4; paragraph [56] lines 1-6; paragraph [74] lines 1-5; Table 1; Table 2).
Regarding claim 30, Kim teaches the method for analyzing the methylation status includes quantitative PCR (qPCR) (paragraph [51] lines 1-5).
Regarding claim 31, Kim teaches the biological sample include blood tissue samples (abstract lines 1-3; paragraph [16] lines 1-6; claim 5 lines 1-5).
Regarding claim 32, Kim teaches assessing the prognosis or risk stratification of liver cancer through measuring the methylation level of at least one CpG site including the CpG site(s) of SEQ ID NOs: 1-15 (the level of methylation of at least two genes is determined simultaneously or sequentially) (paragraph [0008] lines 1-17).
Claim(s) 25, 32, & 42 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cai (Cai et al.; Journal for ImmunoTherapy of Cancer, Vol. 7, pages 1-11, July 2019).
Regarding claim 25, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene (determining the methylation level in a biological sample of the patient of MROH6 gene), comparing to a control, and using the methylome-wide analysis for assessing clinical outcome with PD-L1 treatments (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Regarding claim 32, Cai teaches assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array covering CpG sites across the human whole genome (the level of methylation of at least two genes is determined simultaneously in the biological sample of the patient) (pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-5).
Regarding claim 42, Cai teaches a method for assessing DNA methylation profiles in lung cancer samples through the Infinium HumanMethylation 850K EPIC BeadChip array, in which the 850K encompasses the MROH6 gene (assessing the methylation level in a biological sample of the patient of MROH6 gene), comparing to a control (comparing level of methylation of the selected gene to a reference value), and using the methylome-wide analysis for assessing clinical outcome with PD-L1 treatments (predicting clinical outcome on the basis of the comparison step) (pg. 2 column 1 3rd full paragraph lines 1-15; pg. 3 column 1 1st full paragraph lines 1-24; pg. 3-4 paragraph bridging pg. 3 & 4 lines 1-28; pg. 9 column 1 1st full paragraph lines 1-21; pg. 9 paragraph bridging column 1 & 2 lines 15-29).
Claim(s) 25-28, 30-32, & 42 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tai (EP 2966183 A1), as cited on the IDS dated 01/26/2023.
Regarding claim 25, Tai teaches a method for indicating a biological sample contains a cancer cell derived from lung cancer through analyzing the methylation status and frequency of a CpG site located in the promoter region of HOXB4 (determination the level of methylation of at least one gene selected from HOXB4) (paragraph [0008] lines 1-17).
Regarding claim 26, Tai teaches that the biological sample contains a cancer cell derived from lung cancer when the methylation frequency obtained is higher than a predetermined threshold (hypermethylation is indicative of lung cancer) (paragraph[0008] lines 18-22; paragraph [0044] lines 1-2).
Regarding claim 27, Tai teaches a method for indicating a biological sample contains a cancer cell derived from lung cancer through analyzing the methylation status and frequency of a CpG site located in the promoter region of HOXB4 (assessing in a biological sample of a patient the level of methylation of at least one gene selected from HOXB4) and that the biological sample contains a cancer cell derived from lung cancer when the methylation frequency obtained is higher (superior) than a predetermined threshold when compared to cells of normal tissues or cells of non-cancerous tissues (comparing the level of methylation in HOXB4 with the level of methylation in a control sample) (paragraph [0008] lines 1-22; paragraph [0044] lines 1-2; paragraph [0047] lines 1-8).
Regarding claim 28, Tai teaches a method for indicating a biological sample contains a cancer cell derived from lung cancer through analyzing the methylation status and frequency of a CpG site located in the promoter region of HOXB4 gene in which positions 2874 to 2705 of SEQ ID NO: 1 of Tai comprises SEQ ID NO: 2 of the instant application (level of methylation is determined in at least one nucleotide region selected from the nucleotide region of SEQ ID NO: 2 in the HOXB4 gene) (paragraph [0008] lines 1-17; Table 1; Sequencing Listing SEQ ID NO: 1).
Regarding claim 30, Tai teaches the method for analyzing the methylation status includes quantitative PCR (qPCR) (paragraph 0024] lines 1-3; paragraph [0026] lines 1-2).
Regarding claim 31, Tai teaches the biological sample include blood samples (paragraph [0011] lines 1-4).
Regarding claim 32, Tai teaches indicating a biological sample contains a cancer cell derived from lung cancer through analyzing the methylation status and frequency of a CpG site located in the promoter region of HOXB4 (the level of methylation of at least two genes is determined simultaneously or sequentially) (paragraph [0008] lines 1-17).
Regarding claim 42, Tai teaches a method for obtaining information on lung cancer in a biological sample of a subject through indicating a cancer cell is derived from lung cancer through analyzing the methylation status and frequency of a CpG site located in the promoter region of HOXB4 (assessing in a biological sample of a patient the level of methylation of at least one gene selected from HOXB4) and that the biological sample contains a cancer cell derived from lung cancer when the methylation frequency obtained is higher (superior) than a predetermined threshold when compared to cells of normal tissues or cells of non-cancerous tissues (comparing the level of methylation in HOXB4 to a reference value) in which this information can include prognosis or degree of progression of lung cancer in a subject (predicting the clinical outcome) (paragraph [0008] lines 1-22; paragraph [0042] lines 1-9; paragraph [0044] lines 1-2; paragraph [0047] lines 1-8).
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tai (EP 2966183 A1), as cited on the IDS dated 01/26/2023, in view of Olek (EP 1676927 A2).
The teachings of Tai with respect to claim 25 is discussed above and incorporated herein.
Regarding claim 29, Tai teaches the method for analyzing the methylation status and frequency of a CpG site located in the promoter region of HOXB4 gene comprises a primer set for analyzing the methylation status of at least one CpG sites located in the promoter region of HOXB4 gene in which the base sequence of each primer is appropriately selected by a person skilled in the are based on the base sequence in the promoter region of the gene (developing methylation specific primers based on the base sequence of SEQ ID NO: 1 of Tai for the HOXB4 gene) (paragraph [0008] lines 23-25; paragraph [0053] lines 1-7).
Tai does not teach the primers of SEQ ID NO: 12 and SEQ ID NO: 13 and the probe sequence of SEQ ID NO: 29 for specifically determining the level of methylation of the HOXB4 gene.
Olek teaches a method for providing the chemically modified DNA of genes associated with diseases, including HOX genes indicating in a wide range of diseases including diabetes and cancer, for developing oligonucleotides for detecting the cytosine methylation state in the chemically pretreated DNA for diagnosis of these diseases, in which SEQ ID NO: 145 comprises SEQ ID NO: 12 (from positions 249 to 268) from the instant application, SEQ ID NO: 13 (from positions 347 to 328) from the instant application, and SEQ ID NO: 29 (from positions 301 to 282) from the instant application (paragraph [0004] lines 1-3; paragraph [0018] lines 1-6; paragraph [0021] lines 1-8; Sequence Listing SEQ ID NO: 145). In addition, Olek teaches that this method can be used for diagnosis and therapy of genetic and epigenetic parameters of the cytosine methylation pattern of genes and diseases associated with those genes in an effective manner (paragraph [0018] lines 3-6; paragraph [0021] lines 6-8).
Tai and Olek are considered to be analogous to the claimed invention because they are all in the same field of detection of methylated genes associated with HOX gene in cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of analyzing the methylation status and frequency in the promoter region of the HOXB4 gene using primers in Tai to incorporate the specific methylation primers of SEQ ID NO: 12 and SEQ ID NO: 13 and the probe of SEQ ID NO: 29 as taught in Olek because Olek teaches that doing so would provide a suitable and effective method for detecting cytosine methylation patterns in genes associated with diseases such as cancer. Therefore, it would have been prima facie obvious to one or ordinary skill in the art, prior to the effective filing date, to have constructed primers and probes for analysis of methylated HOXB4, as taught in Tai and Olek, including the claimed primers and probe. Absent secondary considerations, these oligonucleotides are considered obvious in view of the teachings of the cited prior art.
Claim(s) 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kim (WO 2019/103421 A2, May 2019), machine translation obtained from Science & Technical Information Center (STIC), in view of Olek (EP 1676927 A2).
The teachings of Kim with respect to claim 25 is discussed above and incorporated herein.
Regarding claim 29, Kim teaches a method for assessing the prognosis or risk stratification of liver cancer through measuring the methylation level of at least one CpG site including the CpG site(s) of SEQ ID NO: 4 located from 144649774 to 144651774 on chromosome 8, comprising SEQ ID NO: 1 of the instant application (MROH6 gene) from positions 821-1060 on SEQ ID NO: 4 of Kim (determination of the methylation level of at least one gene selected from MROH6) (abstract lines 1-3; paragraph [49] lines 1-3; paragraph [50] lines 1-5; paragraph [55] lines 1-4; paragraph [56] lines 1-6; paragraph [74] lines 1-5; Table 1; Table 2). In addition, Kim teaches the methylation level of at least one CpG site can be analyzed with PCR, methylation specific PCR, real time methylation specific PCR, etc. (developing methylation specific primers based on the sequence of SEQ ID NO: 4 of Kim for the MROH6 gene) (paragraph [22] lines 1-5).
Kim does not teach the primers of SEQ ID NO: 10 and SEQ ID NO: 11 and the probe sequence of SEQ ID NO: 28 for specifically determining the level of methylation of the MROH6 gene.
Olek teaches a method for providing the chemically modified DNA of genes associated with diseases, including diabetes and cancer in which aberrant methylation is present in genes of certain tumors, for developing oligonucleotides for detecting the cytosine methylation state in the chemically pretreated DNA for diagnosis of these diseases, in the DNA sample is chemically treated in such a manner that cytosine bases which are unmethylated are converted to uracil for chemical pretreatment and following this the fragments of chemically pretreated DNA are amplified using sets of primers (paragraph [0004] lines 1-3; paragraph [0007] lines 1-4; paragraph [0018] lines 1-6; paragraph [0021] lines 1-8; paragraph [0031] lines 1-3; paragraph 0035] lines 1-5; paragraph [0047] lines 1-5). In addition, Olek teaches that this method can be used for diagnosis and therapy of genetic and epigenetic parameters of the cytosine methylation pattern of genes and diseases associated with those genes in an effective manner (paragraph [0018] lines 3-6; paragraph [0021] lines 6-8).
Kim and Olek are considered to be analogous to the claimed invention because they are all in the same field of detection of methylated genes associated with aberrantly methylated genes in cancer. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of analyzing the methylation status through measuring the methylation level of at least one CpG site in SEQ ID NO: 4 of the MROH6 gene using primers in Kim to incorporate the specific methylation primers of SEQ ID NO: 10 and SEQ ID NO: 11 and the probe of SEQ ID NO: 28 as taught in Olek because Olek teaches that doing so would provide a suitable and effective method for detecting cytosine methylation patterns in genes associated with diseases such as cancer. Therefore, it would have been prima facie obvious to one or ordinary skill in the art, prior to the effective filing date, to have constructed primers and probes for analysis of methylated MROH6, as taught in Kim and Olek, including the claimed primers and probe. Absent secondary considerations, these oligonucleotides are considered obvious in view of the teachings of the cited prior art.
Conclusion
Claims 25-32 & 42 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAILEY C BUCHANAN whose telephone number is (703)756-1315. The examiner can normally be reached Monday-Friday 8:00am-5:00pm ET.
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/BAILEY BUCHANAN/Examiner, Art Unit 1682
/JEHANNE S SITTON/Primary Examiner, Art Unit 1682