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 .
The amendment filed on 4/15/2026 has been entered.
Claims 1-18 were canceled in the claim set filed on 4/15/2026.
Claims 19-40 were added in the claim set filed on 4/15/2026. No new matter was added.
Applicant’s election without traverse of Group I, Claims 1-9, drawn to a method for diagnosis of presence of colorectal cancer in a subject, prognosis of colorectal cancer patient after surgery, predicting recurrence for a colorectal cancer patient after surgery, and assessing treatment efficacy for a colorectal cancer patient in the reply filed on 10/10/2025 is acknowledged.
Applicant’s election without traverse of the following species in the reply filed on 10/10/2025 is acknowledged:
a) for the tables, Applicant elects Table 3;
b) for the markers, Applicant elects the combination of markers MBSF9, MBSF10, MBSF15, MBSR5, MBSR6, MBSR7, MBSR8, MBSR9, MBSR11 and MBSR16;
c) for the primer sets and probes, Applicant elects the combination of primers and probes for detecting the above combination from Table 4, that is, the combinations of the primer pair of SEQ ID NOs: 10 and 11, the primer pair of SEQ ID NOs: 13 and 14, the primer pair of SEQ ID NOs: 16 and 17, the primer pair of SEQ ID NOs: 19 and 20, the primer pair of SEQ ID NOs: 22 and 23, the primer pair of SEQ ID NOs: 25 and 26, the primer pair of SEQ ID NOs: 28 and 29, the primer pair of SEQ ID NOs: 31 and 32, the primer pair of SEQ ID NOs: 34 and 35, and the primer pair of SEQ ID NOs: 37 and 38, and the combination of probes of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36 and 39;
d) for PCR primers, extension primers and competitors of tables 9-11, Applicant elects the combination of tables 9-11, for they are directed to PCR primers, extension primers and competitors respectively, and should be used together; specifically, for the PCR primers, Applicant elects the combination of all the sequences listed in table 9, i.e., the combination of SEQ ID NOs: 61-90; for the extension primers, Applicant elects the combination of all the sequences listed in table 10, i.e., the combination of SEQ ID NOs: 91-105; and for the competitors, Applicant elects the combination of all the sequences listed in table 11, i.e., the combination of SEQ ID NOs: 106-120.
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 20-23, 25-28, and 30-40 are withdrawn as being drawn to a nonelected Groups II-IV and non-elected species.
Claims 19, 24 and 29 in the claim set filed on 4/15/2026 are currently under examination.
Response to the Arguments
The previously mailed Notice of Non-Compliant Amendment has been addressed in light of applicants Claim amendments.
New grounds of objection are necessitated by amendment to claim 19.
Previous rejection(s) of claim(s) 1-3, 5, and 9 under 35 U.S.C. 112 have been considered but are moot due to claim cancellation. The 35 U.S.C. 112 rejections documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments and arguments on Pg.14. However, upon further consideration of the newly added claims, new grounds of rejection for claims 19, 24 and 29 are made as documented below in the 35 U.S.C. 112 rejection in this office action on Pg. 5-6.
Applicant’s arguments regarding previous notice improper Markush of claim(s) 1-3, 5, and 9 have been considered but are moot due to claim cancellation.
Previous rejection(s) of claim(s) 1-3, 5, and 9 under 35 U.S.C. 103 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. As necessitated by amendment, the 35 U.S.C. 103 rejections of claim(s) 1-3, 5 and 9 documented in the previously mailed non-final have been withdrawn in light of applicants claim amendments. However, upon further consideration and search, new grounds of rejection are made for the newly added claims 19, 24, and 29 as documented below in the 35 U.S.C. 103 rejection in this office action on Pg. 6-21.
The new grounds of rejections for claims 19, 24 and 29 are documented below in this Final Office Action are necessitated by claim amendments filed on 04/15/2026.
Priority
This application is a 35 U.S.C. § 371 national stage filing of International Application No. PCT/CN2020/101835 filed on July 14, 2020, which in turn claims priority to Chinese Application No. 20201045301 1.0, filed May 25, 2020. Acknowledgment is made of applicant' s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of CN202010453011.0 has been submitted of the record on Nov. 23, 2022. An English translation of the CN202010453011.0 is required for the record to be considered for the priority date of May 25, 2020. Accordingly, the priority date of instant claims is determined to be July 14, 2020, the filing date of PCT/CN2020/101835.
Claim Objections
Claim 19 is objected to because of the following informalities: “comprising,” (ln 3). should be amended to “comprising:” Appropriate correction is required.
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 19, 24 and 29 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.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The terms “MBSF9, MBSF10, MBSF15, MBSR5, MBSR6, MBSR7, MBSR8, MBSR9, MBSR11 and MBSR16” in claim 19 are used by the claim to mean “markers”, while the accepted meaning is “mortgage backed securities ETF”, “Mindfulness-Based Stress Reduction” and “region of difference 1 of Mtb”. The terms are indefinite because the specification does not clearly redefine the terms. Claims 24 and 29 depend on claim 19.
Response to Arguments
Applicant's arguments filed 4/15/2026 do not contemplate the rejection of newly added claims 19, 24, and 29 in regards to the terminology of the terms “MBSF9, MBSF10, MBSF15, MBSR5, MBSR6, MBSR7, MBSR8, MBSR9, MBSR11, MBSR16. While the previous rejections are moot since the claims were canceled, new grounds of rejection are made in regards to the newly added claims containing the same indefinite terms.
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.
Claim(s) 19 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Pedersen et al. (“Pedersen”; WO 2019051554 A1, March 21, 2019).
Pedersen discloses “A method and kit for assessing DNA methylation. More particularly, a method of either qualitatively or quantitatively assessing, with improved sensitivity, the cytosine methylation of either fully or partially methylated DNA. The method and kit are useful in a range of applications including, but not limited to, the diagnosis of conditions or monitoring the development of phenotypes which are characterized by cytosine methylation changes.” (Abstract)
Regarding claim 19, Pedersen teaches a method comprising “the present invention provides methods for determining whether a mammal (e.g., a human) has neoplasia, whether a biological sample taken from a mammal contains neoplastic cells or DNA derived from neoplastic cells, estimating the risk or likelihood of a mammal developing a neoplasm, monitoring the efficacy of anti-cancer treatment, or selecting the appropriate anti-cancer treatment in a mammal with cancer. Such methods are based on the determination that many neoplastic cells have a different methylation status than normal cells… ” (Pg. 54 last para.-Pg 55, Para. 1). Pedersen teaches a method comprising “colorectal cancer” (Pg. 73). Pedersen teaches that “the present methods may be used to assess the efficacy of a course of treatment. For example, the efficacy of an anti-cancer treatment can be assessed by monitoring DNA methylation over time in a mammal having cancer. For example, a reduction or absence of methylation in any of the relevant diagnostic sequences in a biological sample taken from a mammal following a treatment, compared to a level in a sample taken from the mammal before, or earlier in, the treatment, indicates efficacious treatment.” (Pg. 55, Para. 3). Pedersen teaches “the method of the present invention is therefore useful as a one-time test or as an on-going monitor of those individuals thought to be at risk of disease development or as a monitor of the effectiveness of therapeutic or prophylactic treatment regimens... Accordingly, the method of the present invention should be understood to extend to monitoring for increases or decreases in methylation levels in an individual relative to their normal level, or relative to one or more earlier methylation levels determined from a biological sample of said individual” (Pg. 55, Para. 4). “neoplasia” and “cancer” read on colorectal cancer. The “a reduction or absence of methylation in any of the relevant diagnostic sequences in a biological sample taken from a mammal following a treatment, compared to a level in a sample taken from the mammal before, or earlier in, the treatment, indicates efficacious treatment.” reads on “wherein when the methylation level in the test subject is higher than the levels in control samples, it is indicated that the subject suffers from colorectal cancer, the subject with colorectal cancer has poor prognosis after surgery, is more likely to recur, or has poor treatment efficacy”. One of skill in the art would expect from the example provided by Pedersen that if reduction or absence of methylation in any of the relevant diagnostic sequences in a biological sample taken from a mammal following a treatment, compared to a level in a sample taken from the mammal before, or earlier in, the treatment, indicates efficacious treatment than an higher levels of methylation of relevant diagnostic sequences indicate poor treatment efficacy.
Pedersen also teaches “the present invention is directed to a method of diagnosing or monitoring a condition in a patient, which condition is characterized by modulation of the methylation of a DNA region of interest, said method comprising... amplifying the DNA sample of step (ii) wherein if one or more of the probes of step (ii)( c) are used, the extension of said primers along said gene effects the detection of said hybridized probe; and (iv) qualitatively or quantitatively analyzing the detection output of step (iii). In one embodiment, said DNA region of interest is a gene target or region thereof. In another embodiment, said gene target is ccfDNA, such as disease specific ccfDNA of any one or more of:… (68) SEPTIN9” (Pg. 56, Para. 1-2). Furthermore, Pedersen teaches a method wherein “GRCh38 hg38 chromosomal coordinates corresponding to the genes… (68) SEPTIN9 chr 17: 77,281,451 -77,499,029” (Pg. 26-27) and “Reference to "genes" should be understood as a reference to all forms of these molecules and to fragments or variants thereof” (Pg. 25 Para. 2). Pedersen teaches a method wherein “Where multiple methylated DNA regions are to be amplified, the skilled person may design multiplexed amplification reactions. This multiplexing may be designed at the level of amplifying both the target and the opposite strands in the one tube or, alternatively, amplifying multiple regions of either the target or opposite strand in a single tube.” (Pg. 53, Para. 4). The “characterized by modulation of the methylation of a DNA region of interest”, “DNA region of interest is a gene target or region thereof”, “gene target is ccfDNA, such as disease specific ccfDNA of any one or more of:… (68) SEPTIN9”” and “SEPTIN9 chr 17: 77,281,451 -77,499,029”” reads on “methylation markers comprise: MBSF9 which corresponds to genomic location hg38 chrl7: 77373456-77373518, MBSF10 which corresponds to genomic location hg38 chrl7: 77373564-77373617, MBSF15 which corresponds to genomic location hg38 chrl7: 77373973-77374049, MBSR5 which corresponds to genomic location hg38 chrl7: 77373985- 77374054, MBSR6 which corresponds to genomic location hg38 chrl7: 77373914-77373986, MBSR7 which corresponds to genomic location hg38 chrl7: 77373843-77373898, MBSR8 which corresponds to genomic location hg38 chrl7: 77373747-77373824, MBSR9 which corresponds to genomic location hg38 chrl7: 77373691-77373745, MBSR11 which corresponds to genomic location hg38 chrl7: 77373520-77373600, and MBSR16 which corresponds to genomic location hg38 chrl7: 77373100-77373185”.
Thus, Pedersen suggests a method for diagnosis of presence of colorectal cancer in a subject, prognosis of a colorectal cancer patient after surgery, predicting recurrence for a colorectal cancer patient after surgery, and assessing treatment efficacy for a colorectal cancer patient, comprising determining methylation level of cell-free DNA by detecting methylation markers in the said cell-free DNA, wherein when the methylation level in the test subject is higher than the levels in control samples, it is indicated that the subject suffers from colorectal cancer, the subject with colorectal cancer has poor prognosis after surgery, is more likely to recur, or has poor treatment efficacy, wherein the detection of DNA methylation markers is performed by multiplex quantitative methylation specific PCR, and wherein said methylation markers comprise: MBSF9 which corresponds to genomic location hg38 chrl7: 77373456-77373518, MBSF10 which corresponds to genomic location hg38 chrl7: 77373564-77373617, MBSF15 which corresponds to genomic location hg38 chrl7: 77373973-77374049, MBSR5 which corresponds to genomic location hg38 chrl7: 77373985- 77374054, MBSR6 which corresponds to genomic location hg38 chrl7: 77373914-77373986, MBSR7 which corresponds to genomic location hg38 chrl7: 77373843-77373898, MBSR8 which corresponds to genomic location hg38 chrl7: 77373747-77373824, MBSR9 which corresponds to genomic location hg38 chrl7: 77373691-77373745, MBSR11 which corresponds to genomic location hg38 chrl7: 77373520-77373600, and MBSR16 which corresponds to genomic location hg38 chrl7: 77373100-77373185.
Lastly, Pedersen teaches that “Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or 5 collectively, and any and all combinations of any two or more of said steps or features” (Pg. 79, Para. 1).
Therefore, the invention as recited in claim 19 is prima facie obvious over the prior art Pedersen et al. One of ordinary skill in the art would have had a reasonable expectation of success given the obviousness of the claim limitations in view of the teachings and the known method of Pedersen et al. It would have been obvious to provide a method for diagnosis of presence of colorectal cancer in a subject, prognosis of a colorectal cancer patient after surgery, predicting recurrence for a colorectal cancer patient after surgery, and assessing treatment efficacy for a colorectal cancer patient, comprising determining methylation level of cell-free DNA by detecting methylation markers in the said cell-free DNA, wherein when the methylation level in the test subject is higher than the levels in control samples, it is indicated that the subject suffers from colorectal cancer, the subject with colorectal cancer has poor prognosis after surgery, is more likely to recur, or has poor treatment efficacy, wherein the detection of DNA methylation markers is performed by multiplex quantitative methylation specific PCR according to the limitations of the instant application claim 19 based on Pedersen et al. (Patent App. Pub. No. WO 2019051554 A1).
The teachings of Pedersen are documented above in the rejection of claims 19 under 35 U.S.C. 103. Claim 29 depends on claim 19.
Regarding claim 29, Pedersen teaches a method wherein “said DNA sample is blood, plasma, serum, saliva, stool, ascites fluid or urine” (Pg. 56, 5th Para from end). Pederson also teaches a method wherein “The DNA that is tested in accordance with the method of the present invention may be isolated from a biological sample. Reference to a "biological sample" should be understood as a reference to any sample of biological material derived from any source, such as animal, plant or bacterial, including but not limited to, cellular material, biofluids (e.g. blood, plasma, serum, urine, saliva, ascites fluid, semen), faeces (stool), tissue biopsy specimens, surgical specimens” (Pg. 30, Para. 5) Thus, Pedersen suggests a method wherein the said sample is selected from body fluids, blood, serum, plasma, urine, saliva, sweat, sputum, semen, mucus, tear, lymphatic fluid, amniotic fluid, interstitial fluid, pulmonary lavage fluid, cerebrospinal fluid, stool and tissues.
Response to Arguments
Applicant's arguments filed 4/15/2026 (Pg. 15-18) with respect to claims 19 and 29 have been fully considered but they do not apply to the new grounds of rejections in view of Pedersen.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Pedersen et al. (“Pedersen”; WO 2019051554 A1, March 21, 2019) as applied to claim 19 above, and further in view of Zhao et al. ("Zhao" Patent App. No. CN-108796080-A, Nov. 13, 2018, English translation provided), Song et al. ("Song" Patent App. No. CN-109207592-A , Jan. 15, 2019 English translation provided), Joern Lewin ("Lewin" Patent App. No. EP-2309005-A1, April 13, 2011), Olek et al. (WO 0218632 A2, 03/07/2002), and Wu et al. (CN-107326089 A, 11/07/2017).
The teachings of Pedersen are documented above in the rejection of claims 19 and 29 under 35 U.S.C. 103. Claim 24 depends on claim 19.
Regarding claim 24, Pedersen teaches a method wherein “Facilitating the interaction of the primers and probes with the target DNA may be performed by any suitable method. Those methods will be known to those skilled in the art.” (Pg. 53, Para. 3) and “primers and probes are methylation specific” (Pg. 56, ln 18).
However, Pedersen does not explicitly teach the limitations of claim 24.
Zhao discloses “a kind of for diagnosis of colorectal carcinoma, detection or the primer and probe of screening group, including the amplimer of SEPT9, the amplimer of Blocker primer and probes and SDC2, Blocker primer and probes. The forward primer of SEPT9 is selected from SEQ ID NO： The reverse primer of any one of 1 ~ 25, SEPT9 are selected from SEQ ID NO: The Blocker primers of any one of 26-51, SEPT9 are selected from SEQ ID NO： Any one in 52-67, the probe of SEPT9 is selected from SEQ ID NO: Any one in 68-90.The forward primer of SDC2 is selected from SEQ ID NO: The reverse primer of any one of 91 ~ 117, SDC2 are selected from SEQ ID NO: The Blocker primers of any one of 118-143, SDC2 are selected from SEQ ID NO: Any one in 144-156, the probe of SDC2 is selected from SEQ ID NO: Any one in 157-174.Compared with the existing technology, the beneficial effects of the invention are as follows: SEPT9 and SDC2 methylation levels are detected simultaneously, and high sensitivity, specificity is good, is used for screening/detection/diagnosis early stage colorectal cancer.” (Abstract)
SEQ ID NO:
Source
Ref Seq ID NO:
Query match
10
Reference ID: CN108796080-A Date: 2018-11-13
26
94%
11
Reference ID: CN108796080-A Date: 2018-11-13
72
100
12
Reference ID: CN108796080-A Date: 2018-11-13
38
100
Regarding claim 24, Zhao teaches a method wherein “the invention adopts the following technical scheme: for colorectal cancer diagnosis, detecting or screening of primer and probe set, comprising amplification primer SEPT9, Blocker primer and probe” (Pg. 2). Zhao teaches SEQ ID NO: 26, 72, and 32, which align with SEQ ID NO: 10, 11, and 12, respectively, with 94%, 100%, 100% sequence identity, respectively. (see table below). Zhao also suggests “it completely can be suitable for various fields suitable for the invention, for people familiar with the art can easily realize the addition of modified, thus without departing from the general concept of claims and equivalent range defined, the present invention is not limited to specific details” (Pg.6).
Thus, Pedersen and Zhao suggest a method wherein the said multiplex quantitative methylation specific PCR uses primers and probes for detecting the DNA methylation markers in claim 19, wherein the primers for detecting MBSF9 comprise the sequences of SEQ ID NO: 10 and SEQ ID NO:11 or sequences with at least 80% identity thereto, and the probe of detecting MBSF9 comprises the sequence of SEQ ID NO: 12 or a sequence with at least 80% identity thereto.
Song discloses “The invention claims a kit for colorectal cancer detection and application thereof, wherein the kit comprises a primer composition, probe composition, primer composition comprises BS-S9-F, BS-S9-R, BS-N4-F, BS-N4-R, BS-SDC2-F, BS-SDC2-R, BS-ACT-F, and BS-ACT-R; probe composition comprises BS-S9-P, BS-N4-P, BS-SDC2-P, and BS-ACT-P. The kit of this invention can be applied to colorectal cancer, detection with high sensitivity and high specificity.” (Abstract).
SEQ ID NO:
Source
Ref Seq ID NO:
Query match
13
Reference ID: CN109207592-A Date: 2019-01-15
17
100
14
Reference ID: CN109207592-A Date: 2019-01-15
17
100
15
Reference ID: CN109207592-A Date: 2019-01-15
17
100
Regarding claim 24, Song teaches a method comprising “a primer composition, probe composition” (Pg. ). Song teaches a method wherein “SEPT9 methylated gene transformed sequence (SEQ ID NO.17)” (Pg. 2). Song teaches SEQ ID NO: 17 which align with SEQ ID NO: 13, 14, and 15, respectively, with 100%, 100%, 100% sequence identity, respectively. (see table below).
Song reviews that previously “only SEPT9-based methylation detection of plasma sample for product of colorectal cancer related gene methylation detection, specificity is high, but the sensitivity cannot reach the clinical requirement” and “The technical problem to be solved by the invention is to overcome the deficiency of the existing technology and claims a kit for colorectal cancer detection, has high sensitivity, high specificity and so on. further claims application of the kit in visible detection cancer… can effectively improve discovery rate of ..cancer” (Pg. 2-3). Song also teaches a method wherein “means of joint detection can effectively improve positive detection rate and reduce false negative and improve the sensitivity of detection” (Pg. 5). Song also suggests “any familiar with the field of the art, and without departing from the essence and technical solution of the invention is capable of using the disclosed method and technical contents for the technical scheme of the invention many variations and modifications, or modification is the equivalent change of equivalent embodiments.” (Pg. 11)
Thus, Pedersen and Song suggest a method wherein the said multiplex quantitative methylation specific PCR uses primers and probes for detecting the DNA methylation markers in claim 19, wherein the primers for detecting MBSF10 comprise the sequences of SEQ ID NO: 13 and SEQ ID NO:14 or sequences with at least 80% identity thereto, and the probe of detecting MBSF10 comprises the sequence of SEQ ID NO: 15 or a sequence with at least 80%
identity thereto.
Lewin discloses “The present invention relates to methods and kits for preserving genomic DNA sequence complexity within chemically and/or enzymatically converted DNA by an enzyme or series of enzymes that adds a methyl group to a cytosine outside of CpG dinucleotide sequences of genomic DNA. Further, the present invention relates to methylation analysis of the genomic DNA.” (Abstract)
Regarding claim 24, Lewin teaches a method wherein “the present invention discloses use of the methods, nucleic acids and kits according to the present invention in the diagnosis, prognosis, monitoring and/or classification of cellular proliferative disorders. In a further embodiment, the said cellular proliferative disorder is… colorectal… proliferative disorder. … Additional embodiments provide use of the methods, nucleic acids, and/or kits for methylation analysis of the genomic DNA, for diagnosis of cancer or other diseases associated with an alteration of the methylation status, and for prognosis of unwanted drug side effects, for differentiating of cell types, tissue, or for examination of cell differentiation, in particular… colorectal… proliferative disorder” (Para. 27). Lewin teaches SEQ ID NO: 110, 114, and 107, wherein one or more align with SEQ ID NO: 16-30 and/or 37-39, with more than 80% sequence identity, respectively (see table below). Furthermore, Lewin teaches a method wherein “The
oligonucleotides or oligomers according to particular embodiments of the present invention are typically used in 'sets,' which contain at least one oligomer for analysis of each of the CpG dinucleotides of a genomic sequence selected from the group consisting… treated nucleic acids according to SEQ ID NO: 36-63 to SEQ ID NO: 92-119” (Para. 101 ). Lewin also suggests “various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description which do not depart from the spirit or scope of the present inventive discovery. Such modifications are also intended to fall within the scope of the appended claims” (Para. 174).
SEQ ID NO:
Source
Ref Seq ID NO:
Query match
16
Reference ID: EP2309005-A1 Date: 2011-04-13
100
84
17
Reference ID: EP2309005-A1 Date: 2011-04-13
100
100
18
Reference ID: EP2309005-A1 Date: 2011-04-13
100
100
19
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
20
Reference ID: EP2309005-A1 Date: 2011-04-13
114
93
21
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
22
Reference ID: EP2309005-A1 Date: 2011-04-13
107
91
23
Reference ID: EP2309005-A1 Date: 2011-04-13
107
89
24
Reference ID: EP2309005-A1 Date: 2011-04-13
107
100
25
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
26
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
27
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
28
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
29
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
30
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
37
Reference ID: EP2309005-A1 Date: 2011-04-13
107
100
38
Reference ID: EP2309005-A1 Date: 2011-04-13
114
100
39
Reference ID: EP2309005-A1 Date: 2011-04-13
114
91
Thus, Pedersen and Lewin suggest a method wherein the said multiplex quantitative methylation specific PCR uses primers and probes for detecting the DNA methylation markers in claim 19, wherein the primers for detecting MBSF15 comprise the sequences of SEQ ID NO: 16 and SEQ ID NO:17 or sequences with at least 80% identity thereto, and the probe of detecting MBSF15 comprises the sequence of SEQ ID NO: 18 or a sequence with at least 80% identity thereto; the primers for detecting MBSR5 comprise the sequences of SEQ ID NO: 19 and SEQ ID NO:20 or sequences with at least 80% identity thereto, and the probe of detecting MBSR5 comprises the sequence of SEQ ID NO:21 or a sequence with at least 80% identity thereto; the primers for detecting MBSR6 comprise the sequences of SEQ ID NO:22 and SEQ ID NO:23 or sequences with at least 80% identity thereto, and the probe of detecting MBSR6 comprises the sequence of SEQ ID NO:24 or a sequence with at least 80% identity thereto; the primers for detecting MBSR7 comprise the sequences of SEQ ID NO:25 and SEQ ID NO:26 or sequences with at least 80% identity thereto, and the probe of detecting MBSR7 comprises the sequence of SEQ ID NO:27 or a sequence with at least 80% identity thereto; the primers for detecting MBSR8 comprise the sequences of SEQ ID NO:28 and SEQ ID NO:29 or sequences with at least 80% identity thereto, and the probe of detecting MBSR8 comprises the sequence of SEQ ID NO:30 or a sequence with at least 80% identity thereto; and the primers for detecting MBSR16 comprise the sequences of SEQ ID NO:37 and SEQ ID NO:38 or sequences with at least 80% identity thereto, and the probe of detecting MBSR16 comprises the sequence of SEQ ID NO:39 or a sequence with at least 80% identity thereto.
Olek discloses “The invention relates to a method for detecting the degree of methylation of a defined cytosine in the sequence context 5´-CpG-3´ of a genomic DNA sample. The first stage involves chemically treating the genomic DNA in such a way that the cytosine bases, but not the 5-methylcytosine bases, are converted into uracil. Parts of the genomic DNA containing the defined cytosine are then amplified. The amplified parts are given a detectable mark and the extent of the hybridization of the amplified parts on the two classes of oligonucleotide is then determined by detecting the mark of the amplified parts. The degree of methylation of the defined cytosine in the genomic DNA sample can be deduced on the basis of the relationship between the marks detected on the two classes of oligonucleotides following the hybridization.” (Abstract)
Regarding claim 24, Olek teaches a method wherein “The present method serves for detecting the methylation level of at least one particular cytosine in the sequence context 5'-CpG-3'of a genomic DNA sample. The method is particularly preferably used for the simultaneous detection of many different methylation positions.” (Pg. 6, Description). Olek teaches “This ensures that primers complementary to bisulfite-treated DNA are used which are capable of amplifying regulatory regions (CpG islands), which can then be subsequently examined for methylation.” (Pg. 8, Description) and “Also among the nucleic acids listed in the sequence listing or significant portions thereof (Seq. ID 1 to Seq. ID 40712) preferably uses at least one for the analysis of a set of genetic and/or epigenetic parameters for the diagnosis of existing diseases or for the diagnosis of predisposition to certain diseases” (Pg.12, Description).
SEQ ID NO:
Source
Ref Seq ID NO:
Query match
31
Reference ID: WO200218632-A2 Date: 2002-03-07
12693
100
32
Reference ID: WO200218632-A2 Date: 2002-03-07
12693
100
33
Reference ID: WO200218632-A2 Date: 2002-03-07
12693
100
Olek teaches a method wherein “The present invention also relates to a set of at least two nucleic acids which are used as primer oligonucleotides for the amplification according to the invention of at least one of the Seq. ID 1 to Seq. ID 40712 or portions thereof… The invention also relates to… oligomer probes for detecting the cytosine methylation state and/or single nucleotide polymorphisms (SNPs) in chemically pretreated genomic DNA according to one of the Seq. ID 1 to Seq. ID 40712 comprising at least ten of the oligomers mentioned above according to the invention.” (Pg. 12, Description). Olek teaches SEQ ID NO: 12693 which aligns with SEQ ID NO: 31, 32, and 33, respectively, with 100%, 100%, 100% sequence identity, respectively. (see table below).
Thus, Pedersen and Olek suggest a method wherein the said multiplex quantitative methylation specific PCR uses primers and probes for detecting the DNA methylation markers in claim 19, wherein the primers for detecting MBSR9 comprise the sequences of SEQ ID NO:31 and SEQ ID NO:32 or sequences with at least 80% identity thereto, and the probe of detecting MBSR9 comprises the sequence of SEQ ID NO:33 or a sequence with at least 80% identity thereto.
Wu discloses “The invention discloses a kind of method and its application that Septin9 gene promoter methylations are detected based on NGS. The method that the present invention provides a kind of detection septin9 gene promoter methylations site methylation state based on high-flux sequence (NGS), comprising methylation sites sequencing depth, methylates and non-depth and the methyl rate of methylating. It is experimentally confirmed: The method of the present invention can accurately, quickly and efficiently detect the methylation state in septin9 gene promoter methylations site, and the method for the present invention is simple to operate, false positive rate is low, cost is relatively low, as a result more directly perceived. There is good application prospect in diagnosis or auxiliary diagnosis colorectal cancer.” (Abstract)
Regarding claim 24, Wu teaches a method wherein “septin9 gene promoter methylation detection primer design and synthesis” (Pg. 4). Wu teaches a method wherein “ In the present embodiment, the test samples are genomic DNA of normal people at Beijing Maigeno Medical Laboratory and a case of fresh tissue of patients with stage III liver metastasis of colorectal cancer (referred to as colorectal cancer patients); … the synthetic methylated bisulfate-treated sequence (Bis-Methyl-Seq plasmid) as a positive control…The positive control … DNA molecule shown in SEQ ID NO: 5” (Pg. 4-5).
Wu teaches a positive control sequence SEQ ID NO: 5 which align with SEQ ID NO: 34, 35, and 36, with 100%, 100%, 100% sequence identity, respectively. (see table below).
SEQ ID NO:
Source
Ref Seq ID NO:
Query match
34
Reference ID: CN107326089-A Date: 2017-11-07
5
100
35
Reference ID: CN107326089-A Date: 2017-11-07
5
100
36
Reference ID: CN107326089-A Date: 2017-11-07
5
100
Thus, Pedersen and Wu suggest a method wherein the said multiplex quantitative methylation specific PCR uses primers and probes for detecting the DNA methylation markers in claim 19, wherein the primers for detecting MBSR11 comprise the sequences of SEQ ID NO:34 and SEQ ID NO:35 or sequences with at least 80% identity thereto, and the probe of detecting MBSR11 comprises the sequence of SEQ ID NO:36 or a sequence with at least 80% identity thereto.
Therefore, Pedersen, Zhao, Song and Lewin suggest a method according to the limitations of claim 24.
Pedersen, Zhao, Song and Lewin are considered to be analogous to the claimed invention because they are in the same field of DNA methylation detection. 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 method f or diagnosis of presence of colorectal cancer in a subject, prognosis of a colorectal cancer patient after surgery, predicting recurrence for a colorectal cancer patient after surgery, and assessing treatment efficacy for a colorectal cancer patient according to the limitations of claim 19, wherein said multiplex quantitative methylation specific PCR uses primers and probes for detecting the DNA methylation markers of SEPTIN 9 as suggested by Pedersen to incorporate the methods wherein detecting methylation comprises the SEQ ID Nos 10-39 as suggested by Zhao, Song and Lewin and provide a method according to the limitations of claim 24. Furthermore, designing of the primers and probes to DNA methylation site regions of interest of SEPTIN 9 are characteristic of nucleic acids of SEPTIN 9 methylation biomarkers which are equivalents to those taught in the art and are considered to require only routine experimentation. The ordinary artisan would have been motivated at the time of filing to pursue known methods of methylation detection in colorectal cancer diagnosis, prognosis and monitoring after surgery or treatment by assessing multiple known methylation site regions of the target gene (SEPTIN 9) using primer and probes comprising known methylation site sequences in multiplex methylation PCR in view of Pedersen, Zhao, Song and Lewin. Doing so would improve methods that enable accurate and sensitive detection of DNA methylation, thereby improving the sensitivity of the applications for DNA methylation analysis, such as diagnosis, prognosis or monitoring of disease. (Pedersen, Pg. 3, Para. 2).
Response to Arguments
Applicant's arguments filed 4/15/2026 (Pg. 15-18) with respect to claim 24 have been fully considered but they do not apply to the new grounds of rejections in view of Pedersen, Zhao, Song, Lewin, Olek, and Wu.
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
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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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