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 .
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claim 21 has been added. Claims 2-4, 7, 11-13, and 17-18 remain withdrawn. Claims 1, 5-6, and 19-21 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Specification Objection
The specification was objected to because the priority paragraph was incomplete. In light of Applicant’s amendments to the specification submitted 11/18/2025, this objection has been withdrawn.
Claim Objections
Claims 1, 5, and 19-20 were rejected for various informalities. In light of Applicant’s amendments to the claims submitted 11/18/2025, these objections have been withdrawn. See also new grounds of objection below.
35 USC 112(b) Rejections
Claims 1, 5-6, and 19-20 were rejected for various indefiniteness issues. These rejections have been maintained-in-part. See “Response to Applicant’s Arguments” and new grounds of rejection below.
35 USC 102 Rejections
Claims 1, 5-6, and 19-20 were rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sukumar et al. (US 2015/0094222 A1). In light of Applicant’s amendments to the claims submitted 11/18/2025, these rejections have been withdrawn, but see new grounds of rejection below.
Double Patenting
Claims 1, 5, and 19-20 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 8 of U.S. Patent No. 10,450,609 B2 in view of US 8,062,849 B2. In light of Applicant’s amendments to the claims submitted 11/18/2025, these rejections have been withdrawn, as none of the explicitly required genes in instant claim 1 are taught by the ‘609 patent.
Claims 1, 5-6, and 20 were rejected on the ground of nonstatutory double patenting as being unpatentable over claim 32 of U.S. Patent No. 8,062,849 B2. In light of Applicant’s amendments to the claims submitted 11/18/2025, these rejections have been withdrawn, as none of the explicitly required genes in instant claim 1 are taught by the claims of the ‘849 patent. It is noted that in the Non-Final Rejection, CCND2 is taught as being recited in the ‘849 patent, but the QM-MSP primer and probe sequences used for this gene in the ‘849 patent do not precisely match those used in the instant claims.
Response to Applicant’s Arguments
Regarding the 35 USC 112(b) Rejection over claim 19, Applicant argues that cMethDNA primer and probe sets are defined by the instant specification because said specification incorporated by reference several patents/applications in their entirety which discuss said primers and probes (Remarks, page 10). Of the patents and applications cited, US 8,062,849 B2 and US 9,416,404 B2 do not discuss cMethDNA, and US 10,450,609 B2 does discuss cMethDNA but does not specifically define “cMethDNA primer and probe sets”, nor does application 16/601,269. To “specifically define” a term requires more than a mere mention – there must be a sentence that specifically states the meaning of the term as used in the particular patent/application, where this meaning applies to all inventive embodiments. The indefiniteness rejection of claim 19 does not claim that the instant application has no support for the use of cMethDNA primers and probes generally, but argues that in the context of the instant claims, the scope of “cMethDNA primer and probe sets” is not defined, and the specification does not elucidate this scope. Thus, this rejection is reiterated below.
Regarding the 35 USC 102 Rejections, the Examiner agrees that Sukumar et al. (US 2015/0094222 A1) does not meet all of the limitations of newly amended claim 1, particularly the new requirement that at least one of the examined genes be APC, CCND2, CDKL2, EVI1, or ZNF671. This is the basis for the withdrawal of these rejections.
Claim Objections
Claim 1 is objected to because of the following informalities: in line 2, the “a” before “breast tissue samples” should be removed. In the final line of step a), “genes coprises” should read “genes comprise.” Finally, in line 3 of step c), the “a” before “normal/benign” should be removed. Appropriate correction is required.
Claim 6 is objected to because of the following informality: a comma should be inserted after “tissues” and before “or core biopsies.” Appropriate correction is required.
Claim 19 is objected to because of the following informality: “wherein at step a)” should read “wherein in step a).” Appropriate correction is required.
Claim 21 is objected to because of the following informality: in line 1 “is deteced between” should read “is detected in between.” Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 1, 5-6, and 19-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected because the scope of the phrase “two or more QM-MSP primers and probes” is not clear. In the instant specification, “QM-MSP primers and probes” are specified as those in Table 1 (see para. 51), but the sequences labeled STD appear to be cMethDNA sequences, which would not be included in standard QM-MSP (see the rejection of claim 19 below). It will be interpreted as though the STD primers and probes are not required to be present in QM-MSP primers and probes, even though they are present in Table 1. This is because of the QM-MSP explanation described in para. 84 of the instant specification, which requires one set of external primers and two sets of internal primers and probes, along with paras. 100-101, which explain cMethDNA methods.
Claims 5-6 and 19-21 are rejected due to their dependence on rejected claim 1.
Claim 19 is also rejected because it is unclear what is included in the “cMethDNA primer and probe sets” and how they are to be used in the context of the QM-MSP primers, probes, and method recited in claim 1. The phrase “cMethDNA primer and probe sets” is not defined by the specification. Paras. 100-101 of the instant specification note that cMethDNA methods use QM-MSP along with STDgene standards, and so the cMethDNA primers and probes are interpreted to be those in Table 1 labeled STD, but this is not explicitly clear. Additionally, claim 19 does not require performing any cMethDNA methods – it simply states that at least one primer and probe set is used in step a), which is a hybridizing step. Therefore, only one gene in claim 1 may have a cMethDNA primer and probe hybridized, and it is unclear how this would be used in the QM-MSP. It is recommended to amend this claim to make the structure of “cMethDNA primer and probe sets” explicit, and to state how these sets are used with the QM-MSP primers, probes, and methods of claim 1.
Claim 20 is also rejected because the phrase “sets of different CpG regions of genes” is unclear. In claim 1, from which this claim depends, no “sets” of CpG regions are claimed. It is therefore unclear whether a set refers to a particular group of CpG regions in one gene, all regions for a single gene, or both. It will be interpreted as though a “set” refers to a particular group of CpG regions for a single gene. It is recommended to amend this language to be similar to that used in claim 5 – namely “wherein hypermethylation is detected in specific CpG regions of 3 to 10 genes selected from the group consisting of…”
Claim 21 is also rejected because the phrase “sets of different CpG regions of genes” is unclear. In claims 1 and 5, from which this claim depends, no “sets” of CpG regions are claimed. It is therefore unclear whether a set refers to a particular group of CpG regions in one gene, all regions for a single gene, or both. It will be interpreted as though a “set” refers to a particular group of CpG regions for a single gene. It is recommended to amend this language to be similar to that used in claim 5 – namely “wherein hypermethylation is detected in specific CpG regions of 3 to 10 genes selected from the group consisting of…”. Additionally, the claim requires the use of 3-10 sets of CpG regions, and then measures “any 3 or more” of a set of 20 genes. It is unclear how more than 10 genes could be examined when the claim requires that a maximum of 10 sets of CpG regions be examined. Finally, the claim is unclear because it appears to recite a Markush group due to the “selected from the group consisting of” language, but then “or” appears between the final two gene options in the list. If a Markush group is intended, this “or” should be amended to an “and.”
Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Sukumar et al. (US 2005/0239101 A1).
Sukumar teaches QM-MSP methods for analyzing multiple genes for hypermethylation in association with a condition such as a carcinoma (Abstract). This condition can specifically be breast cancer (para. 32), and the methylation examined focuses on CpG sites (paras. 15, 36, 47-48, 62-64, and 71). QM-MSP was used, with particular primers and probes (paras. 47-49), and Sukumar utilized samples from frozen tissues, ductal lavage material, nipple aspiration fluid, fine needle aspirates, and core tissue biopsies (para. 74; instant claim 6). The genes CCND2 (called cyclin D2 here), RARB, TWIST, RASSF1 (called RASSF1A here), and HIN1 showed hypermethylation in breast cancer samples compared to normal samples (paras. 71, 75, and 77-78, Figures 5-7, and Tables 5-6). The QM-MSP primers and probes specifically used are listed in Tables 1-2 (para. 53), and for RASSF1A, these primers and probes are the same as the QM-MSP primers and probes cited in the instant invention. For RASSF1A, SEQ ID NOs: 3-4 and 19-24 correspond to instant SEQ ID NOs: 153-160, respectively.
Sukumar also teaches the use of APC, and teaches that this gene is associated with breast cancer tissues (para. 180), and particularly that it is hypermethylated in association with cancer tissue (claims 7 and 32). APC was analyzed in several samples from subjects at high risk of developing breast cancer, but were not specifically known to have said cancer (paras. 28-30). Figs. 11-13 detail hypermethylation in this gene in some of these high risk samples. The reference also generally teaches hypermethylation of APC in breast cancer in the art (para. 7). In the QM-MSP primers and probes for APC, also listed in Tables 1 and 2, SEQ ID NOs: 48-49, 67-69, and 64-66, correspond to instant SEQ ID NOs: 12-19, respectively.
Sukumar is not clear that replicate samples are used in their analysis, which would lead to multiple samples being used per subject, as required by instant claim 1. However, the reference does teach in para. 29 that to generate the data displayed in Figure 12 (which shows data from patients at high risk of breast cancer), ductal lavage fluid from the breasts of subjects were sampled multiple times longitudinally. Therefore, it would be prima facie obvious that the same longitudinal sampling could be applied to breast cancer samples/subjects, resulting in multiple samples being taken per subject over time and analyzed for methylation in the genes described by Sukumar. The ordinary artisan would be motivated to do this to determine how the breast cancer is progressing, and if particular treatments appear to be effective. In combination with other methods, these longitudinal samples can also show methylation patterns associated with advancing stages of disease, which could then be used as a diagnostic tool. There would be a reasonable expectation of success as Sukumar already teaches utilizing multiple samples per subject, and this would not involve a change to the actual methylation process/analysis for each sample.
Thus, claims 1 and 6 are prima facie obvious over Sukumar.
Claims 5 and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Sukumar et al. (US 2005/0239101 A1), hereby referred to as Sukumar 1, in view of Sukumar et al. (US 2015/0094222 A1), hereby referred to as Sukumar 2.
Sukumar 1 teaches the method of claims 1 and 6, as described above. However, this reference does not teach the instant QM-MSP primers and probes associated with more than two of the claimed genes.
Sukumar 2 teaches QM-MSP and cMethDNA methods (Abstract). Para. 24 of Sukumar 2 states that the primers listed in Table 1 may be used in detecting primary breast cancer. Table 1 lists primers for AKR1B1, ARHGEF7, COL6A2, GPX7, HIST1H3C, HOXB4, MAL, RASGRF2, RASSF1 (called RASSF1A in Sukumar 2), TM6SF1, TMEFF2, TWIST1 (called TWIST in Sukumar 2), GAS7C, and HIN1. These primers comprise the QM-MSP primers and probes, as well as the cMethDNA primers and probes (labeled STD), of the instant invention for the recited genes. Paras. 22-29 explain this method, including how it utilizes CpG sites. Para. 22 also notes that cMethDNA methods include performing QM-MSP with the addition of additional gene standards.
Paras. 61-62 explain detail an embodiment in which breast cancer samples taken from ductal lavage, nipple aspirate fluid, and core biopsies are analyzed with cMethDNA methods. The samples are used to compare methylation of CpG sites in a group of genes comprising the target genes listed above in breast cancer and normal samples, and where the results indicate hypermethylation in the breast cancer samples.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the teachings of Sukumar 2 to add to the genes analyzed in Sukumar 1. By adding additional genes to the analysis of Sukumar 1, this would increase the accuracy and diagnostic power of the method, which would improve breast cancer detection and patient outcomes. As these genes (and their associated primers and probes) are known by Sukumar 2, and this reference teaches their use in a QM-MSP assay as is done in Sukumar 1, there would be a reasonable expectation of success.
It is noted that some of the genes of Sukumar 1 and Sukumar 2 overlap, but use slightly different QM-MSP primers and probes (e.g. HIN1 and TWIST). As these references show that either set of QM-MSP primers and probes is capable of amplifying and detecting the target gene, using either set would amount to simple substitution, and would be possible for the ordinary artisan. MPEP 2143 I B states, “The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.” The use of either the QM-MSP primers and probes of Sukumar 1 or Sukumar 2 would be predictable in that it would result in a quantifiable amount of methylation produced for each target gene, and so it would be prima facie obvious to use the specific QM-MSP primers and probes taught by Sukumar 2 that coincide with those of the instant invention in Sukumar 1 in view of Sukumar 2 (instant claims 5 and 20-21).
Thus, claims 5 and 20-21 are prima facie obvious over Sukumar 1 in view of Sukumar 2.
Specifically regarding claim 19, Sukumar 2 teaches that cMethDNA methods are a slight modification of QM-MSP methods that involve additional standards, where these methods allow for quantitative detection of tumor DNA in fluid samples in very small amounts (para. 9). Unmethylated DNA also does not affect cMethDNA results (para. 7). Figure 3 shows a comparison of QM-MSP to cMethDNA methods, and it is clear that more methylation is captured with the cMethDNA modification (para. 16). Therefore, it would be prima facie obvious to use the cMethDNA primer and probe sets of Sukumar 2 in Sukumar 1 in view of Sukumar 2, to increase methylation yields and produce more accurate diagnostic results. Sukumar 2 shows a clear improvement in cMethDNA methods compared to QM-MSP methods, motivating the ordinary artisan. There would be a reasonable expectation of success as Sukumar 2 already teaches the successful use of cMethDNA primer and probes sets, and teaches that these methods are simply an extension of QM-MSP methods, showing their compatibility for use together.
Thus, claim 19 is prima facie obvious over Sukumar 1 in view of Sukumar 2.
Conclusion
No claims are currently allowable.
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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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681