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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/28/2026 has been entered.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 23-33 remain withdrawn. Claims 17-18 and 22 are pending and are examined on the merits herein.
Response to Applicant’s Amendments
Claim Objections
Claims 17 and 18 were objected to due to minor informalities. In light of Applicant’s amendments to the claims submitted 7/28/2026, these objections have been withdrawn. However, see new grounds of objection below.
35 USC 112(b) Rejections
Claims 17-18 and 22 were rejected for various indefiniteness issues associated with claim 17.
In light of Applicant’s arguments and amendments to the claims submitted 7/28/2026, these rejections have been withdrawn. It is noted that regarding the 35 USC 112(b) Rejection of the phrase “a tumor detection agent or kit,” Applicant’s arguments were persuasive to overcome this rejection.
35 USC 103 Rejections
Claims 17-18 and 22 were rejected under 35 U.S.C. 103 as being unpatentable over Zwarthoff et al. (US 2012/0101023 A1), in view of Pfeifer et al. (US 2009/0305256 A1), in view of Berlin (WO 2007/009755 A2), and in view of Ye et al. (2012).
In light of Applicant’s amendments to the claims, these rejections have been withdrawn, but see new grounds of rejection and “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
Regarding the 35 USC 103 Rejections, Applicant argues that the references as cited in the Final Rejection mailed 1/28/2026 do not teach instant claim 17 as currently amended, particularly as the references do not teach examining one of the tumor sites listed in the claim (Remarks, page 10).
As the combination of Zwarthoff, in view of Pfeifer, in view of Berlin, and in view of Ye is drawn mainly to bladder cancer, as this is the cancer taught in Zwarthoff, this argument is persuasive. This is the basis for the new grounds of rejection recited below.
On page 11 of their Remarks, Applicant discusses potential superior/unexpected qualities associated with the primers claimed in instant claim 17. Namely, the primers exhibit high sensitivity and specificity across an array of cancer assays, encompassing 9 of the 10 claimed cancers (the data for gastric cancer in Example 5 does not appear to have sensitivity and specificity listed, though the results show that STAMP-EP1 methylation is increased in this cancer).
MPEP 716.02 discusses analyses related to allegations of unexpected results. In order to provide sufficient evidence supporting these allegations, Applicant must explain why the results are unexpected and significant, compare the results with those of the closest prior art, and have the results be commensurate in scope with the claimed invention.
Regarding the sensitivity and specificity shown by the claimed primers, said primers are being used to detect methylation of a particular region (named the STAMP-E1 region in the instant disclosure). In the working examples of the instant specification pointed to by Applicant, it appears that in each case, SEQ ID NOs: 13 and 14 are used with pyrosequencing methodology to detect STAMP-EP1 methylation (note that in each working example after Example 3, it states that steps 2-7 of Example 3 were used). That is to say, though the samples may be from different starting material, each example is using the same primers to detect the same sequence in the same general manner. Thus, it is not clear why the results of similar specificity and sensitivity for each of these examples would be particularly unexpected. In other words, the primers are simply well-matched for detecting STAMP-EP1, and it is the increase in STAMP-EP1 methylation that the primers are detecting in each sample. As variations in primer specificity and sensitivity are expected depending on particular primer design (e.g. primer sequence, length, etc.), the fact that certain primers are particularly sensitive and specific is not enough in itself to show unexpected or superior results. To bolster this finding, Applicant must provide additional evidence. For example, a showing that primers that show characteristics similar to the instant primers are uncommon in the art, or that for STAMP-EP1, developing primers that act as the claimed primers do is particularly difficult or troublesome. This relates to the comparison with the closest prior art requirement described in MPEP 716.02, which Applicant does not appear to have addressed in their current remarks.
Regarding the scope of the claimed invention versus the results presented by Applicant, though claim 17 does encompass detecting up to ten tumors, it also comprises only detecting a single tumor. Additionally, though pyrosequencing may be used, this is not a requirement in the instant claims. Thus, the results of the working examples are not currently commensurate in scope with the claimed invention.
Thus, these arguments are not considered persuasive.
Finally, on page 12 of their Remarks, Applicant argues that there is no motivation provided in the obviousness rejection for arriving at the claimed primers, particularly discussing para. 31 of the Final Rejection. Though the 35 USC 103 Rejections below are new grounds of rejection, the following rationale is still considered relevant. As noted above, the claimed SEQ ID NOs are not currently considered to produce unexpected or superior results. Additionally, the claimed SEQ ID NOs are simply part of larger, known sequences that are successfully detected in the prior art (see SEQ ID NOs: 372 and 694 of Berlin). As methods of primer design are known, and are readily both possible and available for the ordinary artisan (see Ye), any possible primer sequences that can be developed to detect the known sequences could be made. This, combined with reasoning to detect said sequences, is the basis for the previous obviousness rejection. In said rejection, Zwarthoff and Pfeifer teach that SIX6 methylation is implicated in bladder cancer and provide motivation for SIX6 detection, while Berlin teaches specific sequences to detect SIX6 and Ye provides insight on primer design.
Thus, while the combination of references presented below is not the same as was presented in the Final Rejection, similar rationale is used and is considered proper.
Claim Objections
Claim 17 is objected to because of the following informalities: in the detecting step, it is recommended that “detecting a modification on a CPG site of a polynucleotide” read “detecting modifications on CPG sites of a polynucleotide,” as in the wherein clause beneath this step and in claim 22, multiple modifications are recited. Additionally in the detecting step, line 3 reads “amplifying human genomic DNA treated using primers” but should read “amplifying treated human genomic DNA using primers” to clarify that the treated DNA described earlier in the claim must be amplified and that this DNA must be human genomic DNA. Finally, in the final wherein clause, the “from a group consisting of” language is recommended to read “from the group consisting of” and the “or renal cancer” should read “and/or renal cancer” as one or more of the listed tumor types may be used. Appropriate correction is required.
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.
Claims 17-18 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Lofton-Day et al. (WO 2005/001141 A2; cited by Applicant’s IDS) and in view of Ye et al. (2012; cited in a previous action).
Lofton-Day teaches an analysis of methylation in the detection of colorectal cell proliferative disorders (Abstract). Said colorectal cell proliferative disorder can be a colorectal carcinoma (page 9, para. 2). Page 9, para. 4 states the general method of contacting genomic DNA isolated from cells from blood with a reagent to distinguish between methylated and non-methylated CpG sites and using this information to detect the colorectal cell proliferative disorder. The method can be used to analyze a gene, and the gene analyzed can be SIX6 (page 10, para. 2). The reference states that, “the method characterised in that at least one nucleic acid, or a fragment thereof, from the group consisting of SEQ ID NO:1 to SEQ ID NO:535 is/are contacted with a reagent or series of reagents capable of distinguishing between methylated and non-methylated CpG dinucleotides within the genomic sequence, or sequences of interest,” (page 10, para. 4). Pages 21-22 of the reference discuss the use of bisulfite as a reagent, specifically to assess CpG sites. Page 25, para. 4 specifically states that methylation specific PCR can be used, where bisulfite treatment is followed by amplification with primers for both methylated and non-methylated sequences. This method can also involve the use of specific probes, and these components can be found in a “typical MSP-based kit,” (page 25, para. 4). Pages 29-30 similarly note that when using a method of the invention to detect colon cancer, kits can be used that include primers and other components needed for hybridization, amplification, or detection reactions.
SIX6 is associated with SEQ ID NO: 20 in Lofton-Day, with SEQ ID NOs: 342 and 458 being associated with bisulfite treatment for this gene (Table 3, page 234). Both of these latter sequences contain instant SEQ ID NOs: 13 and 14. See the alignments below:
Instant SEQ ID NO: 13 with SEQ ID NO: 342 of Lofton-Day
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79
371
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Greyscale
Instant SEQ ID NO: 14 with SEQ ID NO: 342 of Lofton-Day
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91
358
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Greyscale
Instant SEQ ID NO: 13 with SEQ ID NO: 458 of Lofton-Day
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78
368
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Greyscale
Instant SEQ ID NO: 14 with SEQ ID NO: 458 of Lofton-Day
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77
365
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Greyscale
Page 11, para. 3 of Lofton-Day notes that SEQ ID NOs: 342 and 458 can be used for distinguishing methylated and non-methylated CpG dinucleotide sequences, and page 12, para. 1 notes that primers hybridize to these sequences.
Regarding the specific sample limitations of instant claims 17 and 18, page 9, para. 4 of Lofton-Day notes using cells from blood. However, page 11, para. 2 notes that tissue or cells can generally be used. Page 14, para. 3 notes that data from colon tumor samples is shown in Figure 36, and page 183, para. 1 states that in Example 11, DNA was specifically prepared and extracted from colon tumor samples. Thus, Lofton-Day teaches that their methods can be used by extracting DNA from tumor samples (which would naturally contain tumor cells). Therefore, it would be prima facie obvious that tumor samples could be used in the method of Lofton-Day described above, as this would be a simple substitution of the blood sample taught on page 9, para. 4 of the reference. 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.” Changing the type of sample that the genomic DNA is extracted from would not change the bisulfite, amplification, or methylation analyses of Lofton-Day, and so with either sampling method, the results would simply depend on SIX6 expression, and are thus considered predicable.
Ye teaches the use of the publicly available tool Primer-BLAST, which is able to design target-specific PCR primers (Abstract). This method is flexible, user-friendly, and fast compared to other design tools (pages 9-10, “Conclusions”).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to create primers consisting of instant SEQ ID NOs: 13 and 14 using the teachings of Lofton-Day and Ye, and to use these sequences to amplify and detect the SIX6 gene in the method of Lofton-Day to perform the method described by instant claim 17. The teachings of Ye indicate that software for PCR primer design is available and can be used by the ordinary artisan to obtain primers suitable for amplifying a known target sequence (page 2, column 2, para. 2). In view of the above, the ordinary artisan would have been motivated to use the publicly available software disclosed in Ye and the known SIX6 gene sequences described by Lofton-Day to design primers for use in the method of Lofton-Day, and in the absence of unexpected results, the claimed primers (instant SEQ ID NOs: 13 and 14) simply represent the result of an obvious series of steps. Lofton-Day also notes that their methods involve the design of hybridization sequences (e.g. page 162, “1.1.2 Hybridization,”), providing an additional reasonable expectation of success that such primers could be designed.
Thus, claims 17-18 are prima facie obvious over Lofton-Day in view of Ye.
Regarding claim 22, Lofton-Day teaches that bisulfite treatment results in the formation of 5-methylcytosine (page 21, paras. 5-6 and page 23, para. 1, for example), and thus this treatment results in 5-methylation as claimed.
Thus, claim 22 is prima facie obvious over Lofton-Day in view of Ye.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/F.F.G./Examiner, Art Unit 1681
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
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