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 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 Claims 23-33 remain withdrawn.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
Claim 18 was objected to for informalities. In light of Applicant’s amendments to the claims submitted 12/11/2025, this objection has been withdrawn, but see new grounds of objection below.
35 USC 112(b) Rejections
Claims 17-18 and 22 were objected to due to various informalities. In light of Applicant’s amendments to the claims submitted 12/11/2025, these rejections have been withdrawn, but see new grounds of rejection below.
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 submitted 12/11/2025, these rejections have been maintained, and see “Response to Applicant’s Arguments” below.
Response to Applicant’s Arguments
Regarding the 35 USC 103 Rejections, Applicant argues that the currently amended claim 17 is directed to a “pan-tumor detection method” that is capable of detecting a wide variety of cancers, and the currently cited references do not address this pan-tumor context (Remarks, pages 9-10).
Firstly, while Applicant has amended the preamble of claim 17 to cite a “pan-tumor detection method,” this alone is considered intended use. This is because the preamble imparts no structural limitations on the claim, particularly when considering the scope of the claim. Claim 17 utilizes “one or more samples” and specifically notes the detection of a single tumor type in the final wherein clause. Thus, the claim does not explicitly require the detection of multiple tumor types, and thus can be directly to detecting a single tumor for a single cancer. See MPEP 2111.02.
Zwarthoff, in view of Pfeifer, in view of Berlin, and in view if Ye teach the detection of bladder cancer (i.e. a urinary system tumor) by analyzing the methylation of the SIX6 gene and utilizing primers of SEQ ID NOs: 13 and 14. Zwarthoff specifically teaches the use of urine samples (paras. 14 and 40), and also teaches the use of urine samples that contain tumor cells (paras. 3 and 41), addressing the newly added limitation of lines 3-4 of claim 17. In addressing the new wherein clause, it is noted that Zwarthoff teaches the use of methylation-specific PCR (para. 66, which was noted in para. 23 of the Non-Final Rejection) and bisulfite sequencing (para. 65). Thus, these references teach all of the limitations of the newly amended claim and fall within the single sample/single tumor examination scope of the claim.
Therefore, Applicant’s arguments are not considered persuasive. The teachings used in the Non-Final Rejection and those described in the paragraph above are reiterated below.
Claim Objections
Claim 17 is objected to because of the following informalities: in the newly added wherein clause, “wherein the detection methods include” should read “wherein the detecting includes” to better match the language used earlier in the claim. Additionally, in the newly added wherein clause, “methylation chip” should read “use of a methylation chip.” Finally, in the newly added wherein clause, “simplified bisulfide sequencing technology” should read “use of simplified bisulfite sequencing technology.” Appropriate correction is required.
Claim 18 is objected to because of the following informality: in the final two lines of the claim, “and any combination thereof” should read “or any combination thereof.” 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 17-18 and 22 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 17 is rejected because the metes and bounds of the method are overall unclear. Specifically, in the first newly amended portion of the claim, DNA from one or more samples is treated with a reagent. In the next clause, “a polynucleotide” is recited, where said polynucleotide is “obtained by amplifying human genomic DNA treated with bisulfite.” This is similar to, though not exactly the same as, the newly amended portion of the claim, and so it is unknown if the polynucleotide from the human genomic DNA is also from the treated and extracted DNA first recited in the claim. Additionally, because this second phrase also recites the use of bisulfite, but does not clearly relate this reagent to the reagent recited in the newly amended portion, it is unclear if the DNA must be treated once or twice. Finally in this phrase, “a tumor detection agent or kit” is described, but “a tumor” is not recited earlier in the claim – only a sample containing “tumor cells” is recited. Because this language is not identical, it is further unclear if this agent or kit is meant to act on DNA from the tumor cells in the sample.
Additionally, claim 17 contains the trademark/trade name MassArray. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a particular system for detecting genetic variation and, accordingly, the identification/description is indefinite.
In the fourth clause of claim 17, the phrase “simplified bisulfite sequencing technology” is unclear. This phrase is not defined in the instant specification, and does not appear to be used in the art. Particularly, it is unclear what “simplified” sequencing technology would be, and how the ordinary artisan would determine which sequencing technologies are “simplified.” For the purposes of applying prior art, this phrase will be interpreted to encompass any teaching involving technology used for bisulfite sequencing.
Finally, the final wherein clause of the claim describes “the tumor” that must be used in the method. This phrase lacks antecedent basis, as “a tumor” is not recited earlier in the claim. As similar to the issue described above with the use of the “tumor detection agent or kit,” it is unknown if or how this tumor is related to the “tumor cells” recited in the one or more samples due to the language discrepancy, and so it is unclear how it is encompassed by the overall method.
Claims 18 and 22 are rejected due to their dependence on rejected claim 17.
Claim Interpretation
As noted above in the “Response to Applicant’s Arguments” section, the preamble of the claim (“A pan-tumor detection method”) is considered to be intended use, and so prior art is not required to teach pan-tumor detection methods in order to read on the instant claims.
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 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).
Zwarthoff teaches a method for detecting at least one hypermethylated CpG island associated with a cancer, where said detection indicates a high risk of cancer, and the cancer is preferably bladder cancer (paras. 9 and 11). The sample used can be a urine sample, and tumor cells in the urine can be analyzed, specifically by extracting the DNA from the cells (paras. 3, 14, and 40-41; instant claim 18). Bisulfite treatment can be used in methylation detection methods (paras. 63, 65-66, and 91). PCR primers and probes can be used to detect the hypermethylated CpG island regions (para. 32), and specifically, methylation-specific PCR may be used in conjunction with bisulfite treatment (para. 66) and bisulfite sequencing (para. 65). Zwarthoff teaches that these methods, including required primer design, are well known in the art (para. 66). The CpG islands can consist of those listed in Table 7 of Zwarthoff (para. 10), and Table 7A notes that one such island is on gene SIX6 (Table 7A, page 40). This gene is hypermethylated in NMI-wt (non-muscle invasive bladder cancer) compared to controls. Table 8 also notes methylation in the SIX6 gene in NMI bladder cancer compared to controls. Zwarthoff also teaches SEQ ID NO: 262.
However, Zwarthoff does not clearly link SEQ ID NO: 262 to bladder cancer or the SIX6 gene, and also does not discuss the claimed primer sequences.
Pfeifer teaches diagnosing a tumor through measuring methylation levels in a sample, though the reference is primarily focused on lung cancer (Abstract and para. 3). This reference teaches SEQ ID NO: 50, which is the same sequence as SEQ ID NO: 262 of Zwarthoff, and is associated with the SIX6 gene (claim 5 of Pfeifer states that SEQ ID NOs: 1-59 are present in Table 2, and the 50th entry in the table contains the sequence for SIX6).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to use the teachings of Pfeifer to inform the method of Zwarthoff. Specifically, Pfeifer provides evidence that SEQ ID NO: 262 of Zwarthoff contains the SIX6 gene, and as Zwarthoff teaches that this gene is hypermethylated in bladder cancer patients, this would motivate the ordinary artisan to detect this gene in the method of Zwarthoff to develop better diagnostic techniques. There would be a reasonable expectation of success because Zwarthoff already provides evidence that the SIX6 gene can successfully be detected, and the sequence of this gene is well-known, as evidenced by Zwarthoff and Pfeifer. Additionally, as noted in the instant specification, “Based on the sequence of the polynucleotide [to be detected], those skilled in the art know how to design primer(s),” (page 10, para. 1), and so the design of primers for the detection of the known SIX6 gene would be possibly for the ordinary artisan.
However, Pfeifer does not teach the claimed primer sequences.
Berlin teaches methods for identifying methylation patterns in genes associated with cancers (Abstract). In Table 1, they list disease markers, and note SIX6. SEQ ID NOs: 372 and 694 are associated with this gene as methylated and unmethylated DNA, respectively. Both of these sequences comprise instant SEQ ID NOs: 13 and 14.
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 a primer pair consisting of instant SEQ ID NOs: 13 and 14 using the teachings of Berlin and Ye, and to use these sequences to amplify and detect the SIX6 gene in the method of Zwarthoff in view of Pfeifer 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 Berlin to design primers for use in the method of Zwarthoff in view of Pfeifer, 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. Zwarthoff also notes that such primer design is possible for the ordinary artisan, providing a reasonable expectation of success (para. 66).
Thus, claims 17-18 are prima facie obvious over Zwarthoff, in view of Pfeifer, in view of Berlin, and in view of Ye.
Regarding claim 22, Zwarthoff teaches that the preferred method of methylation detection for the invention is to use PCR-based technology (such as methylation-specific PCR) in combination with bisulfite sequencing methods (paras. 65-66). These sequencing methods provide data on 5-methylcytosines, and provide “detailed information on the methylation status of all CpG-sites,” (para. 65).
Thus, claim 22 is prima facie obvious over Zwarthoff, in view of Pfeifer, in view of Berlin, and in view of Ye.
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
/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681