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 .
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 16, 17, 30 and 31 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.
The terms “methylation percentage”, “hypermethylation ratio”, “methylation frequency” and “methylation pattern” are not defined in the specification as to an unequivocal meaning. For “methylation percentage”, this could mean the percent of CpG sites of the gene that are methylated, the percent of samples of a particular sample type (e.g. samples from HPV+ OPSCC) exhibiting methylation at a particular locus, the percent of molecules of a particular target in the sample that are methylated, or something other meaning. The term “hypermethylation ratio” could mean a ratio of the number of methylated molecules of a target in a sample to the number of unmethylated molecules of the same target (or to the total number of molecules of that target) in a sample, the ratio of the number of methylated molecules of a target in a sample to the number of molecules of a reference gene, or some other meaning. The terms “methylation frequency” and “methylation pattern” are similarly vague and indefinite. As such, a broad interpretation will be given to these claims.
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) 1-3, 15-23, 25-31 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ren (Int. J. Cancer 143:2425-2436 (2018), IDS reference), as evidenced by Ren Supplemental Table 3 and GenBank Accession NR_003955. Because the version of this reference provided with the IDS was a pre-print document have a different formatting than the version relied upon in the rejection, the examiner has lined through this reference on the IDS and provided the published version on PTO form 892, so that locations referenced in the rejection below match the document.
Regarding claims 1 and 3, Ren determined methylation profiles in the following differentially methylated genes in DNA samples obtained from 24 subjects having HPV+ OPSCC compared to 22 normal controls (see Table 2 and section entitled “Confirmation of methylation levels of top 20 methylation markers in an independent control” on page 2432): EMBP1, DPP4, CTNND2, ELMO1, SFMBT2, CIQL3, MIR129-2, NID2, HOXB4, VSTM2B, ZNF773. Each of these is among the genes listed in claim 3. This was done using QMSP (quantitative methylation-specific PCR), which involved treating the DNA with bisulfite (id., and see section entitled “Bisulfite treatment and quantitative methylation-specific PCR (QMSP)” beginning on page 2427). Bisulfite is a reagent that modifies DNA in a methylation-specific manner.
Regarding claim 2, the methylation profiles of these differentially methylated genes is indicative of HPV+ OPSCC, as evidenced by the instant specification as well as Ren’s findings.
Regarding claim 15, each of these genes had an AUC greater than 0.5 and discriminates DNA from a subject having HPV+ OPSCC from control samples (see Table 2).
Regarding claims 16 and 17, it is noted that the cited genes from Ren’s Table 2 are the same as those recited in instant claim 3. Therefore, these markers must have the same properties, including those properties recited in claims 16 and 17. For example, according to Table 2, each of the genes is methylated in a higher percentage of HPV+ OPSCC samples than in normal samples (hence, a higher “methylation percentage”). Likewise, a higher ratio of HPV+ OPSCC samples at a give locus are methylated as compared to normal samples (e.g., for EMBP1, HPV+ OPSCC samples are methylated at a ratio of 23:24 samples, whereas in normal samples the ratio is 0:22; hence, a higher “hypermethylation ratio”).
Regarding claims 18-20, Ren indicated that the cohort presented in Table 2 (the “independent validation cohort”) comprised 24 primary HPV-positive OPSCC tissues and 22 normal samples from noncancer patients; see page 2427, left column starting at the end of line 5. Given that these control samples were obtained from “uvulopalatopharyngoplasty (UPPP) surgeries of cancer unaffected patients”, it would be understood these would include the types of tissues recited in claim 20 (at the very least soft palate tissues).
Regarding claim 21, while Ren did not explicitly indicate these subjects were “human”, the use of the terms “patient” and “informed consent” (page 2426, “Tissue samples”) clearly indicates these were humans.
Regarding claim 22, Ren states: “DNA from tissue samples were subjected to bisulfite conversion…” (page 2427, last paragraph in right column, emphasis provided), which indicates that DNA was extracted from the tissue samples.
Regarding claim 23, as the samples were tissue samples, they must have been collected using some “collection device” (e.g., scalpel, forceps). Tissue cannot just be “willed” to materialize from a patient into a container.
Regarding claim 25, Ren used bisulfite (see discussion above).
Regarding claim 26, Ren indicated primers were used in the quantitative methylation-specific PCR (see page 2427, last paragraph in right column).
Regarding claim 27, Ren used quantitative methylation-specific PCR (see page 2427, last paragraph in right column).
Regarding claim 28, Ren determined the presence or absence of methylation at one or more CpG sites using methylation-specific PCR (see page 2427, last paragraph in right column).
Regarding claim 29, Ren Supplemental Table 3 evidences the sequences of the primers and probes used for the quantitative methylation-specific PCR of the genes in Ren Table 2. GenBank Accession NR_003955 evidences the sequence of the EMBP1 gene. Shown below is a screen shot of a portion of the GenBank sequence, where the first boxed sequence corresponds to Ren’s forward primer for this gene. Note that the primer was designed to be used on bisulfite-treated DNA, which converts any unmethylated cytosines to uracils. Therefore, in designing the primer, any C that is not in a CpG, would be replaced with T (the equivalent of uracil). Therefore, in the first boxed sequence below, the replacement of any C not in a CpG with T results in Ren’s primer sequence. The second boxed sequence corresponds to Ren’s probe. However, the probe was designed based on the complementary strand. Therefore, taking the second boxed sequence, replacing any C not in a CpG with T, and then taking the reverse complement of that sequence, yields Ren’s probe sequence:
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As evidenced by GenBank Accession NR_003955, the EMBP1 gene encodes a “non-coding RNA”. The GenBank sequence itself is the sequence of this RNA (it is composed entirely of the exons, as indicated by the annotation information). Therefore, at least for EMBP1, Ren’s primer and probe are designed to detect methylated CpG sites in the coding region of this gene (even though the gene encodes a “non-coding RNA”, i.e. an RNA that is not translated into a protein). This is sufficient to anticipate claim 29. Whether Ren’s primers and probes for the other genes in Ren Table 2 target coding regions, non-coding regions, or regulatory regions has not been determined. Should amendment necessitated further analysis of the other genes in Ren’s Table 2, any new information provided will not preclude finality in the next Office action.
Regarding claim 30, one meaning of “methylation frequency” could be determining how often a locus is methylated in a particular disease state, such as HPV+ OPSCC. In this regard, as shown in Table 2, Ren determined the number of HPV+ OPSCC out of 24 having methylation at the various genes. For example, the “methylation frequency” of EMBP1 was 23 out of 24.
Regarding claim 31, Ren also performed DNA methylation sequencing (see section entitled “DNA methylation sequencing analysis”, page 2427). This would inherently determine the methylation pattern (i.e. which CpGs in a target were methylated and which were not).
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.
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.
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ren (Int. J. Cancer 143:2425-2436 (2018), IDS reference) in view of Song (US 2020/0370114, IDS reference).
The teachings of Ren have been discussed. Ren did not treat the DNA with a borane reducing agent (Ren treated with bisulfite).
Song disclosed an alternative to bisulfite treatment for assessment of methylation state utilizing TET oxidation and reduction by borane derivatives (paragraph [0010]). Song disclosed this as advantages over the use of bisulfite, because bisulfite treatment is a harsh chemical reaction which degrades more than 90% of the DNA due to depurination, which severely limits its application to low-input samples (paragraph [0007]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to modify the method of Ren by assessing DNA methylation using the TET oxidation/borane reduction method of Song to obtain the advantage of a less harsh chemical treatment thereby reducing loss of DNA and improving sensitivity.
Conclusion
No claims are free of the prior art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, GARY BENZION can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681
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