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 .
Information Disclosure Statement
The IDS filed 06/16/2023 has been considered. However, item #5 (Bodor) has not been considered as only the last page of the article was provided. Certain corrections have been made on the IDS by the examiner (corrected journal title and provision of omitted page numbering and year of publication).
Drawings
The drawings are objected to because shading obscures text and text size is too small to read. See 37 CFR 1.84(l), (m) and (p). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 9, 10, 19 and 20 are objected to because of the following informalities: the word “analogous” should be “analogues” or “analogs”. 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 12 and 13 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 “high” and “low” in claim 12 and “high” in claim 13 are relative terms which render the claims indefinite. The terms “high” and “low” are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 13 is additionally unclear due to the term “single exon level”. It is not understood what is meant by a gene being highly expressed “at single exon level”.
Claim 9 is 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 9 recites the limitation "the first primer". There is insufficient antecedent basis for this limitation in the claim.
Claims 9, 10, 19 and 20 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 language “at least about” raises an issue of indefiniteness. “At least” implies a minimum value, whereas “about” implies values above or below a recited value. In addition, the term “about” is not explicitly defined in the specification. The effect is that reasonable people could differ in their opinions as to whether, say, 75%, or 82%, falls within the range of “at least about” 80%.
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, 5-8 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Song (Clinical Chemistry 66(1):178-187 (2020)).
Song disclosed a method comprising the steps of:
(a) reverse transcribing RNA into complementary DNA (cDNA) resulting in a mixture of cDNA and genomic DNA (gDNA);
See figure 1. See also section “NGS ASSAY” spanning pages 179-180.
(b) ligating a universal sequencing adaptor to a terminal of the gDNA and cDNA from step (a);
See figure 1. See also section “NGS ASSAY” spanning pages 179-180.
(c) conducting a first polymerase chain reaction process to produce a single-stranded primer extension product comprising a complementary sequence, wherein the complementary sequence is complementary to the target sequence on the gDNA, the cDNA, or a combination thereof, and is complementary to the universal sequencing adaptor;
See figure 1. See also section “NGS ASSAY” spanning pages 179-180.
(d) conducting a second polymerase chain reaction process to amplify the single-stranded primer extension product;
See figure 1. See also section “NGS ASSAY” spanning pages 179-180.
and (e) performing a next-generation sequencing process
See figure 1. See also section “NGS ASSAY” spanning pages 179-180.
and calculating the relative ratio of cDNA sequencing reads to gDNA sequencing reads, namely the RNA-to-DNA ratio, of the same target sequence,
Page 180, right column, first complete sentence: “Read depths of the housekeeping gene CHMP2A cDNA and gDNA were used to calculate the RNA/DNA ratio, which was used as a QC for RNA quality.”
wherein the target sequence is selected from a group consisting of a gene sequence, an exon of a gene, and a combination thereof.
See figure 3A. Reads for cDNA were distinguished from reads for gDNA as the former comprised the targeted exon plus the neighboring exon, while the latter comprised the targeted exon plus the neighboring intron.
Regarding claim 2, see figure 1 and section “NGS ASSAY” spanning pages 179-180: “Ligated templates were SPRI-cleaned and mixed with the first pool of target-specific primers and thermal stable DNA polymerase (Thermo Fisher), and subjected to multiple linear amplification cycles, each producing a complementary strand copy of the input template.”
Regarding claim 3, see figure 1 and section “NGS ASSAY” spanning pages 179-180: “After cleanup, a second pool of target-specific primers nested to the first pool, a common adaptor primer, and an indexed P7 primer were applied for PCR amplification.”
Regarding claim 5, see figure 3A, where for CHMP2A a single primer is used for both cDNA and gDNA.
Regarding claim 6, Song used FFPE samples; see page 179, section “CLINICAL SAMPLE COLLECTION”.
Regarding claim 7, Song analyzed CHMP2A, a housekeeping gene.
Regarding claim 8, Song extracted total nucleic acid (TNA) for reverse transcription, without removing genomic DNA; see figure 1, and section “NGS ASSAY” spanning pages 179-180.
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) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Song (Clinical Chemistry 66(1):178-187 (2020)) in view of Henikoff (US 2023/0332213).
The teachings of Song have been discussed. Song stated that the first PCR comprised “multiple linear amplification cycles” (page 180, left column, lines 12-16). This would necessarily be more than one, but Song did not say how many cycles were used, so it cannot be known whether it was less than 100 cycles.
Henikoff disclosed performing 12 cycles of a linear pre-amplification prior to performing PCR; paragraph [0063].
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 carry out 1-100 cycles of linear amplification in the method of Song, since Henikoff demonstrates that 12 cycles of linear pre-amplification were a sufficient number of cycles to follow with conventional two-primer, exponential PCR. See MPEP 2144.05 regarding the obviousness of ranges.
Claim(s) 11-16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Song (Clinical Chemistry 66(1):178-187 (2020)) in view of Song Supplemental Data Table 2 [online] 30 December 2019 [retrieved on 15 November 2025] retrieved from https://academic.oup.com/clinchem/article/66/1/178/5688840, and Song (Cancer Res 2020;80(16 Suppl): Abstract nr 6490; hereafter “Song Abstract”).
The teachings of Song have been discussed. The samples Song used were from cancer patients; page 181, section “PROOF-OF-CONCEPT STUDY IDENTIFIED BOTH FUSIONS AND MUTATIONS”: “From a cohort of 66 freshly sectioned lung tissue samples (see Table 2 in the online Data Supplement), mutations were found…”. As shown in Table 2 of Song Supplemental Data, these patients included those having non-small cell lung cancer, including squamous cell carcinoma and adenocarcinoma, as recited in claims 14 and 15.
Song did not expressly “treat” a cancer patient with an immune checkpoint inhibitor as recited in claim 11. However, Song did state (page 186, last paragraph):
Potentially detecting multiple genetic variations (SNV/indel/copy number variation through DNA and fusion/expression through RNA) in a single-tube NGS assay holds further clinical and investigational potentials. For example, immune checkpoint therapies have seen a remarkable expansion in prescription; however, NGS panels have not proved very useful other than their limited capability for tumor mutation burden evaluation, while programmed death-ligand 1 protein assay by immunohistochemistry lacks complex genetic information that may affect therapeutic outcome (37). Such obstacles could be overcome by a consolidated NGS approach measuring PDCD1/CD274 amplification and/or transcription, preferably in the context of other molecular biomarkers for targeted therapies.
Song also did not expressly measure expression of CD274 or GZMA as recited in claims 12 and 13.
Song did not expressly mention a PD-1 inhibitor as an immune checkpoint therapy as recited in claim 16.
Song Abstract disclosed (emphasis added):
Cohort II included 33 patients who failed first-line therapies and further received anti-PD-1 therapy, prior to which needle biopsies were obtained.
Song Abstract disclosed (emphasis added):
Tumor tissues [from NSCLC patients] were used for total nucleic acids (DNA and RNA) extraction and subjected to an anchored multiplex PCR NGS panel for one-tube enrichment of 63 genes relevant in NSCLC, including EGFR, KRAS, BRAF, ALK, ROS1, RET, MET, NTRK1/2/3, NRG1 and immune related genes CD274, GZMA (encoding granzyme A) and PRF1 (encoding perforin). We calculated exon-level mRNA expression per copy genomic DNA of the same target, expressed as RNA-to-DNA ratio, without relying on the conventional housekeeping gene normalization.
Song Abstract found:
In Cohort II, the analysis of pre-ICI treatment needle biopsies showed that a high expression of CD274 was associated with response to ICIs [immune checkpoint inhibitors] and with a better PFS [progression free survival] compared to patients with low CD274 expression (P value < 0.01). Further, among patients with high CD274 expression, a high GZMA expression was associated with a trend towards better PFS (P value = 0.06), whereas a high PRF1 expression level was not.
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 use the method disclosed by Song to identify NSCLC patients with high expression of CD274 and treat such patients with PD-1 inhibitors, as Song Abstract indicated that such patients tended to respond to anti-PD-1 therapy.
Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Song (Clinical Chemistry 66(1):178-187 (2020)) in view of Song Supplemental Data Table 2 [online] 30 December 2019 [retrieved on 15 November 2025] retrieved from https://academic.oup.com/clinchem/article/66/1/178/5688840, and Song (Cancer Res 2020;80(16 Suppl): Abstract nr 6490; hereafter “Song Abstract”) as applied to claims 11-16 above, and further in view of Garon et al (NEJM 372:2018-2028 (2015), IDS reference).
The teachings of Song, Song Supplemental Data Table 2, and Song Abstract have been discussed. The Song Abstract did not mention which particular PD-1 inhibitor was used for the anti-PD-1 therapy.
Garon disclosed the use of pembrolizumab (an anti-PD-1 antibody) for the treatment of non-small-cell lung cancer, and disclosed that “Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer.”
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 use pembrolizumab as the anti-PD-1 therapy in the method suggested by the combined teachings of Song, Song Supplemental Data Table 2 and Song Abstract, as Garon taught this was a safe and effective treatment for some patients with NSCLC.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zheng (Nature Medicine 20(12):1479-1484 (2014), IDS reference) in view of Polansky (US 2004/0023207).
Zheng taught a method for amplifying either cDNA derived from RNA, or genomic DNA, using a “first primer” (figure 1, “GSP1 pool”) and a “second primer” (figure 1, “GSP2 pool”), wherein the second primer was located between the first primer and the target sequence being amplified (figure 1). The method included ligating a universal sequencing adaptor (figure 1, “Adapter ligation”). In the case of cDNA, Zheng taught reverse transcriptase for reverse transcribing the RNA into cDNA; “ONLINE METHODS” (following page 1484), section titled “Anchored multiplex PCR”, “SuperScript III”.
Zheng did not teach putting these reagents into a “kit”.
Polansky taught (paragraph [0919]): “Well known advantages of commercial kits include convenience and reproducibility due to manufacturing standardization, quality control and validation procedures.”
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 put the reagents for the method disclosed by Zheng into a “kit” to obtain the benefits of kits disclosed by Polansky.
Conclusion
All claims are rejected. Claims 9, 10, 19 and 20 are free of the prior art but are rejected for other reasons. These claims require the use of primers not found in the prior art. The primers are composed of a constant arbitrary 5’ region and gene-specific 3’ regions. Therefore, these primers have sequences that are not found in nature, and there is no particular reason for combining the particular arbitrary 5’ sequence used with the particular 3’ gene-specific sequences chosen.
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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/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681