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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 7/21/2026 has been entered in view of the request for continued examination mailed 8/19/2026.
Applicant’s arguments and amendments have been thoroughly reviewed and considered. Claims 4-16, 22, and 24-34 remain withdrawn. Claims 1-3, 17-21, and 23 are pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8/19/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Applicant’s Amendments and Arguments
Claims 1, 3, 17-19, and 23 were rejected under 35 U.S.C. 103 as being unpatentable over Moon et al. (US 2013/0237427 A1) in view of Dagland et al. (US 2011/0129824 A1).
Claim 2 was rejected under 35 U.S.C. 103 as being unpatentable over Moon et al. (US 2013/0237427 A1), in view of Dagland et al. (US 2011/0129824 A1), and further in view of Oldham-Haltom et al. (US 2016/0010161 A1).
Claims 20-21 were rejected under 35 U.S.C. 103 as being unpatentable over Moon et al. (US 2013/0237427 A1), in view of Dagland et al. (US 2011/0129824 A1), and further in view of Kristiansen et al. (Journal of Clinical Microbiology, 2016).
In light of Applicant’s amendments to the claims submitted 7/21/2026, these rejections have been withdrawn, but see new grounds of rejection below.
The currently pending claims require that the first and second probe be provided free in solution (see claim 1). In Moon, the primary reference used in the Final Rejection mailed 5/21/2026, the reference teaches a double-stranded probe that is attached to a microarray (see para. 23 of the Final Rejection, for example). In Applicant’s Remarks, they state that at least for this reason, Moon in view of Dagland does not read on the currently amended claims (Remarks, page 11). The Examiner agrees, and through further search and consideration of the prior art, has found additional prior art that is considered to read on the claims as currently amended. This is the basis for the new grounds of rejection provided below.
Applicant has supplied other arguments not wholly related to the previous combination(s) of references that were addressed in the Advisory Action mailed 8/14/2026 and are reiterated below.
On pages 19-20 of their Remarks, Applicant alleges unexpected results/advantages from the use of their invention.
These results are shown in Example 5 and Table 6 of the instant specification. At the very least, as pointed out in the Final Rejection mailed 5/21/2026, these teachings are not commensurate in scope with the claimed invention as they describe the detection of a particular type of nucleic acid (M. genitalium), and use specific primer (SEQ ID NOs: 1 and 7) and probe sequences (SEQ ID NOs: 9-14) that are not claimed. MPEP 716.02(d) notes that for allegedly unexpected results to be commensurate in scope with the claimed invention, “the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.” Because the example provided by Applicant is much more narrow than the method presented in instant claim 1, said example cannot be said to be commensurate in scope with the claimed invention.
On pages 20-21 of their Remarks, Applicant argues that the use of multiple amplification steps is not encompassed by the claim.
Regarding the structure of the claim, the Examiner does not argue that the “amplification reaction” recited in steps (b) and (c) of the claim are not the same reaction. The Examiner is merely applying the guidance of MPEP 2111.03 I, which states that the term comprising, “is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” Thus, the method of claim 1 comprises the listed steps, and so does not exclude any additional steps, such as the use of additional amplification reactions (e.g. performing additional amplification after steps (b) and (c)).
Thus, these arguments are not considered persuasive.
Claim Objections
Claim 3 is objected to because of the following informality: it is recommended that one instance of the word “both” be removed from the phrase “when both the positive control sequence and the nucleic acid target sequence are both present” to remove redundancy. 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.
Claim 23 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 23 requires that the nucleic acids obtained in step (a) of claim 1 be obtained via hybridization capture onto a solid support, where the solid support is not limited. However, in claim 1, the newly amended portion states that the probes are provided free in solution with “the test sample of (a) and pair of primers from step (b).” If the nucleic acids from the test sample are separated from the test sample via hybridization onto a solid support substrate such as an array, and the nucleic acids are amplified in step (b) with the pair of primers and detected with the probes of step (c), it is unclear how this would all occur free in solution with the test sample, which would no longer hold the nucleic acids in this scenario. Thus, the scope of the claim is indefinite.
Claim Rejections - 35 USC § 102
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 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.
Claims 1 and 17-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wada et al. (J. of Clinical Microbiology, 2004; cited in Applicant’s IDS).
Wada teaches an analysis of mutations in genes related to drug resistance in Mycobacterium tuberculosis (Abstract). Clinical samples of sputum were used, and real-time PCR was performed using primer and TaqMan probes (see “Materials and Methods” on page 5278). Table 1 details the various primers and probes used for real-time PCR. Note the single primer pair used for rpoB. Figure 1 shows the orientation of the various probes on the M. tuberculosis genomic area of interest. For rpoB, see Figure 1A, and note that the TB control and rpo520/524 probes hybridize to different strands of the amplicons, as noted by the different directional arrows. Page 5278, joining para. of columns 1-2 notes that the number of amplification cycles to reach ΔRn=0.2 is referred to as the cycle threshold (Ct), and that this Ct value increases when a mutation is present. For each mutation probe, the Ct value was compared with that of the control probe to create a ΔCt value (page 5279, column 2, para. 2; instant claim 17). Table 3 shows ΔCt values for the extracted DNA, specifically showing the value for the rpo520/524 probe. The presence of any particular mutation is indicated by a positive and bolded ΔCt value (see explanation below the table; instant claims 1 and 18).
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 2-3 are rejected under 35 U.S.C. 103 as being unpatentable over Wada et al. (J. of Clinical Microbiology, 2004; cited in Applicant’s IDS) in view of Cooksey et al. (Antimicrobial Agents and Chemotherapy, 2000).
Regarding claim 2, Wada teaches the method of claim 1, as described above. However, Wada does not teach the use of invader cleavage reactions in their amplification.
Cooksey teaches an analysis of drug resistance in M. tuberculosis using an Invader assay (Abstract). The reference notes that this amplification does not involve temperature cycling, that this method has sensitivity to single point mutations, and “the linear amplification of the cleaved product makes possible the detection of low levels of the target, potentially enabling the discrimination of small subpopulations in mixed DNA samples,” (page 1297, column 1, paras. 1-2). The reference analyzed wild-type and rpoB mutations (see Table 1). Cooksey concluded that the Invader assay was able to identify different alleles affecting the same nucleotide, was able to discriminate different gene mutations simultaneously, and detected various mutant subpopulations in heterogeneous samples, showing a high level of sensitivity. The reference then states, “Thus, the Invader assay offers the potential to become a high throughput screen for identifying mutations proven to be associated with antituberculosis drug resistance,” (page 1300).
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 Cooksey to incorporate invader cleavage methods into the method of Wada described above. Specifically, the probes of Wada are already designed for specific mutations, and so could be used as the signal probes described by Cooksey (see Figure 1). The probes would still produce a fluorescent signal upon successful cleavage, which would indicate the presence of the mutant or wild-type sequence, and thus could still be used to determine Ct values. By utilizing an invader cleavage assay for the production of fluorescent signal during amplification, rather than only a probe binding to a target, the signal is more likely to accurately reflect the amount of target in a sample, as more correct conditions would need to occur, and there would likely be less background noise. Increased accuracy would be motivating to the ordinary artisan, particularly when intending to use detection methods for disease diagnosis. Cooksey also describes benefits related to a lack of thermocycling and high sensitivity that would be of interest to the ordinary artisan. Altering the method in this way would likely require a slight alteration of primer and probe design, but this would be possible for the ordinary artisan, particularly as both Wada and Cooksey both discuss such design (e.g. Wada page 5278, “Real-time PCR” and Cooksey page 1297, “Invader reactions”). As Cooksey teaches both wild-type and mutant detection, and particularly analyses the same M. tuberculosis gene that is of interest in Wada (rpoB), there would be a reasonable expectation of success.
Therefore, claim 2 is prima facie obvious over Wada in view of Cooksey.
Regarding claim 3, Wada in view of Cooksey teaches the method of claim 2, as described above. Wada also makes clear that a positive ΔCt would indicate presence of a particular mutation, as evidenced by the explanation in Table 3 described above. The same explanation is shown in Table 2, which shows that when rpoB 520 mutants are present in a sample (in this case, in laboratory strains), the ΔCt are high, showing values of 14.47 and 16.06. Thus, it would be prima facie obvious that in an extracted sample from a patient, the same ΔCt guidance would also apply, and the ΔCt value would be much higher than 0 when a rpoB 520-524 mutant is present.
Therefore, claim 3 is prima facie obvious over Wada in view of Cooksey.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Wada et al. (J. of Clinical Microbiology, 2004; cited in Applicant’s IDS) in view of University of Cape Town (“New diagnostic approach for early detection of Tuberculosis”, 2015), hereby “Cape Town”.
Wada teaches the methods of claims 1 and 17-18, as described above. However, as noted above, the reference uses sputum samples from patients to analyze for the presence of M. tuberculosis, and does not specify that swabs are used.
Cape Town teaches that the traditional sputum method for diagnosing tuberculosis has downsides in that it increases the risk of infection of healthcare workers, because it can be difficult to dislodge bacteria from the mucus in the sample (“Problem of undetected TB,” para. 1). Researchers at the South African Tuberculosis Vaccine Initiative and the University of Washington used oral swabs to test for TB instead, and found that the results from these swabs provide “better results than previous efforts to test for TB in materials other than sputum,” and that oral swab collecting requires minimal training for use (“New test,” para. 2). The article concludes by stating that the use of oral swabs can make TB diagnosis easier and cheaper (“Early Detection of TB,” para. 1).
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 guidance provided by Cape Town to substitute the use of sputum samples for oral swab samples in the method of Wada. Cape Town lists many benefits of using oral swabs – including less risk for those collecting the samples, increased diagnostics compared to other types of samples, low cost, and ease of use – that would motivate the ordinary artisan to use this sampling method. Additionally, 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.” Both sample collection methods result in positive TB detection in samples, as shown in Wada and Cape Town, and both show this specifically with qPCR, and so there would be the predictable results of successful TB detection in the relevant samples.
Thus, claim 19 is prima facie obvious over Wada in view of Cape Town.
Claims 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Wada et al. (J. of Clinical Microbiology, 2004; cited in Applicant’s IDS) in view of Kristiansen et al. (Journal of Clinical Microbiology, 2016; cited in a previous Office Action).
Wada teaches the methods of claims 1 and 17-18, as described above. However, the reference is focused on M. tuberculosis, and does not reference Mycoplasma genitalium.
Kristiansen teaches that M. genitalium is a bacterium that causes disease symptoms in both men and women, and while antibiotics can be used for treatments, macrolide-resistant M. genitalium strains are not uncommon (page 1593, column 1, para. 1). Two of the most frequent macrolide resistance mutations, A2058G and A2059G, are single base mutations compared to the wild type sequences (Abstract and Figure 1). Kristiansen detected M. genitalium in clinical samples, where total nucleic acid was extracted and purified, RT-PCR occurred utilizing primers and probes, where each probe was specific for the wild-type or a specific mutant sequence, and sequencing then took place (page 1593, column 2, para. 2 through page 1594, column 1, para. 3). Results showed that swabs could be successfully identified as having wild-type (macrolide-susceptible) M. genitalium sequences, macrolide-resistant M. genitalium sequences, or both (Figure 2 and page 1594, column 2, “Sanger Sequencing of 23S rRNA”).
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 Kristiansen to specifically examine macrolide-sensitive and macrolide-resistant M. genitalium in the method of Wada to arrive at the inventions of instant claims 20-21. Kristiansen teaches that the strain of M. genitalium in a sample has bearing on treatment options, and therefore knowing the specific strain (and its bacterial resistance/susceptibility) would be important for patients and clinicians. As the wild-type and mutant M. genitalium sequences are known, as shown in Figure 1 of Kristiansen, the primers and probes of Wada could be developed to target the region where the mutations take place as the target nucleic acid, while retaining a non-target genomic region as a control for detection (as is done with the TB control probe in the Wada reference). The ordinary artisan would be motivated to detect macrolide-resistant M. genitalium because this detection would prevent wasted time and resources on non-effective treatments and potentially improve patient outcomes. As Kristiansen teaches the sequences of the target mutations and shows that primers can be developed to target these regions (page 1594, column 1, para. 5), there would also be a reasonable expectation of success in this detection. Additionally, as Kristiansen teaches that both wild-type (i.e. macrolide-susceptible) and macrolide-resistant M. genitalium can both exist in a sample and can be used in their method (Figure 2), the ordinary artisan would know that use of such a sample with PCR methods is possible.
Thus, claims 20-21 are prima facie obvious over Wada in view of Kristiansen.
Claims 23 is rejected under 35 U.S.C. 103 as being unpatentable over Wada et al. (J. of Clinical Microbiology, 2004; cited in Applicant’s IDS) in view of Fraser (WO 2017/006108 A1).
Wada teaches the methods of claims 1 and 17-18, as described above. However, the reference does not teach that the target sequences are hybridized to a solid support via immobilized oligonucleotides before amplification. The reference teaches that DNAs were extracted with AMPLICOR technology (page 5278, para. 4).
Fraser teaches target amplification of DNA (Abstract). Pages 1-2, joining para. describes a method in which a biological sample containing different target nucleic acids is provided, probe sets hybridize with the different targets, and then those targets are amplified. Page 2, para. 3 describes that the hybridization can be done with bead based solid supports. The sample used may be a sputum sample (page 19, para. 1). These methods can be used with PCR amplification (page 22, para. 4). Fraser teaches that, “An advantage of the methods set forth herein is that they provide for rapid and efficient detection of a plurality of target nucleic acid in parallel,” (page 33, para. 4).
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 substitute the extraction method for DNA described by Wada with that of the bead hybridization method of Fraser. 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.” Both references teach extraction methods that can operate on sputum samples, and both are designed so that target sequences can then be subsequently amplified with PCR. Thus, the results of the substitution would lead to the predictable results of amplified target nucleic acids.
Thus, claim 23 is prima facie obvious over Wada in view of Fraser.
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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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681
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