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 information disclosure statement (IDS) submitted on 4/30/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informality: the priority paragraph of the specification states that the instant application is a PCT application, which is not accurate, and does not list priority to PCT/US2022/039194.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informality: it is noted that the abbreviations for various components in the claim (i.e. AQ, RQ, and corrected AQ) are recited and are then not used in the dependent claims. These abbreviations are then not used in claim 27, which recites a method similar to claim 1, or in any of the claims dependent on claim 27. It is recommended that Applicant either include these abbreviations throughout the claim set or remove them from claim 1 for clarity. Appropriate correction is required.
Claim 19 is objected to because of the following informality: it is recommended that the phrase “subsequent test samples relative to the baseline correction factor,” be amended to read “subsequent test samples relative to the first test sample.” This clarifies that the subsequent test samples are to be taken after the first test sample (i.e. at a subsequent time point), which is believed to be Applicant’s intention, and thus the “subsequent correction factors” associated with these subsequent test samples would also naturally be associated with this subsequent time point. Appropriate correction is required.
Claim 40 is objected to because of the following informality: the semicolon after “first time point” in line 2 should be a comma – this then matches the format for this language as it is used in claim 19. It is also recommended that the objection for claim 19 above concerning the “relative to the baseline correction factor” language also be employed here. In other words, it is recommended that the final two lines of the claim be amended to read “determining subsequent correction factors for subsequent test samples relative to the first test sample.” 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 1, 5, 7, 10-11, 13, 19, 24-27, 31-33, 35, 37, 40-41, and 45-46 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.
Claims 1 and 27 are rejected due to the use of the phrasing “based on relative levels of endogenous nucleic acid in a respective one of the test samples,” in step (h) of both claims. In both claims, step (g) requires amplifying an endogenous nucleic acid in each of the test samples used. It is thus unclear where multiple “levels” would originate from, as only a single endogenous nucleic acid is required to be amplified in each test sample. Additionally, it is unclear what these levels would be relative to – for example, they could be relative to the quantity of the target nucleic acid in the test sample or the control nucleic acid in the control sample. Prior art will be considered to read on this limitation if the correction factor is based on any value associated with the expression of the endogenous nucleic acid.
Claims 5, 7, 10-11, 13, 19, and 24-26 are also rejected due to their dependence on rejected claim 1. Claims 31-33, 35, 37, 40-41, and 45-46 are also rejected due to their dependence on rejected claim 27.
Claims 25-26 and 46 are all also rejected for the use of the phrase “no more than about.” In the instant specification, there is no definition or range recited for the term “about,” and so the degree of closeness required for a value to be “about” the claimed values is not known. This is further compounded by the use of “no more than,” as it renders the entirety of the claimed ranges unclear, particularly with regard to an upper limit, and thus the phrase as a whole is indefinite.
Claim Interpretation
The use of the term “endogenous” in the instant claims will be taken to mean generally endogenous to the test sample, and thus, if the test sample is from a human, an endogenous gene can be from human nucleic acids. This is supported in the instant specification by the exemplary endogenous nucleic acid RNase P (e.g. paras. 84 and 106) and typical housekeeping genes (see para. 146, which mentions the use of GAPDH). The endogenous nucleic acid may also be from viral nucleic acid (instant specification para. 88). Para. 146 states, “Preferable endogenous nucleic acids are stably expressed across test samples and minimally affected by test conditions, extraction processes, and subject differences.” While not a limiting definition, this statement supports that the endogenous nucleic acid simply needs to exist in the test sample.
Regarding the claimed “correction factor,” this term is not defined in the instant specification. Correction factors may be based on Cq differences between the target and the endogenous control (see paras. 148-150 for example), but this is not required. As the correction factor in the instant claims must be based on values related to the expression level of the endogenous nucleic acids in the test samples and be used for normalizing the absolute amount of the target nucleic acid, any value or factor which can accomplish these limitations will be considered to read on this term in the instant claims.
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, 5, 7, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Van Wesenbeeck et al. (Virology, 2014; cited in Applicant’s IDS).
Van Wesenbeeck teaches an analysis of viral load shedding of influenza A (Abstract; instant claim 5). For each patient examined, two mid-turbinate flocked nasal swabs (Swab A and Swab B) were used, one in each nostril (page 2, column 1, para. 2; instant claim 7). This creates two test samples per patient. When swabs were ready for processing, viral RNA on the swab was isolated using the Easymag system from Biomerieux (page 2, column 1, para. 2; instant claim 10). Viral RNA then underwent qRT-PCR. As an internal control to detect the amount of human cells in the swabs, detection of the human RNase P gene was performed via qPCR, thus acting analogously to the claimed endogenous control. As an external quantification control, a standard RNA dilution series was tested with qRT-PCR. A standard curve was made from this data (page 2, column 1, para. 2). This standard curve was then used to determine upper and lower limits of quantification and was used to absolutely quantify the viral load of the swab samples (Figure 1A). Thus, the RNA dilution series acts as the claimed set of control samples. As seen in Figure 3, the Ct value of RNase P for both nasal samples was calculated. This is considered analogous to the claimed correction factor. A ΔCq value was then made combining both of these factors, and Swab A sample quantifications were corrected with this value. Page 4, column 1, para. 1 also states that Swab B sample quantifications were then also corrected (also see the insert in Figure 3B). Though a ΔCq value is used for correcting the quantification values, this is still considered to be “using the correction factor” of the respective test samples as stated in step (i) of instant claim 1, as the individual Cq factors are both included in the ΔCq value (instant claim 1).
Claims 11, 13, 27, 32-33, and 35 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Van Wesenbeeck et al. (Virology, 2014), hereby Van Wesenbeeck 1, as evidenced by Van Wesenbeeck et al. (Journal of Clinical Microbiology, 2013), hereby Van Wesenbeeck 2.
Van Wesenbeeck 1 teaches the methods of claims 1, 5, 7, and 10, as described above. In creating the external quantification control, the method of Van Wesenbeeck 2 is cited (page 2, column 1, para. 2 of Van Wesenbeeck 1).
Van Wesenbeeck 2 describes the detection of respiratory pathogens, and specifically focuses on influenza (Abstract). In describing the external quantification control, the reference states, “a standard RNA dilution series was tested in duplicate on each real-time PCR plate with the same reaction mix (influenza virus A) used to process the samples in order to determine the dynamic range, the performance of the real-time PCR reagents during each run, and absolute quantification,” and notes that the matrix gene was used (page 2978, column 2, para. 2). The reaction mixture used to process the samples contains target-specific forward and reverse primers (page 2979, column 1, para. 1).
Thus, the external quantification control of Van Wesenbeeck 1 uses known amounts of influenza nucleic acid to obtain absolute quantification values for the target samples, and utilizes the same target-specific primer pairs for amplification as is done in the amplification of the target nucleic acid in the test sample (instant claims 11 and 13).
In comparing the method of instant claim 27 to that of instant claim 1, in instant claim 27 the use of a viral target sample is specifically required, and the claim states that the set of controls must be focused on the same viral target and amplified with the same target-specific primers as the target viral nucleic acid. This is accomplished by Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2, as shown above in the rejection of instant claims 1, 5, 11, and 13.
Instant claims 32-33 require the use of swabs/nasal swabs, which is accomplished by Van Wesenbeeck 1, as shown in the rejection of instant claim 7 above.
Instant claim 35 requires the extraction of the test nucleic acid from the swab before amplification analysis, which is accomplished by Van Wesenbeeck 1, as shown in the rejection of instant claim 10 above.
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 19 is rejected under 35 U.S.C. 103 as being unpatentable over Van Wesenbeeck et al. (Virology, 2014).
Regarding claim 19, Van Wesenbeeck teaches the methods of claims 1, 5, 7, and 10, as described above. The reference also states that, “With the clinical development of several antiviral intervention strategies for influenza, it becomes crucial to explore viral load shedding in the nasal cavity as a biomarker for treatment success, but also to explore sampling strategies for sensible and reliable virus collection,” (page 2, column 1, para. 1) and notes, “Influenza viral load monitoring (on different timepoints) in nasal swabs could be very valuable as virological endpoints in clinical trials to monitor treatment efficacy, in analogy to HIV, HBV & HCV viral load monitoring,” (page 4, column 1, para. 2). Thus, Van Wesenbeeck teaches that measuring influenza viral load over time would be helpful in developing influenza treatments, which would be particularly valuable for those to whom influenza poses a potentially fatal threat (e.g. young children, the elderly, and those who are immunocompromised). This would motivate the ordinary artisan to perform the method of Van Wesenbeeck at multiple time points over the course of a patient’s viral infection. In order to accurately quantify the viral load at each time point, and to ensure comparisons are accurate between time points, each time point sample would need to be evaluated in the same manner, with the same endogenous control sample/correction factor methodology. There would be a reasonable expectation of success in adding time point sampling to Van Wesenbeeck as the actual sampling and sample analysis methods of Van Wesenbeeck, which have already been shown to be successful, would not be altered. Thus, this would result in corrected absolute quantification of viral load values for patient’s test samples over time, allowing comparison of not only the corrected absolute quantification values themselves, but also a comparison of the correction factors. Since these factors in Van Wesenbeeck are based on the number of human cells in a sample, changes in the correction factor can also indicate changes in the number of human cells relative to viral nucleic acids in the sample, which can also provide information about viral load/disease progression, treatment efficacy, and general immune response.
Thus, claim 19 is prima facie obvious over Van Wesenbeeck.
Claims 40-41 are rejected under 35 U.S.C. 103 as being unpatentable over Van Wesenbeeck et al. (Virology, 2014), hereby Van Wesenbeeck 1, as evidenced by Van Wesenbeeck et al. (Journal of Clinical Microbiology, 2013), hereby Van Wesenbeeck 2.
Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 teaches the methods of claims 11, 13, 27, 32-33, and 35, as described above.
In the rejection of claim 19 above, Van Wesenbeeck 1 renders prima facie obvious measuring viral loads at multiple time points. This same rationale would apply to Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2, and thus Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 renders prima facie obvious calculating corrected absolute quantification of viral load values for a patient’s test samples over time, allowing comparison of not only the corrected absolute quantification values themselves, but also a comparison of the correction factors.
Thus, claims 40-41 are prima facie obvious over Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2.
Claims 31 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Van Wesenbeeck et al. (Virology, 2014), hereby Van Wesenbeeck 1, as evidenced by Van Wesenbeeck et al. (Journal of Clinical Microbiology, 2013), hereby Van Wesenbeeck 2, and further in view of Miranda et al. (Virus Research, 2021; cited in Applicant’s IDS).
Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 teaches the methods of claims 11, 13, 27, 32-33, 35, and 40-41, as described above. However, neither reference describes the use or detection of SARS-CoV-2 target nucleic acids.
Miranda teaches that SARS-CoV-2 and COVID-19 are associated with mortality and hospitalization, and notes that examining viral loads in this disease is of great interest, as they are needed to “guide antiviral treatment, infection control and epidemiological metrics,” and are associated with disease outcomes (page 1, column 1, paras. 1-2). Miranda performs a method that is generally similar to that of Van Wesenbeeck 1 in that nasal swab samples were taken from patients, samples underwent PCR analyses (specifically analyzing the N gene; instant claim 37), RNase P was used as an endogenous internal control, and a 10-fold serial dilution of SARS-CoV-2 virus was used as an external control sample to determine a standard curve (page 2, “2.2 RT-qPCR”). RNase P mean Ct was then later used to correct viral target Ct values (page 3, column 2, para. 1). Miranda notes that these reference gene correction methods are extremely important when drawing conclusions related to COVID-19 viral load (pages 4-5, joining para.).
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 overall method and analysis of Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 on the SARS-CoV-2 target nucleic acids (and the associated controls) of Miranda. The main difference between Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 and Miranda, aside from the use of different target viruses, is the sampling method - Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 uses two samples per patient, which Miranda only uses one. The two nasal swabs of Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 were used to determine if swab collection in larger or smaller volumes makes a difference in terms of viral loads (page 2, column 1, para. 2). There was in fact a difference (page 2, column 2, para. 2), though this could be controlled for in later analyses. Van Wesenbeeck 1 later notes that, “The differences in InfA viral load between the left and right nostrils, as observed in this study, could be related to variability of the qRT-PCR, biological differences between the nostrils, sampling bias or any combination of these…A right- or left-handed person may obtain the swab differently from the right/left nostril or the order of taking the swabs could also introduce variability…The biological differences could include anatomic nose/septum abnormalities, variability in virus shedding or clogging of the nostrils. The differences in Inf A viral load between left and right nostrils, as observed in this study, highlight the importance of proper sampling and the need for standardized sampling procedures,” (page 4, column 1, para. 2). Thus, Van Wesenbeeck 1 highlights that different results may be obtained by sampling different nostrils in the case of influenza. As Miranda is concerned with accurately determining viral load associated with SARS-CoV-2, performing sampling in both nostrils of patients to determine if differences in viral load detection exist would be valuable, as any differences uncovered would inform future sampling methods to ensure better accuracy, which would therefore lead to more effective and accurate treatment options as well as better estimates of patient outcomes. There would be a reasonable expectation of success as the methods of Van Wesenbeeck 1 and Miranda are already incredibly similar in terms of the controls and analyses used, showing that SARS-CoV-2 can be accurately detected with such controls and analyses, and the only difference in using SARS-CoV-2 in place of influenza in the method of Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 would be the PCR primers/parameters used. As Miranda already teaches these elements, the ordinary artisan could easily transfer/adapt them for the method of Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2.
Thus, claims 31 and 37 are prima facie obvious over Van Wesenbeeck 1, as evidenced by Van Wesenbeeck 2, and further in view of Miranda.
Claims 24-26 and 45-46 are rejected under 35 U.S.C. 103 as being unpatentable over Van Wesenbeeck et al. (Virology, 2014), hereby Van Wesenbeeck 1, as evidenced by Van Wesenbeeck et al. (Journal of Clinical Microbiology, 2013), hereby Van Wesenbeeck 2, and further in view of Miranda et al. (Virus Research, 2021), as evidenced by ThermoFisher Scientific (“Using Standard Curve to Estimate DNA Quantity,” 2016).
Regarding claims 45-46, Miranda indicates that with their particular PCR reactions for the SARS-CoV-2 nucleic acids, 100.177% amplification efficiency was achieved for the N1 assay, 98.322% for the N2 assay, and 107.274% was achieved with the RNase P assay (page 2, column 2, para. 3). These amplification efficiencies were evaluated compared to the standard curve analysis from the external control nucleic acids (page 2, column 1, para. 4). Thus, the amplification efficiencies between the control nucleic acids and the internal RNase P control are about 7-9% different from one another. These amplification efficiencies were obtained using linear evaluations for each of the targets and the internal control gene, which generated slope values. Though Miranda does not specifically show the standard curve plot for their data, standard curves are generally made by plotting Ct values on the y-axis and quantity on the x-axis. See ThermoFisher Scientific, which notes these axis measurements, and notes that standard curves show dilution reactions that generally have an efficiency of around 100% (see the information under the numbered list and the video provided on the webpage). If they did not, then this would indicate a problem with the standard, and said standard would no longer be useful. Thus, the ordinary artisan would understand that the external controls of both Van Wesenbeeck 1 and Miranda would have about 100% amplification efficiency. Furthermore, as the amplification efficiencies of Miranda are based on analyzing the data for the target nucleic acids and the internal control with the standard curve and, in particular, involve obtaining slope values (see page 2, column 2, para. 3), the ordinary artisan would recognize that these efficiencies are based on Cq/quantity calculations.
As Van Wesenbeeck 1, as evidenced by Van Wesenbeeck 2, and further in view of Miranda uses the target nucleic acids of Miranda and the same controls as Miranda, these amplification efficiencies, teachings, and associated rationales would apply to this combination of references.
Thus, claims 45-46 are prima facie obvious over Van Wesenbeeck 1, as evidenced by Van Wesenbeeck 2, and further in view of Miranda, as evidenced by ThermoFisher Scientific.
Regarding claims 24-26, claims 24 and 26 are identical in language to instant claims 45-46. Van Wesenbeeck 1 as evidenced by Van Wesenbeeck 2 described above details that the external quantification control of Van Wesenbeeck 1 and the target nucleic acids are the same target genes. Van Wesenbeeck 1, as evidenced by Van Wesenbeeck 2, and further in view of Miranda then renders obvious the use of SARS-CoV-2 targets and associated controls. Van Wesenbeeck 1, as evidenced by Van Wesenbeeck 2, and further in view of Miranda, as evidenced by ThermoFisher Scientific renders obvious instant claim 45-46, and so renders claims 24 and 26 obvious for the same reasoning.
For claim 25 specifically, this claim requires similar amplification efficiencies between the external control nucleic acids and the target nucleic acids, which is also demonstrated by Miranda and the rationale provided in the rejection of claims 45-46 above – namely, these teach amplification efficiencies of around 100% for the external control nucleic acids and 100.177% and 98.322% for the target nucleic acid assays.
Thus, claims 24-26 are prima facie obvious over Van Wesenbeeck 1, as evidenced by Van Wesenbeeck 2, and further in view of Miranda, as evidenced by ThermoFisher Scientific.
Conclusion
No claims are currently allowable.
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/F.F.G./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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