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. The claims have not been amended. Claims 4-16, 22, and 24-34 remain withdrawn.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.
Response to Applicant’s Arguments
Regarding the 35 USC 103 Rejection, Applicant argues that the combination of Moon in view of Dagland, cited in the Non-Final Rejection mailed 12/4/2025, does not teach each limitation of instant claim 1, and in particular does not teach producing an amplification product with two strands, where the first strand has a control sequence and the second strand may comprise a target sequence (as recited in step (b) of claim 1), nor do the references allegedly teach the required probes and Ct value detections of step (c) of claim 1 (Remarks, pages 3-4). Specifically, Applicant argues that the Y-shaped probe described by Moon cannot act as the first and second probes described by the instant claims, because the function of the probe as described in the reference could not be used to determine separate Ct values for control and target sequences (Remarks, page 5). The probe teachings of Dagland do not overcome this alleged deficiency, and also allegedly do not teach the probe limitations of the instant claims (Remarks, page 6).
Regarding Applicant’s specific argument that Moon in view of Dagland does not teach an amplification product as recited in step (b) of claim 1, Moon explicitly teaches using their probes to detect a double-stranded oligonucleotide, where the sense strand contains an SNP and the antisense strand does not contain the SNP (para. 57). This is taught in conjunction with the use of a Y-shaped probe. A “positive control” sequence as claimed has no specific definition in the instant specification (though can be a wild-type sequence, see para. 81 of the application as published, for example), and a target sequence is defined as simply “a nucleic acid that is to be detected or analyzed,” (para. 34 of the application as published). Thus, such an oligonucleotide as described in para. 57 of Moon would be considered to contain a control (without the SNP) on one strand and a target (with the SNP) on another strand. The reference also notes that amplification of nucleic acids before hybridization with probes can be performed (e.g. paras. 26, 68, 190, 267. 279, 287). Thus, an amplification product with a control and target sequence, each on separate strands, is encompassed by the teachings of Moon, meeting the limitations of step (b) of instant claim 1.
In response to the arguments against the references in teaching step (c) of instant claim 1, it is noted that the focus of the microarray methods and probes of Moon is specifically to test two genes, such as a control and target, at the same time (Abstract). Regarding the probe of Moon, para. 22 of the reference states, “two hybridization reactions with nucleic acids having nucleotide sequences complementary to the probes may occur concurrently, and the reactions may be analyzed by using two different dyes,” and para. 25 notes, “since testing with the internal reference or control is performed concurrently, false negative result or false positive result can be minimized and, hence, the sensitivity and specificity of test can be improved.” This probe is specifically stated to be used with microarray methods of the reference (e.g. para. 24), and so it is unclear why Applicant believes that the presence of an array, and the linking of the probe to such an array, would eliminate the function of the probe to be able to hybridize to control and target genes at the same time.
In the instant specification, a “probe” is defined in para. 21 as “an oligonucleotide that interacts with a target nucleic acid to form a detectable complex.” There is no requirement that a probe be part of (or not part of) a duplex, or that the probes be single or double-stranded. Thus, the individual strands of the Y-shaped probe of Moon are analogous to the first and second probes of instant claim 1.
In combining Moon with Dagland, it is specifically stated in the Non-Final Rejection that Moon does not teach measuring Ct values with their probes or the detection of the control/target during amplification (see para. 16 of the Non-Final Rejection). This paragraph also generally notes that Ct values can be measured with real-time PCR, and as noted above, the reference teaches that different dyes can be used with the Y-shaped probes for control and target detection.
Dagland teaches the use of double-stranded probes for use during PCR reactions as an alternative to typical TaqMan probes. These probes are Y-shaped at their ends and contain fluorophore/quencher moieties, and when each strand of the probe hybridizes to its desired sequence, fluorescence can be detected. When different fluorescent moieties are used, different targets can be detected (para. 169). These probes can be used to find Ct values (see para. 17 of the Non-Final Rejection).
MPEP 2141.03 I states, “"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.
In combining Moon in view of Dagland, the teachings of Dagland regarding using non-TaqMan, double stranded probes are combined with the control and target concurrent detection of the probes of Moon to arrive at the rejection of claim 1. The probes of Moon would thus be altered to include the double fluorophore/quencher design of the probes of Dagland, so to have fluorescent detection occur via the probes rather than dyes on the target nucleic acids, as is shown in Moon. This change would not hinder the probes of Moon from acting in accordance with microarrays, particularly as linkers (which attach the probes to the substrate, see Abstract and para. 23, for example) could still be used, at least in the case of initial probe binding, and the arrays can include wells, which would ensure that desired probes remain in desired locations during amplification (paras. 49, 51, and 91, for example). Additionally, as Moon teaches that two different dyes can be used with the control and target sequences, the ordinary artisan would also recognize that similarly, two different fluorophores could be used to distinguish between the control and target sequences.
Paragraph 18 of the Non-Final Rejection provides a motivation (“Performing real-time PCR in this manner would overall simplify the method of Moon in that a separate labeling step would not be needed, and would eliminate the need to utilize both the double-stranded probe and the TaqMan probes when performing real-time PCR, in addition to providing the benefits described by Dagland above.”) and a reasonable expectation of success (“There would be a reasonable expectation of success because Dagland teaches the successful use of a double-probe design similar to that of Moon with real-time PCR, the design of the PCR primers would not be changed, and general methods of real-time PCR are well-known in the art.”). Applicant does not appear to address this specific rationale in their remarks.
Thus, the Examiner’s position is that the ordinary artisan, with ordinary skill, creativity, and knowledge, would be capable of utilizing the teachings of Moon and Dagland to arrive at the claimed invention, and would have rationale for doing so.
Applicant then describes the allegedly unexpected advantages of their invention over the prior art, specifically in reducing error and simplifying workflow, particularly in Example 5 and Table 6 of the instant specification (Remarks, pages 6-7). Finally, Applicant argues with the Examiner’s interpretation of the number of reactions that may be performed in the claimed method (Remarks, page 7).
In describing these allegedly unexpected advantages, Applicant states, “A person of ordinary skill in the art would have understood from the present application that a single amplification reaction would be expected to (1) eliminate the possibility of experimental errors that are likely to occur when performing two separate amplification reactions involving two unrelated nucleic acid sequences, and (2) simplify the experimental workflow needed to determine the presence of a target sequence in a sample,” (Remarks, pages 6-7). Therefore, it is unclear if Applicant believes that the advantages of the instant invention would be expected or unexpected given the teachings of the specification. MPEP 716.02 describes the requirements for persuasively arguing unexpected results. These include explaining why the results achieved would be unexpected (e.g. they show a superior property compared to the prior art or they show greater than expected results), a comparison with the closest prior art, and a showing that unexpected results are commensurate in scope with the claimed invention. These points have not yet been shown by Applicant. Particularly regarding the final point, Example 5 and Table 6 of the instant specification focus on M. genitalium, which is not described in instant claim 1, as well as the use of particular primers, fluorophores, and quenchers that are not presented in the claim.
Regarding the Examiner’s interpretation of the claims, the Examiner does not argue that the target and control can be present in two different reaction vessels. The Examiner merely pointed out in the “Response to Applicant’s Arguments” section of the Non-Final Rejection that Applicant stated that their results are directed to the use of a single amplification reaction for detecting a control and target, but the claim itself comprises the listed steps, and therefore may involve multiple amplification reactions (e.g. an amplification reaction as described in step (b) of claim 1, and then potential additional amplification reactions). See MPEP 2111.03 I.
In considering the rejection of claim 2, Applicant reiterates their previous arguments, and also states that the combination of Moon, in view of Dagland, and in view of Oldham-Haltom does not have proper reasoning or motivation (Remarks, page 10). Specifically, Applicant objects to the “alteration of primer and probe design” language used by the Examiner. This quotation alone is an oversimplification of the Examiner’s rationale used to combine the references. Paragraph 27 of the Non-Final Rejection extensively details the differences between Oldham-Haltom and the probes of Moon in view of Dagland, and also provides a motivation (“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. Thus, the ordinary artisan would be motivated and capable of utilizing each strand of the already existing probe design of Moon in view of Dagland as the first cleaved probes in an invader cleavage assay, and then using the cleaved portions to generate a signal on a FRET cassette, as is shown in Figure 3 of Oldham-Haltom. Each of the forward and reverse primers of the double-stranded target of Moon in view of Dagland would thus be acting as an invader oligonucleotide.”). The Examiner states that the changes in primer design that would be required would be possible for the ordinary artisan based on ordinary skill and the teachings provided by Moon, Dagland, and Oldham-Haltom, and also provides an additional reasonable expectation of success (“Additionally, Oldham-Haltom shows that multiple signals can be generated with these methods (as shown by their multiplex results). Thus, there would be a reasonable expectation of success.”). Applicant does not substantively discuss this reasoning in their arguments.
Therefore, Applicant’s arguments are not considered persuasive. The 35 USC 103 Rejections provided in the Non-Final Rejection are maintained.
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.
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.
Claims 1, 3, 17-19, and 23 are 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).
Moon teaches particular probe and microarray methods, particularly methods where two different genes, such as a control and target, may be measured at once. These methods may be used for the analysis of gene expression, mutation, or disease diagnosis (Abstract). The probes of the invention are double-stranded, and can bind to genes labeled with different fluorophores (Figure 1 and paras. 19-20). The different strands of the probe may hybridize to a control and target simultaneously (paras. 22 and 25). The control and target may be situated on the sense and antisense strand of an oligonucleotide, where one strand contains the target and the other does not (para. 57). The probes of the invention can be designed to be complementary to any target gene (para. 124). In para. 134, Moon teaches that when detecting a target and control gene, the desired genes can be labeled and attached to the probes, which are anchored to a microarray (see paras. 20 and 24 for example). This microarray attachment can be done by utilizing a linker attached to the solid support (para. 113; instant claim 23). The labels would be different for the control and target genes, allowing both to be quantified (paras. 82 and Example 14, for example). This labeling is explicitly used in embodiments in which the control and target are on a sense and antisense strand (e.g. paras. 372 and 413). Moon also teaches throughout their invention and in their examples that PCR may be performed on nucleic acids before they are hybridized with the probes (e.g. paras. 190, 197, and 413).
However, Moon does not teach that probe hybridization (and therefore detection) occurs during amplification, nor does the reference teach measuring Ct values with their probes. The reference does measure Ct values is conjunction with real-time PCR, but these values are not generated from the fluorescent moieties on the genes (Figures 15A-15B and para. 329).
Dagland teaches double-stranded probes for fluorescent detection (Abstract), where these probes can be used with real-time PCR reactions (e.g. para. 209). Each strand of the probe has a fluorophore and quencher moiety (Figure 1 and para. 186), and fluorescent signal is achieved when the strands of the probe are separated from one another. The reference teaches several drawbacks related to using TaqMan probes that do not apply to their inventive probes – particularly that TaqMan probes require the use of a particular polymerase during extension and can create unwanted subproducts (para. 14). Dagland also teaches that when attempting to detect different targets (such as in a multiplex reaction), different fluorescent moieties should be used with each target-specific probe (para. 169). The reference specifically notes that double-stranded targets may be used (para. 170). Dagland also shows the measurement of Ct values in associated with their double stranded probes (Figure 4B and see the tables throughout the working examples).
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 combine the teachings of Moon in view of Dagland to arrive at the invention of instant claim 1. Specifically, Dagland shows that double-stranded probes that are not TaqMan probes may be used in real-time PCR reactions, and provides reasons why TaqMan probes may not be ideal in all scenarios. Thus, in a scenario such as that taught by Moon, where a double-stranded probe is designed to detect control and target sequences situated on opposite strands of a double-stranded nucleic acid, the ordinary artisan would recognize that this probe could act with real-time PCR primers, as taught in Dagland, to detect control and target genes. This combination would involve adding the fluorophore and quencher design described by Dagland to the probe of Moon, and using this fluorescence detection in place of the fluorescent dye labeling taught by Moon. Then, real-time PCR would proceed normally, and Ct values would be detected, as taught by Dagland (and generally by Moon). Though Dagland does not explicitly teach measuring multiple Ct values with a single given probe, the reference recognizes that different targets require different fluorophores. The target nucleic acids of Dagland are not a control/target on a sense and antisense strand as taught in Moon, but in combining these references, the ordinary artisan would use Moon’s teachings regarding the use of multiple dyes to distinguish between the control and target and Dagland’s teachings regarding multiple fluorescent moieties to recognize that two different types of fluorophores would be needed in Moon in view of Dagland. Dagland teaches multiple fluorophores (e.g. para. 51), so utilizing two would be possible, thus producing separate Ct values for each of the control/target strands. Performing real-time PCR in this manner would overall simplify the method of Moon in that a separate labeling step would not be needed, and would eliminate the need to utilize both the double-stranded probe and the TaqMan probes when performing real-time PCR, in addition to providing the benefits described by Dagland above. There would be a reasonable expectation of success because Dagland teaches the successful use of a double-probe design similar to that of Moon with real-time PCR, the design of the PCR primers would not be changed, and general methods of real-time PCR are well-known in the art.
Thus, claims 1 and 23 are prima facie obvious over Moon in view of Dagland.
Regarding claim 3, Dagland teaches that Ct values are proportional to the starting amounts of DNA present in a sample (para. 210). Moon teaches detecting the presence and amount of target genes (para. 82), and utilizes examples in which the amount of Cy5 and Cy3 fluorescence detected (i.e. the fluorescence dyes for the target and control genes) are different (see Figures 19 and 20 and para. 362, which explains the differences in quantification of a target and control gene). In Example 14 of Moon, it is also noted that the mutant genes examined are present in a smaller amount than the normal genes (paras. 420-421). Thus, in the combination of Moon in view of Dagland described above in the rejection of claim 1, the Ct values determined for each fluorescent label corresponding to each of the target and control would naturally vary depending on the amount of each gene in the sample. And in particular, when examining mutant targets, such as when diagnosing a patient for cancer or infection, the mutants will naturally be present in a smaller amount than the control sequence, and thus the target and control will naturally not have the same Ct values. As both Moon and Dagland teach disease/cancer contexts for their inventions (e.g. Moon Abstract and para. 111 and Dagland para. 59), and the ordinary artisan would be motivated to improve diagnostic methods to improve patient outcomes, utilizing samples which meet the requirements of instant claim 3 would be prima facie obvious over Moon in view of Dagland.
Regarding claims 17-18, Moon teaches comparing the target fluorescent label signals with those of the control (para. 71). The reference also teaches dividing the fluorescent signals by one another to provide normalization for the target (e.g. para. 134). In Dagland, when calculating the Ct values for their double-stranded probe, a single value is produced, but in their examples, Dagland compares these Ct values to those of molecular beacons. These comparisons are in part ratio measurements (e.g. paras. 299 and 300, where Ct values appear to be higher for the molecular beacons compared to the double-stranded probes), but also include general comparisons of the shapes of the fluorescence graphs (para. 303), where the double-stranded probes show more sigmoidal curves compared to those of the molecular beacons, which Dagland teaches enables better distinguishing from controls or samples with low amounts of a target. Figures 4A and 4B show the molecular beacon probes and the double-stranded probes, respectively, and the slightly lower Ct values for the double-stranded probes can be seen. Dagland also generally teaches that Ct values are the point at which fluorescence from PCR is measured above a background level (para. 4). As the reference already teaches comparing Ct values via ratios, it would be prima facie obvious that Ct values could be compared in ways that reveal similar information – e.g. by noting the difference between two Ct values. This would involve simple arithmetic (i.e. subtraction) that would determine, for a given amount of a sample, how Ct values vary between different methods. If a difference is found (which would indicate that a threshold number of cycles differs between the two groups), then the method with the lower Ct value could be used, as this would require less amplification (and less resources) to produce an efficient, accurate, and substantially quantifiable PCR. In considering this in the method of Moon in view of Dagland described above, controls and targets are compared with different fluorescent moieties, and so different Ct values are calculated for each, depending on how much of the target and control are in the sample (as noted above in this paragraph and discussed in the rejection of claim 3). Thus, the ordinary artisan would recognize in this context that calculating and comparing a difference of Ct values between control and target genes would be an indicator of how much target was in the sample compared to the control. This would be useful for diagnostic purposes, as very low or no amounts of target may indicate a lack of a mutant or disease, and Ct values very close to those of the control might indicate advanced disease. These determinations may therefore affect patient prognoses and treatment decisions, thus motivating the ordinary artisan. As Moon in view of Dagland already teaches calculation, manipulation, and analysis of Ct values, and finding a difference between Ct values would be possible for the ordinary artisan, there would be a reasonable expectation of success.
Thus, claims 17-18 are prima facie obvious over Moon in view of Dagland.
Regarding claim 19, Moon teaches taking test samples from a patient, where said test sample is a swab (paras. 229, 251, 279, and 309). Therefore, it would be prima facie obvious to use samples taken as swabs from patients in the methods of Moon in view of Dagland described above in the rejection of claim 1.
Claim 2 is 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).
Moon in view of Dagland teaches the methods of claims 1, 3, 17-19, and 23, as described above. Moon also teaches flap endonuclease discrimination (para. 367). However, neither reference teaches the use of invasive cleavage assays.
Oldham-Haltom teaches a reagent mixture comprising multiplexed amplification reagents and flap assay reagents for detecting point mutations in the KRAS gene (Abstract). The point mutation can occur on either strand of a double-stranded DNA molecule (para. 38). The method comprises the teachings of para. 76 and Figures 1 and 2, involving the use of an invader assay where the forward primer can hybridize to the target point mutation and cleavage is performed. Oldham-Haltom teaches that this assay generates a fluorescent signal that can be measured to determine if the mutants are in the sample (para. 76). The reference goes on to teach that the amount of product produced can be compared to the amount of a control nucleic acid present in a sample, and that the amount of this control may be measured in parallel with the target, where control specific reagents may be used (para. 77). Specifically, this would involve using flap assay reagents for both controls and targets. Ct values specifically can be calculated and compared between target and control nucleic acids (para. 79). Oldham-Haltom also teaches comparing different KRAS mutants to an ACTB internal control, where cycle threshold is calculated for the two genes (paras. 7, 10, 92, 102, 104, 113, 115, Table 2, and Figures 4 and 7). Both forward and reverse primers are taught for KRAS mutants and ACTB (“Mutation QuARTS Assay Primer” in para. 114). Additionally, Oldham-Haltom teaches that QuARTS reactions contain probes (para. 101 and Figure 3), and specifically notes KRAS specific probes and ACTB probes (paras. 103 and 113, and see Tables 3-4). These probes can be used to provide signals for detection in a multiplex reaction (para. 113). Generally, Oldham-Haltom states that their methods can be used to diagnose cancer and other diseases (para. 2).
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 Oldham-Haltom to incorporate invader cleavage methods into the method of Moon in view of Dagland described above. Specifically, the double-stranded probes of Moon in view of Dagland already have a portion that is not designed for a control/target (i.e. the stem portion of each strand) that is described as being specifically there to support the probe parts and “may have any nucleotide sequence” (para. 23). Thus, these sequences need not be complementary to the target/control regions, and so would be similar to the non-complementary flaps shown in Figure 3 of Oldham-Haltom. In Moon in view of Dagland, the double-stranded probes provide the Ct values, as they contain fluorophores. In Oldham-Haltom, a flap endonuclease is used to cleave the probe at a particular spot, and then that cleaved portion is used to induce further cleavage in a FRET cassette to produce a signal. Thus, the signal is produced due to successful cleavage, which is dependent on correct probe, primer, and nuclease activity. 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. Thus, the ordinary artisan would be motivated and capable of utilizing each strand of the already existing probe design of Moon in view of Dagland as the first cleaved probes in an invader cleavage assay, and then using the cleaved portions to generate a signal on a FRET cassette, as is shown in Figure 3 of Oldham-Haltom. Each of the forward and reverse primers of the double-stranded target of Moon in view of Dagland would thus be acting as an invader oligonucleotide. Altering the method in this way would require a slight alteration of primer and probe design (e.g. ensuring the primers bind in the proper positions and removing the fluorophores and quenchers from the probes), as well as the design of the secondary FRET cassette, both of which would be possible for the ordinary artisan, particularly as Moon and Dagland each extensively discuss probe design (e.g. Moon paras. 118-129 and Dagland paras. 9-11 and 250). Oldham-Haltom teaches that the FRET cassettes are hairpin oligonucleotides that contain fluorophores and quenchers (para. 34), and thus do not contain specialized features that the ordinary artisan would be incapable of designing. Additionally, Oldham-Haltom shows that multiple signals can be generated with these methods (as shown by their multiplex results). Thus, there would be a reasonable expectation of success.
Therefore, claim 2 is prima facie obvious over Moon, in view of Dagland, and further in view of Oldham-Haltom
Claims 20-21 are 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).
Moon in view of Dagland teaches the methods of claims 1, 3, 17-19, and 23, as described above. Moon cites references that discuss Mycoplasma genitalium (see paras. 260 and 279), and does generally teach methods for detecting bacteria and other pathogens (paras. 54 and 55). Dagland generally teaches detecting bacteria such as Mycobacteria (para. 59). Neither reference specifically teaches the detection of M. genitalium in their methods however.
Kristiansen teaches that Mycoplasma 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 (Abstract and Figure 1). Kristiansen detected M. genitalium in clinical samples, where total nucleic acid was extracted and purified, RT-PCR occurred, 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 Moon in view of Dagland to arrive at the inventions of instant claims 20-21. Kristiansen teaches that the strain of M. genitalium in 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 Moon in view of Dagland could be developed to target the region where the mutations take place as the target nucleic acid, while retaining a housekeeping gene as a control sequence. Moon teaches RT-PCR methods, as well as real-time RT-PCR methods (e.g. paras. 102 and 104), as does Dagland (e.g. para. 292), and so the successful amplification methods of Kristiansen are encompassed by the teachings of Moon and Dagland. 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 exist in a sample and 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 Moon, in view of Dagland, and further in view of Kristiansen.
Conclusion
No claims are currently allowable.
THIS ACTION IS MADE FINAL. 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
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