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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claims 6 and 9 are objected to because of the following informalities:
Claims 6 and 9 should read as “…comprising counting the number of copies of the plurality of genetic mutations, the number of copies of the plurality of genetic mutations in a cis form, and the number of copies of the plurality of genetic mutations in a trans form for the DNA contained in the test biological sample…”
Appropriate correction is required.
Claim Interpretation
Claim 5 is directed to a first database and claims 7 and 8 are directed towards a second database. These databases are defined by the information that is stored within them: the first databases contains melting temperatures and the second database can contain melting temperatures as well or one of a selection of melting curve characteristics. The claimed method does not appear to require use of both databases. Therefore, it could be reasonably assumed that the designations of “first” and “second” do not refer to a specific order of use or two different databases, but rather represent two embodiments of the same database
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 1-12 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.
Claim 1 recites preparing “probes” (plural), performing an amplification with “the probes” (plural), but then recites measuring a binding of an amplicon to “the probe” (singular). It is unclear which of “the probes” is “the probe” for which binding is measured. As claims 2-12 ultimately depend from claim 1, they are rejected for the same reason. The same issue occurs in claims 2 and 3, which refer to “the probe”.
Claims 6, 9, and 14 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 6 and 9 are indefinite because they recite “counting the number of copies…using the first/second database”. However, the databases are defined in claims 5, 7, and 8 as storing information related to melting temperatures and melting curve characteristics. Therefore, it is unclear how these databases would be used to count the number of copies in a sample.
Claim 14 is indefinite because it recites both a product (a kit) and a process (a method of using the kit). MPEP 2173.05(p)(II) states Katz, 639 F.3d at 1318, 97 USPQ2d at 1749 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.3d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005), in which a system claim that recited "an input means" and required a user to use the input means was found to be indefinite because it was unclear "whether infringement … occurs when one creates a system that allows the user [to use the input means], or whether infringement occurs when the user actually uses the input means."); Ex parte Lyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990). In the case of the instant, it is unclear if infringement would occur when a kit is created which generally comprises primers and probes or if infringement would occur when those kits are used to perform the method steps. These method steps are directed towards the actions which would be performed by the user of the kit, rather than the capabilities of the kit itself.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 13-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to either an abstract idea or a product of nature without significantly more.
Claim 13 recites “a kit...comprising…a primer pair…and a plurality of probes…”. This is a natural product. Primers and probes are nothing more than strands of nucleic acids whose characteristics are innate to naturally occurring DNA, thus lacking markedly different characteristics from nature (see MPEP 2106.04(C).II.C.2; Ambry Genetics, 774 F.3d at 760-61, 113 USPQ2d at 1244).
The additional limitations of claim 13 further define the characteristics of the primers and probes. However, these limitations do not meaningfully distinguish them from their natural counterpart. For example, the probes, regardless of their target, are simply fragments of DNA which are complementary, and thus indistinguishable from, to their naturally occurring target. Therefore, these limitations are considered to be insignificant extra-solution activity.
The additional limitations of claim 14 are method steps which dictate a specific use of the kit. However, these are equivalent to mere instruction to apply a judicial exception and insufficient to integrate the judicial exception into a practical application. These method steps do not meaningfully alter the structure of the product of nature in such a way as to distinguish it from its natural counterpart. Rather, the method steps merely describe how these product of nature are used.
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception?
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.
Claims 1 and 2 are rejected under 35 U.S.C. 102(a)1 as being anticipated by Pont-Kingdon [Pont-Kingdon G, Lyon E. Nucleic acids research. 2005 Jan 1;33(10):e89, p1-8] as evidenced by ThermoFisher [ThermoFisher Scientific. “DNA Polymerase – Four Key Characteristics for PCR”. 2021 Dec 09: p1-4. Accessed from the WayBack Machine on 2026 July 29].
Regarding claim 1, while genetic variations are known to cause or increase risk of disease as well as affect an individual’s response to therapeutic treatments, studies have shown that the combination of multiple polymorphisms on the same DNA molecule, or an individual’s haplotype, can sometimes be a stronger predictor of phenotypes than a single polymorphism. While molecular haplotyping has been historically difficult, melting curve analysis of hybridization probes is used extensively as a genotyping tool and Pont-Kingdon adapted this method for use in SNP haplotyping. During amplification, fluorescein-labeled probes are annealed to the target adjacent to probes labeled with an accepter dye. While annealed to the target, fluorescence signal is generated. During the melting cycle, as the sample is heated, the probes melt from the template and fluorescent signal is lost. This melting temperature (Tm) is specific to the length of the probes, their nucleotide composition, as well as their homology with the template [Pont-Kingdon, p1].
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To demonstrate this method, Pont-Kingdon performed haplotyping of three well-documented single nucleotide polymorphisms (SNPs), SNP-20, SNP46, and SNP79, in the beta 2-adrenergic receptor (β2AR) gene [p1]. The three SNPs were amplified together using gene-specific forward and reverse primers resulting in a 219nt long PCR fragment. This PCR fragment was then interrogated by multiple hybridization probes specific to either SNP-20/46 or SNP46/79 (Figure 1B below). During the melting cycle, fluorescence was continuously monitored and resulted in six melting curves for each probe determined by the number of probe-template mismatches (Figures 1C and 1D below). Probes were most stable (had the highest Tm) when there were no mismatches and corresponded to haplotype 2; haplotype 6 had an intermediate Tm with one mismatch; and haplotype 4 had the lowest Tm with two mismatches. Homozygous samples displayed a single melting curve, while heterozygous samples displayed two melting curves. Using this information, Pont-Kingdon was able to determine the phase (haplotype) of the SNPs, thereby determining whether they reside on the same (cis) allele or on different (trans) alleles [Pont-Kingdon, p2].
Pont-Kingdon also hypothesized that each probe dissociates from the template as a single unit, rather than as two domains, regardless of the number of mismatches. To test this theory, Pont-Kingdon designed a probe set to interrogate all three SNPs simultaneously such that haplotype 2 would have no mismatches, haplotype 6 would have two mismatches, and haplotype 4 would have three mismatches. By labeling each end of the probe with different fluorophores, they were able to examine the melting temperature of each end of the probe independently. The result was identical melting curves confirming the theory that the probe dissociates as a unit (Figure 2B below) [Pont-Kingdon, p3-4].
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To summarize, Pont-Kingdon teaches (1) designing probes corresponding to a plurality of genetic mutations; (2) amplifying a region comprising the plurality of genetic mutations using target specific primers, the designed probes, and test samples; (3) performing melting curve analysis at varying temperatures to determine the melting temperature of the probe-amplicon complex; and (4) using the results of the melting curve analysis to determine if the haplotype of the SNPs which informs on their chromosomal configuration (i.e., cis or trans). While Pont-Kingdon does not explicitly state that an enzyme was included in their amplification reaction mix, they do indicate that PCR was performed which requires the use of a DNA polymerase as evidenced by ThermoFisher [ThermoFisher, p1].
As such, the method of Pont-Kingdon anticipates the method of the instant application.
Regarding claim 2, the SNP-20/46 and SNP46/79 probes were labeled with fluorescein and the probe containing all three SNPs was labeled on one end with LCred640 and on the other end with LCred705 [Pont-Kingdon, p1, 3]. Melting curves were generated based upon the changing levels of fluorescence in a sample as temperature was adjusted reflecting the stability of the binding between the amplicon and the probe [Pont-Kingdon, p6].
Claim 3 is rejected under 35 U.S.C. 102(a)1 as being anticipated by Pont-Kingdon as evidenced by ThermoFisher and Public Health Research Institute [Public Health Research Institute. “Introduction on Molecular Beacons”. Molecular Beacons. 2023 Mar 14: p1-3. Accessed from the WayBack Machine on 2026 July 29].
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Regarding claim 3, Pont-Kingdon teaches that other probe systems can be used in their method including molecular beacons [Pont-Kingdon, p7]. The Public Health Research Institute (PHRI) describes molecular beacons as single stranded oligonucleotide hybridization probes that form a stem-and-loop structure wherein the loop contains a probe sequence complementary to a given target and the stem is formed by the annealing of complementary arm sequences. When the probe encounters and binds to its target, the stem-loop structure is lost [PHRI, p2].
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.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Pont-Kingdon as evidenced by ThermoFisher.
As discussed in the rejection of claim 1, Pont-Kingdon teaches a method for determining the molecular haplotype of a sample by performing melting curve analysis. Briefly, Pont-Kingdon teaches (1) designing probes corresponding to a plurality of genetic mutations; (2) amplifying a region comprising the plurality of genetic mutations using target-specific forward and reverse primers, the designed probes, and test samples; (3) performing melting curve analysis at varying temperatures to determine the melting temperature of the probe-amplicon complex; and (4) using the results of the melting curve analysis to determine if the haplotype of the SNPs which informs on their chromosomal configuration (i.e., cis or trans).
Pont-Kingdon does not describe performing this method on a subject and using the results to assess if said subject has the trait associated with the plurality of genetic mutations. However, they teach that combinations of SNPs in-cis can be a stronger phenotypic predictor of disease risk and treatment response than the presence of the SNPs alone and expressly state that their method could be used as the basis for clinical genetic testing of individual samples [Pont-Kingdon, p1, 7]. Therefore, one of ordinary skill in the art prior to the effective filing date of the claimed invention, would have been motivated to apply the method of Pont-Kingdon to assess patient samples in order to determine whether or not they had an increased risk of disease or therapeutic resistance based upon the configuration of a selection of SNPs.
Claims 4, 5, 7, 8, and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Pont-Kingdon as evidenced by ThermoFisher as applied to claim 1 above, and further in view of Gupta [US 20120070820 A1].
Pont-Kingdon is applied to the relevant teachings of claim 1 as discussed above and is incorporated herein by reference. Briefly, Pont-Kingdon teaches (1) designing probes corresponding to a plurality of genetic mutations; (2) amplifying a region comprising the plurality of genetic mutations using target-specific forward and reverse primers, the designed probes, and test samples; (3) performing melting curve analysis at varying temperatures to determine the melting temperature of the probe-amplicon complex; and (4) using the results of the melting curve analysis to determine if the haplotype of the SNPs which informs on their chromosomal configuration (i.e., cis or trans).
Pont-Kingdon does not teach (1) performing asymmetric PCR, (2) comparing the melting temperature/melting curve of the DNA contained in a test biological sample to a database of known melting temperatures and/or melting curve characteristics in order to determine if the mutations within the sample are in-cis or in-trans, or (3) including the method’s primers and probes in a kit.
Regarding claims 5, 7, and 8, Gupta is directed towards a method for determining the genotype or subtype of an HCV isolate. Hybridization complexes between HCV-probes and known HCV samples are characterized by their melting temperatures which is compared to the melting characteristics of the HCV-probes and unknown isolates. While ideally each probe-target complex would result in a unique Tm, the large number of known HCV types results in a range of Tm values for each complex as opposed to one single value. Gupta’s method overcomes this issue by utilizing a multidimensional approach which is capable of typing HCV as well as quantitating (e.g. determine viral load or copy number) the HCV genomic material in a sample [Gupta, 0038-0040].
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A portion of the HCV genome is amplified and the amplicons are hybridized to at least two probes with known melting temperature profiles for each of the HCV types. The melting temperature obtained from the unknown sample is then compared to each probe. The combination of information is what allows for unique identification of probe type. Figure 9 (below) shows an example of this where probe A can distinguish types 1, 3, and 6 but cannot distinguish types 2 and 4; probe B can distinguish types 1, 2, 3, and 5 but not types 4 and 6. Individually neither probe is able to fully distinguish all six types from one another, but together they can [Gupta, 0042]. This also has the added benefit of making the method less susceptible to the false typing results that can occur from single probe analyses of clinical specimens where intragenotype variance is expected [Gupta, 0174].
Gupta additionally teaches a “correlation module” which calculates the Tm of the unknown sample and derives the HCV type by comparing it to a database of known HCV types. This database can comprise predicted or experimentally predetermined values for hybridization properties, such as Tm. By integrating the systems that obtain the data and the correlation module which interprets it, an automated assay for determining HCV type is obtained, which removes any need for operator input after initialization [Gupta, 0254-0268].
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention, to modify the melting curve haplotyping method of Pont-Kingdon to incorporate Gupta’s automated comparison process in which an unknown sample is compared to a database of known values, providing the benefits of reducing the amount of hands-on time required for analysis, eliminating any human subjectivity in the interpretation, and standardizing the overall method for implementation across a range of clinical and research spaces. As both Pont-Kingdon and Gupta are amplifying nucleic acids and measuring the melting behavior of probe-target complexes in order to identify a particular genetic state, this combination amounts to nothing more than applying a known technique to a known device (method or product) ready for improvement to yield predictable results which is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, D.).
Regarding claim 4, Gupta performed asymmetric PCR in the amplification step. This results in an abundance of amplicons which are identical to the HCV genomic strand and which will hybridize to the HCV typing probes [Gupta, 0282]. The skilled artisan would recognize that this would have the benefit of increasing the amount of detectable fluorescence present in a sample, particularly for samples in which there was minimal starting material such as a blood or serum sample.
Regarding claims 13-14, Gupta also discloses a kit comprised of a plurality of reagents, including probes and primers, for use in their HCV typing method [Gupta, 0247-0253].
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Pont-Kingdon as evidenced by ThermoFisher as applied to claim 1 above, and further in view of Nakagawa [Nakagawa T et al. Analytical chemistry. 2020 Aug 7;92(17):11705-13; IDS Reference].
Pont-Kingdon is applied to the relevant teachings of claim 1 as discussed above and is incorporated herein by reference. However, Pont-Kingdon does not teach the inclusion of a wild-type probe in the amplification solution.
Nakagawa teaches performing amplification and melting curve analysis of samples using both mutation-specific probes and wild-type-specific probes. Specifically, Nakagawa’s amplification mixture includes a wild-type KRAS detection probe, probes for specific KRAS mutations (G12A, G13D, G12R, G12D, G12V, G12S, and G12C), a wild-type BRAF detection probe, and a probe for the BRAF mutant V600E. The results showed that the wild-type and mutant groups were clearly identified and could be quantified by combining the fluorescence intensities, dye color, and Tm values [Nakagawa, p11706].
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Pont-Kingdon to include an additional wild-type probe in the amplification solution because Nakagawa demonstrates that wild-type probes and mutation-specific probes can be used together to obtain melting curve data which distinguishes between mutant and wild-type. This would have had the benefit of providing more information regarding the genetic state of the sample being examined. For example, an individual may have one mutant chromosome and one wild-type chromosome while another individual is homozygous for the mutant chromosome. By including the wild-type probe in the reaction solution, the skilled artisan will be able to distinguish between them which would not be possible without it.
Claims 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Pont-Kingdon and Gupta as evidenced by ThermoFisher as applied to claims 1, 5, and 7 above, and further in view of Nakagawa.
Pont-Kingdon and Gupta are applied to the relevant teachings of claims 1, 5 and 7 as discussed above and are incorporated herein by reference.
Nakagawa teaches a method for performing multiplex genotyping using digital PCR (dPCR) and melting curve analysis. First, a sample is partitioned and asymmetric PCR is performed in each of the partitions. Asymmetric PCR is used in order to increase the number of single-stranded amplicons present in each partition that are complementary to the molecular beacon probes used by Nakagawa for melting curve analysis. Genotype is then determined by using the fluorescence intensity, the dye color of the probe, and the melting temperature of the probe/template complex. Using this method, Nakagawa was able to simultaneously identify and quantify wild-type KRAS and BRAF, as well as eight mutants of these genes [Nakagawa, abstract].
In dPCR, a sample solution containing target DNA is divided into wells before PCR so that each well contains one or zero copies of DNA. If after amplification the well is positive for a given target, then it can be assumed that that well represents one copy of the target. By counting all the positive wells, the skilled artisan is able to determine the copy number of the original sample. By using the fluorescence intensity, probe dye color, and melting temperature information of each well, Nakagawa was able to determine exactly how many copies of each target were present in the original sample.
Therefore, one of skill in the art prior to the effective filing date of the claimed invention, would have been motivated to modify the method of Pont-Kingdon and Gupta to employ the dPCR approach of Nakagawa. In order to perform haplotyping, Pont-Kingdon modified genotyping assays based off of melting curve analysis. Gupta and Pont-Kingdon both employ probe-based melting analyses for genotype determination with Nakagawa further teaching that such analysis can be performed in a dPCR format to additional quantify target copy number. Accordingly, the combined teachings would have resulted in a method in which a sample is interrogated with probes specific for a single mutation, two mutations together, or the absence of mutations wherein the resultant melting curve data is compared to a computerized reference database to quantitatively identify the genomic state of the sample.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 13 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-14 of copending Application No. 18/765,470.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
Claim 13 (and its dependent claim 14) is directed to a kit comprising a primer pair and a plurality of probes. Claims 11-12 and claim 14 of the copending application are directed to two kits each comprising a primer pair, a fluorescent-labeled probe, an additive, and a DNA polymerase. While the instant kit does not claim an additive or a DNA polymerase, use of “comprising” allows for other components to be present in addition to those specifically claimed. Similarly, while the kits of the copending application only require one probe, the use of “comprising” allows for additional probes (i.e., a plurality of probes) to be present.
This is a provisional nonstatutory double patenting rejection.
Claims 1-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of copending Application No. 18/765,470 in view of Pont-Kingdon.
Copending application 18/765,470 describes a method for DNA detection in which a reaction mix comprising probes, primers, a sample, an enzyme, and an additive is divided into a plurality of micro partitions in which amplification is performed. Using fluorescence information obtained from the probe as the temperature is changed, melting curve analysis is performed in each of the partitions in order to calculate a melting temperature. Using this information, the presence, absence and/or type of DNA in each of the partitions is determined.
It further teaches:
The target DNA comprises a plurality of target genes and melting curve analysis is performed on each (claim 6). The application does not specify that these targets are mutations; therefore, one such target could be a wild-type.
The probe comprises a fluorescent dye and a quenching dye where the fluorescent dye is used to measure the binding between the amplified DNA and the probe (claim 2).
The probe has complementary terminal sequences wherein the probe in free form would cause the fluorescent dye to be quenched (claim 3).
Amplification is performed by asymmetric PCR (claim 8)
Counting the number of target DNA using the results (claim 4).
The copending application does not disclose using the melting temperature to determine if a plurality of mutations are present in cis or in trans, the use of a melting temperature database to make this determination, or using the results to assess if a subject has a trait (i.e., susceptibility to a disease/disorder or drug responsiveness) associated with a plurality of mutations.
As discussed in detail above, Pont-Kingdon teaches performing a method for determining the molecular haplotype of a sample by performing melting curve analysis. Briefly, Pont-Kingdon teaches (1) designing probes corresponding to a plurality of genetic mutations; (2) amplifying a region comprising the plurality of genetic mutations using target-specific forward and reverse primers, the designed probes, and test samples; (3) performing melting curve analysis at varying temperatures to determine the melting temperature of the probe-amplicon complex; and (4) using the results of the melting curve analysis to determine if the haplotype of the SNPs which informs on their chromosomal configuration (i.e., cis or trans). In order to arrive at this method, Pont-Kingdon adapted similar melting temperature analysis methods used for genotyping (like that of the copending application). Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention, that the method taught by the copending application could be used to determine the chromosomal configuration of specific mutations, as demonstrated by Pont-Kingdon. While Pont-Kingdon does not describe performing this method on a subject and using the results to assess if said subject has the trait associated with the plurality of genetic mutations, they do teach that combinations of SNPs in-cis can be a stronger phenotypic predictor of disease risk and treatment response than the presence of the SNPs alone and expressly state that their method could be used as the basis for clinical genetic testing of individual samples [Pont-Kingdon, p1, 7].
Gupta teaches a method for typing HCV isolates which includes the use of a “correlation module” which calculates the Tm of the unknown sample and derives the HCV type by comparing it to a database of known HCV types. This database can comprise predicted or experimentally predetermined values for hybridization properties, such as Tm. By integrating the systems that obtain the data and the correlation module which interprets it, an automated assay for determining HCV type is obtained, which removes any need for operator input after initialization [Gupta, 0254-0268].
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention, to modify the melting curve haplotyping method of the copending application and Pont-Kingdon to incorporate Gupta’s automated comparison process in which an unknown sample is compared to a database of known values, providing the benefits of reducing the amount of hands-on time required for analysis, eliminating any human subjectivity in the interpretation, and standardizing the overall method for implementation across a range of clinical and research spaces.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/K.N.K./Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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