DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 24, 2026 has been entered. Applicant’s remarks have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any rejections or objections not reiterated herein have been withdrawn.
Claims 31-45, 47-48, and 50 are currently pending and have been examined herein.
Double Patenting
3. 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
4. Claims 31-45, 47-48, and 50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of US Patent 12,416,050 in view of Bruinsma (US 2012/0288868 Pub 11/15/2012) and Maibach (Journal of Clinical Microbiology July 2002 pages 2466-2471). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding Claim 31 both sets of claims are drawn to methods of producing an amplified product from a stool sample (see clm 1 and 9 of the Patent). Both sets of claims require forming a complex comprising: i) a target sequence-specific capture reagent comprising a particle covalently attached to a target-specific capture probe oligonucleotide complementary to methylated human ZDHHC1 DNA and ii) a strand of methylated ZDHHC1 DNA (see clms 1, 5-7 of the Patent). Both sets of claims require amplifying a region of ZDHHC1 DNA from the sample using a pair of primers that hybridize within a region of ZDHHC1 DNA corresponding to SEQ ID NO:26 (see clm 1 of the Patent). Regarding Claim 41 both sets of claims recite that detecting the amplified product comprises nucleic acid sequencing or mass based separation (see clm 5 of the Patent). Regarding Claim 42 both sets of claims recite that prior to amplification, the DNA is treated with bisulfite (see clms 2-3 of the Patent). Regarding Claim 43 both sets of claims state that the particle is a magnetic particle (clm 8 of the Patent).
The instant claims are different from the Patent claims because they recite a clarified stool supernatant sample comprising guanidine thiocyanate (clm 31 step a). The instant claims are different from the Patent because they state that the target specific capture probe oligonucleotide is covalently attached to the particle by a non-nucleic acid chemical linkage (clm 31 step a). The instant claims are different from the Patent claims because they recite a step of separating the complex from the clarified stool supernatant sample prior to amplification (clm 31 step b). The instant claims are different from the Patent claims because they recite that the non-nucleic acid chemical linkage comprises a multi carbon chain (clm 47). The instant claims are different from the Patent claims because they recite that the multi carbon chain is attached to a 5’ nucleotide of the target specific capture probe oligonucleotide (clm 48).
However Bruinsma teaches a method of isolating a target nucleic acid from a stool sample, the method comprising removing an assay inhibitor, if present, from the sample to produce a clarified sample; capturing the target nucleic acid, if present, from the clarified sample with a capture reagent to form a capture complex; isolating the capture complex from the clarified sample; and recovering the target nucleic acid, if present, from the capture complex in a nucleic acid solution (para 0008). Additionally Bruinsma teaches that DNA in the clarified supernatant is denatured by adding guanidine thiocyanate (para 0075). Further Bruinsma teaches capture probes attached to beads via a 5’ six-carbon amino modified linkage (para 0127).
It would have been obvious to have modified the method of the Patent in view of the teachings of Bruinsma. One of skill in the art would have been motivated to analyze a clarified stool supernatant sample comprising guanidine thiocyanate because a clarified stool sample would be expected to be free of contaminants and assay inhibitors. One of skill in the art would have been motivated to add guanidine thiocyanate to a clarified stool sample for the benefit of denaturing DNA so that target capture can occur. It would have been obvious to have modified the method of the Patent by attaching capture probes to beads using a 5’ six-carbon amino modified linkage particularly since Bruinsma demonstrates that this type of attachment is sufficient for attaching nucleic acids to beads. Finally one of skill in the art would have been motivated to separate the complex from the clarified stool supernatant sample prior to amplification for the benefit of further being able to enrich for the target DNA sequences and increase the sensitivity of detection.
The instant claims are different from the Patent because they state that the target-specific capture probe oligonucleotide is complementary to methylated human ZDHHC1 DNA at a site within SEQ ID NO: 26 (clm 31). The instant claims are different from the Patent because the complex further comprises a strand of methylated ZDHHC1 DNA comprising SEQ ID NO 26 (clm 31).
However Maibach teaches total bacterial DNA was isolated from stool specimens using Qiagen columns followed by a T. whipplei-specific hybridization step with a biotinylated capture probe and streptavidin-coated magnetic particles. The captured DNA was then amplified using the same seminested PCR targeting the 16S rRNA gene of the organism that had been applied to other specimens without capturing (abstract). For sequence capturing of the T. whipplei DNA, 5-biotinylated oligonucleotides TW963f (5-GTAGAGATACGCCCCCCGCAAGGT) and TW1084r (5-GTCTCCTGTGAGTCCCCGCCATTAC) designed using the software Oligo 4.1 (Wojciech Rychlik, National Biosciences) were used. These oligonucleotides are complementary to the 16S rDNA specific for T. whipplei in the area between primers TW1 and TW3 (Fig. 1) (page 2467).
It would have been obvious to have modified the method of the Patent by forming a complex between a target specific capture probe complementary to methylated human ZDHHC1 DNA at a site within SEQ ID NO: 26 and a strand of methylation ZDHHC1 DNA comprising SEQ ID NO: 26. It is noted that the Patent recites amplifying a region of ZDHHC1 using a pair of primers that hybridize within SEQ ID NO: 26. Maibach teaches that when performing target capture prior to PCR one should use capture probes that hybridize between the primers that will be used for amplification. Based on this teaching the skilled artisan would have been motivated to design a target specific capture probe complementary to SEQ ID NO: 26 for the benefit of enriching for sequences comprising SEQ ID NO: 26 since SEQ ID NO: 26 is the target region that is going to be amplified.
The instant claims are different from the Patent claims because they recite further detecting the amplified product (clm 32). The instant claims are different from the Patent claims because they recite that the measuring comprises a quantitative amplification reaction (clm 33). The instant claims are different from the Patent claims because they state that the quantitative amplification reaction comprises real-time fluorescence detection (clm 34). The instant claims are different from the Patent claims because they state that measuring comprises detecting hybridization of the-amplified product to a detection probe (clm 35). The instant claims are different from the Patent claims because they state that the detection probe comprises a flap sequence (clm 36). The instant claims are different from the Patent claims because they state that the detection probe comprises a reporter molecule (clm 37). The instant claims are different from the Patent claims because they state that the reporter molecule comprises a fluorophore (clm 38). The instant claims are different from the Patent claims because they state that detecting hybridization of the amplified product to said detection probe comprises use of a FEN-1 endonuclease (clm 39). The instant claims are different from the Patent claims because they state that detecting hybridization of the amplified product to said detection probe comprises use of a FRET cassette (clm 40). It is noted that claims 32-41 recite the methods and reagents that are used to perform the QuARTS method.
However Bruinsma teaches that the captured DNA can be used in methylation assays. Bruinsma teaches that methylated markers were quantified by the QuARTS method. This method combines a polymerase-based target DNA amplification process with an invasive cleavage-based signal amplification process. We treated captured DNA with bisulfite and the bisulfite-treated DNA was assayed with the QuARTS method on a 96-well PCR plate. PCR plates were cycled in a LightCycler 480 (Roche) (para 0129). Bruinsma teaches that QuARTS assays were designed to detect the methylated markers vimentin, NDRG4, BMP3, and TFPI2 using ACTB as a reference gene for each. Each QuARTS reaction incorporated primers and detection probes, invasive oligonucleotide, fluorescence resonance energy transfer reporter cassettes (FRETs), Cleavase 2.0 (Hologic), and DNA polymerase. For each target there were two methylation-specific primers and a probe (para 0129).
Accordingly, it would have been obvious to have modified the method of the Patent application by performing the QuARTS assay to measure the amount of ZDHHC1 as suggested by Bruinsma. In the instant case Bruinsma demonstrates that this methylation assay works well and has multiplex capacity. Thus one of skill in the art would have been motivated to use the QuARTS assay to detect methylation in order to achieve the known benefits of multiplex capacity.
The instant claims are different from the Patent claims because they state that the
capture probe is 15-100 nucleotides long (clm 44). The instant claims are different from the Patent claims because they state that the complete length of the capture probe hybridizes to the target (clm 45).
However Bruinsma discloses capture probes that are 15-100 nucleotides long (see para 0127). Further Bruinsma teaches that the complete length of a capture probe may bind to the target (para 0054).
It would have been obvious to have modified the method of the Patent application by using capture probes that are between 15-100 nucleotides long and completely hybridizes to the target as suggested by Bruinsma. This length and specificity would have been obvious to use based on the teachings of Bruinsma for the benefit of being able to capture target nucleic acids.
The instant claims are different from the Patent claims because they state that the clarified stool supernatant is pretreated to remove assay inhibitors (clm 50).
Bruinsma teaches removal of assay inhibitors from a stool sample (para 0077).
It would have been obvious to have modified the method of the Patent application by adding guanidine thiocyanate to stool samples and then treating the sample to remove assay inhibitors for the benefit of being able to prepare the DNA for amplification.
Response To Arguments
5. In the response the Applicants traversed the double patenting rejection over US Patent 12,416,050. The Applicants argue that claim 1 of the '050 patent is silent with respect to using target capture in the method, makes no mention of using "a target-specific capture probe oligonucleotide complementary to methylated human ZDHHC 1 DNA" and is also silent regarding formation of "a complex" having the features set forth in instant claim 31. While claim
7 of the '050 patent recites using "capture reagents [that] comprise oligonucleotides complementary to the marker genes and the methylated ZDHHC1 DNA", the claims of the '050 patent are silent with respect to the location of hybridization of a capture probe complementary to the methylated human ZDHHC1 DNA.
This argument has been fully considered. It is noted that the double patenting rejection has been modified to address this discrepancy. The claims are now rejected over the Patent in view of Bruinsma and Maibach. Maibach teaches total bacterial DNA was isolated from stool specimens using Qiagen columns followed by a T. whipplei-specific hybridization step with a biotinylated capture probe and streptavidin-coated magnetic particles. The captured DNA was then amplified using the same seminested PCR targeting the 16S rRNA gene of the organism that had been applied to other specimens without capturing (abstract). Maibach teaches that the capture probe was complementary to the target in between the primers that were used in the PCR step (page 2467). It would have been obvious to have modified the method of the Patent by forming a complex between a target specific capture probe complementary to methylated human ZDHHC1 DNA at a site within SEQ ID NO: 26 and a strand of methylation ZDHHC1 DNA comprising SEQ ID NO: 26. It is noted that the Patent recites amplifying a region of ZDHHC1 using a pair of primers that hybridize within SEQ ID NO: 26. Maibach teaches that when performing target capture prior to PCR one should use capture probes that hybridize between the primers that will be used for amplification. Based on this teaching the skilled artisan would have been motivated to design a target specific capture probe complementary to SEQ ID NO: 26 for the benefit of enriching for sequences comprising SEQ ID NO: 26 since SEQ ID NO: 26 is the target region that is going to be amplified.
Additionally the Applicants argue that the claims of the '050 patent also do not recite or suggest a clarified stool supernatant sample comprising guanidine thiocyanate, nor that the target-specific capture probe oligonucleotide is covalently attached to the particle by a non-nucleic acid chemical linkage.
This argument has been fully considered. The Exmainer agrees that the claims of the Patent do not recite these limitations. However the instant claims are rejected over the Patent in view of Bruinsma and Maibach. Bruinsma is being relied upon to teach these limitations and it would have been obvious to modify the method of Patent in view of the teachings of Bruinsma for the reasons set forth above.
Further, the Applicants argue that the additionally cited reference (Bruinsma) does not cure the deficiencies or supply the missing elements of the '050 claims to arrive at Applicant's claims.
This argument has been fully considered. The Applicants arguments regarding what is missing in the Patent have been fully addressed above. The response to Applicants arguments, as set forth above, applies equally to the present ground of rejection.
6. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached on Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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