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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election of Group I, claims 1-24, and the required species, a specific first group of oligonucleotides and primer probe combination of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9 in the reply filed on 4/15/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 25-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/15/2026.
Claims 1-24 are under examination on the merits.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 5/16/2023 is in compliance with 37 CFR 1.97. Accordingly, the references listed in the IDS are being considered by the examiner.
Claim Objections
Claims 1-5, 10, 12, 16, 20, 23, and 24 are objected to because of the following informalities: the claims recite “oligonucleotides having the nucleic acid sequence of SEQ ID NO: 7, SEQ ID NO:8, and SEQ ID NO:9”, or the like. To put the claims in better form, and to avoid the claims from reading on a single oligonucleotide comprising a fusion of such sequences on the same molecule, it is suggested to change the claim language to indicate that each oligonucleotide has one of the sequences. Appropriate correction is required.
Additionally, Claims 1 and 16 recite “selected from the groups consisting of”, which is not a proper Markush format, by reciting “the groups consisting of” instead of “the group consisting of”. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: claim 2 recites “wherein the composition optionally includes a second composition comprises oligonucleotides” on lines 1-2. The claim appears to recite a typographical error, where it should instead read “wherein the composition optionally includes a second composition that comprises oligonucleotides [..]”. Appropriate correction is required.
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 1-4 and 16-18 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 16 recite “selected from the groups consisting of”. The claim limitation renders the claims indefinite because it is unclear whether compositions are limited to the oligonucleotides (claim 1) or primer probe combination (claim 16) of a single group (e.g., “a)”), or instead one may mix and match between different oligonucleotides or primer probe combinations from different groups. Accordingly, the metes and bounds of the claims are unclear.
As indicated in the Claim Objection above, claims 1 and 16 use an improper Markush format, rendering the claims unclear. E.g., it is not clear if the composition as claimed is limited to the grouping of oligonucleotides as specified in each individual recited group, or if the claimed combination can also encompass a group oligonucleotides mixed and matched from different groups of the specified groups of oligonucleotides.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 recites “a composition according to claim 1, wherein the composition optionally includes a second composition comprises oligonucleotides having the sequence of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18”. Claim 2 does not further limit claim 1, because the claim limitation presented after “optionally” are not required. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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.
Claims 1-3, 5-11, 15-19, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Gagnieur, et al. (Biologicals. 2014 May;42(3):145-52. Epub 2014 Mar 22. PMID: 24661556, on IDS), in view of GenBank accession: MG026728.1 (1/28/2018), Huang, et al. (BMC Bioinformatics. 2014 Sep 25;15(1):317. PMID: 25252611), Poetter, et al. (WO 2013049891 A1, published 4/11/2013, filed 10/4/2012), and Kavlick, et al. (Biotechniques. 2018 Nov;65(5):275-280. doi: 10.2144/btn-2018-0034. PMID: 30394127; on IDS).
The claimed invention encompasses a composition comprising oligonucleotides of: c) oligonucleotides having the nucleic acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9 (claim 1, elected species).
The Prior Art
Gagnieur discloses methods of detecting viral contaminants in fetal bovine serum (FBS) and trypsin reagents used in cell culture (Abstract). Gagnieur specifically discloses, to assess the frequency and serum load of BPV3 in FBS, qPCR was performed, and a load of 5.9-6.0 log gc/mL of BPV3 was detected (pp. 148-149, bridging para.; Table). Gagnieur also discloses that the risks of contamination of cell culture by the use of biological reagents are well known, FBS is one of the biological reagents of animal origin used in cell culture, and FBS was the likely source of infection of fermenters by several different viruses (p. 145, col. 1). Gagnieur further teaches that virus testing of raw materials has been set up with the objective of controlling the corresponding risks (p. 145, col. 1). Gagnieur also discloses that nucleic acid extraction of samples was conducted (p. 146, col. 1, last para).
Accordingly, Gagnieur teaches the detection of BPV-3 by qPCR. However, Gagnieur does not specifically disclose oligonucleotides having the nucleic acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, or SEQ ID NO: 9, which represent primer/probe sequences for qPCR.
GenBank accession: MG026728.1 discloses bovine parvovirus 3 isolate ujs497 nonstructural protein and structural protein genes, complete coding sequence, which comprises genetic segments which are identical to SEQ ID NOs: 7-9. SEQ ID NO: 7: is identical to nucleotides 1280-1301, SEQ ID NO: 8: is reverse and complement to nucleotides 1423-1402, and SEQ ID NO: 9 is identical to nucleotides 1326-1340 of MG026728.1, which are each within the sequence of the nonstructural protein of the BPV-3 genome, the coding sequence of which occupies nucleotides 210 to 2165 of the genome (p. 1). Teachings of GenBank accession: MG026728.1 indicate that the genome nucleic acid sequence of BPV-3 is known in the art.
Huang, et al. discloses PRISE2, a software tool for designing sequence-selective PCR primers and probes (Abstract). PRISE2 allows the user to specify a collection of target sequences that the primers are supposed to amplify, and users can specify desired properties of primers, including length, GC content, and others, and a similar process is used to add probes to selected primer pairs (Abstract). Huang teaches that although designing PCR primers manually is tedious and time consuming, it can be streamlined and greatly simplified with the aid of appropriate software, which can be used to identify target and non-target sequences (p. 1, col. 2, para. 3). Huang further teaches that designing primers and probes in PRISE2 is accomplished in three stages: 1) Identification of target and non-target sequences, where the user can download a collection of sequences from GenBank and use the provided interactive tools to choose from them (or from other collections of sequences) the desired sets of target and non-target sequences, 2) Generation of candidate primer pairs, where the program computes a set of primer candidates, according the specified parameters, and groups them into primer pairs, and the user can use sorting tools to manipulate the list of primer pairs to choose a smaller collection of high quality primer pairs, and 3) Adding probes, where for each primer pair, PRISE2 determines a list of candidate probes (p. 3, col. 1). Huang teaches that the module for adding probes for the primer pairs may be used for quantitative PCR (qPCR) analyses, such as Taqman assays, where probes play an essential role in monitoring the amount of sequence amplification (p. 4, col. 2, para. 3), and that the process of probe design is similar to that for primers, involving selecting probe properties such as probe length, GC content, etc., and that one probe attribute that assures that the probes will function properly during the qPCR process is the difference of melting temperatures between the primer pair and its associated probe (p. 4, col. 2, para. 4).
Accordingly, teachings of Huang suggest that design of primers/probes for qPCR assay is a routine process.
It would have been obvious to one of ordinary skill in the art to modify the method of detecting bovine parvovirus 3 disclosed by Gagnieur to arrive at the invention as claimed. Design of primers/probes for qPCR is known and routine, and the primer/probe sequences as claimed are considered as being able to be obtained through routine experimental optimization unless there is evidence that they are critical.
Regarding claims 1-3, 5, and 10, which requires a composition comprising oligonucleotides having the nucleic acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, one of ordinary skill in the art would arrive at the primers through routine experimental optimization, see MPEP §2144.05(II), because MG026728.1 discloses the full coding sequence of a bovine parvovirus 3 isolate, which is identical in parts to SEQ ID NOs: 7, 8, 9, and programs such as Huang demonstrate that primer design is a routine process in the art. Additionally, Huang discloses generating a nucleotide probe that is complementary to the amplicon of the target of interest. Regarding claim 5, and its dependent claims’ requirement to detect BPV-3 genomic DNA in extracted DNA of a test sample, Gagnieur discloses extraction of viral DNA from FBS samples. One of ordinary skill in the art would have been motivated to use the primers for methods in detecting BPV-3 contamination. There would be a reasonable expectation of success because Gagnieur demonstrates that its method is capable of detecting BPV-3, and Huang discloses that primer design is routine.
Regarding claim 8, which requires that the primer probe combination detects DNA encoding the structural capsid (VP) protein and/or the non-structural (NS) protein of BPV-3 in the test sample, MG026728.1 discloses BPV-3 isolate ujs497 nonstructural protein and structural protein genes, complete coding sequence, which comprises genetic segments which are identical to SEQ ID NOs: 7-9. SEQ ID NO: 7: is identical to nucleotides 1280-1301, SEQ ID NO: 8: is identical to nucleotides 1423-1402, and SEQ ID NO: 9 is identical to nucleotides 1326-1340 of MG026728.1, which are each within the sequence of the nonstructural protein of the BPV-3 genome, the coding sequence of which occupies nucleotides 210 to 2165 of the genome. Accordingly, it would have been obvious to one of ordinary skill in the art to design a primer probe combination to detect the non-structural protein of BPV-3. One of ordinary skill in the art would have been motivated of detecting BPV-3 contamination.
Therefore, claims 1-3, 5, 8, and 10 were prima facie obvious before the priority date of the instant invention.
However, Gagnieur, Genbank accession: MG026728.1, and Huang do not teach SEQ ID NO: 9 has a fluorescent reporter dye and/or a non-fluorescent quencher (claim 6) and the fluorescent reporter is 6-carboxyfluorescein (FAM) at the 5’ end (claim 7).
Poetter discloses compositions and methods of detecting respiratory pathogens using nucleic acid probes (Abstract). Poetter discloses methods wherein specific primers are used to amplify a nucleic acid sequence in a sample, wherein the amplified region has the general structure of a nucleotide sequence which is conserved across members of the target taxon of interest (para. [57]). Poetter further discloses that the amplicon should comprise a distinct nucleotide sequence for a particular strain of a respiratory pathogen, wherein the amplicon generated is putatively complementary to an oligonucleotide probe (para. [0133]). Poetter further discloses that at least one member of the primer pair comprises a detectable label, also referred to as a fluorophore (paras. [0080-81]), which emits fluorescence, phosphorescence, and/or incandescence (para. [0080]), and an exemplary fluorophore to use is 6-FAM (fluorescein; para. [0082]). Additionally, the label is typically attached to the 5’ end of a primer suitable for the amplification of the amplicon, although labeling at other positions within the primer, such as 3’ labeling or non-terminal labeling, is also contemplated (para. [0084]). Also, in an embodiment, a second optically detectable label is attached to the oligonucleotide probe (para. [0024]). Poetter further discloses a kit comprising two or more oligonucleotide primer pairs and a corresponding primer probe (para. [0028]).
Accordingly, Poetter teaches attaching an optically detectable label to the oligonucleotide probe, wherein the label is typically attached to the 5’ end of a primer suitable for the amplification of the amplicon, and an exemplary fluorophore to use in its methods and compositions is 6-FAM (fluorescein), as well as a kit comprising two or more oligonucleotide primer pairs and a corresponding primer probe.
It would have been obvious to one of ordinary skill in the art to label a probe corresponding to SEQ ID NO: 9 with 6-carboxyfluorescein on the 5’ end. One of ordinary skill in the art would have been motivated to enable optical detection in the method of detecting BPV-3. There would have been a reasonable expectation of success because Poetter discloses such labeling techniques and their use in methods of detecting viral nucleic acids.
Regarding claim 24, which requires a kit for detecting BPV-3 genomic DNA contamination in the extracted DNA in the extracted DNA of a test sample, with a primer probe combination having the nucleic acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, Poetter discloses a kit comprising two or more oligonucleotide primer pairs and a corresponding primer probe, and Gagnieur discloses extraction of viral DNA from a sample. Accordingly, it would have been obvious to put the primer probe combination having the nucleic acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9 into a kit. One of ordinary skill in the art would have been motivated to detect BPV-3 contamination. There would have been a reasonable expectation of success because Poetter discloses kits comprising primer probe combinations.
Therefore, claims 1-3, 5-8, 10, and 24 were prima facie obvious before the priority date of the instant invention.
Gagnieur, GenBank accession: MG026728.1, Huang, and Poetter fail to teach an internal positive control primer probe combination.
Kavlick discloses a novel, universal exogenous internal positive control (IPC), which is fully synthetic for unparalleled quality control (Abstract). Kavlick explains that an exogenous internal positive control is often included in amplification reactions to confirm DNA amplification, detect false negatives, and qualitatively detect the presence of amplification inhibitory substances in a sample (p. 275, col. 1, para. 1). Kavlick teaches that for intercalating dye qPCR and isothermal amplification, an IPC is a system that includes a DNA template and amplification primers, and in probe-based qPCR assays the internal positive control will also contain a separate fluorescent probe that is specific and uniquely labeled for the IPC template (p. 275, col. 1, para. 2), and since the IPC template is exogenous, it is not inherent to the sample to be amplified, rather it is an additional component of the amplification reaction (p. 275, col. 2, para. 2). Kavlick discloses cross-reactivity testing of 33 different commercially available species DNA preparations, including humans and other mammals including bovine (p. 276, col. 3, para. 2).
Accordingly, Kavlick suggests use of internal positive controls, including a DNA template, amplification primers, probes qPCR assays.
It would have been obvious to one of ordinary skill in the art to modify the primer probe combination of SEQ ID NOs: 7-9 to incorporate an internal positive control primer probe combination.
Regarding claims 9, 11, and 15-19, which require an internal positive control primer probe, Kavlick teaches an exogenous internal positive control is often included in amplification reactions to confirm DNA amplification, detect false negatives, and qualitatively detect the presence of amplification inhibitory substances in a sample. One of ordinary skill in the art would have been motivated to an exogenous internal positive control is often included in amplification reactions to confirm DNA amplification, detect false negatives, and qualitatively detect the presence of amplification inhibitory substances in a sample. There would be a reasonable expectation of success because Kavlick demonstrates the suitability of a universal exogenous internal positive control in qPCR assays.
Therefore, claims 1-3, 5-11, 15-19, and 24 were prima facie obvious before the priority date of the instant invention.
Conclusion
No claim is allowed.
Claims 12-14 and 20-22 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671
/NIANXIANG ZOU/Primary Examiner, Art Unit 1671
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