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 .
Election/Restrictions
Applicant’s election without traverse of group I and SEQ ID NO: 1, 2, and 3 in the reply filed on 12/17/2025 is acknowledged.
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, 6-13 and 22 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.
In claim 1, it is indefinite what it means to require that “the product of the secondary amplification is a single strand” because it is not clear when to consider a “product” of an amplification. For example, even in PCR, in each round only a single strand is synthesized, so is the synthesized single strand “a product” of the secondary amplification that it is a single strand? Furthermore, claim 2 lists preferred secondary amplification methods yet at least some of these generate double-stranded products (e.g. RCA: see specification ¶0019). Therefore, a contradiction exists so the claims are unclear- that is it is unclear what it means for the second amplification to have a product that “is a single strand.”
Claims 11, 12, 13 and 22 are drawn using language that does not conform to US practice and amendment should be considered. The claims refer to “use of the method according to claim 1” and “the use according to claim 12” but it is not clear how they actually further limit claim 1. It is not clear if they are a statement of intended use or if they are meant to require that the “nucleic acid to be detected” was obtained from a sample suspected of having one of the elements recited in the claims. Furthermore, the recitation of the group of what appear to be alternatives is an improper Markush group because it does not clearly set forth that the recited elements are in fact alternatives. Furthermore, claims 12 and 13 recite “include” and this is indefinite language because it is not clear if the claim intends to require that the pathogenic bacteria detected is salmonella, for example. Furthermore, claim 12 recites what appears to be two alternatives joined using “and” it this is improper language for setting forth alternatives. Furthermore, it is noted that although it appears claim 12 is setting forth narrower embodiments of pathogenic bacteria and viruses, it is still not clear that the claim requires detecting either of these or if the claim is merely further limiting the alternative s of claim 11. Claim 13 is similarly indefinite for using the “includes” and it is not clear what exactly the further recitation requires. Furthermore, “the detection of transgenic nucleic acid, food components, genetic material variation, and DNA methylation variation” lacks proper antecedent basis because although claim 11 sets these forth as alternative “uses” it does not clearly set forth the detection of any one or all of these.
In claim 22, “the nucleotide sequence of the isothermal amplification primers” lacks antecedent basis since claims 1 and 12 do not recite isothermal amplification primers.
All claims not specifically mentioned are indefinite because they depend from claim 1 and incorporate the indefiniteness of that claim.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 6, 7, 9, 10, 11, 12, 13, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bau (WO 2017/123921) in view of Geiss et al. (WO 2021/188395).
Bau teaches a method for detecting nucleic acid comprising performing isothermal amplification, performing secondary amplification and then hybridizing the product of the secondary amplification with a probe and detecting the product. See ¶0006, ¶0045.
With regard to claim 2, Bau teaches that the first isothermal amplification is recombinase polymerase amplification, and the second isothermal amplification is loop mediated amplification. See ¶0041-0042.
With regard to claims 6 and 7, these claims further modify an optional part of claim 2, and since claim 2 is met by addressing the isothermal amplification techniques, the is sufficient to also address claims 6 and 7.
With regard to claim 10, Bau teaches detecting DNA or RNA, ¶0034.
With regard to claim 11-13, Bau teaches detecting infectious agents such as pathogens bacteria and virus, including foodborne Salmonella see ¶0048-0051.
With regard to claim 22, the claim further limits primers “for the detection of Salmonella”, but does not require that salmonella be the subject of detection. Since Bau also teaches detection of viruses and other pathogens encompassed within claim 11, and claims 12 and 22 further limit but do not require the detection of pathogenic bacteria, the limitations recited in claim 22 are not in fact required if the target is a food component for example (i.e. a pathogen in food). If claim 22 is amended to clearly require using SEQ ID NO: 1, this claim would be allowable.
Bau does not teach adding a nuclease to the hybridized product to degrade redundant single-stranded product and then detecting the product.
Geiss teaches a method wherein DNA amplification products, including those produced by isothermal techniques are exposed to “nuclease protection probes” and “nucleases” (p. 2). The target is bound to the nuclease protection probes and the single stranded sections are digested using nucleases. The resulting double stranded nuclease protection probes are detected. Nuclease digestion cleaves single-stranded DNA and unhybridized nuclease protection probe (p. 3).
The nuclease protection probes may be labeled and detected for analysis (p. 3). Geiss teaches the labeled probes can be labeled with fluorescein or a fluorescent dye and detected using a photodetector (p. 7).
Geiss teaches an embodiment wherein the nuclease protection probe is labeled with 5’ biotin and 3’ digoxigenin (p. 8).
Following binding/hybridization nuclease digestion cleaves single stranded regions of the hybridized nucleic acids thereby freeing up double-stranded nucleic acids having the detection probe for detection. Geiss teaches using P1 nuclease to degrade single stranded nucleic acids (p. 6).
It would have been obvious to have modified the method taught by Bau so as to have employed the nuclease protection assay for the detection of amplified targets as taught by Geiss. One would have been motivated to do so by the teachings of Geiss that nuclease protection assay can be used to specifically detect amplified products (p. 4). Furthermore, the invention would have been obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change to their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art of being able to detect target amplicons. Furthermore, it would have been obvious to have used a fluorescent dye labeled protection probe for detection of target in the sample, motivated by the fact that Geiss specifically teaches fluorescent dye labeled probes, and thus, detecting that was a “fluorescent dye method” would have been obvious.
Claim(s) 3 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bau (WO 2017/123921) in view of Geiss et al. (WO 2021/188395) as applied to claims 1, 2, 6, 7, 9, 10, 11, 12, 13 and 22 above, and further in view of Qian et al. (Analytica Chimica Acta 1050 (2019) 1-15).
The teachings of Bau and Geiss are given previously in this Office action and are fully incorporated here. Bau and Geiss do not teach a method where in the second amplification is nicking endonuclease amplification reaction, and do not teach using one of the nicking endonucleases recited in claim 4.
Qian teaches that nicking enzyme-assisted amplification is an emerging nucleic acid isothermal amplification approach (section 2). The reference teaches that nicking enzyme assisted amplification (NEAA) is also referred to as nicking enzyme assisted reaction (NEAR) (section 1). Further, “nicking endonuclease” is a synonym for “nicking enzyme.” Qian teaches that NEAA has obvious advantages, including that it involves only the use as a simple heater and so testing instruments are simple to operate, inexpensive, and portable. In addition, it can be used with several other analytical methods, including other amplification methods (Section 2.5).
Regarding claim 4, Qian teaches that NEAA can be carried out with a variety of nicking enzymes, including Nt.BstNBI and others (see Figure 2 and Table 1).
It would have been obvious to have modified the method by Bau and Geiss so as to have substituted the second stage amplification taught by Bau with a nicking endonuclease assisted reaction for the amplification of target sequence. One would have been motivated to do so because Qian teach this technique is an emerging isothermal technique with meany obvious advantages. Furthermore, it would have been obvious to employ the known NEAR technique instead of LAMP because the substitution of one known element for another would have yielded predictable results of amplifying a nucleic acid target to one of ordinary skill at the time of the invention.
Claim(s) 3 and 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bau (WO 2017/123921) in view of Geiss et al. (WO 2021/188395) as applied to claims 1, 2, 6, 7, 9, 10, 11, 12, 13, and 22 above, and further in view of Kumar (US 5770370).
The teachings of Bau and Geiss are given previously in this Office action and are fully incorporated here. Bau and Geiss do not teach a method wherein the nuclease employed is one of those listed in claim 8.
Kumar teaches nuclease protection assays and teaches that exonucleases such as exonuclease VII are generally used in NPA to supplement to the activity of an endonuclease. The reference additionally teaches that if an exonuclease is to be used alone, validating experiments should be conducted to ensure that it removes imperfectly hybridized sequences (Col. 9, lines 40 and following).
It would have been prima facie obvious to have modified the method taught by Bau in view of Geiss so as to have included exonuclease VII in the reaction to supplement the activity of the P1 nuclease and ensure complete digestion of single stranded molecules in the reaction system. One would have been motivated to do so by the suggestion of Kumar.
Conclusion
Claim 22 would be free of the prior art if it were amended to clearly require a method which employs SEQ ID NO: 1. The prior art does not teach or suggest the primer of SEQ ID NO: 1. While Bau teaches detection of Salmonella using a two-step isothermal amplification technique, Bau does not teach SEQ ID NO: 1 and a method which uses the sequence is free of the prior art.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1682