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 .
Status of Claims
Currently, claims 1-4 and 6-20 are pending in the instant application. Claims 15-20 are withdrawn from consideration as being drawn to a non-elected invention. Claims 1-4 and 6-14 are currently under examination. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections contain new grounds of rejection. They constitute the complete set being presently applied to the instant Application. Response to Applicant's arguments follow. This action is NON-FINAL.
Any rejection not reiterated is withdrawn in view of the amendments to the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
Claims 1-2, 4, 8, 9, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Cordray (Cordray et al; Anal Biochem; 2012; vol 431, pages 1-14) in view of Corman (Corman et al; Euro Surveill.; January 23, 2020; 25(3) pages 1-8) and Kim (Kim et al; ACS Sens, 2019, vol 4, pages 1306-1312; cited in the office action dated 5/15/2024).
With regard to claims 1 and 8, Cordray teaches a method of detecting target oligonucleotides using gold nanoparticle aggregation. As an example, Cordray teaches targeting of the 18S gene of Plasmodium. Cordray specifically teaches constructing i) a plurality of first antisense oligonucleotide sequences to first nucleotide region of the Plasmodium 18S target gene, where each is functionalized with a 6 carbon spacer and a terminal thiol moiety at the 5’ end, ii) a plurality of second antisense oligonucleotide sequences to a second region of the Plasmodium 18S gene, near the first region, where each is functionalized with a 6 carbon spacer and a terminal thiol moiety at the 5’ end, and iii) a plurality of plasmonic gold nanoparticles (claims 4, 11) comprising covalently bound thiol moieties, where the probes are covalently bound to the gold nanoparticles via a covalent bond between the thiol moiety on the probe and the gold nanoparticle (see pages 2-3). With regard to claim 12, Cordray teaches a colorimeter to detect the color change when the oligonucleotide capped gold nanoparticles aggregate in the presence of the target gene (see page 3). With regard to claims 1 and 8, Cordray does not exemplify detecting SARS-CoV-2, however Corman teaches the existence of a novel coronavirus of concern as a public health emergency. Corman teaches that sequences of the isolates were deposited and teaches a real time RT-PCR nucleic acid based assay targeting different genes (page 1, col 2), including the N gene of the RNA virus (table 1) for accurate detection of the presence of SARS-CoV-2 in patient samples. Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date, to have modified the method of Cordray to include construction of oligonucleotides capped gold nanoparticles and apparatus for detection of SARS-CoV-2, because Corman teaches the need for accurate methods of detection of SARS-CoV-2 due to the public health emergency. The ordinary artisan would have had a reasonable expectation of success in detecting SARS-CoV-2 using the assay taught by Cordray because Cordray teaches the successful detection of Plasmodium by targeting its 18S gene. Cordray teaches that the assay was capable of detecting small quantities of nucleic acids in 30 minutes, and also teaches the ability for dynamic measurement of aggregation in 10 minutes.
With regard to claims 1 and 8, the instant claims are differentiated from Cordray in view of Corman in that the claims require that the second plurality of oligonucleotides be functionalized with a 6 carbon spacer at the 3’ end. It is noted that although Cordray teaches that the thiol group was attached to the 5’ end of each probe to allow for conjugation with the gold nanoparticle, there is no indication that the 5’ end modification is critical to the method of Cordray. Kim also exemplifies a method of detecting a clinically relevant target (MERS-CoV) using gold nanoparticles and thiol modified ASO probes. Kim teaches ASO probes modified with a thiol moiety on the 5’ end of a first plurality of probes and the 3’ end of a second plurality of probes (see figure 1) as well as plasmonic gold nanoparticles (figure 1). It is clear from the figure taught by Kim that ASO probes can be conjugated to gold nanoparticles with a thiol moiety at either the 5’ or the 3’ end. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date that the method of Cordray in view of Corman could also be carried out with a set of probes where the thiol moiety was on the 5’ end and a set of probes where the thiol moiety was on the 3’ end. The ordinary artisan would immediately recognize that the purpose of the thiol moiety is to allow conjugation with the gold nanoparticle, which can be achieved by two different sets of probes both modified with thiol moieties at a) the 5’ end, b) the 3’ end, or c) one set with thiol moieties at the 5’ and and the second set with thiol moieties at the 3’end. In any of these possible predictable solutions, the probe would also be capable of hybridizing to its intended target, as exemplified by Cordray and Kim. Therefore, absent secondary considerations, this limitation is considered obvious in view of the prior art cited.
With regard to claims 2 and 9, Cordray in view of Corman and Kim do not teach using 3rd and 4th antisense probes to the same target sequence, however this is considered prima facie obvious absent secondary considerations. As noted in the MPEP 2144.04(VI)(B) Duplication of Parts, the mere duplication of target specific antisense probes does not appear to have patentable significance unless an unexpected result is produced.
Claims 3, 6 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Cordray in view of Corman and Kim as applied to claims 1-2, 4, 8, 9, 11, and 12 above, and further in view of Ding (Ding et al; Nucleic Acids Research. 2004, vol 32, pages 135-141), and Genbank Accession number MT127114 (NLM, NCBI, April 6, 2020).
The teachings of Cordray in view of Corman are set forth above. Cordray and Corman do not teach probes with SEQ ID NOS 6-9, or antisense oligonucleotides having a binding energy of less than -8 kcal/mol, however Ding teaches that single stranded regions in RNA secondary structure are likely accessible for RNA targeting nucleic acids through base pairing (see page 135, col 2). Ding teaches that target accessibility has long been established as an important factor for the potency of antisense oligonucleotides. Ding teaches software, available via the world wide web, that offers computational tools for the rational design of RNA targeting nucleic acids such as antisense nucleic acids. Regarding the design of antisense oligonucleotides, Ding teaches Soligo which uses filters where antisense oligo binding energy is less than -8 kcal/mol (claim 6), the GC % is between 40 and 60 percent, and the absence of GGGG runs in the target sequence (see page 138). Furthermore, the sequence of the N gene of SARS CoV-2 was taught and available for design by, for example, Genbank Accession number MT127114. The sequences of SEQ ID NOS 6 and 7 are comprised by the reverse complement of positions 563-605, while the reverse complement of SEQ ID NOS 8 and 9 are taught at positions 978-997 and 1028-1047. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to use the software taught by Ding and the known sequence taught by MT127114 for the design and construction of antisense probes in the method of Crodray and Corman, including SEQ ID NOS 6-9 (claims 3, and 10), absent secondary considerations. The ordinary artisan would have been motivated to use the software taught by Ding for design of antisense probes to the RNA virus taught by Corman because Ding teaches that target accessibility is an important factor in the design of antisense probes to RNA targets.
Claims 7, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Cordray in view of Corman and Kim, as applied to claims 1-2, 4, 8, 9, 11, and 12, and further in view of Jung (Jung et al; Biosensors and Bioelectronics; 2011, vol 26, pages 1953-1958) .
The teachings of Cordray in view of Corman are set forth above. Cordray and Corman do not teach the concentrations of the antisense oligonucleotides or the use of a nuclease, such as RNAse H, however Jung teaches and exemplifies the routine nature of optimizing gold nanoparticle colorimetric detection of target nucleic acids. Jung teaches that optimum ratios of probes to nanoparticles is very important for enhancing the discriminatory power between positive and negative samples through the provision of sufficient color difference in the colorimetric assay. Jung teaches different probe to gold nanoparticle concentrations (see page 1955, col 2, figure 3). Jung also teaches further optimization using RNAse H (see figure 2). Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date to optimize the method of Cordray in view of Corman as taught by Jung for the purpose of arriving at an optimal method of colorimetric detection of biological pathogens as taught by Corman. As set forth in the MPEP 2144.05 II A, “Optimization of Ranges”:
Generally, differences in concentration or temperature will not support the patentability of
subject matter encompassed by the prior art unless there is evidence indicating such
concentration or temperature is critical. “[W]here the general conditions of a claim are
disclosed in the prior art, it is not inventive to discover the optimum or workable ranges
by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235
(CCPA 1955) (Claimed process which was performed at a temperature between 40°C
and 80°C and an acid concentration between 25% and 70% was held to be prima facie
obvious over a reference process which differed from the claims only in that the reference
process was performed at a temperature of 100°C and an acid concentration of 10%.)…
Response to Arguments
The response traverses the rejection. Arguments regarding the 5’ and 3’ thiolated probes of the instant claims have been thoroughly reviewed but were not found persuasive in view of the modified rejection set forth above. To reiterate: Cordray in view of Corman differ from the instant claims in that the instant claims require that the second plurality of oligonucleotides be functionalized with a 6 carbon spacer at the 3’ end. It is noted that although Cordray teaches that the thiol group was attached to the 5’ end of each probe to allow for conjugation with the gold nanoparticle, there is no indication that the 5’ end modification is critical to the method of Cordray. Kim also exemplifies a method of detecting a clinically relevant target (MERS-CoV) using gold nanoparticles and thiol modified ASO probes. Kim teaches ASO probes modified with a thiol moiety on the 5’ end of a first plurality of probes and the 3’ end of a second plurality of probes (see figure 1) as well as plasmonic gold nanoparticles (figure 1). It is clear from figure 1 taught by Kim that ASO probes can be conjugated to gold nanoparticles with a thiol moiety at either the 5’ or the 3’ end. Therefore, it would have been prima facie obvious to the ordinary artisan prior to the effective filing date that the method of Cordray in view of Corman could also be carried out with a set of probes where the thiol moiety was on the 5’ end and a set of probes where the thiol moiety was on the 3’ end. The ordinary artisan would immediately recognize that the purpose of the thiol moiety is to allow conjugation with the gold nanoparticle, which can be achieved by two different sets of probes both modified with thiol moieties at a) the 5’ end, b) the 3’ end, or c) one set with thiol moieties at the 5’ and and the second set with thiol moieties at the 3’end. In any of these possible predictable solutions, the probe would also be capable of hybridizing to its intended target, as exemplified by Cordray and Kim. Therefore, absent secondary considerations, this limitation is considered obvious in view of the prior art cited.
The response also asserts that the probes taught by Cordray are designed to detect malaria, not SARS-CoV2. This argument has been thoroughly reviewed but was not found persuasive because Cordray teaches the structural and functional requirements of the method. Although the method exemplified is directed to detecting Plasmodium, it would have been obvious to the ordinary artisan that the teachings of Cordray are generally applicable to detecting any known target, because Cordray teaches it is the purpose of the study. The response also asserts that Cordray “does not discuss gold, thiol probes, aggregation based detection, or how to modify Cordray to achieve this for malaria, much less for SARS-CoV2”. This argument has been thoroughly reviewed but was not found persuasive because Cordray does in fact teach gold nanoparticles (AuNP), thiol modified probes (see “methods”), as well as aggregation based detection (see figures 1-5). Since this is the subject of the Cordray reference, the argument that Cordray does not teach these elements is factually incorrect.
The response asserts that Corman does not make up for the failures of Cordray because it only teaches raw sequence data and does not provide instruction or suggests on what portions would make good probes for a gold aggregation assay. This argument has been thoroughly reviewed but was not found persuasive because Corman was cited as providing motivation for modifying the method of Cordray for the detection of SARS-CoV-2. The remainder of the response continues to argue against the references individually. However one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). For these reasons and the reasons made of record above, the claims remain rejected under 35 USC 103.
Conclusion
No claims are allowed herein.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682
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