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 .
Status of the Application
2. Applicant’s response filed on May 18, 2026 has been entered.
Claims 1-6 and 9-15 are pending.
Response to Arguments
3. Applicant’s arguments filed on May 18, 2026 have been fully considered.
Objections to the Drawings
Applicant argues that the objections should be withdrawn in view of the replacement drawing sheets submitted with the response (Remarks, page 4).
This argument was persuasive. The objections have been withdrawn.
Objections to claims 1, 8, and 15
Applicant argues that the objections should be withdrawn in view of the amendments to claims 1 and 15 and the cancellation of claim 8 (Remarks, page 4).
This argument was persuasive. The objections have been withdrawn.
Rejection of claims 8 and 12-15 under 35 U.S.C. 112(b)
Applicant argues that the rejection should be withdrawn in view of the cancellation of claim 8 and the amendments to claims 12-15 (Remarks, pages 4-5).
This argument was persuasive. The rejection has been withdrawn.
Rejection of claims 11 and 13 under 35 U.S.C. 112(d)
Applicant argues that the rejection should be withdrawn in view of the amendments to claims 11 and 13 (Remarks, page 5).
This argument was persuasive. The rejection has been withdrawn.
Rejection of claims 1-3, 7, and 10-16 under 35 U.S.C. 102(a)(1) as being anticipated by Nguyen
Applicant argues that the rejection should be withdrawn in view of the amendments to step (b) of claim 1 (Remarks, page 5).
This argument was persuasive. The rejection has been withdrawn.
Rejection of claims 1-3, 6, 7, and 9-16 under 35 U.S.C. 102(a)(1) as being anticipated by Luo
Applicant argues that the rejection should be withdrawn in view of the amendments to step (b) of claim 1 (Remarks, page 5).
This argument was persuasive. The rejection has been withdrawn.
Rejections of claims 4-6, 8, and 9 under 35 U.S.C. 103 citing Nguyen as the primary reference
Argument:
Applicant presents three arguments as to why the rejections should be withdrawn (Remarks, pages 5-7).
First, Applicant argues that none of the previously cited references teaches or suggests use of a carrier with the structural features now required by step (b) in amended claim 1 (Remarks, pages 5-6).
Second, Applicant argues that the detection methods of Saka and O’Malley are fundamentally different from the claimed methods, such that the ordinary artisan would not have been motivated by their teachings to modify Nguyen to arrive at the claimed methods (Remarks, page 6). Here, Applicant argues that detection in the method of Saka is based on a “bulk linear architecture” (i.e., DNA-barcoded antibodies hybridized to orthogonal single-stranded DNA concatemers generated by primer exchange), whereas the claimed poly-oligonucleotide conjugate is a compact, multivalent structure (Remarks, page 6). Similarly, as to O’Malley, Applicant argues that the reference uses the disclosed PAMAM dendrimers in the relatively controlled environment of a microarray/solid support assay, whereas the claimed methods are practiced using FFPE tissue samples, which are much more complex (Remarks, page 6).
Third, Applicant argues that the claimed methods are associated with unexpected results (Remarks, pages 6-7). More specifically, Applicant argues that the claimed carrier “can be used to detect a biomarker in an FFPE sample with increased signal intensity and signal to background ratio” (Remarks, page 6). Applicant points to Examples 2-4 in the specification and also Exhibit 1 to support this argument (Remarks, pages 6-7).1
Response:
In response, it is first noted that the rejection of claim 8 is withdrawn as moot since that claim has been canceled.
As well, Applicant’s first argument was persuasive. None of the references cited previously teaches a carrier comprising PEG polymers linked to a tripentaerythritol core. A new reference has been added to address this new requirement in step (b) of independent claim 1. Applicant’s additional arguments regarding unexpected results and also the Saka and O’Malley references are pertinent to the new rejections and are addressed below.
Applicant’s argument regarding Saka was unpersuasive because that reference is only used to bolster the teachings of Nguyen concerning protein detection.
Applicant’s argument regarding O’Malley was unpersuasive because it is not clear that the ordinary artisan would have considered dendrimers as disclosed in O’Malley to be unsuitable for use outside of microarray or other solid support-based assays since DNA-conjugated dendrimers were known to be a suitable vehicle for delivery therapeutics or imaging. See, e.g., Choi et al. (Chemistry & Biology 2005; 12: 35-43). Therefore, the ordinary artisan would not necessarily have considered the dendrimers of O’Malley to be unsuitable for use with an FFPE tissue sample.
Lastly, Applicant’s arguments regarding unexpected results were unpersuasive for the following reasons. First, the results are not commensurate in scope with the claimed invention, at least because the carrier used in the examples is much narrower than the carrier recited in the claims, and it is not clear that the observed results will extend to the other carriers encompassed by the claims. As discussed in MPEP 716.02(d), evidence of unexpected results must be commensurate in scope with the claimed invention. Second, it is not clear that the observed results are actually unexpected. As discussed in MPEP 716.02(c), “Expected beneficial results are evidence of obviousness.” In this case, the teachings of Nguyen indicate that signal amplification results from the presence of the Pre-Amplifier and Intermediate Amplifier probes, which allow for the use of more Amplifier probes per target nucleic acid, and in turn, more Label probes per target nucleic acid (see, e.g., paras. 77-79). The ordinary artisan would have recognized from these teachings of Nguyen that any modification (e.g., the use of a carrier as claimed) that results in the ability to use more labeled probes per target nucleic acid would be expected to result in increased signal intensity and a better signal-to-noise ratio. This is also supported by similar teachings in the newly cited Luo reference (see, e.g., paras. 66, 71-74, 78, 80, and 92-98). Therefore, it does not appear that the improved signal intensity and signal to background results reported in the working examples are unexpected in view of the teachings in the prior art.
Since Applicant’s arguments were not persuasive, the claims are not free of the prior art.
Priority
4. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Provisional Application Serial No. 63/700,794, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. More specifically, all of the pending claims contain new matter for the reasons discussed in the rejection set forth below. The disclosure of prior-filed ‘794 application, which is incorporated by reference into the disclosure of the instant application, has also been reviewed as part of the new matter analysis, and it also fails to provide support for the full scope of “a carrier comprising polyethylene glycol (PEG) polymers linked to a tripentaerythritol core” as recited in step (b) of amended claim 1. As with the specification of the instant application, the ‘794 application only provides support for a particular member of this genus (see, e.g., Example 1 on pages 16-17 of the ‘794 application, where the multi-functionalized maleimide-terminated PEG polymer with a tripentaerythritol core is disclosed). Thus, the effective filing date of the instant claims 1-6 and 9-15 is June 12, 2025 (i.e., the filing date of the instant application).
Drawings
5. Applicant’s submission of replacement drawing sheets on May 18, 2026 is acknowledged. The replacement drawings are acceptable.
Claim Rejections - 35 USC § 112
6. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6 and 9-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 has been amended to recite “wherein the carrier comprises polyethylene glycol (PEG) polymers linked to a tripentaerythritol core” in step (b).
Applicant’s response states that support for this limitation may be found at least in original claims 7 and 8 as well as Example 1 (Remarks, page 4).
The original disclosure, including the portions cited by Applicant, has been reviewed, but support was not found for the full scope of the above language in amended claim 1. Original claims 7 and 8 provide support for polymer carriers, wherein the polymer is PEG or a PEG derivative, but they do not provide support for the specific core required in amended claim 1. Example 1 discloses the use of a particular carrier encompassed by the new language in step (b). See page 17, para. 77, where the multi-functionalized maleimide-terminated PEG polymer with a tripentaerythritol core is disclosed. The remainder of the specification does not disclose any other examples of a carrier encompassed by amended claim 1, nor does it recite the new language in step (b) of claim 1 concerning the carrier.
Therefore, although step (b) in amended claim 1 encompasses a genus of PEG-based carriers, the original disclosure only specifically describes one member within the claimed genus and also fails to provide support for the particular genus now recited in claim 1. In other words, the generic disclosure in original claims 7 and 8 (and also para. 11 on page 3 of the specification) only provides support for a much broader genus of carriers (e.g., polymer carriers or PEG carriers) and fails to provide support for the much narrower subgenus now recited in amended claim 1 (i.e., a PEG carrier containing a particular core) because it contains nothing that would lead the ordinary artisan to the particular genus of PEG-based carriers now recited in amended claim 1.
See also MPEP 2163.05 II, which notes that a claim drawn to a subgenus may not be supported by a generic disclosure in combination with a specific example within the subgenus. In this case, the disclosure contains an example within the claimed subgenus in combination with a generic disclosure that would not lead the ordinary artisan to the claimed subgenus. Thus, the amendment to step (b) in claim 1 is not supported by the original disclosure, and the claim is rejected for containing new matter.
Claims 2-6 and 9-15 are also rejected for containing new matter since they depend from claim 1 and do not correct its new matter issue.
Claim Rejections - 35 USC § 103
7. 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.
8. 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.
9. Claims 1-3, 6, 9, 10, 12, 14, and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyen et al. (US 2016/0046984 A1) in view of O’Malley (US 2004/0023248 A1) and further in view of Nikiforov (US 2010/0261185 A1).2
The instant claims are drawn to a method for detecting a biomarker in a sample that comprises hybridization.
Regarding claim 1, Nguyen discloses a method for detecting a biomarker in a sample that comprises all of the required steps (see Fig. 14, which appears below as well as the accompanying description at paras. 36, 52, 54, and 55).
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More specifically regarding claim 1, as can be seen in Figure 14 above, the method of Nguyen comprises the following steps:
(a) applying a capture probe (i.e., the Label Extender in Fig. 14) to a sample containing a biomarker to be detected (i.e., the Target Nucleic Acid in Fig. 14), wherein the capture probe has a tail polynucleotide sequence (i.e., the L-2 sequence in the Label Extender);
(b) applying a poly-oligonucleotide conjugate to the sample, wherein the poly-oligonucleotide conjugate comprises a carrier (i.e., the Intermediate Amplifier) conjugated with a plurality of oligonucleotides (i.e., the Amplifier oligonucleotides and also the Preamplifier oligonucleotide), wherein each oligonucleotide comprises a first region comprising multiple repeating polynucleotide sequences (i.e., the A-2 sequences in the Amplifier oligonucleotides and the P-2 sequences in the Preamplifier), and wherein at least one of the plurality of oligonucleotides comprises a second region capable of directly or indirectly associating with the tail polynucleotide sequence (i.e., the P-1 sequence in the Preamplifier), thereby associating the poly-oligonucleotide conjugate with the capture probe (i.e., Label Extender) bound to the biomarker (i.e., Target Nucleic Acid) in step (a);
(c) applying a plurality of label probes (i.e., Label Probes) to the sample, wherein each label probe is capable of directly or indirectly associating with the repeating polynucleotide sequence, thereby associating a plurality of label probes with the poly-oligonucleotide conjugate bound to the capture probe (i.e., Label Extender) in step (b) (see Fig. 14, where the LP-1 sequence in the Label Probes directly binds to the repeated polynucleotide sequences (A-2) in the Amplifiers and is capable of indirectly associating with the repeated polynucleotide sequences (P-2) in the Preamplifier); and
(d) detecting the label probes associated with the poly-oligonucleotide conjugate in step (c) (see, e.g., paras. 52, 55, and 56; see also paras. for more specific description of the detection step).
Further regarding amended claim 1, Nguyen also teaches that the disclosed methods may be practiced using an FFPE sample (see, e.g., para. 96).
Further regarding steps (b) and (c) in claim 1, it is also noted that neither the claim language nor a specific definition in the application requires the repeating polynucleotide sequences to be the same amongst all of the oligonucleotides conjugated to the carrier, so long as each label probe “is capable of directly or indirectly associating with the repeated sequence.” It is also noted that any probe or region is necessarily “capable of associating” with any other sequence since a bridge probe may be used to link them. In other words, due to the use of the “capable of directly or indirectly associating” language, the claim currently encompasses oligonucleotides such as the Amplifier and Preamplifier of Nguyen in which the repeating polynucleotide sequences are the same within a particular type of oligonucleotide but different between the Amplifier and Preamplifier, and in which the label probes bind directly to the Amplifier and are capable of indirectly associating with the Preamplifier.
Regarding claims 2 and 3, Nguyen teaches that the biomarker may be a target nucleic acid (see, e.g., Fig. 14 and para. 96). Nguyen teaches that target nucleic acids may be genomic DNA, mRNA, or miRNA (paras. 97-98).
Regarding claim 10, in the method of Nguyen, the second region in one oligonucleotide attached to the carrier hybridizes to the tail polynucleotide sequence. See Figure 14, where the tail polynucleotide sequence (i.e., region L-2 in the Label Extender) hybridizes to region P-1 of the Preamplifier, which is attached to the carrier (i.e., the Intermediate Amplifier).
Regarding claim 12, the label probes in Nguyen have a binding sequence (LP-1) that hybridizes to the repeat sequences (A-2) in the Amplifier oligonucleotides (see Fig. 14).
Regarding claims 14 and 15, the label probes in Nguyen may contain a detectable label that may be a fluorophore, horseradish peroxidase, or alkaline phosphatase (see, e.g., paras. 51, 56, and 62).
Nguyen is not anticipatory because the reference does not meet the new requirement in step (b) of amended independent claim 1 for the carrier to comprise PEG polymers linked to a tripentaerythritol core. As well, regarding claims 6 and 9, Nguyen does not specify the length of the tail polynucleotide sequence (i.e., the L-2 sequence in the Label Extender in Fig. 14) or the length of the repeating polynucleotide sequence (i.e., the A-2 sequence in the Amplifier in Fig. 14). Therefore, the reference fails to teach a length within the range of 10-40 nucleotides recited in each of claims 6 and 9.
O’Malley, though, teaches that a plurality of oligonucleotides may be attached to a dendrimer and used to directly or indirectly hybridize to a target nucleic acid of interest (see, e.g., Figure 1 and paras. 5-8, 19, 49, and 59-68). O’Malley further teaches that oligonucleotides may be attached to a PAMAM dendrimer and also that hyperbranched dendrimers are suitable (see, e.g., paras. 40 and 42). Still further, O’Malley teaches that dendrimers can offer enhanced detection since they can be attached to a large number of detection labels (paras. 40, 44, and 58).
The dendrimers (i.e., oligonucleotide-conjugated carriers) taught by O’Malley do not include carriers comprising PEG polymers linked to a tripentaerythritol core as required by step (b) in amended independent claim 1, but Nikiforov discloses conjugates (carriers) in which PEG polymers is linked to a biomolecule (e.g., an oligonucleotide) (see, e.g., Figure 1 and para. 18). The conjugates may be used to detect or analyze biomolecules of interest (see, e.g., paras. 5, 90, 243, and 244). As well, the PEG polymers may contain a tripentaerythritol core (para. 287).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to substitute the polynucleotide carrier of Nguyen (i.e., the Intermediate Amplifier in Fig. 14 of Nguyen) with a dendrimer to which the plurality of oligonucleotides containing repeat polynucleotide sequences are attached. More specifically, the ordinary artisan would have recognized from the teachings of O’Malley that the plurality of oligonucleotides in the poly-oligonucleotide conjugate of Nguyen could either be attached (i.e., conjugated) to a polynucleotide carrier as taught in Nguyen or attached to a dendrimer carrier (e.g., a PAMAM dendrimer) as taught in O’Malley, and that either option would have been expected to serve the same function of providing oligonucleotides for hybridization to the polynucleotide tail of the capture probe or hybridization to label probes, with the dendrimer option potentially providing enhanced detection in the manner discussed in O’Malley (see, e.g., paras. 40, 44, and 58). Accordingly, the ordinary artisan would have been motivated to select either alternative with a reasonable expectation of success. As discussed in MPEP 2144.07, it is prima facie obvious to select a known material or method based on its suitability for the intended purpose in the absence of unexpected results. In this case, the teachings of O’Malley indicate that a dendrimer can be used as a carrier to form a poly-oligonucleotide conjugate, analogous to the polynucleotide carrier used in Nguyen, and no persuasive evidence of unexpected results has been presented. This is sufficient to establish a prima facie case of obviousness per MPEP 2144.07.
The ordinary artisan also would have recognized that other dendrimers with the same general features as, e.g., the PAMAM dendrimer taught in O’Malley could also be substituted for the polynucleotide carrier in the method of Nguyen and would be reasonably expected to offer the same potential benefit of enhanced detection taught in O’Malley. Accordingly, the ordinary artisan would have been motivated to substitute the oligonucleotide-conjugated PAMAM dendrimer taught in O’Malley for a dendrimer comprising a plurality of oligonucleotides linked to the PEG polymers with a tripentaerythritol core taught in Nikiforov. The ordinary artisan would have had a reasonable expectation of success since the teachings in Nikiforov indicate that conjugating biomolecules (e.g., oligonucleotides) to PEG polymers with a tripentaerythritol core was routine for the ordinary artisan.
Thus, the methods of claims 1-3, 10, 12, 14, and 15 are prima facie obvious.
Further regarding claims 6 and 9, it also would have been prima facie obvious for the ordinary artisan to conduct routine experimentation to determine the best length for each of the different regions in the oligonucleotides used to practice the method of Nguyen. Nguyen provides motivation to do so by noting the importance of stable hybridization between the L-1 sequence of the Label Extender and the target nucleic acid (paras. 79-80). The ordinary artisan would have recognized that stable hybridization would be generally desirable throughout the method of Nguyen, and accordingly, would have been motivated to optimize the length of each different region destined to participate in hybridization reactions, using the lengths of 5-40 nucleotides disclosed in para. 79 for the L-1 sequence as a starting point, along with the guidance provided by Nguyen concerning hybridization (paras. 44-46 and 79-82).
See also MPEP 2144.05 II, which notes that routine optimization of results-effective variables is prima facie obvious in the absence of unexpected results. In this case, the teachings of Nguyen would have indicated to the ordinary artisan that the length of each region participating in a hybridization reaction was a results-effective variable, and accordingly, would have been motivated to optimize each of these lengths to their optimal value using no more than routine experimentation. The ordinary artisan would have had a reasonable expectation of success in view of the guidance provided by Nguyen concerning hybridization (paras. 44-46 and 79-82).
Thus, the length range of 10-40 nucleotides recited in each of claims 6 and 9 is considered to be prima facie obvious in view of the teachings of Nguyen in para. 79, where length ranges of 20-40 nucleotides, 20-30 nucleotides, 20-25 nucleotides, 5-20 nucleotides, 10-20 nucleotides, 5-14 nucleotides, 7-13 nucleotides, 5-13 nucleotides, 7-10 nucleotides, or 5-10 nucleotides are taught to be potentially useful for the L-1 sequence in Nguyen. The ordinary artisan would have recognized from these teachings and also the teachings of the reference related to hybridization in paras. 44-46 and 79-82 that the length ranges in para. 79 could be used as starting points for optimizing the length of other regions participating in hybridization reactions, and accordingly, would have been motivated to test values within said ranges with a reasonable expectation of success. Thus, in the absence of any evidence of unexpected results, the methods of claims 6 and 9 are also prima facie obvious over Nguyen in view of O’Malley and further in view of Nikiforov.
10. Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyen et al. (US 2016/0046984 A1) in view of O’Malley (US 2004/0023248 A1) and further in view of Nikiforov (US 2010/0261185 A1) and further in view of Saka et al. (Nature Biotechnology 2019; 37: 1080-1090).3
As discussed above, the teachings of Nguyen in view of O’Malley and further in view of Nikiforov render obvious the methods of claims 1-3, 6, 9, 10, 12, 14, and 15.
Regarding claims 4 and 5, Nguyen teaches that the disclosed methods “can be employed in conjunction with techniques for detection of one or more proteins, e.g., immunohistochemistry (IHC)” (para. 93). Thus, Nguyen teaches the desirability of detecting protein biomarkers. The reference does not teach using the disclosed methods for protein detection as recited in claims 4 and 5, however.
O’Malley and Nikiforov do not remedy this deficiency in Nguyen.
Saka, though, discloses a method for detecting protein biomarkers in a sample that comprises antibody binding and nucleic acid hybridization (see, e.g., Figs. 1b and 1c). More specifically, as can be seen in Figures 1b and 1c, the method of Saka comprises binding an antibody specific for the protein biomarker to the protein biomarker and then hybridizing a concatemer to a nucleic acid tail on the antibody. Labeled detection probes are then hybridized to the concatemer. Thus, the method of Saka is similar to that of Nguyen in that (i) it uses a capture probe with a polynucleotide tail to bind a biomarker of interest, and (ii) detection is based on labeled oligonucleotide probes attaching (directly in the case of Saka or indirectly in the case of Nguyen) to a nucleic acid hybridized to the tail polynucleotide.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious to use the method suggested by Nguyen in view of O’Malley and Nikiforov to detect protein biomarkers. As noted above, the teachings of Nguyen in para. 93 indicate that detecting protein biomarkers can be desirable. Saka provides additional motivation to detect protein biomarkers since the teachings throughout that reference indicate that it is desirable to detect protein biomarkers. In adapting the method suggested by Nguyen in view of O’Malley and Nikiforov to detect protein biomarkers, the ordinary artisan would have been motivated to use a capture probe comprising an antibody against the protein biomarker since Saka taught that this was a suitable way to detect protein biomarkers in a very similar hybridization-based detection method (Fig. 1). The ordinary artisan would have had a reasonable expectation of success in view of the guidance concerning obtaining the antibody and performing the hybridization-based detection step (Fig. 1 and the Online Methods section). Thus, the methods of claims 4 and 5 are prima facie obvious.
11. Claims 11 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Nguyen et al. (US 2016/0046984 A1) in view of O’Malley (US 2004/0023248 A1) and further in view of Nikiforov (US 2010/0261185 A1) and further in view of Luo et al. (US 2021/0032690 A1).4
As discussed above, the teachings of Nguyen in view of O’Malley and further in view of Nikiforov render obvious the methods of claims 1-3, 6, 9, 10, 12, 14, and 15.
Regarding claim 11, as can be seen in Figure 14, the second region in one of the carrier-conjugated oligonucleotides in Nguyen (i.e., region P-1 in the Preamplifier) hybridizes directly to the tail polynucleotide sequence (i.e., region L-2 in the Label Extender). Therefore, Nguyen does not teach hybridization of these two regions via a bridge probe as required by claim 11.
Regarding claim 13, as can be seen in Figure 14, Nguyen teaches direct hybridization between the label probe and a repeating polynucleotide sequence in one of the carrier-conjugated oligonucleotides rather than hybridization via a bridge probe.
Luo, though, discloses a hybridization-based nucleic acid detection method that is quite similar to that of Nguyen in that it uses a Z-shaped probe to capture the target nucleic acid, label probes for detection, and a plurality of amplifier probes that provide signal amplification (see, e.g., Figs. 1-3 of Luo and paras. 57-59). Luo further teaches that the “amplification molecule segments” (pre-pre-amplifier, pre-amplifier, and amplifier) can be hybridized to one another directly or indirectly via a bridge probe (see, e.g., para. 94). Luo additionally teaches that the bridge probe can “provide further structural stabilization” to the hybridization complex being assembled (para. 94).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for the ordinary artisan practicing the method suggested by Nguyen in view of O’Malley and further in view of Nikiforov to use a bridge probe to (i) bind the second region of a carrier-conjugated oligonucleotide to the tail polynucleotide sequence and/or (ii) bind the label probe to a repeating sequence in one of the carrier-conjugated oligonucleotides. Luo provides motivation to do so by teaching that the different components of a hybridization-based nucleic acid detection method may be hybridized to each other directly or indirectly via a bridge probe, with the bridge probe potentially providing additional structural stabilization to the hybridization complex (see, e.g., para. 94). The ordinary artisan would have recognized that the teachings of Luo concerning the advantage of structural stabilization associated with the use of a bridge probe would apply to any hybridization occurring within the method suggested by Nguyen in view of O’Malley and Nikiforov, and accordingly, would have been motivated to incorporate a bridge probe at any desired hybridization within that method. The ordinary artisan would have had a reasonable expectation of success in view of the guidance throughout Luo and also since factors influencing hybridization reactions were known. Thus, the methods of claims 11 and 13 are prima facie obvious.
Conclusion
12. No claims are currently allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Angela Bertagna whose telephone number is (571)272-8291. The examiner can normally be reached 8-5, M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANGELA M. BERTAGNA/Primary Examiner, Art Unit 1681
1 It is noted that Exhibit 1, discussed on page 6 of the Remarks, does not appear to have been provided since it does not appear in the electronic application file. Therefore, the Office cannot evaluate this evidence of unexpected results.
2 Nguyen and O’Malley were cited previously. Nikiforov is newly cited.
3 Nguyen, O’Malley, and Saka were cited previously. Nikiforov is newly cited.
4 Nguyen, O’Malley, and Saka were cited previously. Nikiforov and Luo are newly cited.
Prosecution Insights