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 Please note that the examiner for this application has changed. Please address future correspondence to Robert T. Crow (Art Unit 1683) whose telephone number is (571) 272-1113.
Continued Examination Under 37 CFR 1.114
3. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9 January 2026 has been entered.
Amendments and Status of the Claims
4. This action is in response to papers filed 9 January 2026 in which claims 1 and 21 were amended, no claims were canceled, and new claims 22-23 were added. All of the amendments have been thoroughly reviewed and entered.
Any previous objections and/or any previous rejections not reiterated below are withdrawn in view of the amendments.
Claims 1-3, 7-16, and 18-23 are under prosecution.
Information Disclosure Statement
5. The Information Disclosure Statement filed 9 January 2026 is acknowledged and has been considered.
It is noted that the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Interpretation
6. Claims 21-23 are drawn to a “system.” The specification recites a “system” wherein the “system” is defined in terms of structural limitations. In addition, the claims recite structural limitations of the “system.” Thus, the “system” is interpreted to encompass any collection of reagents and parts used together that are not necessarily part of a completely integrated single unitary device. Any further interpretation of the word is considered an “intended use” and does not impart any further structural limitation on the claimed subject matter.
7. It is also noted that the courts have held that “while features of an apparatus may be recited either structurally or functionally, claims directed to an apparatus must be distinguished from the prior art in terms of structure rather than function.” In re Schreiber, 128 F.3d 1473, 1477-78, 44 USPQ2d 1429, 1431-32 (Fed. Cir. 1997). In addition, “[A]pparatus claims cover what a device is, not what a device does.” Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1469, 15 USPQ2d 1525, 1528 (Fed. Cir. 1990) (emphasis in original). Therefore, the various uses recited in the claims (e.g., detecting molecules, contacting the sample with the tags, detecting the relative spatial order, etc.) fail to define additional structural elements of the claimed system. Thus any prior art that teaches the structural elements of the claims either anticipates, or renders obvious, the claimed systems. See MPEP § 2114.
Claim Rejections - 35 USC § 103
8. 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.
9. 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.
10. Claims 1-3, 7-16, and 18-23 are rejected under 35 U.S.C. 103 as being unpatentable over Edelman (U.S. Patent Application Publication No. US 2018/0171329 A1, published 21 June 2018) and Cai et al. (PCT International Application Publication No. Wo 2018/026873 A1, published 8 February 2018).
Regarding claims 1-2 and 22, Edelman teaches methods comprising contacting a sample (i.e., target DNA) with at least two oligonucleotide tags, wherein each tag comprises target recognition domains G1 and G2, respectively, and respective streets (i.e., the regions upstream of the recognition domains) comprising cassettes (i.e., subunits of the streets) comprising barcode regions B1 and B2, which are respectively flanked by anchor sequences A1/C1 and A2/C2 (paragraph 0167 and Figure 10). Barcode regions B1 and B2 each have different sequences (paragraph 0038); thus, each sequence of each barcode region of the tags are different.
It is noted that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments (see MPEP § 2123). While claim 1 does not explicitly state that there is a plurality of different tags, the claim does reference “each” tag, which is interpreted as requiring at least two tags.
Edelman teaches the barcode molecules of the multimeric barcodes may be linked on a (i.e., single) nucleic acid molecule (paragraph 0029; see also Figure 11 and paragraph 0188), which encompasses the alternate embodiment wherein the barcode molecules are not linked on a single molecule. Thus, it would have been obvious to have barcode readout molecule 1 comprising D1E1F1 (complementary to A1B1C1) and barcode readout molecule 2 comprising D2E2F2 (complementary to A2B2C2) as separate molecules (as depicted in Figure 8) that contact the target in the manner depicted in Figure 10.
In addition, Edelman teaches readout molecule regions D1 and D2 (which are respectively complementary to anchor regions A1 and A2) may be identical, which encompasses the alternate embodiment wherein they are not identical. Thus, each of tag sequences A1 and A2 are unique to each cassette (i.e., claims 1 and 22) because they are complementary to the unique readout sequences of D1 and D2.
Edelman also teaches the readout prove adapter regions F1 and F2 (which are respectively complementary cassette street regions C1 and C2) to may comprise a constant region (paragraph 0033) encompasses embodiments not constant, there therefore are all different. In addition, Edelman teaches F1 and F2 are substantially identical (paragraph 0033), which means they are not entirely identical.
Thus, the totality of the teachings of Edelman reasonable suggest that each of A1 and A2 are different, B1 and B2 are different, C1 and C2 are different, D1 and D2 are different, E1 and E2 are different, and F1 and F2 are different, as is also clearly suggested by differentiating each of them with a different number (i.e., 1 or 2), and that the readout probes (i.e., comprising D1E1F2 and D2E2F2, respectively) respectively hybridize to the two respective complementary tags comprising A1B1C1 and A2B2C2.
Edelman also teaches the barcode length is 10 nucleotides (i.e., claim 2; paragraph 0025), and that the anchor regions have the added advantage of being useful for nucleic acid manipulation or amplification (Figure 1 and paragraphs 0038-0041). Thus, Edelman teaches the known techniques discussed above.
With respect to the order of steps, it is noted that the courts have held that any order of performing process steps is prima facie obvious in the absence of new or unexpected results (In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930); Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959)). See MPEP §2144.04 IV C. Thus, ligating C1 and C2 to B1 and B2, respectively prior to binding to the target (as depicted in Figure 10 of Edelman) is an obvious variant of the steps of the cited prior art.
It is also noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01).
The courts have further found that “where 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). See MPEP 2144.05 II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Applicant is advised that MPEP 716.01(c) makes clear that “[t]he arguments of counsel cannot take the place of evidence in the record” (In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965)). Thus, counsel’s mere arguments cannot take the place of evidence in the record.
While Edelman teaches spatial sequencing, which indicates where each sequenced nucleic acid (i.e., target) is located within a particular space (paragraph 0012). Edelman does not teach the redout probes are labeled.
However, Cai et al. teach methods comprising contacting a sample with oligonucleotide tags (i.e., probes; paragraph 0030), wherein each probe comprises a recognition domain that binds to a target (i.e., a gene specific region) and a street (i.e., regions of the probe flanking the recognition domain) comprising cassettes (i.e., sub-regions within the flanking regions) comprising a barcode (Figure 9 and paragraph 0160). Cai et al. further teach hybridization to labeled readout (i.e., secondary) probes (paragraph 0393 and 0160 and Figure 9). Cai et al further detection of spatial localization (Figure 1), and thar the methods have the added advantage of allowing both in vitro and in situ analysis (Abstract). Thus, Cai et al. teach the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Edelman and Cai et al. to arrive at the instantly claimed methods with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in methods having the added advantages of being useful for nucleic acid manipulation or amplification as explicitly taught by Edelman (Figure 1 and paragraphs 0038-0041) and allowing both in vitro and in situ analysis as explicitly taught by Cai et al. (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in methods useful for nucleic acid detection.
Regarding claims 3 and 11, the method of claim 1 is discussed above. Edelman teaches at least 5 cassettes (paragraph 0034). Cai et al. also teach at least five sequences bound by readout probes (paragraph 00284).
Regarding claims 7-8, the method of claim 1 is discussed above. Cai et al. teach detection of fluorophores (i.e., Alexa 488) with fluorescence microscopy (paragraph 00451).
Regarding claim 9, the method of claim 1 is discussed above. Cai et al teach the detection molecule (i.e., dye) is attached to the probe via an amine-NETS reaction (paragraph 00378).
Regarding claim 10, the method of claim 1 is discussed above. Cai et al. teach detection and single cell resolution (paragraph 0005).
Regarding claim 12-13, the method of claim 1 is discussed above. Cai et al. teach the use of 5 distinguishable detection molecules (i.e., paragraph 0409).
Regarding claims 14-16, the method of claim 1 is discussed above. Cai et al teach multiplex (i.e., concurrent) analysis of 1000 target molecules (paragraph 0381).
Regarding claim 18-19, the method of claim 1 is discussed above, Cai et al. teach detection of DNA and mRNA molecules (paragraph 0016), as does Edelman (paragraph 0049).
Regarding claim 20, the method of claim 1 is discussed above. Cai et al. teach detection is performed in a cell (paragraph 0007), as does Edelman (paragraph 0256).
Regarding claims 21 and 23, Edelman teaches systems comprising a detector for detecting two molecules (i.e., an optical detection system; paragraph 0012), as well as at least two oligonucleotide tags, wherein each tag comprises target recognition domains G1 and G2, respectively, and respective streets (i.e., the regions upstream of the recognition domains) comprising cassettes (i.e., subunits of the streets) comprising barcode regions B1 and B2, which are respectively flanked by anchor sequences A1/C1 and A2/C2 (paragraph 0167 and Figure 10). Barcode regions B1 and B2 each have different sequences (paragraph 0038); thus, each sequence of each barcode region of the tags are different.
It is reiterated that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments While claim 21 does not explicitly state that there is a plurality of different tags, the claim does reference “each” tag, which is interpreted as requiring at least two tags.
Edelman teaches the barcode molecules of the multimeric barcodes may be linked on a (i.e., single) nucleic acid molecule (paragraph 0029; see also Figure 11 and paragraph 0188), which encompasses the alternate embodiment wherein the barcode molecules are not linked on a single molecule. Thus, it would have been obvious to have barcode readout molecule 1 comprising D1E1F1 (complementary to A1B1C1) and barcode readout molecule 2 comprising D2E2F2 (complementary to A2B2C2) as separate molecules (as depicted in Figure 8) that contact the target in the manner depicted in Figure 10.
In addition, Edelman teaches readout molecule regions D1 and D2 (which are respectively complementary to anchor regions A1 and A2) may be identical, which encompasses the alternate embodiment wherein they are not identical. Thus, each of tag sequences A1 and A2 are unique to each cassette (i.e., claims 21 and 23) because they are complementary to the unique readout sequences of D1 and D2.
Edelman also teaches the readout prove adapter regions F1 and F2 (which are respectively complementary cassette street regions C1 and C2) to may comprise a constant region (paragraph 0033) encompasses embodiments not constant, there therefore are all different. In addition, Edelman teaches F1 and F2 are substantially identical (paragraph 0033), which means they are not entirely identical.
Thus, the totality of the teachings of Edelman reasonable suggest that each of A1 and A2 are different, B1 and B2 are different, C1 and C2 are different, D1 and D2 are different, E1 and E2 are different, and F1 and F2 are different, as is also clearly suggested by differentiating each of them with a different number (i.e., 1 or 2), and that the readout probes (i.e., comprising D1E1F2 and D2E2F2, respectively) respectively hybridize to the two respective complementary tags comprising A1B1C1 and A2B2C2.
Edelman also teaches the barcode length is 10 nucleotides (paragraph 0025), and that the systems have the added advantage of being useful for nucleic acid manipulation or amplification (Figure 1 and paragraphs 0038-0041). Thus, Edelman teaches the known techniques discussed above.
It is also reiterated that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists, and that where 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.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Applicant is reminded that counsel’s mere arguments cannot take the place of evidence in the record.
While Edelman teaches spatial sequencing, which indicates where each sequenced nucleic acid (i.e., target) is located within a particular space (paragraph 0012). Edelman does not teach the redout probes are labeled.
However, Cai et al. teach systems (paragraph 0004) comprising a detector for detecting at least two detectable molecules (i.e., an epifluorescence microscope; paragraph 00451), and further comprising oligonucleotide tags (i.e., probes; paragraph 0030), wherein each probe comprises a recognition domain that binds to a target (i.e., a gene specific region) and a street (i.e., regions of the probe flanking the recognition domain) comprising cassettes (i.e., sub-regions within the flanking regions) comprising a barcode (Figure 9 and paragraph 0160). Cai et al. further teach hybridization to labeled readout (i.e., secondary) probes (paragraph 0393 and 0160 and Figure 9). Cai et al further detection of spatial localization (Figure 1), and thar the systems have the added advantage of allowing both in vitro and in situ analysis (Abstract). Thus, Cai et al. teach the known techniques discussed above.
It would therefore have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Edelman and Cai et al. to arrive at the instantly claimed systems with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in systems having the added advantages of being useful for nucleic acid manipulation or amplification as explicitly taught by Edelman (Figure 1 and paragraphs 0038-0041) and allowing both in vitro and in situ analysis as explicitly taught by Cai et al. (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of the cited prior art could have been combined with predictable results because the known techniques of the cited prior art predictably result in systems useful for nucleic acid detection.
Response to Arguments
11. Applicant's arguments filed 9 January 2026 (hereafter the “Remarks”) have been fully considered but they are not persuasive for the reasons discussed below.
A. Pages 7-8 of the Remarks summarize the amendments, refer to previous rejection that are withdrawn in view of the amendments, and refer to a previous claim interpretation no longer applied to the instant claims.
B. Applicant argues on pages 8-9 of the Remarks that the adapter regions of Edelman are designed to anneal to an adapter oligonucleotide capable of binding the target.
However, as noted in the rejections above, oligonucleotides comprising A1-B1-C1-G1 are the claimed tags, and the oligonucleotides comprising D1-E1-f1 are the claimed readout molecules.
C. Applicant argues on pages 9-10 of the Remarks that the inclusion of the two anchor regions have unexpected technical benefits.
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., stable hybridization, tunable binding affinity) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In addition, improved hybridization based on additional sequences that flank the barcode region is hardly unexpected, as more nucleotides hybridizing to a complementary strand will increase the stability because each additional hybridized based pair increases the melting temperature (and thus stability) of the duplex.
In response to applicant's argument that the claimed invention has unexpected benefits, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Conclusion
12. No claim is allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert T. Crow whose telephone number is (571)272-1113. The examiner can normally be reached M-F 8:00-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Robert T. Crow
Primary Examiner
Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683