DETAILED ACTION
Notice of Pre-AIA or AIA Status and New Examiner
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.
Election/Restrictions
3. Applicant’s election without traverse of Group I in the reply filed on 20 August 2026 is acknowledged.
Claims 18-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 20 August 2026.
Claims 1-17 are under prosecution.
Drawings
4. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by:
I. The appropriate fee set forth in 37 CFR 1.17(h);
II. One set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web; and, unless already present,
III. An amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
5. A statement from Applicant that there is no intention to have color drawings will result in acceptance of the drawings; otherwise, the conditions set forth above must be met in order for the color drawings to be accepted.
Specification
6. The use of trade names or marks used in commerce (including but not necessarily limited to those listed in paragraph 0052 of the instant specification), has been noted in this application. Any trade names or marks should be accompanied by the generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Information Disclosure Statement
7. The Information Disclosure Statement filed 23 April 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
8. The claims are subject to the following interpretation:
Claim 1 (upon which claims 2-17 depend) is directed to detecting “biomolecules.” However, the claims only refer to “target polynucleotides.” Thus, the “biomolecules” are limited to polynucleotides.
Claim Rejections - 35 USC § 112
9. 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.
10. Claim 8 is 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.
Claim 8 is indefinite in the recitation “the nucleotide,” which lacks antecedent basis in the previous recitation of “a labeled nucleotide.”
Claim Rejections - 35 USC § 103
11. 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.
12. 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.
13. Claims 1-5, 12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (U.S. Patent Application Publication No. US 2016/0369329 A1, published 22 December 2016) and Lee et al. (Nature Protocols, vol. 10, pages 442-458, published online 12 February 2015).
Regarding claim 1, Cai et al. teach methods comprising hybridizing a first oligonucleotide with a detectable label to a target polynucleotide (i.e., transcript or DNA locus) within a cell, detecting the hybridized and labeled first oligonucleotide via imaging, removing the first oligonucleotide and hybridizing a second target oligonucleotide in the cell with a second oligonucleotide (i.e., a differently labeled fourth oligonucleotide) and detecting via imaging (Figure 1 and paragraphs 0014-0021). Cai et al. also teach the methods have the added advantage of allowing high-throughput profiling of a large number of targets (Abstract). Thus, Cai et al. teach the known techniques discussed above.
While Cai et al. teach labeled probes having cleavable linkers (paragraph 0294), Cai et al. do not teach the first oligonucleotide is cleaved into two fragments.
However, Lee et al. teach methods wherein probes are hybridized to target molecules in intact cells and tissues (Title and Abstract), wherein the proves are labeled probes that are cleaved into two fragments (e.g., Figure 1). Because each fragment is smaller than the full length probe, the melting temperatures of each fragment is lower that the melting temperature of the (full-length) probe. Lee et al. also teach the cleavable probes have the added advantage of allowing RNA localization studies (Abstract), which is a stated goal of Cai et al. (paragraph 0003). Thus, Lee 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 cited prior art to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantages of allowing high-throughput profiling of a large number of targets as explicitly taught by Cai et al. (Abstract) and allowing RNA localization studies as explicitly taught by Lee et al. (Abstract), which is a stated goal of Cai et al. (paragraph 0003). 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 detection nucleic acids in cells and tissues.
Regarding claim 2, the method of claim 1 is discussed above. Lee et al. teach the hybridization is performed at 37oC (Protocol Step 3, pages 450) and Cai et al. teach the cleaving (i.e., digestion) is also done at 37oC (paragraph 0241) .
In addition, with respect to claims 2-4, it is noted that the courts have held that optimization through routine experimentation, and in particular, when related to differences in temperature, do not support patentability (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)). Thus, the claimed temperature range merely represents routine optimization of the teachings 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, Applicant should not merely rely upon counsel’s arguments in place of evidence in the record.
Regarding claim 5, the method of claim 1 is discussed above. Cai et al. teach the labels are fluorescent (i.e., are fluorophores; paragraph 0024) as well as covalent attachment (e.g., Figure 27).
Regarding claim 12, the method of claim 1 is discussed above. Cai et al. teach the cleavable site is a restriction site (paragraph 0053), and the first oligonucleotide comprises two (i.e., at least one) restriction sites (paragraph 0285).
Regarding claim 14, the method of claim 1 is discussed above. Cai et al. teach the process is repeated to detect additional biomolecules (i.e., overlapping target nucleic acids; paragraph 0013). Lee et al. also teach repeating the steps to interrogate additional biomolecules (i.e., sequences; Figure 1).
Regarding claim 15, the method of claim 1 is discussed above. Lee et al. teach the target nucleic acid molecules (i.e., cDNA) are produced by rolling circle amplification (page 442, column 2).
14. Claims 5-9 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (U.S. Patent Application Publication No. US 2016/0369329 A1, published 22 December 2016) and Lee et al. (Nature Protocols, vol. 10, pages 442-458, published online 12 February 2015) as applied to claim 1 above, and further in combination with Berrios (U.S. Patent Application Publication No. US 2023/0416809 A1, published 28 December 2023).
It is noted that while claim 5 is rejected as described above, the claim is also obvious using the interpretation outlined below.
Regarding claims 5-9, the method of claim 1 is discussed above in Section 13.
While Lee et al. teach the probe is a sequencing primer to which a label is incorporated (Figure 1) and while Cai et al. teach the incorporated of labeled nucleotides (paragraph 0192), the previously cited prior art does not teach incorporation using a polymerase.
However, Berrios teaches methods wherein labeled nucleotides are bound (i.e., claim 6) via incorporation (i.e., claim 7) into an oligonucleotide using a polymerase (paragraph 0080). Berrios further teaches the nucleotides comprises a reversible terminator and a label that is covalently attached via a cleavable linker (i.e., claims 5 and 8; paragraph 0079). Berrios also teaches the incorporation of multiple (i.e., one or more) labels into an oligonucleotide in a plurality of sequencing cycles (i.e., claim 9; paragraph 0080), and that the methods have the added advantage of allowing spatial detection of biomolecular interactions (Abstract), which is a stated goal of Cai et al. (paragraph 0003). Thus, Berrios teaches 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 Berrios with the previously cited prior art to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of allowing spatial detection of biomolecular interactions as explicitly taught by Berrios (Abstract), which is a stated goal of Cai et al. (paragraph 0003). In addition, it would have been obvious to the ordinary artisan that the known techniques of Berrios could have been combined with the previously cited prior art with predictable results because the known techniques of Berrios predictably result in methods useful for detection of nucleic acids in cells and tissues (paragraph 0106 of Berrios).
15. Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (U.S. Patent Application Publication No. US 2016/0369329 A1, published 22 December 2016) and Lee et al. (Nature Protocols, vol. 10, pages 442-458, published online 12 February 2015) as applied to claim 1 above, and further in combination with Boutell et al. (U.S. Patent Application Publication No. US 2020/0190578 A1, published 18 June 2020).
Regarding claims 10-11, the method of claim 1 is discussed above in Section 13.
While Lee et al. teach the first oligonucleotide comprises a cleavable site (Figure 10, and while Cai et al. teach cleavage of disulfide linkers with reducing agents (paragraph 0162), none of the previously cited prior art teaches the claimed cleavage sites within an oligonucleotide.
However, Boutell et al. teach methods wherein oligonucleotides contain cleavable linkages, including disulfides (i.e., claim 10), which have the added advantage of not disrupting hybridization with a complementary strand (paragraph 0129), and 8-oxo-buanine (i.e., claim 11), which has the added advantage of being capable of being copied by a polymerase during amplification (paragraph 0139). Thus, Boutell et al. teach the known techniques discussed above.
In addition, the courts have stated:
similar properties may normally be presumed when compounds are very close in structure. Dillon, 919 F.2d at 693, 696, 16 USPQ2d at 1901, 1904. See also In re Grabiak, 769 F.2d 729, 731, 226 USPQ 870, 871 (Fed. Cir. 1985) (“When chemical compounds have very close’ structural similarities and similar utilities, without more a prima facie case may be made.”). Thus, evidence of similar properties or evidence of any useful properties disclosed in the prior art that would be expected to be shared by the claimed invention weighs in favor of a conclusion that the claimed invention would have been obvious. Dillon, 919 F.2d at 697-98, 16 USPQ2d at 1905; In re Wilder, 563 F.2d 457, 461, 195 USPQ 426, 430 (CCPA 1977); In re Linter, 458 F.2d 1013, 1016, 173 USPQ 560, 562 (CCPA 1972) (see MPEP 2144.08(d)).
Therefore, the claimed d-8-oxoG is an obvious variant of the 8-oxo-guanine of the cited prior art.
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 Boutell et al. with the previously cited prior art to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantages of not disrupting hybridization with a complementary strand and/or being capable of being copied by a polymerase during amplification as explicitly taught by Boutell et al. (paragraphs 0129 and 0139, respectively). In addition, it would have been obvious to the ordinary artisan that the known techniques of Boutell et al. could have been combined with the previously cited prior art with predictable results because the known techniques of Boutell et al. predictably result in reliable cleavable linkers.
16. Claims 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Cai et al. (U.S. Patent Application Publication No. US 2016/0369329 A1, published 22 December 2016) and Lee et al. (Nature Protocols, vol. 10, pages 442-458, published online 12 February 2015) as applied to claim 15 above, and further in combination with
Fredriksson (U.S. Patent Application Publication No. US 2023/027467 A1, published 26 January 2023).
Regarding claims 16-17, the method of claim 15 is discussed above in Section 13.
While Lee et al. each rolling circle amplification (Figure 1) and barcoding (page 445, column 1), and while Cai et al. teach barcoding (e.g., Abstract), none of the previously cited prior art teaches the antibody conjugation of barcode sequence.
However, Fredriksson teaches methods of in situ production of rolling circle (i.e., RCA) products (paragraph 0008) wherein the RCA products are bound to an oligonucleotide comprising an antibody or aptamer (i.e., claim 16; paragraph 0064). Fredriksson further teaches the circularized probe comprises a barcode (i.e., claim 17; paragraph 0147), and that the methods have the added advantage of providing the relative location of each RCA product (paragraph 0158). Thus, Fredriksson teaches 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 Fredriksson with the previously cited prior art to arrive at the instantly claimed method with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in a method having the added advantage of providing relative location of each RCA product as explicitly taught by Fredriksson (paragraph 0158). In addition, it would have been obvious to the ordinary artisan that the known techniques of Fredriksson could have been combined with the previously cited prior art with predictable results because the known techniques of Fredriksson predictably result in methods useful for detection of nucleic acids in tissues (paragraph 0064 of Fredriksson).
Conclusion
17. No claim is allowed.
18. 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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Robert T. Crow
Primary Examiner
Art Unit 1683
/Robert T. Crow/Primary Examiner, Art Unit 1683
