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.
Election/Restrictions
3. Applicant’s election of Group I in the reply filed on 18 September 2025 and the species elected therein is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Election was made without traverse in the reply filed on 18 September 2025.
The following claims are therefore withdrawn:
Claims 9-11 are withdrawn pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, because claim 9 (upon which claims 10-11 depend) recite “the third hybridization domain,” which is part of unelected species b-3 in claim 1;
II. Claim 41 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention: and
Claim 113 is withdrawn pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species.
There is no allowable generic or linking claim.
Claims 1-2, 5-6, 12,14-17, 21-22, 24-25, 32, 37, and 40 are under prosecution.
Specification
4. The amendments to the specification filed 9 June 2022, 30 November 2022, and 5 March 2024 are acknowledged and have been entered.
5. The use of trade names or marks used in commerce (including but not necessarily limited to Alexa Fluor and at least the other labels starting on page 23 of the instant specification) has been noted in this application. The terms 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
6. The Information Disclosure Statements filed 9 June 2022, 6 January 2025, 3 February 2025, 15 May 2025, and 13 November 2025 are acknowledged and have 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 Rejections - 35 USC § 112
7. 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.
8. Claims 12, 15-16, 24, 32, and 37 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.
A. Claim 12 is indefinite in the recitation “and optionally,…or the first nucleic acid further…” at the end of the claim. It is unclear if the alternative “or the first nucleic acid further…” at the end of the claim is an optional limitation as the phrase occurs after the word “optionally.”
Forth the purposes of examination, the claim is interpreted as requiring either a) an RNA or RNA transcript; b) a 5’ primer sequence, and, optionally, the poly(A) sequence.
B. Regarding claim 15 (upon which claim 16 depends), the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
C. Claim 24 (upon which claim 32 depends) is indefinite in the recitation “a light source,” as it is unclear how the light source is parge of a composition.
D. The term “small” in claim 32 is a relative term which renders the claim indefinite. The term “small” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
E. Claim 37 is indefinite in the recitations “CNVK” and “CNVD.” The meanings of acronyms may change over time, and the specification does not define what is encompassed by the cited terms.
While it is suggested that Applicant amend the claim to recite a specific compound, Applicant is strongly cautioned against the introduction of new matter when amending the claims..
9. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
10. Claims 10-12, 17, 21, and 32 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, for the following reasons:
A. Claims 10-11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 10 (upon which claim 11 depends), recites “when n is 0.” However, claim 9, upon which claim 10 depends, states that n is an integer from 1 to 100, and thus cannot be zero.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
B. Claims 12, 17, 21, and 32 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 12 and 32 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
A. Claim 12 lists three disparate groups; i.e., RNA, polyA, or a primer.
B. Claim 17 lists three disparate groups: i.e., letter codes, modified nucleotides, and lengths.
C. Claim 21 requires the UMI the UMI to be incorporated in one of the other domains. However, claim 1, upon which claim 21 depends, requires the UMT to be at the 5’ end. Thus, the UMI cannot be within the first targeting domain (as it would no longer be at the 5’ end), nor can the UMI be downstream of the first target domain.
For the purposes of examination, the UMI of claim 21 is interpreted as being present anywhere in the first nucleic acid, and it can be grouped with any “one of the other domains.”
D. Claim 32 list three disparate groups; i.e., immobilization surfaces, a pattern, and types of molecules.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 1-2, 5, 17, 21-22, 24-25, 32, 37, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Gaublomme et al. (U.S. Patent Application Publication No. US 2018/0320224 A1, published 8 November 2018) and Gelman et al. (U.S. Patent Application Publication No. US 2014/0005253 A1, published 2 January 2014).
Regarding claim 1, Gaublomme et al. teach a barcode composition in the form of Figure 2H, which comprises a first strand (i.e., the top strand of Figure 2H) comprising, starting from the 5’ end, a first targeting domain, in the form of an aptamer, followed by a first hybridization domain comprising a spacer and NXT2*, wherein the spacer is a photocleavable linker (paragraph 0085). Figure 2H further comprises a second (i.e., the bottom) strand having from the 5’ end a barcode domain and a second hybridization domain hybridized to the first barcode domain (e.g., NXT2*). Gaublomme et al. also teach the compositions have the added advantage of allowing mRNA detection in single cells (Abstract). Thus, Gaublomme et al. teach the known techniques discussed above.
While Gaublomme et al. teach the use of aptamers and the detection of mRNA molecules (Abstract). Gaublomme et al. do not teach the aptamer itself binds the mRNA molecule.
However, Gelman et al. teach compositions wherein nucleic acid aptamer molecules are designed to bind target mRNA molecule, which has the added advantage of allowing detection to target molecules that do not naturally bind to nucleic acids (i.e., probes; paragraph 0437). Thus, Gelman et al. teach the known techniques discussed above.
In addition, it is noted that the courts have held that the rearrangement of parts within a device is obvious when the arrangement does not specifically modify the operation of the device (In re Japikse, 181 F.2d 1019, 86 USPQ 70 (CCPA 1950)). See MPEP §2144.04. Thus, any arrangement of the claimed domains and sequences is an obvious variant 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.
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 Gaublomme et al. and Gelman et al. to arrive at the instantly claimed composition 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 composition having the added advantage of allowing mRNA detection in single cells as explicitly taught by Gaublomme et al. (Abstract) as well as the added advantage of allowing detection of target molecules that do not naturally bind nucleic acids as explicitly taught by Gelman et al. (paragraph 0437). 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 compositions useful for detecting mRNA molecules.
Regarding claim 2, the composition of claim 1 is discussed above. Gaublomme et al. teach the second nucleic acid comprises a primer sequence (e.g., NXT1*; paragraph 0039) at the 5’ end (e.g., Figure 2H).
Regarding claim 5, the composition of claim 1 is discussed above. Gaublomme et al. teach a third nucleic acid which also comprises a barcode domain (e.g., the molecule comprising aptamer 2 of Figure 2I).
Gaublomme et al. also teach sets of molecules have identical barcodes (paragraph 0065). Thus, in the embodiment wherein the barcode of the third nucleic acid is identical to the barcode of the first nucleic acid of Figure 2I, they both would be complementary to the clamed first barcode, which is in the second nucleic acid of Figure 2I.
Applicant is again cautioned against merely relying upon counsel’s arguments in place of evidence in the record.
Regarding claim 17, the composition of claim 1 is discussed above. Gaublomme et al. teach each of the domains is independently 1-1000 nucleotides in length (paragraphs 0007, 0052, and 0065-0066).
It is 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 also 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 again cautioned against merely relying upon counsel’s arguments in place of evidence in the record.
Regarding claim 21, the composition of claim 1 is discussed above. It is noted that in embodiments where the optional UMI is not present, the claim is not further limiting.
In addition, Gaublomme et al. teach a UMI in the first nucleic acid (Figure 2G), which is interpreted as being in a domain (e.g., included with NXT2* or barcode 1) as discussed above.
It is reiterated that the courts have held that the rearrangement of parts within a device is obvious when the arrangement does not specifically modify the operation of the device. Thus, any arrangement of the claimed UMI of the cited prior art is an obvious variant.
Applicant is again cautioned against merely relying upon counsel’s arguments in place of evidence in the record.
Regarding claim 22, the composition of claim 1 is discussed above. Gaublomme et al. teach at least one nucleic acid comprises and additional photocleavable spacer (e.g., Figure 2H).
Regarding claims 24-25, the composition of claim 1 is discussed above. Gaublomme et al. teach the composition comprises a detectable labeled (i.e., a labeled target; paragraph 0073). In addition, Gelman et al. teach labeled target elements comprising fluorescent molecules (e.g., Cy3; paragraph 0617).
Regarding claim 32, the composition of claim 24 is discussed above. Gaublomme et al. teach the target element is a nucleic acid (i.e. an mRNA molecule; Abstract), as do Gelman et al. (paragraph 0437).
Regarding claim 37, the composition of claim 24 is discussed above. Gaublomme et al. teach the spacer is a sequence and comprises a photocleavable linker (paragraph 0085), and the use of 5-iododeoxyruidine as a photoreactive group (paragraph 0194). Thus, would have been obvious to use the photoreactive nucleotide 5-iododeoxyruidine as the photoreactive group in the spacer.
Regarding claim 40, the composition of claim 1 is discussed above. Gaublomme et al. teach kits (paragraph 0059), as do Gelman et al. (Abstract)
In addition, the specification does not define the term “kit,”, and so it is being interpreted to encompass any collection of reagents that includes all of the elements of the claims. Any further interpretation of the word is considered an “intended use” and does not impart any further structural limitation of on the claimed subject matter.
13. Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Gaublomme et al. (U.S. Patent Application Publication No. US 2018/0320224 A1, published 8 November 2018) and Gelman et al. (U.S. Patent Application Publication No. US 2014/0005253 A1, published 2 January 2014) as applied to claim 1 above, alternatively further in view of Karube et al. (U.S. Patent Application Publication No. US 2003/0170650 A1, published 11 September 2003).
Regarding claims 14-15, the composition of claim 1 is discussed above in Section 12.
It is reiterated that the courts have held that the rearrangement of parts within a device is obvious when the arrangement does not specifically modify the operation of the device. Thus, rearrangement of the target mRNA binding domain (i.e., poly T) of Figure 3 of Gaublomme et al.to be on the first (i.e., upper) nucleic acid and aptamer 1 to be on the second (i.e., lower) nucleic acids is an obvious variant (i.e., claims 14-15).
Applicant is again cautioned against merely relying upon counsel’s arguments in place of evidence in the record.
Alternatively, Karube et al. teach compositions wherein aptamers are formed by having a (i.e., the claimed first) nucleic acid comprise a nucleic acid sequence (i.e., the claimed first targeting domain) that hybridizes to a target nucleotide sequence (paragraph 0011). Because the first targeting domain hybridizes to the target nucleic acid, they are substantially complementary (see also paragraph 0036). Karube et al. further teach the target nucleic acid binds to a target binding agent (i.e., a ligand), and that the compositions have the added advantage of detecting SNPs and low molecular weight compounds ( Abstract and paragraph 0024). Thus, Karube et al. teach the known techniques discussed above.
It would therefore have alternatively 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 Karube et al. with Gaublomme et al. and Gelman et al. The combination would result in aptamer 1 of Figure 2H of Gaublomme et al being a nucleic acid strand as the first targeting domain, which is hybridized to a target nucleic acid which, in turn, is bound to a target binding agent (e.g., ligand; similar to the lower half of Figure 2I for claims 14-15), thus arriving at the instantly claimed compositions 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 composition having the added advantage of detecting SNPs and low molecular weight compounds as explicitly taught by Karube et al. (Abstract and paragraph 0024). In addition, it would have been obvious to the ordinary artisan that the known techniques of Karube et al. could have been combined with the cited prior art with predictable results because the known techniques of Karube et al. predictably result in compositions useful for detecting various molecules.
Regarding claim 16, the composition of claim 15 is discussed above. Gaublomme et al. teach the target binding agent is a protein (Figure 2I), as do Karube et al (paragraph 0024).
14. Claims 6 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Gaublomme et al. (U.S. Patent Application Publication No. US 2018/0320224 A1, published 8 November 2018) and Gelman et al. (U.S. Patent Application Publication No. US 2014/0005253 A1, published 2 January 2014) as applied to claims 1 and 5 above, alternatively further in view of Tsuji et al. (U.S. Patent Application Publication No. US 2012/0129720 A1, published 24 May 2012).
Regarding claims 6 and 12, the compositions of claims 1 and 5 are discussed above in Section 12.
It is reiterated that the courts have held that the rearrangement of parts within a device is obvious when the arrangement does not specifically modify the operation of the device. Thus, any arrangement of the claimed primer (i.e., at the 5’ end upstream of the first binding domain (i.e., aptamer; claim 12)) of the cited prior art is an obvious variant.
In addition, placement of the primer NXT3* (paragraph 0039) of the third nucleic acid upstream of aptamer 2 of Figure 2I, or the placement of a UMI in the third nucleic acid at the 5’ end, is an obvious variant (i.e., claim 6).
Applicant is again cautioned against merely relying upon counsel’s arguments in place of evidence in the record.
Alternatively, Tsuji et al teach binding domains (i.e., aptamers) having a 5’ (i.e., upstream) primer sequence, which has the added advantage of allowing amplification of the aptamer (paragraph 0110). Thus, Tsuji et al. teach the known techniques discussed above.
In addition, it is noted that Tsuji et al teach aptamer is an RNA molecule (i.e., is amplified by RNA polymerase; paragraph 0110). Thus, the primer and the aptamer are RNA. Gaublomme et al teach the aptamers are RNA (paragraph 0052), the barcodes are RNA (paragraph 0060), and the UMI is RNA (paragraph 0066). Thus, it would have been obvious that the entire first nucleic acids is RNA.
It would therefore have alternatively 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 Tsuji et al. with Gaublomme et al. and Gelman et al. to arrive at the instantly claimed compositions with a reasonable expectation of success. The ordinary artisan would have been motivated to make the combination because said combination would have resulted in compositions having the added advantage of allowing amplification of the aptamer (and thus the entire first nucleic acid) as explicitly taught by Tsuji et al. (paragraph 0110). In addition, it would have been obvious to the ordinary artisan that the known techniques of Tsuji et al. could have been combined with the cited prior art with predictable results because the known techniques of Tsuji et al. predictably result in compositions useful for amplifying nucleic acids.
Conclusion
15. No claim is allowed.
16. 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