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 .
New Examiner and Status of the Claims
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.
3. As noted in the Notice of Panel Decision from Pre-Appeal Brief Review mailed 23 June 2026, the previous Final Office Action mailed 20 November 2025 is vacated and withdrawn.
4. Claim 56 is withdrawn. Claims 1, 3-6, 8, 10, 12-14, 24-35, 53-54, and 57-58 are under prosecution.
Claim Interpretation
5. The claims are subject to the following interpretation:
A. It is noted that while paragraph 0065 of the instant specification states that a “retarding moiety” is an agent that is “when linked to a nucleotide, capable of slowing incorporation of the next nucleotide, in the absence of a reversible terminator,” none of the instant claims actually require an active method step wherein the incorporation of a nucleotide is slowed in any way.
B. Claim 1 (upon which claims 3-6, 8, 10, 12-14, 24-35, 53-54, and 57-58 depend) recites sequencing nucleotides that comprise “a first reversible terminator moiety and a first detectable label moiety covalently bound …via a first cleavable linker.” This limitation is interpreted as having only the detectable label moiety attached via the cleavable linker, as depicted in Figure 3C.
C. The word “unbound” in claim 5 is interpreted as referring to each of the nucleotides listed in the claim ; i.e., not just the first sequencing nucleotide.
D. Claims 25-26 depict B1A/ B1B and claims 28-29 depict B2A, respectively, as having two points of connection (designated by wavy lines). The attachment points of B1A/B1B to the sugars shown in claim 8 (upon which claims 25-26 depend) and of B2A to the sugars shown claim 10 (upon which claims 28-29 depend) are interpreted as the nitrogen atoms in the aromatic rings of the bases as depicted in Figure 3A.
E. Claims 30-31 depict L100A and L100B and claims 32-33 depict L200A, respectively, as having two points of connection (designated by wavy lines). The attachment points of L100A and L100 to B1A and B1B, respectively, shown in claim 8 (upon which claims 30-31 depend) of L200A to B2A in claim 10 (upon which claims 32-33 depend) are interpreted as the oxygen atoms as depicted in Figure 3A.
Claim Rejections - 35 USC § 112
6. 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.
7. Claims 1, 3-6, 8, 10, 12-14, 24-35, 53-54, and 57-58 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 1 (upon which claims 3-6, 8, 10, 12-14, 24-35, 53-54, and 57-58 depend) is indefinite in each of the following:
I. The recitation of “the sequence” in lines 5 and 13 of claim, as there are two recitations of “a sequence.” It is suggested that the two sequences be designated as a/the “first” sequence and a/the “second” sequence.
II. The recitation “the designed primer” in line 26 of the claim, which lacks antecedent basis in the previous recitations of “a first designed primer” and “a second designed primer.”
B. Claim 4 is indefinite in the recitation “comprise the same sequence.” Claim 1 (upon which claim 4 depends) appears to limit each designed primer to a different template polynucleotide; thus, it is unclear how they can comprise the same sequence.
C. Claim 6 is indefinite in the including of a “reversible terminator moiety.” As noted above, paragraph 0065 of the instant specification states that a “retarding moiety” is an agent that is “when linked to a nucleotide, capable of slowing incorporation of the next nucleotide, in the absence of a reversible terminator.” Thus it is unclear how the first chase nucleotide can have a reversible terminator moiety as still have a retarding moiety, as the retarding moiety will no longer work.
It is also reiterated that none of the instant claims actually require an active method step wherein the incorporation of a nucleotide is slowed in any way.
D. Claim 10 (upon which claims 27-29 and 32-33 depend) is indefinite in the recitation “the first chase reversible terminator moiety,” which lacks antecedent basis because claim 1 does not recite a “chase reversible terminator moiety.”
E. Claim 57 (upon which claim 58 depends) is indefinite in the recitation “the specific sequence,” which lacks antecedent basis because there is no previous recitation of a “specific sequence.”
Claim Rejections - 35 USC § 103
9. 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.
10. 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.
11. Claims 1, 3-6, 8, 10, 12, 24-35, 53-54, and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Gatti-Lafranconi et al. (U.S. Patent Application Publication No. US 2020/0190576 A1, published 18 July 2020), Ju et al. (U.S. Patent Application Publication No. US 2018/0274024A1, published 27 September 2018), and Zhang et al. (US Patent Application Publication No. US 2018/0163265 A1, published 14 June 2018).
Regarding claims 1 and 57-58, Gatti-Lafranconi et al. teach methods comprising contacting first and second primers with respective polynucleotide templates (Figures 1-2 and Cover figure, and paragraph 0044), incorporation of blocked, labeled nucleotides, detection of the incorporate nucleotide, and addition of blocked, unlabeled (i.e., the claimed chase) nucleotides and unblocking and unlabeling (paragraphs 0050-0051 and Figures 1-2). Gatti-Lafranconi et al. further teach Figures 4A-G, which show one strand extended with a first nucleotide 510 that is reversibly blocked and labeled nucleotide, as well as a second strand being extended with a blocked, unlabeled nucleotide 515 (i.e., the claimed chaser; see Figure 4C and paragraphs 0087-0094). Gatti-Lafranconi et al. further teach a second extension step of the first polynucleotide that was extended with the blocked, labeled nucleotide 520 (Figure 4E and paragraph 0092), and that the methods have the added advantage of allowing short cycle times with reduced phasing (paragraph 0007). Thus, Gatti-Lafranconi et al. teach the known techniques discussed above.
While Gatti-Lafranconi et al. teach the labels are attached with cleavable linkers (paragraph 0102), Gatti-Lafranconi et al. do not teach the retarding moiety is Alexa Fluor 488 ; i.e.,
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However, Ju et al. teach methods using the claimed chase nucleotide having Alexa 488 (Figure 2), as well as primers that hybridize based on sequence complementarity, temperature, ionic strength, etc. (paragraphs 0123-0124), as well as sequence identity of 99% or higher (paragraph 0145). Thus, it would have been obvious have primers with 100% complementarity as well as stringent conditions allowing primers to only hybridize to their intended targets. Ju et al. also teach the methods have the added advantage of allowing long read lengths (paragraph 0004). Thus, Ju et al. teach the know techniques discussed above.
In addition, Zhang et al. teach nucleic acids having 100% complementarity and hybridization under stringent conditions (i.e., claim 1), and that melting temperatures are defined as 50% hybridization at select pH and ionic strength conditions, and that stringent conditions that are 50C lower than the melting temperature have the added advantage of being highly stringent (i.e., claims 57-58; paragraph 0372). Thus, Zhang et al. teach the known techniques discussed above.
It is also noted that the courts have 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. Thus, the claimed complementarity and stringent conditions merely represent routine optimization of primer design and hybridization with the primers.
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 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 short cycle times with reduced phasing as explicitly taught by Gatti-Lafranconi et al. (paragraph 0007);
Allowing long reads as explicitly taught by Ju et al. (paragraph 0004); and
Being highly stringent as explicitly taught by Zhang et al. paragraph 0372).
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 techniques and molecules useful in nucleic acid sequencing.
Regarding claims 3-4, the method of claim 1 is discussed above. Gatti-Lafranconi et al. teach the same templates (i.e., claim 4) and that the sequencing nucleotide and chase nucleotide have the same nucleobase (i.e., claim 3; Figures 4C-4D).
Regarding claim 5, the method of claim 1 is discussed above. Gatti-Lafranconi et al. teach removing unbound first sequencing nucleotides (Figures 1-2).
Regarding claim 6, the method of claim 1 is discussed above. Ju et al. teach the first chase nucleotide also comprises a reversible terminator moiety (Figure 2).
Regarding claims 8 and 10, the method of claim 1 is discussed above. Ju et al. teach the formulas of claim 8 (Figure 2).
Regarding claim 12, the method of claim 1 is discussed above. Gatti-Lafranconi et al. teach the label is a fluorophore (i.e., a fluorescent label; paragraph 0036).
Regarding claims 24-25 and 27-28, the methods of claims 8 and 10 are discussed above. Ju et al. teach the claimed bases (Figure 2).
Regarding claims 26 and 29, the methods of claims 8 and 10 are discussed above. Ju et al. teach the structure of paragraph 0005-0016, wherein L1 is heteroalkynylene (paragraph 0190), which comprises an alkyne and a nitrogen, and therefore comprises
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Regarding claims 30-33, the methods of claim 8 and 10 are discussed above. Ju et al. teach the linker is
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; i.e., the structure of paragraphs 0005-0016, wherein L1 is a bond, R4A is hydrogen, R4B is alkyl, and L2 is a carbon atom (paragraphs 0005-00016 and 0190).
In addition, with respect to claims 26 and 29-33, 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)).
The courts have also stated:
[c]ompounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious) (see MPEP 2144.09).
Therefore, the claimed groups, which merely comprise the required chains, are obvious variants of the prior art.
Applicant is again cautioned to not merely rely upon counsel’s arguments in place of evidence in the record.
Regarding claims 34-35, the method of claim 1 is discussed above. Gatti-Lafranconi et al. teach detection of the first sequencing nucleotide before the second step (Figures 1-2).
In addition, 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, any claimed order of steps is an obvious variant of the steps of the cited prior art.
Applicant is again cautioned to not merely rely upon counsel’s arguments in place of evidence in the record.
Regarding claims 53-54, the method of claim 1 is discussed above. Ju et al. teach the reversible terminator moieties (i.e., R7 of the structure described in paragraphs 0005-0016), is an azido moiety (paragraph 0175) or a disulfide (paragraph 0277). Ju et al. also tech photocleavable allyl linkers (paragraph 0171).
12. Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Gatti-Lafranconi et al. (U.S. Patent Application Publication No. US 2020/0190576 A1, published 18 July 2020) and Ju et al. (U.S. Patent Application Publication No. US 2018/0274024A1, published 27 September 2018) as applied to claim 12 above, and further in view of Heffelfinger (U.S. Patent Application Publication No. US 2005/0157385 A, published 21 July 2005).
Regarding claims 13-14, the method of claim 12 is discussed above.
While Gatti-Lafranconi et al. teach excitation of the fluorophore with a light source and detecting emission (paragraph 0043, neither Gatti-Lafranconi et al. nor Ju et al. teach excitation beams.
However, Heffelfinger teaches methods of detection of nucleic acids on an array (paragraph 0008), wherein detection utilizes excitation beams to excite fluorescence (paragraph 0050) and detection on a sensor (i.e., detector) array (i.e., claim 13; paragraph 0026), and wherein the emission is a beam (i.e., claim 14; paragraph 0068). Heffelfinger also teaches the methods have the added advantage of reduced optically degrading effects (Abstract). Thus, Heffelfinger teaches the know 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 Heffelfinger 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 reduced optically degrading effects allowing long reads as explicitly taught by Heffelfinger (Abstract). In addition, it would have been obvious to the ordinary artisan that the known techniques of Heffelfinger could have been combined with the cited prior art with predictable results because the known techniques of Heffelfinger predictably result in techniques useful for inducing and detecting fluorescence.
Prior Art
13. The following prior art is hereby made of record, but not presently relied upon for any rejection, as it is considered pertinent to Applicant's disclosure.
A. Hayden et al (U.S. Patent Application Publication No. US 2019/0367976 A, published 5 December 2019) teach terminating (i.e., retarding) moieties including Alexa Fluor 350, 405, and 488 (paragraphs 0031 and 0099), which are
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, and
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B. Drmanac et al. (U.S. Patent Application Publication No. US 2018/0223358 A1, published 9 August 2018) coumarin-bases blocking (i.e., retarding) groups (paragraph 0095), which is related to
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,as well as Alexa Fluor 488 (paragraph 0171).
C. Lafferty et al (U.S. Patent Application Publication No. US 2016/0047747 A1, published 18 February 2016) teach terminating (i.e., retarding) moieties including Rhodamine 110 (paragraph 0175), which is similar to
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Conclusion
14. No claim is allowed.
15. 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
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