DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, a method for sequencing a nucleic acid template, in the reply filed on 10/9/25 is acknowledged.
Claims 1-8, 12, 15-16, 28-29, 32, 40, 42, 46, 49 and 55-56 are pending. Claims 15-16, 28-29, 32, 40, 42 and 55-56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 10/9/25.
Claims 1-8, 12, 46 and 49 are currently under examination.
Priority
The instant application 18/069,078 filed on 12/20/22 is a CON of 371 US national phase of PCT/US22/20776 filed on 3/17/22, and claims domestic priority to provisional applications 63/162,383 filed on 3/17/21 and 63/229,252 filed 8/4/21. The priority date is determined to be 3/17/21.
Claim Rejections - 35 USC § 103
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.
Claims 1-6, 12, 46, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over Iyidogan et al. (2017; US 2017/0314064 Al; publication of US application 15/581,828, which claims the priority of provisional applications 62/329,933 filed on 4/29/16 and 62/487,586 filed on 4/20/17).
Relevant to claim 1, Iyidogan et al. teaches "In one aspect, the disclosure relates to a method of identifying a nucleotide having a base complementary to the next base of a template strand immediately downstream of a primer in a primed template nucleic acid molecule. The method includes the steps of: (a) providing a blocked primed template nucleic acid molecule… (b) contacting the blocked primed template nucleic acid molecule with a first reaction mixture that includes a polymerase, and a plurality of different nucleotide molecules… (c) contacting the stabilized ternary complex with a second reaction mixture that includes at least one of the different nucleotide molecules and that does not include a first nucleotide molecule of the plurality of different nucleotide molecules… (d) monitoring interaction of the polymerase and the blocked primed template nucleic acid molecule… and (e) identifying the nucleotide that includes the base complementary to the next base of the template strand using results from step (d). According to one generally preferred embodiment, the method further includes the step of (f) removing the reversible terminator moiety from the blocked primed template nucleic acid molecule after step (d)… According to other embodiments, where the method further includes the step of (f) removing the reversible terminator moiety from the blocked primed template nucleic acid molecule after step (d)… step (a) can involve incorporating, with a polymerase, a reversible terminator nucleotide at the 3'-end of the primer of the primed template nucleic acid molecule, whereby there is produced the blocked primed template nucleic acid molecule including the reversible terminator moiety that precludes the 3'-terminus of the blocked primed template nucleic acid molecule from participating in phosphodiester bond formation…" (paragraph 0011).
Further relevant to claim 1, Iyidogan et al. teaches "When the primed template nucleic acid is immobilized to a solid support, there are alternatives for how the contacting steps are performed… In another example, the primed template nucleic acid is immobilized to a solid support inside a flow cell or chamber. In this instance, different contacting steps can be executed by controlled flow of different liquid reagents through the chamber, or across the immobilized primed template nucleic acid" (paragraph 0062).
Further relevant to claim 1, Iyidogan et al. teaches "Optionally, multiple contacting steps occur after every round of sequencing, wherein each contacting step may comprise different subsets of nucleotides. Optionally, the method further comprises one or more washing steps after contacting. Optionally, the subset comprises two or three nucleotides. Optionally, the subset comprises three nucleotides… Optionally, each round of contacting comprises the same subset or different subsets of nucleotides" (paragraph 0221).
These teachings provide for a sequencing-by-synthesis system that would allow the user to contact the template nucleic acid with sequencing solutions in a predetermined non-cyclic binary or non-cyclic ternary sequence flow order for the two nucleotide type solutions (binary) or three nucleotide type solutions (ternary).
Relevant to claims 2-6, Iyidogan et al. teaches "Optionally, the method further includes repeating the examination step and the incorporation step to sequence a template nucleic acid molecule. The examination step may be repeated one or more times prior to performing the incorporation step. Optionally, two consecutive examination steps include reaction mixtures with different nucleotide molecules (e.g., different nucleotides that are labeled or unlabeled). Optionally, prior to incorporating the single nucleotide into the primed template nucleic acid molecule, the first reaction mixture is replaced with a second reaction mixture including a polymerase and 1, 2, 3, or 4 types of nucleotide molecules (e.g., different unlabeled nucleotides)" (paragraph 0086).
More specifically, Iyidogan et al. Example 1 uses a first wash of three dNTPs (dGTP, dCTP, dATP), a second wash of two dNTPs (dCTP, dATP), and a third wash of one dNTP (dATP). Iyidogan et al. Example 2 uses a first wash with no nucleotides, a second wash with two nucleotides (dTTP, dATP), and a third wash with two nucleotides (dCTP, dGTP).
These teachings provide for the claimed combinations of nucleotide types within claims 2-6.
Relevant to claim 12, Iyidogan et al. teaches "There is flexibility in the nature of the nucleotides that may be employed in connection with the presently described technique… Optionally, the phosphate group is modified with a moiety. The moiety may include a detectable label. Optionally, the 3' OH group of the nucleotide is modified with a moiety, where the moiety may be a 3' reversible or irreversible terminator moiety" (paragraph 0109).
Further relevant to claim 12, Iyidogan et al. teaches "Optionally, non-incorporable nucleotides include a blocking moiety that inhibits or prevents the nucleotide from forming a covalent linkage to a second nucleotide (3' OH of a primer) during the incorporation step of a nucleic acid polymerization reaction. The blocking moiety can be removed from the nucleotide, allowing for nucleotide incorporation" (paragraph 0114).
These teachings provide for the claimed subsets of nucleotides of claim 12.
Relevant to claims 46 and 49, Iyidogan et al. teaches "The examination and incorporation steps may be repeated until the desired sequence of the template nucleic acid is obtained" (paragraph 0096). Further relevant to claims 46 and 49, Iyidogan et al. teaches "Optionally, the contacting occurs after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 65, 70, 75, 80, 85, 90, 95, or 100 rounds or more of sequencing, i.e., rounds of examination and incorporation" (paragraph 0221).
Thus, although Iyidogan et al. does not explicitly teach template length limitations or numbers of incorporated nucleotides, these teachings allow the skilled artisan to recognize that repeated incorporations of nucleotides would obviously result in the recited limitations of claims 46 and 49.
Iyidogan et al. does not teach a specific embodiment having all the claimed elements. That being said, however, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. AG. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is... a person of ordinary creativity, not an automaton.” Id. at 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed elements – including nucleic acid templates; nucleotide types; template nucleic acid lengths; and numbers of incorporated nucleotides – for a method for sequencing a nucleic acid template within a prior art disclosure, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Iyidogan et al. (2017; US 2017/0314064 Al; publication of US application 15/581,828, which claims the priority of provisional applications 62/329,933 filed on 4/29/16 and 62/487,586 filed on 4/20/17), as applied to claims 1-6, 12, 46, and 49 above, and further in view of Hubbell et al. (2013; US 2013/0288904 Al; publication of US application 13/859,360, which is a CON of application 13/440,849 filed on 4/5/12).
The teachings of Iyidogan et al. are applied to instantly rejected claims 7-8 as they were previously applied to claims 1-6, 12, 46, and 49 as rendering obvious a method for sequencing a nucleic acid template.
Relevant to claims 7-8, Iyidogan et al. teaches "In the sequencing methods provided herein, the reaction mixture used for forming ternary complexes, that includes the DNA polymerase and at least one test nucleotide, can include at least 1, 2, 3, or 4 types of nucleotide molecules (e.g., either labeled or unlabeled nucleotides). Optionally, the nucleotides are native nucleotides selected from dATP, dTTP, dCTP, and dGTP. Optionally, the reaction mixture includes one or more triphosphate nucleotides and one or more diphosphate nucleotides" (paragraph 0054).
This teaching provides for a combination of less than four nucleotide types (claim 7) and a combination of two nucleotide types (claim 8).
Although Iyidogan et al. is silent to specifics regarding randomly determined combinations (relevant to claims 7-8), these limitations were known in the prior art and taught by Hubbell et al.
Relevant to claims 7-8, Hubbell et al. Abstract teaches "A method for nucleic acid sequencing includes: disposing a plurality of template polynucleotide strands, sequencing primers, and polymerases in a plurality of defined spaces of a sensor array; exposing template polynucleotide strands to a series of flows of nucleotide species, the series comprising a sequence of random flows; and obtaining, for each of the series of flows of nucleotide species, a signal indicative of how many nucleotide incorporations occurred for that particular flow to determine a predicted sequence of nucleotides corresponding to the template polynucleotide strands."
Further relevant to claims 7-8, Hubbell et al. teaches "FIG. 11 illustrates an exemplary graph showing trade-offs between efficiency of extension and dephasing merit for eight exemplary flow orderings. It shows simulated performance for eight particular flow orderings (referred to as REGULAR, SAMBA, CD_DBTAP, CONTRADANZON, TANGO_HYBRID, SAMBA.GAFIEIRA, SLOWSEQ, and RANDOM64 herein) used against 500 random sequences of length 300 drawn from a uniform distribution of the four bases… A randomly chosen sequence (RANDOM64) shows that a high degree of randomness is associated with excellent phase-protection (albeit at the cost of relatively low efficiency of extension)" (paragraph 0111).
Although Iyidogan et al. does not explicitly teach the Hubbell et al. randomly determined combinations, it would have been prima facie obvious to the skilled artisan. It is noted that Iyidogan et al. and Hubbell et al. are analogous disclosures to the instant sequencing-by-synthesis.
The skilled artisan would have been motivated to combine the analogous art. The skilled artisan would have been motivated to include the Hubbell et al. randomness within the Iyidogan et al. methodology because Hubbell et al. teaches that “A randomly chosen sequence (RANDOM64) shows that a high degree of randomness is associated with excellent phase-protection” (paragraph 0111). Thus, the skilled artisan would have been motivated by the “excellent phase-protection”.
The skilled artisan would have a reasonable expectation of success based on the disclosure of Iyidogan et al., and further in view of Hubbell et al.
Conclusion
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/SARAH JANE KENNEDY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682