U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
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`Attorney Docket No. 44854-701.304
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`REMARKS
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`Claims 23, and 25-40 are currently pending in this application. With this amendment,
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`claims 23, 35, and 37 are currently amended, claim 36 is cancelled without prejudice or
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`disclaimer, and claims 41-43 are new. Support for the amendments to the claims can be found
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`throughout the as-flled application and original claims. No new matter is believed to be
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`introduced.
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`Upon entry of this amendment, claims 23, 25-35, and 37-43 are pending in this
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`application. Allowance of the application is respectfully requested.
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`1) Claim Rejections — 35 USC § 102/103
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`Claims 23 and 25-40 are rejected under 35 USC. § 102 as allegedly being anticipated by
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`or, in the alternative, under 35 USC. § 103 as obvious over Church et al. (W0 2012/ 154201
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`A1) (herein after “Church”). Applicant respectfully traverses the rejection for at least the
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`following reasons.
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`i. Church fails to recite each and every element of independent claim 23
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`Amended independent claim 23 recites a method for computer-assisted nucleic acid
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`synthesis, comprising, inter alia, “releasing synthesis reagents from the material deposition
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`device to synthesize the plurality of polynucleotides each at least 100 bases in length, wherein
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`the plurality of polynucleotides encode sequences with an aggregate error rate of less than 1 in
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`1000 bases without correcting errors compared to the cDNA sequences received in the
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`instructions in the computer readable non-transient medium.”
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`Applicants submit that Church does not disclose the above quoted step recited in claim
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`23. Accordingly, Applicant respectfully requests the rejection to independent claim 23 and
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`dependent claims therefrom under 35 USC. § 102 be withdrawn.
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`ii. Church fails to teach or suggest each and every element of independent claim 23
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`To render a claim obvious, the cited reference(s) must be shown to teach or suggest each
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`and every claim feature. See In re Royka, 490 F.2d 981, 985 (CCPA 1974) (to establish prima
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`facie obviousness of a claimed invention, all the claim features must be taught or suggested by
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`the prior art), see also CFMT, Inc. v. YieldUp Int’l Corp, 349 F.3d 1333, 1342 (Fed. Cir. 2003).
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`Amended independent claim 23 recites a method for computer-assisted nucleic acid
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`synthesis, comprising, inter alia, “releasing synthesis reagents from the material deposition
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`U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
`
`Attorney Docket No. 44854-701304
`
`device to synthesize the plurality of polynucleotides each at least 100 bases in length, wherein
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`the plurality of polynucleotides encode sequences with an aggregate error rate of less than 1 in
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`1000 bases without correcting errors compared to the cDNA sequences received in the
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`instructions in the computer readable non-transient medium.”
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`Applicants submit that the Office Action’s reliance on Church fails to establish that the
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`error rate recited in amended independent claim 23 is taught or suggested by the publication.
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`Church is explicit that the oligonucleotides described therein were produced by the
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`Agilent OLS platform technology: “OLS pools were synthesized by Agilent Technologies.”
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`Church at [0148]. More specifically, Church describes three libraries generated using the
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`Agilent Technologies’ Oligo Library Synthesis (OLS) platform (130mers, 150mers, 200mers):
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`Assuming 6% correct sequence per construct and no selection against errors in the
`assembly process, the error rate was approximately 1/250 bp for 200mer OLS
`Pool 2. This error rate is significantly above that of the estimates for 130mer OLS
`Pool
`1 (approximately 1/1000 bp) and the sequenced 55K 150mer OLS pool
`(approximately 1/500 bp).
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`Church at [106].
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`The lowest error rate described in Church for the oligonucleotide material from the three
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`OLS pools described therein is for the 130mer Agilent OLS library, which is approximated at
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`1/1000 bp. As the oligonucleotide length for the libraries increases, the estimated error
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`frequency is described to increase (1/500 bp for 150mers and 1/250 bp for 200mers).
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`Notably, at no point in Church is there description of a method of oligonucleotide
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`synthesis providing for an error rate of “leg than 1 in 1000 bases” as recited in claim 23.
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`To the extent that any elaboration is needed, a later filed publication authored by all listed
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`inventors of Church recognizes that polynucleotide libraries of 100-200mers synthesized by the
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`same underlying technology as those described in Church (Agilent Technologies’ OLS
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`platform), in fact, has an error rate “on the order of 1/500”:
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`Most of our experience with the set of protocols provided in this paper comes
`from working with Agilent Technologies’ Oligo Library Synthesis
`(OLS)
`platform, which can synthesize oligonucleotide 100-200 bp in length with an error
`rate on the order of 1/500 errors/bp. [ ] Because the OLS platform is still under
`development, OLS pools are not yet widely sold.
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`Eroshenko et al. (2012) at page 15 (emphasis added) (citation omitted).
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`

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`U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
`
`Attorney Docket No. 44854-701304
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`Moreover, Applicants submit that the Office Action erroneously asserts that the
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`“assembled” genes described in Example 1 of Church equate to “the plurality of
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`polynucleotides” recited in the synthesis step of claim 23 for the sake of comparing error rates.
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`See Final Office Action dated September 17, 2019, at page 7. Specifically, the Office Action
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`alleges that the disclosure of error rates of 1/ 1,500 bp and 1/1130 bp for the assembled genes
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`GFP43 and GFP35 of Church in Example 1 is without error correction. Applicants respectfully
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`disagree for two separate reasons. First, Applicants submit that such a comparison is incorrect
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`because the libraries being compared are structurally different (gene fragments V. genes).
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`Second, the assembled genes of Church necessarily have a form of error correction (selection by
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`hybridization during assembly) that the Office Action fails to account for when comparing the
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`two different polynucleotide populations.
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`As such, Applicants submit that the cited disclosure of Church fails to teach or suggest
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`each element recited in independent claim 23.
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`iii. The Office Action erroneously invokes a “common sense” basis for a claim
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`element
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`To the extent that the Office Action at page 7 argues that the Agilent OLS 130mer Pool
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`of Church necessarily has an aggregate error rate of less than 1/ 1000 bp based on errors “for the
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`synthesized polynucleotides, prior to their use in the subsequent amplification and assembly
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`steps (which also introduce errors), is less than 1/ 1000 bp,” Applicants do not agree. Even
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`assuming arguendo that amplification and assembly steps of Church were to hypothetically
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`introduce significant errors prior to generating the error rate for the 130mer library of Church,
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`which Applicants strenuously believe is not the case, the Office Action provides no evidence for
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`quantification of such error introduced. Thus, the Office Action provides only conclusory
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`statements:
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`When the polynucleotides are 130-mers, the overall error rate, which reflects
`errors introduced in both the synthesis step and the subsequent amplification and
`assembly steps, is approximately ‘1/ 1000 bp.’ Thus, the aggregate error rate for
`the synthesized polynucleotides, prior to their use in the subsequent amplification
`and assembly steps (which also introduce errors), is less than 1/ 1000 bp.
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`Office Action dated May 30, 2019, at p. 6 (emphasis in original).
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`Moreover, it appears that the Office Action improperly relies on a “common sense”
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`rationale to support an erroneous conclusion that Church discloses a method of synthesizing a
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`U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
`
`Attorney Docket No. 44854-701304
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`plurality of polynucleotides each at least 100 bases in length having an aggregate error rate of
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`less than 1 in 1000 bases.
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`The Federal Circuit in Arendl' SARI. v. Apple Inc., No. 2015-2073 (Fed. Cir. 2016),
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`emphasized three important aspects of using “common sense” in an obvious analysis: (1)
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`common sense is not typically invoked to supply a missing claim limitation; (2) if common sense
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`is invoked to supply a missing claim limitation from the prior art, the missing limitation must be
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`“unusually simple” and straightforward—it cannot be a limitation that plays a major role in the
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`claimed invention; and (3) when common sense is invoked, it cannot be used as a “wholesale
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`substitute for reasoned analysis and evidentiary support, especially when dealing with a
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`limitation missing from the prior art[.]” Id. at 11-13.
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`Applicants submit that the common sense approach applied by the Office Action serves
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`(i) to supply a missing claim limitation (that the 130-mer oligonucleotide library of Church
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`reaches an error rate of “less than 1 in 1000 bases”), (ii) that the limitation plays a major role in
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`the claimed invention as it is being argued as a point of novelty, and (iii) that the Office
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`Action’s analysis is entire conclusory without evidentiary support for a limitation missing in the
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`cited art. As such, Applicants submit that it was an error for the Office Action to rely on such a
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`basis in Church for meeting the error rate limitation recited in independent claim 23.
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`iv. Church fails to provide a reasonable expectation of success for generation of a
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`plurality of polynucleotides having the error rate recited in claim 23
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`Evidence showing there was no reasonable expectation of success may support a
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`conclusion of nonobviousness. In re Rineharl, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976)
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`(finding there was no reasonable expectation that a process combining the prior art steps could
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`be successfully scaled up in view of unchallenged evidence showing that the prior art processes
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`individually could not be commercially scaled up successfully). See also MPEP 2143.02.
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`Moreover, an obviousness determination requires finding both “that a skilled artisan would have
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`been motivated to combine the teachings of the prior art .
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`.
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`. and that the skilled artisan would
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`have had a reasonable expectation of success in doing so.” In re Slepcm C0. (Fed. Cir. 2017).
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`“[T]o have a reasonable expectation of success, one must be motivated to do more than merely to
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`vary all parameters or try each of numerous possible choices until one possibly arrived at a
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`successful result.” Id.
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`U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
`
`Attorney Docket No. 44854-701304
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`The Office Action’s cited sections of Church fail to provide for a reasonable expectation
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`of success for a method of synthesis of a plurality of polynucleotides having the error rate
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`recited in claim 23.
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`The oligonucleotide libraries of Church were purchased from a commercial provider.
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`The Office Action fails to point to any guidance from Church for how to generate improved
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`starting material for such libraries. In fact, Church provides explicit guidance for methods to
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`improve upon the error rates associated with the Agilent OLS generated libraries is withw
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`assembly error correction (i.e., improving error frequency of the assembly genes as opposed to
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`the gene fragment oligonucleotides):
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`“In order to improve the error rates of the genes assembled from OLS Pool 2,
`ErrASE, a commercially-available enzyme cocktail, was used to remove errors in
`the assembled fluorescent proteins. Briefly, assembled genes are denatured and
`re- annealed to allow for the formation of hetero-duplexes.”
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`Church at [107].
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`As such, absent description in the cited sections of Church for a method to attain
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`oligonucleotides with an error rate of less than 1 in 1000 bases without error correction, one of
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`skill in the art is left without guidance sufficient to establish a reasonable expectation of success
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`sufficient to establish a primafacie case of obviousness.
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`v. The Office Action fails to consider Church’s strong preference for use of longer
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`oligonucleotides with higher error rates when scaling up
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`The US. Court of Appeals for the Federal Circuit has held that “even if a reference is not
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`found to teach away, its statements regarding preferences are relevant to a finding regarding
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`whether a skilled artisan would be motivated to combine that reference with another reference.”
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`Polaris Indus. v. Arctic Cat, 882 F.3d 1056, 1069 (Fed. Cir. 2018).
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`As addressed above, Church fails to disclose synthesis of a polynucleotides having at
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`least 100 bases in length with the error rate recited in independent claim 23. In addition, Church
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`fails to provide guidance for improving upon the oligonucleotide libraries disclosed therein. In
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`fact, Church expresses a strong preference for use of oligonucleotides of longer length (ie.
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`200mers) despite their higher error rates (i.e. 1/250 bases):
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`Despite the higher error rate, there were several advantages to the 200mer OLS
`Pool 2. First, the extensive overlaps designed in OLS Pool
`1 caused spurious
`processing of the primers from the assembly subpools. The use of Type IIs
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`U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
`
`Attorney Docket No. 44854-701304
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`restriction endonucleases to process primers to form dsDNA resulted in more
`robust processing. Second, while the 13,000 features in OLS Pool 1 can be used
`to construct greater than 700 genes, each subpool amplification used l/500th of
`the total chip-eluted DNA. While it may be possible to run this process with
`1/1000th the total material, there was a concern that the use of larger OLS Pools
`would be difficult (e.g., a 55,000 feature OLS pool would require l/3,000th of the
`total material). The longer 200mers of OLS Pool 2 allowed for a first plate
`amplification before the assembly amplification, which facilitated process scaling
`to larger OLS Pools. Third, the assemblies of OLS Pool 1 produced many smaller
`bands and required lower-throughput gel isolation procedures. Without intending
`to be bound by scientific theory, this could be due to mispriming during PCR
`assembly because of the long overlap lengths used in the design process. The
`assemblies in OLS Pool 2 used much shorter overlap lengths, and resulted in no
`smaller molecular weight misassembledproducts
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`Church at [106] (emphasis added).
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`The extensive discussion from Church above is clear: the longer 200mer library of higher
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`error rate (1/250) is a preferable material for gene assembly over the 130mer library. Moreover,
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`the shorter 130mers are stated to have several shortcomings in the system of Church. Applicants
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`submit that, and consistent with Polaris Indus. v. Arctic Cat, the strong preference for use of
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`longer more error prone oligonucleotides of Church cannot be ignored when consideration the
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`express guidance of Church.
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`In sum, Applicants submit that the Office Action’s obviousness rejection based on
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`Church fails to support a primafacz'e case of obviousness for independent claim 23.
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`Accordingly, Applicants respectfully request the rejection to independent claim 23 and
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`dependent claims therefrom under 35 U.S.C. § 103 be withdrawn.
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`11) Double Patenting
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`Claims 23 and 25-40 are rejected on the ground of nonstatutory double patenting as being
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`obvious over claims 1-25 of US Patent No. 9,409,139.
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`Claims 23 and 25-40 are rejected on the ground of nonstatutory double patenting as being
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`obvious over claims 1-29 of US Patent No. 9,833,761 in view of Church at al. (WO
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`2012/154201A1).
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`Applicant respectfully disagrees with the Office Action’s assertions and requests that the
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`rejections to the claims on the ground of nonstatutory double patenting be held in abeyance until
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`allowable subject matter is identified by the Office.
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`U.S. Serial No.: 15/187,714
`Response to Final Office Action filed December 16, 2019
`
`Attorney Docket No. 44854-701304
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`CONCLUSION
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`Applicant respectfully solicits the Examiner to expedite examination of this application to
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`issuance. Should the Examiner have any questions, Applicant requests that the Examiner contact
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`the undersigned at 617-598-7824. The Commissioner is hereby authorized to charge any fees that
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`may be required, or credit any overpayment to Deposit Account No. 23-2415, referencing
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`Attorney Docket No. 44854-701304.
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`Respectfully submitted,
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`WILSON SONSINI GOODRICH & ROSATI
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`A Professional Corporation
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`Date: _December 16 2019
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`By:
`
`/DaVid S. Harburger/
`David S. Harburger
`Registration No. 65,159
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`WILSON SONSINI GOODRICH & ROSATI
`
`650 Page Mill Road
`Palo Alto, CA 94304
`Phone (Direct Dial): (617) 598-7824
`Customer No. 021971
`
`-10-
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