U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
`
`REMARKS
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`Claims 1-2, 4-5 and 7-39 are currently pending in this application. With this amendment,
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`claims 1, 14, 15, 22, 24, 31, 32, and 38 are currently amended, and claims 2, 16, 17, 25 and 33
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`are cancelled without prejudice or disclaimer. Support for the amendments to the claims can be
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`found 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 1, 4-5, 7-15, 18-24, 26-32, and 34-39 are pending.
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`The Office has restricted claims 24, 26-32, and 34-3 9, accordingly they are currently withdrawn
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`from consideration. Entry of the claim amendments and allowance of the application is
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`respectfully requested.
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`1)
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`Claim Rejections — 35 USC § 112
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`The Office Action rejects claim 16 under 35 USC. § ll2(d) or pre-AIA 35 USC. 112,
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`4th paragraph, as being of improper dependent form for failing to further limit the subject matter
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`of the claim upon which it depends, or for failing to include all the limitations of the claim upon
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`which it depends. $01er to expedite prosecution, claim 16 has been cancelled. As such, the
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`rejection to claim 16 under 35 USC. § ll2(d) is no longer relevant.
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`II) Claim Rejections — 35 USC § 103
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`A) The Office Action rejects claims 1-2, 4-5, and 7-23 under 35 USC. § 103 as
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`allegedly being unpatentable over Church et a1. (W0 2012/ 154201 A1) (hereafter “Church”).
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`This rejection is respectfully traversed for at least the following reasons.
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`i. Church fails to teach or suggest each and every element of claim 1
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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 1 recites a polynucleotide cDNA library, wherein the
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`polynucleotide cDNA library comprises at least 20,000 polynucleotides, wherein, inter alia,
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`“each of the at least 20,000 polynucleotides is at least 100 bases in length” and “the at least
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`20,000 polynucleotides encode sequences with an aggregate error rate of less than 1 in 1000
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`

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`U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
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`bases compared to the preselected cDNA sequences received in the instructions provided in the
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`computer readable non-transient medium.”
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`Applicants submit that Office Action’s reliance on Church fails to establish that the error
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`rate recited in amended independent claim 1 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 an oligonucleotide library having an
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`error rate of “leg than 1 in 1000 bases” as recited in claim 1.
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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 synthesized by the same underlying
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`technology as those described in Church (Agilent Technologies’ OLS platform), in fact, has an
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`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 0f1/500 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. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
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`It is noted that the Office Action asserts that one of skill in the art would interpret the
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`Agilent OLS Libraries of Church WITH ERRORS as the desired sequences:
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`Furthermore, since the recited “sequences received in the instructions provided in
`the computer readable non-transient medium” are neither disclosed nor defined in
`any way, the recited comparison is completely arbitrary and is thus meaningless.
`For example, when the actual sequences of the polynucleotides in library of
`Church et al. are the sequences received in the instructions provided in a computer
`readable
`non-transient medium,
`100% of
`the
`polynucleotides
`in
`the
`polynucleotide cDNA library of Church et al. have no errors (i.e., zero aggregate
`error rate) compared to the sequences received in the instructions provided in the
`computer readable non-transient medium).
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`Non-Final Office Action dated May 30, 2019 at p.6.
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`Applicants respectfully disagree with this erroneous, conclusory statement, lacking
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`support in Church. Error rate in the context of oligonucleotide libraries refers to a measurement
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`of the frequency of deviation from desired sequence. Thus, any reference in Church, and the
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`instant claims for that matter, to libraries having an error rate is far from meaningless as alleged
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`by the Office Action. In fact, Church explicitly conveys at several locations that errors in large
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`oligonucleotide libraries for subsequent assembly are n_ot desirable, and repeatedly discloses
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`means for performing error correction on assembled products (not the starting Agilent OLS
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`Pools) to obtain desired sequences:
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`Church at [004]:
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`Oligonucleotides from DNA microchips can reduce costs by at least an order of
`magnitude, yet efforts to scale microchip use have been largely unsuccessful due
`to the high error rates and complexity of the oligonucleotide mixtures.
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`Church at [029]:
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`role to the
`A number of features were discovered to play an important
`functionality of nucleic acid synthesis platform described herein, including the
`use of low-error starting material, well-chosen orthogonal primers, subpool
`amplification of individual
`assemblies, optimized assembly methods,
`and
`enzymatic error correction.
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`

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`U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
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`Attorney Docket No. 44854-701309
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`Church at [039]:
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`The term "error correction" refers to a process by which a sequence error in a
`nucleic acid molecule is corrected (e.g., an incorrect nucleotide at a particular
`location is changed to the nucleic acid that should be present based on the
`predetermined sequence). Methods for error correction include, for example,
`homologous recombination or sequence correction using DNA repair proteins.
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`In sum, the notion advanced by the Office Action of “actual sequences” of Church’s
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`oligonucleotide library encompassing the errors in an oligonucleotide library as being the
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`desired library sequences finds no support in Church.
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`As such, Applicants submit that the cited disclosure of Church fails to teach each and
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`every element recited in independent claim 1.
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`ii. 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 argues that the Agilent OLS l30mer Pool of Church
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`necessarily has an aggregate error rate of less than 1/ 1000 bp based on errors “for the synthesized
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`polynucleotides, prior to their use in the subsequent amplification and assembly steps (which
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`also introduce errors), is less than 1/ 1000 bp,” Applicants do not agree. Even assuming
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`arguendo that amplification and assembly steps of Church were to hypothetically introduce
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`errors prior to generating an error rate, which Applicants strenuously believe is not the case, the
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`Office Action provides no evidence for quantification of such error introduced. Thus, the Office
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`Action provides only conclusory statements:
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`When the polynucleotides are l30-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 improperly relies on a “common sense” rationale to
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`support an erroneous conclusion that Church discloses a polynucleotide library having an error
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`rate of less than 1 in 1000 bases.
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`The Federal Circuit in Arendl' S.A.R.L. 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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`U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
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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 1.
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`iii. Church fails to provide a reasonable expectation of success for generation of a
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`cDNA polynucleotide library having the error rate recited in claim 1
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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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`The Office Action’s cited sections of Church fail to provide for a reasonable expectation
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`of success for synthesis of a polynucleotide cDNA library, wherein the polynucleotide cDNA
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`library comprises at least 20,000 polynucleotides, wherein, inter alia, “the at least 20,000
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`polynucleotides encode sequences with an aggregate error rate of less than 1 in 1000 bases
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`U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
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`compared to the preselected cDNA sequences received in the instructions provided in the
`
`computer readable non-transient medium,” as recited in claim 1.
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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, the only guidance from Church for methods to
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`improve upon the error rates associated with the Agilent OLS generated libraries is with mt-
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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 how to attain an
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`oligonucleotide library with an error rate of less than 1 in 1000 bases, one of skill in the art is left
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`without guidance sufficient to establish a reasonable expectation of success sufficient to establish
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`a primafacie case of obviousness.
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`iv. 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 a polynucleotide library of have at least 100
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`bases in length with the error rate recited in independent claim 1. In addition, Church fails to
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`provide guidance for improving upon the oligonucleotide libraries disclosed therein. In fact,
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`Church expresses a strong preference for use of oligonucleotides of longer length (i.e. 200mers)
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`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
`restriction endonucleases to process primers to form dsDNA resulted in more
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`

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`U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
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`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
`l/lOOOth 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 high
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`error rate (l/250) is a preferable material for gene assembly over the l30mer library. Moreover,
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`the shorter l30mers 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 longer
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`more error prone oligonucleotides of Church cannot be ignored when consideration the express
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`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 1. Accordingly,
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`Applicants respectfully request the rejection to independent claim 1 and dependent claims
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`therefrom under 35 U.S.C. § lO3(a) be withdrawn.
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`B) The Office Action rejects claim 4 under 35 U.S.C. § 103 as allegedly being
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`unpatentable over Church as applied to claim 1, and in further view of Hodgson (US
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`2002/0025561 A1) (hereinafter “Hodgson”) and Kini et al. (US 2009/0285825). This rejection is
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`respectfully traversed for at least the following reasons.
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`Applicants submit that Hodgson and Kini, alone or in combination, fail to cure the
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`deficiencies of Church addressed above. For at least these reasons, Applicants respectfully
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`request that this rejection to claim 4 under 35 U.S.C. § 103 be withdrawn.
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`-12-
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`

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`U.S. Serial No. 15/729,564
`Response to Non-Final Office Action Filed November 26, 2019
`
`Attorney Docket No. 44854-701309
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`CONCLUSION
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`Applicants respectfully solicit the Examiner to expedite examination of this application to
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`issuance. Should the Examiner have any questions, Applicants request that the Examiner contact
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`the undersigned at 617-598-7824. The Commissioner is hereby authorized to charge any fees
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`that may be required, or credit any overpayment to Deposit Account No. 23-2415, referencing
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`Attorney Docket No. 44854-701309.
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`Respectfully submitted,
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`WILSON SONSINI GOODRICH & ROSATI
`
`A Professional Corporation
`
`
`Date: November 26 2019
`
`By:
`
`/David S. Harburger/
`David S. Harburger
`Registration No. 65,159
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(617) 598-7824 (Direct Dial)
`Customer No. 021971
`
`-13-
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`