US. Patent Application No. 12/954,634
`Final Office Action mailed on October 3, 2013
`Response filed on December 3, 2013
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`SUMMARY OF THE INTERVIEW
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`Applicants thank Examiners Horlick and Oyeyemi for the telephonic interview on
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`November 26, 2013 with Kimberly S. Stopak, Ali R. Alemozafar and Benjamin C. Li. During the
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`interview, claim amendments and arguments consistent with those detailed herein were discussed.
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`US. Patent Application No. 12/954,634
`Final Office Action mailed on October 3, 2013
`Response filed on December 3, 2013
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`Claim Amendments
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`REMARKS
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`Claims 1, 10, 39 and 59 have been amended. Claims 9, 40-58, 60-74, 76-88, 90-100, 103
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`and 104 have been canceled. Claims 75 and 89 have been withdrawn. No new matter is added by
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`any of these amendments. Accordingly, claims 1-39, 59, 101, 102 and 105 are pending.
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`Reconsideration and allowance of this application is respectfully requested.
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`Re'ection under 35 U.S.C.
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`103
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`Claims l-39, 59, and 101-105 stand rejected under pre-AIA 35 U.S.C. 103(a) as allegedly
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`being unpatentable over Brenner et al. (US2007/0172873, published Jul 2007; previously cited) in
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`View ofBeer et al., (2007, Anal Chem 79: p847l-8475).
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`Applicants respectfully submit that neither Brenner, nor Beer, alone or in combination
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`teach or suggest each and every element of the claims as currently amended. Brenner does not
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`disclose partitioning ligated products, much less partitioning circular ligated products. Brenner
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`also does not disclose amplifying circular ligated products within the partitions, or detecting the
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`amplified products within the partitions. In particular, Brenner teaches a method comprising:
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`ligating probes to generate linear ligated products; amplifying the linear ligated products with
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`biotinylated primers; isolating the biotinylated amplicons using streptavidinated beads; nicking the
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`amplicons and releasing the resulting fragments; combining the fragments and amplification
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`reagents with beads in microdroplets formed in an emulsion; performing PCR amplification on the
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`beads; and analyzing the loaded beads by sequencing by synthesis (paragraph [0075] and Figures
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`7A-7B, Brenner). In this embodiment,
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`fragments of the amplicons are partitioned; and the
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`ligated products are not partitioned. Further, since the ligation products of Brenner are amplified
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`with biotinylated primers and linearized, which is necessary for isolation with the streptaVidin
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`beads, the method of Brenner is incompatible with the circular ligation products taught in claim 1.
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`Brenner also teaches analyzing the loaded beads by sequencing by synthesis, which requires
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`“breaking the emulsion and isolation of loaded beads”, and therefore does not disclose
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`determining the number of partitions that contain amplified products by “detecting said partitions”
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`as recited in pending claim 1 (paragraph [0075], Brenner).
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`US. Patent Application No. 12/954,634
`Final Office Action mailed on October 3, 2013
`Response filed on December 3, 2013
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`While Brenner describes circular ligated products in a separate embodiment, the circular
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`ligated products are not partitioned into aqueous droplets or amplified in the aqueous droplets
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`(paragraph [0071], Brenner). Further, after the ligated products are amplified into biotinylated
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`amplicons, the “tag-containing regions are excised, concatenated, cloned and sequenced”, and
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`Brenner therefore again teaches away from determining the number of partitions that contain
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`amplified products by “detecting said partitions” as recited in pending claim 1 (paragraph [0071],
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`Brenner).
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`Contrary to the contentions of the Office, Beer does not cure the deficiencies of Brenner.
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`For example, like Brenner, Beer also does not disclose partitioning ligated products. Beer
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`provides a digital PCR amplification method with the ability to detect a single copy of target
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`nucleic acid in a complex background, which does not teach or suggest partitioning ligation
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`products, much less circular ligation products. Therefore, neither Brenner nor Beer, alone or in
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`combination, teach or suggest every claim limitation of claim 1.
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`Further, a person of ordinary skill in the art would have no motivation to combine or
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`modify the teachings of the selected references to arrive at the current invention. Brenner actually
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`teaches away from digital-PCR techniques, because Brenner teaches that “[d]igital measurements
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`of polynucleotides. .. are usually more difficult and expensive to implement” (paragraph [0003],
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`Brenner) (emphases added). As such, Brenner presents its technology as an alternative to digital-
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`PCR. By “providing a method of counting molecules in a sample by converting the problem of
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`counting molecules into one of counting sequences of oligonucleotide tags”, Brenner discloses
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`methods for preparing samples to be analyzed by sequencing techniques (paragraph [0005],
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`Brenner). In contrast, Beer describes digital PCR methods. Given the teachings of Brenner, a
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`person of skill in the art would have no motivation to combine Brenner with Beer.
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`Furthermore, Beer describes a digital-PCR technique “ideal for isolating single-copy
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`nucleic acids in a complex environment” (Abstract, Beer) (emphases added). Indeed, a highlight of
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`Beer is “[the real-time PCR amplification of a sample] encapsulating less than one copy of viral
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`genomic DNA... with a cycle threshold ~18, 20 cycles earlier than commercial instruments”
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`(Abstract and Conclusions, Beer). Since the ligated products obtained by the methods of Brenner
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`are typically enriched by PCR amplification, they exist as multiple copies in a relatively non-
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`US. Patent Application No. 12/954,634
`Final Office Action mailed on October 3, 2013
`Response filed on December 3, 2013
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`complex environment. Therefore, a person of ordinary skill in the art would have no motivation to
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`combine the sample preparation methods of Brenner with the digital-PCR techniques of Beer.
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`For the foregoing reasons, Applicants respectfially submit that claim 1 is not obvious.
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`Accordingly, Applicants respectfully request that the 35 USC §103(a) rejection of claim 1 be
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`withdrawn.
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`Claims 2-8, 10-38 and 101 depend from and include all of the elements of claim 1 and
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`fiarther recite additional features of particular advantage and utility. Brenner and Beer, alone or in
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`combination, do not teach or disclose all of the elements of claim 1, much less the unique
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`combination of elements of claims 2-8, 10-38 and 101. For at least the above reasons, Applicants
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`respectfully request that the 35 USC §103(a) rejections of claims 2-8, 10-38 and 101 also be
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`withdrawn.
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`Claim 39 recites a method of detecting copy number of a target polynucleotide within a
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`population of genetic material, comprising the same “circular ligation probes” and “detecting said
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`partitions” elements as claim 1. Claim 59 recites a method of detecting a fetal genetic condition
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`comprising similar limitations. For the same reasons that claim 1 is not obvious, claims 39 and 59
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`are not obvious. Since claims 102 and 105 depend from and include all of the elements of claim 59
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`and fiarther recite additional features of particular advantage and utility, claims 102 and 105 are
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`also not obvious. Therefore, Applicants respectfully request that the 35 USC §103(a) rejection of
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`claims 39, 59, 102 and 105 be withdrawn.
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`Claim 30 stands rejected under AIA 35 USC. 103(a) as allegedly being unpatentable over
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`Brenner et al. (US2007/0172873, published Jul 2007; previously cited) in view of Beer et al.,
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`(2007, Anal Chem 79: p847l-8475) as applied to claim 1 above, fiarther in view of Wang et al.
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`(Genome Biology 2007, vol. 8: Iss. 1 l: ppR246.l — R246. 14: previously cited). Applicants
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`respectfully disagree.
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`Claim 30 depends from and includes all of the elements of claim 1 and fiarther recites
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`additional features of particular advantage and utility. Brenner and Beer, alone or in combination,
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`do not teach or disclose all of the elements of claim 1, much less the unique combination of
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`elements of claim 30. This deficiency is not cured by Wang. For at least the above reasons,
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`Applicants respectfully request that the 35 USC §103(a) rejections of claim 30 also be withdrawn.
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`US. Patent Application No. 12/954,634
`Final Office Action mailed on October 3, 2013
`Response filed on December 3, 2013
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`CONCLUSION
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`Applicants submit that this paper fially addresses the Office Action mailed October 3, 2013.
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`Should the Examiner have any questions, the Examiner is encouraged to contact the undersigned.
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`If fees are believed to be required, the Commissioner is authorized to charge any fees to Deposit
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`Account No. 23-2415 (Attorney Docket No. 44347-705201). Early and favorable consideration is
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`respectfully requested, and the Examiner is encouraged to contact the undersigned attorney with
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`any questions or to otherwise expedite prosecution.
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`Respectfully submitted,
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`WILSON SONSINI GOODRICH & ROSATI
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`Dated: December 3 2013
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`By:/A1iA1emozafar/
`Ali Alemozafar.
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`Registration No.: 68,180,
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`WILSON SONSINI GOODRICH & ROSATI
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`650 Page Mill Road
`Palo Alto, CA 94304-1050
`Direct Dial: (650) 493-9300
`Customer No. 21971
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