DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 19 November 2025 has been entered.
Comments
The present application is being examined under the pre-AIA first to invent provisions. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claims 1-18 are pending in the instant application.
Claims 1-18 are examined in the instant Office action.
Subject Matter Eligibility Comments
Even though the claims recite judicial exceptions (i.e., a law of nature, a natural phenomenon, or an abstract idea), the judicial exception of background modeling equations and fittings of claims 1-18 results in the practical application of improvement of the function of the sequencing device by facilitating the function of sequencing polynucleotides through simplifying the signals. Consequently, the claims 1-18 are interpreted to be patent eligible.
Priority
The instant application is a continuation of parent application 15929565 (filed 5/11/2020). Application ‘565 is a continuation of parent application 15498591 (filed 4/27/2017). Application ‘591 is a divisional of parent application 13892116 (filed 5/10/2013). Application ‘116 claims benefit to provisional application 61645951 (filed 5/11/2012).
However, the restriction requirement in application ‘116 was withdrawn before the first action on the merits in the parent application. In addition, the subject matter of the instant set of claims is not patentably distinct from the subject matter of the parent application ‘116. Consequently, for the purpose of the double patenting rejections, the 121 bar does not apply.
While Figures 6A and 7A of provisional application ‘951 generally describes a fitting algorithm, provisional application ‘951 does not have possession of the specific fitting algorithm requiring “fitting an output signal model based on at least the estimated background signal component to the received output signals, wherein the fitting is used to generate sequence data representative of nucleotide incorporations into the copies of the polynucleotide stands resulting from the series of nucleotide flows.”
Consequently, the benefit date of claims 1-18 is 5/10/2013.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
The following rejection is reiterated:
35 U.S.C 103 Rejection #1:
Claims 1-4, 6-14, and 16-18 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rearick et al. [US PGPUB 2012/0172241 A1; on IDS] in view of Flowers et al. [Cancer Chemother Phamacol, volume 45, 2000, pages 335-344].
Claim 1 is drawn to a system for sequencing-by-synthesis. The system comprises a reactor array having multiple reaction confinement regions. One or more copies of a polynucleotide strand is located in a reaction confinement region of the reactor array wherein the loaded reaction confinement region is located in the vicinity of one or more neighboring reaction confinement regions. The system comprises receiving output signals at the processor from the reactor array in response to flowing a series of nucleotide flows onto the reactor array. The system comprises estimating a background signal component for the loaded reaction confinement region using the received output signals and a nearest-neighbor background model representing at least an exchange of ions between one or more neighboring reaction confinement regions. The nearest-neighbor background model is derived using a first characteristic equation. The first characteristic equation comprises a term related to a different between a proton concentration in each of the neighboring reaction confinement regions and a proton concentration in the headspace. The system comprises fitting an output signal model based on at least the estimated background signal component to the received output signals. The fitting is used to generate sequence data representative of nucleotide incorporations into the copies of the polynucleotide stands resulting from the series of nucleotide flows.
The document of Rearick et al. studies models for analyzing data from sequencing-by-synthesis operations [title]. Claim 1 of Rearick et al. and Figure 3 of Rearick et al. teach an array of multiple neighboring reaction confinement regions. Figure 9 and 10 of Rearick et al. illustrate the computer limitations of the claim. Figure 4 of Rearick et al. illustrates series of nucleotides flowing across headspace in the reactor array. Figure 1 of Rearick et al. more deeply illustrates the relationship between the reaction confinement region and headspace. Equations 1-3 on page 5 of Rearick et al. teach a background model comprising a characteristic equation with a term representing the different between the proton concentration in the reaction confinement regions and the proton concentration is the headspace. Claims 1, 4, and 7 of Rearick et al. teach fitting an output signal model based on the background signal component and is used to generate sequence data representative of nucleotide incorporations into copies of polynucleotide strands resulting from the series of nucleotide flows.
While Rearick et al. teaches a background model, Rearick et al. does not teach a nearest neighbor background model.
The document of Flowers et al. teaches the evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide [title]. The abstract, the paragraph bridging columns on pages 342, and Figure 3 of Flowers et al. teach a nearest-neighbor model to analyze the cytotoxicity of drugs in treated wells of a microarray in affecting cells in control neighboring wells in each microarray of wells.
With regard to claims 2-4, Figure 3 of Rearick et al. illustrates the recited geometries of reaction confinement regions.
With regard to claims 6-14, Equations 1-9 on page 5 of Rearick et al. teach mathematically manipulated versions of the recited characteristic equations and required mathematical terms.
With regard to claim 18, claims 4 and 7 of Rearick et al. teach fitting the background model to output signals resulting from a non-incorporation event in response to a nucleotide flow in the series of nucleotide flows.
Claims 16-17 recite a different characteristic equation than recited in previous claims.
Equations 12 and 14 on page 5 of Rearick et al. teach mathematically manipulated obvious variants of the recited characteristic equation and required mathematical terms.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the mathematical equations in Rearick et al. to correspond to the recite mathematical equations because the equations of Rearick et al. are mathematically analogous variants of the recited equations.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the background model in Rearick et al. to be used on nearest-neighbor wells as in Flowers et al. wherein the motivation would have been that the nearest-neighbor modeling and analysis of Flowers et al. gives a physiological application to the reactor array well and headspace analysis of Rearick et al. [abstract of Flowers et al.].
The following rejection is reiterated:
35 U.S.C 103 Rejection #2:
Claim 5 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rearick et al. in view of Flowers et al., as applied to claims 1-4, 6-14, and 16-18 above, further view of Chen et al. [US PGPUB 2010/0035763 A1].
Claim 5 recites six neighboring reaction confinement regions arranged hexagonally around a loaded reaction confinement region.
Rearick et al. and Flowers et al. make obvious arrays of reaction confinement regions, as discussed above.
Rearick et al. and Flowers et al. do not teach six neighboring reaction confinement regions arranged hexagonally around a loaded reaction confinement region.
The document of Chen et al. studies a method for screening single cells for the production of biologically active agents [title]. Paragraph 209 of Chen et al. teaches a hexagonal array of wells.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the arrays of reaction confinement regions in Rearick et al. and Flowers et al. by use of the hexagonal arrays of Chen et al. because it is obvious to substitute known elements in the prior art to yield a predictable result. In this instance, the hexagon array is an alternative to the rectangular array. There would have been a reasonable expectation of success in combining Rearick et al., Flowers et al., and Chen et al. because all three studies are analogously applicable to analysis of biological molecules within arrays of wells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The following rejection is reiterated:
Double Patenting Rejection #1:
Claims [1 or 18] and 2-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17, respectively, of U.S. Patent 10,679,724 B2 [on IDS] in view of DePristo et al. [Nature Genetics, volume 43, 10 April 2011, pages 491-498]. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to flowing a series of nucleotide flows onto a reactor array, receiving output signals from the reactor array, headspace analysis, and estimating a background signal component using a characteristic equation. The claims of ‘724 do not teach fitting an output signal model based on at least the estimated background signal component to the received output signals, wherein the fitting is used to generate sequence data representative of nucleotide incorporations into the copies of the polynucleotide stands resulting from the series of nucleotide flows.
The document of DePristo et al. studies a framework for variation discovery and genotyping using next-generation DNA sequencing data [title]. Figure 3 on page 495 of DePristo et al. teaches fitting a sequencing model to sequencing data to generate data representative of nucleotide incorporations.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the analysis of the arrays of reaction confinement spaces of the claims of ‘724 by use of the fitting algorithm of DePristo et al. wherein the motivation would have been that DePristo et al. adds additional modelling data to facilitate the analysis of sequencing signals [Figure 3 of DePristo et al.].
The following rejection is reiterated:
Double Patenting Rejection #2:
Claims 1-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18, respectively, of U.S. Patent 11,657,893 B2 in view of DePristo et al. [Nature Genetics, volume 43, 10 April 2011, pages 491-498]. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to flowing a series of nucleotide flows onto a reactor array, receiving output signals from the reactor array, headspace analysis, and estimating a background signal component using a characteristic equation. The claims of ‘893 do not teach fitting an output signal model based on at least the estimated background signal component to the received output signals, wherein the fitting is used to generate sequence data representative of nucleotide incorporations into the copies of the polynucleotide stands resulting from the series of nucleotide flows.
The document of DePristo et al. studies a framework for variation discovery and genotyping using next-generation DNA sequencing data [title]. Figure 3 on page 495 of DePristo et al. teaches fitting a sequencing model to sequencing data to generate data representative of nucleotide incorporations.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the analysis of the arrays of reaction confinement spaces of the claims of ‘893 by use of the fitting algorithm of DePristo et al. wherein the motivation would have been that DePristo et al. adds additional modelling data to facilitate the analysis of sequencing signals [Figure 3 of DePristo et al.].
The following rejection is reiterated:
Double Patenting Rejection #3:
Claims 1-15 and [16 and 17] are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16, respectively, of U.S. Patent 9,646,132 B2 [on IDS]. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to flowing a series of nucleotide flows onto a reactor array, receiving output signals from the reactor array, headspace analysis, and estimating a background signal component using a characteristic equation. Even the claims of ‘132 recite additional subject matter than the instantly rejected claims, the claims of ‘132 anticipate the instantly rejected claims.
The following rejection is reiterated:
Double Patenting Rejection #4:
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent 9,646,132 B2 [on IDS] in view of DePristo et al. [Nature Genetics, volume 43, 10 April 2011, pages 491-498]. Although the claims at issue are not identical, they are not patentably distinct from each other because both claims are drawn to flowing a series of nucleotide flows onto a reactor array, receiving output signals from the reactor array, headspace analysis, and estimating a background signal component using a characteristic equation. The claim of ‘132 does not teach that the background model is fit to signals resulting from the non-incorporation event in response to a nucleotide flow.
The document of DePristo et al. studies a framework for variation discovery and genotyping using next-generation DNA sequencing data [title]. Figure 3 on page 495 of DePristo et al. teaches fitting a sequencing model to sequencing data to generate data representative of nucleotide incorporations and non-incorporations.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the analysis of the arrays of reaction confinement spaces of the claims of ‘893 by use of the fitting algorithm of DePristo et al. wherein the motivation would have been that DePristo et al. adds additional modelling data to facilitate the analysis of sequencing signals [Figure 3 of DePristo et al.].
The following rejection is reiterated:
Double Patenting Rejection #5:
Claims 1 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims [1 or 8] and 5, respectively, of U.S. Patent 10,146,906 B2 [on IDS] in view of Flowers et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to flowing a series of nucleotide flows onto a reactor array, headspace analysis, and estimating a background signal component using a characteristic equation.
While the claims of ‘906 teaches a background model, the claims of ‘906 do not teach a nearest neighbor background model.
The document of Flowers et al. teaches the evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide [title]. The abstract, the paragraph bridging columns on pages 342, and Figure 3 of Flowers et al. teach a nearest-neighbor model to analyze the cytotoxicity of drugs in treated wells of a microarray in affecting cells in control neighboring wells in each microarray of wells.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the background model in the claims of ‘906 to be used on nearest-neighbor wells as in Flowers et al. wherein the motivation would have been that the nearest-neighbor modeling and analysis of Flowers et al. gives a physiological application to the reactor array well and headspace analysis of the claims of ‘906 [abstract of Flowers et al.].
The following rejection is reiterated:
Double Patenting Rejection #6:
Claims 1 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims [1 or 9] and 3, respectively, of U.S. Patent 11,386,978 B2 [on IDS] in view of Flowers et al. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to flowing a series of nucleotide flows onto a reactor array, receiving output signals from the reactor array, headspace analysis, and estimating a background signal component using a characteristic equation.
While the claims of ‘978 teaches a background model, the claims of ‘978 do not teach a nearest neighbor background model.
The document of Flowers et al. teaches the evidence for a role of chloroethylaziridine in the cytotoxicity of cyclophosphamide [title]. The abstract, the paragraph bridging columns on pages 342, and Figure 3 of Flowers et al. teach a nearest-neighbor model to analyze the cytotoxicity of drugs in treated wells of a microarray in affecting cells in control neighboring wells in each microarray of wells.
It would have been obvious to someone of ordinary skill in the art at the time of the instant invention to modify the background model in the claims of ‘978 to be used on nearest-neighbor wells as in Flowers et al. wherein the motivation would have been that the nearest-neighbor modeling and analysis of Flowers et al. gives a physiological application to the reactor array well and headspace analysis of the claims of ‘978 [abstract of Flowers et al.].
Response to Arguments
Applicant's arguments filed 19 November 2025 have been fully considered but they are not persuasive.
Applicant argues that the prior art does not teach “a nearest-neighbor model to analyze an exchange of ions between one or more neighboring reaction confinement regions and a headspace adjacent to the loaded reaction confinement region and one or more neighboring reaction confinement regions.” In response, the document of Rearick et al. teaches a model to analyze an exchange of ions between one or more reaction confinement regions and a headspace adjacent to the loaded reaction confinement region and another reaction confinement regions (i.e. as discussed in the rejection statement above). The document of Flowers et al. teaches analogous modeling wherein the modeling comprises application to one or more neighboring reaction confinement region and adjacent headspace (i.e. Figure 3 of Flowers et al.). Consequently, the combination of Rearick et al. and Flowers et al. make obvious “a nearest-neighbor model to analyze an exchange of ions between one or more neighboring reaction confinement regions and a headspace adjacent to the loaded reaction confinement region and one or more neighboring reaction confinement regions.”
Applicant argues that Chen et al. does not overcome the alleged deficiencies of the combination of Rearick et al. and Flowers et al. Since the combination of Rearick et al. and Flowers et al. is not deficient, this argument is not persuasive.
Applicant argues that double patenting rejections #1, #2, #3, and #4 should be held in abeyance.
Applicant reiterates the argument regarding the combination of Rearick et al. and Flowers et al. for double patenting rejections #5 and #6. For the reasoning discussed above, the combination of Rearick et al. and Flowers et al. is not deficient.
Related Prior Art
The document of Rothberg et al. [WO 2008/076406 A2 A1; on IDS] studies methods and apparatus for measuring analytes [title]. The abstract of Rothberg et al. teaches using FET and chemFET arrays for monitoring chemical and/or biological reactions. The abstract of Rothberg et al. teaches that the methods relate to facilitating DNA sequencing techniques based on monitoring changes in hydrogen ion concentration relating to DNA synthesis. The cover figure of Rothberg et al. illustrates flowing nucleic acids through reaction confinement regions via a computer controlled valve. The cover figure of Rothberg et al. illustrates a computer that analyzes output signals from the array controller. Figure 13 of Rothberg et al. illustrates a chemFET sensor array wherein each cell is interpreted to be either a loaded or unloaded neighboring reaction confinement regions. Paragraph 202 of Rothberg et al. teaches that the arrays are constructed to reduce cross-talk and isolate noise.
Rothberg et al. does not teach estimating a background signal for the loaded reaction confinement region using the output signals and a model that accounts for exchange of ions in headspace between neighboring confinement regions. Rothberg et al. does not teach fitting an output signal model based on the estimated background component.
The document of Yu et al. [US PGPUB 2003/0232354; on IDS] studies nucleic acid reactions using labels with different redox potentials [title]. Paragraph 202 of Yu et al. reduces the background signal in neighboring containers with redox reactions.
Allowable Subject Matter
Claim 15 is free of the prior art because the prior art does not teach or suggest the mathematical relationship recited in the claims.
E-mail Communications Authorization
Per updated USPTO Internet usage policies, Applicant and/or applicant’s representative is encouraged to authorize the USPTO examiner to discuss any subject matter concerning the above application via Internet e-mail communications. See MPEP 502.03. To approve such communications, Applicant must provide written authorization for e-mail communication by submitting the following statement via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300):
Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file.
Written authorizations submitted to the Examiner via e-mail are NOT proper. Written authorizations must be submitted via EFS-Web (using PTO/SB/439) or Central Fax (571-273-8300). A paper copy of e-mail correspondence will be placed in the patent application when appropriate. E-mails from the USPTO are for the sole use of the intended recipient, and may contain information subject to the confidentiality requirement set forth in 35 USC § 122. See also MPEP 502.03.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Russell Negin, whose telephone number is (571) 272-1083. This Examiner can normally be reached from Monday through Thursday from 8 am to 3 pm and variable hours on Fridays.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s Supervisor, Larry Riggs, Supervisory Patent Examiner, can be reached at (571) 270-3062.
/RUSSELL S NEGIN/ Primary Examiner, Art Unit 1686 2 December 2025
Prosecution Insights