Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The Amendment filed 05/13/2025 has been entered. Claims 1, 5-7, 10, 13-14, 16-17, 22-24, and 111-115 remain pending in the application.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5-7, 10, 13-14, 16-17, 22-24, and 111-115 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 20150133307 A1) in view of O’Keefe et al. (US 20180245133 A1; filed 04/27/2018), and further in view of Badran et al. (US 20180087046 A1), and further in view of Liu et al. (US 9771574 B2; cited in the IDS 11/25/2019) and Lapham et al. (US 20160045918 A1).
Regarding claim 1, Zhang teaches a system (abstract) comprising:
(a) at least ten receptacles (paragraph [0250], teach “microtiter plate” comprising wells for reactions, such as 100 reactions, i.e. at least 10 receptacles);
(b) a liquid-handling robot (paragraphs [0250]-[0251] teach a high throughput screening system is employed that automate all sample and reagent pipetting, liquid dispensing, timed incubation, and final readings of the microplate in detectors appropriate for an assay, wherein the structures that perform “sample and reagent pipetting, liquid dispensing” are interpreted as a liquid handling robot) comprising:
(ii) dispensing elements (paragraphs [0250]-[0251] teach a high throughput screening system is employed that automate all sample and reagent pipetting, wherein the pipetting is implied to comprise dispensing elements, e.g. pipettes, tips, pumps, electrical components, for automated pipetting) configured to deliver at least the independently selected liquid exchange fluids comprising the host cell culture of the first reservoir and the bacteriophage or the conjugative plasmids of the second reservoir to prepare the plurality of continuous evolution circuits in ten or more of the at least ten receptacles (interpreted as functional limitations of the claimed dispensing elements, see MPEP 2114; paragraphs [0250]-[0251] teach a high throughput screening system is employed that automate all sample and reagent pipetting, therefore, the dispensing elements of Zhang’s automated screening system is structurally capable of pipetting the claimed fluids to prepare the claimed circuits in the receptacles);
(c) a sensor (paragraph [0232] teach a “detector” that detects a fluorescent signal; paragraph [0234] teach an ISFET ion sensor, which indicates a reaction has occurred) configured to ongoingly monitor the prepared plurality of continuous evolution circuits and to detect at least one independently selected detectable parameter in the prepared continuous evolution circuits (interpreted as a functional limitation of the sensor, see MPEP 2114; paragraph [0232], teaches the “detector”, which is capable of detecting fluorescent signal, thus is capable of performing the functional limitation at a later time; paragraph [0250] teaches at least two wells are used to run separate assays; thus, the detector is capable of detecting a parameter in the claimed circuits at a later time).
Zhang teaches directed evolution methods increase the efficiency in honing in on the candidate biomolecules having advantageous properties and directed evolution of proteins is dominated by various high throughput screening and recombination formats, often performed iteratively (paragraph [0002]). Zhang teaches performing one or more rounds of directed evolution using the plurality of oligonucleotides (paragraph [0015]). Zhang teaches embodiments may combine in silico and physical techniques (paragraph [0191]), wherein physical methods can be used (paragraph [0248]). Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc. (paragraph [0250]). Zhang teaches that integrated systems of the invention and reagent manipulation provides high throughput (paragraph [0250]). Zhang teaches that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]). Zhang teaches high throughput screening systems to automated liquid dispensing (paragraph [0251]). Zhang teaches a computer with specialized algorithms and software (paragraph [0254]). Zhang teaches cell colonies, i.e. host cell, can be inoculated into 96 well microtiter dishes (paragraph [0255]).
Zhang fails to teach: the liquid-handling robot comprising:
(i) a plurality of reservoirs, wherein each reservoir holds an independently selected liquid exchange fluid, wherein the independently selected liquid exchange fluid in a first reservoir of the plurality of reservoirs comprises a host cell culture, the independently selected liquid exchange fluid in a second reservoir of the plurality of reservoirs comprises bacteriophage or conjugative plasmids each comprising horizontally transferable nucleic acids preselected to be evolved in a plurality of continuous evolution circuits, and the independently selected liquid exchange fluid in a third reservoir of the plurality of reservoirs comprises an inducer solution that increases a mutation rate of a gene encoding a biomolecule, wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line; and
(d) a feedback controller, configured to:
(i) select one or more independently selected real-time adjustment based on the at least one independently selected detectable parameter detected by the sensor monitoring the plurality of continuous evolution circuits, and
(ii) trigger the liquid-handling robot to perform the selected one or more real-time adjustment in the plurality of continuous evolution circuits for which the adjustment was selected, to generate independently selected experimental conditions for simultaneous, discretized continuous directed evolution in parallel in the plurality of continuous evolution circuits in the ten or more of the at least ten receptacles.
O’Keefe teaches an apparatus for conducting multiple simultaneous micro-volume chemical biochemical reactions in an array format, allowing for multiple parallel reactions (abstract). O’Keefe teaches there is a continued need for apparatuses and methods suitable for microvolume liquid reactions, and a need for improved methods of transferring polynucleotides (paragraph [0010]). O’Keefe teaches delivery of samples and reagents to a microhole can be achieved through pipetting robots (paragraph [0080]) and a reaction component in a suitable container (paragraph [0038]). O’Keefe teaches delivery of samples and reagents through the use of pipetting robots (paragraph [0080]) and a robotically controlled syringe to dispense volumes of reagent (paragraph [0081]). O’Keefe teaches a means for dispensing water, i.e. real-time adjustment, to counter evaporation can also be used to dispense other reagents or chemicals of interest, mixed in a solution such that evaporation is countered (paragraph [0090]), wherein in this way chemical assays can be carried out in real time and the evolution of the assay can be directed via feedback from the assay in progress (paragraph [0090]); and further wherein optical data obtained by placing the apparatus on an optical detector, such as a CCD or fiber optics cable, can be input to a computer, i.e. feedback controller, which automatically adjusts reagent dispensers and guides them to dispense a precise amount of reagent into each sample chamber (paragraph [0090]), i.e. real-time adjustment based on an independently selected parameter. O’Keefe teaches the apparatuses, when used in a biochemical reaction format, provides advantages of high density, high throughput, ease of handling, performance of low-volume reactions, thermal cycling, and advantageous optical access of samples (paragraph [0092]). O’Keefe teaches monitoring optical properties of reactions in real time (paragraph [0099]), i.e. independently selected parameter. O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), i.e. real-time adjustment.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the system and liquid handling robot of Zhang to incorporate O’Keefe’s teachings of parallel reactions (abstract), reaction components in a suitable container (paragraph [0038]), pipetting robots and robotically controlled syringes (paragraphs [0080]-[0081]), and real-time adjustment of evolution of assays (paragraph [0090]), and Zhang’s teachings of performing directed evolution (paragraph [0015]) and a computer with specialized algorithms and software (paragraph [0254]) to provide: the liquid-handling robot comprising: (i) a plurality of reservoirs, wherein each reservoir holds an independently selected liquid exchange fluid, wherein the independently selected liquid exchange fluid in a first reservoir of the plurality of reservoirs comprises a host cell culture. Doing so would have a reasonable expectation of successfully holding desired fluids for sample preparation and analysis, improving automation of pipetting and dispensing procedures, and improving automation and optimization of multiple reactions as they proceed in real-time as discussed by O’Keefe (paragraph [0141]), thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the system of modified Zhang to incorporate the O’Keefe’s teachings of real-time monitoring and adjustment of samples (paragraphs [0090]-[0092], [0099],[0141]) and Zhang’s teaching of performing different assays, parallelizing processes, and adjusting rules at various arounds of directed evolution (paragraphs [0230], [0250], [0228], [0288]) and a computer with specialized algorithms and software (paragraph [0254]) to provide: (d) a feedback controller, configured to: (i) select one or more independently selected real-time adjustment based on the at least one independently selected detectable parameter detected by the sensor monitoring the plurality of continuous evolution circuits, and (ii) trigger the liquid-handling robot to perform the selected one or more real-time adjustment in the plurality of continuous evolution circuits for which the adjustment was selected, to generate independently selected experimental conditions for simultaneous, discretized continuous directed evolution in parallel in the plurality of continuous evolution circuits in the ten or more of the at least ten receptacles. Doing so would prevent evaporation of samples during evolution of an assay, as discussed by O’Keefe (paragraph [0090]) and improve automation and optimization of multiple reactions as they proceed in real-time as discussed by O’Keefe (paragraph [0141]), thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]).
Modified Zhang fails to teach: the independently selected liquid exchange fluid in a second reservoir of the plurality of reservoirs comprises bacteriophage or conjugative plasmids each comprising horizontally transferable nucleic acids preselected to be evolved in a plurality of continuous evolution circuits, and the independently selected liquid exchange fluid in a third reservoir of the plurality of reservoirs comprises an inducer solution that increases a mutation rate of a gene encoding a biomolecule, wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line.
Badran teaches strategies and systems for modulating the mutation rate in cells and control over a broad range of mutation rates in the context of diversifying a nucleic acid sequence for generation of diversified nucleic acid libraries, and for directed evolution of nucleic acids (abstract). Badran teaches carrying out continuous directed evolution processes (paragraphs [0193]-[0197]). Badran teaches modulating the mutation rate as desired, e.g. during different phases of a directed evolution experiment (paragraph [0006]), which includes providing a promoter (paragraph [0022]). Badran teaches directed evolution including bacteriophage-mediated evolution (paragraph [0007]). Badran a bacteriophage carrying a constitutive expression cassette or genetic materials (paragraphs [0036],[0154]), i.e. horizontally transferable nucleic acids preselected to be evolved in the plurality of continuous evolution circuits. Badran teaches constructs for modulating mutagenesis rate includes introduction of a conjugative plasmids or bacteriophages (paragraphs [0162],[0177], [0192]). Badran teaches cells are exposed to an external mutagen during processes to increase mutation rate (paragraph [0211]). Badran teaches methods for modulating the mutation rate in a cell, such as a host cell for bacteriophage (paragraph [0200]). Badran teaches adding or withdrawing inducing agent from a host cell culture media during a PACE experiment to increase rate of mutagenesis (paragraph [0215]). Badran teaches the stringency of selection can be increased by removing the inducing agent (paragraph [0226]). Badran teaches modulating the selection stringency during evolution by introducing a selection viral vector (paragraph [0284]). Badran teaches visual tracking of infected cells is used to adjust flow rate of the system to keep the system flowing as fast as possible without risk of vector washout (paragraph [0259]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the reservoirs and dispensing elements of modified Zhang to incorporate the teachings of modulating evolution processes using bacteriophage or plasmids and inducing agents of Badran (paragraphs [0007],[0177],[0192],[0215]) and the teachings of reaction components in a suitable container of O’Keefe (paragraph [0038]) to provide: the independently selected liquid exchange fluid in a second reservoir of the plurality of reservoirs comprises bacteriophage or conjugative plasmids each comprising horizontally transferable nucleic acids preselected to be evolved in a plurality of continuous evolution circuits, and the independently selected liquid exchange fluid in a third reservoir of the plurality of reservoirs comprises an inducer solution that increases a mutation rate of a gene encoding a biomolecule. Doing so would have a reasonable expectation of successfully providing desired reagents or components for sample processing and analysis and optimizing the desired directed evolution, such as improving mutagenesis or stringency of selection (Badran, paragraphs [0006],[0226],[0284],[0259]).
Modified Zhang fails to teach: wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line.
Liu teaches an apparatus for continuous directed evolution of a gene of interest (abstract; Fig. 2). Liu teaches a reservoir (Fig. 2, “lagoon”) comprising four ports fluidly coupled to individual lines (Fig. 2 shows the lagoon has four ports with four lines that leads to respective elements, such as the turbidostat, waste, mutagen, and inducers).
Lapham teaches a high-throughput sample processing system (abstract) comprising sample processing plates (paragraph [0049]; Fig. 5, element 504) and a liquid handling robot (Fig. 5 element 502). Lapham teaches the liquid handling robot comprises one or more reservoirs (Fig. 5, interpreted as element 15; paragraph [0102], “reservoir” is being broadly interpreted as the fluid valve(s) 512). Lapham teaches the reservoir (Fig. 5, element 512) is configured to allow liquid to be pulled from one or more fluid reservoirs (paragraph [0102]). Lapham teaches the reservoir (512) comprises multiple ports fluidly coupled to fluid lines (Fig. 5 shows element 502 and fluid reservoirs 514 and 516 connected to element 512, which implies the presence of at least three ports and lines for fluid connection). Lapham teaches any number of fluid solutions may be used in processing a sample in a high-throughput sample processing system, such as a suspension solution, deionized water, non-deionized water, a lysis solution, a wash solution, an elution solution, an assay solution, or a reactive reagent (paragraph [0045]). Lapham teaches the scalability of these reservoirs helps allow for unattended operation of the system during operation (paragraph [0102]). Lapham teaches in some embodiments wherein liquid and solution is removed by draining into a sewage system (paragraph [0072]), wherein a drainage valve may be opened (paragraph [0133]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the one or more plurality of reservoirs of modified Zhang to further incorporate Liu’s teachings of a lagoon comprising four ports coupled each coupled to different lines (Fig. 2) and Lapham’s teachings of reservoirs and lines (Fig. 5), processing a sample using solutions such as water and wash solution (paragraph [0102]), and draining a liquid and solution (paragraphs [0072],[0133]) to provide: wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line. Doing so would have a reasonable expectation of successfully improving the ability of the system to be utilize different fluids and couple to different containers, allowing for drainage of the reservoir, and thus improve automation and versatility of the system when used with processes that require a plurality of different fluids.
Regarding claim 5, modified Zhang further teaches wherein the triggered one or more independently selected real-time adjustment modulates the experimental conditions in the continuous evolution circuit for which the adjustment was selected (see above claim 1; O’Keefe, paragraphs [0090], [0141] teaches real-time adjustments, e.g. dispensing of water or reagents, which modulates the experimentation conditions of the circuit, e.g. changing a concentration of the environment or causing a reaction via the reagents).
Regarding claim 6, Zhang further teaches wherein the sensor detects one or more of: absorbance, luminescence, and fluorescence in the samples (paragraph [0232] teach a “detector” that detects a fluorescent signal).
Regarding claim 7, while Zhang teaches a sensor (paragraph [0232] teach a “detector” that detects a fluorescent signal; paragraph [0234] teaches a microwell well containing a template DNA strand and teaches an ISFET ion sensor, which indicates a reaction has occurred) modified Zhang fails to explicitly teach wherein the sensor is part of an integrated plate reader.
O’Keefe teaches fluorescence emission can be read by an integrated plate reader (paragraph [0111] teaches “standard fluorescent plate reader”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the sensor of Zhang to incorporate the teachings of O’Keefe to provide the sensor is part of an integrated plate reader. Doing so would utilize known sensors used for measuring fluorescence, as taught by O’Keefe, which would have a reasonable expectation of successfully detecting at least one parameter of the one or more samples in the plurality of receptacles.
Regarding claim 10, while Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc. (paragraph [0250]), and that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]), and O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), modified Zhang fails to teach wherein the one or more independently selected real-time adjustment comprises adjusting in the continuous evolution circuit for which the adjustment was selected, one or more of (i) an amount of an inducer chemical for positive selection strength, (ii) an amount of an inducer chemical for negative selection, (iii) a selection goal, (iv) an evolving property of at least one of the biomolecules, (v) a flow rate, (vi) a mutagenesis rate, and (vii) a selection stringency.
Badran teaches strategies and systems for modulating the mutation rate in cells and control over a broad range of mutation rates in the context of diversifying a nucleic acid sequence for generation of diversified nucleic acid libraries, and for directed evolution of nucleic acids (abstract). Badran teaches carrying out continuous directed evolution processes (paragraphs [0193]-[0197]). Badran teaches modulating the mutation rate as desired, e.g. during different phases of a directed evolution experiment (paragraph [0006]), which includes providing a promoter (paragraph [0022]). Badran teaches cells are exposed to an external mutagen during processes to increase mutation rate (paragraph [0211]). Badran teaches methods for modulating the mutation rate in a cell, such as a host cell for bacteriophage (paragraph [0200]). Badran teaches adding or withdrawing inducing agent from a host cell culture media during a PACE experiment to increase rate of mutagenesis (paragraph [0215]). Badran teaches the stringency of selection can be increased by removing the inducing agent (paragraph [0226]). Badran teaches modulating the selection stringency during evolution by introducing a selection viral vector (paragraph [0284]). Badran teaches visual tracking of infected cells is used to adjust flow rate of the system to keep the system flowing as fast as possible without risk of vector washout (paragraph [0259]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the one or more independently selected real-time adjustment of modified Zhang to incorporate the teachings of modulating evolution processes of Badran to provide wherein the one or more independently selected real-time adjustment comprises adjusting in the continuous evolution circuit for which the adjustment was selected, one or more of (i) an amount of an inducer chemical for positive selection strength, (ii) an amount of an inducer chemical for negative selection, (iii) a selection goal, (iv) an evolving property of at least one of the biomolecules, (v) a flow rate, (vi) a mutagenesis rate, and (vii) a selection stringency. Doing so would utilize known adjustments of directed evolution processes as taught by Badran to optimize the desired directed evolution, such as improving mutagenesis or stringency of selection, with a reasonable expectation of success.
Regarding claim 13, while Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc. (paragraph [0250]), and that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]), and O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), modified Zhang fails to teach wherein the one or more real-time adjustment comprises the liquid handling robot performing one or more of adding an inducing agent and adjusting a flow rate in the continuous evolution circuit for which the adjustment was selected.
Badran teaches strategies and systems for modulating the mutation rate in cells and control over a broad range of mutation rates in the context of diversifying a nucleic acid sequence for generation of diversified nucleic acid libraries, and for directed evolution of nucleic acids (abstract). Badran teaches carrying out continuous directed evolution processes (paragraphs [0193]-[0197]). Badran teaches modulating the mutation rate as desired, e.g. during different phases of a directed evolution experiment (paragraph [0006]), which includes providing a promoter (paragraph [0022]). Badran teaches cells are exposed to an external mutagen during processes to increase mutation rate (paragraph [0211]). Badran teaches methods for modulating the mutation rate in a cell, such as a host cell for bacteriophage (paragraph [0200]). Badran teaches adding or withdrawing inducing agent from a host cell culture media during a PACE experiment to increase rate of mutagenesis (paragraph [0215]). Badran teaches the stringency of selection can be increased by removing the inducing agent (paragraph [0226]). Badran teaches modulating the selection stringency during evolution by introducing a selection viral vector (paragraph [0284]). Badran teaches visual tracking of infected cells is used to adjust flow rate of the system to keep the system flowing as fast as possible without risk of vector washout (paragraph [0259]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the one or more independently selected real-time adjustment of modified Zhang to incorporate the teachings of modulating evolution processes of Badran to provide wherein the one or more real-time adjustment comprises the liquid handling robot performing one or more of adding an inducing agent and adjusting a flow rate in the continuous evolution circuit for which the adjustment was selected. Doing so would utilize known adjustments of directed evolution processes as taught by Badran to optimize the desired directed evolution, such as improving mutagenesis or stringency of selection with a reasonable expectation of success.
Regarding claim 14, while Zhang teaches a temperature controlled incubator (paragraph [0256]), modified Zhang fails to teach wherein the independently selected real-time adjustment comprises a temperature adjustment of the continuous evolution circuit for which the temperature adjustment was selected.
O’Keefe teaches finer control of temperature profile within a sample (paragraph [0092]). O’Keefe teaches contents of a kit may be a chamber for maintaining appropriate environmental conditions, such as temperature, for reactions (paragraphs [0088], [0153]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the independently selected real-time adjustment of modified Zhang to incorporate the teachings of temperature control of O’Keefe to wherein the independently selected real-time adjustment comprises a temperature adjustment. Doing so would have a reasonable expectation of successfully improving optimization and control of environmental conditions of reactions of samples.
Regarding claim 16, modified Zhang fails to teach wherein the liquid handling robot further comprises two, three, four, or more additional reservoirs, wherein each additional reservoir holds an additional independently selected liquid exchange fluid.
Liu teaches multiple reservoirs that each hold an additional independently selected liquid exchange fluid (Fig. 2 shows a reservoir for “mutagen” and a reservoir for “inducers”).
Lapham teaches a high-throughput sample processing system (abstract) comprising sample processing plates (paragraph [0049]; Fig. 5, element 504) and a liquid handling robot (Fig. 5), element 502. Lapham teaches the liquid handling robot comprises one or more reservoirs (Fig. 5, interpreted as element 15; paragraph [0102], “reservoir” is being broadly interpreted as the fluid valve(s) 512). Lapham teaches the reservoir are configured to allow liquid to be pulled from one or more fluid reservoirs which may include a variety of fluids, such as washes, reagents, rinses etc. (paragraph [0102]; Fig. 5, elements 514, 516). Lapham teaches the scalability of these reservoirs helps allow for unattended operation of the system during operation (paragraph [0102]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the liquid handling robot of modified Zhang to incorporate the teachings of multiple reservoirs for fluids of Liu (Fig. 2) and the teachings of reservoirs of Lapham (paragraph [0102]) to provide wherein the liquid handling robot further comprises two, three, four, or more additional reservoirs, wherein each additional reservoir holds an additional independently selected liquid exchange fluid. Doing so would have a reasonable expectation of successfully providing fluids to the liquid handling robot and also allow for unattended operation of the system during operation, thus improving automation of the system.
Regarding claim 17, Zhang further teaches wherein the liquid handling robot selectively dispenses a bacteriophage solution into the at least ten of receptacles (paragraph [0251] teach a system that automate sample and reagent pipetting and liquid dispensing, thus is capable of the claimed functional limitation).
Regarding claim 22, Zhang further teaches wherein the sensor detects at least one individually selected detectable parameter in all the at least ten receptacles (paragraph [0232] teach a “detector” that detects a fluorescent signal; paragraph [0234] teach an ISFET ion sensor, which indicates a reaction has occurred; paragraph [0250] teaches at least two wells are used to run separate assays; thus, the detector is capable of detecting an individually selected detectable parameter in the all of the receptacles at a later time).
Regarding claim 23, modified Zhang fails to explicitly teach wherein the feedback controller triggers a different independently selected real-time adjustment in at least two of the prepared continuous evolution circuit to make a different experimental condition in each of the prepared continuous evolution circuits that receive the different real-time adjustments.
Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc. (paragraph [0250]). Zhang teaches that integrated systems of the invention and reagent manipulation provides high throughput (paragraph [0250]). Zhang teaches that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]).
O’Keefe teaches a means for dispensing water to counter evaporation can also be used to dispense other reagents or chemicals of interest, mixed in a solution such that evaporation is countered (paragraph [0090]), wherein in this way chemical assays can be carried out in real time and the evolution of the assay can be directed via feedback from the assay in progress (paragraph [0090]); and further wherein optical data obtained by placing the apparatus on an optical detector, such as a CCD or fiber optics cable, can be input to a computer which automatically adjusts reagent dispensers and guides them to dispense a precise amount of reagent into each sample chamber (paragraph [0090]), i.e. real-time adjustment based on an independently selected parameter. O’Keefe teaches the apparatuses, when used in a biochemical reaction format, provides advantages of high density, high throughput, ease of handling, performance of low-volume reactions, thermal cycling, and advantageous optical access of samples (paragraph [0092]). O’Keefe teaches monitoring optical properties of reactions in real time (paragraph [0099]), i.e. independently selected parameter. O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), i.e. real-time adjustment.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the feedback controller of modified Zhang to incorporate the teachings of real-time monitoring and adjustment of samples of O’Keefe (paragraphs [0090]-[0092], [0099],[0141]) and performing different assays, parallelizing processes, and adjusting rules at various arounds of directed evolution of Zhang (paragraphs [0230], [0250], [0228], [0288]) to provide wherein the feedback controller triggers a different independently selected real-time adjustment in at least two of the prepared continuous evolution circuit to make a different experimental condition in each of the prepared continuous evolution circuits that receive the different real-time adjustments. Doing so would have a reasonable expectation of successfully ensuring optimized conditions for different assays that would require different experimental conditions, thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]).
Regarding claim 24, Zhang further teaches wherein the liquid handling robot is configured to transfer an aliquot of each of a plurality of the at least ten receptacles to a separate detection receptacle (interpreted as a functional limitation, see MPEP 2114; paragraphs [0250]-[0251] teach a high throughput screening system is employed that automate all sample and reagent pipetting and liquid dispensing, therefore the liquid handling robot is structurally capable an aliquot of each receptacle to a separate receptacle; note that “aliquot” and “separate detection receptacle” are not positively recited structurally)
Regarding claim 111, modified Zhang fails to explicitly teach wherein the one or more independently selected real-time adjustments modifies at least one of a: (a) fluid exchange frequency, (b) fluid exchange volume, (c) sample composition, (d) selection parameter, (f) selection stringency, (g) selection goal, and (h) a temperature in the receptable comprising the continuous evolution circuit that receives the one or more independently selected real-time adjustment.
Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc., i.e. sample composition (paragraph [0250]). Zhang teaches that integrated systems of the invention and reagent manipulation provides high throughput (paragraph [0250]). Zhang teaches that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]).
O’Keefe teaches a means for dispensing water to counter evaporation can also be used to dispense other reagents or chemicals of interest, mixed in a solution such that evaporation is countered (paragraph [0090]), wherein in this way chemical assays can be carried out in real time and the evolution of the assay can be directed via feedback from the assay in progress (paragraph [0090]); and further wherein optical data obtained by placing the apparatus on an optical detector, such as a CCD or fiber optics cable, can be input to a computer which automatically adjusts reagent dispensers and guides them to dispense a precise amount of reagent into each sample chamber (paragraph [0090]), i.e. real-time adjustment based on an independently selected parameter. O’Keefe teaches the apparatuses, when used in a biochemical reaction format, provides advantages of high density, high throughput, ease of handling, performance of low-volume reactions, thermal cycling, and advantageous optical access of samples (paragraph [0092]). O’Keefe teaches monitoring optical properties of reactions in real time (paragraph [0099]), i.e. independently selected parameter. O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), i.e. real-time adjustment.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the feedback controller of modified Zhang to incorporate the teachings of real-time monitoring and adjustment of samples of O’Keefe (paragraphs [0090]-[0092], [0099],[0141]) and performing different assays compositions, parallelizing processes, and adjusting rules at various arounds of directed evolution of Zhang (paragraphs [0230], [0250], [0228], [0288]) to provide wherein the one or more independently selected real-time adjustments modifies at least one of a: (a) fluid exchange frequency, (b) fluid exchange volume, (c) sample composition, (d) selection parameter, (f) selection stringency, (g) selection goal, and (h) a temperature in the receptable comprising the continuous evolution circuit that receives the one or more independently selected real-time adjustment. Doing so would ensure optimized conditions for different assays compositions that would require different experimental conditions, thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]), with a reasonable expectation of success. Furthermore, doing so would allow for improved throughput by allowing for running and controlling parallel assays involving different conditions, e.g. sample composition, as taught by Zhang, with a reasonable expectation of success.
Regarding claim 112, modified Zhang fails to explicitly teach wherein the at least one independently selected real-time adjustment includes at least one of delivering, removing and mixing a content of the receptacles comprising the continuous evolution circuits for which the adjustment was selected.
Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc., i.e. sample composition (paragraph [0250]). Zhang teaches that integrated systems of the invention and reagent manipulation provides high throughput (paragraph [0250]). Zhang teaches that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]).
O’Keefe teaches a means for dispensing water to counter evaporation can also be used to dispense other reagents or chemicals of interest, mixed in a solution such that evaporation is countered (paragraph [0090]), wherein in this way chemical assays can be carried out in real time and the evolution of the assay can be directed via feedback from the assay in progress (paragraph [0090]); and further wherein optical data obtained by placing the apparatus on an optical detector, such as a CCD or fiber optics cable, can be input to a computer which automatically adjusts reagent dispensers and guides them to dispense a precise amount of reagent into each sample chamber (paragraph [0090]), i.e. real-time adjustment based on an independently selected parameter. O’Keefe teaches the apparatuses, when used in a biochemical reaction format, provides advantages of high density, high throughput, ease of handling, performance of low-volume reactions, thermal cycling, and advantageous optical access of samples (paragraph [0092]). O’Keefe teaches monitoring optical properties of reactions in real time (paragraph [0099]), i.e. independently selected parameter. O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), i.e. real-time adjustment that would mix a sample.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have altered modified Zhang to incorporate the teachings of Zhang and O’Keefe to provide wherein the at least one independently selected real-time adjustment includes at least one of delivering, removing and mixing a content of the receptacles comprising the continuous evolution circuits for which the adjustment was selected. Doing so would prevent evaporation of samples during evolution of an assay, as discussed by O’Keefe (paragraph [0090]) and improve automation and optimization of multiple reactions as they proceed in real-time as discussed by O’Keefe (paragraph [0141]), thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]) with a reasonable expectation of success.
Regarding claim 113, Zhang further teaches the feedback controller triggers the liquid handling robot to perform one or more independently selected real-time adjustment in the prepared continuous evolution circuits, wherein the one or more independently selected real-time adjustment: (i) is triggered in response to the at least one independently selected detectable parameter (see above claim 1, wherein modified Zhang teaches limitation (e)).
While Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations (paragraph [0250]), and that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]), and O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), modified Zhang fails to explicitly teach: wherein each of the receptacles comprising the continuous evolution circuits comprise one or more one or more horizontally transferable nucleic acids, host cells, and a bacteriophage population; wherein the one or more independently selected real-time adjustment: (ii) is different in two or more of the prepared continuous evolution circuits, and (iii) comprises one or more of: (a) modifying a positive selection strength in the adjusted prepared continuous evolution circuits for which the adjustment was selected; (b) modifying a negative selection strength in the adjusted prepared continuous evolution circuits for which the adjustment was selected; (c) modifying a mutation rate in the adjusted prepared continuous evolution circuits for which the adjustment was selected; (d) modifying a selection goal in the adjusted prepared continuous evolution circuits for which the adjustment was selected; and (e) modifying a flow rate in the adjusted prepared continuous evolution circuits for which the adjustment was selected.
Badran teaches strategies and systems for modulating the mutation rate in cells and control over a broad range of mutation rates in the context of diversifying a nucleic acid sequence for generation of diversified nucleic acid libraries, and for directed evolution of nucleic acids (abstract). Badran teaches carrying out continuous directed evolution processes (paragraphs [0193]-[0197]). Badran teaches modulating the mutation rate as desired, e.g. during different phases of a directed evolution experiment (paragraph [0006]), which includes providing a promoter (paragraph [0022]). Badran teaches directed evolution including bacteriophage-mediated evolution (paragraph [0007]). Badran a bacteriophage carrying a constitutive expression cassette or genetic materials (paragraphs [0036],[0154]), i.e. horizontally transferable nucleic acids preselected to be evolved in the plurality of continuous evolution circuits. Badran teaches constructs for modulating mutagenesis rate includes introduction of a conjugative plasmids or bacteriophages (paragraphs [0162],[0177], [0192]). Badran teaches cells are exposed to an external mutagen during processes to increase mutation rate (paragraph [0211]). Badran teaches methods for modulating the mutation rate in a cell, such as a host cell for bacteriophage (paragraph [0200]). Badran teaches adding or withdrawing inducing agent from a host cell culture media during a PACE experiment to increase rate of mutagenesis (paragraph [0215]). Badran teaches the stringency of selection can be increased by removing the inducing agent (paragraph [0226]). Badran teaches modulating the selection stringency during evolution by introducing a selection viral vector (paragraph [0284]). Badran teaches visual tracking of infected cells is used to adjust flow rate of the system to keep the system flowing as fast as possible without risk of vector washout (paragraph [0259]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the one or more independently selected real-time adjustment of modified Zhang to incorporate the teachings of modulating evolution processes using bacteriophages and enclosed genetic materials of Badran (paragraphs [0007],[0177],[0154],[0192]) and the teachings of running different assays of Zhang (paragraph [0250]), to provide wherein each of the receptacles comprising the continuous evolution circuits comprise one or more one or more horizontally transferable nucleic acids, host cells, and a bacteriophage population; wherein the one or more independently selected real-time adjustment: (ii) is different in two or more of the prepared continuous evolution circuits, and (iii) comprises one or more of: (a) modifying a positive selection strength in the adjusted prepared continuous evolution circuits for which the adjustment was selected; (b) modifying a negative selection strength in the adjusted prepared continuous evolution circuits for which the adjustment was selected; (c) modifying a mutation rate in the adjusted prepared continuous evolution circuits for which the adjustment was selected; (d) modifying a selection goal in the adjusted prepared continuous evolution circuits for which the adjustment was selected; and (e) modifying a flow rate in the adjusted prepared continuous evolution circuits for which the adjustment was selected. Doing so would have a reasonable expectation of successfully optimizing a desired directed evolution, such as improving mutagenesis or stringency of selection (Badran, paragraphs [0215],[0284]), for different assays, thus improving automation and throughput of the overall system.
Regarding claim 114, while Zhang teaches a temperature controlled incubator (paragraph [0256]) and that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc. (paragraph [0250]), modified Zhang fails to teach wherein the one or more independently selected real-time adjustment is selected and carried out in each of the prepared continuous evolution circuits for which the one or more adjustment was selected, and the adjustments include one or more of (i) adjusting an amount of an inducer chemical for positive selection strength, (ii) adjusting an amount of an inducer chemical for negative selection, (iii) adjusting a selection goal, (iv) adjusting an evolving property of at least one of the biomolecules, (v) adjusting a selection stringency, (vi) adjusting a flow rate, (vii) adjusting a mutation rate, and (viii) adjusting a temperature.
O’Keefe teaches finer control of temperature profile within a sample (paragraph [0092]). O’Keefe teaches contents of a kit may be a chamber for maintaining appropriate environmental conditions, such as temperature, for reactions (paragraphs [0088], [0153]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the independently selected real-time adjustment of modified Zhang to incorporate the teachings of temperature control of O’Keefe to provide wherein the one or more independently selected real-time adjustment is selected and carried out in each of the prepared continuous evolution circuits for which the one or more adjustment was selected, and the adjustments include one or more of (i) adjusting an amount of an inducer chemical for positive selection strength, (ii) adjusting an amount of an inducer chemical for negative selection, (iii) adjusting a selection goal, (iv) adjusting an evolving property of at least one of the biomolecules, (v) adjusting a selection stringency, (vi) adjusting a flow rate, (vii) adjusting a mutation rate, and (viii) adjusting a temperature. Doing so would improve optimization and control of environmental conditions of reactions of samples with a reasonable expectation of success.
Regarding claim 115, modified Zhang fails to explicitly teach wherein the one or more independently selected real-time adjustment is different for each of (i) a portion of, or (ii) all the prepared continuous evolution circuits, and the adjustments generate different experimental conditions in each of the portion of, or all the continuous evolution circuits, respectively.
Zhang teaches that each well of a microtiter plate can be used to run a separate assay, wherein different assays may involve different nucleic acids, encoded proteins, concentrations, etc., i.e. sample composition (paragraph [0250]). Zhang teaches that integrated systems of the invention and reagent manipulation provides high throughput (paragraph [0250]). Zhang teaches that criterion values and rules may be adjusted in different applications and at various rounds of directed evolution (paragraph [0288]).
O’Keefe teaches a means for dispensing water to counter evaporation can also be used to dispense other reagents or chemicals of interest, mixed in a solution such that evaporation is countered (paragraph [0090]), wherein in this way chemical assays can be carried out in real time and the evolution of the assay can be directed via feedback from the assay in progress (paragraph [0090]); and further wherein optical data obtained by placing the apparatus on an optical detector, such as a CCD or fiber optics cable, can be input to a computer which automatically adjusts reagent dispensers and guides them to dispense a precise amount of reagent into each sample chamber (paragraph [0090]), i.e. real-time adjustment based on an independently selected parameter. O’Keefe teaches the apparatuses, when used in a biochemical reaction format, provides advantages of high density, high throughput, ease of handling, performance of low-volume reactions, thermal cycling, and advantageous optical access of samples (paragraph [0092]). O’Keefe teaches monitoring optical properties of reactions in real time (paragraph [0099]), i.e. independently selected parameter. O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), i.e. real-time adjustment.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the feedback controller of modified Zhang to incorporate the teachings of real-time monitoring and adjustment of samples of O’Keefe (paragraphs [0090]-[0092], [0099],[0141]) and performing different assays compositions, parallelizing processes, and adjusting rules at various arounds of directed evolution of Zhang (paragraphs [0230], [0250], [0228], [0288]) to provide wherein the one or more independently selected real-time adjustment is different for each of (i) a portion of, or (ii) all the prepared continuous evolution circuits, and the adjustments generate different experimental conditions in each of the portion of, or all the continuous evolution circuits, respectively. Doing so would ensure optimized conditions for different assays compositions that would require different experimental conditions, thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]) with a reasonable expectation of success. Furthermore, doing so would have a reasonable expectation of successfully allowing for improved throughput by allowing for running and controlling parallel assays involving different conditions, e.g. sample composition, as taught by Zhang.
Response to Arguments
Applicant’s arguments, see pages 7-8, filed 12/01/25, with respect to the rejections under 35 U.S.C. 112(a) and 112(b) have been fully considered and are persuasive. The rejections under 35 U.S.C. 112(a) and 112(b) of 05/29/2025 have been withdrawn.
Applicant's arguments, see pages 8-13, filed 12/01/2025, with respect to the rejections of claims 1, 5-7, 10, 13, 14, 17, 22-24, 111-115, specifically regarding claim 1, under 35 U.S.C. 103 have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references (Remarks, pages 9-12), the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, regarding the limitations of: “the liquid-handling robot comprising: (i) a plurality of reservoirs, wherein each reservoir holds an independently selected liquid exchange fluid, wherein the independently selected liquid exchange fluid in a first reservoir of the plurality of reservoirs comprises a host cell culture”, O’Keefe provides teachings of: parallel reactions (abstract), reaction components in a suitable container (paragraph [0038]), pipetting robots and robotically controlled syringes (paragraphs [0080]-[0081]), and real-time adjustment of evolution of assays (paragraph [0090]); and Zhang provides teachings of: performing directed evolution (paragraph [0015]) and a computer with specialized algorithms and software (paragraph [0254]). O’Keefe also provides motivation: O’Keefe teaches the apparatuses, when used in a biochemical reaction format, provides advantages of high density, high throughput, ease of handling, performance of low-volume reactions, thermal cycling, and advantageous optical access of samples (paragraph [0092]); O’Keefe teaches reagents can be added to reactions in progress by means of a dispenser to optimize reactions as they proceed in real-time (paragraph [0141]), i.e. real-time adjustment.
It would have been obvious to one of ordinary skill in the art to have modified the system and liquid handling robot of Zhang to incorporate O’Keefe’s teachings of parallel reactions (abstract), reaction components in a suitable container (paragraph [0038]), pipetting robots and robotically controlled syringes (paragraphs [0080]-[0081]), and real-time adjustment of evolution of assays (paragraph [0090]), and Zhang’s teachings of performing directed evolution (paragraph [0015]) and a computer with specialized algorithms and software (paragraph [0254]) to provide: the liquid-handling robot comprising: (i) a plurality of reservoirs, wherein each reservoir holds an independently selected liquid exchange fluid, wherein the independently selected liquid exchange fluid in a first reservoir of the plurality of reservoirs comprises a host cell culture. Doing so would have a reasonable expectation of successfully holding desired fluids for sample preparation and analysis, improving automation of pipetting and dispensing procedures, and improving automation and optimization of multiple reactions as they proceed in real-time as discussed by O’Keefe (paragraph [0141]), thus improving throughput and handling of the overall system as discussed by O’Keefe (paragraph [0092]).
Regarding the limitation of “the independently selected liquid exchange fluid in a second reservoir of the plurality of reservoirs comprises bacteriophage or conjugative plasmids each comprising horizontally transferable nucleic acids preselected to be evolved in a plurality of continuous evolution circuits, and the independently selected liquid exchange fluid in a third reservoir of the plurality of reservoirs comprises an inducer solution that increases a mutation rate of a gene encoding a biomolecule”, Badran provides teachings of modulating evolution processes using bacteriophage or plasmids and inducing agents (paragraphs [0007],[0177],[0192],[0215]) and O’Keefe provides teachings of reaction components in a suitable container (paragraph [0038]). Badran provides motivation of: cells are exposed to an external mutagen during processes to increase mutation rate (paragraph [0211]); adding or withdrawing inducing agent from a host cell culture media during a PACE experiment to increase rate of mutagenesis (paragraph [0215]); the stringency of selection can be increased by removing the inducing agent (paragraph [0226]).
It would have been obvious to one of ordinary skill in the art to have modified the reservoirs and dispensing elements of modified Zhang to incorporate the teachings of modulating evolution processes using bacteriophage or plasmids and inducing agents of Badran (paragraphs [0007],[0177],[0192],[0215]) and the teachings of reaction components in a suitable container of O’Keefe (paragraph [0038]) to provide: the independently selected liquid exchange fluid in a second reservoir of the plurality of reservoirs comprises bacteriophage or conjugative plasmids each comprising horizontally transferable nucleic acids preselected to be evolved in a plurality of continuous evolution circuits, and the independently selected liquid exchange fluid in a third reservoir of the plurality of reservoirs comprises an inducer solution that increases a mutation rate of a gene encoding a biomolecule. Doing so would have a reasonable expectation of successfully providing desired reagents or components for sample processing and analysis and optimizing the desired directed evolution, such as improving mutagenesis or stringency of selection (Badran, paragraphs [0006],[0226],[0284],[0259]).
Regarding the limitations of: “wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line”, Liu provides teachings of a lagoon comprising four ports coupled each coupled to different lines (Fig. 2) and Lapham provides teachings of reservoirs and lines (Fig. 5), processing a sample using solutions such as water and wash solution (paragraph [0102]), and draining a liquid and solution (paragraphs [0072],[0133]).
It would have been obvious to one of ordinary skill in the art to have modified the one or more plurality of reservoirs of modified Zhang to further incorporate Liu’s teachings of a lagoon comprising four ports coupled each coupled to different lines (Fig. 2) and Lapham’s teachings of reservoirs and lines (Fig. 5), processing a sample using solutions such as water and wash solution (paragraph [0102]), and draining a liquid and solution (paragraphs [0072],[0133]) to provide: wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line. Doing so would have a reasonable expectation of successfully improving the ability of the system to be utilize different fluids and couple to different containers, allowing for drainage of the reservoir, and thus improve automation and versatility of the system when used with processes that require a plurality of different fluids.
Therefore, there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art to have arrived at the claimed invention.
In response to applicant’s specific argument that Liu teaches a reservoir comprising three ports, not four (Remarks, page 9, last paragraph - page 10, first paragraph), the examiner disagrees. Liu et al. (US 9771574 B2; cited in the IDS 11/25/2019). As shown below, Liu teaches a reservoir (Fig. 2, “lagoon”) comprising four ports fluidly coupled to individual lines (Fig. 2 shows the lagoon has four ports, i.e. openings, with four lines that leads to respective elements, such as the turbidostat, waste, mutagen, and inducers).
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Fig. 2 of Liu et al. (US 9771574 B2): Lagoon comprises four ports coupled to four lines.
In response to applicant's arguments against the references individually (Remarks, pages 9-11, regarding Liu and Lapham), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant's argument that the references (i.e. Lapham) fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., Remarks, page 10, “fluids such as reservoir-cleaning fluids”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additionally, note that limitations of “reservoir-cleaning-fluid”, “water”, “drain” preceding the term “line” are interpreted as an intended use of the lines. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. MPEP 2114. Therefore, any structural line, tube, channel, etc. are structurally capable of being used for “reservoir-cleaning-fluid”, “water”, and/or “drain” at a later time by a user. As discussed above, the combination of Zhang in view of Liu and Lapham provides the claimed ports and lines.
In response to applicant’s arguments that Lapham’s teachings of removing liquid and solution into a sewage system and a waste management system are not relevant to the elements of claim 1 (Remarks, page 11), the examiner disagrees. The examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). As discussed above, it would have been obvious to one of ordinary skill in the art to have modified the one or more plurality of reservoirs of modified Zhang to further incorporate Liu’s teachings of a lagoon comprising four ports coupled each coupled to different lines (Fig. 2) and Lapham’s teachings of reservoirs and lines (Fig. 5), processing a sample using solutions such as water and wash solution (paragraph [0102]), and draining a liquid and solution (paragraphs [0072],[0133]) to provide: wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line. Doing so would have a reasonable expectation of successfully improving the ability of the system to be utilize different fluids and couple to different containers, allowing for drainage of the reservoir, and thus improve automation and versatility of the system when used with processes that require a plurality of different fluids.
Therefore, there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art to have arrived at the claimed invention. Specifically, Lapham’s teachings of a sewage or waste management system for draining a liquid and solution (paragraphs [0072],[0133]) provides teachings and suggestion for providing the claimed drain line coupled to the fluid reservoir in view of Lapham, Zhang and Liu. I.e. one of ordinary skill in the art would be motivated to provide the claimed fluid reservoir with a port coupled to a drain line for removing desired fluids that are not needed throughout a process, such as waste.
In response to applicant’s argument that the office action and prior art fails to teach or suggest motivation or reasoning to arrive at the claimed: “wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line”; and that the combination would not result in a system with the elements as claimed (Remarks, page 12), the examiner disagrees. As discussed above, Liu provides teachings of a lagoon comprising four ports coupled each coupled to different lines (Fig. 2) and Lapham provides teachings of reservoirs and lines (Fig. 5), processing a sample using solutions such as water and wash solution (paragraph [0102]), and draining a liquid and solution (paragraphs [0072],[0133]).
It would have been obvious to one of ordinary skill in the art to have modified the one or more plurality of reservoirs of modified Zhang to further incorporate Liu’s teachings of a lagoon comprising four ports coupled each coupled to different lines (Fig. 2) and Lapham’s teachings of reservoirs and lines (Fig. 5), processing a sample using solutions such as water and wash solution (paragraph [0102]), and draining a liquid and solution (paragraphs [0072],[0133]) to provide: wherein one or more of the plurality of reservoirs comprises a first port fluidly coupled to a water line, a second port fluidly coupled to a reservoir-cleaning-fluid line, a third port fluidly coupled to a line for the liquid exchange fluid of that reservoir, and a fourth port fluidly coupled to a drain line. Doing so would have a reasonable expectation of successfully improving the ability of the system to be utilize different fluids and couple to different containers, allowing for drainage of the reservoir, and thus improve automation and versatility of the system when used with processes that require a plurality of different fluids.
Therefore, there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art to have arrived at the claimed invention. One of ordinary skill in the art of fluidic systems for processing samples that include reactions would have motivated to provide the one or more of the plurality of reservoirs with four ports coupled to respective lines as claimed in order to improve the ability of the system to receive/remove desired fluids from the reservoirs, such as samples, waste, and reagents (i.e. mutagen and inducers) as taught by Liu and Lapham.
In response to applicant’s arguments regarding the dependent claims (Remarks, page 13), the examiner disagrees for the same reasons as discussed above regarding claim 1.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 HENRY H NGUYEN whose telephone number is (571)272-2338. The examiner can normally be reached M-F 7:30A-5:00P.
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/HENRY H NGUYEN/Primary Examiner, Art Unit 1758