DETAILED ACTION
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 .
Election/Restrictions
Applicant's election with traverse of Group I, Claims 1 - 19 in the reply filed on 06 March 2026 is acknowledged. The traversal is on the ground that Group III is related to Group I because claim 22 depends from claim 1, resulting in a lack of undue search burden. Regarding Groups I and III, this argument is persuasive. Due to the dependency, Group I (Claims 1 – 19) is grouped with Group III (Claims 22 – 24) and is examined below.
Group II, Claims 20 and 21 remains restricted.
The requirement is still deemed proper and is therefore made FINAL.
Specification
The abstract of the disclosure is objected to because
The first sentence and 3rd sentence phrasing of “Provided are electrochemical sensors…” and “Also provided are” are implied language.
There is a purported merit of the device presented in lines 7 – 12 include purported merits or speculative applications of the invention.
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Information Disclosure Statement
There is a list of references in the specification at [0014], [0038], [0093], [0113]. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: Regarding the term “wherein the microfluidic channel, sampling port, and reagent channel is formed from a unitary substrate”. It is suggested to amend to “wherein the microfluidic channel, the sampling port, and the reagent channel are formed from a unitary substrate” for grammatic consistency and readability in the claim. Appropriate correction is required.
Claim 19 is objected to because of the following informalities: there appears to be a typographical error such that an “r” is missing from “potion” (portion) twice in line 3. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 – 19 and 22 – 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the phrase "as small as 4 µm" in line 20, which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purposes of examination, the term "as small as 4 µm" is deemed to claim “of less than or equal to 4 µm." Claims 2 – 19 and 22 – 24 are similarly rejected due to their dependence on Claim 1.
Regarding Claim 1, the phrase "such as" in “such as a pressure of up to 4 atmospheres” in lines 21 - 22 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Furthermore “high pressure”, high is a relative term. It is unclear at what pressure a pressure becomes high. For the purposes of examination, the term “withstanding a high pressure during fluid flow, such as a pressure of up to 4 atmospheres, without leakage” is deemed to claim “capable of withstanding a pressure during fluid flow of up to 4 atmospheres without leakage.” Claims 2 – 19 and 22 – 24 are similarly rejected due to their dependence on Claim 1.
Regarding Claim 3, the statutory category of this claim is unclear, as it recites a method step of “wherein the reagent solution…is introduced to the microfluidic channel to reduce microelectrode fouling” that depends from Claim 1, which is an apparatus. For the purposes of examination, the term “wherein the reagent solution…is introduced to the microfluidic channel to reduce microelectrode fouling” is deemed to claim “wherein the reagent solution…is configured to be introduced to the microfluidic channel to reduce microelectrode fouling.”
Claim 3 (lines 1 – 2) and Claim 10 (line 1) each recite the term “the reagent microchannel”. There is insufficient antecedent basis for this limitation in the claim. It is unclear if this is intended to be the same or different than the previously-recited reagent channel. For the purposes of examination, the term “the reagent microchannel” is deemed to claim “the reagent channel.”
Claim 3 recites the term “the environment surrounding the electrochemical sensor”. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited environment. For the purposes of examination, the term “the environment surrounding the electrochemical sensor” is deemed to claim “an environment surrounding the electrochemical sensor”.
Claim 4 recites the term “the microfluidic channel cross-section”. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited cross-section. For the purposes of examination, the term “the microfluidic channel cross-section” is deemed to claim “a cross-section of the microfluidic channel”.
Regarding claim 6, the phrase "e.g.. Ag/AgCl" in the term “an ion-selective electrode (e.g. Ag/AgCl)” renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purposes of examination, the term “an ion-selective electrode (e.g. Ag/AgCl)” is deemed to claim “an ion-selective electrode”.
Regarding Claim 8, the phrase “compared to” in the term “and the microelectrode positioned in the microfluidic channel resists fouling, thereby increasing operational lifetime of the implanted electrochemical sensor compared to an electrochemical sensor that is not embedded in a microfluidic channel” of lines 24 - 27 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. It is unclear if there is an additional electrochemical sensor that is not embedded in a microfluidic channel present within the claimed invention or not. For the purposes of examination, the term “and the microelectrode positioned in the microfluidic channel resists fouling, thereby increasing operational lifetime of the implanted electrochemical sensor compared to an electrochemical sensor that is not embedded in a microfluidic channel” is deemed to claim “and the microelectrode positioned in the microfluidic channel resists fouling, thereby increasing operational lifetime of the implanted electrochemical sensor.”
Claim 8 recites the term “operational lifetime of the implanted electrochemical sensor” in lines 25 - 26. There is no previously-recited electrochemical sensor that is positively implanted in the claim. Rather, as claimed, the electrochemical sensor has a form factor configured for implantation. It is unclear if the implanted electrochemical sensor is intended to be the same or different than that sensor configured for implantation. For the purposes of examination, the term “operational lifetime of the implanted electrochemical sensor” is deemed to claim “operational lifetime of the electrochemical sensor.”
Claim 9 recites the term “the group” in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited group. For the purposes of examination, the term “the group” is deemed to claim “a group”.
Claim 10 recites the term “the electrode” in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited “electrode”. For the purposes of examination, the term “the electrode” is deemed to claim “the microelectrode.”
Claim 10 recites the term “wherein the reagent microchannel is configured to convey a regeneration solution the electrode for regenerating an electrode surface parameter”. It appears that there is a word missing such that it is unclear where or how the regeneration solution is intended to be conveyed relative to the electrode. For the purposes of examination (and in light of the interpretation above), the term “wherein the reagent microchannel is configured to convey a regeneration solution the electrode for regenerating an electrode surface parameter” is deemed to claim “wherein the reagent microchannel is configured to convey a regeneration solution across the microelectrode for regenerating an electrode surface parameter”.
Claim 10 (line 2) and Claim 11 (line 2) each recite the term “the implanted electrochemical sensor” in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited “implanted electrochemical sensor”. For the purposes of examination, the term “the implanted electrochemical sensor” is deemed to claim “the electrochemical sensor.”
Claim 13 recites the term “having an implanted cross-sectional area that does not adversely impact surrounding tissue, including less than 1 mm2 ; less than or equal to 1200 µm2 .” To begin, it is unclear if the second “less than or equal to” is supposed to refer to a value of the implanted cross-sectional area, or if that is a number of µm2 that happen to be included in the previously-recited range of 1 mm2. As recited, it appears to be a broad range followed by a narrow range. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation “including less than 1 mm2”, and the claim also recites “less than or equal to 1200 µm2 ” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For the purpose of examination, the term “having an implanted cross-sectional area that does not adversely impact surrounding tissue, including less than 1 mm2 ; less than or equal to 1200 µm2 .” is deemed to claim “having an implanted cross-sectional area that does not adversely impact surrounding tissue, including less than 1 mm2.”
The term “corresponding to about 15 µm x 75 µm ” in line 4 of claim 13 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear how close to 15 µm x 75 µm a measurement must be to be “about” those amounts or the collective area amount. For the purposes of examination, the term “corresponding to about 15 µm x 75 µm ” is deemed to claim “corresponding to 15 µm x 75 µm”.
Claim 14 recites the term “the electrode” in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited “electrode”. For the purposes of examination, the term “the electrode” is deemed to claim “the microelectrode.”
Claim 16 recites the term “further comprising one or more flow controllers” in lines 1 – 2. It is unclear if these are intended to be the same or different than that previously-recited “flow controller”. For the purposes of examination, the term “further comprising one or more flow controllers” is deemed to claim “comprising the flow controller connected to.”
Claim 16 recites the term “wherein the flow controller is a variable pressure pump” in line 5. It is unclear if this is intended to be the same or different than the previously-recited one more flow controllers and the flow controller. Based on the rejection and interpretation above for the “one or more flow controller” to “the flow controller”, the term “wherein the flow controller is a variable pressure pump” is deemed to claim “wherein the flow controller is configured as a variable pressure pump.”
Claim 16 recites the term “optionally without any flow valves” in line 7. As the term is recited as “optional”, it is unclear if this term is required within the metes and bounds of the claim or not. For the purposes of examination, the term “wherein the flow controller is a variable pressure pump to control pressure and corresponding flow-rate and flow direction in each of the microfluidic channel and reagent channel, optionally without any flow valves” is deemed to claim “wherein the flow controller is a variable pressure pump to control pressure and corresponding flow-rate and flow direction in each of the microfluidic channel and reagent channel.”
Claim 17 recites the term “wherein the flow controllers are configured” in lines 1 – 2. There is insufficient antecedent basis in the claim. There is only a singular flow controller previously recited in Claim 1, from which this claim depends. It is unclear if these controllers are intended to be the same or different than these flow controllers. For the purposes of examination, the term “wherein the flow controllers are configured” is deemed to claim a singular controller, with “wherein the flow controller is configured.”
Claim 17 recites the term “the modes” in line 2. It is unclear if these are intended to be the same or different than the previously-recited electrochemical sensor modes. For the purposes of examination, the term “the modes” is deemed to claim “the electrochemical sensor modes”.
Claim 17 recites the term “a cleaning (rinse) mode” with “rinse” in parentheses in line 7, which is indefinite because it is unclear if the “rinse” is intended to considered in the context of the claim or not. For the purposes of examination, the term “a cleaning (rinse) mode” is deemed to claim “a cleaning mode.”
Claim 19 recites the term “and the sensor is positioned” in line 2. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited “sensor”. It is unclear if this is intended to be the same or different than the previously-recited electrochemical sensor. It appears that “the sensor” cannot be “the electrochemical sensor” in its entirety without introducing additional clarity issues, since the electrochemical sensor of Claim 1 (from which this claim depends) comprises the “sampling port”, which is positioned on an insertable portion, but the “sensor” is positioned on a non-insertable portion. For the purposes of examination, the term “and the sensor is positioned” is deemed to claim “and a sensor is positioned”.
Claim 19 recites the term “and the average thickness of the insertable portion” in line 3. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited “average thickness of the insertable portion”. For the purposes of examination, the term “and the average thickness of the insertable portion” is deemed to claim “and an average thickness of the insertable portion.”
Claim 22 recites the term “detecting the presence or absence of the analyte” in line 8. There is insufficient antecedent basis for this limitation in the claim. There is no previously-recited presence or absence. For the purposes of examination, the term “detecting the presence or absence of the analyte” is deemed to claim “detecting a presence or an absence of the analyte.” Claims 23 – 24 are similarly rejected due to their dependence on Claim 22.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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 – 2, 6, 8, 9, 11 – 12, 14 - 19, 22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1).
Regarding Claim 1, Boutelle discloses An electrochemical sensor for detecting an analyte ([Abstract]) comprising:
a microfluidic channel (Fig 1 and Fig. 2, “analyte conduit 5”; [0094] “Microfluidic flow…analyte conduit 5”; [0122]; Fig 4) having a lumen surface extending between a proximal end (Fig 1 and Fig. 2, “analyte conduit 5” with “inlet 17” at a proximal end) to and a distal end (Fig 1 and Fig. 2, “analyte conduit 5” with “interconnector 26” at a distal end) to define a microfluidic lumen ([0094] “microfluidic flow…analyte conduit 5…”; [0122] “microfluidic fluid analysis…an analyte flow channel/conduit 41. “; Fig. 4)
a microelectrode that forms a portion of the lumen surface ([0122] “sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41. “; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”; [0025]; [0094] “…microfluidic flow…”) and configured for fluid contact with a fluid sample that flows in the microfluidic lumen to detect the analyte in the fluid sample ([0122] “configured for sensing different chemical/biochemical molecules/ions flowing through the analyte flow channel 41.”; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”)
a sampling port (Fig 1 and Fig. 2, “fluid source connect 2” to “suitable connection apparatus 3”) fluidically connected to the microfluidic channel distal end (Fig 1 and Fig. 2, “Dialysate” fluid flows through the “any suitable connection apparatus 3 including a fluid line”; [0094] to “analyte conduit 5” and “interconnector 26” ; [0094]) configured to introduce the fluid sample from a sampling area adjacent to the sampling port to the microelectrode of the microfluidic lumen (Fig 1 and Fig. 2, “fluid source connector 2” and “suitable connection apparatus 3” flows to “Analysis Chip”—“analysis module 16”; ([0122] “…electrodes 40 positioned within…channel/conduit 41. “; [0094] “…fluid source connect 2 for receiving a flow of fluid analyte from a suitable source S…fluid line from the probe P and source S…”; )(Examiner notes that the sampling area is the area of tissue that is adjacent to the fluid line.)
a reagent channel (Fig. 1 and Fig. 2 channel between “interconnectors 23” and “interconnectors 26”) fluidically connected to the microfluidic channel ([0106] “…interconnector 23 and flow to the analyte conduit 5 as shown by arrow 25”; Fig 1 and Fig. 2, “analyte conduit 5”), wherein the reagent channel is configured to introduce a reagent solution to the microelectrode ([0029] “…calibration fluid to the analyte conduit…”; [0094] “…suitable reservoirs 14, 15 of first and second calibration fluids”; [0106] “interconnector 23 and flow to the analyte conduit 5 as shown by arrow 25”) for microelectrode calibration ([0029] “deliver calibration fluid to the analyte conduit”; [0099];[0039] “ calibration fluid source inlet”) and/or cleaning ([0041] “flush valve…flush mode…deliver flush fluid to the analyte conduit…flush fluid to pass…clear gas bubbles and obstructions”);
a flow controller fluidically connected to the microfluidic channel (Fig 1 and Fig. 2, “controller 20”; [0097] “control the operation of the valves 4, 8, 11; the pumps 9, 12, and the analysis module 16”; [0115] ““controller 20…flow volume reaching analysis module…”) and/or the reagent channel (Fig. 1 and Fig. 2 “controller 20”; Fig 12, [0115] “controller 20…flow volume reaching analysis module…from…calibration fluid valves…maintained…”) to control flow of the fluid sample through the sampling port and the microfluidic channel ([0034] “the flow controller being thereby configured to maintain a steady flow rate of fluid through the analyte conduit during both the analysis mode and the calibration mode.“; [0114] “microfluidic flow controller such as the microfluidic flow controller 1 of Fig. 1…”; [0115] “…controller 20…ensure the…flow volume reaching the analysis module...from the first valve 4…”)
wherein the microfluidic channel, (Fig 1 and Fig. 2, “analyte conduit 5”; [0094] “Microfluidic flow…analyte conduit 5”; [0122]; Fig 4), sampling port (Fig 1 and Fig. 2, “fluid source connect 2”) and reagent channel (Fig. 1 and Fig. 2 channel between “interconnectors 23” and “interconnectors 26”) is formed from a unitary substrate ([0111] “Some or all of the valves 4, 8, 11, analyte conduit 5, pumps 9, 12, reservoirs 14, 15, fluid source connector 2, interconnectors 23, 26, analysis module 16 and conduits therebetween may be integrated onto a unitary substrate”), wherein the microfluidic lumen has an effective radius as small as 4 µm ([0092] ”…flow conduits may be in the size range 1 to 1000 microns in diameter/width”)
Boutelle does not particularly teach a silicon (Si) substrate, and capable of withstanding a high pressure during fluid flow, such as a pressure of up to 4 atmospheres, without leakage.
Huff teaches a microfluidic device for analyte analysis on a silicon-on-oxide wafer substrate ([Abstract]; [0349]; [0592]). Specifically for Claim 1, Huff teaches a silicon (Si) substrate ([0349] “The first and second substrates may be made from any suitable material…silicon…”; [0312] “the device of FIGS. 2A and 2B can also be manufactured as a unitary device”; [0592] “etching processes to modify a silicon-on-oxide (SOI) wafer”), and capable of withstanding a high pressure during fluid flow, such as a pressure of up to 4 atmospheres, without leakage ([0592] “…a silicon-on-oxide (SOI) wafer”)(Examiner notes that Applicant’s specification at [0010] describes that the capability of withstanding the pressure is achieved by a material choice of using a silicon-on-insulator wafer (SOI).)
Huff provides a motivation to combine at [0243] with “…any suitable material that is electrically insulating or has a high electrical resistance, such as… silicon.” A person having ordinary skill in the art before the effective filing date of the claimed invention would recognize that silicon, such as a SOI, is a useful material for making a microfluidic channel electrochemical device, since it is electrically insulating or has a high electrical resistance.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the microchannel microfluidic device on a unitary substrate of non-specified material disclosed by Boutelle with the specific silicon SOI wafer taught by Huff, creating a single microfluid analysis device on a unitary SOI substrate, which has a high electrical resistance suitable for use in an electrochemical measurement device.
Regarding Claim 2, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 2, Boutelle discloses comprising a plurality of microelectrodes ([0122] “an analysis module 16 which may comprise a number of sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41.”; [0025] “ analysis using microelectrodes…”; [0094] “Microfluidic flow…analyte conduit 5”) for multiplex detection of a plurality of analytes from the fluid sample introduced to the microfluidic channel [(0122] “…sensing different chemical/biochemical molecules/ions flowing through the analyte flow channel 41”; [0275] – [0276] “…analysis of lactate and/or glucose and/or pyruvate and/or another one or more metabolites or molecules…can be carried out on any sample, for example a single sample taken from a subject.”; [0094] “Microfluidic flow…analyte conduit 5”).
Regarding Claim 6, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 6, Boutelle discloses wherein the microelectrode is one or more ([0122] “sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41. “; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”; [0025]; [0094] “…microfluidic flow…”) of
a functionalized electrode comprising an analyte-specific recognition element, such as a polypeptide, a polynucleotide, an antibody, a molecular imprinted polymer (MIP),
a carbon-fiber electrode ([0169] “…carbon fibres…);
a parylene-C passivated electrode;
a pyrolyzed photoresist;
a gold electrode ([0169] “…gold…”);
a platinum electrode ([0169] “…platinum…”);
an ion-selective electrode (e.g., Ag/AgCI)([0171] “a silver/silver chloride wire may act as a combined reference and auxiliary electrode”);
a boron-doped diamond electrode ([0169] “…Boron doped diamond…”); and
a titanium electrode
Regarding Claim 8, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 9, Boutelle discloses, having a form factor configured for implantation into a living animal or person and the analyte is from a biological sample (Fig. 1; “suitable connection apparatus 3”; [0094] “Microfluidic flow controller 1 comprises…human patient undergoing online microdialysis by way of microdialysis probe P. Any suitable connection apparatus 3 including a fluid line from the probe P and source S…”), and the microelectrode positioned in the microfluidic channel resists fouling ([0210] – [0211] “The at least one working electrode…coated in a first layer…”, “The first layer is…protect the electrode from damage and from fouling.”; ([0122] “sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41. “; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”; [0025]; [0094] “…microfluidic flow…”)), thereby increasing operational lifetime of the implanted electrochemical sensor compared to an electrochemical sensor ([0211] “protect the electrode from damage and from fouling…protects against poisoning of the working electrode function…”)(Examiner notes that the limitation is claimed such that by resisting fouling then also increases the operations lifetime…of the implanted electrochemical sensor” Also, see the 112b interpretation above for the compared limitation).
Regarding Claim 9, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 9, Boutelle discloses wherein the reagent solution ([0099] “one or more calibration fluids”; [0118] “ fluids from the valves 8, 11 delivered to the analysis module…together with reagent fluid…from reagent valve 125 (FIG 13.)…”) is selected from the group consisting of:
a calibration solution ([0033] “delivery of calibration fluid”);
a cleaning solution ([0040] “delivery of flush fluid”);
an activating solution ([0045] “ deliver reagent to the analyte conduit.” [0232] “a sensing reagent for the detection of pyruvate”; [0233] “sensing reagent…an enzyme”); and
an electrode regeneration solution.
Regarding Claim 11, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 11, Boutelle discloses having a measurement run time of at least 90 seconds before introduction of the reagent solution to the microelectrode to provide a reset of the measurement run time ([0298] “comprise monitoring the metabolite(s) or molecule(s) for at least one hour…This continuous monitoring may be interrupted for periods of calibration…at intervals of…for example 6 hours…”; [0128]”) , without disturbing tissue surrounding the implanted electrochemical sensor (Fig. 1; “suitable connection apparatus 3”; [0094] “Microfluidic flow controller 1 comprises…human patient undergoing online microdialysis by way of microdialysis probe P. Any suitable connection apparatus 3 including a fluid line from the probe P and source S…”; [0029] “…valve…delivery of calibration fluid to the analyte conduit”; [0099] [Abstract] “the analyte fluid is passed to an alternative destination and calibration fluid is passed to the analysis module, thereby maintaining flow rate of analyte fluid from a source and maintaining a steady flow rate of fluid through the analysis module in both analysis mode and calibration mode.”)(Examiner notes that the control of the direction of the flows does not disturb the probe’s location in the tissue of the sensor, nor the direction of the fluid movement directly at the “source S” probe interface with the subject. The conditions at the tissue are unchanged.)
Regarding Claim 12, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 12, Boutelle discloses further comprising a membrane positioned upstream of the microfluidic channel for membrane microdialysis ([0358] “a sterile clinical microdialysis catheter (CMA 70, 60-cm flexible shaft, 10-mm membrane length…”; [0357] “microfluidic device containing sensors…”; [0360] “The outlet tubing of the probe was adapted to connect to a continuous online analysis system…clinical analysis system…inside this system was the microfluidic analysis system”; Fig. 1 and Fig. 2).
Regarding Claim 14, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 14, Boutelle discloses having an in-line calibration mode ([0029] “a calibration mode”; [0051] “alternatingly pass the analyte fluid and the calibration fluid…”; [0328] “Online calibrations”; Fig 26) to calibrate the electrode without disturbing an environment surrounding the electrochemical sensor ([0051] “alternatingly pass the analyte fluid and the calibration fluid to an analysis module…maintain a steady flow rate of fluid through the analysis module during both an analysis mode and a calibration mode. “; [0099] “periodically calibrated by the introduction of one or more calibration fluids, without disrupting flow through the dialysis probe P itself…“[0055]; [0029])(Examiner notes that the control of the direction of the flows does not disturb the probe’s location in the tissue of the sensor, nor the direction of the fluid movement directly at the “source S” probe interface with the subject. The conditions at the tissue are unchanged.)
Regarding Claim 15, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 15, Boutelle discloses wherein the reagent channel (Fig. 1 and Fig. 2 channel between “interconnectors 23” and “interconnectors 26”) is connected to the microfluidic channel ([0106] “…interconnector 23 and flow to the analyte conduit 5 as shown by arrow 25”; Fig 1 and Fig. 2, “analyte conduit 5”), to form a microfluidic junction (Fig 1., “interconnectors 26”) positioned between the sampling port and the microelectrode (Fig 1., . “interconnectors 26” is between the “fluid source connect 2” + “suitable connection apparatus 3” and the Analysis Chip “analysis module 16”; [0122] “an analysis module 16 which may comprise a number of sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41.”)
Regarding Claim 16, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 16, Boutelle discloses further comprising one or more flow controllers operably connected (Fig. 1 and Fig. 2; Pump 1 and Pump 2 (labelled features 9 and 12); [0097] “…controller 20 is operable to control the operation of the valves 4, 8, 11; the pumps 9, 12, and the analysis module 16”) to:
the microfluidic channel proximal end (Fig. 1 and Fig. 2, “analyte conduit 5” with “inlet 17” at a proximal end fluidly connected to Pump 1 and Pump 2 (labelled features 9 and 12); [0097] “…controller 20 is operable to control the operation of the valves 4, 8, 11; the pumps 9, 12, and the analysis module 16”; [0094] “microfluidic flow…analyte conduit 5…”) and/or
a proximal end of the reagent channel (Fig. 1 and Fig. 2 channel between “interconnectors 23” and “interconnectors 26”, proximal end is “interconnectors 23”, fluidly connected to Pump 1 and Pump 2 (labelled features 9 and 12); [0097] “…controller 20 is operable to control the operation of the valves 4, 8, 11; the pumps 9, 12”);
wherein the flow controller is a variable pressure pump ([0110] “pumps 9, 12 may be non-reciprocating pumps”) to control pressure and corresponding flow-rate ([0342] “By mixing the flows, a multi-point calibration was carried out by varying the relative flow rates of the two pumps…”; [0110] “…non-reciprocating pumps”), and flow direction (Fig. 1 and Fig. 2; [0110] “…non-reciprocating pumps…for single direction pumping…”) in each of the microfluidic channel and reagent channel ([0342] “By mixing the flows, a multi-point calibration was carried out by varying the relative flow rates of the two pumps…”), optionally without any flow valves (See 112b rejection and interpretation above), wherein the variable pressure pump ([0110] “pumps 9, 12 may be non-reciprocating pumps”) generates a fluid sample flow rate through the microfluidic channel that is between 1 nL/min and 300 nL/min ([0153] “microfluidic domain…preferred flow rates of analyte fluid flow and calibration fluid flow… 0.3…microlitres per minute“).
Regarding Claim 17, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 17, Boutelle discloses wherein the flow controllers are configured to provide a plurality of electrochemical sensor modes, the modes comprising:
a sampling mode ([0033] “an analysis mode”);
a calibration mode ([0033] “a calibration mode”);
a regeneration mode ([0033] “a divert mode”);
a cleaning (rinse) mode ([0041] “…flush fluid to pass through the analyte conduit to clear gas bubbles and obstructions from the analyte conduit…”; [0112] “…an analyte conduit flushing arrangement…flush pump 120 and flush reservoir 122…may operate in the same manner as the calibration fluid pumps 9, 12…”; Fig 11.)(Examiner notes that when the “flushing arrangement” is connected and active, that it is configured to provide a cleaning mode,”); and
a transient mode ([0029] “a standby mode”).
Regarding Claim 18, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 18, Boutelle discloses configured for use as:
an in-brain sensor ([0358] - [0361] “a 15 minute period of the continuously analysed data from the brain microdialysis stream…brain glucose levels…”)
a continuous glucose sensor ([0128] “detection of pyruvate, glucose…in the analyte flow…”);
an oxygen reduction sensor in a fuel cell; a water quality sensor; a toxin detector; a corrosion sensor;
a scanning electrochemical microscopy probe; a pH sensor; an impedance sensor; a component of a battery, or a component of a desalination device.
Regarding Claim 19, Boutelle in view of Huff discloses as described above, The electrochemical sensor of claim 1. For the remainder of Claim 19, Boutelle discloses wherein the sampling port (Fig 1, “fluid source connect 2” and “suitable connection apparatus 3”; [0094] “…fluid source connect 2 for receiving a flow of fluid analyte from a suitable source S…fluid line from the probe P and source S…”) is positioned in an insertable portion having a needle geometry ([0340] “fit the 27 G needle (0=ca. 413 µm) biosensors…”) and the sensor is positioned in a non-insertable potion ([0340] “The microfluidic chip was fabricated using a 3D printer ULTRA® 3SP™…microfluidic channels…”; Fig 14-j), and the average thickness of the insertable potion is less than the average thickness of the non-insertable portion ([0340] “The microfluidic chip was fabricated using a 3D printer ULTRA® 3SP™…fit the 27 G needle (0=ca. 413 µm) biosensors…sizes of microfluidic channels (1) 520x520 µm”; Fig 14-j)
Regarding Claim 22, Boutelle discloses A method of detecting an analyte ([Abstract]; [0051]), the method comprising the steps of:
inserting the electrochemical sensor of claim 1 (See rejection of Claim 1 above) into a subject at an implantation site (Fig. 1; “suitable connection apparatus 3”; [0094] “Microfluidic flow controller 1 comprises…human patient undergoing online microdialysis by way of microdialysis probe P. Any suitable connection apparatus 3 including a fluid line from the probe P and source S…”).;
introducing a biological sample from the subject to the microfluidic channel via the sampling port ([0094] “…receiving a flow or fluid analyte from a suitable source S”);
energizing the microelectrode and detecting an electrical output from the microelectrode ([0123] “electrical voltage outputs 42 from the electrodes…may be sensed and digitised by the sampler…The digitised samples…“) ;
detecting the presence or absence of the analyte based on the electrical output from the microelectrode, thereby detecting the analyte ([0123] “…digitised samples can then be passed to a calibration processor 44….the digitised outputs of the electrodes 40 may be used to define one or more calibration curves/profiles defining the analysis module sensitivity.”; [0304] “calibration profiles relating electrical current and analyte concentration as a function of time…autocalibration”).
Regarding Claim 24, Boutelle in view of Huff discloses as described above, The electrochemical sensor of claim 22. For the remainder of Claim 24, Boutelle discloses further comprising the step of:
controlling a relative pressure between the reagent channel and the microelectrode channel ([0110] “pumps 9, 12 may be non-reciprocating pumps”; [0034] “the flow controller being thereby configured to maintain a steady flow rate of fluid through the analyte conduit during both the analysis mode and the calibration mode.“; Fig. 1 and Fig. 2) to flow the reagent fluid through the microelectrode channel ([0342] “varying the relative flow rates of the two pumps, while keeping the overall flow rate constant…”; [0033] “…(ii) a calibration mode in which the valve is configured to deliver calibration fluid to the analyte conduit, the flow controller…maintain a steady flow rate…”; Fig. 1 and Fig. 2);
wherein the reagent fluid is a cleaning solution or a calibration solution ([0033] “…a delivery of calibration fluid”), thereby increasing an operational lifetime of the implanted electrochemical sensor to one hour or greater without having to remove the electrochemical sensor from the implantation site ([0128] “A typical calibration interval in this context may be, for example, of the order of every 2 to 3 hours…”; [0298]; [0357] “microfluidic device containing sensors for glucose and lactate was tested for periods of up to 120 h of continuous monitoring”; [0358] “…microdialysis probe…placed in at risk cortical tissue…”)
Claim 4 is rejected under 35 U.S.C. 102(a)(2) as being anticipated by Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1), as evidenced by Orwar (US 2006/0223164 A1).
Regarding Claim 4, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 4, Boutelle discloses wherein a characteristic dimension of the microfluidic channel cross-section ([0092] “ cross-sectional area of about 1 micron2 up to 1 mm2”) is less than a diffusion layer formed by the fluid sample undergoing laminar flow in the microfluidic channel ([0352] “Laminar flow inside the connection tubing and microfluidic channel…time response of the sensor to a step change…reduced by decreasing the channel size…fastest response time…channel 1”; Table 1: channel dimensions 375 x 508 µm.”)(Examiner notes the Applicant’s Specification at [0056] “the diameter of the microfluidic channel is preferably less than the diffusion layer in the channel for laminar flow (e.g., Reynolds number less than 2000, preferably less than 1000).” As evidenced by Orwar [0194] “Fluid flows inside micron-sized channels are laminar and reversible…transition between laminar reversible flow and turbulent flow appears to occur at a Re number of about 2000... Even at high flow rates (m/s), Re for channels measuring a few microns in width is ˜<10. This means that fluid flow in micron-sized channels fall well within the laminar reversible regime.” Based on this, the laminar flow disclosed inside the microchannels of Boutelle would have dimension less than a diffusion layer formed by the fluid sample undergoing laminar flow in the microfluidic channel with a Reynolds number less than 2000.)
Claims 3 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1), further in view of Manica et. al., (“Characterization of Electrode Fouling and Surface Regeneration for a Platinum Electrode on an Electrophoresis Microchip”).
Regarding Claim 3, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 3, Boutelle discloses wherein the reagent solution from the reagent microchannel (Fig. 1 and Fig. 2 channel between “interconnectors 23” and “interconnectors 26”; [0029] “…calibration fluid to the analyte conduit…”; [0094] “…suitable reservoirs 14, 15 of first and second calibration fluids”) is introduced to the microfluidic channel ([0029] “…switch the first valve…switch the second valve…deliver calibration fluid to the analyte conduit”), wherein the reagent fluid does not exit the sampling port into the sampling area ([0029] “…switch the first valve…switch the second valve…deliver calibration fluid to the analyte conduit…controller configured to maintain a steady flow rate of fluid through the analyte conduit during both the analysis mode and the calibration mode.”)(Examiner notes that calibration fluid turns toward the analysis chip at “interconnectors 26” and does not enter or exit the sampling port at 2, and the valves are such that the reagent fluid cannot reach the sampling port to head toward the sampling area of the human interface with the probe.)
Boutelle does not particularly disclose that its fluids have the intended purpose to reduce microelectrode fouling associated with a fouling material from the environment surrounding the electrochemical sensor.
Manica teaches a method of electrochemically cleaning biomedical analyte electrodes of electrode fouling by applying a waveform with a reagent to the electrodes [Abstract]. Specifically for Claim 3, Manica teaches reagent solution is introduced to the microfluidic channel to reduce microelectrode fouling [Page 4575, 1st Full Paragraph] “After fouling, the electrode can be reproducibly regenerated by applying the stripping waveform…”) associated with a fouling material from the environment surrounding the electrochemical sensor ([Page 4574, “Electrode Treatment” section] “applying a programmed waveform to the working electrode versus the reference electrode…the pulse waveform was applied only between runs and while rinsing all reservoirs with run buffer.”; [Page 4574, “Reagents and Solutions” Section] “Reagents…run buffer…”; [Page 4574, “Results and Discussion” section] “This treatment serves to strip off any adsorbed species and regenerate a reproducible, oxide-free electroactive surface”, “…analytes…adsorbed species…”)
Boutelle and Manica both address fouling elimination for electrodes: Boutelle with an electrode coating layer to protect the electrode from damage and fouling (Boutelle: [0210] – [0211]), Manica with a Manica provides a motivation to combine at [Page 4575, 1st Full Paragraph] with “After fouling, the electrode can be reproducibly regenerated by applying the stripping waveform.” A person having ordinary skill in the art before the effective filing date of the claimed invention would recognize that electrode fouling would occur during use, and having a way to repeatably regenerate the electrode would be useful to return the electrode to a proper measurement accuracy in response to instances of measurement degradation from fouling.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the fluid flow system to flush (with a reagent) the analyte microchannel with electrodes therein disclosed by Boutelle with the Manica’s programmed waveform and rinse using a flowing reagent to regenerate the electrode from fouling, creating a single microfluid analysis device with an anti-fouling coating that can further use a programmed waveform and rinse to regenerate the electrode and increase the long-term measurement accuracy of the sensor.
Regarding Claim 10, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 10, Boutelle discloses wherein the reagent microchannel is configured to convey a solution [across] (See 112 b interpretation above) the electrode ([0040] “delivery of flush fluid…to the analyte conduit…”; [0122] “sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41. “; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”; [0025]; [0094] “…microfluidic flow…”); and without disturbing tissue surrounding the implanted electrochemical sensor (Fig. 1; “suitable connection apparatus 3”; [0094] “Microfluidic flow controller 1 comprises…human patient undergoing online microdialysis by way of microdialysis probe P. Any suitable connection apparatus 3 including a fluid line from the probe P and source S…”)(Examiner notes that the control of the direction of the flows does not disturb the probe’s location in the tissue of the sensor, nor the direction of the fluid movement directly at the “source S” probe interface with the subject. The conditions at the tissue are unchanged.)
Manica teaches convey a regeneration solution [across] (See 112 b interpretation above) the electrode for regenerating an electrode surface parameter ([Page 4574, “Electrode Treatment” section] “applying a programmed waveform to the working electrode versus the reference electrode…the pulse waveform was applied only between runs and while rinsing all reservoirs with run buffer.”)
The motivation to combine Boutelle and Manica for Claim 10 is the same as that described in more detail above for Claim 3. In summary, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the fluid flow system to flush (with a reagent) the analyte microchannel with electrodes therein disclosed by Boutelle with the Manica’s programmed waveform and rinse using a flowing reagent to regenerate the electrode from fouling, creating a single microfluid analysis device with an anti-fouling coating that can further use a programmed waveform and rinse to regenerate the electrode and increase the long-term measurement accuracy of the sensor.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1), further in view of Wilsey (US 2007/0170055 A2).
Regarding Claim 5, Boutelle in view of Huff discloses The electrochemical sensor of claim 1. For the remainder of Claim 5, Boutelle discloses the microelectrode ([0122] “sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41. “; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”; [0025]; [0094] “…microfluidic flow…”)
Boutelle does not particularly disclose wherein the microelectrode is one or more thin film electrodes having a thickness less than 1 µm and a total fluid contact surface area of between 100 pm2 and 100 mm2.
Wilsey teaches a microfluidic analysis device used “to identify levels of glucose…and the like” with thin film electrodes ([0043]; [0048]). Specifically for Claim 5, Wilsey teaches an array of microelectrodes in a microchannel ([0098] “A microchannel or capillary more specifically refers to a space or channel that is defined over the array to allow the flow of a fluid over the array. “) that are a thin film with a total fluid contact surface area of 0.1 to 0.5 mm2 ([0042] – [0043]) for measuring analytes such as glucose [0121]. Regarding Claim 5, Wilsey teaches wherein the microelectrode is one or more thin film electrodes having a thickness less than 1 µm ([0043] “…thickness of the electrode components…Exemplary thicknesses can be in the range from about 30 to 200 nanometers (nm), with a preferred thickness being about 100 nm.”) and a total fluid contact surface area of between 100 pm2 and 100 mm2([0042] “An exemplary area of an electrode having 10 electrode elements can be in the range from about 0.1 to about 0.5 square millimeters…”).
Wilsey provides a motivation to combine at [0043] with “…thickness of the electrode components can be sufficient to support a desired electric current.” A person having ordinary skill in the art before the effective filing date of the claimed invention would recognize that choosing the thickness of the microelectrode would be useful for passing a desired electric current through the electrode for the desired analyte measurement.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the electrode within a microchannel for analyte measurement disclosed in Boutelle with the thin film electrode of 30 to 200 nanometers thickness for measuring analytes (such as [0048] “glucose…and the like”) taught by Wilsey, creating a single microfluid analysis device using thin film electrode for passing a desired electric current through the electrode for the desired analyte measurement within a microfluidic channel geometry.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1), further in view of Brunner et. al., (US 2005/0212016 A1).
Regarding Claim 7, Boutelle in view of Huff discloses as described above, The electrochemical sensor of claim 1. For the remained of Claim 7, Boutelle discloses the microelectrode ([0122] “sensors such as electrodes 40 positioned within an analyte flow channel/conduit 41. “; Fig. 4; Fig 1 and Fig. 2, “analyte conduit 5”; [0025]; [0094] “…microfluidic flow…”)
Boutelle does not disclose wherein the microelectrode is part of a field-effect transistor (FET).
Brunner teaches an on-chip microchannel detector for analyzing fluids for analytes using a FET with a gate electrode to bias the FET ([Abstract], [0007-0008], [0012], [0058]). Specifically for Claim 7, Brunner teaches wherein the microelectrode is part of a field-effect transistor (FET) ([0007] “FET is part of the housing or of the walls of the cavity which accommodates the analyte”; [0008] “the cavity is formed as a channel.”; [0012] “a gate electrode is provided for biasing the gate of the FET”; Fig 6, [0058] “gate electrode 45”, “the transistor channel…”).
Brunner provides a motivation to combine at [0012] with “ The additional gate electrode rather serves to bias the channel of the FET by a fixed amount in order to adjust the working range of the FET.” A person having ordinary skill in the art before the effective filing date of the claimed invention would recognize that using an electrode as a gate for a FET would allow for detection of analytes in a microchannel with also allowing to adjust the working range of the sensor.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the electrodes within a microchannel cavity disclosed in Boutelle with the electrode as a gate for a FET taught by Brunner, creating a single microfluid analysis device for detecting analytes with a tunable working range of its FET using a gate electrode, for more particularly analyte targeting.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1), further in view of Schwerdt et. al., (“Subcellular Probes for Neurochemical Recording from Multiple Brain Sites”, Ref U on PTO-892)
Regarding Claim 13, Boutelle in view of Huff discloses as described above, The electrochemical sensor of claim 1. For the remained of Claim 13, Boutelle discloses having an implanted cross-sectional area that does not adversely impact surrounding tissue, including less than 1 mm2 ([0340] “27 G needle (0=ca. 413 μm) biosensors.”)(Examiner notes the 112b interpretation above); less than or equal to 1200 µm2 (Examiner notes the 112b interpretation above for the broad-to-narrow limitation); including a probe cross-section ([0340] “27 G needle (0=ca. 413 μm) biosensors.”)
Boutelle does not specifically disclose including a probe cross-section corresponding to about 15 m x 75 pm.
Schwerdt teaches a microarray of implantable probes to permit electrochemical sampling of dopamine and other neurotransmitters using microelectrodes, with the individual probes having a spatial footprint of 9 μm [Abstract]. Specifically for Claim 13, Schwerdt teaches including a probe cross-section corresponding to about 15 μm x 75 μm ([Page 5, Top] “The fabricated CF arrays…diameters of 8–10 μm.“; [Abstract] “The microfabricated probe occupies a spatial footprint (9 μm)”)(Examiner notes that the diameter of 8 to 10 μm would correspond to an area within 15 μm x 75 μm, as it is smaller.)
Boutelle is open to combine with a different probe interface with the tissue, as disclosed at [0094] with “Any suitable connection apparatus 3 including a fluid line from the probe P and source S may be used to couple the flow controller 1 to the source.” Schwerdt provides a motivation to combine at [Page 2, “Introduction” Section] with “…smaller sizes help reduce brain damage, which will help increase opportunities to safely employ these sensors in therapeutic applications, for example, in improving deep brain stimulation treatment in Parkinson’s disease patients.” A person having ordinary skill in the art before the effective filing date of the claimed invention would recognize that using a probe of a reduced size would be useful for reducing tissue damage associated with implanting a probe in brain tissue to obtain fluid for analyte sensing.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the microfluidic analysis device with a fluid source connector with a fluid line and probe for obtaining fluid analyte from a patient (including from brain tissue ([0269]) disclosed by Boutelle with Schwerdt’s taught small-sized probe array, each with a diameter of 8 to 10 μm, creating a single microfluidic analysis device that can obtain analyte fluid from a patient’s brain with reduced levels of tissue injury.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Boutelle et. al., (US 2018/0136247 A1) in view of Huff et. al., (US 2021/0325334 A1), further in view of Pelssers (US 2022/0175280 A1).
Regarding Claim 23, Boutelle in view of Huff discloses The electrochemical sensor of claim 22. For the remainder of Claim 23, Boutelle discloses wherein the biological sample flows through the microfluidic channel at a flow-rate ([0153] “ preferred flow rates of analyte fluid flow and calibration fluid flow envisaged in the apparatus and methods described may be between 0.3 and 2 microlitres per minute”).
Boutelle does not disclose at a flow-rate that is less than or equal to 50 nL/min
Pelssers teaches a wearable device for detecting a biomarker in a sweat sample that is obtained using microchannels at a low flow rate ([Abstract]; [0021]; [0021]). Specifically for Claim 23, Pelssers teaches wherein the biological sample flows through the microfluidic channel at a flow-rate that is less than or equal to 50 nL/min ([0025] “pump the carrier fluid at a predetermined flow rate of from 10 nL/min to 60 nL/min…”; [0021] “…a sweat flow rate of between 0.03 and 20 nL/min/gland”).
Pelssers provides a motivation to combine at [0071] with “…the flow rate of carrier fluid being [is] pumped through the device during use and an average sweat rate.“ A person having ordinary skill in the art before the effective filing date of the claimed invention would recognize that a microfluid analysis system could be used to analysis sweat as the fluid of interest, which is obtained from the body at a low flow rate (based on its average rate of excretion from the skin), such that a carrier fluid pump at 10 nL/min – 60 nL/min would be useful.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the flow rate pump for analyte fluid flow in the microfluidic analyte device disclosed by Boutelle with the low flow rate pumping (10 nL/min to 60 nL/min) for sweat fluid analyte analysis taught by Pelssers, creating a single microfluidic analysis method that is useful for detecting analytes when the fluid of interest is sweat obtained from a subject as it is excreted.
Conclusion
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/MELISSA JO MONTGOMERY/Examiner, Art Unit 3791
/PATRICK FERNANDES/Primary Examiner, Art Unit 3791
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