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 .
Status of the Claims
Claims 16-30 are pending and examined herein.
Priority
The present application, filed 02/07/2024, is a 371 of PCT/EP2022/077874, filed 10/06/2022, which claims foreign priority of EP21201778.4, filed 10/08/2021. The benefit is acknowledged and the claims examined herein are treated as having an effective filing date of 10/08/2021.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 02/07/2024, 05/03/2024, and 09/09/2025 are acknowledged and have been considered.
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 28 and 29 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 28 recites “at least one sensor chip according to claim 1;” however, claim 1 has been canceled. Therefore, it is unclear what limitations define the “at least one sensor chip” of claim 28, because there is no pending claim 1 from which the sensor chip may derive its structural limitations. For purposes of compact prosecution, claim 28 will be interpreted as reciting “at least one sensor chip according to claim to 16,” because claim 16 is the only pending independent claim directed to a sensor chip. Appropriate correction is required.
Claim 29 depends from claim 28, which is indefinite for reciting “at least one sensor chip according to claim 1,” where claim 1 has been canceled. Accordingly, the scope of claim 29 is unclear since claim 29 incorporates the indefinite limitations of claim 28.
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.
Claims 16, 17, 18, 20, 21, 22, 23, 24, 26, 28, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Miller et al. (WO 2004/016727 A1 – IDS dated 02/07/2024) in view of Kralicek et al. (WO 2019/239360 A1) and Rothberg et al. (EP 2092322 B1)
Regarding claim 16, Miller teaches chemical, biological, and/or biochemical reactor chips and other reaction systems such as microreactor systems, as well as systems and methods for constructing and using such devices (Abstract, p. 1). Miller teaches a chip, which is an integral article that includes one or more reactors (p. 12). With respect to detecting one or more bioactive agents in a surrounding medium, Miller discloses a gaseous agent and that the chip is arranged to allow gaseous non-liquid transport of the agent to the predetermined reaction site (p. 2). Miller further teaches that an environmental factor may be the concentration of a gas or a dissolved gas within or associated with the reaction site, and that the gas may be, for example, oxygen, nitrogen, water (i.e., the relative humidity), CO₂, or the like (p. 33). With respect to a reaction cell, Miller teaches an embodiment including six reaction sites. The reaction sites define a series of generally aligned, elongated, rounded rectangular voids and channels for delivering species to reaction sites (p. 10; Fig. 1). With respect to a membrane separating the reaction cell from the surrounding medium and being permeable for the one or more bioactive agents, Miller teaches that ports also may connect to channels communicating with a chamber aligned with a chamber defining reaction site, separated from the reaction site by a membrane, e.g., semipermeable membrane (p. 11), and semipermeable membranes are membranes permeable with respect to at least one species, but not readily permeable with respect to at least one other species (p. 13). Miller further discloses that reaction sites containing cells may include a region containing a gas (e.g., a gas head space), and the gas head space, in some cases, may be partially separated from the reaction site, through use of a gas-permeable or semi-permeable membrane (p. 16). With respect to the overall chip architecture, Miller discloses that a chip can be connected to or inserted into a larger framework defining an overall reaction system, and the system can be defined primarily by other chips, chassis, cartridges, cassettes, and/or by a larger machine or set of conduits or channels, sources of reactants, cell types, and/or nutrients, inlets, outlets, sensors, actuators, and/or controllers (p. 12).
Additionally, Miller teaches that a reactor is the combination of components including a reaction site, any chambers (including reaction chambers and ancillary chambers), channels, ports, inlets and/or outlets (leading to or from a reaction site), sensors, actuators, processors, controllers, membranes, and the like, which, together, operate to promote and/or monitor a biological, chemical, or biochemical reaction, interaction, operation, or experiment at a reaction site, and which can be part of a chip (p. 14). Here, Miller expressly points a skilled artisan toward sensing/reaction components for monitoring chemical or biological interactions in a chip-based reaction site.
However, Miller does not expressly teach or specify that (1) the reaction cell contains a plurality of receptor protein complexes configured to bind to the one or more bioactive agents such that a detectable state change of at least a part of the receptor protein complexes is induced, nor (2) the sensor chip is configured in shape and size to be at least partly removably inserted into a socket of the sensing device for detecting the one or more bioactive agents.
On the other hand, Kralicek teaches a sensor device comprising an insect odorant receptor complex, comprising an OrX and an Orco (Abstract, p. 1), and that the OrX and Orco proteins together form a complex (p. 15). Kralicek teaches plurality/implementation of receptor protein complexes, disclosing multiple Or22a/Orco channel complexes (p.90), and for preparation of OrX and Orx/Orco SPRi sensors, the OrX and OrX/Orco complexes are immobilized directly via the N-terminal cysteine residue (p. 91). Kralicek further teaches that a purified insect odorant receptor complex (OrX/Orco) has been functionally immobilised on a sensor display surface/substrate (p. 2), and the sensor device comprises the receptor complex in electrical communication with a substrate (p. 2). Furthermore, Kralicek discloses chip-based implementation of the receptor complexes because the invention also contemplates use of chips with multiple sensor substrates each comprising a different or the same receptor in the insect odorant receptor complex, and the sensor device component of the invention may be such a chip (p. 57). With respect to the receptor protein complexes are configured to bind to the one or more bioactive agents in the reaction cell, Kralicek teaches binding to the bioactive agent/analyte, disclosing that the interaction is binding of the analyte (e.g., volatile organic compounds) to the OrX in the insect odorant receptor complex (p. 2). With respect to a detectable state change of at least a part of the receptor protein complexes is induced, Kralicek discloses that the interaction between the analyte and the OrX in the insect odorant receptor complex results in a conformational change in the insect odorant receptor complex, and the conformational change in the insect odorant receptor complex results in the change in the electrical characteristic of the substrate (p. 3). Lastly, Kralicek discloses environmental detection, stating that the sensor is capable of detecting, in an environment, the presence of an analyte that binds to the insect OrX in the insect odorant receptor complex (p. 3).
Rothberg supports the remaining limitation, disclosing a chip comprising the ISFET array and flow cell is seated in the ZIF (zero insertion force) socket of the loading fixture ([0319], p. 50). Rothberg further teaches that the electrical leads protruding from the bottom of the chip are inserted into a socket on the top of a fixture unit ([0319], p. 50). Accordingly, Rothberg teaches a sensor chip configured for removable insertion into, and operative electrical coupling through, a socket of an associated sensing apparatus.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Miller’s chip-based biological/biochemical reactor sensor system to include Kralicek’s insect odorant receptor complexes as the biological receptor sensing components in Miller’s reaction site/reaction cell, and further to implement the sensor chip using Rothberg’s removable socket-mounted chip configuration. Miller provides the teaching, suggestion, or motivation because it teaches chip-based systems for monitoring biological, chemical, and biochemical reactions and interactions at reaction sites, including biological components, membranes, sensors, gaseous-agent delivery, and an insertable/connectable chip architecture. Since Miller teaches transporting gaseous agents to a monitored reaction site and monitoring biological, chemical, and biochemical interactions occurring at that site, a skilled artisan seeking to improve Miller’s selective detection of chemical, biological, and environmental agents would have been directed toward biological recognition components capable of selectively detecting airborne chemical analytes. Kralicek teaches precisely such biological recognition components, namely insect odorant receptor complexes that selectively bind environmental odorant analytes and convert the binding event into detectable conformational and electrical state changes, and further teaches chip-based implementation of those receptor complexes. Thus, Kralicek provides a technically suitable receptor-based sensing component for performing the biological and chemical interaction monitoring already contemplated by Miller.
The skilled artisan also would have looked to Rothberg because Rothberg teaches a known removable socket interface in which the sensor chip itself is seated in a zero-insertion-force socket and electrically coupled through a socket connection, thereby facilitating installation, replacement, and reliable electrical communication between the sensor chip and the associated sensing apparatus. Since Miller already contemplates chips that are connected to or inserted into a larger reaction system, a skilled artisan would have recognized Rothberg’s removable socket interface as a predictable implementation of Miller’s contemplated insertable chip architecture, providing reliable electrical coupling while preserving the biological sensing functionality of the chip. A skilled artisan would have had a reasonable expectation of success because Miller already provides a compatible chip/reaction-site/membrane architecture for biological reactions, Kralicek teaches receptor complexes configured for chip-based sensor implementation, and Rothberg teaches a conventional removable socket interface for analyte-sensing chips. Incorporating Rothberg’s socket-mounted chip configuration into the Miller-Kralicek biosensor would merely apply a conventional chip-mounting technique to an otherwise compatible biological sensing platform while preserving the intended sensing function of the combined device.
Regarding claim 17, refer to the discussion above and here. Kralicek teaches that the detectable state change is indicative of a presence of the one or more bioactive agent in the surrounding medium. Specifically, Kralicek discloses that the sensor is capable of detecting, in an environment, the presence of an analyte that binds to the insect OrX in the insect odorant receptor complex (Kralicek, p. 3). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the detectable state change in the modified Miller-Kralicek-Rothberg sensor chip to be indicative of the presence of the bioactive agent in the surrounding medium because Kralicek teaches that analyte binding to the insect odorant receptor complex is used to detect the presence of the analyte in an environment. A skilled artisan would have had a reasonable expectation of success because Kralicek expressly teaches receptor-based detection through binding-induced state changes, while Rothberg’s removable socket interface merely provides a predictable mechanical and electrical mounting arrangement without altering the biological sensing function of the combined device.
Regarding claim 18, refer to the discussion above and here. Kralicek teaches that the state change is associated with at least a change in conformational state of the receptor protein complexes. Specifically, the interaction between the analyte and the OrX in the insect odorant receptor complex results in a conformational change in the insect odorant receptor complex, and the conformational change in the insect odorant receptor complex results in the change in the electrical characteristic of the substrate (p. 3). Kralicek further teaches that the state change is associated with a change in conductivity/electrical property since the conformational change in the insect odorant receptor complex results in the change in the electrical characteristic of the substrate (Kralicek, p. 3); wherein the electrical characteristic is selected from at least one of: conductivity, resistance, complex resistance, impedance, electrochemical impedance, electrochemical potential, surface plasmon resonance, the flow of current, and the resonance frequency of oscillations induced by an alternating electric field (p. 4). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the state change in the modified Miller-Kralicek-Rothberg sensor chip to be associated with a conformational and/or electrical state change because Kralicek teaches that analyte binding to the insect odorant receptor complex causes a conformational change that produces a detectable electrical characteristic change. A skilled artisan would have had a reasonable expectation of success because Kralicek expressly teaches this binding-induced detection mechanism, while Rothberg’s removable socket interface merely provides a predictable mechanical and electrical mounting arrangement without altering the receptor-based sensing function of the combined device.
Regarding claim 20, Miller teaches that the surrounding medium further includes water. Specifically, Miller teaches that an environmental factor may be the concentration of a gas or a dissolved gas within or associated with the reaction site, and that that the gas may be, for example, oxygen, nitrogen, water (i.e., the relative humidity), CO₂, or the like (p. 33).
Regarding claim 21, refer to the discussion above and here. Miller teaches that the membrane is permeable for gases, disclosing that the gas head space, in some cases, may be partially separated from the reaction site, through use of a gas-permeable or semi-permeable membrane (p. 16). Miller also teaches that semipermeable membranes are permeable with respect to at least one species, but not readily permeable with respect to at least one other species. (p. 13). Miller further specifies that a semipermeable membrane may allow oxygen to permeate across it, but not allow water vapor to do so, or allows water vapor to permeate it, but at a permeability that is at least an order of magnitude less. Or a semipermeable membrane may be selected to allow water to permeate across it, but not certain ions (p. 13).
Regarding claim 22, refer to the discussion above and here. Miller teaches that a chip can be connected to or inserted into a larger framework defining an overall reaction system, and the system can be defined primarily by other chips, chassis, cartridges, cassettes, and/or by a larger machine or set of conduits or channels, sources of reactants, cell types, and/or nutrients, inlets, outlets, sensors, actuators, and/or controllers (p. 12). While Rothberg teaches one or more connectors configured to operatively couple the sensor chip to the associated apparatus. In particular, Rothberg teaches that the electrical leads protruding from the bottom of the chip are inserted into a socket on the top of a fixture unit ([0319], p. 50). Hence, Rothberg teaches electrical connector elements that operatively couple the sensor chip to the associated device through the socket interface. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the modified Miller-Kralicek-Rothberg sensor chip to include one or more connectors configured to operatively couple the sensor chip to the sensing device. Miller already contemplates connecting or inserting its chip into a larger reaction-system framework containing sensors and controllers, while Rothberg teaches a known electrical-lead and socket interface for operatively coupling a sensor chip to associated apparatus. A skilled artisan would have had a reasonable expectation of success because the connectors would predictably provide the electrical and operational coupling required between the chip and the sensing device without altering the receptor-based sensing function.
Regarding claim 23, Kralicek teaches one or more electrodes and determination of a conductivity of a substrate or composition. In particular, Kralicek teaches a bilayer sensor device comprising a first substrate which comprises a first electrode disposed at a first side of the membrane; and a second substrate which comprises a second electrode disposed at a second side of the membrane (p. 50). Kralicek further teaches that the substrate is a working electrode, and that the sensor may further comprise a counter electrode and a reference electrode (p. 50). Kralicek further teaches that the sensor is configured to detect a change in the electrical characteristic of the substrate (p. 3), wherein the electrical characteristic is selected from at least one of: conductivity, resistance, complex resistance, impedance, electrochemical impedance, electrochemical potential, surface plasmon resonance, the flow of current, and the resonance frequency of oscillations induced by an alternating electric field (p. 4). Lastly, Kralicek further discloses measuring the electrical characteristic using electrodes. Specifically, Kralicek discloses that the sensor comprises a control system configured to measure an electrical characteristic, for example a flow of current, between the first and second electrodes (p. 16).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the modified Miller-Kralicek-Rothberg sensor chip to include one or more electrodes at least partly arranged within the reaction cell and configured to determine conductivity of a substrate or composition within the reaction cell. Miller provides the reaction-cell architecture, while Kralicek teaches an electrode-based receptor sensor in which analyte binding is detected by changes in electrical characteristics of the substrate, including conductivity, impedance, electrochemical potential, and current flow. A skilled artisan would have had a reasonable expectation of success because arranging Kralicek’s disclosed electrodes with the receptor-sensing components in Miller’s reaction cell would predictably provide an electrical readout of the receptor-based state change, while Rothberg’s removable socket interface would merely provide mechanical and electrical coupling of the sensor chip without altering the electrode-based sensing mechanism.
Regarding claim 24, Miller teaches an optical structure that functions as at least one detection window translucent for electromagnetic radiation emitted and/or scattered by one or more components of the receptor protein complexes. Specifically, Miller discloses light-interacting components suitable for use in chips and other reactor systems, including waveguides, optical fibers, light sources, photodetectors, optical elements, and the like (Abstract, p. 1). Miller further teaches an apparatus including a membrane substantially transparent to incident electromagnetic radiation in the infrared to ultraviolet range, and in fluid communication with the predetermined reaction site (p. 2). Additionally, Miller teaches a reaction site configured to carry out a chemical or biological reaction promoted by or monitored by electromagnetic radiation within a predetermined wavelength range, and a membrane transparent to electromagnetic radiation within the predetermined wavelength range to the extent necessary to promote or monitor the reaction (p. 4).
Regarding claim 26, Kralicek teaches that the receptor protein complexes each comprise at least one ligand-binding domain of a receptor protein configured to bind one or more bioactive agents. In particular, as discussed above, Kralicek discloses a sensor device comprising an insect odorant receptor complex comprising an OrX and an Orco (p. 2). Kralicek further teaches that the insect odorant receptor complex is embedded in the lipid bilayer in similar or same conformation as found in cell membranes in vivo, such that the ligand/analyte binding domain of the OrX receptor of the accessible to the ligand/analyte (p. 39). Kralicek further teaches that the interaction is binding of the analyte to the OrX in the insect odorant receptor complex (p. 2). Thus, Kralicek expressly teaches that the receptor protein complex comprises the OrX receptor, which includes at least one ligand-binding domain configured to bind the analyte. Also, as discussed above, Kralicek discloses that the receptor protein complex is configured to change conformation upon binding, stating that the interaction between the analyte and the OrX in the insect odorant receptor complex results in a conformational change in the insect odorant
receptor complex (p. 3), and the conformational change in the insect odorant receptor complex results in the change in the electrical characteristic of the substrate (p. 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the receptor protein complexes in the modified Miller-Kralicek-Rothberg sensor chip to comprise at least one ligand-binding domain configured to bind the bioactive agent and undergo a conformational change upon binding. Miller teaches a chip-based biological reaction platform for detecting biological interactions, while Kralicek teaches receptor protein complexes specifically configured for ligand recognition through an accessible ligand-binding domain and for producing a detectable conformational change following analyte binding. A skilled artisan would therefore have incorporated Kralicek’s receptor protein complexes into Miller’s reaction cell to provide a known receptor architecture capable of selectively binding bioactive agents and generating the claimed binding-induced conformational state change. A skilled artisan would have had a reasonable expectation of success because Kralicek teaches that the receptor complexes retain an accessible ligand-binding domain when incorporated into membrane-mimic structures and undergo binding-induced conformational changes suitable for sensor-device implementation, while Rothberg’s removable socket interface merely provides mechanical and electrical coupling of the sensor chip without altering the receptor-based sensing function.
Regarding claim 28, as discussed above, Miller teaches a sensing device operatively couplable to at least one sensor chip. Specifically, Miller discloses that a chip can be connected to or inserted into a larger framework defining an overall reaction system, and the system can be defined primarily by other chips, chassis, cartridges, cassettes, and/or by a larger machine or set of conduits or channels, sources of reactants, cell types, and/or nutrients, inlets, outlets, sensors, actuators, and/or controllers (p. 12). However, Miller does not expressly teach that the larger framework comprises a socket configured to at least partly receive the sensor chip. Rothberg teaches this limitation, disclosing an analyte-sensing chip comprising an ISFET array and flow cell seated in a zero-insertion-force socket of a loading fixture, and further teaches that electrical leads protruding from the bottom of the chip are inserted into a socket on the top of a fixture unit ([0319], p. 50). Accordingly, Rothberg teaches a socket configured to receive and operatively electrically couple the sensor chip to associated apparatus. Miller further teaches at least one sensor coupled with the at least one sensor chip, stating that sensor(s) associated with the chip or reactor may determine characteristics of the reaction site (p. 17).
Furthermore, as discussed above, Kralicek teaches the receptor-complex state change, stating that the interaction between the analyte and the OrX in the insect odorant receptor complex results in a conformational change in the insect odorant receptor complex (p. 3), and the conformational change in the insect odorant receptor complex results in the change in the electrical characteristic of the substrate (p. 3). Kralicek further teaches a processing and detection arrangement configured to determine the receptor-derived state change and provide a detection signal. In particular, Kralicek discloses that the sensor comprises a control system which is configured to measure an electrical characteristic (p. 16), and that that the sensor further comprises an output system, wherein the indication system is configured to indicate that an analyte has been detected. Detection of an analyte may be indicated by any system known in the art, such as an alarm, an electrical signal, a graphical user interface or so forth. The indication system may also indicate the presence or absence of an analyte, the concentration of analyte, etc (p. 52). Also, Kralicek teaches that the sensor is capable of detecting in an environment the presence of an analyte that binds to the insect OrX in the insect odorant receptor complex (p. 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the Miller-Kralicek-Rothberg sensor chip within a sensing device comprising Rothberg’s socket for receiving the sensor chip, Miller’s associated sensors and controllers, and Kralicek’s processing and detection arrangement configured to determine the receptor-complex state change and provide a detection signal indicative of the presence of the bioactive agent. Miller teaches an insertable chip architecture associated with sensors and controllers, Rothberg teaches a known removable socket interface for mechanically receiving and electrically coupling an analyte-sensing chip to associated apparatus, and Kralicek teaches that analyte binding induces a receptor conformational change that produces a measurable electrical characteristic used to detect analyte presence. A skilled artisan would have been motivated to combine these teachings to provide a removable receptor-based sensor chip mechanically and electrically coupled to a sensing device capable of processing the receptor-derived signal and reporting the presence of the analyte. A skilled artisan would have had a reasonable expectation of success because Miller, Kralicek, and Rothberg teach compatible components of a chip-based sensing system, and combining the known socket, sensor, controller, and receptor-signal-processing components would predictably provide the claimed sensing-device operation without altering the underlying receptor-based detection mechanism.
Regarding claim 29, Miller teaches measuring concentrations associated with a reaction site. Specifically, Miller teaches that an environmental factor or environmental condition is a detectable and/or measurable condition (e.g., by a sensor) of the environment within and/or associated with a reaction site (p. 33), and that the environmental factor may be the concentration of a gas or a dissolved gas associated within the reaction site or associated with the reaction site (for example, upstream or downstream of the reaction site, separated from the reaction site by a membrane, etc.) (Miller, p. 33). Miller further teaches that the environmental factor may also be a concentration of a substance in some cases. For example, the environmental factor may be an aggregate quantity, such as molarity, total ion concentration (p. 33). The concentration may also be the concentration of a biologically active compound, such as a protein, a lipid, a carbohydrate source, a hormone, an enzyme, or the like (p. 33).
Kralicek more specifically teaches that the detection signal may be indicative of analyte concentration. In particular, Kralicek teaches that the sensor can detect the presence of the analyte at a concentration based on a dynamic range extending over multiple orders of magnitude (p. 56). Kralicek further teaches comparing the electrical characteristic observed in a sample to a calibration curve of that electrical characteristic that corresponds to data points gathered from a control or standard having a known amount of an analyte of interest. In this way, the user may estimate the concentration of an analyte present in a sample to which the device has been contacted (p. 58). Additionally, Kralicek teaches constructing a library of one or more electrical characteristics of the device that correspond to the device's exposure to one or more known analytes. For example, a user may construct a library of results that represents the electrical characteristic observed when a device is exposed to various concentrations of analytes (p. 58). Thus, Kralicek expressly links the receptor-derived electrical detection signal to quantitative determination of analyte concentration.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the detection signal generated by the modified Miller-Kralicek-Rothberg sensing device to be indicative of the concentration of the bioactive agent in the surrounding medium. Miller teaches measuring concentrations of gases, substances, and biologically active compounds associated with reaction sites, while Kralicek expressly teaches quantitatively relating the receptor-derived electrical signal to analyte concentration using known-concentration standards, calibration curves, and measurements obtained at various analyte concentrations. A skilled artisan would have been motivated to configure the receptor-derived detection signal to provide concentration information in order to obtain a quantitative measurement of the detected analyte rather than merely a presence-or-absence result. A skilled artisan would have had a reasonable expectation of success because Kralicek expressly teaches estimating analyte concentration from the measured electrical characteristic using calibration data, while Miller supplies the reaction-site sensing architecture and Rothberg’s removable socket interface merely provides mechanical and electrical coupling without altering the quantitative receptor-based detection function.
Regarding claim 30, as discussed above, Miller teaches a sensing system comprising at least one sensor chip and a sensing device operatively couplable to the at least one sensor chip. Specifically, Miller discloses that a chip can be connected to or inserted into a larger framework defining an overall reaction system, and the system can be defined primarily by other chips, chassis, cartridges, cassettes, and/or by a larger machine or set of conduits or channels, sources of reactants, cell types, and/or nutrients, inlets, outlets, sensors, actuators, and/or controllers (p. 12). However, Miller does not expressly teach that the sensing device comprises at least one socket configured to at least partly receive the sensor chip. As discussed above, Rothberg teaches this limitation, disclosing an analyte-sensing chip comprising an ISFET array and flow cell seated in a zero-insertion-force socket of a loading fixture, and further teaches that electrical leads protruding from the bottom of the chip are inserted into a socket on the top of a fixture unit ([0319], p. 50). Accordingly, Rothberg teaches a socket configured to receive and operatively electrically couple the sensor chip to associated apparatus. Miller further teaches at least one sensor coupled with the at least one sensor chip, stating that sensor(s) associated with the chip or reactor may determine characteristics of the reaction site (p. 17).
Furthermore, as discussed above, Kralicek teaches determining the state change, stating that the interaction between the analyte and the OrX in the insect odorant receptor complex results in a conformational change in the insect odorant receptor complex (p. 3), and the conformational change in the insect odorant receptor complex results in the change in the electrical characteristic of the substrate (p. 3). Additionally, Kralicek more specifically teaches a control and indication arrangement configured to process the receptor-derived electrical characteristic and provide a detection signal. In particular, Kralicek discloses that the sensor further comprises an output system, wherein the indication system is configured to indicate that an analyte has been detected. Detection of an analyte may be indicated by any system known in the art, such as an alarm, an electrical signal, a graphical user interface or so forth. The indication system may also indicate the presence or absence of an analyte, the concentration of analyte, etc (p. 52). Also, Kralicek teaches that the sensor is capable of detecting in an environment the presence of an analyte that binds to the insect OrX in the insect odorant receptor complex (p. 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the Miller-Kralicek-Rothberg sensor chip as part of a sensing system comprising Miller’s chip-based reaction and sensing framework, Rothberg’s socket configured to receive and electrically couple the sensor chip, and Kralicek’s receptor-complex sensing and signal-processing arrangement configured to determine a binding-induced receptor state change and provide a detection signal indicative of the presence of the bioactive agent. Miller teaches an insertable or connectable chip architecture associated with sensors and controllers, Rothberg teaches a known removable socket interface for receiving and electrically coupling an analyte-sensing chip to associated apparatus, and Kralicek teaches that analyte binding induces a receptor conformational change that produces a measurable electrical characteristic and an indication that the analyte is present. A skilled artisan would have been motivated to combine these teachings to provide a removable receptor-based sensor chip operatively coupled to a sensing device capable of processing the receptor-derived signal and reporting analyte presence. A skilled artisan would have had a reasonable expectation of success because the references teach compatible mechanical, electrical, sensing, and signal-processing components whose combination would predictably provide the claimed sensing-system operation without altering the underlying receptor-based detection mechanism.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al., Kralicek et al., and Rothberg et al., as applied to claim 16 above, and further in view of Marmol et al. (The structural basis of odorant recognition in insect olfactory receptors. bioRxiv. Preprint. January 24, 2021).
With respect to the teachings of Miller et al., Kralicek et al, and Rothberg et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the receptor protein complexes are configured to change a position within the reaction cell upon binding to the one or more bioactive agents.
However, Marmol teaches the physical positional movement associated with odorant-induced conformational gating of an insect odorant receptor. Specifically, Marmol teaches that a comparison of the ion conduction pathways in the apo and eugenol-bound MhOR5 structures offers immediate insight into the conformational changes associated with gating. In the presence of eugenol, upon binding of the odorant eugenol, the extracellular aperture of the pore is dilated due to movement of the S7b helices away from the central pore axis (Fig. 2b-d; pp. 6-7), thereby demonstrating that at least part of the receptor changes position upon odorant binding. Marmol further teaches movement and rearrangement of receptor helices associated with channel gating, including that upon eugenol binding, these three helices move in concert away from the central axis of the channel and towards the binding pocket, a conformational change that displaces the S7b helices outward to gate the ion conduction pathway (p. 9), thereby providing structural evidence that odorant-induced conformational change involves physical movement of at least part of the receptor protein.
Additionally, Marmol establishes the structural relevance of MhOR5 to the OrX/Orco receptor complexes taught by Kralicek. Although MhOR5 and Orco have limited amino-acid sequence identity, Marmol teaches that the structures of these two receptors display striking similarity, both in the fold of each heptahelical subunit as well as in the tetrameric organization of the subunits within the membrane plane (p. 5, Extended Data Fig. 6). Marmol further discloses that the unique architecture of this receptor family can accommodate a high degree of sequence diversification while maintaining the same overall fold (p. 6), and identifies a conserved and critical role in gating and/or ion permeation across members of this receptor family for conserved pore features (p. 7). Also, Marmol further discloses that the striking
structural similarity of MhOR5 with Orco underscores how the architecture of this family is maintained
despite extensive sequence diversification. These observations support the proposal that MhORs lie at
the ancestral origin of the insect olfactory receptor family, from which the massive and divergent family
of Orco/OR heteromeric channels arose (p. 13). Thus, Marmol provides evidence that the ligand-induced helix movement observed in MhOR5 is relevant to the structurally conserved gating architecture of the insect odorant-receptor family, including the OrX/Orco receptor complexes taught by Kralicek, notwithstanding that MhOR5 is a homotetramer rather than the identical OrX/Orco heteromer.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention for the receptor protein complexes of the Miller-Kralicek-Rothberg sensor chip to exhibit a change in position of at least part of the receptor complex upon analyte binding, as taught by Marmol. Kralicek teaches that analyte binding to an OrX/Orco insect odorant receptor complex induces a conformational change, while Marmol demonstrates that odorant-induced conformational gating of a structurally related insect odorant receptor physically involves movement of receptor helices, including movement of the S7b helices away from the central pore axis. Marmol further teaches substantial structural conservation between MhOR5 and Orco in their heptahelical subunit folds, tetrameric membrane organization, and gating architecture. Accordingly, a skilled artisan would have understood that the binding-induced conformational change taught by Kralicek predictably involves movement of at least part of the receptor complex and would have reasonably expected that positional movement to occur within Miller’s reaction cell when the receptor complexes are incorporated therein. Rothberg’s removable socket interface merely provides mechanical and electrical coupling of the sensor chip and would not alter the receptor-based binding, conformational-change, or positional-movement mechanism of the modified sensing system.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al., Kralicek et al., and Rothberg et al., as applied to claim to claim 16 above, and further in view of Handique et al. (US 10857535 B2).
With respect to the teachings of Miller et al., Kralicek et al, and Rothberg et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the at least one reservoir is configured to supply de-ionized water to the reaction cell.
Miller teaches that the sensor chip further comprises at least one reservoir fluidly couplable with the reaction cell. In particular, Miller discloses that in certain other cases, material defining a boundary of the reaction site, such as not in fluidic contact with reaction site, but where the agents may be transported to or proximate the reaction site, for example, by creating at least one fluidic connection between a reservoir and a reaction site (p. 32). Miller further discloses that the chip may contain more than one type of reactor, reservoir, and/or agent (p. 32).
Handique teaches the missing de-ionized-water limitation in a biological microfluidic cartridge. Specifically, Handique discloses reagent reservoirs (R1, R3, and R4) that can be associated with corresponding channels, hydrophobic vents, and actuators within a microfluidic network, and that reagent reservoir R4 typically holds deionized water (Col. 50, p. 121; Figs. 14 and 15). Handique further teaches that, when a reservoir wall is punctured, fluid from the reservoir enters the microfluidic network through a port and travels along a channel. Thus, Handique teaches a reservoir containing de-ionized water and configured to supply the de-ionized water into a microfluidic fluid-delivery network.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the Miller-Kralicek-Rothberg sensor chip so that Miller’s fluidly coupled reservoir supplies de-ionized water to the reaction cell, as taught by Handique. Miller already teaches a chip-based reaction system having reservoir portions, channels, ports, inlets, outlets, and reaction sites for delivering fluids or other species to the reaction site, while Handique teaches a biological microfluidic cartridge having reservoir-channel fluid delivery in which an identified reagent reservoir contains de-ionized water and releases reservoir fluid into the microfluidic network. A skilled artisan would have been motivated to select de-ionized water as the fluid supplied by Miller’s existing reservoir architecture because Handique demonstrates that de-ionized water is a known reservoir-contained fluid suitable for delivery through a biological microfluidic cartridge. A skilled artisan would have had a reasonable expectation of success because implementing Handique’s de-ionized-water reservoir in Miller’s already-disclosed reservoir-and-channel architecture would involve the predictable use of a known reservoir-supplied fluid in a compatible chip-based fluid-delivery system, without changing the receptor-based sensing function supplied by Kralicek or the removable socket interface supplied by Rothberg.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Miller et al., Kralicek et al., and Rothberg et al., as applied to claim to claims 16 and 26 above, and further in view of Bundy et al. (US 2018/0136197 A1)
With respect to the teachings of Miller et al., Kralicek et al, and Rothberg et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the receptor protein is a xenosensor protein or a hormone receptor protein.
However, Bundy teaches the hormone receptor protein limitation. In particular, Bundy teaches that nuclear hormone receptors (NHRs) help regulate vital functions of the cells and organisms ([0005], p. 1), and that NHRs can interact with environmental endocrine disrupting chemicals (EDCs), which have become a public safety concern due to their ability to disrupt naturally occurring endocrine control ([0005], p. 1). These EDCs affect the endocrine system in humans and animals, commonly by mimicking natural hormones and binding to specific NHR ligand binding domains ([0005], p. 1). Bundy further teaches biosensor proteins including: a thyroid receptor beta biosensor protein of various embodiments having inactive amino- and carboxy- terminal intein splicing domains, a thyroid receptor beta ligand binding domain capable of binding to endocrine disrupting compounds, wherein the ligand-binding domain is linked to the inactive amino-terminal intein splicing domain on one end and to the inactive carboxy-terminal intein splicing domain on its other end ([0017], p. 2; FIGS. 2A-2B); and an estrogen receptor beta biosensor protein of various embodiments having inactive amino- and carboxy- terminal intein splicing domains, an estrogen receptor beta ligand-binding domain capable of binding to endocrine disrupting compounds, wherein the ligand-binding domain is linked to the inactive amino-terminal intein splicing domain on one end and to the inactive carboxy-terminal intein splicing domain on its other end ([0019], p. 2; FIGS. 4A-4B).
Additionally, Bundy discloses that the human estrogen receptor beta conformation changes upon interaction with human estrogen receptor beta - specific ligands, and that the conformation change transfers through the intein domain to the reporter enzyme (ß-lactamase) which then becomes active ([0158], p. 15; FIGS. 18A). Thus, Bundy expressly teaches ligand-responsive biosensor proteins comprising hormone-receptor ligand-binding domains that bind corresponding bioactive ligands and undergo ligand-induced conformational changes that produce a detectable biosensor response.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to further modify the Miller-Kralicek-Rothberg receptor-based sensor chip so that the receptor protein comprises a hormone receptor protein, as taught by Bundy. The Miller-Kralicek-Rothberg combination provides a chip-based receptor-sensing architecture for detecting bioactive agents through ligand binding and a detectable receptor-associated state change, while Bundy teaches biosensor proteins comprising nuclear hormone receptor ligand-binding domains, including thyroid receptor beta and estrogen receptor beta ligand-binding domains, for detecting bioactive ligands and nuclear hormone receptor modulators in biological or environmental samples. Bundy further teaches that ligand interaction with the hormone receptor protein causes a conformational change that activates the reporter enzyme and generates the detectable biosensor response. A skilled artisan seeking to configure the receptor-based sensor chip to detect hormone-related bioactive agents would have been motivated to use Bundy’s hormone-receptor ligand-binding domains because Bundy identifies those proteins as selective biological recognition components for such ligands and implements them in ligand-responsive biosensor proteins. A skilled artisan would have had a reasonable expectation of success because Bundy expressly demonstrates that the hormone receptor proteins retain their ligand-binding functionality and undergo ligand-induced conformational changes that produce a detectable biosensor response, while Miller supplies the chip and reaction-cell architecture, Kralicek establishes the suitability of receptor-based analyte recognition within the sensor platform, and Rothberg’s removable socket interface concerns only mechanical and electrical coupling and would not interfere with the hormone-receptor sensing mechanism.
Ultimately, claims 16-30 are rejected under 35 U.S.C. 103 as being unpatentable over the cited combinations of Miller, Kralicek, and Rothberg, and the respective additional references applied to the dependent claims. The cited prior art collectively teaches or suggests each claimed limitation, and one of ordinary skill in the art would have had reason to combine the teachings with a reasonable expectation of success.
Conclusion
No claims are allowable.
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 July 14, 2026
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