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 17-35 are pending and examined herein.
Priority
The present application, filed 02/21/2024 is a continuation of 16/471,552, filed 06/19/2019, which is a 371 of PCT/IB2017/058181, filed 12/20/2017, and claims foreign priority of NZ727745 and NZ727747, filed 12/21/2016.
Information Disclosure Statement
The information Disclosure Statement(s) filed 09/12/2024 are acknowledged and have been considered except for the following reference: “SATO et al. (2008) "Insect olfactory receptors are heteromeric ligand-gated ion channels," Nature, 152, 1002-1006.” The reference fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. The reference has been placed in the application file, but the information referred to therein has not been considered.
Specification
The disclosure is objected to because of the following informalities: The specification incorrectly identifies the subfigures of Figure 22 (lines 14-19, p. 21). It identifies the Or22a liposome response curve as Figure 22(C) and the Or71a liposome response curve as Figure 22(D). However, the drawings identify the Or22a liposome response curve as Figure 22(B) and the Or71a liposome response curve as Figure 22(C). Appropriate correction is required.
The disclosure is objected to because of the following informalities: The specification identifies the methyl hexanoate concentrations shown in Figure 23 as 1.6, 8, 40, and 200 M (lines 20-29, p. 21), whereas Figures 23(A)-23(D) identify those concentrations as 1.6, 8, 40, and 200 µM. The specification therefore omits the “µ” from “µM,” creating a unit discrepancy. Appropriate correction is required.
Claim Objections
Claim 23 is objected to because of the following informalities: Claim 23 recites “the sensor is capable of detecting binding of an analyte to the OrX subunit.” However, claim 17 introduces “a sensor device,” rather than “a sensor.” Although “the sensor” is reasonably understood to refer to the previously recited sensor device, the terminology should be made consistent. Applicant is requested to amend “the sensor” to “the sensor device.” Appropriate correction is required.
Claim 2 is objected to because of the following informalities: Claim 24 recites that the OrX subunit is capable of undergoing a conformational change “in response binding of an analyte.” The phrase is grammatically incomplete because the word “to” is omitted. Applicant is requested to amend the phrase to recite “in response to binding of an analyte.” 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 28, 29, and 34 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.
Claims 28 and 29 are indefinite because both claims recite the phrase “selected from, or composed of, at least one.” The phrase selected from reasonably indicates that the substrate itself is chosen as one or more members of the recited group. By contrast, the phrase composed of reasonably indicates that the substrate is formed from or contains one or more of the listed materials or components. Since the claims join these materially different relationships through the phrase or, it is unclear whether the substrate must itself be a listed item or whether the substrate need only contain or incorporate a listed item. Claim 28 presents additional uncertainty because the recited alternatives are heterogenous. An electrode and a resonator component are device structures, whereas CNTs, an oxide, doped silicon, and a conducting polymer may be materials forming part or all of a structure. It is therefore unclear what it means for a substrate to be “selected from” an electrode while alternatively being “composed of” an electrode, or to be “selected from” a resonator component while alternatively being “composed of” that component. Claim 29 presents the same defect. A “semiconductor material” is a broad material category, while graphene is a specific material that may itself function as a semiconductor. The combined phrase does not establish whether the substrate must be graphene, must be some other semiconductor material, may merely include graphene, or may be a larger structure containing a semiconductor material. Accordingly, a person of ordinary skill in the art would not be able to determine with reasonable certainty whether claims 28 and 29 require the substrate itself to be one or more listed members, require the substrate to be formed entirely from one or more listed members, or merely permit a larger substrate to contain one or more listed materials or components. Claims 28 and 29 therefore fail to particular point out and distinctly claim the subject matter regarded as the invention. For purposes of compact prosecution, the phrase selected from, or composed of, at least one of will be interpreted broadly and inclusively as meaning that the substrate comprises at least one of the listed materials or components. Under this interpretation, the substrate need not consist exclusively of the listed item, and additional unrecited substrate materials or components are not excluded. Applicant is required to amend claims 28 and 29 to state clearly whether the substrate itself is selected from the listed alternatives, consists of the listed alternatives, or merely comprises one or more listed materials or components. Appropriate correction is required.
Claim 34 recites that the change in the electrical characteristic of the substrate comprises a change in the source-gain current of a carbon nanotube-field effect transistor (CNT-FET). However, neither the claim nor the specification defines “source-gain current” or identifies a “gain” terminal, electrode, or current path in the disclosed CNT-FET. The specification instead describes a conventional CNT-FET having source, drain, and gate electrodes. In particular, the specification states that CNT-FET devices typically comprise a source electrode, a drain electrode, and a gate electrode (p. 26). The specification further explains that the gate electrode is used to control the current across the source and drain electrodes and that, when the gate electrode is on, current flow is able to be modulated across the source and drain electrodes through the channel (p. 26). The specification also expressly identifies the current measured by the CNT-FET sensor as the source-drain current, stating that the CNT-FET device may also include a component to measure changes in the source-drain current (p. 26). The specification does not identify a source-gain current as a distinct electrical parameter and does not disclose any “gain” electrode corresponding to such a current.
Although the phrase source-gain current appears elsewhere in the specification, including in connection with detecting a change in source-gain current (p. 13) and configuring the CNT-FET apparatus to detect a change in source-gain current (p. 15), those passages do not define the term or explain how a source-gain current differs from the expressly disclosed source-drain current. Rather, the disclosed CNT-FET structure consistently includes only source, drain, and gate electrodes, and the specification expressly describes current flowing between the source and drain. Accordingly, it is unclear whether “source-gain current” is intended to mean source-drain current, gate current, a gain-related electrical characteristic, or another current parameter. A person of ordinary skill in the art therefore would not be able to determine, with reasonable certainty, the particular electrical current whose change must be detected to satisfy claim 34. Claim 34 is therefore indefinite. For purposes of compact prosecution, the phrase source-gain current will be interpreted as an apparent typographical error intended to recite source-drain current. Applicant is required to amend claim 34 to clarify the intended current parameter. Appropriate correction is required.
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 17, 18, 21-26, 28-31, 34, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al. (US 2015/0065363 A1 – IDS dated 09/12/2024) and Carraher et al. (Recombinant Expression, Detergent Solubilisation and Purification of Insect Odorant Receptor Subunits. Protein Expression and Purification. Vol. 90, No. 2, August 2013 - IDS dated 09/12/2024).
Regarding claim 17, Johnson teaches biomimetic sensor devices that utilize proteins—such as G-protein coupled receptors— and are useful in high-sensitivity analysis of analyte-containing samples. These sensors may be used to determine the presence or concentration of one or more analytes in a sample. The invention also includes methods of fabricating the devices and methods of using the devices to assay samples. (Abstract, p. 1). In particular, Johnson teaches devices that include a semiconductor material and a transmembrane protein capable of changing conformation upon binding to a target, wherein the transmembrane protein is suitably in electrical communication with the semiconductor material ([0041], p. 31). Johnson further states that the devices suitably place the protein (e.g., GPCR) in electronic communication with the semiconducting material and that one way to facilitate such communication is to link the protein to the surface of the semiconducting material ([0048], p. 32). Johnson further teaches that a protein bearing a histidine tag may link or coordinate with nickel-nitrilotriacetic acid (Ni-NTA) present on a carbon nanotube ([0048], p. 32), and that the linkage places the two items in electronic communication with one another ([0057], p. 32).
Johnson experimentally implements this configuration using purified olfactory receptor proteins. Johnson teaches that recombinant mORs were expressed in Sf9 insect cells with an N-terminal His-tag to simplify the purification and guide the attachment to carbon nanotube devices and that target mORs were purified using a Ni-NTA resin ([0063], p. 33). Johnson also teaches that the sensor is configured to detect a change in an electrical characteristic of the substrate. Specifically, Johnson states that the electrodes in contact with the nanotubes permit application of current and monitoring of electronic characteristics of the device ([0069], p. 34). Johnson further teaches that the receptor-functionalized devices exhibited responses to gaseous odorants that do not cause a detectable conductivity change in bare NT devices, that the electrical responses were reproducible, and that the sign and magnitude of the electrical response was OR specific and a function of the odorant tested ([0058], p. 32). Additionally, Johnson expressly teaches that its disclosed sensor architecture is not limited to the mouse olfactory receptors. Johnson states that the claimed invention enables the use of virtually any protein (including transmembrane proteins) or other sensor molecule that may normally reside in a lipid or amphiphile ([0056], p. 32). Johnson further teaches that, although mouse-derived olfactory receptors were used in certain of the non-limiting, illustrative embodiments, the inventive devices and methods are applicable to virtually any membrane protein and a variety of other receptors ([0066], p. 33), and concludes that the process can be generalized to virtually any protein or other biological structure that normally resides in a lipid or amphiphilic environment ([0098], p. 36).
However, Johnson does not teach that the purified odorant receptor is an insect odorant receptor OrX subunit. Johnson’s working examples employ purified mouse olfactory receptors, including mOR174-9, mOR203-1, and mOR256-17.
Carraher teaches insect odorant receptor subunits and expressly identifies the ligand-binding subunit as OrX. Specifically, Carraher states that insect odorant receptors are seven transmembrane domain proteins that comprise a novel family of ligand-gated non-selective cation channels (Abstract, p. 160), and the insect odorant receptor complex comprises at least two subunits, one of which is the ubiquitous co-receptor, Orco, and a second that is a ligand-binding receptor subunit (OrX) (Introduction, p. 160). Carraher further teaches recombinant production and purification of an insect OrX, particularly Drosophila melanogaster DmOr22a. In particular, Carraher teaches that a large-scale purification protocol was then developed for DmOrco and the ligand-binding receptor, DmOr22a, and that the proteins were nickel-affinity purified using a deca-histidine tag in a buffer containing 0.2 mM Zwittergent 3–16, followed by size exclusion chromatography (Abstract, p. 160). Carraher further reports that DmOrco and DmOr22a were successfully purified from both expression systems in two steps, first by his-tag affinity chromatography, then by size exclusion chromatography (Results and Discussion, p. 167; Figs. 3 and 4).
Also, Carraher demonstrates that the purified insect OrX retained an organized structure in the detergent-supported state. Specifically, Carraher reports that DmOr22a was found to contain 79% α-helix, 3.2% β-sheets, 6% turns and the rest is predicted to be random coil and concludes that the CD measurements show a high degree of secondary structure suggesting both the DmOrco and DmOr22a subunits are folded correctly (Results and Discussion, p. 167; Fig. 5). Carraher further states that the purified DmOr22a fractions could be concentrated to 2 mg/mL with no change in the resulting SEC profile, indicating that the proteins were capable of being concentrated without aggregation (Results and Discussionp. 167). Lastly, Carraher expressly identifies biosensor incorporation as an intended downstream application, teaching that the ability to recombinantly express and purify insect ORs is a major step toward their use in OR based biosensors (Abstract, p. 160), and concluding that there is also the potential for these proteins to be incorporated into OR-based biosensors (Conclusion, p. 168).
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 Johnson’s purified-olfactory-receptor electronic sensor by using Carraher’s purified ligand-binding insect OrX subunit, such as DmOr22a, as the receptor protein placed in electrical communication with Johnson’s semiconductor substrate, thereby arriving at the sensor device of claim 17. The motivation arises directly from the references because Johnson expressly teaches that its electronic sensor platform is applicable to virtually any membrane protein and other receptor normally supported in a lipid or amphiphilic environment, while Carraher expressly teaches a purified ligand-binding insect OrX and identifies incorporation of purified insect odorant receptors into OR-based biosensors as a contemplated use. The modification would have applied Carraher’s known insect odorant-recognition component to Johnson’s known receptor-functionalized electronic sensing platform so as to obtain an electronic sensor having insect-receptor analyte-recognition characteristics. One of ordinary skill would have had a reasonable expectation of success because Johnson and Carraher use technically compatible approaches for producing and handling multispanning odorant receptors: both employ recombinant expression, polyhistidine-tagged receptors, nickel-based affinity purification, and detergent-supported stabilization. Accordingly, the proposed modification follows the express teaching and suggestion of the prior art, and additionally constitutes the combination of known elements using known membrane-protein stabilization and affinity-linkage methods to obtain the predictable result of a purified insect-OrX-containing electronic sensor.
Regarding claim 18, Johnson teaches that the transmembrane receptor may be present in a lipid membrane support, stating that the material in which the proteins are suitably disposed includes lipids, amphiphiles, or both and that lipid membranes are considered suitable, including lipid membranes disposed in so-called nanodiscs ([0045], p. 31). Johnson further teaches that the protein is suitably a membrane protein and the protein(s) are suitably disposed in a lipid, an amphiphile/surfactant, or both, and that the lipids and amphiphiles may be in layer or membrane form ([0051], p. 32). Johnson also describes nanodiscs as engineered, self-assembling, disk-shaped protein-lipid particles with well-controlled size and composition ([0065], p.33; Fig. 17).
Regarding claim 21, Johnson states that integration of ORs with carbon nanotube transistors is of particular interest because carbon nanotube transistors exhibit high sensitivity and are compatible with dense arraying ([0038], p. 31). Johnson further teaches the successful integration of exemplary protein receptors with read out electronics based on carbon nanotube (NT) transistors ([0039], p. 31). Johnson also identifies a diagram of a carbon nanotube transistor functionalized with micelle solubilized ORs ([0012], p. 29; Fig. 1(c)). Johnson attaches olfactory receptors directly to this carbon nanotube transistor architecture, teaching that solubilized olfactory receptors (ORs) were attached via a polyhistidine tag (His-tag) to nanotube transistors that were functionalized with nickel-nitrilotriacetic acid (Ni-NTA) ([0058], p. 32). Johnson further reports that the mORs were attached to the nanotube transistors, yielding functional vapor sensors ([0064], p. 33).
Regarding claims 22 and 23, Johnson expressly teaches this limitation. Johnson discloses a sensor system including a detector device capable of detecting changes in one or more electronic characteristics of the protein related to an interaction between the protein and an analyte ([0050], p. 32). Johnson further teaches that the transmembrane protein suitably interacts—e.g., by binding or complexing with an analyte (such as an odorant) in the sample and that the change in conformation may affect an electronic property of the protein-semiconductor device, and the change in electronic property may then be monitored or recorded ([0076], p. 34). Johnson also states that interactions between the analytes and the receptors will result in changes in an electronic characteristic of the device (such as conductivity) ([0080], p. 34). Johnson additionally reports that the devices transduce signals associated with odorant binding to ORs in the gas phase under ambient conditions ([0185], p. 43).
Regarding claim 24, Johnson discloses a sensor comprising a transmembrane protein capable of changing conformation upon binding to a target, wherein the transmembrane protein is suitably disposed in a support material capable of maintaining the protein in essentially its natural conformation, and the protein is suitably in electrical communication with the semiconductor material. ([0041], p. 31). Johnson further teaches that the protein itself changes conformation upon interaction with a complementary analyte and that this change in conformation results in a change in an electronic property of the device that may then be detected ([0042], p. 31).
Regarding claims 25 and 26, Johnson teaches that olfactory receptors may be solubilized using detergent micelles of digitonin or stable, water-soluble, self-assembling nanoscale membrane assemblies known as nanodiscs ([0040], p. 31). Johnson further teaches that the material in which the proteins are suitably disposed includes lipids, amphiphiles, or both, that lipid membranes are considered suitable, including lipid membranes disposed in so-called nanodiscs, and that micelles, such as those made from digitonin, are also suitable ([0045], p. 31). Johnson additionally describes a device in which GPCRs are disposed within amphiphile-made micelles, in which micelles maintain the GPCRs in their natural conformation ([0049], p.32). Johnson’s working embodiments further confirm use of a membrane mimic. Johnson teaches that digitonin forms micelles that serve as temporary surrogate cell membranes, in which individual membrane proteins are embedded ([0064], p. 33).
Regarding claims 28 and 29, Johnson expressly teaches several of the recited alternatives. Johnson teaches that the semiconductor material is suitably a carbon nanotube, graphene, silicon carbide, or any combination thereof and that other semiconducting materials, such as oxides, doped silicon, and the like are suitable ([0043], p. 31).
Regarding claim 30, Johnson expressly teaches several of the recited alternatives. Johnson teaches that interaction of the protein with a complementary analyte may produce a change in an electronic property of the device (e.g., conductivity) that may be detected and correlated with the presence of the analyte ([0042], p. 31). Johnson further teaches that its olfactory-receptor-functionalized nanotube devices exhibited odorant responses that did not occur in bare nanotube devices, including a detectable conductivity change, and that the electrical responses were receptor-specific and dependent on the odorant tested ([0058], p. 32). Johnson also expressly teaches resistance-based detection. Johnson reports that the DC resistance in the hole conduction regime was then monitored during exposure to odorant-containing gas flows and that the measured response is seen as a change in DC resistance ([0081], p. 35). Johnson additionally teaches current-based detection. Specifically, Johnson reports an analyte-induced increase in the device current ([0083], p. 35; Fig. 2).
Regarding claim 31, refer to the discussion above. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Johnson’s method of detecting an analyte by substituting Carraher’s purified insect ligand-binding OrX subunit for Johnson’s purified mammalian olfactory receptor and then contacting the resulting sensor with an analyte, permitting the analyte to bind the OrX, and detecting the resulting change in the substrate’s electrical characteristic. Johnson expressly teaches using receptor–analyte binding to produce an electronic readout and broadly states that its devices are applicable to virtually any membrane protein ([0056], p. 4; [0066], p. 5), while Carraher identifies purified OrX as the ligand-binding insect receptor subunit and expressly proposes its use in OR-based biosensors. One of ordinary skill would have had a reasonable expectation of success because Carraher demonstrates successful purification and correct folding of DmOr22a, and Johnson demonstrates that purified, membrane-supported olfactory receptors retain analyte-binding properties when electronically coupled to a semiconductor and generate measurable receptor-dependent changes in conductivity, resistance, or current.
Regarding claim 34, Johnson discloses three-terminal transistor circuits were fabricated from carbon nanotubes and teaches that device current-gate Voltage (I-V) characteristics at source-drain bias voltage VB = 100 mV were measured ([0067], p. 33). Johnson additionally teaches monitoring current through the CNT-FET at a fixed source-drain voltage. Johnson states that current-gate voltage (I-V) characteristics taken for a fixed source-drain Voltage VB were used to monitor the effect of chemical functionalization on nanotube transistors ([0070], p. 34). Johnson further reports a large positive sensing response to eugenol (i.e., increase in the device current) ([0083], p. 35; Fig. 2), and presents sensing data as a percent change from the baseline current (% ΔI/I) ([0084], p. 35).
Regarding claim 35, refer to the discussion above. Johnson provides methods of assembling a sensor that include placing a transmembrane protein disposed in a lipid, an amphiphile, or both, into electronic communication with a semiconductor material ([0007], p. 29). Johnson also teaches that the manufactured sensor is configured to detect a change in an electrical characteristic of the substrate. Johnson discloses a detector device capable of detecting changes in one or more electronic characteristics of the protein related to an interaction between the protein and an analyte. ([0050], p. 4). However, Johnson does not teach that the purified receptor used in the manufacturing method is specifically an insect odorant receptor OrX subunit. Carraher teaches insect odorant receptor subunits and expressly identifies the ligand-binding subunit as OrX.
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 Johnson’s method of manufacturing an olfactory-receptor sensor by using Carraher’s purified, His-tagged insect ligand-binding OrX subunit as the transmembrane receptor attached to Johnson’s functionalized semiconductor substrate. Johnson expressly teaches establishing electronic communication between a purified, His-tagged olfactory receptor and a semiconductor through complementary Ni-NTA linkage chemistry and teaches that the resulting device detects analyte-responsive electrical changes, while Carraher supplies a purified, correctly folded, His-tagged insect OrX and expressly proposes use of such proteins in OR-based biosensors. One of ordinary skill would have had a reasonable expectation of success because both references employ compatible recombinant-expression, detergent-solubilization, purification, and histidine-tag technologies, and Johnson demonstrates that the same class of purified membrane receptor can be immobilized on a semiconductor while retaining analyte-responsive electronic sensing capability.
Claims 19 and 32 are rejected as being unpatentable over Johnson et al. and Carraher et al., as applied to claims 17 and 31 above, and further in view of Benilova et al. (Electrochemical Study of Human Olfactory Receptor OR 17–40 Stimulation by Odorants in Solution. Materials Science & Engineering C. Vol. 28, No. 5, July 2008).
With respect to the teachings of Johnson and Carraher, see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the sensor device is an electrochemical impedance spectroscopy (EIS) sensor device (claim 19), nor the change in an electrical characteristic of the substrate comprises a change in an electrochemical impedance in a working electrode (claim 32).
Benilova discloses that human olfactory receptor OR 17–40 co-expressed with α-subunit of Golf protein in yeast was attempted as a bio recognition part of impedimetric biosensor, that the receptor in its natural membrane environment was anchored to a gold-coated glass substrate modified with thiol based multilayer, and that stimulation of the OR 17–40 with its cognate odorant helional in phosphate-buffered saline was probed by means of electrochemical impedance spectroscopy (Abstract, p. 633). Benilova further teaches that, after receptor immobilization, the chip was transferred into a three-electrode electrochemical glass cell, that the EIS measurements were performed with an impedance spectrometer Voltalab 40, and that the biofunctionalized chip constituted the working electrode (Materials and Methods, p. 635). Benilova expressly states that after the OR-containing biofilm formation, the SPR chip was employed as the working electrode in the electrochemical cell, and that the receptor-containing biofilm exhibited rather high complex impedance (Results and Discussion, p. 636). Lastly, Benilova establishes analyte-responsive impedance detection. Benilova teaches that the impedance spectrum was registered immediately after ligand injection, that receptor-free control films exposed to the odorants produced insignificant variation of total impedance, and that the Rp shift was taken as a reporter of the OR 17-40 activity, i.e. as the sensor signal (Results and discussion, p. 637).
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 the Johnson-Carraher purified insect OrX sensor and analyte detection method by employing Benilova’s olfactory-receptor-based EIS architecture, including placing the receptor-containing recognition layer in electrical communication with a conductive working electrode and detecting analyte interaction as a change in electrochemical impedance. Benilova itself provides the teaching, suggestion, and motivation for this modification by demonstrating that an olfactory receptor retained in a membrane environment can be anchored to a gold-coated substrate, used as the bio-recognition element of an impedimetric sensor, and interrogated by EIS upon exposure to its cognate odorant. The modification would have predictably provided a label-free electrical readout of OrX-analyte interaction. One of ordinary skill would have had a reasonable expectation of success because Benilova experimentally demonstrates the same operative sequence- immobilizing a membrane bound-olfactory receptor on a biofunctionalized working electrode, exposing the receptor a to a cognate odorant, and detecting the resulting receptor-dependent impedance response-while Johnson and Carraher provide the compatible purified, membrane-stabilized insect OrX recognition element and sensor framework.
Claims 20 and 33 are rejected as being unpatentable over Johnson et al. and Carraher et al., as applied to claims 17 and 31 above, and further in view of Sung et al. (Piezoelectric Biosensor Using Olfactory Receptor Protein Expressed in Escherichia Coli. Biosensors & Bioelectronics. Vol. 21, No. 10, April 2006).
With respect to the teachings of Johnson and Carraher, see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the sensor device is a quartz crystal microbalance (QCM) sensor device (claim 20), nor the change in an electrical characteristic of the substrate comprises a change in an oscillation frequency of a resonator component (claim 33).
Sung discloses that the surface of a quartz crystal microbalance (QCM) was coated with crude membrane extracts, containing the expressed receptor protein, and the interaction between the olfactory receptor and various odorant molecules examined, and that various concentrations of diacetyl were applied to the expressed ODR-10 receptor, and the response of the QCM showed a linear relationship to the logarithmic value of the odorant concentration (Abstract, p. 1981). Sung further teaches that QCM was used to detect the binding of odorants with the olfactory receptor expressed on the E. coli membrane (Introduction, p. 1982), that the QCM included a detection chamber, oscillator and a computer to detect the frequency change (Materials and Methods, p. 1982), and that after the membrane fraction had been coated, the resonant frequency was measured, and the frequency change while applying the odorants was denoted by Fodr (Materials and methods, p. 1983). Sung experimentally confirms that the receptor-containing QCM produced a larger resonant frequency change in response to the receptor’s ligand and that the frequency change increased with increasing diacetyl concentration (Materials and Methods, p. 1984-1985).
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 the Johnson-Carraher purified insect OrX sensor and analyte detection method by applying the receptor-containing recognition material to Sung’s quartz-crystal resonator and detecting OrX-analyte binding as a change in the resonant oscillation frequency. Sung expressly provides the teaching, suggestion, and motivation for this modification by identifying the olfactory receptor as the primary biorecognition element, the QCM as the secondary transducer for detecting odorant binding, and the measured resonant-frequency change as the sensor response. The modification would have provided a known, label-free means for transducing receptor-analyte interaction into a measurable electrical characteristic while preserving the analyte-recognition function of the OrX subunit taught by Carraher. One of ordinary skill would have had a reasonable expectation of success because Sung experimentally demonstrates that membrane-associated olfactory receptors can be coated onto a QCM, retain ligand-responsive activity, and produce specific and concentration-dependent changes in resonant frequency, while Johnson and Carraher provide the compatible purified, membrane-stabilzied insect OrX recognition element for incorporation into that known QCM sensor architecture.
Claim 27 is rejected as being unpatentable over Johnson et al. and Carraher et al., as applied to claims 17 and 23 above, and further in view of Hong et al. (US 8377706 B2).
With respect to the teachings of Johnson and Carraher, see the discussion above, which applies equally here. These references differ from the instant claims in failing to expressly teach or specify that the sensor device can detect the presence of the analyte at a concentration of less than 1x10-3 M.
Hong discloses an olfactory receptor functionalized carbon-nanotube transistor in which the source-drain current was monitored after the introduction of a solution containing specific odorants while maintaining a bias voltage of 100 mV (Example 3, p. 14; Fig. 8). Hong further teaches that FIG. 10 shows a time dependence of the source-drain current of the biosensor after the introduction of amyl butyrate (AB) at various concentrations such as 100 fM, 1 pM, 10 pM, and 100 pM, and that the detection of solutions at 100 fM was enabled (Example 3, p. 14; Fig. 10). Thus, Hong expressly demonstrates olfactory-receptor-based electrical detection at molar concentrations substantially below the claimed upper limit.
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 the Johnson–Carraher purified insect OrX sensor by operating it to detect analytes within the low-concentration ranges expressly demonstrated by Hong, including concentrations below 1x10-3 M. Hong provides an express teaching, suggestion, and motivation for the modification by demonstrating that an olfactory receptor incorporated into a membrane and coupled to a carbon-nanotube transistor can selectively detect its cognate odorant through changes in source-drain current at concentrations as low as 100 fM. The modification would have predictably enabled operation of the Johnson–Carraher sensor within a known low-concentration detection range for sensitive odorant. One of ordinary skill would have had a reasonable expectation of success because Hong experimentally demonstrates the same operative sequence—odorant binding to a membrane-associated olfactory receptor followed by a measurable electrical response in a carbon-nanotube transistor—at expressly stated molar concentrations far below the claimed threshold, while Carraher provides a purified insect OrX suitable for incorporation into receptor-based biosensors.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 17, 18, 21-31, 34, and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12,044,651 B2.
Although the claims at issue are not identical, they are not patentably distinct from each other because patented claim 1 teaches a sensor device comprising a purified insect odorant receptor OrX subunit in electrical communication with a substrate configured to detect a change in an electrical characteristic of the substrate, corresponding to instant claim 17. Patented claims 2-9 further teach the various dependent limitations recited in instant claims 18 and 21-30, including analyte binding to the OrX subunit, detection based upon changes in electrical characteristics, membrane mimics, substrate selections, electrical characteristics, and analyte detection at concentrations less than 1×10⁻³ M. Patented claims 10-12 likewise teach corresponding analyte detection methods and methods of manufacturing the sensor device, rendering instant claims 31, 34, and 35 patentably indistinct. Any differences between the instant claims and the patented claims constitute no more than obvious variations that would have been within the level of ordinary skill in the art at the time of the invention and therefore do not render the instant claims patentably distinct.
Claims 19 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 12,044,651 B2 in view of Benilova et al.
The patented claims teach the purified insect odorant receptor OrX sensor device and corresponding analyte detection method but do not expressly disclose that the sensor device is an electrochemical impedance spectroscopy (EIS) sensor device or that analyte detection is performed by monitoring a change in electrochemical impedance. Benilova teaches the use of electrochemical impedance spectroscopy for receptor-based biosensing. 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 the patented OrX sensor device and corresponding detection method by employing the known electrochemical impedance spectroscopy detection technique taught by Benilova to monitor analyte binding through changes in electrochemical impedance. The modification merely applies a known electrical transduction technique to the patented receptor-recognition platform for its established purpose and would have predictably yielded impedance-based detection while preserving the receptor-binding functionality of the patented device. Accordingly, claims 19 and 32 are not patentably distinct from the patented claims.
Claims 20 and 33 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 12,044,651 B2 in view of Sung et al.
The patented claims teach the purified insect odorant receptor OrX sensor device and corresponding analyte detection method but do not expressly disclose that the sensor device is a quartz crystal microbalance (QCM) sensor device or that analyte detection is performed by monitoring a change in the oscillation frequency of a resonator component. Sung teaches receptor-based quartz crystal microbalance biosensors in which analyte binding is detected by monitoring changes in resonant frequency. 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 the patented OrX sensor device and corresponding detection method by incorporating the known quartz crystal microbalance detection architecture taught by Sung to detect analyte binding through changes in resonant frequency. The modification merely substitutes one known electrical transduction mechanism for another while preserving the patented receptor-recognition system and would have predictably produced the expected electrical response to analyte binding. Accordingly, claims 20 and 33 are not patentably distinct from the patented claims.
Claims 17-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 -11 of U.S. Patent No. 12,663,419 B2 in view of Johnson et al., Carraher et al., Benilova et al., and Sung et al.
The patented claims are directed to a sensor device comprising an insect odorant receptor complex comprising an OrX and an Orco in electrical communication with a substrate, wherein the sensor device detects analyte binding by monitoring a change in an electrical characteristic of the substrate, as well as corresponding methods of analyte detection and manufacture. The instant claims are directed to substantially the same subject matter, namely receptor-based biosensors employing an insect odorant receptor in electrical communication with a substrate to detect analyte binding through changes in an electrical characteristic. However, the instant claims recite a purified insect odorant receptor OrX subunit rather than the OrX/Orco receptor complex recited in the patented claims.
As discussed in the rejection under 35 U.S.C. § 103, Johnson and Carraher teach purification, stabilization, and incorporation of purified insect OrX receptor subunits into electrically coupled biosensor platforms. Those teachings demonstrate that purified OrX subunits were recognized in the art as suitable receptor-recognition elements for receptor-based biosensors. Accordingly, it would have been obvious to one of ordinary skill in the art to modify the biosensor of the patented claims by employing the known purified OrX subunit configuration taught by Johnson and Carraher in place of the OrX/Orco receptor complex, with the predictable result of maintaining analyte-recognition functionality while utilizing a simplified receptor architecture. Such a modification merely substitutes one known receptor configuration for another in the same biosensor environment and therefore does not render the instant claims patentably distinct from the patented claims.
More specifically, claims 17, 18, 21–26, 27, 28–31, 34, and 35 are not patentably distinct from patented claims 1–11 because the only material distinction is the omission of the Orco co-receptor from the receptor complex. As discussed above, Johnson and Carraher teach that purified insect OrX subunits were known and suitable for receptor-based biosensors, rendering this modification an obvious variation of the patented invention.
With respect to claims 19 and 32, the patented claims do not expressly recite an electrochemical impedance spectroscopy (EIS) sensor or impedance-based detection. However, Benilova teaches receptor-based biosensors utilizing electrochemical impedance spectroscopy for analyte detection. It would therefore have been obvious to incorporate the known EIS detection technique into the patented biosensor to achieve the predictable result of impedance-based electrical detection while preserving the patented receptor-based sensing mechanism.
With respect to claims 20 and 33, the patented claims do not expressly teach a quartz crystal microbalance (QCM) sensor or resonance-frequency detection. Sung teaches receptor-based quartz crystal microbalance biosensors in which analyte binding is detected by monitoring changes in oscillation frequency. Accordingly, it would have been obvious to employ the known QCM transduction platform in the patented biosensor to obtain the predictable benefit of resonance-frequency-based analyte detection.
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 August 3, 2026
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