DETAILED ACTION
Response to Amendment
This is a final office action in response to a communication filed on April 15, 2026. Claims 1-2, 4, 10-19, and 21-25 are pending in the application.
Status of Objections and Rejections
The rejection of claims 3, 5-9, and 20 is obviated by Applicant' s cancellation.
All rejections from the previous office action are withdrawn in view of Applicant’s amendment. New grounds of rejection are necessitated by the amendments.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-2, 4, 13, 15-19 and 21-22 is/are rejected under 35 U.S.C. §103 as being unpatentable over Hellinga (US 2003/0129622) in view of Pickup (US 2012/0232251).
Regarding claim 1, Hellinga teaches a sensor (¶26: biosensor) configured to detect a glucose concentration (¶26: to monitor fluctuations in blood glucose; further, this limitation is a statement with regard to the intended use and are not further limiting in so far as the structure of the product is concerned. In article claims, a claimed intended use must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. MPEP § 2111.02(II)), the sensor comprising:
a glucose binding protein (Fig. 1B; ¶8: glucose binding protein (GBP)) configured to have a first conformation and a second conformation, wherein the glucose binding protein is in the first conformation when there is a glucose bound to a glucose binding site of the glucose binding protein, and the glucose binding protein is in the second conformation when there is no glucose bound to the glucose binding site of the glucose binding protein (¶21: the protein undergoes a conformational change upon binding to a ligand (analyte),e.g., glucose-binding protein),
wherein an electric signal is generated when the glucose binding protein is in the first conformation (Fig. 2; ¶9: upon ligand binding, the changes in the protein conformation, from open to closed, alter the interaction between the cofactor and electrode surface; claim 1: a change in the interaction between said redox reporter and said electrode is detectable potentiometrically or amperometrically), and
a sensing electrode (Fig. 2; ¶9: gold electrode) configured to sense the electric signal (claim 1: a change in the interaction between said redox reporter and said electrode is detectable potentiometrically or amperometrically; further, this limitation is functional limitation in apparatus claims. MPEP 2114 (II). It does not differentiate the claimed apparatus from a prior art apparatus because the prior art apparatus teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987)).
Hellinga further discloses L255C-GBP has the Kd(glucose) is 2.0 µM or 0.4 µM, and fails to disclose wherein the glucose binding protein has a binding constant between about 2 mM to about 22 mM.
However, Pickup teaches a glucose sensor based on the bacterial glucose/galactose binding protein (GBP) (¶1), which undergoes a marked conformational change on binding glucose (¶6). The disclosed synthesized mutant protein based on engineered GBP that has a binding constant (Kd) of approximately 11 mM is thus suitable for measurement of glucose in the pathophysiological range, for example for use in the monitoring of glucose in human diabetes mellitus (¶53), which lies in the claimed range.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hellinga by adjusting the binding constant of the glucose binding protein within the claimed range because it represents a suitable range for the binding constant of GBP to measure glucose by biosensors. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). MPEP 2144.05(I). Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). MPEP 2144.05(I).
Regarding claim 2, Hellinga teaches a redox mediator (Fig. 2; ¶5: redox reporter; ¶8: Ru(II) redox cofactor) configured to create the electrical signal (¶9),
wherein
the redox mediator is not active or partially active when the glucose binding protein (Fig. 1B; ¶8: glucose binding protein GBP) is in the first conformation (since the binding of the analyte to the binding protein would alter the interaction between the redox mediator and the electrode surface for generating the electrical signal, the first conformation of the binding protein, i.e., with bound analyte, would be deemed less active because it would not generate more electrical signal),
the redox mediator is active or relatively more active in comparison to the first conformation when the glucose binding protein (Fig. 1B; ¶8: glucose binding protein GBP) is in the second conformation (since the binding of the analyte to the binding protein would alter the interaction between the redox mediator and the electrode surface for generating the electrical signal, the second conformation of the binding protein, i.e., without bound analyte, would be deemed more active because it would generate the electrical signal upon binding of the analyte).
Regarding claim 4, Hellinga teaches wherein the redox mediator is a Ru(II) cofactor (Fig. 2; ¶8: Ru(II) redox cofactor).
Regarding claim 13, Hellinga teaches a method of measuring a concentration of an analyte (¶2), comprising:
exposing the sensor of claim 1 (as described in claim 1) to a sample fluid (¶26: the blood stream); and
measuring an electrical signal generated from the sensor (¶18: a means for measuring a voltage or current generated by interaction between the reporter and the electrode).
Regarding claim 15, Hellinga teaches wherein the analyte comprises glucose (¶26: glucose).
Regarding claim 16, Hellinga teaches wherein the binding protein comprises a glucose binding protein (Fig. 1B; ¶8: glucose binding protein GBP).
Regarding claim 17, Hellinga teaches wherein the binding site comprises a glucose binding site (Fig. 1B: GBP; ¶21; GBP must have a glucose binding site).
Regarding claim 18, Hellinga teaches wherein the electrical signal is generated by a redox mediator (¶9: upon ligand binding, the changes in the protein conformation, from open to closed, alter the interaction between the cofactor and electrode surface, and therefore the observed current flowing between these two component).
Regarding claim 19, Hellinga teaches wherein
the redox mediator is not active or partially active when the binding protein is in the first conformation (since the binding of the analyte to the binding protein would alter the interaction between the redox mediator and the electrode surface for generating the electrical signal, the first conformation of the binding protein, i.e., with bound analyte, would be deemed less active because it would not generate more electrical signal), and
the redox mediator is active or relatively more active in comparison to the first conformation when the binding protein is in the second conformation (since the binding of the analyte to the binding protein would alter the interaction between the redox mediator and the electrode surface for generating the electrical signal, the second conformation of the binding protein, i.e., without bound analyte, would be deemed more active because it would generate the electrical signal upon binding of the analyte).
Regarding claims 21-22, Hellinga and Pickup teaches all limitations of claim 1. Hellinga does not disclose wherein the glucose binding protein comprises an E. coli glucose binding protein wherein at least one of the 16 amino acids of the glucose binding site of the E. coli glucose binding protein are different with respect to a wild-type E. coli glucose binding protein (claim 21) or wherein the E. coli glucose binding protein comprises an arginine (R) at the 213 position (claim 22).
However, Pickup teaches a preferred GBP having three mutations (H152, A213 and L238) (¶35), wherein position A213 is R (¶32), and the numbering is taken with reference to the wild type E. coli amino acid sequence (¶66). Thus, Pickup teaches the GBP is from E. coli (wild-type), as disclosed in the specification (PGpub ¶53), and thus the GBP from E. coli must have 16 amino acids of the glucose binding site and 213 position is one of them. Pickup further discloses a mutated GBP having a suitable R at position 213 (¶32).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hellinga by substituting the GBP with the mutated one having an arginine (R) at the 213 position because the mutated GPB would be helpful and desired in application of glucose sensing (¶132), which is related to a fluorescence intensity- and life-time glucose sensing system (¶131) and making the system more stable and accurate (¶134). Here, the fact that the mutated GGBP having an arginine at the 213 position is a suitable material for a glucose binding protein to detect glucose and the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art. MPEP § 2144.07.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hellinga in view of Lakowicz (US 6,197,534).
Regarding claim 10, Hellinga teaches a sensor (¶26: biosensor) for sensing a concentration of an analyte (¶26: to monitor fluctuations in analyte), the sensor comprising:
a first binding protein (Fig. 1; ¶21: protein which has a nature to be used dependent upon the analyte to be detected) configured to bind the analyte, the first binding protein having a first conformation and a second conformation, wherein the first binding protein is in the first conformation when the analyte is bound to a binding site of the first binding protein, and the first binding protein is in the second conformation when there is no analyte bound to the binding site of the first binding protein (¶21: the protein undergoes a conformational change upon binding to a ligand (analyte)), wherein a first electric signal is generated when the first binding protein is in the first conformation (Fig. 2; ¶9: upon ligand binding, the changes in the protein conformation, from open to closed, alter the interaction between the cofactor and electrode surface; claim 1: a change in the interaction between said redox reporter and said electrode is detectable potentiometrically or amperometrically); and
a sensing electrode (Fig. 2; ¶9: gold electrode) configured to sense the first and second electric signals (claim 1: a change in the interaction between said redox reporter and said electrode is detectable potentiometrically or amperometrically; further, this limitation is functional limitation in apparatus claims. MPEP 2114 (II). It does not differentiate the claimed apparatus from a prior art apparatus because the prior art apparatus teaches all the structural limitations of the claim. Ex parte Masham, 2 USPQ2d 1647 (Bd. Pat. App. & Inter. 1987)).
Hellinga does not disclose a second binding protein configured to bind the analyte, the second binding protein having a first conformation and a second conformation, wherein the second binding protein is in the first conformation when the analyte is bound to a binding site of the second binding protein, and the second binding protein is in the second conformation when there is no analyte bound to the binding site of the second binding protein, wherein a second electric signal is generated when the second binding protein is in the first conformation, and wherein the first binding protein and the second binding protein do not have the same binding constant to the analyte.
However, Lakowicz teaches determination of the presence or concentration of an analyte (col. 1, ll. 18-19), e.g., for glucose monitoring (col. 1, l. 64), using a genetically engineered protein for sit-specific positioning of allosteric signal transducing molecules (col. 1, l. 66 to col. 2, l. 1). The glucose/galactose binding protein (GGBP) is Escherichia coli GGBP (col. 2, ll. 5-6). The protein may be modified in order to adjust its binding constant with respect to the analyte (col. 4, ll. 47-48), and glucose sensors using more than one protein, i.e., multiple sensing molecules with a range of glucose binding constant, would provide accurate measurements over a wide range of glucose concentrations (col. 6, ll. 46-50).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hellinga by incorporating a second binding protein, e.g., a modified protein having different binding constants, as taught by Lakowicz because GGBPs having different binding constants would provide accurate measurements over a wide range of glucose concentrations (col. 6, ll. 46-50). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Regarding claim 23, Hellinga teaches wherein the analyte is glucose (¶26: to monitor fluctuations in blood glucose).
Claim(s) 11-12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hellinga in view of Pickup, and further in view of Shi (Q. Shi, Kinetically controlled synthesis of AuPt bi-metallic aerogels and their enhanced electrocatalytic performances, J. Mater. Chem. A, 2017(5), pp. 19626-31).
Regarding claims 11-12 and 14, Hellinga and Pickup discloses all limitations of claims 1 and 13, respectively. Hellinga and Pickup fail to teach wherein the sensing electrode comprises a nanowire network (claim 11) or the sensing electrode comprising a hydrogel (claim 12) or wherein measuring the electrical signal comprises using an electrode comprising a nanowire network (claim 14).
However, Shi teaches metallic hydrogels/aerogels have ultra-low density, profuse, porosity, and extra-large surface area combined with metals of excellent conductivity and catalytic performances (p. 19626, col. 1, para. 1), and thus result in remarkably enhanced electrochemical performances (p. 19626, col. 2, para. 1). Shi synthesizes AuPt5 metallic hydrogels having a 3D self-supported architectures from the macro-scope with typical jelly-like features, which indicate high electrochemical activities due to numerous open channels for mass diffusion and access to the inner active sites of the catalyst (p. 19629: Scheme 1; Fig. 1C; p. 19627, col. 1, para. 3). The detailed composition distribution of the nanowires was confirmed by HAADF-STEM-EDS mapping images, and the nanowires were composed of elements Pt and Au (Fig. (G-I), p. 19627, col. 1, para. 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hellinga and Pickup by incorporating a metallic hydrogel of nanowires into the sensing electrode as taught by Shi because the synthesizes AuPt5 metallic hydrogels have numerous open channels for mass diffusion and access to the inner active sites of the catalyst and thus result in high electrochemical activities (Fig. 1; p. 19627, col. 1, para. 3). Here, the claimed limitations are obvious because all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results. MPEP 2143(I)(A).
Claim(s) 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hellinga in view of Lakowicz, and further in view of Pickup.
Regarding claims 24-25, Hellinga and Lakowicz teaches all limitations of claim 23. Hellinga and Lakowicz do not disclose wherein the glucose binding protein comprises an E. coli glucose binding protein wherein at least one of the 16 amino acids of the glucose binding site of the E. coli glucose binding protein are different with respect to a wild-type E. coli glucose binding protein (claim 24) or wherein the E. coli glucose binding protein comprises an arginine (R) at the 213 position (claim 25).
However, Pickup teaches a preferred GBP having three mutations (H152, A213 and L238) (¶35), wherein position A213 is R (¶32), and the numbering is taken with reference to the wild type E. coli amino acid sequence (¶66). Thus, Pickup teaches the GBP is from E. coli (wild-type), as disclosed in the specification (PGpub ¶53), and thus the GBP from E. coli must have 16 amino acids of the glucose binding site and 213 position is one of them. Pickup further discloses a mutated GBP having a suitable R at position 213 (¶32).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Hellinga and Lakowicz by substituting the GBP with the mutated one having an arginine (R) at the 213 position because the mutated GPB would be helpful and desired in application of glucose sensing (¶132), which is related to a fluorescence intensity- and life-time glucose sensing system (¶131) and making the system more stable and accurate (¶134). Here, the fact that the mutated GGBP having an arginine at the 213 position is a suitable material for a glucose binding protein to detect glucose and the selection of a known material, which is based upon its suitability for the intended use, is within the ambit of one of ordinary skill in the art. MPEP § 2144.07.
Response to Arguments
Applicant’s arguments have been considered but are unpersuasive in light of new grounds for rejection because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Hsieh (US 2005/0014290) teaches a mutated GPB having a composition with at least two amino acid substitutions, e.g., a cysteine at position 149 and an arginine at position 213 (¶18), for glucose sensing.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAITLYN M SUN whose telephone number is (571)272-6788. The examiner can normally be reached M-F: 8:30am - 5:30pm.
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/C. SUN/Primary Examiner, Art Unit 1795
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