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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August has been entered.
Election/Restrictions
Newly submitted claims 26-27 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
I. Claims 1-2, 4, 10-19, and 21-25, drawn to a sensor configured to detect a glucose concentration (e.g., claim 1) or for sensing a concentration of an analyte (e.g., claim 10), classified in G01N 33/53.
II. Claim 26-27, drawn to a method of detecting a glucose concentration, classified in A61B 5/14532.
The inventions are independent or distinct, each from the other because:
Inventions I and II are related as process and apparatus for its practice. The inventions are distinct if it can be shown that either: (1) the process as claimed can be practiced by another and materially different apparatus or by hand, or (2) the apparatus as claimed can be used to practice another and materially different process. (MPEP § 806.05(e)). In this case, the apparatus as claimed in Invention I can be used to practice another materially different process such as measuring the electric signal with a series of known glucose concentrations for plotting a calibration curve.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 26-27 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Status of Objections and Rejections
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, 10, 13, 15-19 and 21-25 is/are rejected under 35 U.S.C. §103 as being unpatentable over Hellinga (US 2003/0129622) in view of Lakowicz (US 6,197,534), and further in view of Pickup (US 2012/0232251; citing Amiss, Thomas, and Sakaguchi-Mikami).
Regarding claim 1, Hellinga teaches a sensor (¶26: biosensor) configured to detect a glucose concentration (¶26: to monitor fluctuations in blood glucose; further, this preamble 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. MPEP § 2111.02(II)), the sensor comprising:
a first glucose binding protein (Fig. 1; ¶8: glucose binding protein (GBP); ¶21: protein which has a nature to be used dependent upon the analyte to be detected) 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 by a redox mediator when the first 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).
Hellinga does not disclose a second glucose binding protein configured to have a first conformation and a second conformation, wherein the second glucose binding protein is in the first conformation when the glucose is bound to a binding site of the second glucose binding protein, and the second glucose binding protein is in the second conformation when there is no glucose bound to the binding site of the second glucose binding protein, wherein the electric signal is also generated by the redox mediator when the second glucose binding protein is in the first conformation; 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. 4, l. 24), 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 glucose 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).
Hellinga further discloses L255C-GBP has the Kd(glucose) is 2.0 µM or 0.4 µM (¶11), but fails to disclose wherein each of the first and the second glucose binding proteins have a glucose binding constant selected from a group consisting of 2, 4, 8, and 16 mM.
However, Lakowicz teaches using GGBP for glucose monitoring (col. 1, ll. 18-19; col. 4, l. 24). The binding proteins used for binding can be modified to suit sensing molecules (col. 4, l. 46); for example, the protein may be modified in order to adjust its binding constant with respect to the analyte (col. 4, ll. 47-48). Thus, engineered glucose-sensitive proteins would provide an excellent promising near-term method for real-time monitoring of glucose (col. 6, ll. 50-53). Further, Pickup teaches a modified BBGP having a binding constant at 11 mM (Pickup, ¶38); Pickup also cites Amiss (2007) disclosing a modified GGBP having a dissociation constant at 1 mM (Pickup ¶9), Thomas (2006) disclosing a modified BBGP having a binding constant at 7 and 12 mM (Pickup ¶11), and Sakaguchi-Mukami (2008) disclosing a modified BBGP having a binding constant at 3.9 mM (Pickup ¶11).
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 two glucose binding proteins’ binding constants as recited suggested by Lakowicz, Amiss, Pickup (citing Thomas and Sakaguchi-Mukami) because GGBPs are proteins that can be engineered for a glucose biosensor (Lakowicz, col. 4, ll. 47-48) and various dissociation constants of BBGPs that are close to the recited dissociation constants are reported in the prior art. Thus, the dissociation constants of BBGPs can be optimized through routine experimentation. MPEP 2144.05 (II)(B). "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05(II)(A). Furthermore, there is no indication in the present application that the recited dissociation constants of BBGPs is critical to the invention, which would have supported the non-obvious of the claim.
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 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 an electric signal is also generated by a redox mediator when the first binding protein is in the first conformation,
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).
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; wherein an electric signal is also generated by a redox mediator 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 analyte binding constant.
However, Lakowicz teaches determination of the presence or concentration of an analyte (col. 1, ll. 18-19), e.g., for glucose monitoring (col. 4, l. 24), 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).
Hellinga further discloses L255C-GBP has the Kd(glucose) is 2.0 µM or 0.4 µM (¶11), but fails to disclose wherein each of the first and the second binding proteins have an analyte binding constant selected from a group consisting of 2, 4, 8, and 16 mM.
However, Lakowicz teaches using GGBP for glucose monitoring (col. 1, ll. 18-19; col. 4, l. 24). The binding proteins used for binding can be modified to suit sensing molecules (col. 4, l. 46); for example, the protein may be modified in order to adjust its binding constant with respect to the analyte (col. 4, ll. 47-48). Thus, engineered glucose-sensitive proteins would provide an excellent promising near-term method for real-time monitoring of glucose (col. 6, ll. 50-53). Further, Pickup teaches a modified BBGP having a binding constant at 11 mM (Pickup, ¶38); Pickup also cites Amiss (2007) disclosing a modified GGBP having a dissociation constant at 1 mM (Pickup ¶9), Thomas (2006) disclosing a modified BBGP having a binding constant at 7 and 12 mM (Pickup ¶11), and Sakaguchi-Mukami (2008) disclosing a modified BBGP having a binding constant at 3.9 mM (Pickup ¶11).
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 two glucose binding proteins’ binding constants as recited suggested by Lakowicz, Amiss, Pickup (citing Thomas and Sakaguchi-Mukami) because GGBPs are proteins that can be engineered for a glucose biosensor (Lakowicz, col. 4, ll. 47-48) and various dissociation constants of BBGPs that are close to the recited dissociation constants are reported in the prior art. Thus, the dissociation constants of BBGPs can be optimized through routine experimentation. MPEP 2144.05 (II)(B). "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP 2144.05(II)(A). Furthermore, there is no indication in the present application that the recited dissociation constants of BBGPs is critical to the invention, which would have supported the non-obvious of the claim.
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 components).
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, Lakowicz, and Pickup (citing Amiss, Thomas, and Sakaguchi-Mukami) teach all limitations of claim 1. 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 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.
Regarding claim 23, Hellinga teaches wherein the analyte is glucose (¶26: to monitor fluctuations in blood glucose).
Regarding claims 24-25, Hellinga, Lakowicz, and Pickup (citing Amiss, Thomas, and Sakaguchi-Mukami) disclose 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.
Claim(s) 11-12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hellinga in view of Lakowicz and Pickup (citing Amiss, Thomas, and Sakaguchi-Mukami), 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, Lakowicz, and Pickup (citing Amiss, Thomas, and Sakaguchi-Mukami) disclose all limitations of claims 1 and 13, respectively. Hellinga, Lakowicz, 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, Lakowicz, 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).
Response to Arguments
Applicant’s arguments has/have been considered but are unpersuasive.
Applicant argues both Hellinga and Lakowicz fail to teach the glucose binding constant selected from a group consisting of 2, 4, 8, and 16 (Response, pp. 7, 9). This argument is unpersuasive. The prior art, Lakowicz, teaches that GGBPs for glucose binding can be modified to suit sensing molecules (col. 4, l. 46) so that the protein may be modified in order to adjust its binding constant with respect to the analyte (col. 4, ll. 47-48) and provide an excellent promising near-term method for real-time monitoring of glucose (col. 6, ll. 50-53). Further, Pickup teaches a modified BBGP having a binding constant at 11 mM (Pickup, ¶38) and cites various references that teach modified GGBPs having different binding constants. For example, Amiss (2007) discloses a modified GGBP having a dissociation constant at 1 mM (Pickup ¶9); Thomas (2006) discloses a modified BBGP having a binding constant at 7 and 12 mM (Pickup ¶11); and Sakaguchi-Mukami (2008) discloses a modified BBGP having a binding constant at 3.9 mM (Pickup ¶11). Thus, the dissociation constants of BBGPs can be optimized through routine experimentation. MPEP 2144.05 (II)(B). Furthermore, there is no indication in the present application that the recited dissociation constants of BBGPs is critical to the invention, which would have supported the non-obvious of the claim.
Conclusion
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/C. SUN/Primary Examiner, Art Unit 1795
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