DETAILED CORRESPONDENCE
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Amendment filed on April 22, 2025, has been received and entered.
Claim Disposition
3. Claims 7 and 18 have been cancelled. Claims 1-6, 8-17 and 19-20 are pending. Claims 1-5 and 15 are under examination. Claims 6, 8-14, 16-17 and 19-20 are withdrawn from consideration as being directed to a non-elected invention. The claims are only being examined to the extent that they pertain to the elected subject matter.
Specification
4. The specification is objected to because of the following informalities:
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The following is suggested: "Method and Agent for modifying Substrate Specificity of Glucose Dehydrogenase".
Appropriate correction is required.
Claim Objection
5. Claims 1-5 and 15 are objected to because of the following informalities:
For clarity it is suggested that claim 1 is amended to read, “A method of modifying substrate specificity of a glucose sensor comprising…….(FAD), [[said method]]
comprising:
adding a glucose dehydrogenase…….., wherein the modifier is a glucose analog and low molecular weight compound…., and wherein the ratio……”. The dependent claims hereto are also included.
Claim 15 is objected to under 37 CFR 1.75(c), as being of improper dependent form for failing to further limit the subject matter of a previous claim. Applicant is required to cancel the claim(s), or amend the claim(s) to place the claim(s) in proper dependent form, or rewrite the claim(s) in independent form. Note that claim 15 depends from claim 1, a method that has method steps to contact the sensor with a sample containing glucose and measuring glucose using the sensor.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
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.
6. 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.
7. Claim(s) 1-5 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over JP2013224971 (of record in the application) in view of JP2014018096 (of record in the application), Maclean et al. (J. Gen. Micro. of record in the application), EP2017608 (of record in the application), and WO2007/123179 (of record in the application).
The claimed invention is directed to a method of modifying substrate specificity of a glucose sensor comprising FAD-GDH using a modifier such as ribitol or sorbitol wherein the glucose dehydrogenase is from the genus Mucor for example. The method optionally uses a solid phase surface and the method measures glucose.
JP2013224971 provide a biosensor capable of accurate measurement, which is superior in substrate specificity to glucose and can avoid action on sugars except glucose. In the primary reference a biosensor is provided with a reagent layer included and a reagent specifically reacting to glucose in a sample liquid and measures a glucose concentration in the sample liquid. The reagent layer includes an electron carrier, a glucose dehydrogenase with a flavin adenine dinucleotide as a coenzyme, a BSA (bovine serum albumin) and at least one or more additives out of organic acids each having at least one carboxyl group in its molecule (except organic acids having an amino group) or their salts, organic acids or organic acid salts having an amino group or a carbonyl group, and sugar alcohols (see abstract). The genus Mucor is not taught by the primary reference. However, JP2014018096 discloses a composition containing mucor-derived flavin-binding glucose dehydrogenase (FAD-GDH) with sufficient thermal stability. The secondary reference also discloses that the composition includes other compounds such as xylitol, glycolic acid, salt compounds, sucrose, extrin among others used as modifiers. It is also disclosed in the secondary reference a composite that can reduce deactivation of FAD-GDH when a glucose measuring reagent, glucose assay kit and glucose sensor are prepared and stored; and decrease the amount of use of FAD-GDH, as well as can enhance thermal and storage stability of the measuring reagent, the assay kit and the sensor and improve the measurement accuracy (see the abstract and entire reference). The secondary reference does not teach for example sorbitol, however it is established in the art that compounds like sorbitol and ribitol are by products of glucose utilization. Maclean et al. discloses compounds such as glucitol (sorbitol), ribitol, fructose, xylitol, trehalose, inositol and erythritol (see page 1) are soluble carbohydrates (glucose grown cultures) and intermediates of glucose. Moreover, EP2017608 teach the sugar maltose measured via a biosensor (FIG 1 & FIG 3) and utilization in substrate specificity to glucose.
Additionally, WO2007123179 discloses biosensors for measuring glucose in a liquid sample, within a reagent layer containing glucose dehydrogenase using flavin adenine dinucleotide as a coenzyme provided on an insulating substrate. Addition of organic acid or organic acid salt having one carboxyl group, organic acid or organic acid salt having at least one amino group or carbonyl group in the molecule, sugar alcohol, solubilized protein, or a combination thereof, the agent was added. Thereby, the substrate specificity with respect to glucose and storage stability can be improved, and the effect / action to saccharides other than glucose can be avoided (see abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references renders the claimed invention as obvious. One of ordinary skill in the art would be motivated to combine the teaching of the references because they can be construed as analogous art. Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
Response to Arguments
8. Applicant’s comments have been considered in full. Withdrawn objections/rejections will not be discussed herein as applicant’s comments are moot. The objection to the specification remains because applicant did not address it in the remarks or alter the title which has redundancy. In addition, some objections remain over claim 1 that were also not addressed and some new objections have been raised based on amendments to the claim. Note also that the art rejection of record remains for the reasons stated above and herein. Applicant traverses the rejection by separately attacking each of the references when the combined teaching renders the claimed invention as obvious. Applicant argues that the primary reference does not teach or suggest the possibility of being able to modify the substrate specificity of FAD-GDH by adding an organic acid or organic acid salt, which is not being used to modify substrate specificity of FAD-GDH. The combined teaching in the art recognizes that high specificity for glucose is needed with biosensors. The art teaches and demonstrates the claimed invention and suggests usage of the compounds utilized as modifiers. Applicant, admits on the record that the cited ‘JP2013’ reference teaches a mucor-derived flavin-binding glucose dehydrogenase. In addition, the art is replete with references that are similar to the inventive concept. For example, Ryoko Satake et al., 2015 discloses “Novel glucose dehydrogenase from Mucor prainii: Purification, characterization, molecular cloning and gene expression in Aspergillus sojae. It is further that:
A novel FAD-dependent glucose dehydrogenase was identified from Mucor prainii.
The enzyme showed strict substrate specificity for glucose.
The effect of additive saccharides for the reactivity was minimal.
The enzyme was likely suitable for glucose sensor applications.
It is also stated that :
Glucose dehydrogenase (GDH) is of interest for its potential applications in the field of glucose sensors. To improve the performance of glucose sensors, GDH is required to have strict substrate specificity. A novel flavin adenine dinucleotide (FAD)-dependent GDH was isolated from Mucor prainii NISL0103 and its enzymatic properties were characterized. This FAD-dependent GDH (MpGDH) exhibited high specificity toward glucose. High specificity for glucose was also observed even in the presence of saccharides such as maltose, galactose and xylose. The molecular masses of the glycoforms of GDH ranged from 90 to 130 kDa. After deglycosylation, a single 80 kDa band was observed. The gene encoding MpGDH was cloned and expressed in Aspergillus sojae. The apparent kcat and Km values of recombinant enzyme for glucose were found to be 749.7 s−1 and 28.3 mM, respectively. The results indicated that the characteristics of MpGDH were suitable for assaying blood glucose levels.
Diabetes
Glucose dehydrogenase
Glucose sensor
Flavin adenine dinucleotide
Substrate specificity
The self-monitoring of blood glucose at home is important for management of diabetes. There has been a striking evolution in glucose monitoring technology since the first blood glucose tests for self-monitoring were introduced around 1980 (1). The currently available glucose monitoring sensors are mainly based on electron-mediator-dependent glucose oxidoreductases.
Glucose oxidase (GOD) (EC 1.1.3.4) has been widely used as a mediated amperometric glucose sensor based on its high thermostability and high glucose selectivity (2). However, errors in glucose measurement often occur because of variations in the concentration of dioxygen (O2) in the blood samples. To avoid this problem, glucose dehydrogenases have been used in glucose sensors: NAD-dependent glucose dehydrogenase (GDH), NADP-dependent GDH [NAD(P)-dependent GDH, EC 1.1.1.47] and pyrroloquinoline quinine (PQQ)-dependent GDH (EC 1.1.99.17) 3, 4, 5, 6, 7, 8, 9, 10, 11. NAD(P)-dependent GDH has strict substrate specificity, though NAD(P) cofactor must be supplied exogenously together with specific artificial electron mediators to carry out the electrochemical measurement because NAD(P) cofactor is not bound to the enzyme. PQQ-GDH has high catalytic activities for glucose and can use a variety of electron acceptors as redox mediators except for O2 (12). However, PQQ-GDH has broad substrate specificity and thus, when using PQQ-GDH, blood glucose levels higher than the actual value are obtained when the specimen contains high maltose, icodextrin, galactose, or xylose (13). In a patient whose blood glucose level was measured using a simplified self-monitoring blood glucose sensor employing PQQ-GDH during administration of a maltose-containing infusion, hypoglycemia accompanied by a disruption in consciousness was experienced when the insulin dose was adjusted based on the measured value. The strict accuracy guidelines for blood glucose meters were published by the International Organization for Standardization (ISO) (14). Recently, Fraeyman et al. (15) have reported the successful production of a mutant strain of PQQ-GDH which shows no cross-reactivity with maltose.
Flavin adenine dinucleotide (FAD)-GDH was first discovered in 1951 in Aspergillus oryzae (16); however, a detailed characterization of GDH has not been completed. Since the use of FAD-GDH as an electrode catalyst in glucose sensors was published, GDHs from Burkholderia cepacia (17), Aspergillus terreus 18, 19, A. oryzae (20) and Glomerella cingulata (21) have been studied. The advantage of employing FAD-GDH in glucose sensors is its strict substrate specificity toward glucose. Therefore, we tried screening for fungi to get novel FAD-GDH which had substrate specificity suited to glucose sensors.
In this study, it discovered a novel FAD-GDH from Mucor prainii NISL0103 (MpGDH). MpGDH showed high substrate specificity toward glucose. Notably, its reactivity for xylose was much lower than any other FAD-GDH. We also describe the cloning of the gene encoding the MpGDH and its recombinant expression in Aspergillus sojae (see Satake et al., J. of Bioscience and Bioengineering, vol. 120, issue 5, Nov. 2015, pages 498-503 in its entirety).
The cited references are relevant and the invention claimed is within the skill of the ordinary artisan based on common knowledge. Therefore, the claimed invention is deemed to be obvious and the rejection remains. Applicant is urged to contact the examiner to discuss reduction of the remaining issues.
Conclusion
9. No claims are presently allowable.
10. Applicant’s amendment necessitated the new/modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571)272-0957. The examiner can normally be reached 9-5pm, Monday- Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (408)-918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/HOPE A ROBINSON/Primary Examiner, Art Unit 1652