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 1-18 are pending in the application and are the subject of this office action.
Priority
The instant application is a continuation of PCT/JP2021/018405, filed 14 May 2021.
The instant application claims foreign application JP 2020-094490, filed 29 May 2020 in Japan.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 8 September 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Davis et al (US 2015/0177180 A1; IDS entered) in view of Funahashi et al (JP 2016-109666 A; IDS entered) and Garrote et al (Perspectives on and precautions for the uses of electric spectroscopic methods in label-free biosensing applications. ACS Sensors; 4(9), 2216-2227 (2019).; previously cited).
Regarding claims 1, 4-6, 10-13, and 16-18, Davis teaches an insulin detection method (Abstract) comprising:
Adding a sample to an electrode having an insulin binding protein immobilized on a surface of the electrode, the insulin binding protein specifically recognizing insulin (Par. 33: electrodes of the present invention comprise probe molecules disposed on the planar surface of a substrate, wherein the probe molecules are capable of binding selectively to a target species such as insulin; Par. 124, 139: sample applied to electrode); and
Detecting an electrochemical change associated with formation of a complex of the insulin and the insulin binding protein (Abstract: an electrode for use in the electrochemical detection of insulin; Par. 33: the functionalized electrodes may be used for the EIS detection of insulin in a sample).
Davis does not teach that the insulin binding protein includes a first region and second region as described in instant claims 1 and 13, and instead teaches that the insulin binding protein is preferably an anti-insulin antibody (Abstract; Par. 37: most preferably, the probe is an antibody that selectively binds to the target analyte). Davis does not explicitly teach providing the disclosed features and inventions as part of a kit.
Regarding claims 1 and 13, Funahashi teaches an insulin detection kit and method (Par. 1).
Funahashi teaches a method wherein insulin is detected by binding of two labeled polypeptides which are brought into proximity when bound to a common insulin molecule such that they produce a detectable LRET or BRET signal to indicate the presence and concentration of insulin in a sample (Par. 7, 19-20)
Funahashi teaches an insulin binding protein, wherein the insulin binding protein includes:
A first region that includes an alpha-CT segment of an insulin receptor and does not include a beta subunit of the insulin receptor, and a second region that includes an L1 domain of the insulin receptor and receptor and does not include the beta subunit of the insulin receptor, wherein one of the first region and the second region is immobilized on a substrate (Par. 19: a first polypeptide comprising an alpha-CT segment of an insulin receptor and not containing a beta subunit of an insulin receptor. A second polypeptide containing the L1 domain of the insulin receptor and not including the beta subunit of the insulin receptor; Par. 58: the first complex (alpha-CT) and the second complex (L1) may be linked to each other by a linker to form an integrated third complex; Par. 59: linking the alpha-CT segment and L1 domain ensures that both polypeptides are held in proximity to one another such that they may both form a complex with a given molecule of insulin to produce a detectable signal even when concentration of insulin in the sample is low, thus increasing detection sensitivity of the assay; Par. 65: the third complex (i.e. linked alpha-CT segment and L1 domain) can be attached to the surface of a substrate such that the first complex and second complex can be maintained in a suitable arrangement relative to one another).
Regarding claims 4-6, 10-12 and 16-18 Funahashi further teaches that the second polypeptide (i.e. second region) may comprise additional components in addition to the L1 domain (Par. 51: the second polypeptide may consist of the L1 domain of the insulin receptor or may contain a constitution other than the L1 domain of the insulin receptor), and further indicates that an exemplary second polypeptide may have an amino acid sequence which comprises both an L1 domain and a CR domain (Par. 95: L1 encoded by the DNA sequence shown in SEQ ID NO: 3 and having the amino acid sequence shown in SEQ ID NO: 4 was used as L1 in this example; wherein SEQ ID NO: 4 of Funahashi comprises both an L1 domain and a CR domain, as shown in the sequence alignment below which indicates that SEQ ID NO: 4 of Funahashi is a 100% match to SEQ ID NO: 9 of the instant application, which is defined by the instant specification at Pg. 28, Par. 51 to represent an insulin receptor L1 domain and CR domain).
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Garrote discloses limitations and optimizations for electrochemical biosensing (Abstract).
Garrote teaches that one of the limitations of electrochemical biosensing for small molecules is the target to receptor size ratio, wherein a low target to receptor size ratio (i.e. a small target and larger receptor) negatively affects the sensitivity of detection (Abstract; Figs. 5-6; Pg. 2223, Col. 2: low target to receptor size ratio negatively affects sensitivity. It is common for assays with higher target to receptor size ratios to show higher sensitivities than those with lower values; Pg. 2224: the target to receptor size ratio appears to be important in different types of faradaic EIS platforms. This is because the process is based on how the charge transfer resistance between the solution and the metallic electrode surface is impeded or based on changes in the electrochemical occupancy of the redox moieties within the SAM, wherein both receptor and target sizes will proportionally affect the signal. To overcome the lower sensitivity observed in low target to receptor size ratio assay, an ideal solution is to increase the target to receptor size ratio by using a smaller molecular weight receptor).
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 insulin detection taught by Davis to use the insulin binding protein comprising a linked alpha-CT segment and L1 domain (such as the one taught by Funahashi) in place of the anti-insulin antibody taught by Davis (wherein the insulin binding protein in the modified invention would not necessarily comprise the detectable labels taught by Funahashi, given that these would be superfluous in the electrochemical detection method taught by Davis, which does not require the use of labels). One would be motivated to use the linked alpha-CT segment and L1 domain in particular (as opposed to non-linked versions of the polypeptides which are also described in Funahashi) because the incorporation of two different binding components in each insulin binding protein would increase the efficiency and completeness of binding between the insulin binding protein and the insulin in the sample by providing two binding sites per probe instead of one. One would be motivated to use an insulin binding receptor wherein the second region comprises both an L1 domain and a CR domain because Funahashi specifically teaches this as an exemplary and functional example of a polypeptide used to bind and detect insulin.
One would be motivated to make this modification because the insulin binding protein taught by Funahashi is significantly smaller than the anti-insulin antibody taught by Davis, such that substitution of the smaller insulin binding protein of Funahashi for the larger antibody taught by Davis would create a larger target to receptor size ratio, and thereby enable more sensitive detection of lower concentrations of insulin, as taught by Garrote. Wherein both the prior art and the instant specification indicate that an alpha-CT segment of an insulin receptor consists of 16 amino acid residues, an L1 domain consists of about 155 amino acid residues, and the combined L1 and CR domain of Funahashi SEQ ID NO: 4 (equivalent to instant SEQ ID NO: 9) consists of 310 amino acid residues, while the linker used to link the alpha-CT segment and the L1 domain in Funahashi is taught to be 20 or more amino acid residues (Funahashi, Par. 62). Such that the insulin binding protein as a whole may be as small as about 346 amino acid residues in total (when the CR domain is included) which is significantly smaller than an antibody such as the IgG1 anti-insulin antibody taught by Davis (Davis, Par. 119), wherein an IgG antibody has a molecular weight of about 150 kDa. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because Davis teaches that the probe immobilized to the electrode should be capable of selectively binding to insulin and may be a protein (Par. 8, 37), while Funahashi teaches a protein that selectively binds to insulin.
It would have been obvious to one of ordinary skill in the art to further modify Davis in view of Funahashi and Garrote to include the disclosed features in a kit, as taught by Funahashi, because incorporation of the components and reagents required for performing the insulin detection in a single kit is efficient and useful for the end user. One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Davis and Funahashi are directed to assays for insulin detection comprising insulin binding proteins.
Regarding claims 2-3 and 14-15, Davis in view of Funhashi and Garrote teaches that the first region and second region are connected by a linker, as described in the rejection of claim 1 above.
Davis teaches that the insulin binding protein is immobilized to the surface of an electrode, as described above.
Funahashi also teaches that the linked first region and second region may be immobilized on a substrate, but is generic regarding the specific orientation of immobilization.
As such, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to immobilize the insulin binding protein either at the second region (as in claim 2) or at the first region (as in claim 3), because both orientations are obvious to try based on a finite number of potential orientations for immobilizing the insulin binding protein (i.e. the insulin binding protein must be immobilized at one end or the other, such that either orientation is obvious to try from a total of two potential options). One of ordinary skill in the art would have a reasonable expectation of success in making this modification because both Davis and Funahashi are directed to the detection of insulin using an insulin binding protein immobilized to a surface.
Regarding claims 7-9, Davis further teaches the method wherein the electrochemical change associated with the formation of the complex of the insulin and the insulin binding protein is detected by EIS (Par. 33).
Response to Arguments
Applicant’s arguments filed 21 November 2025 have been considered.
Regarding the 103 rejection, applicant argues that the cited prior art is deficient because it’s teachings do not provide a reasonable and predictable expectation of success because Funahashi teaches a method wherein the insulin binding protein is used for LRET or BRET detection wherein the binding protein is provided in solution, and that this does not enable a reasonable expectation of success in an embodiment such as the instant claim wherein the insulin binding protein is immobilized to an electrode. Applicant argues that this immobilization introduces unpredictable changes in the structure and therefore function of the recited insulin binding protein, such that one of ordinary skill in the art could not conclude that the same insulin binding protein as taught in Funahashi would be competent for binding insulin when immobilized to an electrode as in the instant claims.
This argument is not persuasive because Funahashi specifically teaches an embodiment where the insulin binding protein as claimed is immobilized to a substrate, and this embodiment is specifically cited in the original 103 rejection (see Funahashi Par. 65). The teaching indicates that such immobilization to a substrate or surface is advantageous in maintaining a favorable arrangement of the binding fragments relative to one another. As such, the teachings of Funahashi indicate that one of ordinary skill in the art would have a reasonable expectation that the insulin binding protein would be successful and competent for the binding of insulin in the modified invention of Davis in view of Funahashi and Garrote.
The 103 rejection is maintained.
Conclusion
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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
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/ELLIS FOLLETT LUSI/Examiner, Art Unit 1677
/CHRISTOPHER L CHIN/Primary Examiner, Art Unit 1677