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 1-7 are pending and examined herein.
Priority
The present application, filed 09/22/2023, is a continuation of U.S. Patent Application 16/767,575, filed 05/27/2020, which is a 371 of PCT/US2018/063170, filed 11/29/2018, which claims benefit of U.S. Provisional Patent Application 62/591,209, filed 11/28/2017. The benefit is acknowledged and the claims are examined herein are treated as having an effective filing date of 11/28/2017.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because it appears reference characters "404" and "406" have both been used to designate primary binding agent in Fig. 4 (see right side); it appears reference characters "508" and "510" have both been used to designate reporter enzyme in Fig. 5 (see right side). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because reference character “404” has been used to designate both primary binding agent (see Fig. 4, p. 14, ln. 21) and DNA/capture probe (see Fig. 8, p. 16, ln. 9); reference character “406” has been used to designate both conjugate binding agent (see Fig. 4, p. 14, ln. 22) and exemplary target agent/RNA oligomer (see Fig. 8, p. 16, ln. 9); reference character “408” has been used to designate both reporter enzyme (see Fig. 4, p. 15, ln. 4) and reporter enzyme conjugate/conjugate probe or biomolecule (see Fig. 8, p. 16, ln. 10); reference character “410” has been used to designate both enzyme substrate (see Fig. 4, p. 14, ln. 23) and reporter enzyme (see Fig. 8, p. 16, ln. 10); reference character “920” has been used to designate both surface (see Fig. 10(A), p. 19, ln. 27) and array (see Fig. 10(C), p. 20, ln. 1); reference character “922” has been used to designate both surface (see Fig. 10(A), p. 19, ln. 27) and substrate (see Fig. 10(C), p. 20, ln. 3); reference character “1206” has been used to designate both target analyte and conjugate biomolecule (see p. 20, ln. 20); reference character “1208” has been used to designate both reporter enzyme (see p. 20, ln. 20) and tag (see Fig. 12(B), 13(A)). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference signs mentioned in the description: 305 (p. 14, ln. 12); 550 (p. 14, ln. 1); 804 (p. 16, ln. 7); 120 (p. 20, ln. 16). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference characters not mentioned in the description: 114 in Fig. 1; 612 in Fig. 6; 704 in Fig. 7; 1210 in Fig. 12(B), 13(A); 1211 in Fig. 12(A); 1900 in Fig. 15. Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
The drawings are objected to because there is a The reference character “304” designated to “compugate biomolecule,” should be written as “conjugate biomolecule.” Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The abstract is objected to because it does not comply with the word length requirements of 50 to 150 words, as it is fewer than 50 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Furthermore, the disclosure is objected to because of the following informality: it contains The context of the disclosure indicates that the intended term is “complementary substrate,” referring to a corresponding or matching substrate. The term “complimentary” (meaning flattering or expressing praise) is inconsistent with the technical subject matter. The word “complimentary” should read “complementary.” Appropriate correction is required.
Claim Objections
Claims 1, 2, 4, are objected to because of the following informality: the claims contain an apparent typographical error. Specifically, the term “complimentary substrate” appears throughout the claims. The context of the claims indicates that the intended term is “complementary substrate,” referring to a corresponding or matching substrate. The term “complimentary” (meaning flattering or expressing praise) is inconsistent with the technical subject matter. The word “complimentary” should read “complementary.” Appropriate correction is required.
Claim 1 is objected to because of the following informality: in claim 1, line 5, “the target-analyte” should read “the target analyte” for clarity and consistency. 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 1-7 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.
Claim 1 recites the limitations "the environment" and "the surface" in line 10. There is insufficient antecedent basis for this limitation in the claim. Specifically, the claim does not previously introduce: an “environment” prior to referring to “the environment,” or a “surface” prior to referring to “the surface.” Since these elements are not previously defined or introduced in the claim, it is unclear what structure or region is being referenced. As a result, the metes and bounds of the claim are uncertain. Appropriate correction is required.
Additionally, the term “complimentary substrate comprising a capture agent” in claim 1 is a relative term which renders the claim indefinite. The tern “complimentary substrate” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “complimentary substrate” renders the claim indefinite because it is unclear what the substrate is “complementary” to and in what manner the complementarity is defined. The claim does not specify whether the complementary substrate is structurally complementary to the sensor substrate, spatially aligned, geometrically matched, functionally associated, or otherwise related. No structural or functional relationship is defined in claim 1 that explains what makes the substrate “complementary.” Since the term implies a relational characteristic without defining the relationship, the scope of the claim cannot be determined with reasonable certainty. For purposes of compact prosecution, the term “complementary substrate” will be interpreted to mean a substrate distinct from the sensor substrate that functionally cooperates with the sensor substrate in detecting the target analyte, such as by carrying one or more capture agents.
Claims 2–7 are rejected under 35 U.S.C. §112(b) as being indefinite for the same reasons set forth above with respect to Claim 1, from which they depend.
Claim 4 recites the limitation "the array of sensor devices" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 4 depends from Claim 1. However, Claim 1 does not introduce “an array of sensor devices” prior to Claim 4’s reference to “the array of sensor devices.” Since “the array of sensor devices” lacks antecedent basis in Claim 4, it is unclear what specific structure is being referenced. As a result, the scope of the claim is uncertain. Appropriate correction is required.
Additionally, the term “matching array” in claim 4 is a relative term which renders the claim indefinite. The term “matching array” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “matching array” renders the claim indefinite because it is unclear what constitutes “matching.” The claim does not define whether “matching” refers to: identical spatial positioning, corresponding alignment with the array of sensor devices, equal number of elements, or another structural relationship. The term is a relative descriptor without objective boundaries or a defined standard for determining when one array “matches” another. As a result, the scope of the claim cannot be determined with reasonable certainty. For purposes of compact prosecution, the term “matching array” will be interpreted to mean an array of capture agents arranged in spatial correspondence with the array of sensor devices such that respective elements are aligned when the substrates are overlaid. Appropriate correction is required.
Furthermore, the term “unique capture agent” in claim 6 is a relative term which renders the claim indefinite. The term “unique capture agent” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “unique capture agent” renders the claim indefinite because it is unclear what qualifies a capture agent as “unique.” The claim does not define whether “unique” refers to: structurally different capture agents, functionally different capture agents, capture agents specific to different target analytes, or another distinguishing characteristic. The term “unique” is a relative descriptor that lacks objective boundaries in the claim. Without a clear standard for determining when a capture agent is “unique,” the scope of the claim cannot be determined with reasonable certainty. For purposes of compact prosecution, the term “unique capture agent” will be interpreted to mean that each spot comprises a capture agent that is different from at least one other capture agent present at another spot in the plurality of spots.
Lastly, claim 7 recites the limitation "on surface" in line 2. The claim lacks proper antecedent basis for the term “surface.” The claim does not previously introduce a “surface” prior to referring to “surface.” As a result, it is unclear which surface is being referenced (e.g., the sensor substrate surface, the complimentary substrate surface, or another surface). Since the term “surface” lacks antecedent basis and does not clearly identify the structure upon which the fusion-proteins are immobilized, the scope of the claim is uncertain. 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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
Claims 1-3 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Selvanayagam et al. (An ISFET-Based Immunosensor for the Detection of β-Bungarotoxin. Biosensors & Bioelectronics. Vol. 17, No. 9, September 2002) in view of Labaer et al. (US20160041159).
Regarding claims 1-3, Selvanayagam et al. discloses an ion-sensitive field effect transistor (ISFET)-based enzyme-amplified immunosensor system, stating that “an ion-sensitive field effect transistor (ISFET)-based immunosensor was developed to detect/quantitate b-Bungarotoxin (bBuTx)” (Abstract, page 821) and “to develop an electrochemical immunosensing system for the detection/quantitation of b-BuTx, an ISFET was used as a solid phase detector” (Abstract, page 821). Selvanayagam et al. further teaches immobilization of a capture agent on the sensor surface, stating that “a murine monoclonal antibody (mAb 15) specific to b-BuTx” (Abstract, page 821) was “immobilized on the gate region of the ISFET” (Abstract, page 821). Additionally, Selvanayagam et al. further teaches a reporter enzyme bound via a secondary antibody in a sandwich immunoassay, stating that “the antigen antibody reaction was monitored by the addition of urease conjugated rabbit anti-b-BuTx antibodies” (Abstract, page 821). Selvanayagam et al. also discloses the enzyme-substrate reaction, stating that the “antigen antibody reaction was detected with urease conjugated rabbit anti-b-BuTx antibodies (1:100), and urea (0.1 M) was used as substrate” (Materials and methods, paragraph 3, page 823). Lastly, Selvanayagam et al. discloses electrical detection of reaction products, stating that “this final step leads to a pH shift in the system detectable by ISFET, and is directly proportional to the antigen concentration in the sample” (Materials and methods, paragraph 3, page 823); “the concentration of b-BuTx was determined by the change of ISFET drain current” (Materials and methods, paragraph 2, page 823).
Although Selvanayagam et al. teaches the following: a sensor-substrate comprising an ISFET device, a capture agent immobilized on a substrate surface, a reporter enzyme bound via a sandwich immunoassay, an enzyme-substrate reaction, and detection of a change in electrical property due to enzyme reaction products - Selvanayagam et al. does not teach the following: a dual-substrate configuration, a complementary substrate comprising an array of capture agents (claim 2), nor a sensor substrate comprising an array of sensor devices (claim 3).
On the other hand, Labaer et al. teaches microarray-based biosensor architectures and multi-spot detection formats. Specifically, Labaer et al. discloses “a biosensor microarray comprising: (i) a solid support substrate surface; (ii) a plurality of capture moieties linked to the solid support substrate surface; (iii) a plurality of detector polypeptides or detector peptides specifically bound by the capture moieties; and (iv) a plurality of sensors; wherein each sensor in the plurality of sensors is in direct contact or in proximity to a capture moiety in the plurality of capture moieties” (paragraph [0004], page 21). Labaer et al. further discloses that “in some embodiments the plurality of sensors are located on a solid support substrate surface other than the solid support substrate to which the plurality of capture moieties is linked” (paragraph [0024], page 22).
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 ISFET-based immunosensor of Selvanayagam et al. to incorporate the plurality of capture moieties and plurality of sensors taught by Labaer et al. in order to enable multiplex detection, increase assay throughput, and permit simultaneous detection of multiple analytes within a single biosensor platform. Selvanayagam et al. establishes a functioning enzyme-amplified ISFET immunosensor that reliably detects analyte presence through enzyme-generated ionic reaction products. Labaer et al. teaches that biosensor platforms may employ pluralities of capture moieties and pluralities of sensors arranged on solid supports to form microarrays. At the time of the invention, multiplexed biosensor arrays were widely used to improve analytical capacity and efficiency. The adaptation of array architecture to an existing ISFET immunosensor represents the application of a known design strategy—replication of functional sensing units—to achieve parallel detection. The proposed modification does not alter the underlying immunochemical reaction, the enzyme labeling strategy, or the electrical detection mechanism disclosed in Selvanayagam et al. Instead, it simply multiplies the number of sensing sites using known array fabrication techniques. Such scaling of sensing units is a predictable engineering enhancement rather than a redesign of the sensing principle. Accordingly, combining Selvanayagam et al.’s enzyme-ISFET detection platform with Labaer et al.’s plurality-of-capture and plurality-of-sensor architecture would have been a straightforward and predictable modification within the skill of the ordinary artisan.
Lastly, a person having ordinary skill in the arts (PHOSITA) would have had a reasonable expectation of success in making this modification because Selvanayagam et al. demonstrates that an ISFET sensor can reliably detect ionic species generated by enzyme-catalyzed reactions through measurable changes in drain current. Each sensing unit operates independently and responds locally to biochemical events occurring at its surface. Labaer et al. teaches that capture moieties and sensors may be arranged in pluralities on solid supports without altering the fundamental detection chemistry. The proposed modification merely involves replicating the functional sensing unit disclosed in Selvanayagam et al. in spatially distinct locations consistent with the array-based architecture described in Labaer et al. Such replication would have predictably resulted in multiple independently addressable sensing sites capable of parallel detection. No new chemical interaction, no new detection modality, and no incompatible materials are introduced by the combination. Both references operate within the same technological field of solid-state biosensor platforms. Since the modification entails predictable use of prior art elements according to their established functions, one of ordinary skill in the art would have reasonably expected the modified system to function as intended.
Regarding claim 6, as discussed above, Labaer et al. teaches immobilizing capture moieties on a substrate surface in an array format. Labaer et al. further discloses that “typically capture moieties are assembled as a monolayer on the solid support substrate surface, which has been derivatized to link to the capture moieties. Methods for derivatizing various types of substrate surfaces to allow linkage of biomolecules is known in the art. Formation of an array pattern is then established by capture of detector
polypeptides from arrayed in vitro translation reactions as described herein. In other embodiments the capture moieties themselves may be linked to a substrate surface as an array, e.g., by spotting in a grid pattern using a pin spotting device, or dispensed using liquid jet printers, or using vapor coating of chemical linkers” (paragraph [0062], page 25). Labaer et al. further discloses that “in other embodiments the plurality of capture moieties is linked to a plurality of beads or nanoparticles, where different sets of nanoparticles are separately associated with different detector polypeptides rather than being a confined to a two dimensional surface array” (paragraph [0063], page 25).
Here these disclosures teach that capture moieties may be spatially arranged in a grid pattern on a substrate and that different sets are separately associated with different detector polypeptides, thereby indicating that distinct capture agents are immobilized at discrete locations. In array technology, such spatial segregation of different capture moieties inherently enables multiplex detection of different targets at defined spots. Hence, 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 single-analyte capture configuration of Selvanayagam et al. by incorporating the array-based spotting architecture taught by Labaer et al., such that multiple different capture agents are immobilized at discrete spots on the complementary substrate. This modification would have predictably enabled simultaneous detection of multiple analytes while using the same enzyme-based ISFET detection principle disclosed in Selvanayagam et al. The modification merely applies known microarray fabrication techniques to replicate the capture-and-detection unit across multiple spatially distinct locations, which constitutes a routine and predictable optimization to increase assay throughput and analytical capability.
Regarding claim 7, Labaer et al. teaches epitope-tag systems in array-based protein capture platforms. In particular, Labaer et al. states that “in some embodiments, the capture moieties comprise antibodies. In some embodiments, the detector polypeptides or detector peptides comprise an epitope tag and the antibodies bind specifically to the epitope tag. In some embodiments, the epitope tag is glutathione-S transferase (GST), haloalkane dehalogenase, MYC-tag, FLAG-tag, hemagluttinin (HA) tag, a 6X-His tag, a fluorescent protein (e.g., EGFP). These epitope tags and specific antibodies or affinity reagents for such epitope tags are known in the art and commercially available from multiple sources” (paragraph [0058], page 25). Labaer et al. further teaches that “the capture moiety coated slide is then typically overlayed in contact with an array of isolated in vitro translation reactions (e.g., in microwells or nanowells)” (paragraph [0084], page 27).
Thus, 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 enzyme-linked ISFET detection system of Selvanayagam et al. to incorporate the epitope-tag fusion protein capture strategy and in situ array expression format taught by Labaer. This modification would have predictably enabled selective immobilization of fusion proteins via anti-epitope antibodies in an array format while maintaining the enzyme-based electrical detection mechanism disclosed in Selvanayagam et al. The modification constitutes the predictable application of a known epitope-tag capture system to a known solid-state enzyme-based biosensor platform in order to facilitate controlled immobilization and multiplex analysis of expressed proteins.
Claims 4 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Selvanayagam et al. and Labaer et al., as applied to claim 1 above, and further in view of Chow et al. (Microfluidic channel fabrication by PDMS-interface bonding. Smart Materials and Structures. Vol. 15, No. 1, February, 2006).
With respect to the teachings of Selvanayagam et al. and Labaer et al., see the discussion above, which applies equally here. These references differ from the instant claims in failing to teach or specify the following: the sensor substrate comprising the array of sensor devices is aligned and overlaid with the complementary substrate comprising a matching array of capture agents to create a microfluidic channel for fluidic flow between the sensor substrate and the complementary substrate; and the flow initiates a reporter enzyme reaction that results in enzyme-reaction-products. Specifically, neither reference discloses or specify a structural arrangement in which flow between bonded substrates within a defined microfluidic channel initiates the enzymatic reaction.
On the other hand, Chow et al. teaches formation of sealed microfluidic channels by bonding two substrates together. In particular, Chow et al. states that “a thin (10–25 µm) poly(dimethylsiloxane) (PDMS) intermediate layer was used to bond two poly(methyl methacrylate) (PMMA) substrates without distorting them” (Abstract, page S112) and “microfluidic channels with dimensions of 300 µm × 1.6 cm × 100 µm were successfully fabricated using this novel bonding method” (Abstract, page S112). Chow et al. further discloses fluid flow within the formed channels, stating that “the most common concern for microfluidic systems is the leakage problem. Therefore, our fabricated channels were tested for leakage. Colour dye was pumped into the channels at a flow rate of 0.8 ml min−1, and no leakage occurred in the channels” (Experimental results, paragraph 3, page S115).
With respect to claim 5, Selvanayagam et al. teaches that the reporter enzyme (urease) acts on the substrate to produce enzyme reaction products that result in a detectable electrical signal. The introduction of substrate into the reaction region necessarily initiates the enzyme reaction. In view of Chow et al.’s teaching of fluid flow through the microfluidic channel formed between substrates, the flow of substrate-containing solution through the channel would initiate the reporter enzyme reaction resulting in enzyme reaction products, as required by Claim 5.
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 ISFET-based immunosensor system of Selvanayagam et al., as arranged in array form according to Labaer et al. – by aligning and bonding the sensor substrate and complementary substrate in the manner taught by Chow et al. so as to form a microfluidic channel between the substrates to permit controlled fluidic flow across the sensor and capture surfaces. Selvanayagam et al. teaches an enzyme-linked ISFET detection platform operating in a liquid-phase immunoassay environment. Labaer et al. teaches multi-spot and multi-sensor architectures on solid substrates. However, neither reference explicitly describes how two such substrates may be structurally aligned to form a confined fluidic passage between them. Chow et al. teaches a well-established microfabrication method for bonding two polymer substrates to create sealed microfluidic channels capable of supporting controlled fluid flow.
At the time of the invention, microfluidic channel formation by bonding patterned substrates was a widely adopted and predictable engineering technique for enabling controlled reagent delivery and reaction environments in microfluidic devices. Incorporating Chow et al.’s bonding and channel-formation method into the combined Selvanayagam et al. and Labaer et al. biosensor architecture would have represented a straightforward structural implementation to enable controlled delivery of analyte and substrate solutions across aligned sensor and capture arrays. The modification does not alter the enzyme chemistry, the sensing mechanism, or the detection modality. It merely provides a known structural approach for fluid handling between two substrates in a compact and controlled manner. Applying a known microfluidic bonding technique to an existing biosensor platform to enable fluid flow between substrates constitutes the predictable use of prior art elements according to their established functions.
Lastly, a PHOSITA would have had a reasonable expectation of success in making this modification because Chow et al. demonstrates that two polymer substrates can be reliably bonded to form sealed microfluidic channels capable of sustaining fluid flow without leakage. The formation of microchannels by substrate alignment and bonding is a mature and well-characterized fabrication technique. Selvanayagam et al. demonstrates that enzyme reactions occurring at a sensor surface produce measurable electrical changes, and Labaer et al. demonstrates that sensor and capture elements may be arranged on separate substrates. Combining these teachings would simply involve positioning the sensor array and capture array on opposing substrates and forming a microfluidic channel between them using the bonding approach taught by Chow et al. The enzyme reaction chemistry and electrical detection remain unchanged. Fluid flow through the channel would deliver substrate and analyte to the reaction region, thereby initiating the enzyme reaction and producing enzyme reaction products detectable by the ISFET sensor, as already established in Selvanayagam et al. Since the combination involves predictable integration of established microfluidic fabrication methods with established enzyme-based ISFET detection systems, one of ordinary skill in the art would have reasonably expected the modified device to function as intended.
Ultimately, for the reasons set forth above, claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over the cited prior art. The combination of Selvanayagam et al., Labaer et al., and where applicable, Chow et al., teaches or renders obvious each and every limitation of the claimed invention. The references collectively disclose the claimed sensor substrate architecture, capture agent configurations, enzyme-mediated detection mechanisms, array implementations, and microfluidic alignment structures. It would have been obvious to a PHOSITA at the time of the invention to combine these known elements to achieve predictable results using established biosensor and microfluidic techniques.
For the reasons stated above, all claims are rejected.
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 February 24, 2026