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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-7) in the reply filed on 2/6/2026 is acknowledged. The traversal is on the ground(s) that there is no undue burden on the Examiner to consider all of the claims in the single application. This is not found persuasive because Groups I and II as outlined in the Restriction requirement mailed 12/18/2025 are drawn to different categories of invention (a product and a process), and the claims in each group overlap very little in scope – Group I is mainly drawn to the construction of a biochip for measuring GPNMB expression, while Group II is focused on particular sample types and mutations present in lung adenocarcinoma patients. These disparate inventions and claim limitations would at least amount to separate classifications and fields of search, which would lead to search and/or examination burden as established by MPEP 808.02.
The requirement is still deemed proper and is therefore made FINAL.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference sign(s) mentioned in the description: page 8, para. 3 of the instant specification includes reference character 81 that does not appear in the drawings. 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.
Claim Objections
Claim 6 is objected to because of the following informalities: for greater grammatical clarity, it is recommended that in lines 3-4, “an upper cover layer, the lower cover layer…” read “an upper cover layer, wherein the lower cover layer…” Appropriate correction is required.
Claim 7 is objected to because of the following informalities: in lines 2-3, “bare plate layer comprises” should read “bare plate layer further comprises. Appropriate correction is required.
Claim Interpretation
The biochip of claim 1 is stated in the preamble to be for “tracking postoperative recurrence status of a patient with lung adenocarcinoma.” MPEP 2111.02 I and II state that in the case where the preamble limits the structure of the claim, said preamble must be considered limiting. However, if the preamble does not limit the structure of the claim, then the preamble is considered intended use. In the instant case, “tracking postoperative recurrence status of a patient with lung adenocarcinoma” does not limit the structure of the biochip (e.g. it does not impart an additional structural feature to the biochip), and instead merely describes an intended use of the biochip when said biochip measures expression amounts. This preamble is therefore not considered limiting for the purposes of applying prior art.
Additionally, Applicant does not specifically define the terms used in the instant claims for referring to portions of the biochip – i.e. the bare plate layer and sensing electrode of claim 1, the lower cover layer, middle interlayer, and upper cover layer of claim 6, and the relative electrode, reference electrode, micro-channel, and sample dripping area of claim 7. Because of this, prior art will be considered to read on these limitations in each claim if said prior art contains components that read on the broadest reasonable interpretation of each term. For example, as a “relative electrode” is not defined by the instant specification, this may simply refer to any electrode that serves any function. Specifically:
In claim 1, a “sensing electrode” is considered to require the claimed biological agent and the conduction of any electrical signal. The “base plate layer” does not require any additional features except the presence of the sensing electrode.
In claim 7, “reference electrode” appears to be a term used in the prior art to refer to an electrode with a known potential, and so this interpretation will be used in evaluating the prior art.
Claim Rejections - 35 USC § 112(b)
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 4-5 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 4 is rejected because the intent of the limitation is unclear. The claim states that the antibody has a particular concentration, and thus this antibody would have a particular concentration on the sensing electrode, as stated in claim 1. However, the sensing electrode surface that the antibodies may be placed on may be a two-dimensional solid surface, as shown in the sensing electrode of Figure 1A (ref. character 8). It is thus unclear how a particular concentration could exist for the entirety of a given surface area (i.e. the area of the electrode). It will be interpreted as though Applicant’s intent was to state that the antibody is introduced to the biochip at the claimed concentration, and it is recommended that Applicant amend the claim as such if this interpretation is correct.
Claim 5 is rejected because it recites “a limit of detection” but does not make clear what the limit of detection is in relation to. As written, the limit of detection applies to the entirety of the biochip, and not to the detection of any particular substance. The claim will be interpreted as though it is referring to a limit of detection for the GPNMB gene.
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
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.
Claims 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (Sensors and Actuators B, 2015) in view of Zhu et al. (US 2018/0208655 A1).
Cheng teaches the use of field effect transistors (FETs) for sensitive, real-time, quantitative biosensing of tumor markers for lung cancer diagnosis (Abstract). Figure 1 shows the FET chip/biosensor, where antibodies were immobilized on a the sensor to detect specific markers (see also page 330, column 1, para. 1). As the FET can detect electrical changes, it can act as a sensing electrode as claimed (pages 330-331, “Electrical measurements”). Cheng was able to detect the biomarkers of interest in human serum samples (Figure 4 and pages 331-332, “Quantitative detection of tumor markers in human serum using single-analyte FET biosensor”).
However, Cheng does not teach the use of antibodies against GPNMB.
Zhu teaches the use of anti-GPNMB antibodies that can be used to detect GPNMB in tumor cells (Abstract). The antibodies of the invention can detect the expression of GPNMB in biological samples, and specifically samples from cancerous lung tissue (paras. 75 and 146). The biological sample used may be serum (paras. 30).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the guidance provided by Zhu to add anti-GPNMB antibodies to the FET biosensor of Cheng. Cheng teaches that additional markers could be added to their biosensor (e.g. page 330, column 1, para. 1 and page 333, “Conclusions”), which can increase diagnostic power (page 332, column 2, para. 2), and would thus be motivating to the ordinary artisan. Zhu teaches many potential designs for anti-GPNMB antibodies (e.g. those in para. 8), providing evidence that the creation or procurement of such an antibody would be possible for the ordinary artisan. Additionally, as both Cheng and Zhu teach the use of serum samples in their methods, there would be a reasonable expectation of success in combining the teachings of the references.
Thus, claims 1-3 are prima facie obvious over Cheng in view of Zhu.
Regarding claim 5, the claimed limit of detection is not considered critical or to produce unexpected results. Page 3, para. 5 of the instant specification states the claimed limit of detection range is for “one embodiment of the present invention,” and page 13, para. 3 states, “In one embodiment, an LOD of the biochip of the present invention is not limited and can be adjusted appropriately according to a structure of the biochip, types and content of an antibody, etc.” MPEP 2144.05 I states, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990),” and “…a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985).” Thus, prior art will be considered to read on the claimed range of LODs if it teaches values within, overlapping, or close to the claimed range.
In Cheng, using their described antibodies (for CYFRA 21-1 and NSE), the limits of detection when analyzing human serum were 1 ng/ml and ~24 ng/ml, respectively (Figures 4 and 5, page 332, columns 1-2, joining para. and page 333, column 1, para. 2). In combining Cheng in view of Zhu, it would be prima facie obvious to optimize the anti-GPNMB antibodies on the FET biosensor to have a similar limit of detection to those presented in Cheng for their initial antibodies, so that all three biomarkers may be detected in a sample with enough discriminatory power to diagnose lung cancer in a patient. If the limit of detection for GPNMB was much higher than those presented for CYFRA 21-1 and NSE, then the addition of this biomarker would not be particularly useful, a fact which would motivate the ordinary artisan to optimize the limit of detection for GPNMB accordingly. As Cheng teaches multiple instances of determining if their antibodies can detect the desired biomarkers at particular levels, the ordinary artisan would be capable of performing similar analyses for an additional biomarker (GPNMB). As all three antibodies would also be used on the same FET sensor, similar methods for optimization would apply, further providing a reasonable expectation of success.
Thus, claim 5 is prima facie obvious over Cheng in view of Zhu.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (Sensors and Actuators B, 2015), in view of Zhu et al. (US 2018/0208655 A1), and further in view of Ho et al. (US 2021/0389272 A1).
Regarding claim 4, it is first noted that the concentration range described in the claim is not considered critical or to produce unexpected results. Page 3, para. 4 of the instant specification states that the claimed concentration range is for “one embodiment” of the present invention, and page 9, para. 3 states “The concentration of the antibody used in the biochip of the present invention is not limited and can be adjusted appropriately according to a structure of the biochip and a state of a patient with lung adenocarcinoma.” Page 23, para. 2 states that antibody concentrations were adjusted to obtain optimized detection results. MPEP 2144.05 II (A) states, “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”
Cheng in view of Zhu teaches the biochips of claims 1-3 and 5, as described above. In Cheng, the antibody concentrations used for the provided antibodies was 50 µg/mL for a given volume (page 330, column 2, para. 1). In Zhu, concentrations of anti-GPNMB antibodies are shown. Figure 3 shows that concentrations of 0.05 µg/mL-0.9 µg/mL can be used for target detection with Western blotting (paras. 23 and 153). However, this does not provide concentrations of the antibody needed for target capture in a sensor.
Ho teaches biosensors to detect biomarkers (Abstract and paras. 3-4). They specifically utilize carbon nanotube field effect transistors (CNT-FET; para. 6). Paras. 87-88 and Table 1 detail determining the optimal coating concentration for an antibody on the CNT-FET in order to capture the most analyte (E. coli in this instance), where optimal concentrations were determined to be around 10 µg/mL.
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the guidance provided by Cheng, Zhu, and Ho to develop an optimal concentration of anti-GPNMB for use in the method of Cheng in view of Zhu. Ho teaches a method for obtaining an optimal antibody concentration that can successfully recognize a target on a FET, and so said method could be utilized with the anti-GPNMB in the FET of Cheng in view of Zhu. Zhu also provides antibody concentrations at which the anti-GPNMB is functional in a Western blotting scenario, which provides a general idea of the antibody concentrations that would be a good starting point for analysis, particularly in the 0.9 µg/mL range, which showed excellent results in Figure 3 of Zhu. Antibody concentration is therefore considered a result-effective variable, where it produces the recognized result of efficient and reliable target binding. Developing an optimal concentration would therefore be routine optimization, and thus, the ordinary artisan would be capable of arriving at the claimed concentration range (which includes the concentration values described by Zhu) for a particular given biosensor.
Thus, claim 4 is prima facie obvious over Cheng, in view of Zhu, and further in view of
Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng et al. (Sensors and Actuators B, 2015), in view of Zhu et al. (US 2018/0208655 A1), and further in view of Gau et al. (US 2005/0196855 A1).
Cheng in view of Zhu teaches the biochip of claims 1-3 and 5, as described above. And though Cheng teaches a sensing electrode as recited in claim 1, neither reference recites the structures described in instant claims 6 or 7.
Gau teaches a cartridge for the detection of biological agents in a sample (Abstract and paras. 5-7). The cartridge has a storage component (ref. character 12 in Figures 1A-B) and a transport component situated underneath it (ref. character 13 in Figures 1A-B; para. 44-46). The solutions in the storage component can be for use in an assay (para. 46). The transport component moves solutions from the storage component to sensors within the transport component (paras. 42 and 47). Disruption mechanisms (ref. character 16 in Figure 1A) in conjunction with lumens can be used to transport the solution into the transport component from the storage component (para. 47). Figure 3E shows an example of the storage and transport components being used together, where the disruption mechanism/lumen is piercing a portion of the storage component in which solution is stored (para. 60). Figure 4D shows a mechanism involving disrupters which also creates a channel between the storage components and the transport component (paras. 61-63). Figure 5A shows the entirety of a transport component. The transport component can have a cover (ref. character 62 in Figure 5A) that contains the disruption mechanisms (ref. character 16 in Figure 5A, paras. 70-72) that allow the solution to travel down to the sensors. Para. 50 specifically notes that channels bring the solutions from the storage component, through the disruption mechanism, and to the sensors. The base of the transport component (ref. character 60 in Figure 5A) contains sensors that include a working electrode, a reference electrode, and a counter electrode (para. 72, and ref. characters 72. 74, and 76 respectively in Figure 5A). Electrical leads (ref. character 78 in Figure 5A) provide electrical communication for the electrodes (para. 72). Finally, the transport component has a flexible layer (ref. character 64) underneath the base that contains ventilation (ref. character 87 in Figure 5A; para. 75).
In considering the teachings of Gau in light of the terminology used in instant claims 6-7, the storage component layer would be analogous to the upper cover layer, with the actual reservoirs of solution being the sample dripping area. The layer of the transport component with the disrupters and lumens/channels would be analogous to the middle interlayer, and the layer of the transport component containing the sensors would be analogous to the base plate layer containing three electrodes, where the working electrode is analogous to the claimed sensing electrode, the reference electrode remains the same in both Gau and the instant claims, and the counter electrode is analogous to the relative electrode. Finally, the flexible layer of the transport component would be analogous to the lower cover layer.
The assays that may be used with the cartridge of Gau are not specified, other than detecting biological agents in a sample (para. 5). Gau also teaches that their cartridge can be used for assays in the field, as it is small and efficient (para. 5). The reference also notes that multiple different solutions can be prepared and stored in particular conditions at the same time (paras. 42-43).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to utilize the cartridge provided by Gau with the general assay of Cheng in view of Zhu. Specifically, Cheng in view of Zhu teach an assay involving an electrical biosensor containing antibodies for various lung cancer biomarkers (including GPNMB) that detect said biomarkers in a liquid human sample. Gau teaches a portable cartridge that can be used with assays, where the sensor on which the assay is conducted can be used to detect biological agents in a liquid sample. Therefore, the general assays encompassed by Cheng in view of Zhu and Gau overlap. Gau teaches the advantages of utilizing a single cartridge for their assays, including portability for field usage, the ability to perform multiple assays at once, and small and efficient equipment. Therefore, the ordinary artisan would be motivated to use the cartridge of Gau, fitted with the antibodies of Cheng in view of Zhu on the sensors, in order to detect the lung cancer biomarkers of Cheng in view of Zhu within a single cartridge. This would enable biomarker detection rapidly and in a clinical setting, providing quick results that could inform patient treatment plans and outcomes. There would be a reasonable expectation of success because the structure of the cartridge as taught by Gau, which has already been shown by the reference to be successful, would be unchanged, and the antibodies of Cheng in view of Zhu have been shown by the references to successfully detect their desired targets.
Thus, claims 6-7 are prima facie obvious over Cheng, in view of Zhu, and further in view of Gau.
Conclusion
No claims are currently allowable.
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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681