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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/22/2025 has been entered.
Response to Amendment
The amendments and remarks, filed on 12/22/2025, has been entered. The previous prior art rejection is applied to address the claim amendments.
The amendments and remarks, filed on 12/22/2025, has been entered. The claim amendments overcome the previous 112(b) rejection of claim 54.
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 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 4-6 and 54-57 are rejected under 35 U.S.C. 103 as being unpatentable over Alismail et al (A cell-sensory bioscaffold of biocompatible titanate nanofiber, TechConnect Briefs, 2018, ISBN 978-0-9988782-4-9, pp 42-45; already of record on IDS filed 1/25/2022) in view of Hopkins (Customization of Titanate Nanofiber Bioscaffolds, Biomedical Engineering Undergraduate Honors Theses, 2016, pp 1-17; already of record). Examiner notes the publication of Biotech, Biomaterials and Biomedical: TechConnect Briefs 2018 is published on 5/16/2018 and previously attached 2/13/2025.
Regarding claim 4, Alismail teaches a cell sensor (Alismail; pp 42, col 1; Electrochemical cell-sensing), comprising: a sensing member having bioscaffolds (Alismail; pp 42, col 1; turning a bioscaffold into an electrochemical sensor) comprising nanofibers/nanowires of titanate hydrothermally grown directly on a titanium sheet and post-washed to a point of zero charge of about pH 71 (Alismail; Fig. 1; pp 42, col 2; the biocompatible titanate nanowire of wide-bandgap semiconductor has been grown on titanium metal and fabricated into the new bioscaffold; Fig. 1 shows that the nanowire-based bioscaffold is washed with DI water), wherein the nanofibers/nanowires of titanate are entangled atop (Alismail; pp 44, col 2; Fig. 4; The nanowire-entangled bioscaffold) configured to modulate surface charge density upon cell binding; and
an electrode coupled to the titanium sheet to form an electrochemical sensing interface having a defined impedance response (Alismail; Fig. 2; pp 44, col 1; The cell-sensing was done immediately using the two electrode method in which the bioscaffold is the working electrode (WE), and a platinum plate is the counter electrode (CE)),
wherein, in operation, the bioscaffolds of the sensing member are incubated with cells in an aqueous solution (Alismail; pp 45, col 1; Each of the bioscaffolds was incubated first in the 10ml 1xPBS solution containing 1 × 105 live cells/ml for 35 minutes and then taken out) and subjected to an alternative current (AC) excitation signal2;
wherein the cell sensor is configured to (i) generate a frequency-dependent impedance spectrum over a sensing range of about 30 kHz to 1 MHz, (ii) distinguish at least three different live cell types based on reproducible differences in impedance within said frequency range, and (iii) quantify mixing ratios of cancer cells and normal cells in the aqueous solution by linear shifts in impedance correlated to the mixing ratio3 --(Alismail; pp 44, col 1-2; The parameters was setup by varying the frequency starting from 300 kHz to 1MHz…the gold surface, the progression stages of cancer cells were quantified in the label-free manner using the impedance method); and
wherein the impedance response is modeled by an equivalent circuit comprising nanowire induction (L), nanowire resistance (R1), cell-membrane capacitance (C2), cell-membrane resistance (R2), intracellular-matrix capacitance (C1), intracellular-matrix resistance (RCT), and Warburg diffusion impedance (W01), such that the cell sensor electrochemically differentiates normal, benign cancer, and malignant cancer cells through differences in membrane and intracellular electrical properties4 (Alismail; pp 44, col 2;this sensory bioscaffold could potentially lead to the development of a powerful tool for detecting different cells e.g. bacteria, and quantifying the cells behavior when in contact with different therapeutic drugs).
1 The Applicant is advised that the limitation “hydrothermally grown directly on a titanium sheet and post-washed to a point of zero charge of about pH 7” is a product-by-process limitation. There is no apparent difference between the apparatus as claimed and the prior art as taught by Alismail. Generally, even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). MPEP § 2113(I). Thus, the structure implied by the process steps should be considered when assessing the patentability of product- by-process claims over the prior art. The process of post-washing does not structurally change the cell sensor, so Alismails’ cell sensor teaches the structure, barring evidence to the contrary.
2 The limitation “wherein, in operation, the bioscaffolds of the sensing member are incubated with cells in an aqueous solution and subjected to an alternative current (AC) excitation signal” is interpreted as intended use and/or functional language. The Courts have held that the manner in which a claimed apparatus is intended to be employed does not differentiate an apparatus claim from the prior art, if the prior art apparatus teaches all of the structural limitations of the claim. See Ex parte Masham, 2 USPQ2d 1647 (BPAI 1987). A functional recitation of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. See MPEP § 2114. The bioscaffold disclosed by Alismail teaches all of the structural limitations of the claim and thus is configured for and capable of performing the intended use and/or function language of being incubated with cells in an aqueous solution and subjected to an alternative current (AC) excitation signal.
3 The limitation is directed to the function and/or the manner of operating the cell sensor, all the structural limitations of the claim has been disclosed by Alismail and the cell sensor of Alismail is capable of being “configured to (i) generate a frequency-dependent impedance spectrum over a sensing range of about 30 kHz to 1 MHz, (ii) distinguish at least three different live cell types based on reproducible differences in impedance within said frequency range, and (iii) quantify mixing ratios of cancer cells and normal cells in the aqueous solution by linear shifts in impedance correlated to the mixing ratio”. As such, it is deemed that the claimed cell sensor is not differentiated from the cell sensor of Alismail (see MPEP §2114).
4 The limitation “the impedance response” is interpreted as intended use and/or functional language of the electrode. Examiner notes that “impedance response” is not positively recited elements of the claim, and therefore, are not elements of the claimed electrode. The Courts have held that the manner in which a claimed apparatus is intended to be employed does not differentiate an apparatus claim from the prior art, if the prior art apparatus teaches all of the structural limitations of the claim. See Ex parte Masham, 2 USPQ2d 1647 (BPAI 1987).
Alismail does not teach the nanofibers/nanowires being self-assembled into scaffolds with concave nests.
However, Hopkins teaches an analogous art of a bioscaffold (Hopkins; Abstract) comprising nanofibers/nanowires of titanate grown on a titanium sheet (Hopkins; page 6; A titanate nanofiber bioscaffold…This scaffold is self-assembled on a titanium surface), wherein the nanofibers/nanowires being self-assembled into scaffolds with concave nests (Hopkins; Figure 2, 5; page 11; a macrocavity on the surface of a titanate nanofiber bioscaffold). It would have been obvious to one of ordinary skill in the art before the effective filing date to have modified the nanofibers/nanowires of Alismail to be self-assembled into scaffolds with concave nests as taught by Hopkins, because Hopkins teaches that the titanate nanofibers modified by acoustic cavitations experience scaffold regrowth which promotes tissue adhesion (Hopkins; page 14). The examiner notes that Alismail teaches the titanate nanowires have proven to be bioscaffolds for applications in implants, cosmetic, and pharmaceutical fields (Alismail; Abstract).
Regarding claim 6, modified Alismail teaches the cell sensor of claim 4, wherein the nanofibers/nanowires of titanate are grown under a hydrothermal process at a predetermined temperature for a period of treating time (Alismail; pp 43, col 1; the Ti foil was placed in a Teflon-lined lave container pre-loaded with 10 mL of 1.0 M NaOH solution, then sealed and hydrothermally heated at 240°C for 4-12 hours). This limitation is a product-by-process limitation. The patentability of a product is independent of how it was made. "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). The burden is on applicants to show product differences in product by process claims.
Regarding claim 54, modified Alismail teaches the cell sensor of claim 6, wherein the predetermined temperature is in a range of about 128-300°C and the period of treating time is in a range of about 3.2-30 hrs (Alismail; pp 43, col 1; the Ti foil was placed in a Teflon-lined lave container pre-loaded with 10 mL of 1.0 M NaOH solution, then sealed and hydrothermally heated at 240°C for 4-12 hours).
Regarding claim 55, modified Alismail teaches the cell sensor of claim 4, wherein the cells in the aqueous solution include at least one of cancer cells, normal cells, stem cells, and neuron cells, and different types of cells produce differences in impedance change within certain frequencies on the bioscaffolds5 (Alismail; pp 44, col 2; a real-time impedance quantification of the cellular activities to distinguish oral cancer cells from the normal epithelial esophageal Het-1A cells).
5 The limitation “wherein the cells in the aqueous solution include at least one of cancer cells, normal cells, stem cells, and neuron cells, and different types of cells produce differences in impedance change within certain frequencies on the bioscaffolds” is with respect to an article worked upon (cells) and not a positively recited element of the bioscaffolds. Inclusion of the material or article worked upon (cells) by a structure (bioscaffolds) being claimed does not impart patentability to the claims. MPEP § 2115.
Regarding claim 56, modified Alismail teaches the cell sensor of claim 55, wherein different ratios of the cancer cells in the normal cells shifted mixture's electrochemical signals quantitatively and reproducibly. The examiner notes that the cells are not positively recited and is an article worked upon, thus the limitation is not required. The limitation is with respect to an article worked upon (cancer cells and normal cells) and not a positively recited element of the cell sensor. Inclusion of the material or article worked upon (cancer cells and normal cells) by a structure (cell sensor) being claimed does not impart patentability to the claims. MPEP § 2115. Additionally, the claim recites “the cancer cells in the normal cells shifted the mixture's electrochemical signals quantitatively and reproducibly”, while Alismail does not address “[shifting] the mixture's electrochemical signals quantitatively and reproducibly”, it has been determined that where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In the current case, Alismail teaches wherein the cells in the aqueous solution include at least one of cancer cells, normal cells, stem cells, and neuron cells, and different types of cells produce differences in impedance change within certain frequencies on the bioscaffolds. Thus, absent persuasive evidence that the electrochemical signals are different, the prior art is considered to have the same properties with respect to electrochemical signals as that is claimed. MPEP § 2112.01 (I-IV).
Regarding claim 57, modified Alismail teaches the cell sensor of claim 55, wherein the cancer cells alter the surface charge-density of the bioscaffolds more than that of the normal cells while binding to the surface of nanofibers/nanowires of the bioscaffolds. The examiner notes that the cells are not positively recited and is an article worked upon, thus the limitation is not required. The limitation is with respect to an article worked upon (cancer cells and normal cells) and not a positively recited element of the cell sensor. Inclusion of the material or article worked upon (cancer cells and normal cells) by a structure (cell sensor) being claimed does not impart patentability to the claims. MPEP § 2115. Additionally, the claim recites “wherein the cancer cells alter the surface charge-density of the bioscaffolds more than that of the normal cells while binding to the surface of nanofibers/nanowires of the bioscaffolds”, while Alismail does not address “[altering] the surface charge-density of the bioscaffolds more than that of the normal cells while binding to the surface of nanofibers/nanowires of the bioscaffolds”, it has been determined that where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In the current case, Alismail teaches wherein the cells in the aqueous solution include at least one of cancer cells, normal cells, stem cells, and neuron cells, and different types of cells produce differences in impedance change within certain frequencies on the bioscaffolds. Thus, absent persuasive evidence that the surface charge-density are different, the prior art is considered to have the same properties with respect to surface charge-density as that is claimed. MPEP § 2112.01 (I-IV).
Response to Arguments
Applicant’s arguments filed, 12/22/2025, have been considered and the arguments are not found to be persuasive. However, those arguments are directed towards the claim amendments. The non-persuasive arguments are addressed below.
In the Applicant’s arguments, on page 5-6, the applicant argues that Alismail fails to teach a sensor, does not perform cell discrimination, and provides no frequency-dependent analysis. The examiner respectfully disagrees. The Applicant argues Alismail in view of Hopkins fails to disclose “frequency-dependent impedance discrimination in the 30 kHz-1 MHz range; distinguishing different live cell types; quantifying cancer/normal mixing ratios. The limitation is directed to the function and/or the manner of operating the cell sensor, all the structural limitations of the claim has been disclosed by Alismail and the cell sensor of Alismail is capable of being “configured to (i) generate a frequency-dependent impedance spectrum over a sensing range of about 30 kHz to 1 MHz, (ii) distinguish at least three different live cell types based on reproducible differences in impedance within said frequency range, and (iii) quantify mixing ratios of cancer cells and normal cells in the aqueous solution by linear shifts in impedance correlated to the mixing ratio”. As such, it is deemed that the claimed cell sensor is not differentiated from the cell sensor of Alismail (see MPEP §2114).
The Applicant argues “using an equivalent biological-electrochemical circuit model”. The limitation Applicant is referring to is directed to “the impedance response is modeled by an equivalent circuit” which is interpreted as intended use and/or functional language of the electrode. Examiner notes that “impedance response” is not positively recited elements of the claim, and therefore, are not elements of the claimed electrode. The Courts have held that the manner in which a claimed apparatus is intended to be employed does not differentiate an apparatus claim from the prior art, if the prior art apparatus teaches all of the structural limitations of the claim. See Ex parte Masham, 2 USPQ2d 1647 (BPAI 1987).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “PZC-controlled surface chemistry enabling sensing”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Hopkins teaches that the titanate nanofibers modified by acoustic cavitations experience scaffold regrowth which promotes tissue adhesion (Hopkins; page 14). Alismail teaches the titanate nanowires have proven to be bioscaffolds for applications in implants, cosmetic, and pharmaceutical fields (Alismail; Abstract), thus the modification would improve adhesion when the bioscaffold is used for implants.
In response to applicant's argument that Alismail or Hopkins fails to demonstrate the unexpected results of (1) reproducible impedance-based discrimination among normal, benign, malignant, and colon cancer cells, (2) linear mixture-ratio detection from 1:1000 through 1:5, and (3) distinct metabolic and drug-response signatures, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Further, Applicant has not established criticality of the claimed limitations in claim 4. To establish unexpected results over the claim, applicant should compare a sufficient number of tests that distinguish the cells, linear mixture-ratio detection, and. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). The burden is on applicant to establish that results are unexpected and significant. See MPEP § 716.02. Applicant has not shown that the claimed limitations produce unexpected results.
Conclusion
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/A.Q.L./Examiner, Art Unit 1796
/ELIZABETH A ROBINSON/Supervisory Patent Examiner, Art Unit 1796