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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Dec. 29, 2025. Claims 1-16 are pending and are currently examined.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(Previous rejection-withdrawn) Claims 1, 2 and 4-5 are rejected under 35 U.S.C. 102 as being anticipated by Lou et al. (Langmuir. 2017 Jan 31;33(4):1097-1104) as evidenced by Roy et al. (ACS Nano. 2022 Jan 25;16(1):192-210).
This rejection is withdrawn in view of the amendments filed on Dec. 29, 2026.
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.
(New Rejection-necessitated by amendment) Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Lou et al. (Langmuir. 2017 Jan 31;33(4):1097-1104, hereinafter, “Lou”) as evidenced by Roy et al. (ACS Nano. 2022 Jan 25;16(1):192-210, hereinafter, “Roy”) and Wang et al. (Nanoscale. 2014 Nov 7;6(21):12482-9, hereinafter, “Wang”).
The base claim 1 is directed to an array for detecting a target particle, comprising: a substrate with uneven surface, a lipid bilayer coating the uneven surface, and plural capturing substances binding to the target particle, wherein the capturing substances are localized in the lipid bilayer with fluidity, and labeled with a signaling material, wherein the uneven surface comprises a plurality of pillars, grooves, or a combination thereof, and a height and interval of plurality of pillars, or a depth and diameter of the plurality of grooves, are at least 1.2 times an average diameter of the target particle.
Lou teaches a lipid nanopillar array for detecting circulating tumor cells comprising I). a surface with nanopillars substrate (See page 4, paragraph 2); II). a lipid bilayer (SLBs) as a surface coating in quartz nanopillar-based CTC (Circulating tumor cells) capture (See page 3, paragraph 3); III). A lipid coating serves both as an effective passivation layer that helps prevent nonspecific cell adhesion and as a functionalized layer for antibody-based specific cell capture. In addition, the fluidity of lipid bilayers enables antibody clustering that enhances the cell–surface interaction for efficient cell capture (See Abstract), and the lipid bilayer can be easily functionalized by doping lipids with functional groups, such as biotinylated lipid molecules for streptavidin–biotin-based antibody functionalization (See page 3, paragraph 3). Here the description teaches a plural capturing antibodies binding to the target CTC and capturing substance are localized in the lipid bilayer with fluidity and biotinylated labelling as claimed.
As for the “uneven surface”, although Lou does not explicitly use the term “uneven”, a “quartz nanopillar” surface taught by Lou is obviously an uneven surface with a 3D structure of a fabricated Quartz nanopillar arrays (See page 3, paragraph 4). The uneven surface of the fabricated quartz nanopillar can also be evidenced by the study of Roy. Roy teaches that recent studies have used three-dimensional (3D) nanostructures such as nanopillars to imprint well-defined membrane curvatures (the “nano−bio interface”) (See Abstract). Also, Lou teaches that the surfaces with vertical quartz nanowire arrays had been shown to achieve superior capture efficiency compared to flat surfaces for CTCs as well as on T lymphocytes (See page 2, paragraph 2) that indicates an uneven surface as well.
As for the new added limitation “wherein the uneven surface comprises a plurality of pillars, grooves, or a combination”, Lou teaches a Quartz Nanopillar Arrays that were fabricated on square quartz coverslips (See page 3, paragraph 4), and the array are introduced supported lipid bilayers (SLBs) as a surface coating in quartz nanopillar-based CTC capture (See page 3, paragraph 3), where the Lipid bilayer-coated nanopillar arrays with different diameters and pitch size produced similar results with respect to both the capture efficiency and capture purity of the lipid-coated flat surface (Figure S5) (See page 8, paragraph 1). Here this description teaches that the uneven surface of the Quartz Nanopillar contains a plurality of pillars.
Also, Lou teaches the uneven surface comprise a plurality of pillars by stating that quantification of the fluorescence of several nanopillars shows consistent intensities among all of them (Figure 1d), indicating a conformal lipid bilayer coating on all of the nanopillar surfaces. Furthermore, they used Alexa488-labeled streptavidin (SA-488) to visualize the uniformity of the proteins attached to the supported lipid bilayer (See page 6, paragraph 1; Figure 1, page 12 and below).
As for the new limitation “a height and interval of plurality of pillars, or a depth and diameter of the plurality of grooves, are at least 1.2 times an average diameter of the target particle”, although Lou does not explicitly point out the diameter, height, or interval of the pillar or groove is at least 1.2 times the average diameter of the target particle. However, Lou et al. teaches that lipid bilayer-coated nanopillar arrays with different diameters and pitch size produced similar results with respect to both the capture efficiency and capture purity of the lipid-coated flat surface (Figure S5, Supporting information and below). Since Lou teaches using the 500 nm diameter, 3 μm spacing, and 1.3 μm height quartz nanopillar to capture MCF7 cells with high purity and efficiency (See e.g., Figure S5 below; Figure 1, below), determining other workable or optimal diameters, spacings, etc. is routine experimentation. This can be also evidenced by Wang’s study. Wang describes the effects of nanopillar (NP) array diameter and spacing on cancer cell capture and cell behaviors and teaches that a linear relationship between cell capture yield and effective contact area of NP substrate where NP array of small diameter and reasonable spacing is preferred; however, spacing that is too small or too large adversely impairs capture efficiency and specificity, respectively. In addition, the formation of pseudopodia between captured cells and substrate is found to depend not only on cell adhesion status but also on eluting strength and shear direction (See abstract), which indicates that the claimed ratio at “height and interval of plurality of pillars, or a depth and diameter of the plurality of grooves, are at least 1.2 times an average diameter of the target particle” depend on varies factors and can be adjusted through routine experimentation.
Accordingly, one of ordinary skills would be able to test for an optimal condition as claimed to reach 1.2 times ratio between pillar or groove and the diameter of the target particles. Therefore, the claimed “1.2 times” limitation would have been obvious unless there is evidence showing that they produce unexpected results.
Based on the description above, Lou also teaches claim 2 with at least “1.5 times” between pillar or groove and the diameter of the target particles and claim 3 with at least “2 times” between pillar or groove and the diameter of the target particles.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
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Regarding claim 4, it requires a hydrophilic surface. Lou teaches that lipid bilayers are a natural passivation layer. Supported lipid bilayers have been shown to effectively prevent cells from binding to underlying surfaces. They can be easily formed in vitro by applying small unilamellar vesicles (SUVs) to the hydrophilic surface under physiological conditions (See page 3, paragraph 3).
Regarding claim 5, Lou teaches that the target particle is a MC7 cell.
(New Rejection-necessitated by amendment) Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Lou as evidenced by Roy and Wang as applied to claims 1-5 above, and in view of Hartman et al. (Nanoscale, 2015, 7, 66) and Matsubara et al. (Front Microbial. 2016 Apr 7; 7:468).
Claim 6-7 require the detected particles of claims 5 is a virus and coronavirus, an influenza virus, or a combination, respectively.
Relevance of Lou is set forth above, it is silent on the target particle is virus.
Hartman et al. reviews the surface functionalization and applications of nanoparticles tethered to supported lipid bilayers (SLBs). SLBs are synthetic membranes self-assembled on a planar surface (See Introduction), and teaches that lipid vesicles on the nanoscale can also be surface-functionalized, tethered to the bilayer, and tracked by fluorophores on the vesicle surface or enclosed within (See page 68, right column, paragraph 3). Hartman discloses that the viral particle can be detected using the supported lipid bilayers as dynamic platforms for tethered particles by stating that using a fluid bilayer with GM1 to detect the single virus particles that natively attach to the ganglioside lipid from several surface binding sites (See page 70, right column, paragraph 2), which can enhance signal transduction severalfold (See page 72, left column, paragraph 1), and can persist for weeks, and all of these properties enable robust, massive statistical readouts from a single sample of tethered nanoparticles (See page 65, left column, paragraph 1). Fig. 1 of Hartman teaches using the substance of the single streptavidin modified QD in a fluid GM1 bilayer to detect the virus-like particles (See page 68, left column, Fig. 1 and below). Although Hartman does
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not specify if the virus is influenzas virus or coronavirus, one skilled in the art can select a virus as needed to test using the lipid bilayers technique for virus detection as taught by Hartman.
Nevertheless, Matsubara teaches a lipid bilayer composed of pep-PE and an unsaturated phospholipid (DOPC) was immobilized on a mica plate; and the interaction between HA and the pep-PE/DOPC membrane was investigated using atomic force microscopy. The results indicate that peptide-conjugated lipids are a useful molecular device for the detection of HA and IFV (See Abstract and FIGURE 1, page 4 and below). Matsubara also teaches that peptide-conjugated lipids have the potential to detect biomolecules, toxins, viruses, and pathogenic materials. Peptide-conjugated lipids may be useful not only for the diagnosis and surveillance of influenza, but also those of other sugar-related diseases (See page 8, right column).
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Lou, Hartman and Matsubara to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because Hartman teaches that using a fluid bilayer with GM1 can detect the single virus particles (Page 68, right column), and Matsubara teaches that the Peptide-conjugated lipids is useful not only for the diagnosis and surveillance of influenza, but also those of other sugar-related diseases. Lou teaches a method using lipid-nanopillar array for detecting target particle. Furthermore, Hartman and Matsubara teach that the functionalized supported Lipid Bilayers either on glass or mica (see Hartman, page 71; Matsubara, Abstract) can be used to detect the influenza virus. Therefore, there would be a reasonable expectation of success to develop a lipid bilayer-based array to detect virus as claimed.
(New Rejection-necessitated by amendment) Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Lou as evidenced by Roy and Wang as applied to claims 1-5 above,
Regarding claims 8 -10, they require a kit for detecting a target particle, comprising two or more of the arrays for detecting a target particle of claim 1 (claim 8), and wherein the arrays are for detecting the same target particle (claim 9) or detecting different targets (Claim 10).
Lou et al. teaches that lipid bilayer-coated nanopillar arrays with different diameters and pitch size produced similar results with respect to both the capture efficiency and capture purity of the lipid-coated flat surface (Figure S5) (See page 8, paragraph 1), which indicates that one or more arrays are used and tested. Also, in Lou’s study, they basically focused on MCF7 cells, but they also use the Hela and MDA-MB-231 cells to evaluate the capture and separation efficiencies of the supported lipid bilayers (See e.g., page 5, paragraph 2). Based on the description, it is reasonable to consider that the lipid bilayer-coated nanopillar arrays of Lou can be served as detecting array for the same target particle or a different target particle.
However, Lou et al. is silent on a kit including these arrays and the target.
The concept of packaging components into a kit is well known and routine in the art. Lou teaches using one or more lipid bilayer-coated nanopillar arrays to capture the MF7 cells in promoting both the capture efficiency and capture purity of nanostructure-based CTC-capture (See Abstract). It would have been obvious for one of ordinary skill in the art at the time the invention was made to package components into a kit. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. Thus, the claimed invention is obvious over Lou’s research.
(New Rejection-necessitated by amendment) Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lou as evidenced by Roy and Wang as applied to 1-5 and 8-10, and in view of Hartman et al. (Nanoscale, 2015, 7, 66) and Matsubara et al. (Front Microbial. 2016 Apr 7; 7:468).
Claims 11 and 12 require the target particle is a virus (claim 11) and a coronavirus and/or an influenza virus (claim 12).,
Based on the description above, although Lou teaches an array that can capture cancer cells and is silent on virus detection by the array, Hartman teaches using the substance of the single streptavidin modified QD in a fluid GM1 bilayer to detect the virus-like particles (See page 68, left column, Fig. 1 and below), and Matsubara et al. teaches a lipid bilayer detection for influenza virus. However, these teachings do not teach a kit as claimed.
The concept of packaging components into a kit is well known and routine in the art. Hartman et al. teaches using surface functionalization and applications of nanoparticles tethered to supported lipid bilayers (SLBs) to detect viral particles to enhance signal transduction and Matsubara et al. teaches using a lipid bilayer composed of pep-PE and an unsaturated phospholipid (DOPC) to detect a target of influenzas virus for a convenient surveillance application tool. It would have been obvious for one of ordinary skill in the art at the time the invention was made to package components into a kit. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. Thus, the claimed invention is obvious over Lou et al. research.
(New Rejection-necessitated by amendment) Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Lou as evidenced by Roy and Wang as applied to claims 1-5 and 8-10 above.
The base claim 13 is directed to a method of detecting a target particle, comprising:
contacting a sample with the array for detecting target particle of claim 1
or a kit for detecting target particles comprising a plurality of the arrays; and measuring a signal generated from the array or the kit.
Based on the description above, Lou et al. teaches a method for generating a lipid-based functionalization of nanopillars array for detecting the target cancel cells (See Abstract). Lou et al. teaches that the lipid-based functionalization of nanopillars consists of three steps (illustrated in Figure 1a): (1) the formation of a supported lipid bilayer on freshly cleaned quartz by the spontaneous rupture of small unilamellar vesicles that are composed of phosphatidylcholine doped with 1 mol % biotinylated phosphor ethanolamine (biotin-DOPE, Avanti); (2) the binding of streptavidin (SA) on biotinylated lipids; and (3) the binding of biotinylated antibody on an SA-bound supported lipid bilayer. The whole incubation process takes <75 min, which is much faster than covalent methods (~4 h). Visualizing the supported lipid bilayer by adding 0.5 mol % of fluorescence-labeled lipids (See page 6, paragraph 1), which teaches that the signal measurement.
As for a kit, Lou does not explicitly point out a kit. However, the concept of packaging components into a kit is well known and routine in the art. For example, Lou teaches a detailed method for making a fabrication of Quartz Nanopillar Arrays, preparing the Lipid Vesicles, sample isolation and Fluorescence Recovery (See Experimental section), where the Quartz Nanopillar Arrays can be used to detect the circulating tumor cells (CTC) (See Abstract). It would have been obvious to one of ordinary skill in the art at the time the invention was made to package components into a kit. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. Thus, the claimed invention is obvious over Lou’s research.
Regarding claim 14, Lou et al. teaches the sample is from the human blood sample (See page 5, paragraph 4).
(New Rejection-necessitated by amendment) Claims 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Lou as evidenced by Roy and Wang as applied to claims 1-5, 8-10 and 13-14 above, and in view of Hartman et al. (Nanoscale, 2015, 7, 66) and Matsubara et al. (Front Microbial. 2016 Apr 7; 7:468).
Regarding claims 15 and 16, they require the target particle is virus or coronavirus/an influenza virus.
Relevance of Lou et al. is set forth above, it is silent on the target particle is virus.
Hartman et al. reviews the surface functionalization and applications of nanoparticles tethered to supported lipid bilayers (SLBs). SLBs are synthetic membranes self-assembled on a planar surface (See Introduction), and teaches that lipid vesicles on the nanoscale can also be surface-functionalized, tethered to the bilayer, and tracked by fluorophores on the vesicle surface or enclosed within (See page 68, right column, paragraph 3). Hartman et al. discloses that the viral particle can be detected using the supported lipid bilayers as dynamic platforms for tethered particles by stating that using a fluid bilayer with GM1 to detect the single virus particles that natively attach to the ganglioside lipid from several surface binding sites (See page 70, right column, paragraph 2), which can enhance signal transduction severalfold (See page 72, left column, paragraph 1), and can persist for weeks, and all of these properties enable robust, massive statistical readouts from a single sample of tethered nanoparticles (See page 65, left column, paragraph 1). Fig. 1 of Hartman teaches using the substance of the single streptavidin modified QD in a fluid GM1 bilayer to detect the virus-like particles (See page 68, left column, Fig. 1 and below). Although Hartman does not specify if the virus is influenzas virus or coronavirus, one skilled in the art can select a virus as needed to test the lipid
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bilayers technique taught by Hartman.
Nevertheless, Matsubara teaches a lipid bilayer composed of pep-PE and an unsaturated phospholipid (DOPC) was immobilized on a mica plate; and the interaction between HA and the pep-PE/DOPC membrane was investigated using atomic force microscopy. The result indicate that peptide-conjugated lipids are a useful molecular device for the detection of HA and IFV (See Abstract and FIGURE 1, page 4 and below). Matsubara also teaches that peptide-conjugated lipids have the potential to detect biomolecules, toxins, viruses, and pathogenic materials. Peptide-conjugated lipids may be useful not only for the diagnosis and surveillance of influenza, but also those of other sugar-related diseases (See page 8, right column).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings from Lou, Hartman and Matsubara to arrive at an invention as claimed. One of skill in the art would have been motivated to do so because Hartman teaches that using a fluid bilayer with GM1 can detect the single virus particles, and Matsubara teaches that the Peptide-conjugated lipids is useful not only for the diagnosis and surveillance of influenza, but also those of other sugar-related diseases. Lou teaches a method using lipid-nanopillar array for detecting target particle, Hartman and Matsubara teach that the functionalized supported Lipid Bilayers either on glass or mica (see Hartman, page 71; Matsubara, Abstract) can be used to detect the influenza virus. Therefore, there would be a reasonable expectation of success to develop a lipid bilayer-based array to detect virus as claimed.
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Responses to Applicant’s Remarks
Applicant’s arguments filed on Dec. 29, 2025 has been received and fully considered as follows:
Applicant’s argument and amendment regarding the rejections under 35 U.S.C. § 102 is considered. The rejections are withdrawn and the argument is moot.
Applicant argued that Lou fails to suggest the technical feature that "the height and interval of plurality of pillars are at least 1.2 times an average diameter of the target particle" as defined in Claim I of the present application” (See Remarks, bridging pages 6-7).
The argument is not persuasive.
1). Applicant allegedly use the Lou’s Fig. S5 and Annex 1 to argue the pillar spacing (3 μm) for being significantly smaller than the diameter of the target cells (about 15-20 μm), This is not persuasive because Lou’s data is specifically for the cancer cells, however, the claimed target particles is a generic particle. When using a target particle with smaller diameter, the difference between the pillar spacing and the target particles would be different. Therefore, the claims “1.2 times”, “1.5 times” or “2 times” would be achieved by routine experimental optimization.
2). Based on the teaching of Table S1, Lou teaches different size of pillar spacing (See Table S1 and below). With different cell sizes, a claimed “1.2 times”, “1.5 times” or “2 times” can be reaches by routine experimentation based on the different pillar spacing size. Applicant’s claims do not recite a limitation on a “"on top" of the nanopillar array” as argued (See Remarks, page 7).
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3). Applicant claims that the comparison between the pillar and the target particles is based on “the height and interval of plurality of pillars”, not just the spacing size as argued.
4). In addition, Lou teaches that Lipid bilayer-coated nanopillar arrays with different diameters and pitch size produced similar results with respect to both the capture efficiency and capture purity of the lipid-coated flat surface (Figure S5) (See page 8, paragraph 1). The Office does not have the facilities and resources to provide the factual evidence needed in order to establish that the Lipid bilayer-coated nanopillar arrays with different diameters and pitch size does not make similar results with respect to both the capture efficiency and capture purity of the lipid-coated flat surface. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed invention is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
3. Applicant argued that the structural differences outlined about lead to a fundamental difference in the mechanism of detection, specifically Signal Clustering vs. Target Cell Staining. since in Lou, the target cells are stained, it requires to remove (wash away) cells that are not bound to the substrate (See Remarks, bridging pages 7 and 8).
The argument is not persuasive because the instant application claims a generic pillars and generic target particles. There is no mechanism limitation and cell staining requirements.
Accordingly, Lou in view of Hartman and Mastubara teaches the current claims.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am-5:00 pm, EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached on (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/RUIXUE WANG/Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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