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 .
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.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-12, in the reply filed on 8/24/2026 is acknowledged.
Claims 13 and 15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/24/2026.
Claims 1-12 are examined below.
Priority
The present application was filed on 12/15/2023 and is a CON of PCT/EP2022/066333, filed 06/15/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. EP21180002.4, filed on 06/17/2021 in Europe.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 5/30/2024 and the information disclosure statement filed 1/22/2025 are being considered by the examiner.
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 4 and 9 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 recites “wherein said linking agent is a covalently cross-linking enzyme, preferably, a transglutaminase or sortase”.
However, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is not clear whether the covalently cross-linking enzyme must be a transglutaminase or sortase or if these are merely exemplary. Because of this, a person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
Claim 9 recites “wherein said solid support is a bead, well or predetermined subdivided detection area, preferably, of a plasmonic resonator”.
However, similar to claim 4 above, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is not clear whether the bead, well or predetermined subdivided detection area must be of a plasmonic resonator, or if this limitation is optional. Because of this, a person having ordinary skill in the art would not be capable of recognizing the metes and bounds of the claim.
Claims 10-12 are included in this rejection because they depend from rejected claim 9 but fail to clarify the scope of patent protection sought.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3 and 5-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Smith (WO 2015006503 A1).
Regarding claim 1, Smith teaches a method for determining an analyte suspected to be present in a sample (“A method and system is provided which uses cleavable linkers to detect an analyte in an immunoassay” Abstract, “all components of the cleavable linker system remain bound during sample incubation. This allows for the potential for subsequent sample analysis even when only a single drop of blood is drawn” para. 11, “the analyte detection system is used to identify the concentration of each of the target analytes and in some instances to provide more direct diagnostic information through the analysis of analyte profile” para. 85) comprising: (a) contacting said sample with (i) a first binding agent which is capable of specifically binding to the analyte and which is immobilized on a solid support (“Figure 1 illustrates a system with cleavable linkers for detecting analytes 100 according to an embodiment of the present invention. The system 100 includes a solid support 110, a linker 120, a cleavable linker 130, a capture antibody 140… The solid support 110 is chemically bound to the linker 120 and the cleavable linker 130. The capture antibody 140 is chemically bound to the linker 120… an analyte is introduced to the system 100” paras. 28-30); and (ii) a second binding agent which is capable of specifically binding to the analyte and which is capable of reversibly binding at least one detectable label (“Figure 1 illustrates…a detection antibody 150, and a detection agent 160… The detection antibody is chemically bound to the cleavable linker 130 and the detection agent 160” paras. 28-30); wherein said first and/or second binding agent is linked to an linking agent which is capable of covalently binding the at least one reversibly bound detectable label to the solid support (“the detection agent 160 is Horseradish Peroxidase (HRP), and the substrate is 3,3 ',5,5 '-tetramethylbenzi dine (TMB)…ELISA… In another alternative embodiment, the detection agent 160 is replaced with a fluorophore. This embodiment represents the FLISA protocol” paras. 31 and 33, “The solid support 610 is chemically bound to the N-oxysuccinimide moiety 620. The amide linker 630 reacts with the N-oxysuccinimide moiety 620 to form the amide in solid support with linker 640. In operation, the reaction in the method 600 is used to bind a linker to a solid support” para. 60) when the first and second binding agents are in physical proximity, for a time and under conditions which allow: specific binding of the analyte to the first and the second binding agent such that an complex of first binding agent, analyte and second binding agent is formed; and which allow for covalently binding the at least one detectable label to the solid support (“When an antigen is added, binding to one antibody results in the binding to the second antibody as a result of the close proximity and intramolecular binding kinetics. This phenomenon results in the formation of a complex where the analyte is bound by both a capture and detection antibody in a manner similar to that formed in the second step of the conventional sandwich ELISA. When this bond has formed, the cleavable linker is no longer needed to secure the detection antibody to the surface” para. 13, see Figures 1-2); and (b) removing the complex of first binding agent, analyte and second binding agent from the solid support such that the solid support having covalently bound the at least one detectable label remains (“Following the wash of the active analyte binding region and removal of the unbound antibody-detection agent complexes, the analyte detection system is used to identify the concentration of each of the target analytes” para. 85); and (c) detecting the at least one covalently bound detectable label on the solid support whereby the analyte is determined (“the detection of the agents remaining bound is conducted at specific reading areas where binding agents directed to a known analyte are adhered… Detection of analyte binding occurs through the adhesion of optically active probes when the analyte is present. The detection limit of ELISA systems are dependent on the enzyme and substrate used… Finally, the TYE 573 fluorescence with excitation at 530 nm and emission at 590 nm on a 96-well plate reader is recorded to determine the amount of analyte present in each well in step 1130.” paras. 85-87). Note that although Smith fails to use the language “a second binding agent which is capable of specifically binding to the analyte and which is capable of reversibly binding at least one detectable label when the first and second binding agents are in physical proximity”, the teaching of using antibodies as the second binding agent and fluorophores or enzymes as detectable labels and producing a complex with the analyte when in close proximity inherently provides the capability of specifically binding to the analyte and reversibly binding at least one detectable label when in close proximity. Note that the specification discloses that “[t]ypically, said second binding agent is selected from the group consisting of: an antibody…” (pages 9 lines 18-19) and “[t]he detectable label shall be reversibly bound to the second binding agent. To this end, the detectable label may be a molecule which is capable of reversibly binding to the second binding agent or it may be a molecule or moiety which is already part of the said second binding agent. Typical detectable labels include…enzymatically active labels…or fluorescent labels” (page 9 lines 32-37). Therefore, the teachings of antibodies, enzymatically active labels or fluorescent labels, and the proximity-based complex formation addresses this limitation.
Regarding claim 2, Smith further teaches wherein said first binding agent is selected from the group consisting of: an antibody or fragment thereof (para. 13), an aptamer, a receptor molecule or fragment thereof, and a ligand molecule or fragment thereof (“In one alterative embodiment, the capture antibody 140 and detection antibody 150 are replaced by DNA, RNA, or peptide aptamers” para. 32).
Regarding claim 3, Smith further teaches wherein said second binding agent is selected from the group consisting of: an antibody or fragment thereof (para. 13), an aptamer, a receptor molecule or fragment thereof, and a ligand molecule or fragment thereof (para. 32).
Regarding claim 5, Smith further teaches wherein said linking agent comprises covalently cross-linking chemical moieties (“[t]he solid support 610 is chemically bound to the N-oxysuccinimide moiety 620. The amide linker 630 reacts with the N-oxysuccinimide moiety 620 to form the amide in solid support with linker 640. In operation, the reaction in the method 600 is used to bind a linker to a solid support” para. 60).
Regarding claim 6, Smith further teaches wherein said detectable label is selected from the group consisting of: fluorescent labels, chemiluminescent label, radioactive labels, magnetic labels, and electrochemical labels (“the detection agent 160 is Horseradish Peroxidase (HRP), and the substrate is 3,3 ',5,5 '-tetramethylbenzi dine (TMB)…ELISA… In another alternative embodiment, the detection agent 160 is replaced with a fluorophore. This embodiment represents the FLISA protocol” paras. 31 and 33, “An alternative embodiment is employed using magnetic or impedance immunoassays” para. 37).
Regarding claim 7, Smith further teaches wherein said detectable label comprises a linker which can be covalently linked by the linking agent to the solid support (“Figure 7 illustrates a method of linker cleavage 700 according to an embodiment of the present invention. The method 700 includes a capture antibody with DNA linker 710, a detection antibody with DNA linker and enzyme 720, a capture antibody with uncleaved DNA linker 730, and a detection antibody with cleaved DNA linker and enzyme 740” para. 62, see Figure 7 showing the DNA linker attached to the HRP chemiluminescent detectable label).
Regarding claim 8, Smith further teaches wherein said solid support comprises on its surface a linker to which the label can be covalently bound by the linking agent (“Figure 6 illustrates a method for binding a linker to a solid support 600 according to an embodiment of the present invention. The method 600 includes a solid support 610, a N-oxysuccinimide moiety 620, an amide linker 630 in pre-binding linker chemistry, and a solid support with linker 640 in post-binding linking chemistry…The solid support 610 is chemically bound to the N-oxysuccinimide moiety 620. The amide linker 630 reacts with the N-oxysuccinimide moiety 620 to form the amide in solid support with linker 640. In operation, the reaction in the method 600 is used to bind a linker to a solid support” paras. 59-60, see Figure 6 showing the solid support comprising on its surface the linker “R1” to which the label can be covalently bound by the linking agent).
Regarding claim 9, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the limitation following “preferably” is interpreted as optional and not required to be explicitly taught in the prior art in order to address the claim over the art.
Smith further teaches wherein said solid support is well or predetermined subdivided detection area (“microfluidic and 96-well plate” para. 10, “the detection of the agents remaining bound is conducted at specific reading areas where binding agents directed to a known analyte are adhered” para. 85, claim 10)
Regarding claim 10, Smith further teaches wherein each bead, well or predetermined subdivided detection area has immobilized a predefined amount of first binding agent (“While antibodies adhered directly and using specific binding agents are limited to a concentration of 400-500 ng/cm2 (2.7-3.3 pmol/cm2), biotin conjugated or covalently attached DNA is plated at an optimum concentration nearly 10 times higher (25-33.2 pmol). Beyond the benefits of linker-mediated attachment, the use of linkers of varying length is employed to reduce steric hindrance between antibodies to further increase the antibody surface concentration” para. 79).
Regarding claim 11, Smith further teaches wherein said determining an analyte comprises determining the amount of said analyte (“measured to determine the amount of analyte in the sample” para. 31, “to determine the amount of analyte present in each well” para. 87, “This wavelength is then measured to calculate the amount of analyte in a sample” para. 92).
Regarding claim 12, Smith further teaches wherein said amount is determined by counting the beads, wells or predetermined subdivided detection areas which comprise at least one covalently bound detectable label (“the absorbance of each well at 450 nm is measured using a 96-well plate reader in step 1050. The absorbance is used to calculate the quantity of analyte in each well of the plate” para. 84). Note that although Smith fails to use the language “wherein said amount is determined by counting the beads, wells or predetermined subdivided detection areas which comprise at least one covalently bound detectable label” the teaching of using a plate reader to measure the absorbance of each well at a specific wavelength and calculate the quantity of analyte in each well inherently provides the step of counting the wells or predetermined subdivided detection areas that comprise at least one covalently bound detectable label because the optical signal measured from a plate reader would only come from the counted areas that contain at least one detectable label.
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.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Smith as applied to claim 1 above, and further in view of Kwon et al. Anal. Chem. 2004, 76, 5713-5720 https://doi.org/10.1021/ac049731y ("Kwon").
Regarding claim 4, although the claim is indefinite (see 112b rejection above), in the interest of compact prosecution, the limitation following “preferably” is interpreted as optional and not required to be explicitly taught in the prior art in order to address the claim over the art.
Smith teaches the method of claim 1 as discussed above.
Smith further teaches that “[e]xperiments have shown that nonspecific binding results in nearly 90% of antibodies being adhered in nonproductive orientations. While the use of specific binding agents intended to bind the conserved region of the antibody increase antibody activity nearly 9 fold, the overall concentration of antibodies remains dependent on the surface area” (para. 78).
Smith fails to teach wherein said linking agent is a covalently cross-linking enzyme, preferably, a transglutaminase or sortase.
Kwon teaches “Antibody Arrays Prepared by Cutinase-Mediated Immobilization on Self-Assembled Monolayers” (Title). Kwon further teaches that “[a]ntibody arrays hold considerable potential in a variety of applications including proteomics research, drug discovery, and diagnostics. Many of the schemes used to fabricate the arrays fail to immobilize the antibodies at a uniform density or in a single orientation; consequently, the immobilized antibodies recognize their antigens with variable efficiency. This paper describes a strategy to immobilize antibodies in a single orientation, with a controlled density, using the covalent interaction between cutinase and its suicide substrate. Protein fusions between cutinase and five antibodies of three different types (scFv, VHH, and FN3) were prepared and immobilized upon self-assembled monolayers (SAMs) presenting a phosphonate capture ligand. The immobilized antibodies exhibit high affinity and selectivity for their target antigens, as monitored by surface plasmon resonance and fluorescence scanning. Furthermore, by changing the density of capture ligand on the SAM the density of the immobilized antibody could be controlled” (Abstract). Kwon further teaches that the antibody is immobilized to a solid support surface using the cutinase, i.e. a covalently cross-linking enzyme (“The preparation of an antibody array requires immobilization of immunoglobulins to a solid support” page 5713 col. 2 para. 1, “cutinase-mediated method to immobilize antibodies” page 5714 col. 2 para. 1, “Substrates for SPR spectroscopy were prepared by electron beam evaporation of titanium (40 Å) followed by gold (450 Å) onto glass coverslips” page 5715 col. 2 para. 2).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the teachings of Smith to rely on the covalently cross-linking enzyme taught by Kwon because Kwon teaches that this linking agent enables the immobilization of antibodies onto solid supports with uniform density and orientation, thereby increasing the efficacy of analyte detection and Smith is interested in immobilizing antibodies onto solid supports in an orientation and density that facilitates analyte detection. One would be motivated to make such a modification because Kwon teaches that this covalently cross-linking enzyme is applicable to proteomics research, drug discovery, and diagnostics. A person having ordinary skill in the art would have had a reasonable expectation of success because both Smith and Kwon teach the immobilization of antibodies onto solid supports using a linking agent for analyte detection and diagnostic applications.
Conclusion
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/Fernando Ivich/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
