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 without traverse of Group I (claims 1-15), drawn to a method for neutralizing biotin interference in a binding assay for detection of an analyte in a biological sample, to in the reply filed on 03/05/2026 is acknowledged.
Applicant’s species election without traverse of “i. Powder, granular material, or microfiber," (claims 3-4), for a porous adsorbent substance, in the reply filed on 03/05/2026 is acknowledged.
Claim 16 is withdrawn by Examiner from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, drawn to a device for neutralizing biotin interference in a binding assay for detection of an analyte in a sample, , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/05/2026.
Claims 5-6 and 9 are withdrawn by Examiner from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species for ,” there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/05/2026.
Claim Status
Claims 1-16 are pending. Claims 5-6, 9, and 16 are withdrawn by Examiner as being drawn to a nonelected species and a nonelected invention. Claims 1-4, 7-8 and 10-15 are examined herein.
Priority
The instant application claims priority under 35 U.S.C. §119 to European Patent Application No.22178270.9, filed June10, 2022, the entire contents of which are incorporated herein by reference. The effective filing date for the instant claims of this application is June 10, 2022.
Information Disclosure Statement
One Information Disclosure Statement (IDS), filed 05/30/2023, is acknowledged and considered.
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.
Claims 1-2, 4, 10-11, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Lakshmipriya et al., (Lakshmipriya et al., Biotin-Streptavidin Competition Mediates Sensitive Detection of Biomolecules in Enzyme Linked Immunosorbent Assay, 2016, PLOS ONE, 11, 3, e0151153, 1-14), in view of Exner et al., (T. Exner et al., The effect of DOACs on laboratory tests and their removal by activated carbon to limit interference in functional assays, 2020, Int J Lab Hematol, 41, 41-48), and Phothong et al., (Phothong et al., The Analysis of Pore Development and Formation of Surface Functional Groups in Bamboo-Based Activated Carbon during CO2 Activation, 2021, Molecules, 26, 5641, 1-26), as evidenced by Pelekani et al., (C. Pelekani and V.L. Snoeyink, Competitive adsorption in natural water: Role of activated carbon pore size, 1999, Wat. Res., 33, 5, 1209-1219).
Throughout the article, Lakshmipriya teaches a competition-based assay comprising pre-mixed free biotin with a biotin-binding component, streptavidin-HRP, to reduce free biotin interference when detecting an analyte. Lakshmipriya teaches this assay system improves detection sensitivity and this improvement is attributed to the four binding sites for biotin on the streptavidin. Lakshmipriya further teaches that since free biotin blocks some of the binding sites for biotin on streptavidin, this provides more opportunities for streptavidin-HRP to bind with biotinylated component (antibody).
Regarding claims 1, Lakshmipriya teaches a method for neutralizing biotin interference in a binding assay for detection of an analyte in a sample, wherein the binding assay comprises contacting the sample at least with a biotinylated component and with a biotin-binding component (Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, pg. 1, Abstract, pg. 3, and pgs. 5-6), but Lakshmipriya does not teach wherein the sample is contacted with an adsorbent substance before or during contacting with the biotinylated component and with the biotin-binding component.
Throughout the article, Exner, in the same field of endeavor, teaches the interfering effect of direct oral anticoagulants (DOACs) on tests for haemostatic function and further reviews prior art teachings for overcoming these using activated carbon (AC) adsorbent substance to eliminate DOAC issues from test samples. Exner examines and reports the state of the art regarding lab tests detecting DOACs, lupus anticoagulant, factor assays, and activated protein C (APC) resistance in the presence and absence of activated carbon (AC). Exner further teaches that the prior art shows that sample pretreatment by AC extracts DOACs from plasma samples with minimal effect on underlying lab tests/assays. Exner teaches separating the sample from AC via centrifugation. Exner teaches that DOAC extraction by AC in human blood samples results in reduced false positive detection for lupus anticoagulant and provides more reliable clotting factor assays and tests for APC resistance and thrombophilia.
Exner teaches the limitations in instant claim 1 reciting wherein the sample is contacted with an adsorbent substance before or during the contacting with the sample testing components and reagents, a method that can be adapted to perform the limitation of contacting a sample with the “adsorbent substance before or during the contacting with the biotinylated component and with the biotin-binding component” (Exner et al., 2020, Int J Lab Hematol, pg. 41, Abstract and pg. 42, full para 4). Exner does not teach the adsorbent substance has a range of pore sizes, a range for total surface area, or a range for micropore volumes.
Throughout the article, Phothong, in the same field of endeavor, teaches using bamboo as a precursor for the synthesis of activated carbon, an adsorbent material, at different temperatures and activation times for pore development. Phothong teaches that increasing activation conditions promotes porous properties of produced activated carbons but may cause a decrease in micropore volume with each increase in mesopore volume. Phothong teaches that under specific conditions activated carbon prepared from bamboo generates a distribution of pores with the majority of pores in the microporous range. Phothong teaches that under these conditions the activated carbon material had a maximum surface area of 907 m2/g and a total pore volume of 0.446 cm3/g. Phothong further teaches that with increasing activation temperature the concentration of acid and basic groups increases.
Phothong teaches the limitations in instant claim 1 reciting the adsorbent substance has a porous structure having a total surface area of from 300 to 6500 m2/g (Phothong et al., 2021, Molecules, 26,pg. 24, Appendix A, Table A1) and has at least macropores, mesopores and micropores, and wherein the volume of the micropores is from 0.15 to 0.75 cm3/g (Phothong et al., 2021, Molecules, 26, pg. 2, full para 1 and pg. 24, Appendix A, Table A1).
It would have been prima facie obvious, at the time of filing, to combine the method of neutralizing free biotin interference using a competitive biotin-streptavidin binding assay for detection of an analyte, as taught by Lakshmipriya, with the method of contacting the human blood sample with an adsorbent substance before or during the immunoassay (binding) reaction, as taught by Exner. A skilled artisan would have been motivated to combine these methods because it would reduce false positives thus providing more reliable assay results. It would have been further prima facie obvious, at the time of filing, to combine the adsorbent substance that is contacted with sample to reduce interferents in a human blood sample, as taught by Exner, with the porous, adsorbent substance with the range in surface area and micropore volume taught by Phothong. A skilled artisan would have been further motivated to combine the teachings of Exner with the teachings of Phothong because it would generate an adsorbent substance with an extended surface area with high adsorption capacity, which would enhance reduction of free biotin interference, a small organic molecule, in a sample. Further, the prior art teaches that porous activated carbon as an adsorbent for interferents in biological samples consists predominantly of micropores, which selectively adsorb small organic molecules like free biotin (see Phothong et al., 2021, Molecules, 26, 5641, pgs. 23-24 and C. Pelekani et al., 1999, Wat. Res., 33, 5, pgs. 1209-1210).Thus a skilled artisan would have been further motivated to combine the teachings of Exner with the porous adsorbent substance predominantly consisting of micropores taught by Phothong because the average pore sizes would selectively adsorb the small organic target interferent (free biotin) and not adsorb the larger macromolecules including the target analyte and those required to sustain life. At the time of filing, the prior art taught a method for reducing biotin interference in a sample for a biotin-streptavidin assay (see Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, 1-14 ). Additionally, at the time of filing, the prior art taught methods for reducing interference in samples by contacting the sample with an adsorbent substance prior or during a lab test or binding assay for the sample (Exner et al., 2020, Int J Lab Hematol, 41, 41-48). Further, at the time of filing, the prior art taught methods for generating a porous adsorbent substance with the surface area and pore volume ranges required for selective adsorption of the small interferent (see Phothong et al., 2021, Molecules, 26, 5641, 1-26 ). Thus, a person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings amounts to combining known prior art elements (adsorbent, porous substance, surface area and volume ranges for selective adsorption of small organics) with a known method (reducing biotin interference in biotin-streptavidin binding assay) to yield expected and predictable results (reducing small organic interferent, free biotin, without losing analyte).
Regarding claim 2, Lakshmipriya, Exner, and Phothong teach all the limitations of claim 1. Exner and Phothong further teach, wherein the adsorbent substance is activated carbon (Exner et al., 2020, Int J Lab Hematol, pg. 41, Abstract and Phothong et al., 2021, Molecules, 26, pg. 2, full para 1 and pg. 24, Appendix A, Table A1).
It would have been prima facie obvious, at the time of filing, to combine the teachings of Lakshmipriya with the teachings of Exner and Phothong. A skilled artisan would have been motivated to combine the method of reducing biotin interference in a biotin-streptavidin binding assay taught by Lakshmipriya with the activated carbon as an adsorbent substance taught by Exner and Phothong because the extended surface area, high adsorption capacity, and high degree of surface reactivity of activated carbon would maximize the amount of free biotin interference that can be removed from a sample allowing for less false positive test results and thus more reliable assay results. At the time of filing, the prior art taught porous activated carbon as an adsorbent substance capable of removing interferents like biotin from blood samples (see Exner et al., 2020, Int J Lab Hematol, pg. 41, Abstract and Phothong et al., 2021, Molecules, 26, 5641, 1-26). Thus, a person having ordinary skill in the art would have a reasonable expectation of success because this combination amounts to combining known prior art elements (activated carbon as adsorbent material to remove interferents in biological fluid sample) with a known method (reducing biotin interference in biotin-streptavidin binding assay) to yield expected and predictable results (maximizing reduction of free biotin in a sample).
Regarding claims 10-11 and 14-15, Lakshmipriya, Exner, and Phothong teach all the limitations of claim 1. Lakshmipriya further teaches wherein the biotin-binding component contains streptavidin (instant claim 10), wherein the biotin-binding component and/or the biotinylated component contains a protein or an antibody [instant claim 11] (Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, pg. 1, Abstract, pg. 3, and pgs. 5-6). Lakshmipriya further teaches wherein the sample is a body fluid sample from a human or an animal (instant claim 14) and wherein the body fluid sample is blood serum or urine [instant claim 15] (Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, pg. 9).
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Lakshmipriya et al., (Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, 1-14), in view of Exner et al., (T. Exner et al., 2020, Int J Lab Hematol, 41, 41-48), and Phothong et al., (Phothong et al., 2021, Molecules, 26, 5641, 1-26), as applied to claim 1, further in view of Hiroyuki et al., (International Application No. WO 2012050025 A1), as evidence by Potwora (R.J. Potwora, Activated Carbon Particle Size: Balance Between Kinetics and Capacity, WCP International, June 15, 2016, URL: wcponline.com/2016/06/15/activated-carbon-particle-size-balance-kinetics-capacity/).
Regarding claim 3, the teachings of Lakshmipriya, Exner and Phothong are discussed herein above. Lakshmipriya, Exner and Phothong teach all the limitations of claim 1 (see above). Lakshmipriya, Exner and Phothong do not teach wherein the sample is contacted with the adsorbent substance by mixing the sample with the substance in the form of a powder, granular material or microfiber mixture to form a suspension.
Throughout the disclosure, Hiroyuki teaches an activated carbon adsorbent material in the form of an oral pharmaceutical adsorbent made from purified cellulose or regenerated cellulose. Hiroyuki further teaches a method for producing the same, and in particular, composed of activated carbon derived from cellulose with high adsorption capacity particularly for toxic substances in biological fluids. Hiroyuki teaches an embodiment where the activated carbon adsorbent substance is a granular form of the activated carbon with pore diameters between 1.5 to 2.2 nm, specific BET surface area between 700 to 3000 m2/g, average particle diameter of 100 to 1100 μm, surface oxidation at or above 0.05 meq/g, and a packing density of 0.4-0.8 g/mL.
Hiroyuki teaches the limitation of claim 3 reciting a sample contacted with the adsorbent substance, in form of granular activated carbon, by mixing the sample with the substance to form a suspension (WO 2012050025 A1: Espacenet Translation pgs. 1-3).
It would have been prima facie obvious, at the time of filing, to combine the teachings of Lakshmipriya, in view of with Exner and Phothong, with the teachings of Hiroyuki. The prior art teaches that the adsorption rate of organic interferents rapidly increases as the particle size decreases (see R.J. Potwora, Activated Carbon Particle Size: Balance Between Kinetics and Capacity, WCP International, June 15, 2016, URL above). Phothong teaches an adsorbent activated carbon substance with a particle size of 2.2 mm (see 2021, Molecules, 26, 5641, pg. 3) and Hiroyuki teaches a granular form of the adsorbent activated carbon substance with particle size ranging between 0.1-1 mm (see WO 2012050025 A1: Espacenet Translation pg. 3, full para 3). Thus, a skilled artisan would have been motivated to combine these teachings to modify the method of contacting a sample with an adsorbent substance (activated carbon) before or during a lab test or assay on the sample, as taught by Exner, and further modify the particle size of the porous adsorbent, as taught by Phothong, with the teachings of mixing the sample with the granular form of the adsorbent substance (granulated activated carbon with smaller particle sizes), as taught by Hiroyuki, because the granular form of the adsorbent would increase the selective adsorption rate of the small organic interferent (free biotin) in a sample. A person having ordinary skill in the art would have a reasonable expectation of success because combining the teachings known in the art at the time of filing to modify the particle size of the adsorbent material by using a granular form to improve adsorption rate of the sample interferent amounts to applying a known improvement to a similar method/product to yield expected and predictable results.
Regarding claim 4, Lakshmipriya, Exner and Phothong teach all the limitations of claim 1 and Hiroyuki teaches the additional limitations of claim 3. Exner, in the same field of endeavor, further teaches wherein the sample is removed from the suspension of the adsorbent substance before the subsequent sample testing via centrifugation (pg. 41, Abstract and pg. 44, all paras under Topic #9).
It would have been prima facie obvious, at the time of filing, to combine the method of neutralizing biotin interference in a binding assay for detecting an analyte, as taught by Lakshmipriya, with the adsorbent substance and method of separating the sample from the adsorbent prior to assaying the sample, as taught by Exner. A skilled artisan would have been motivated to combine these teachings because separating the sample from the adsorbent material, saturated with interferents, prior to testing and/or assaying the sample would minimize false positive detection and increase reliability of assay results. At the time of filing, a method for removing free biotin interferents from a biological sample for analyte detection in a biotin-streptavidin binding assay was known in the art. Further, at the time of filing, the prior art taught separating the sample from an adsorbent substance that removed interferents from a biological sample using centrifugation, allowing for the sample to be assayed or undergo lab tests with minimal to no interferents (see Exner, et al., 2020, Int J Lab Hematol, 41, 41-48). Thus, a person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings to improve accuracy of assay results, or of disease diagnosis, would amount to applying a known improvement (methods of mixing sample and adsorbent material to remove interferents and separating sample from adsorbent material) to a base/known method (method of removing biotin interference from sample prior or during binding assay for analyte detection) to yield predicable results (increased reduction of biotin interference, lower false positives, and more reliable test/assay results) .
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Lakshmipriya et al., (Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, 1-14), in view of Exner et al., (T. Exner et al., 2020, Int J Lab Hematol, 41, 41-48), and Phothong et al., (Phothong et al., 2021, Molecules, 26, 5641, 1-26), as applied to claim 1, further in view of Opet et al., (Opet et al., Efficacy of coating activated carbon with milk proteins to prevent binding of bacterial cells from food for PCR detection, 2013, Journal of Microbiological Methods, 94, 6, 69-72).
The teachings of Lakshmipriya, Exner, and Phothong are discussed herein above. Lakshmipriya, Exner, and Phothong teach all the limitations of claim 1. Lakshmipriya, Exner, and Phothong do not teach wherein the adsorbent substance has been pretreated with one or more blocking proteins or blocking peptides and wherein the one or more blocking proteins are dextran, albumin, polygeline or milk protein.
Throughout the article, Opet teaches method comprising activated carbon coated with milk proteins to adsorb small soluble interferent compounds, such as PCR inhibitors, in food. Opet teaches activated carbon coated with milk proteins allows for a near maximum target analyte recovery from an aqueous cell suspension while removing significant amounts of interferents from the sample.
Regarding claims 7-8, Opet teaches wherein the adsorbent substance has been pretreated with one blocking protein (instant claim 7) and wherein the one blocking protein is milk protein [instant claim 8] (Opet et al., 2013, Journal of Microbiological Methods, 94, 6, pgs. 70, para 2.3).
It would have been prima facie obvious, at the time of filing, to combine the method of reducing biotin interference for detecting an analyte by contacting sample with a porous adsorbent substance as taught by Lakshmipriya, in view of Exner and Phothong, with the method of pretreating the adsorbent substance with a blocking milk protein, as taught by Opet. A skilled artisan would have been motivated to combine these teachings because it would enable adsorption of the small interferent molecule but not of the target analyte, minimizing loss of target analyte concentration, which would also enable the analyte detection to become a quantitative measure (see Opet et al., 2013, Journal of Microbiological Methods, 94, 6, pg. 69). A person having ordinary skill in the art would have a reasonable expectation of success because combining these teachings would amount to applying a known improvement (milk protein block) to a base/product (adsorbent material) to yield predicable results (minimize loss of analyte and maximize selective adsorption of small interferent).
Claims 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Lakshmipriya et al., (Lakshmipriya et al., 2016, PLOS ONE, 11, 3, e0151153, 1-14), in view of Exner et al., (T. Exner et al., 2020, Int J Lab Hematol, 41, 41-48), and Phothong et al., (Phothong et al., 2021, Molecules, 26, 5641, 1-26), as applied to claim 1, further in view of Zhang et al., (Zhang et al., Photodynamic therapy of cancers with internal light sources: chemiluminescence, bioluminescence, and Cerenkov radiation, 2020, Front Chem., 8, 770, 1-7), as evidenced by Mao et al., (Mao et al., Chemiluminescence-Guided Cancer Therapy Using a Chemiexcited Photosensitizer, 2017, Chem, 3, 991-1007).
The teachings of Lakshmipriya, Exner, and Phothong are discussed herein above. Lakshmipriya, Exner, and Phothong do not teach wherein a first and second signal-forming system and wherein first and the second component of the signal-forming system are brought in close proximity to interact and form a detectable signal and wherein the first signal-forming system is by chemiluminescence and the second signal-forming system is a photosensitizer or vice versa.
Throughout the article, Zhang teaches the state of the art by reviewing recent advances in the development of self-illuminating photodynamic therapy (PDT) systems, a promising medical technique for the treatment of several types of cancers, skin diseases, and bacterial and fungal infections. Zhang teaches that traditionally, PDT requires an external light source, to excite a photosensitizer, which limits the use of PDT as a treatment to superficial use because the light intensity rapidly reduces as it travels through layers of tissue. Zhang teaches that as a result, the light that reaches the target area has insufficient energy to activate the photosensitizer, leaving infected or malignant cells alive. Zhang teaches chemiluminescence (CL), bioluminescence and Cerenkov radiation, as an internal light source, have been proven capable of producing light with sufficient intensity and energy to excite certain photosensitizers to produce reactive oxygen species (ROS) that cause oxidative damage to essential cellular components and efficiently destroy target cells.
Regarding claims 12-13, Zhang teaches wherein the biotinylated component contains a first component of a signal-forming system and the biotin-binding component contains a second component of the signal-forming system, and wherein the first and the second component of the signal-forming system interact in such a way that a detectable signal is formed if the first and the second component of the signal-forming system are brought into physical proximity with one another. Zhang further teaches wherein the first component of the signal-forming system is a chemiluminescent agent and the second component of the signal-forming system is a photosensitizer or vice versa (Zhang et al., 2020, Front Chem., 8, 770, pgs. 2-3).
It would have been prima facie obvious, at the time of filing, to combine the method of reducing biotin interference for detecting an analyte as taught by Lakshmipriya, in view of Exner, and Phothong, with the chemiluminescent (CL)-photodynamic therapy (PDT) method taught by Zhang, which is capable of functioning as signaling system for detecting an analyte. A skilled artisan would have been motivated to combine and improve the chemiluminescent (CL) signaling system for detecting an analyte in an immunoassay, as taught by Lakshmipriva, with the coupled CL-PDT method, taught by Zhang, because with the CL-mediated excitation efficiency, ROS production by the photosensitizer would be enhanced, generating a brighter signal in the presence of analyte, thus increasing the detection sensitivity of the assay (see Mao et al., Chemiluminescence-Guided Cancer Therapy Using a Chemiexcited Photosensitizer, 2017, Chem, 3, pg. 992). A skilled artisan would have been motivated to further improve the signaling system for detecting an analyte because combining these teachings would allow for tuning of emission wavelengths enabling detection of more than one analyte (multiplexing) [see Zhang et al., 2020, Front Chem., 8, 770, pg. 5]. A person having ordinary skill in the art would have a reasonable expectation of success because combining these prior art teachings amounts to applying a known improvement (coupled CL-PDT) to a base/known method (chemiluminescence [CL] signaling system) to yield predicable results (enhanced detection sensitivity of an analyte).
Conclusion
All examined claims (1-4,7-8 and 10-15) are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA L LIRIANO whose telephone number is (571)272-0085. The examiner can normally be reached Monday-Friday, 7:30 am-3:30 pm (EST).
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/MELISSA LIZETTE LIRIANO/ Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 April 14, 2026
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