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 .
Duplicate Claim Warning
Applicant is advised that should claim 1 be found allowable, claim 2 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Specifically, the claims differ in the last line reciting “removing biomarkers from the biological sample” for claim 1 and “isolating biomarkers from the biological sample” for claim 2. For biomarkers from the biological sample “removing” and “isolating” have the same meaning.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 March 27, 2026 has been entered.
Status of the Claims
Claims 1-6, 9, 17-21, 30-35, and 45-53 were pending. Claims 7, 8, 10-16, 22-29, 33, 36-44, 54, and 56-60 were canceled. Claim 55 was withdrawn.
Claim 50 is cancelled. Claims 1, 2, 30, and 35 are amended. Claims 61-62 are added.
Claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61-62 are examined herein.
Claim Objections
Claims 1, 2, and 61 are objected to because:
Claims 1 and 2 recite “an indicator of bacterial infection” (line 2), should be “an indicator of a bacterial infection”.
Claim 61 recites “antigens derived frm bacterium lysis”, should be “antigens derived from bacteria lysis”; and “comprising surface presenting antigens”, should be “comprising surface antigens”.
Appropriate correction is required.
Withdrawn Rejections
The rejection of claims 1-6, 17-21, 30-32, 35, 45-49, and 51-53 under 35 U.S.C. §103 is withdrawn in view of claims 1-2 amendments. However, the claims are still rejected under 35 U.S.C. §103 in view of previously presented prior art of Kirakossian.
The rejection of claims 1-6, 17-21, 30-32, 35, 45-49, and 51-53 on the ground of nonstatutory double patenting is withdrawn in view of claims 1-2 amendments. However, the claims are still rejected on the ground of nonstatutory double patenting in view of previously presented prior art of Kirakossian and new prior art of Branda et al. (WO 2014028726).
The rejection of claims 30 and 35 under 35 U.S.C. §112(b) is withdrawn in view of claims amendments.
The rejection of claim 50 is withdrawn in view of claim cancellation.
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.
Claim 61 is 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 61 recites the method of claim 53, wherein the capture moieties comprise antibodies specific for the bacterium causing the infection, comprising surface antigens or antigens derived from bacterium lysis. Claim 53 does not recite any bacterium. It is unclear what is claimed. However, claim 51 does recite the capture moiety captures a bacterium.
For the purpose of compact prosecution and applying prior art under 35 U.S.C. 102 and 103, the instant claim is interpreted as reciting the method of claim 51.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS. —Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 49 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 49 recites “wherein the biomarker(s) is biotin, human anti-mouse antibodies (HAMA), rheumatoid factor (RF), or anti-streptavidin (Sav)”. Parent claim 1 recites “wherein the biomarkers are an indicator of bacterial infection”. Biotin, human anti-mouse antibodies (HAMA), rheumatoid factor (RF), or anti-streptavidin are not necessarily indicators of bacterial infection. Biotin is a vitamin, mice are not a bacterial infection, and rheumatoid factor is a naturally occurring human protein. Therefore, claim 49 fails to include the limitation of claim 1 “wherein the biomarkers are an indicator of bacterial infection”.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 17-21, 30-32, 35, 45-49, and 51-53, and 61 are rejected under 35 U.S.C. 103 as being unpatentable over Kunkel et al. (IDS; PGPub 2014/0045274), in view of Piketty et al. (Clin Chem Lab Med. 2017 May 1;55(6):817-825), Schilffarth et al. (PGPub 2011/0204874), Dunbar (Clin Chim Acta. 2006 Jan;363(1-2):71-82), and Kirakossian et al. (IDS; PGPub 2004/0157271).
Regarding claims 1-2, 17, 35, 51, and 61, Kunkel teaches a method for removing biomarkers from a biological sample “the present invention relates to particles capable of sequestering a biomarker from a mixture, allowing for the separation of the biomarker from the mixture, as well as methods for sequestering biomarkers” ([0002]).
Specifically, Kunkel teaches combining the sample with particles “the capture particles have the ability to specifically capture molecular species having a defined molecular size, mass, and or affinity characteristic and are used to isolate molecules of interest from a sample typically containing a plurality of different molecular species. The capture particles are added to the sample and then utilized to capture the molecular species of interest” ([0014]).
Regarding the plurality of particles, the reference teaches “different populations of
capture particles can be used at the same time, each having different characteristics with respect to the molecule species they are able to capture” ([0084]).
Regarding step b) of claims 1 and 2, mixing the mixture to provide one or more particle complexes comprising the particles and biomarkers, Kunkel teaches “method is comprised of mixing N-isopropylacrylamide (NIPAm) based particles that contain a type of bait in a solution and performing affinity capture of analytes, the analytes contained in the solution” ([0228]).
Regarding removing or isolating the particle complexes to provide a depleted solution and an enriched isolate the reference teaches that “separation of particles from solution was obtained by centrifugation” ([0179]). The biomarkers bound to the particles form the enriched isolate and the solution separated from the particles by centrifugation becomes a solution depleted of the biomarkers.
The method taught by Kunkel can isolate analytes present in a mixture (Abstract) and sequester a biomarker from a mixture ([0002]) – both isolate and sequester meeting the limitation of claims 1 and 2 reciting removing and isolating biomarkers from the biological sample.
Kunkel does not teach the first population of particles is present at a greater concentration than the second population of particles, and pretreating a sample with a particle comprising a capture moiety lacking specificity for the biomarkers.
Regarding claims 1-2, 17, 35, 51, and 61, Piketty teaches a method to overcome biotin interference in immunoassays that utilize streptavidin-biotin capture techniques (Abstract. Background). Piketty also teaches pretreating a sample with a particle comprising a capture moiety lacking specificity for the biomarkers.
Specifically, Piketty teaches that in some situations a presence of certain molecules in patient’s samples can lead to analytical interference in immunoassays. For example, high-dose biotin therapy can result in interference with immunoassays that utilize streptavidin-biotin capture techniques (id.). In order to prevent such interference, Piketty teaches adsorption of interfering biotin to magnetic microparticles coated with streptavidin and removing the microparticles from the sample (pg. 819, Col. 1, paragraph 1, and Fig. 1). The streptavidin-coated microparticles bind biotin and provide a biotin-depleted solution which corresponds to a depleted solution with reduced interference of instant invention. The depletion of high biotin concentrations efficiently suppresses biotin interference which otherwise would lead to a risk of misdiagnosis (pg. 817, col. 2, par. 2 – Conclusions).
Kunkel and Piketty do not specifically teach the first population of particles is present at a greater concentration than the second population of particles.
Regarding claims 1-2, 17, 35, 51, and 61, Schilffarth teaches particle assays including at least two particle sets (Abstract and [0011]). The reference teaches that the particles provide a substrate for carrying a reagent configured to react with the analyte of interest within a sample such that the analyte may be detected ([0006]). The reference further teaches that a multiplexing scheme is employed such that multiple analytes may be evaluated in a single analysis process for a single sample. Schilffarth also teaches different populations of particles present at different concentrations.
Specifically, Schilffarth teaches that particle subsets may have different concentrations “[i]n some cases, different analytes of interest may have substantially different concentration levels … it may be advantageous for a particle subset having a reactant for an analyte of interest in great abundance in a sample to have a greater concentration of particles within an assay than a particle subset having a reactant for a rare analyte of interest” ([0032]). This teaching meets the limitation of claim 35 reciting the first population of particles is present at a first concentration that is different than the concentration of at least one of the third population through tenth population of particles.
Regarding the limitation “wherein the ratio of the first population of particles to the second population of particles is 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1”, Schilffarth teaches particle quantity among different particle sets, such as ratios of 1:10 or less ([0031]). Particle ratios 1:10 and 10:1 are equivalent since there is no specifically designated “the first” and “the second” populations of particles.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kunkel by employing sample pretreatment with a particle comprising a capture moiety lacking specificity for the biomarkers as taught by Piketty, in order to provide the sample with depleted interfering substances. One having ordinary skill in the art would have been motivated to make such a change to be able to avoid misleading results caused by interfering substances present in the sample (Piketty, Abstract. Background). The use of such combination would have been desirable to those of ordinary skill in the art for the reason mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Piketty successfully demonstrated this approach with a number of routine immunoassays (Abstract. Methods).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kunkel and Piketty by employing one population of particles present at a greater concentration than the other population of particles as taught by Schilffarth, in order to provide the sample with depleted interfering substances, as an "obvious to try" approach of choosing from a finite number of identified, predictable solutions.
The finite number of identified, predictable solutions come from the fact that a mixture of two populations of particles can only have two possible combinations of concentrations: (1) the first population of particles is present at a greater concentration than the second population of particles and (2) the second population of particles is present at a greater concentration than the first population of particles. These are the only variants a skilled artisan with no knowledge of the claimed invention could select from and combine with the prior art of Kunkel and Piketty.
The required concentration of each population of particles depends on concentrations of the biomarkers these particles are expected to capture and the specific nature of the first and second populations of particles, for example, relative sizes of particles in the first and second populations of particles, and affinities of the first and second capture moieties. A reasonable expectation of success necessarily follows from the need to adjust the concentrations of the first and second populations of particles based on specific biomarkers nature and concentration.
Since Applicant has not disclosed that the relative concentrations of the first and second populations of particles are for any particular purpose or solve any stated problem and the prior art teaches that affinities of different capture moieties vary, and the biomarkers are usually present at different concentrations, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the populations of particles. It would have been obvious to label the population of particles with higher concentration as “the first population of particles” and another population as “the second population of particles”.
Kunkel, Piketty, and Schilffarth do not specifically teach “the plurality of particles comprises from a third to a tenth population of particles, each comprising a third to a tenth type or species of capture moiety”.
Regarding claims 1-2, 17, 35, 51, and 61, Dunbar teaches Luminex® xMAPTM technology for multiplexed analyte detection (Title). Specifically, the Luminex® xMAPTM system is a multiplexed microsphere-based suspension array platform capable of analyzing and reporting up to 100 different reactions in a single reaction vessel (Abstract. Methods), where each microsphere set can possess a different reactant on its surface (pg. 72. Col. 1, last paragraph). Up to 100 different reactants on microbeads meet the limitation of claim 9 reciting 10 types/species of particles/capture moieties. The teaching of Dunbar meets the limitation of claim 17 reciting removing or isolating a first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth biomarker(s) from the biological sample.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kunkel, Piketty, and Schilffarth by employing multiplex beads as taught by Dunbar, in order to provide capture of multiple biomarkers from a sample, as an obvious matter of combining prior art elements according to known methods to yield predictable results. The prior art elements of Kunkel, Piketty, and Schilffarth (depletion method) and Dunbar (capture elements for multiple analytes) would have been expected to contribute their own known properties to the final process and would not produce a ‘new’ or ‘different function’.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references of Kunkel, Piketty, and Schilffarth with the reference of Dunbar because each particle in the plurality of particles binds biomarkers and interfering substances independently from all other particles and Dunbar successfully demonstrated up to 100 different populations of particles working in the same sample.
Kunkel, Piketty, Schilffarth, and Dunbar do not specifically teach “the biomarkers are an indicator of bacterial infection”.
Regarding claims 1-2, 17, 35, 51, and 61, Kirakossian teaches a method for detecting biomarkers in rare
circulating cells by forming an enriched population of cells immunomagnetically (Abstract). Kirakossian also teaches the biomarkers are an indicator of bacterial infection.
Specifically, Kirakossian teaches that “the invention is directed to methods and kits for
detecting rare cell types in a biological specimen, such as a blood sample. Rare cell types may include many different types of cells, including … cells of infectious microorganisms” ([0036]). The presence of infectious microorganisms is an indicator of bacterial infection.
The immunomagnetical enrichment means that the bacterial cells are captured by antibodies, meeting the limitation of claim 51 reciting the capture moiety captures a bacterium.
Kirakossian’s teaching of immunomagnetical enrichment of “cells of infectious microorganisms” ([0036]) meets the limitation of claim 61 reciting the capture moieties comprise antibodies specific for the bacterium causing the infection.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kunkel, Piketty, Schilffarth, and Dunbar by employing the biomarker which is an indicator of bacterial infection as taught by Kirakossian, as an obvious matter of simple substitution of one known element for another to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because cells of infectious microorganisms of Kirakossian are biomarkers as well as other molecules taught by Kunkel: polypeptides, carbohydrates, nucleic acids, lipids, lipoproteins, glycoproteins, fatty acids, and glycans.
Regarding claims 3 and 4, Kunkel teaches that interaction of particles with protein analytes can be charge driven and solution pH may need adjustment in order to achieve optimal binding: myoglobin was efficiently sequestered by NIPAm/AAc particles at pH 5.5, while at pH 8 no bound myoglobin was detected ([0172]). As such, Kunkel teaches phosphate buffer as a conditioning agent of claim 3 and a pH adjusting agent of claim 4.
Regarding claims 5 and 19, Kunkel teaches capture and elution of hGH protein from particles ([0222]) and then assaying it using Immulite immunometric assay ([0220]), where the Immulite immunometric assay is a diagnostic test.
Regarding claim 6, Kunkel teaches “different populations of capture particles can be used at the same time, each having different characteristics with respect to the molecule species they are able to capture” ([0084]), “capture-particles can further comprise an analyte binding, affinity ligand or "bait" ([0116]) and “affinity ligands can be associated with the capture-particle in any suitable way … they can be conventionally coupled (covalently or noncovalently)” ([0117]).
Regarding claim 18, Kunkel teaches adding a releasing agent to provide an enriched isolate “the capture particles are removed from the mixture and the biomarkers are released from the capture particles” ([0048]), “an ability to capture and/or release the desired molecule in response to a physical or chemical treatment” ([0049]), and “possible means of eluting native proteins from the particles include modifying the temperature or pH of the solution, increasing the ionic strength” ([0191]). Increasing the ionic strength necessarily teaches the releasing agent/reagent.
Regarding claim 20, Kunkel teaches detection of two biomarkers concurrently: PSA and {alpha}-Methylacyl-CoA racemase ([0134]).
Regarding claims 21 and 30, Kunkel teaches the first particle is different in size, shape, chemistry, or color than at least one of the second through tenth particles and the first particle is different in selectivity, affinity, or avidity to a biomarker than at least one of the second through tenth particles. The reference teaches detection of two biomarkers concurrently, where the first particle has a single chain antibody for PSA and the second particle has an antibody for {alpha}-Methylacyl-CoA racemase (Kunkel [0134]). Both capture moieties clearly have different selectivity, because PSA and {alpha}-Methylacyl-CoA racemase are unrelated proteins.
Regarding claims 31 and 32, Kunkel teaches that “the particle, itself, can be of any suitable size, e.g., 1 nm or less; from about 1 nm-100 μm; from about 5 nm-50 μm; from about 10 nm-20 μm; from about 10 nm-10 μm; including any and all values in between” (Kunkel [0051]). Particles “from about 1 nm-100 μm” fall within and therefore meet the limitation of claims 31-32, which recite the size is 50-1000 nm and 1-3 micron.
Regarding claims 45-48, Kunkel teaches that “capture-particles can also further comprise detectable labels … This enables the property of the particle class (e.g., able to bind to a specific antigen) to be identified by determining which detectable label it bears” ([0134]). Kunkel further teaches a particle with a single chain antibody for PSA labeled with FITC, and a particle containing an antibody for {alpha}-Methylacyl-CoA racemase (AMACR) labeled with TRITC (id.), so the particles can be sorted using fluorescent-activated cell sorting with incorporated FITC and TRITC labels acting as control labels/indicators facilitating sorting of particles into different classes based on their specificity to selected antigens. Either particle (PSA-FITC or AMACR-TRITC) meets the limitation for a control particle (e.g., particle comprising a label or indicator (e.g., a label or indicator of known quantity, abundance) of claim 45. Claims 46-48 further limit alternatives without necessarily requiring a label.
Regarding claim 49, Kunkel teaches that “capture particles can further comprise an attractant capable of attracting and interacting with a biomarker” and “the attractant is an affinity ligand and may be: … binding pairs (such as streptavidin/biotin)” ([0058]). As such, Kunkel teaches both biotin and streptavidin can be biomarkers depending on which component of this pair is used as a capture moiety.
Regarding claim 52, Kunkel teaches capture (hGH solution was incubated with 100 ul of dye particles) and elution of hGH protein from particles “protein were eluted from the washed particles with Acetonitrile 60%/NH40H 4% buffer” ([0222]), meeting the limitation of claim 52 reciting removing or isolating the particle complexes comprises cleaving, eluting, or selectively releasing a capture moiety-biomarker complex.
Regarding claim 53, Kunkel teaches that “capture-particles can also further comprise detectable labels … the detectable label can be associated with any region of the capture-particle … detectable labels are useful in a number of ways, including for sorting different classes of capture particles” ([0134]). As such, the labeled capture particles can be used for measurement in a test system – “by flow cytometry using fluorescent-activated cell sorting” (id.).
Claim 62 is rejected under 35 U.S.C. 103 as being unpatentable over Kunkel, in view of Piketty, Schilffarth, Dunbar, and Kirakossian, as applied to claim 1 above, and further in view of Branda et al. (WO 2014028726).
The teachings of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian have been set forth above.
Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian do not specifically teach the capture moieties comprise antigens derived from the bacterium causing the infection.
Regarding claim 62, Branda teaches methods of assaying biological samples for the presence of antibodies or antigens indicative of infection by a bacterium (Abstract). Branda also teaches the capture moieties comprise antigens derived from the bacterium causing the infection.
Specifically, Branda teaches a method of evaluating a subject for infection by Borrelia burgdorferi sensu lato. The method involves detecting anti-bacterial antibodies present in a fluid test biological sample from the subject using a whole-cell lysate of the bacteria. Although any type of assay could be used for this analysis, preferred assays are enzyme immunoassays (EIAs)” (pg. 3, lines 24-28). The anti-bacterial antibodies are the biomarkers in instant invention. The whole-cell lysate of the bacteria immobilized on a surface (e.g., EIA) is the capture moieties comprising antigens derived from the bacterium causing the infection of instant invention. Borrelia is a genus of spirochete bacteria known for causing Lyme disease.
Branda does not specifically teach immobilizing the capture moieties on particles, but the reference teaches that “any type of assay could be used for this analysis” and enzyme immunoassays do involve immobilization of the capture moieties on a solid surface. One having ordinary skill in the art would have found it obvious to use a particle-based assay for detection of anti-bacterial antibodies taught by Branda.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian by employing the capture moieties comprising antigens derived from the bacterium causing the infection of instant invention as taught by Branda (pg. 3, lines 24-28), in order to detect anti-bacterial antibodies present in a human body during Lyme disease, as an obvious matter of simple substitution of one known analyte for another to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Kunkel teaches that “any molecule of interest may be harvested using the present invention, including, … antibodies” ([0083]).
Double patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 13 of U.S. Patent No. 10,948,484 in view of Kunkel et al. (IDS; PGPub 2014/0045274), in view of Piketty et al. (Clin Chem Lab Med. 2017 May 1;55(6):817-825), Schilffarth et al. (PGPub 2011/0204874), Dunbar (Clin Chim Acta. 2006 Jan;363(1-2):71-82), and Kirakossian et al. (IDS; PGPub 2004/0157271).
Claim 1 of ‘484 recites a method of depleting sample interferences from a sample comprising: a) combining a microparticle with a sample; b) mixing the sample with the microparticles; c) incubating the microparticles with the sample to bind and capture the interferences; d) separating, removing microparticles.
Claim 13 of ‘484 recites the interference is selected from the group consisting of human anti-mouse antibodies (HAMA) and biotin.
The issued claims do not teach the limitations of claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61. These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian as follows:
Regarding instant claims 1-2, Kunkel teaches a method for removing biomarkers from a biological sample “the present invention relates to particles capable of sequestering a biomarker from a mixture, allowing for the separation of the biomarker from the mixture, as well as methods for sequestering biomarkers” ([0002]).
Piketty teaches a method to overcome biotin interference in immunoassays that utilize streptavidin-biotin capture techniques (Abstract. Background). Piketty also teaches pretreating a sample with a particle comprising a capture moiety lacking specificity for the biomarkers.
Specifically, Piketty teaches that in some situations a presence of certain molecules in patient’s samples can lead to analytical interference in immunoassays. For example, high-dose biotin therapy can result in interference with immunoassays that utilize streptavidin-biotin capture techniques (id.). In order to prevent such interference, Piketty teaches adsorption of interfering biotin to magnetic microparticles coated with streptavidin and removing the microparticles from the sample (pg. 819, Col. 1, paragraph 1, and Fig. 1). The streptavidin-coated microparticles bind biotin and provide a biotin-depleted solution which corresponds to a depleted solution with reduced interference of instant invention. The depletion of high biotin concentrations efficiently suppresses biotin interference which otherwise would lead to a risk of misdiagnosis (pg. 817, col. 2, par. 2 – Conclusions).
Schilffarth teaches particle assays including at least two particle sets (Abstract and [0011]). The reference teaches that the particles provide a substrate for carrying a reagent configured to react with the analyte of interest within a sample such that the analyte may be detected ([0006]). The reference further teaches that a multiplexing scheme is employed such that multiple analytes may be evaluated in a single analysis process for a single sample. Schilffarth also teaches different populations of particles present at different concentrations.
Specifically, Schilffarth teaches that particle subsets may have different concentrations “[i]n some cases, different analytes of interest may have substantially different concentration levels … it may be advantageous for a particle subset having a reactant for an analyte of interest in great abundance in a sample to have a greater concentration of particles within an assay than a particle subset having a reactant for a rare analyte of interest” ([0032]). This teaching meets the limitation of claim 35 reciting the first population of particles is present at a first concentration that is different than the concentration of at least one of the third population through tenth population of particles.
Regarding the limitation “wherein the ratio of the first population of particles to the second population of particles is 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1”, Schilffarth teaches particle quantity among different particle sets, such as ratios of 1:10 or less ([0031]). Particle ratios 1:10 and 10:1 are equivalent since there is no specifically designated “the first” and “the second” populations of particles.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of ‘484 by employing the method for removing biomarkers from a biological sample as taught by Kunkel and sample pretreatment with a particle comprising a capture moiety lacking specificity for the biomarkers as taught by Piketty, in order to provide the sample with depleted interfering substances. One having ordinary skill in the art would have been motivated to make such a change to be able to avoid misleading results caused by interfering substances present in the sample (Piketty, Abstract. Background). The use of such combination would have been desirable to those of ordinary skill in the art for the reason mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Piketty successfully demonstrated this approach with a number of routine immunoassays (Abstract. Methods).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of ‘484, Kunkel, and Piketty by employing one population of particles present at a greater concentration than the other population of particles as taught by Schilffarth, in order to provide the sample with depleted interfering substances, as an "obvious to try" approach of choosing from a finite number of identified, predictable solutions.
The finite number of identified, predictable solutions come from the fact that a mixture of two populations of particles can only have two possible combinations of concentrations: (1) the first population of particles is present at a greater concentration than the second population of particles and (2) the second population of particles is present at a greater concentration than the first population of particles. These are the only variants a skilled artisan with no knowledge of the claimed invention could select from and combine with the prior art of Kunkel and Piketty.
The required concentration of each population of particles depends on concentrations of the biomarkers these particles are expected to capture and the specific nature of the first and second populations of particles, for example, relative sizes of particles in the first and second populations of particles, and affinities of the first and second capture moieties. A reasonable expectation of success necessarily follows from the need to adjust the concentrations of the first and second populations of particles based on specific biomarkers nature and concentration.
Since Applicant has not disclosed that the relative concentrations of the first and second populations of particles are for any particular purpose or solve any stated problem and the prior art teaches that affinities of different capture moieties vary, and the biomarkers are usually present at different concentrations, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the populations of particles. It would have been obvious to label the population of particles with higher concentration as “the first population of particles” and another population as “the second population of particles”.
Kunkel, Piketty, and Schilffarth do not specifically teach “the plurality of particles comprises from a third to a tenth population of particles, each comprising a third to a tenth type or species of capture moiety”.
Dunbar teaches Luminex® xMAPTM technology for multiplexed analyte detection (Title). Specifically, the Luminex® xMAPTM system is a multiplexed microsphere-based suspension array platform capable of analyzing and reporting up to 100 different reactions in a single reaction vessel (Abstract. Methods), where each microsphere set can possess a different reactant on its surface (pg. 72. Col. 1, last paragraph). Up to 100 different reactants on microbeads meet the limitation of claim 9 reciting 10 types/species of particles/capture moieties. The teaching of Dunbar meets the limitation of claim 17 reciting removing or isolating a first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth biomarker(s) from the biological sample.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of ‘484, Kunkel, Piketty, and Schilffarth by employing multiplex beads as taught by Dunbar, in order to provide capture of multiple biomarkers from a sample, as an obvious matter of combining prior art elements according to known methods to yield predictable results. The prior art elements of Kunkel, Piketty, and Schilffarth (depletion method) and Dunbar (capture elements for multiple analytes) would have been expected to contribute their own known properties to the final process and would not produce a ‘new’ or ‘different function’.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references of Kunkel, Piketty, and Schilffarth with the reference of Dunbar because each particle in the plurality of particles binds biomarkers and interfering substances independently from all other particles and Dunbar successfully demonstrated up to 100 different populations of particles working in the same sample.
Kunkel, Piketty, Schilffarth, and Dunbar do not specifically teach “the biomarkers are an indicator of bacterial infection”.
Kirakossian teaches a method for detecting biomarkers in rare circulating cells by forming an enriched population of cells immunomagnetically (Abstract). Kirakossian also teaches the biomarkers are an indicator of bacterial infection.
Specifically, Kirakossian teaches that “the invention is directed to methods and kits for
detecting rare cell types in a biological specimen, such as a blood sample. Rare cell types may include many different types of cells, including … cells of infectious microorganisms” ([0036]). The presence of infectious microorganisms is an indicator of bacterial infection.
The immunomagnetical enrichment means that the bacterial cells are captured by antibodies, meeting the limitation of claim 51 reciting the capture moiety captures a bacterium.
Kirakossian’s teaching of immunomagnetical enrichment of “cells of infectious microorganisms” ([0036]) meets the limitation of claim 62 reciting the capture moieties comprise antibodies specific for the bacterium causing the infection.
Claim 62 is rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 10,948,484 in view of Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and further in view of Branda et al. (WO 2014028726).
Claim 1 of ‘484 recites a method of depleting sample interferences from a sample comprising: a) combining a microparticle with a sample; b) mixing the sample with the microparticles; c) incubating the microparticles with the sample to bind and capture the interferences; d) separating, removing microparticles.
The issued claims do not teach the limitations of claim 62.
Regarding claim 62, Branda teaches methods of assaying biological samples for the presence of antibodies or antigens indicative of infection by a bacterium (Abstract). Branda also teaches the capture moieties comprise antigens derived from the bacterium causing the infection.
Specifically, Branda teaches a method of evaluating a subject for infection by Borrelia burgdorferi sensu lato. The method involves detecting anti-bacterial antibodies present in a fluid test biological sample from the subject using a whole-cell lysate of the bacteria. Although any type of assay could be used for this analysis, preferred assays are enzyme immunoassays (EIAs)” (pg. 3, lines 24-28). The anti-bacterial antibodies are the biomarkers in instant invention. The whole-cell lysate of the bacteria immobilized on a surface (e.g., EIA) is the capture moieties comprising antigens derived from the bacterium causing the infection of instant invention. Borrelia is a genus of spirochete bacteria known for causing Lyme disease.
Branda does not specifically teach immobilizing the capture moieties on particles, but the reference teaches that “any type of assay could be used for this analysis” and enzyme immunoassays do involve immobilization of the capture moieties on a solid surface. One having ordinary skill in the art would have found it obvious to use a particle-based assay for detection of anti-bacterial antibodies taught by Branda.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of ‘484 by employing the teachings of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian , as presented above for claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61 and by employing the capture moieties comprising antigens derived from the bacterium causing the infection of instant invention as taught by Branda (pg. 3, lines 24-28), in order to detect anti-bacterial antibodies present in a human body during Lyme disease, as an obvious matter of simple substitution of one known analyte for another to obtain predictable results.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Kunkel teaches that “any molecule of interest may be harvested using the present invention, including, … antibodies” ([0083]).
Claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 35 of copending Application No. 17/160,196 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claims 1 of ‘196 recites a method comprising combining a sample with a particle comprising a capture moiety for a biomarker in a sample to provide a mixture; mixing the mixture and isolating biomarker from the sample.
Claim 1 of ‘196 recites biotin interference.
Claims 3 and 35 of ‘196 recite a method comprising combining a sample with a particle comprising a capture moiety for an interference in a sample to provide a mixture; mixing the mixture; and removing the particle from the sample.
The copending claims do not teach the limitations of claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61. These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian as presented in this section above.
It would have been obvious to have modified claims 1, 3, and 35 of ‘196 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 62 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, and 35 of copending Application No. 17/160,196 in view of Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and further in view of Branda et al. (WO 2014028726).
Claim 1 of ‘196 recite a method comprising combining a sample with a particle comprising a capture moiety for a biomarker in a sample to provide a mixture; mixing the mixture and isolating biomarker from the sample.
Claims 3 and 35 of ‘196 recite a method comprising combining a sample with a particle comprising a capture moiety for an interference in a sample to provide a mixture; mixing the mixture; and removing the particle from the sample.
The copending claims do not teach the limitations of claim 62.
These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda as presented in this section above.
It would have been obvious to have modified claims 1, 3, and 35 of ‘196 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda.
Claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 17/636,012 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 1 of ‘012 recites a method comprising combining a sample with a particle comprising a streptavidin to provide a mixture; mixing the mixture; and separating the particle from the sample.
Claim 2 of ‘012 recites biotin or anti-streptavidin as interference.
The copending claims do not teach the limitations of claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 62. These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian as presented in this section above.
It would have been obvious to have modified claims 1 and 2 of ‘012 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 62 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/636,012 in view of Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and further in view of Branda et al. (WO 2014028726).
Claim 1 of ‘012 recites a method comprising combining a sample with a particle comprising a streptavidin to provide a mixture; mixing the mixture; and separating the particle from the sample.
The copending claim does not teach the limitations of claim 62.
These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda as presented in this section above.
It would have been obvious to have modified claim 1 of ‘012 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda.
Claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/917,479 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 1 of ‘479 recites a method comprising combining a sample with a particle comprising a capture moiety for an antibody to provide a mixture; mixing the mixture and separating the particle from the sample.
The copending claim does not teach the limitations of claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61. These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian as presented in this section above.
It would have been obvious to have modified claim 1 of ‘479 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 62 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/917,479 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 1 of ‘479 recites a method comprising combining a sample with a particle comprising a capture moiety for an antibody to provide a mixture; mixing the mixture and separating the particle from the sample.
The copending claims do not teach the limitations of claim 62.
These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda as presented in this section above.
It would have been obvious to have modified claim 1 of ‘479 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda.
Claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 19/185,839 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claims 1 and 3 of ‘839 recite a method comprising combining a sample with a particle comprising a capture moiety for an antibody to provide a mixture; mixing the mixture and separating the particle from the sample.
The copending claims do not teach the limitations of claims 1-6, 17-21, 30-32, 35, 45-49, 51-53, and 61. These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian as presented in this section above.
It would have been obvious to have modified claims 1 and 3 of ‘839 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claim 62 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of copending Application No. 19/185,839 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian.
Claims 1 and 3 of ‘839 recite a method comprising combining a sample with a particle comprising a capture moiety for an antibody to provide a mixture; mixing the mixture and separating the particle from the sample.
The copending claims do not teach the limitations of claim 62.
These limitations are taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda as presented in this section above.
It would have been obvious to have modified claims 1 and 3 of ‘839 to have incorporated the limitations taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda in order to provide a method for enriching particles that has all of the advantages taught by Kunkel, Piketty, Schilffarth, Dunbar, Kirakossian, and Branda.
Response to Arguments
Applicant's arguments filed March 27, 2026 have been fully considered.
Claims 50-51 were rejected as obvious over Kunkel and Piketty and Schilffarth and Dunbar, and further in view of US 2004/0157271 ("Kirakossian"). Applicant traverses the rejection “the independent claims are amended herein to specify "wherein the biomarkers are an indicator of bacterial infection." In contrast, Kirakossiian describes the detection of bacterial cells” (pg. 7, last par.).
The rejection of claims 1-6, 17-21, 30-32, 35, 45-49, and 51-53 under 35 U.S.C. §103 is withdrawn in view of claims 1-2 amendments. However, the claims are still rejected under 35 U.S.C. §103 in view of previously presented prior art of Kirakossian.
Applicant’s argument is not persuasive because Kirakossian teaches that “the invention is directed to methods and kits for detecting rare cell types in a biological specimen, such as a blood sample. Rare cell types may include many different types of cells, including … cells of infectious microorganisms” ([0036]). The cells of infectious microorganisms are the biomarkers indicating a bacterial infection.
Claims 1-6, 17-21, 30-32, 35, 45-49, and 51-53, and 61 are rejected under 35 U.S.C. §103 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian (see above for details).
Claims 1-6, 17-21, 30-32, 35, 45-49, and 52-53 were rejected as obvious over US 2014/0045274 ("Kunkel") in view of Clin Chem Lab ("Piketty") and US 2011/0204874 ("Schilffarth") and further in view of Clin Chim Acta ("Dunbar'').
Applicant traverses the rejection. However, to expedite prosecution, the independent claims are amended herein to include the limitation of un-rejected claim 50 (pg. 7, Rejections under § 103, #1).
The argument is not persuasive because claim 50 cannot be called an un-rejected claim. It was rejected under 35 U.S.C. §103 (see OA, 29 December, 2025, pg. 10).
The amended claims are rejected 1-6, 17-21, 30-32, 35, 45-49, and 51-53, and 61 are rejected under 35 U.S.C. §103 in view of Kunkel, Piketty, Schilffarth, Dunbar, and Kirakossian (see response #1 above for details).
Applicant requested that the nonstatutory double patenting (NSDP) rejection be held in abeyance (pg. 8, par. 2). The applicant is reminded that a complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims, or the filing of a terminal disclaimer. Such a response is required even when the nonstatutory double patenting rejection is provisional (MPEP 804.I.B.1).
Conclusion
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/ALEXANDER ALEXANDROVIC VOLKOV/Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677