Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/25/2026 has been entered.
Applicants’ amendment filed 08/25/2026 is acknowledged. Claims 2-5 and 13-16 are withdrawn (see office action of 04/10/2024 and 09/07/2023). Therefore, claims 1, 6-10, 12, 18 and 19 are examined on merits in this office action.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 6-10, 12 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al (US 2015/0038355A1) in view of Rulander et al (Arch Pathol Lab Med 2013) and Lee et al (Nanotechnology 2008) and further in view of Chauhan et al (US 9,642,925), Poynton et al (EP 0156537A2) and Ross et al (US 8603345B2).
Claims 1 is interpreted as directed to a microparticle comprising a microparticle binding surface, wherein the microparticle binding surface comprises a microparticle support surface couple to at least one component recited in (ii) and a triblock copolymer recited in iii), wherein the microparticles are lyophilized in primary blood collection tube (PBCT).
In regard to claims 1, 6 and 18, Tan teaches removing interfering substance/molecules prior to immunoassay from a sample utilizing beads having specific binding ligands that binds the interfering substance to be removed. Tan teaches that immunoassay interfering molecules include but not limited to animal serum, non-animal serum, immunoglobulins or immunoglobulin aggregates, heterophilic antibody, commercial blocking substances, and natural or synthetic peptides (paragraph [0057]). Tan teaches depleting/removing heterophilic sample interference from a sample prior to immunoassay detection (Abstract), which results in increased sensitivity of an immunoassay (paragraph [0004]). Tan teaches utilizing binding agent that binds interfering molecules in the sample prior to immunoassay wherein the binding agent comprises beads (i.e. microparticle binding surface) linked to binding agents that binds to interfering substances in the sample (paragraph [0005]). Tan teaches contacting the beads containing the binding agent with the sample, mixing and incubating the sample to bind the interfering substances to the binding agent, thereby forming complex of interfering substance with the binding agent, separating the complex by centrifugation (paragraph [0005] [0106] and [0117])), and then collecting the sample which is free of or substantially free of interfering molecules (paragraph [0106] and [0117] and Fig.1) for immunoassays (paragraph [0123] and claim 9).Tau teaches that any relevant method can be used to separate the non-specific binding complex (i.e. bead-binding ligand that forms complex with the interfering substance) from the sample. Tan teaches that in some embodiments, the binding agent and the non-specific binding complex are separated from the sample by centrifugation and in other embodiments, if the binding agent is responsive to a magnetic field, a magnetic field is applied to the non-specific binding complex, and then the sample or assay mixture is separated from the complex (Fig 1). Tan teaches magnetic and non-magnetic beads wherein the beads can be of various types including DYNABEADS and magnetic beads (paragraph [0053]) wherein the beads may comprise various reactive groups (paragraphs [0082-0086]). Tan teaches that the binding agent for binding to interfering substance from a sample for immunoassay can be selected from the group consisting of BSA, protein L, collagen, PEG4000/6000, animal serum, a murine based IgG aggregate, and an antibody derived from goat, mouse, rabbit or sheep that recognizes a HAGA, HAMA, HARA, HASA, or rheumatoid factor (paragraph [0006]). Tan teaches binding agent comprising antibody against HAMA (paragraph [0103]).
Tan does not mention other commonly known interfering substances such as anti-avidin know to interfere during immunoassays and Tan does not teach the microparticle having capture moiety as lyophilized.
Rulander teaches interference from anti-streptavidin antibody in a sample during immunoassay (Title and abstract). Rulander teaches anti-streptavidin antibodies potentially affect multiple diagnostic platforms (Abstract). Rulander teaches streptavidin coated microparticle for removal of anti-streptavidin interfering antibody.
Lee teaches magnetic nanoparticle linked to specific binding substance, e.g. antibody (Abstract). Le discloses modifying the magnetic nanocrystals (MNC) coated (page 5, first col.) with amphiphlilic tri-block copolymer {dicarboxyl poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)} (dicarboxylated PEG-PPG-PEG, i.e. a carboxylated pluroric F127) to provide aqueous solubility and colloidal stability of the MNCs (abstract). Lee teaches that dicarboxylated PEG-PPG-PEG are well dispersed in the aqueous phase due to the spontaneous PEGlylation by hydrophilic PEG chains (page 5). Lee teaches conjugating an antibody (e.g. anti-HER2 antibody) to surface functional group (carboxyl group) of tri-block copolymer (page 3, section 2.5). Lee teaches that pluronic coated magnetic nanocrystal showed excellent colloidal stability in aqueous phase over broad range of pH and high salt concentration (page 7). Therefore, as described above, Lee discloses microparticle comprising a microparticulate binding surface comprising a microparticle support surface, a binding partner or capture moiety and a binding surface that is blocked with triblock copolymer Pluronic F 127 wherein the binder, binding partner or capture moiety is an antibody.
Chauhan teaches magnetic nanoparticle blocked with pluronic polymer which provides colloidal stability. Chauhan teaches that the magnetic particle can be lypphilized to obtain solid particles using freeze drying system.
Polyton teaches lyophilized biological magnetic colloid comprising magnetic colloidal particles coated with biologically compatible polymer (page 31, claim 49). Polyton teaches that biological magnetic fluids may be lyophilized for storage and transport and reactivated by adding liquid (page 14).
Ross is directed to removing/one-step clean up of undesired and interfering substance from blood immediately after collection of blood in blood collection tube for downstream testing (column 8, lines 20-60). Ross teaches the collection tube
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having particles coated with affinity molecules that binds to the undesired or interfering substance (column 7, lines 36-55) and separating undesired or interfering substance bound particles, as for example, by centrifugation (column 8, lines 62-65). Ross teaches that the affinity molecules may be in lyophilized form (col. 5, lines 15-20). Ross teaches that the purpose of contacting the affinity molecules with the blood during the time of collection is to reduce the number of handling and processing steps (col. 8, lines 36-38).
Therefore, given the fact that removing interfering substance/molecules prior to immunoassay from a sample utilizing beads having specific binding ligands that binds the interfering substance to be removed, results in increased sensitivity of an immunoassay (Tau and Rulander) and given the fact that anti-avidin antibody is a potential interfering substance in immunoassay and anti-avidin antibody potentially affect multiple diagnostic platforms (Rulander), it would be obvious to one of ordinary skilled in the art to easily envisage providing the magnetic particle of Tau or Lee with avidin with the expectation of removing anti-avidin interfering molecules from a sample prior to immunoassays with a reasonable expectation of success because Rulander discloses removing interfering anti-avidin antibody from sample utilizing avidin coated microparticle. One of ordinary skilled in the art would be motivated to utilizing magnetic particle coated with avidin because one of ordinary skill in the art would easily envisage magnetic separation utilizing magnetic particle and since Tau teaches magnetic particle coated with various anti-interfering molecule for separation of interfering molecules from sample prior to immunoassays. One of ordinary skilled in the art, from the description in mind of Lee would easily envisage and would be motivated to block the magnetic particle with triblock copolymer because Lee teaches that amphiphlilic tri-block copolymer {dicarboxyl poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)} (dicarboxylated PEG-PPG-PEG, i.e. a carboxylated pluroric F127) provides aqueous solubility and colloidal stability of the MNCs and because Lee teaches that pluronic coated magnetic nanocrystal showed excellent colloidal stability in aqueous phase over broad range of pH and high salt concentration.
The combination of the references of Tan in view of Rulander and Chauhan as described above, provides obviousness of utilizing magnetic particle coated with avidin and blocked with triblock copolymer for removing interfering anti-avidin antibody from sample prior to immunoassay. The combination of the references however, do not disclose lyophilizing the magnetic particle having capture moiety for storage and other application and does not teach the particle in blood collection device such as blood collection tubes.
However, given the fact that lyophilizing biologically compatible polymer coated magnetic particles is useful for storage (Poynton) and given the fact that pluronic coated magnetic particle can be lyophilized (Chauhan), it would be obvious to one of ordinary skilled in the art to easily envisage providing the avidin coated and pluronic blocker magnetic particles in lyophilized form with the expectation of providing the particle with long term storage capability with a reasonable expectation of success. Moreover, since Ross teaches the providing blood collection reservoirs/tubes with affinity coated beads are very useful for removing interfering substance immediately after collection of blood and which reduce the number of handling and processing steps for downstream test/analyses, it would be obvious to one of ordinary skilled in the art to easily envisage the coated magnetic particles lyophilized in blood collection tube with the expectation of providing lyophilized beads in blood collection tube ready to be used for immediate removal of interfering/undesired components from blood with a reasonable expectation of success.
In regards to claim 7, as described above, Tan and Lee teaches support surface comprising metal.
In regards to claim 8, Tan and Lee teach microparticle support surface comprising carboxyl group (see para [0090] of Tan).
In regards to claim 9, Lee teaches particle sizes of 20-60 nm (Fig. 4(c)), which overlaps with the sizes as claimed in claim 9. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Moreover, a change in size is generally recognized as being within the level of ordinary skill in the art. In re Rose, 105 USPQ 237 (CCPA 1955).
In regards to claims 10 , Tan teaches blocking agent can be beads linked to binding agent wherein the bead of the blocking agent is coupled to one or more binding agents which includes BSA, protein L, collagen, animal serum and antibody (paragraph [0112] and claim 5) and thus BSA including various BSA conjugates would be obvious absent showing of unexpected advantages with a particular binding molecule.
In regards to claim 12, Lan teaches that the binding agent for binding to interfering substance from a sample for immunoassay can be selected from the group consisting of BSA, protein L, collagen, PEG4000/6000, animal serum, a murine based IgG aggregate, and an antibody derived from goat, mouse, rabbit or sheep that recognizes a HAGA, HAMA, HARA, HASA, or rheumatoid factor (paragraph [0006]). Tan teaches binding agent comprising antibody against HAMA (paragraph [0103]). Thus various antibodies including antibody against HAMA with the magnetic particle of Lee would be obvious to one of ordinary skilled in the art.
Claims 1, 6-10, 12, 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Tan et al (US 2015/0038355A1) in view of Rulander et al (Arch Pathol Lab Med 2013), Lee et al (Nanotechnology 2008), Chauhan et al (US 9,642,925), Poynton et al (EP 0156537A2) and Ross et al (US 8603345B2) as described for claims 1, 6-10, 12 and 18 above and further in view of Chen et al (PlosOne 2012).
Tan, Rulander, Lee, Chauhan, Poynton and Ross have been applied above that provides obviousness for lyophilized microparticle comprising triblock copolymer and streptavidin in blood collection tube ready to be used for immediate removal of interfering anti-streptavidin antibody from blood for downstream detection process.
The references do not suggest removing other known interfering substances such a anti-biotin interfering antibody from blood.
Chen teaches biotin IgM antibodies in blood are common interfering substance that provide false results in biotinylation-based immunoassays (Title). Chen teaches that 3% of adults regardless of age have IgM antibodies reactive to biotin and this provides adverse effect on biotinylation-based immunoassays (Abstract). Chen teaches that serum samples with high levels of biotin IgM affected adversely all virus IgM assays, while samples containing low levels of the antibody showed low interference level in most assays and biotin IgM was shown to be an important contributor to false positivity in virus IgM assays (page 4, 1st col.).
Therefore, given the fact that biotin IgM antibodies are common interfering substance in blood and provides false positive results in biotinylation-based immunoassays, it would be obvious to one of ordinary skilled in the art to easily envisage providing the microparticle of Tan with biotin coated microparticle with the expectation of expanding the arsenal of microparticle of Tan for removal of other interfering molecules, such a interfering biotin IgM antibody from blood with a reasonable expectation of success. Since the basic concept of utilizing microparticle having binding substance binding to interfering molecules have been disclosed by the combination of the references, various binding substances that binds to various known interfering molecules in blood, would be obvious to one of ordinary skilled in the art.
Response to argument
In regard to the rejection under 35 USC 103, Applicant's arguments and amendments filed 08/25/2026 have been fully considered and but are not found persuasive to overcome the rejections under 35 USC 103.
Applicant argued that the element (ii) and (iii) define together is a particular two part architecture: 1. The capture moiety coupled directly to the support surface, and 2. The binding surface blocked with the recited triblock copolymer. Applicant argued that because the claim recites that the microparticle are lyophilized in the PBCT, the claimed tube enables the particles to be reconstituted and dispersed by the addition of the sample to the PBCT. Applicant argued that the references are not analogous art and combination reaches across fields unrelated to the claimed article. Applicant further argued that the applied art does not teach element (iii): a binding surface blocked with a triblock copolymer. Applicant argued that on a particle whose capture moiety is coupled directly to the support surface (element (ii)), the copolymer blocks the remaining surface so that the particle binds and holds its targeted interferent without non-specifically binding the biomarker of interest or other sample components. Applicant argued that element (iii) is thus not the mere presence of copolymer, but its deployment as a blocking layer over a directly coupled capture surface, so that the capture is selective. Applicant argued that neither Lee nor Chauhan discloses that. Applicant further argued that the applied art does not teach element (ii) capture moiety coupled directly to the support surface.
The above arguments have fully been considered but are not found persuasive.
The recitation “wherein said microparticles comprising the capture moiety and blocked binding surface are lyophilized in the PBCT and are reconstituted and dispersed by the addition of a sample to the PBCT” is a product by process language. Claim 1, as recited is a product claim comprising a ready-to-use microparticle in a blood collection tube (PBCT) wherein the microparticle comprises a capture moiety coupled on it’s surface and wherein the microparticle comprises a triblock pluronic copolymer coated on the surface. The recitation of the “product by process limitation” as described above, provides the microparticle dispersed in a sample within the PBCT tube (which is the final product claimed). In regard to Applicant’s assertion that the capture moiety is coupled directly to the support surface (element (ii)), the copolymer blocks the remaining surface and deployment of the pluronic blocking layer over a directly coupled capture surface, the claim does not recite so. The sequence of binding has not been described in the claims and since the support surface has not been claimed, the support surface as claimed may encompass support surface comprises the triblock copolymer and the capture moiety directly bound to the support surface having the triblock copolymer without any linker moiety. Moreover, as asserted, the claim does not recite the capture moiety bound to the support surface and rest of the support surfaces are coated with the triblock copolymer as recited in the arguments. “Consideration of Applicant's Rebuttal Arguments,” arguing limitations which are not claimed is improper:
“Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. In reVan Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993) (Claims to a superconducting magnet which generates a “uniform magnetic field” were not limited to the degree of magnetic field uniformity required for Nuclear Magnetic Resonance (NMR) imaging. Although the specification disclosed that the claimed magnet may be used in an NMR apparatus, the claims were not so limited.); Constantv. Advanced Micro-Devices, Inc., 848 F.2d 1560, 1571-72, 7 USPQ2d 1057, 1064-1065 (Fed. Cir.), cert. denied, 488 U.S. 892 (1988) (Various limitations on which appellant relied were not stated in the claims; the specification did not provide evidence indicating these limitations must be read into the claims to give meaning to the disputed terms.); Ex parteMcCullough, 7 USPQ2d 1889, 1891 (Bd. Pat. App. & Inter. 1987) (Claimed electrode was rejected as obvious despite assertions that electrode functions differently than would be expected when used in nonaqueous battery since “although the demonstrated results may be germane to the patentability of a battery containing appellant’s electrode, they are not germane to the patentability of the invention claimed on appeal.”).
Contrary to Applicant’s assertion of non-analogous arts, the references are directed to analogous arts of microparticle based assays and reducing interference. The reference of Lee is cited to show magnetic nanoparticle linked to specific binding substance, e.g. antibody (Abstract). Le discloses modifying the magnetic nanocrystals (MNC) coated (page 5, first col.) with amphiphlilic tri-block copolymer {dicarboxyl poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)} (dicarboxylated PEG-PPG-PEG, i.e. a carboxylated pluroric F127) to provide aqueous solubility and colloidal stability of the MNCs (abstract). Lee teaches conjugating an antibody (e.g. anti-HER2 antibody) to surface functional group (carboxyl group) of tri-block copolymer (page 3, section 2.5). Lee teaches that pluronic coated magnetic nanocrystal showed excellent colloidal stability in aqueous phase over broad range of pH and high salt concentration (page 7). Therefore, Lee discloses microparticle comprising a microparticulate binding surface comprising a microparticle support surface, a binding partner or capture moiety and a binding surface that is blocked with triblock copolymer Pluronic F 127 wherein the binder, binding partner or capture moiety is an antibody. Therefore, Lee is directed to same field of providing colloidally stable magnetic particle having binding partner and thus directed to utilizing the particles having specific binding partner for specific binding to specific analyte (immune detection) and Tan is directed to particles containing binding agent for specific binding and removing interfering molecules.
Regarding Tan, Tag teaches particles with specific binders binding specifically to assay interfering molecules to capture and targeted removal of the assay interference molecules. Moreover, it is the product (microparticle having surface with interference capturing molecules) that is obvious from the combination of the references, and it does not need to be the same process utilized in the instant claims (note that the claims are product claims, not a process claim). It is noted that the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) (“One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”); In re Linter, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991). The court held “it is not necessary in order to establish a prima facie case of obviousness . . . that there be a suggestion or expectation from the prior art that the claimed [invention] will have the same or a similar utility as one newly discovered by applicant,” and concluded that here a prima facie case was established because “[t]he art provided the motivation to make the claimed compositions in the expectation that they would have similar properties.” In re Dillon, 919 F.2d at 693, 16 USPQ2d at 1901.
In regards to Applicant’s arguments that Chauhan appears to described lyophilization of the solid microparticle alone and Polyton describes lyophilization after addition of fetal bovine serum wherein the instant application does not include the addition of FBS, Chauhan reference provides disclosure that magnetic particle comprising attached biomolecule (protein) can be lyophilized, which would provide a motivation to one of ordinary skilled in the art that magnetic particles to easily envisage providing the avidin coated and pluronic blocker magnetic particles in lyophilized form with the expectation of providing the particle with long term storage capability with a reasonable expectation of success.
Conclusion
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
