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 .
Claim Status
Claims 12-20, 22-23, 25, 30, 32-40, 42-50 and 52-60 were canceled.
Claims 1-11, 21, 24, 26-29, 31, 41 and 51 are pending.
Claims 41 and 51 stay withdrawn from further consideration.
Claims 1-11, 21, 24, 26-29, and 31 are under consideration.
Withdrawn Objections
Objections of claims 1, 4, 7, 9, 11, 21, 24, 27, 29, and 31 are withdrawn. Applicant amended the claims, thereby obviating this rejection/objection.
MAINTAINED - 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:
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.
Claim(s) 1-11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Awan et al (Pakistan J. Zool., vol. 44(1), page 217-226, 2012) in view of van den Doel et al (BMC Veterinary Research (2015) 11:203) as evidenced by Vafajoo et al (Biomed Microdevices, 2019, 20(3): 66).
Regarding claims 1-3, 6, and 9-10, Awan teaches expression and purification of Mycobacterium tuberculosis antigens for use in immunoassays for serodetection of M. tuberculosis infection in TB patients (title). Awan teaches that antigenic proteins are His-tagged (page 219, right column, “Purification of antigenic proteins” section). Awan teaches that plasma samples were collected from human TB patients (page 220, bridging paragraph). Awan teaches “All six purified antigenic proteins were chemically cross linked to microbeads” (page 220, right column, second paragraph). Awan teaches that human plasma samples were mixed with bead (page 221, left column, last paragraph; corresponds to “(i) incubating a liquid biological sample” of claim 1). Awan teaches “Beads were washed twice with 100 ul of wash buffer” (page 221, right column, first paragraph; corresponds to “(ii) washing the bead particle” of claim 1). Awan teaches “For detection of human IgG (corresponds to claim 3), R-phycoerythrin conjugated goat antihuman IgG (corresponds to “detectably labeled antibody” of subpart (iii) of claim 1) was used as secondary antibody at a dilution of 1:1,000 in wash buffer, by adding 100 ul per well. After mixing, beads were incubated for 1 hr at room temperature (corresponds to “(iii) incubating the bead particle with a detectably labeled antibody” of claim 1), and were washed twice after antibody treatment. Finally, resuspension was done in 100 ul PBS-T. The plate was read on Luminex 100 instrument (corresponds to “determining the presence or absence of the detectably labeled antibody” of claim 1)” (page 221, right column).
Regarding claim 4, R-phycoerythrin taught by Awan is a pigment.
Regarding claim 5, Mycobacterium tuberculosis is bacteria.
Regarding claim 7, Awan teaches that the antigen was produced recombinantly from expression strain BL21DE3 (page 219, “Expression of antigenic genes” section, bridging paragraph).
Regarding claim 8, Awan teaches “Microbeads were purchased from Luminex Corporation (Austin, TX)” (page 220, right column, second paragraph). As evidenced by Vafajoo, the microbead taught by Awan is a polystyrene microparticle. Vafajoo teaches “The first commercially available platform that used microbead-based technology, was from Luminex (Austin, TX, USA). As shown in Fig. 8, the Luminex system consists an array of 100 polystyrene microbeads, each bead has a unique optical address with immobilized specific probe molecules like antigens, antibodies and nucleic acids attached onto the surface of the microbeads.”
Regarding claim 11, antibody present in human plasma sample binds to the antigenic protein cross linked to microbead. This human antibody is recognized by detectably labeled secondary antibody R-phycoerythrin conjugated goat antihuman IgG as taught by Awan. Therefore, it is obvious that the amount of the detectable label correlates to the amount of anti-pathogen or anti-microbe IgG and/or IgM.
The difference between prior art and the instant invention is that while Awan teaches that antigen is directly chemically cross-linked to microbead, instant invention binds antigen to microbead via anti-His antibody.
Regarding claims 1 and 6, van den Doel teaches a novel antigen capture ELISA for the specific detection of IgG antibodies to elephant endotheliotropic herpes virus (title). van den Doel teaches “Here we describe a novel ELISA that specifically detects EEHV antibodies circulating in Asian elephant plasma/serum” (abstract, result section). van den Doel teaches “sandwich ELISA using a mouse monoclonal anti-His antibody as a capture antibody for the target antigen” (Figure 3). van den Doel teaches His-tagged glycoprotein B as antigen (Method section, page 2 of 10). van den Doel teaches “mouse-anti 6His antibody (ClonTech) as a capture antibody was coated in high binding 96-well microtiterplate. … The purified EEHV-gB antigen was diluted in PBS containing 0.1 % Triton-X to a concentration of 750 ng/well and bound to the capture antibody for 1 h at 37 °C. After washing, primary incubation (corresponds to step (i) incubating biological sample of claim 1) was performed with 100 μl/well diluted (1:100 and 1:200) elephant serum in ELISA buffer containing PBS, 0.2 % BSA, 0.1 % non-fat dried powder milk and 3 % w/v NaCl and incubated for one hour at 37 °C. After washing (corresponds to step (ii) washing of claim 1), elephant specific IgG’s bound to glycoprotein B were detected by incubation with 100 μl/well of rabbit anti-elephant IgG (1:1000 diluted in ELISA buffer) for one hour at 37 °C followed by an incubation step with swine anti-rabbit IgG HRPO conjugate (1:1000 diluted in ELISA buffer).” (page 4 of 10, left column).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have linked anti-His antibody to microbead as a capture antibody and bound purified His-tagged antigen to this anti-His antibody because van den Doel teaches that this method can be effectively used to detect anti-microbe antibody in the serum against microbial antigen. One of ordinary skill in the art would understand that anti-His antibody as a capture antibody has advantage because anti-His antibody can be bound to any recombinant microbial antigen with His tag. Therefore, when microbead is linked to anti-His antibody, the microbead can be used for any target microbial antigen. Thus, with one crosslinking to microbead, the assay can be performed with many different His-tagged antigens. Furthermore, one of ordinary skill in the art would understand that microbead linked to anti-His antibody as a capture antibody has another advantage because the space between microbead and the target antigen created by anti-His antibody allows anti-microbe antibodies in the serum to freely access to the target antigen because anti-His antibody is much bigger than usual chemical linkers. In contrast, when the target antigen is chemically linked to microbead, some portion of the target antigen is not accessible to anti-microbe antibody due to steric hindrance in proximity to chemical linker. Thus, anti-microbe antibodies with specificity to this region cannot be detected. Therefore, one of ordinary skill in the art would be motivated to modify ELISA assay of Awan using anti-His antibody as a capture antibody as taught by van den Doel to arrive at the instant invention. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because van den Doel teaches that anti-His antibody as a capture antibody can be effectively used to detect anti-microbe antibody in the serum against microbial antigen. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 1-11, 21, 24, 26-29 and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Awan et al in view of van den Doel et al as applied to claims 1-11 above, and further in view of Tokarz et al (US2020/0255889; published 8/13/2020).
Regarding claims 1-11, teachings of Awan and van den Doel were discussed above.
However, Awan and van den Doel do not teach determining exposure of a subject to Borrelia miyamotoi using glycerophosphodiester phosphodiesterase as a target antigen.
Regarding claims 21, 24, 26-29 and 31, Tokarz teaches “Tick-borne diseases (TBD) are the most common vector-borne diseases in the United States … Other agents implicated in TBD throughout the United States include Borrelia miyamotoi” [004]. Tokarz teaches “The current invention provides compositions, methods, and kits for detecting the exposure to and infection by certain agent or pathogens. Specifically, the current invention allows for the rapid differential serological detection of exposure to, and infection by tick-borne agents or pathogens using specific antigenic peptides.” (abstract). Tokarz teaches “The peptides, and collections and sets of peptides of the invention for the detection of the antibodies to the TBD pathogens can used in any number of immunodetection techniques, which include but are not limited to Western blot, enzyme-linked immunosorbent assay (ELISA)” [0036]. Tokarz teaches “For B. miyamotoi, serological diagnosis is typically performed using the glycerophosphodiester phosphodiesterase, as this antigen is present in B. miyamotoi infection but not B. burgdorferi” [0175].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used glycerophosphodiester phosphodiesterase as a target antigen to detect exposure to Borrelia miyamotoi because Tokarz teaches that glycerophosphodiester phosphodiesterase can be effectively used as a peptide antigen to detect B. miyamotoi infection. Because Tokarz teaches that glycerophosphodiester phosphodiesterase is present in B. miyamotoi infection but not B. burgdorferi, one of ordinary skill in the art would be motivated to use glycerophosphodiester phosphodiesterase as a target antigen to detect only B. miyamotoi infection but not B. burgdorferi infection. The differentiating two species in same genus is beneficial because medical staff can treat the infection according to the specific species of the pathogen. One of ordinary skill in the art would be motivated to detect B. miyamotoi infection because Tokarz teaches that B. miyamotoi causes tick-borne disease. Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success because Tokarz teaches that glycerophosphodiester phosphodiesterase can be effectively used as a peptide antigen to detect B. miyamotoi infection. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
In the response filed on 8/4/2026, Applicant argued at page 8,
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Applicant's arguments have been fully considered but they are not persuasive. In 103 rejection, the used reference does not need to be 100% identical to instant invention. As long as the reference teaches a portion (e.g. in instant case, anti-His antibody as a capture antibody taught by van den Doel) which provides a benefit, one of ordinary skill in the art would be motivated to combine this beneficial portion of the reference to the other reference to make new invention with advantage. As discussed above, van den Doel teaches that anti-His antibody can be linked to plate and be used as a capture antibody to bind to His-tagged antigen. Applicant failed to provide any evidence that anti-His antibody cannot be linked to microbead. One of ordinary skill in the art would be motivated to link anti-His antibody (capture antibody) to microbead of Awan instead of direct chemical crosslinking of antigen because one of ordinary skill in the art would recognize the benefit of anti-His antibody as discussed above.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CHEOM-GIL CHEONG/Examiner, Art Unit 1645
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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