DETAILED ACTION
Claims 1-17 and 19-32 are pending.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/03/2026 has been entered.
Status of Claims
Claims 1-17 and 19-32 are pending. Claim 18 has been cancelled. Claims 19-32 have been withdrawn. Claims 6-9 have been withdrawn as they are drawn to a nonelected species (see response to restriction filed on 05/16/2025 and the non-final office action mailed on 08/22/2025).
Claims 1-5 and 10-17 are under examination.
Withdrawn Claim Objections and/or Rejections
The rejection of claims 1-5 and 10-17 under 35 USC 112(a) for failing to comply with written description as set forth on p. 3-4 of the previous office action (mailed on 03/06/2026) has been withdrawn in view of the amended claims, as the amendments overcome the written description rejection (filed on 05/19/2026).
The rejection of claims 1-5 and 10-17 under 35 USC 112(b) for being indefinite as set forth on pp. 5-6 of the previous office action (mailed on 03/06/2026) has been withdrawn in view of the amended claims, as the amendments overcome the indefinite rejection (filed on 05/19/2026).
Claim Objections
1.Claims 1-5 and 10-17 are objected to because of the following informalities: Claim 1 recites “…is present at at least”. It appears that there is a typo resulting in the use of the same word twice. Appropriate correction is required.
Claim Rejections - 35 USC § 103: New, Necessitated by Amendments.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
There is a new 35 USC 103 rejection that is necessitated by the amendments to the claims. The newly added prior art is to address the new limitation “at least one detectably labeled anti-ZnT8 antibody or antigen-binding fragment thereof is present at least a two-fold molar excess relative to ZnT8 so as to maintain full binding occupancy of the cytoplasmic-domain of ZnT8”. Since this is an RCE, it is a non-final rejection.
2.Claims 1-13 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al., (WO2019014044A1) (IDS filed on 12/06/2021), in view of Merriman et al., (US 62719016) (effective filing date of 08/16/2018) (List of References cited on 08/22/2025).
Fu teaches a method comprising the steps of:
(a) contacting in a first mixture a biological sample obtained from a patient with a zinc transporter 8 (ZnT8) -antibody complex (see claim 1), wherein the ZnT8-antibody complex comprises ZnT8 and at least one detectably labeled anti-ZnT8 antibody or antigen-binding fragment thereof that specifically binds to the cytoplasmic domain of ZnT8 (see claim 1);
(b) contacting in a second mixture the first mixture of step (a) with an immunoglobulin G (IgG) labeled with a tag molecule (see page 25 lines 8-13 “PLR-ZnT8 immobilized on pGOLD (PLR-ZnT8/pGOLD) was used to capture ZnT8A in human serum samples diluted by 20-fold with fetal bovine serum (FBS), and the captured autoantibody was subsequently labeled with NIR fluorophore-conjugated secondary antibody (i.e., anti-human IgG-IRDye800). The amounts of ZnT8A were then analyzed through the fluorescence intensity of the fluorophore (Fig. 2A).”);
(c) contacting the second mixture of step (b) with a solid substrate coated with a capture molecule that specifically binds the tag molecule (see page 25 lines 8-13); and
(d) detecting a signal emitted from the detectably labeled anti- ZnT8 antibody or antigen-binding fragment thereof (see page 5 lines 21-22 “The amount of antibodies bound to the ZnT8 proteins maybe determined by measuring the signal provided by the detection probe.”, see page 35 lines 4-9 “After the assay process, each biochip was scanned with a MidaScan-IR near-infrared scanner. MidaScan-IR is a dual channel (700 and 800 nm) near-infrared confocal microscope scanner for imaging tissues, cells and microarrays on standard glass or plasmonic slides. IRDye680 and IRDye800 fluorescence images were generated, and the median fluorescence signal for each channel on each microarray spot was quantified by MidaScan software.”) (instant claim 1).
Fu teaches wherein the biological sample is blood, plasma or serum (see abstract “Methods of detecting ZNT8 antibodies in serum are described”) (instant claim 2). Fu teaches wherein the at least one detectably labeled anti- ZnT8 antibody or antigen-binding fragment thereof comprises a Fab (see page 7 lines 7-9 “the term "antibody" also includes antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, dAb, and other antibody fragments that retain antigen-binding function, i.e., the ability to bind, for example, PD-Ll, specifically.”) (instant claim 3). Fu teaches wherein ZnT8 is full length ZnT8 (See page 11 line 11 "By "PLR-ZnT8" is meant purified full length ZnT8 protein in proteoliposomes.") (instant claim 10). Fu teaches wherein ZnT8 lacks an N-terminal domain (see page 23 lines 5-8 "Human ZnT8 is encoded by the SLC30A8 gene expressed in pancreatic beta-cells to produce two protein isoforms. Isoform-1 is a full-length 369- aa protein while isoform-2 is a product of alternative splicing with a 49 aa deletion from the N-terminus. The N-terminal domain of ZnT8 is largely missing in isoform-2.") (instant claim 11). Fu teaches wherein ZnT8 comprises amino acids 66-369 of SEQ ID NO:64 and wherein the cytoplasmic domain of ZnT8 comprises amino acids 276-369 of SEQ ID NO:64 (see SEQ ID NO: 1) (instant claims 12 and 15). Fu teaches wherein the detectable label is an electrochemiluminescent label (See page 25 lines 10-12 "and the captured autoantibody was subsequently labeled with NIR fluorophore-conjugated secondary antibody (i.e., anti-human IgG-IRDye800).". A NIR fluorophore-conjugated antibody is known in the art to be an electrochemiluminescent label) (instant claim 13) and wherein the tag molecule is biotin (see page 5 lines 18-19 "labelled captured autoantibody used in the present invention may comprise a detection probe such as a biotin probe or a fluorescent probe, as examples.") (instant claim 16).
Fu does not teach at least one detectably labeled anti-ZnT8 antibody or antigen-binding fragment thereof is present at least a two-fold molar excess relative to ZnT8 so as to maintain full binding occupancy of the cytoplasmic-domain of ZnT8.
Merriman teaches that mAbs in excess to ZnT8 (see page 16207).
Although Merriman does not teach the excess being at least two-fold, it would have been obvious to one of ordinary skill in the art to perform routine optimization for determining the amount of labeled anti-ZnT8 antibody or antigen-binding fragment that is present relative to ZnT8 in order to maintain full binding occupancy of the cytoplasmic-domain of ZnT8. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of the amount of labeled anti-ZnT8 antibody relative to ZnT8 would have been obvious at the time of the invention (instant claim 1). As noted in In re Aller, 105 USPQ 233 at 235, More particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.
Merriman teaches wherein the Fab comprises SEQ ID NO:32 and SEQ ID NO:37 (see SEQ ID NO: 32 and SEQ ID NO: 37 of Merriman.) (instant claim 4). Merriman teaches wherein the Fab comprises:(a) heavy chain complementary determining regions (CDRs) 1, 2, and 3, wherein the heavy chain CDR1 comprises SEQ ID NO:33 (see SEQ ID NO: 3 of Merriman), or the amino acid sequence of SEQ ID NO:33 with a substitution at two or fewer amino acid positions the heavy chain CDR2 comprises SEQ ID NO:34, or the amino acid sequence of SEQ ID NO:34 with a substitution at two or fewer amino acid positions (see SEQ ID NO: 14 of Merriman), and the heavy chain CDR3 comprises SEQ ID NO:35 (see SEQ ID NO: 35 of Merriman), or the amino acid sequence of SEQ lD NO:35 with a substitution at two or fewer amino acid positions (see SEQ ID NO: 35 of Merriman); and(b) light chain CDRs 1, 2, and 3, wherein the light chain CDR1 comprises SEQ ID NO:38 (see SEQ ID NO: 38 of Merriman), or the amino acid sequence of SEQ ID NO:38 with a substitution at two or fewer amino acid positions, the light chain CDR2 comprises SEQ ID NO:39 (see SEQ ID NO: 39 of Merriman), or the amino acid sequence of SEQ ID NO:39 with a substitution at two or fewer amino acid positions, and the light chain CDR3 comprises SEQ ID NO:40 (see SEQ ID NO: 30 of Merriman), or the amino acid sequence of SEQ ID NO:40 with a substitution at two or fewer amino acid positions (see [0017]) (instant claim 5).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to combine the methods of detecting autoantibodies targeting ZnT8 taught by Fu, with the methods of using highly specific monoclonal antibodies to detect ZnT8 taught by Merriman. Merriman teaches that adding mAbs in excesses is beneficial because it allows for the formation of cross-linked aggregates, allowing for increased completion (see page 16207). Merriman teaches that adding mAb20 (a Fab that comprises SEQ ID NO: 32-35 and SEQ ID NO: 37-40 is beneficial because it (see page 17 line 11 and page 18 line 1 of the instant application) can detect remaining ZnT8 in a supernatant (see [0023]), allowing for greater reactivity. The artisan would have reasonable expectation of success based on the cumulative disclosures of these prior art references.
3.Claims 14 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Fu and Merriman as applied to claims 1-13 and 15-16 above, and in view of Lenardo et al., (WO 2013071055A1) (IDS filed on 12/06/2021).
The teachings of Fu and Merriman as it pertains to claims 1-13 and 15-16 are discussed in the 35 USC 103 rejection above.
Fu and Merriman do not teach electrochemiluminescent label being sulfo-tag and the capture molecule being streptavidin.
Leonardo teaches wherein the electrochemiluminescent label is a sulfo-tag (see [00138] “Sulfo-NHS-LC Biotin; Conjugate Purification Buffer (100mM Acetic Acid)”), see [00144] “Recombinant human insulin (MBL® International Corporation, Woburn, MA) was biotinylated using Biotin-LC-Sulfo-NHS Ester (Pierce Biotechnology, Rockford, IL) and conjugated to the streptavidin Dynabeads® and stored at 4°C until used.”) (instant claim 14). Lenardo teaches wherein the capture molecule is streptavidin (see [0026] “wherein the first and second binding partners are selected from the following binding partner pairs: biotin/streptavidin”, see [0027] “The present disclosure further provides methods for detecting diabetes-associated autoantibodies against at least one antigen in a sample, wherein the first binding partner is streptavidin and the second binding partner biotin.”) (instant claim 17).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to combine the methods of detecting autoantibodies targeting ZnT8 taught by Fu, with the methods of using highly specific monoclonal antibodies to detect ZnT8 taught by Merriman, with the capture molecules taught by Leonardo. Leonardo teaches that the use of a sulfo-tag is beneficial because it allows for the capture reagent/antibody complex to be captured through antigen bound to a tag, because both of those interactions depend on the avidity of the autoantibody within the subject which is variable, leading to greater and more accurate reactivity (see [00109]). Leonardo teaches that the use of the streptavidin-biotin system for linkage of antigens in immunosorbent assays is beneficial because it has been shown to be superior in preserving antigen conformation and antibody-binding capacity than absorption methods of immobilizing antigens used in most ELISAs and streptavidin-coated beads increase sensitivity since antigen in fluid phase allows better antibody binding (see [00160]). The artisan would have reasonable expectation of success based on the cumulative disclosures of these prior art references.
Conclusion
No claim is allowed.
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/MCKENZIE A DUNN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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