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 .
Status of Application, Amendments and/or Claims
1. Claims 1, 4-5, 7, 11-12 and 20 have been amended, claims 2 and 18-19 have been canceled, and new claim 21 has been added as requested in the amendment filed February 5, 2026. Following the amendment, claims 1, 3-17 and 20-21 are pending in the present application.
2. Claim 19 does not appear in the listing of claims filed February 5, 2026, although Applicant indicates that it was canceled. Each amendment document must include a complete listing of all claims ever presented, as well as their status identifier in a parenthetical expression, i.e., (Cancelled). See MPEP 714. Applicant is required to submit a full claim listing with their appropriate status identifiers, including cancelled claim 19, with their next response.
3. Accordingly, claims 1, 3-17 and 20-21 are under examination in the current office action.
Information Disclosure Statement
4. The information disclosure statements (IDSs) filed 02/05/2026 have been considered and the references therein are of record.
Withdrawn Claim Objections and Rejections
5. Any objection or rejection of record pertaining to any of canceled claims 2 or 18-19 is rendered moot by applicant’s cancellation of said claims.
6. The objection to claim 4 for minor informalities is withdrawn in view of applicant’s amendment to the claim.
7. The rejection of claim 20 under 35 USC 112(b) as being indefinite, set forth at section 3 of the 11/05/2025 office action, is withdrawn in view of applicant’s clarifying amendment to the claim.
8. The rejection of claims 1, 3, 5-6, 11-16 and 20 under 35 USC 102(a)(1) as being anticipated by Azzouz et al. (2019), as set forth at section 4 of the 11/05/2025 office action, is withdrawn in view of applicant’s claim amendments. In particular, Azzouz does not teach that the detected IgA antibody is IgA1, IgA2 or IgA anti-nuclear antigen (IgA-ANA) as now required by the claims.
9. The rejection of claims 15-17 under 35 USC 103 as being unpatentable over Azzouz et al. (2019) in view of Michot et al. (2019), as set forth at section 5 of the previous office action, is withdrawn in view of applicant’s claim amendments. In particular, the combination of Azzouz and Michot does not teach or suggest that the detected IgA antibody is IgA1, IgA2 or IgA anti-nuclear antigen (IgA-ANA) as now required by the claims.
10. The rejection of claims 5-17 under 35 USC 101 as being directed to a judicial exception (JE), set forth at section 7 of the 11/05/205 office action, is withdrawn in view of applicant’s amendments to claim 5. In particular, claim 5 now recites treatment of a subject identified by the diagnostic method as having an autoimmune disease, wherein the treatment is specific and therefore integrates the JE into a practical application.
Maintained and New Claim Rejections, Necessitated by Amendment
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.
11. Claim(s) 1, 3-16 and 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Azzouz et al. (Ann Rheum Dis, 2019, 78:947-956; ePub: 19 Feb 2019; with Supplementary materials) in view of Vyse et al. (WO 2014/195730 A2) and O’Sullivan et al. (Australian Family Physician, 2013, 42(10): 718-721) (all of record).
The rejection is maintained for reasons of record for claims 4 and 7-10, and is further applied to amended claims 1, 3, 5-6, 11-16 and 20-21 as discussed below.
Azzouz et al. teach a method that comprises determining the amount of total IgA present in a fecal sample from a patient diagnosed as having systemic lupus erythematosus (SLE). See Fig. 1D at p. 948. The supplemental materials section describes how fecal IgA levels were measured, indicating that patients were requested to provide fecal samples (iobtaining a fecal sample from the subject, claims 1 and 5; providing a fecal sample from a subject suspected of having/has a symptom of an autoimmune disease, claim 20), and contacting the sample with PE-conjugated anti-human IgA (contacting with…a capture molecule that specifically binds to at least one IgA autoantibody; claims 1 and 5) and separating the IgA-positive fraction to obtain an IgA-enriched fraction (selectively extracting total IgA antibodies from the fecal sample; claim 20) (see Isolation of sIgA-coated fecal bacteria at p. 2 of Supplemental Materials).
In particular, fecal samples were obtained from SLE patients (see Clinical trial design, p. 1), which addresses the limitations of: obtaining a fecal sample from [a] subject (claim 1 and step (a) of claim 5); and providing a fecal sample comprising at least one IgA autoantibody, wherein the subject is suspected of having an autoimmune disease or disorder or the subject has a symptom of an autoimmune disease or disorder (step (a) of claim 20). At p. 3, the section titled “Fecal Igs extraction and assays” teaches that fecal Igs were purified and total fecal IgA was determined by ELISA in which plates were coated overnight with an affinity purified anti-human IgA, alpha chain specific antibody, and diluted fecal samples were added to the plates. This is on point to claim 1 and step (b) of claim 5 (contacting a portion of the sample with a capture molecule which specifically binds to at least on IgA autoantibody) and step (b) of claim 20 (selectively extracting total IgA antibodies from the fecal sample). Finally, total IgA was detected and measured with HRP-conjugated goat anti-human IgA (alpha chain specific), wherein the goat anti-human IgA is a detector molecule and HRP (horse radish peroxidase) is a detectable moiety within the ELISA used to measure the level of IgA in the fecal samples. Such teachings address steps (c) and (d) of claim 5 (contacting the sample with a detector molecule, wherein the detector molecule is linked to a detectable moiety; and measuring a detectable signal generated from the detectable moiety) and step (c) of claim 20 (performing an assay on the extracted total IgA antibodies in order to quantitatively or qualitatively detect the level of IgA antibodies in the sample).
Further, the SLE patients are also taught as being treated with various medications including: prednisone (Pred) or methylprednisone (Meth) (both corticosteroids as well as immunosuppressant drugs); hydroxychloroquine (HCQ); mycophenolate mofetil (MMF) (immunosuppressant drug); methotrexate (MTX) (immunosuppressant drug); belimumab (Bel)(immunosuppressant drug); and azathioprine (AZA) (immunosuppressant drug). Such teachings are on point to amended to See “Clinical trial design” at p. 1 of Supplementary methods, and Supplementary Table 1, Patients with autoimmunity: NYU cohort SLE patients with microbiome data. The continued administration of these agents to the SLE patients would meet the broadest reasonable interpretation (BRI) of claim 5 step (e)(administering a treatment to a subject having an autoimmune disease).
Regarding claims 3 and 12, the HRP-conjugated goat anti-human IgA (a detector molecule) meets the limitation of a secondary antibody against IgA that is linked to a detectable moiety (HRP), and which is used to measure a detectable signal generated by the detectable moiety (i.e., performing an ELISA).
Regarding claim 6, steps b-d of claim 5 were performed sequentially in the ELISA method taught by Azzouz.
Regarding claim 11, the capture molecule of Azzouz was an antibody against IgA (an anti-human IgA antibody), which was used as used in Azzouz’s ELISA to measure the abundance of IgA antibodies (see also Fig. 1D).
Regarding claims 13-15, Azzouz teaches that fecal IgA levels were compared between female SLE patients and female healthy control subjects (a comparator control; a negative control; an expected normal background value of a population that the subject is a member of), and that the IgA levels in SLE patients was significantly higher than in control subjects. See Fig. 1D, “Clinical trial design” at p. 1 of Supplementary methods, and Supplementary Table 1, Patients with autoimmunity: NYU cohort SLE patients with microbiome data.
Regarding claim 16, the subjects were symptomatic for SLE (see “Clinical trial design” at p. 1 of Supplementary methods).
However, Azzouz does not teach that the method comprises detecting at least one IgA autoantibody that is IgA anti-nuclear antigen (IgA-ANA) (claims 1, 5, 20), wherein the nuclear antigen is selected from RNP/SM, SS-A, Ro-52, SS-B, Scl-70, Pm-Scl, Jo-1, centromere B, Pcna, dsDNA, nucleosomes, nucleohistones, histones, ribosomal P-protein or AMA-M2 (claims 4, 8, 10, 21). And while Azzouz teaches that the detection method comprises an anti-IgA antibody as a capture molecule, it does not teach that the method further comprises the step of contacting the captured IgA total antibodies with at least one nuclear antigen prior to the step of contacting the sample with a detector molecule (claim 7-8). Nor does the reference teach that the capture molecule comprises a natural, synthetic or recombinant nuclear antigen or fragment thereof (claims 9-10).
Vyse et al. teach methods for diagnosing SLE and other autoimmune diseases and disorders in a subject, comprising determining the level of auto-antibodies that bind to certain biomarker antigens in a subject sample (p. 3 lines 2-12, 17-19). Vyse teaches that in addition to the consideration of medical history, the age and gender of the patient, and physical examination, the diagnosis of lupus typically comprises a number of laboratory tests, including tests for the presence of antinuclear antibodies (ANA) and other autoantibodies such as anti-dsDNA, anti-Smith (Sm), anti-RNP, anti-RO (SSA), anti-La (SSB) and anti-cardiolipin antibodies (p. 1 line 28 – p. 2 line 2).
In particular, Vyse discloses that determining a panel of auto-antibodies in a subject sample is useful for diagnosing whether a subject has lupus, wherein such determination involves not only analyzing the level of auto-antibodies against particular biomarker antigens, but also determining the level of known biomarkers autoantibodies such as ANA (antinuclear antibodies), anti-dsDNA, anti-Ro (Ro-52), or anti-histone antibodies (p. 4 lines 16-29). For example, one panel of biomarker autoantibodies to be detected include autoantibodies against different biomarkers from Table 1 in combination with autoantibodies against one or more of dsDNA, SSA or SSB (p. 4 lines 16-19 and Table 3 at p. 52). Such teachings address limitations regarding the anti-ANA antibodies and nuclear antigens recited in present claims 2, 4, 8 and 10.
In addition to these autoantibody biomarkers, Vyse indicates that biomarkers for lupus can also include “any other known biomarkers e.g. see above” (p. 4 lines 27-28). At p. 2 lines 9-10, (e.g. “above”) Vyse teaches that “antibodies to double-stranded DNA and/or nucleosomes were associated with lupus over 50 years ago”, indicating that anti-dsDNA and anti-nucleosome autoantibodies were known biomarkers, and thus are encompassed by the diagnostic biomarkers and methods of Vyse.
Regarding new claim 21, it is noted that nucleosomes are the nucleohistone subunits of chromatin (see abstract of Studitsky VM et al. Science, 1997, 278:1960-1963). See also Burlingame RW et al. (Autoimmun. Rev. 2002, 1:321-328) which teaches that anti-chromatin autoantiobodies are also called anti-nucleosome autoantibodies. Thus, an autoantibody that binds nucleosomes would also necessarily and inherently bind nucleohistones and/or chromatin, as these molecules are essentially the same structure and their names are used interchangeably in the relevant art.
Vyse indicates that the biomarker autoantibody may be of any class, subtype or isotype, and is detected using a detection reagent which recognizes the appropriate class, such as IgA (see p. 14 lines 21-27). According to Vyse, a suitable biological sample containing autoantibodies for detection by the invention can include feces, wherein fecal sample typically require physical treatment prior to protein detection, e.g. suspension, homogenization and centrifugation (p. 11 lines 21-24; p. 12 lines 1-2).
Regarding claims 7 and 9, Vyse teaches that the detection antigens can be a natural antigen recognized by the autoantibody, or it may be a recombinant or synthetic peptide, or an epitope peptide (p. 12 lines 21-24; p. 13 lines 1-10). Vyse discloses that these antigens can be immobilized on a solid substrate of a diagnostic device for determination of whether a sample contains biomarker autoantibodies (p. 14 lines 28-30), which is on point to a capture molecule. Vyse indicates that sandwich assays are typical for immunological methods, including ELISA, colorimetric or fluorescence-based detection methods (p. 13 lines 26-34).
Consistent with the teachings of Vyse, O’Sullivan et al. teach that the antinuclear antibody (ANA) test is widely used in the diagnosis of autoimmune disease, such as SLE, mixed connective tissue disease, drug induced lupus, juvenile idiopathic arthritis, Sjögren’s syndrome, polymyositis, dermatomyositis, and diffuse systemic sclerosis/scleroderma (Abstract and Table 1 at p. 719). The test is performed by indirect immunofluorescence, EIA or ELISA (p. 718, left column). In ELISAs, wells are coated with antigens from cell nuclei, sample is added, and antibodies binding to the antigens are detected using a detection antibody which has been conjugated with an enzyme tag. Antibody levels may be quantified by the amount of color change of a substrate by the enzyme tag (p. 718, top of right column).
It would have been obvious to one of ordinary skill in the art at the time of filing to have included the detection of ANAs using various nuclear antigens as taught by Vyse and O’Sullivan in the diagnostic method of Azzouz and thereby arrive at the presently claimed invention. Given the teachings of Vyse and O’Sullivan, the skilled artisan would have recognized that the presence of biomarker autoantibodies such as ANAs, or anti-dsDNA, anti-SSA, anti-SSB or anti-nucleosome (i.e., anti-nucleohistone) antibodies is indicative of the presence of autoimmune disease, and SLE in particular. Therefore, the skilled artisan would have been motivated by these teachings to have used nuclear antigens (dsDNA, SSA, SSB, RNP/Sm, nucleosome (nucleohistone), etc.) as capture molecules in order to detect the presence of antinuclear IgA autoantibodies in fecal samples of subjects suspected of having or at risk of having SLE. Given that Vyse teaches that such antigens can be used with fecal samples in the detection of any antibody class, subtype or isotype, including IgA, and given Azzoz’s demonstrated success in detecting fecal IgA autoantibodies in samples from SLE patients, the artisan would have had a reasonable expectation that such a method could be successfully practiced. Accordingly, the prior art teachings of the above references render obvious the invention recited in present claims 1, 3-16 and 20-21.
Response to Arguments
12. In the response filed 02/05/2026, Applicant argues that Azzouz does not teach detecting an IgA antibody that is an IgA1, IgA2 or IgA anti-nuclear antigen (ANA) antibody, and Vyse and O’Sullivan do not remedy these deficiencies.
13. Applicant’s arguments have been considered but are not persuasive. As discussed above, Vyse and O’Sullivan provide for the added limitations to amended claims 1, 5 and 20, and in combination with Azzouz render obvious the presently claimed invention as discussed above. Note that the Studitsky and Burlingame references above were added simply to evidence features already present within the Vyse reference.
14. Claim(s) 15-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Azzouz et al. (Ann Rheum Dis, 2019, 78:947-956; ePub: 19 Feb 2019; with Supplementary materials) in view of Vyse et al. (WO 2014/195730 A2) and O’Sullivan et al. (Australian Family Physician, 2013, 42(10): 718-721) as applied to claims 1, 3-16 and 20-21 above, and further in view of Michot et al. (Ann Rheum Dis. 2019, 78:e67, 3 pages) (all of record).
The reasons why the teachings of Azzouz et al. in view of Vyse et al. and O’Sullivan et al. render obvious the instantly recited invention of claims 1, 3-16 and 20-21 are discussed above. In particular, the prior art references provide for a method of diagnosing a subject as having or being at increased risk for an autoimmune disease, wherein the autoimmune disease is SLE, comprising obtaining a fecal sample from a subject, contacting a portion of the sample with a capture molecule that binds to at least one IgA autoantibody, wherein the IgA is an IgA anti-ANA autoantibody. While the prior art references teach that the disease or disorder is SLE and the subject is a symptomatic subject, it does not teach that the disease or disorder is drug induced lupus (claim 15), the subject is receiving a cancer treatment therapy (claim 16), or the cancer treatment is selected from Ipilimumab, Durvalumab, Avelumab, Atezolizumab, Pembrolizumab, Nivolumab, or Cemiplimab (claim 17).
Michot et al. teach that in five cases reported between 2013 and 2017, cancer patients receiving immunotherapy with agents that inhibit the programmed death-(ligand) 1 (PD(L)1) pathway developed drug-induced lupus erythematosus (DI-LE). Two of these patients also tested positive for antinuclear antibodies in serum (SSA-positive patients) (see page 1). Michot reports that the patients who developed DI-LE had been receiving therapy for cancer with anti-PD(L)1 antibodies, including Atezolizumab, Nivolumab and Pembrolizumab (see Table 1 at p. 2). Such teachings address limitations of present claim 15 (the disease is drug induced lupus), claim 16 (the subject is receiving cancer treatment therapy), and claim 17 (the cancer treatment is Atezolizumab, Nivolumab, or Pembrolizumab).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to have applied the diagnostic findings of Azzouz, Vyse and O’Sullivan for the evaluation of the DI-LE subjects taught by Michot and thereby arrive at the presently claimed invention. In particular, given the teachings of Michot, one of skill in the art would have recognized that there is a risk of developing drug-induced lupus in cancer patients who are treated with anti-PD(L)1 immunotherapies, such as Atezolizumab, Nivolumab and Pembrolizumab. Given also that Azzouz teaches that significantly elevated fecal IgA levels are found in patients having SLE, the skilled artisan would have been motivated to utilize this non-invasive diagnostic method to aid in the identification of cancer patients receiving anti-PD(L)1 therapeutics who are at risk of developing DI-LE. The skill level to perform such a diagnostic technique was well within the scope of those of ordinary skill in the art (i.e., a laboratory technician, medical researcher or physician), and therefore there would have been a reasonable expectation that the ELISA used by Azzouz to detect fecal IgA autoantibodies could be successfully applied to test cancer patients receiving anti-PD(L)1 immunotherapy and therefore at risk of developing DI-LE. Accordingly, the teachings of the prior art render obvious the presently claimed invention of claims 15-17.
Response to Arguments
15. In the response filed 02/05/2026, Applicant argues that Azzouz does not teach detecting an IgA antibody that is an IgA1, IgA2 or IgA anti-nuclear antigen (ANA) antibody, and Michot do not remedy these deficiencies.
16. Applicant’s arguments have been considered but are not persuasive. As discussed above, the new rejection also now includes Vyse and O’Sullivan, which references provide for the added limitations to amended claims 1, 5 and 20, and in combination with Azzouz and Michot render obvious the presently claimed invention as discussed above.
Conclusion
17. No claims are allowed.
18. 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.
Advisory Information
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/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675
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