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 .
Claim Status
Claims 2, 8, 13-17, 22-26, and 29 have been cancelled and claims 1 and 27-28 have been amended, as requested in the amendment filed on 07/08/2026. Following the amendment, claims 1, 3-7, 9-12, 18-21, and 27-28 are pending in the instant application.
Claims 1, 3-7, 9-12, 18-21, and 27-28 are under examination in the instant office action.
Claim Rejections - 35 USC § 112 - Withdrawn
Claim 29 was rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Claim 29 has been canceled, rendering its rejection moot. As such, the rejection of claim 29 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn.
Claim 27 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Claim 27 has been amended to recite “the immunosuppressive drug”, which has proper antecedent basis. As such, the rejection of claim 27 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim Rejections - 35 USC § 112 - Maintained, Updated as Necessitated by Amendment
Claim 28 stands as 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.
As amended, claim 28 now recites the limitation "the " in line 1. It is noted that there are two separate recitations of “a steroid hormone” in independent claim 1, pertaining to (i) a previous treatment or (ii) treatment administered according to the instantly claimed method in a patient identified as needing treatment. As such, it is unclear as to if the recitation of “the steroid hormone” is intended to refer to the agent used to successfully treat the patient previously, or if the recitation of “the steroid hormone” is intended to refer to the agents administered to the patient identified as needing treatment in the method of claim 1. For the purposes of examination, “the steroid hormone” is being interpreted as referring to the agents administered to the patient identified as needing treatment, which is consistent with the interpretation of the previous Office Action (dated 04/08/2026).
Claim Rejections - 35 USC § 112 - New, as Necessitated by Amendment
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.
Claims 5 and 18-19 are 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. Claims 5 and 18-19 each fail to include all the limitations of the claim(s) upon which they depend. Claim 5 recites the method of claim 1, wherein the sample is a body fluid containing cells; however, claim 1 from which claim 5 depends, recites isolating PBMCs from the sample collected, and thus requires that the sample collected comprise PBMCs. As such, claim 5 is broader than, and fails to incorporate all of the limitations of claim 1 from which it depends, because claim 1 requires a sample comprising PBMCs whereas claim 5 is drawn to any sample comprising any kind of cells. Claim 18 depends from claim 5, and therefore claim 1, wherein claim 18 further limits claim 5 such that the body fluid sample is selected from blood, plasma, serum, urine, cerebrospinal fluid, and lymph; however, not all of the recited samples in claim 18 comprise PBMCs as required by claim 1 and therefore claim 18 is broader, and fails to include all of the limitations of claim 1 from which it ultimately depends. Claim 19 recites the method of claim 1, wherein the sample is a biopsy sample of a tissue or an organ; however, claim 1 from which claim 19 depends, recites isolating PBMCs from the sample collected, and thus requires that the sample collected comprise PBMCs. Solid tissue samples do not comprise PBMCs, and thus the samples of claim 19 do not comprise PBMCs as required by claim 1 and therefore claim 19 is broader, and fails to include all of the limitations of claim 1 from which it depends. 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 - Maintained, Updated as Necessitated by Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
It is specifically noted that the statements of rejection below have been updated, and the order of cited references have been changed to address the amendment of claim 1 regarding the new limitation requiring the isolation of peripheral blood mononuclear cells (PBMCs). However, all rejections rely upon references and teachings cited in the previous Office Action (dated 04/08/2026), wherein some previously cited teachings are further expanded upon to address the instant claim amendments, and therefore do not constitute new grounds of rejection.
Claims 1, 3-7, 9-12, 18-21, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over US 2011/0177534 A1 (previously cited on PTO-892; herein after referred to as "Salant") in view of non-patent literature published by Kao et. al. (J Am Soc Nephrol, 2015, 26, 291-301; previously cited on PTO-892; herein after referred to as "Kao"), non-patent literature by Moody and Haynes (Cytometry Part A, 2008, 73A, 1086-1092; previously cited on PTO-89; herein after referred to as “Moody”), and non-patent literature by Degauque et. al. (PLOS ONE, 2013, 8(12), 1-10; previously cited on PTO-892; herein after referred to as “Degauque”).
With regard to claim 1, Salant teaches a method for diagnosing MN in a subject, the method comprising detecting the presence of antibodies that are reactive to a PLA2R, wherein the antibodies are found in a sample from a subject (Paragraph 0004). The antibodies can be detected by an immunoassay wherein an antibody-protein complex is formed wherein the antibodies are found in the sample of the subject, e.g., serum (Paragraph 0005; emphasis added). Salant indicates that a detectable amount of antibodies that are reactive to a PLA2R indicates likelihood of membranous nephropathy in the subject (Paragraph 0028). Since the sera from control healthy individuals and non-MN nephropathy patients do not contain or have a very low amount or undetectable amount of auto-antibodies that react with PLA2R unlike the sera of MN patients, the detection of the presence of PLA2R antibodies can be used as a diagnostic tool for MN; a simple blood sample can be used to test for and detect antibodies reactive against PLA2R wherein a method of diagnosing membranous nephropathy in a subject can comprise detecting the presence of antibodies that are reactive to a phospholipase A2 receptor, wherein the antibodies are found in a sample from a subject (who can be suspected of having MN) and the antibodies can be detected by an immunoassay wherein an antibody-protein complex is formed (Paragraph 0073). In one embodiment, provided is an immunoassay comprising: contacting a sample from a subject with a PLA2R or PLA2R fragment thereof; forming an antibody-protein complex between the antibody present in a sample with the PLA2R or PLA2R fragment thereof; washing to remove any unbound antibody; adding a detection antibody that is labeled and is reactive to the antibody from the sample; washing to remove any unbound labeled detection antibody; and converting the label to a detectable signal, wherein the presence of a detectable signal indicates the likelihood of MN in the subject (Paragraph 0074) and in other embodiments the devices or kits of the invention can further comprise a second labeled PLA2R protein or a fragment thereof which produces a detectable signal (Paragraph 0118). Detection antibodies and PLA2R can alternatively be labeled with any of a number of fluorescent compounds such as fluorescein isothiocyanate, europium, lucifer yellow, or rhodamine B isothiocyanate (Paragraph 0129). The amount of anti-PLA2R auto-antibodies in a healthy non-MN individual or a population of healthy non-MN individuals as determined by conventional ELISA or Western blot set forth in Example 1 can be considered as the background, reference or the control level (Paragraph 0073). Salant further discloses that upon treatment, for example with immunosuppressive therapy, over time, there is a decrease in the amount of detectable auto-antibodies against PLA2R (Figures 6A and 6B). In an ideal case, the amount of auto-antibodies should fall below the detectable level of the detection methods described herein and the subject is deemed to be in remission for the disorder (Paragraph 0086). Salant describes embodiments wherein the subject has successfully been treated for MN, has no detectable auto-antibodies
against PLA2R in blood circulation and is currently not under any treatment for MN; the subject had previously been diagnosed with MN and has a detectable amount of auto-antibodies against PLA2R, then upon treatment, for example with immunosuppressive therapy, over time, the amount of auto-antibodies against PLA2R drops to below the detectable level of the detection methods described herein, and the subject is in remission for MN (Paragraph 0095). The re-emergence of a detectable amount of auto-antibodies against PLA2R, and the gradual increase of the auto-antibodies over time indicates that MN has recurred in the subject (Id.). Salant further teaches a treatment for MN comprising immunosuppressive drugs, for example, cyclosporin, tacrolimus, azathioprine, infliximab, omalizumab, daclizumab, adalimumab, eculizumab, efalizumab, natalizumab, omalizumab and rapamycin; in a further embodiment, the immunosuppressive treatment for MN additionally includes but is not limited to cyclophosphamide, chlorambucil, and rituximab (Paragraph 0105). In one embodiment, the fragments suitable for treatment or adsorption of the auto-antibodies to PLA2R from the serum are fragments comprising the CTLDs or CRDs 4, CTLDs or CRDs 4,5,6 of PLA2R (Paragraph 00017). In another embodiment, the fragments comprise the extracellular domain of human or pig PLA2R (Paragraph 0109). In one embodiment, the PLA2R fragment is SEQ. ID. NO. 5 or smaller portions of SEQ. ID. NO. 5, such as at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least or smaller portions of SEQ ID NO: 5, such as at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% including all the percentages between 10-95% (Paragraph 0109). Also disclosed are peptides between 10-50 amino acid residues derived from the sequence of SEQ ID NO: 5 that can be used in the treatment of MN (Id.). It is noted that residues 1-367 of SEQ ID NO: 5 of Salant is a 100% match to instant SEQ ID NO: 9. Thus, Salant teaches an immunoassay for the identification/diagnosis of MN, identifying a patient as having been successfully treated with immunosuppressive therapy based on the level of autoantibodies dropping below the detectable level, and the administration of immunosuppressive drugs for the treatment of MN.
However, it is noted that Salant does not teach the diagnosis/identification of MN by detecting binding of conformational PLA2R epitopes to an auto-antibody producing B cell population. These deficiencies are remedied by Kao and Moody.
Kao teaches that membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults and recent clinical studies established that >70% of patients with idiopathic (also called primary) MN (IMN) possess circulating autoantibodies targeting the M-type phospholipase A2 receptor-1 (PLA2R) on the surface of glomerular visceral epithelial cells (podocytes) wherein, in situ, these autoantibodies trigger the formation of immune complexes, which are hypothesized to cause enhanced glomerular permeability to plasma proteins (Abstract). The auto-antibody only recognizes the nonreduced form of PLA2R, suggesting that disulfide bonds determine the antigenic epitope conformation and the authors identified the immunodominant epitope region in PLA2R by probing isolated truncated PLA2R extracellular domains with sera from patients with IMN that contain anti-PLA2R autoantibodies; patient sera specifically recognized a protein complex consisting of the cysteine-rich (CysR), fibronectin-like type II (FnII), and C-type lectin-like domain 1 (CTLD1) domains of PLA2R only under nonreducing conditions (Id.). The absence of either the CysR or CTLD1 domain prevented auto-antibody recognition of the remaining domains, additional analysis suggested that this three-domain complex contains at least one disulfide bond required for conformational configuration and auto-antibody binding, and the three-domain complex completely blocked the reactivity of autoantibodies from patient sera with the full-length PLA2R, and the reactivity of patient sera with the three-domain complex on immunoblots equaled the reactivity with full-length PLA2R; such results indicated that the immunodominant epitope in PLA2R is exclusively located in the CysR-FnII-CTLD1 region (Id.). The authors identified that the immunodominant antigenic epitope in PLA2R responsible for auto-antibody binding is exclusively formed by a region encompassing the CysR, FnII, and CTLD1 domains, wherein the conclusion is supported by the following evidence: (1) auto-antibody did not recognize the CysR, CysR-FnII, or FnII-CTLD1 domain but strongly recognized the CysR-FnII-CTLD1 domain complex (1–3 construct); (2) auto-antibody only recognized the nonreduced 1–3 construct but not the reduced form; (3) when the 1–3 construct was absent, auto-antibody did not recognize any of the remaining domains; (4) the 1–3 construct in its native conformation completely blocked the reactivity of 10 patient sera containing high levels of autoantibodies with the full-length PLA2R; and (5) the 1–3 construct was recognized as effectively as the full-length PLA2R by autoantibodies from various serum samples from patients with IMN (Page 296, Column 2, Paragraph 2). The anti-PLA2R auto-antibody is known to recognize only the nonreduced form of PLA2R. The results showed that the isolated 1–3 construct containing CysR, FnII, and CTLD1 domains indeed contain the critical intramolecular disulfide bonds required for the antigenic epitope formation and that auto-antibody recognition of the 1–3 construct is sensitive to β-ME reduction; because auto-antibody does not recognize the isolated CysR, CysR-FnII, or FnII-CTLD1 domain, the CyR and CTLD1 domains are likely to be responsible for the 1–3 construct recognition, and potentially, a cryptic region in the FnII domain is also involved (Page 296, Column 2, Paragraph 3). Results showed that patient sera recognizing the full-length PLA2R also strongly recognized the 1–3 construct, whereas patient sera negative on the full-length PLA2R were also negative on the 1–3 construct, showing that the CysRFnII- CTLD1 domain complex can serve as the universal autologous antigen in all patients with IMN possessing the auto-antibody (Page 297). Thus, Kao teaches a conformational epitope of PLA2R comprised within the 1–3 construct containing CysR, FnII, and CTLD1 domains wherein it is noted that the 1-3 construct corresponds to instant SEQ ID NO: 9 (i.e., residues 1-367 of PLA2R; see Kao Figure 1/instant application Figure 1). As such, Kao teaches that a conformational epitope is comprised within instant SEQ ID NO: 9, which is a fragment of PLA2R.
Moody teaches that B cells produce both secreted antibody and a membrane bound form as part of the B cell receptor (BCR) complex; surface and secreted immunoglobulin from individual cells has been studied by the use of antigen-specific labeling and flow cytometric analysis wherein the monospecificity of surface immunoglobulin on individual B cells was established by the same technique and, since the discovery of the BCR, many investigators have used surface antibody both to label and to sort B cells for investigation (Page 1088, Column 1First Full Paragraph). Techniques reported using antigen-specific reagents for the detection of B cells via the BCR have fallen into three broad categories: haptens on carriers, labeled proteins or whole virions/organisms, and epitopes presented by a display system (Page 1088, Column 1, Second Full Paragraph; Table 1). Regardless of the reagent type, the desired interaction is that of the antigen of interest with the cell surface BCR (Fig. 1) and in each case, a fluorochrome, biotin, or other detection reagent is used to label or capture the cell by using the cell surface bound immune complex (Id.). Using a biotinylated epitope peptide that inhibited a pathogenic dsDNA antibody, Newman, et al. described a system where that peptide was reacted with fluorochrome-labeled streptavidin and was subsequently used to detect antigen-specific cells in immunized mice (Page 1088, Column 2, Last Partial Paragraph).
However, none of Salant, Kao, or Moody explicitly detail (i) isolating PBMCs from a sample and contacting said PBMCs with a first conformational epitope PLA2R epitope. These deficiencies are remedied by Degauque.
Degauque teaches the use of fluorescent Bio-plex COOH beads that contain a fluorescent internal core and can be covalently linked to any protein wherein a broad variety of antigens can be analyzed simultaneously through varying the ratio of two fluorescent molecules within the bead internal core (Page 1, Column 2, Paragraph 2). B cells purified from healthy human blood and immunized individuals were then tested for their ability to interact with various nominal antigens, including viral, vaccine, self and alloantigens, all of which may have some usefulness to the study of various pathological processes (Page 2, Column 1, Paragraph 1). Notably, peripheral blood mononuclear cells (PBMCs) were separated on a Ficoll gradient layer and either frozen in DMSO-10% autologous serum or used to purify CD19+ B cells using the human B Cell Isolation Kit (Miltenyi Biotech) according to the manufacturer’s instructions (Page 2, Column 1, Blood Samples and B Cell Isolation). Using a FACS-sorter or antigen-coated on magnetic beads, the authors show that CD19+ cells can be efficiently depleted of CD19+ cells that interact with MOG₁-₁₂₅-coated beads or HLA class I-coated beads and after depletion, the negative fraction did not contain any CD19+ cells able to interact with antigen-coated beads; in contrast, the positive fraction was enriched in CD19+ that interact with either MOG1-125- or HLA class I-coated beads and it was observed that FACS-sorter based strategy was efficient for enrichment when the BBR frequency was higher than 0.8% (initial frequency of HLA class I specific B cells 0.871% and 2.71%; post-sorting frequency 21.1% and 32.6% respectively) (Page 4, Column 2, Paragraph 2; Figure 4). Degauque further teaches that T and B-cell ELISPOT have also been used to measure committed B cell frequency against a given antigen (Page 8, Column 1, Paragraph 1). Thus, Degauque teaches methods of measuring interactions (i.e., binding) between B cells, said B cells comprised within PBMCs isolated from a blood sample, and antigen through the use of FACS and discloses that ELISPOT assays have also been used.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to develop a method of identifying and treating MN, based on the methods of diagnosis and treatment taught by Salant, wherein it would have been obvious to try modifying the method of Salant such that a conformational PLA2R epitope (i.e., the most immunogenic epitope) disclosed by Kao could be employed in the method of detection, because it is established in the art that antigen-specific reagents (e.g., reagents that are also detectably labeled) are used to detect B cells via their association with the BCR, as supported by Moody. One of ordinary skill in the art would have been motivated try to modifying the methods of Salant, based on the teachings of Kao, Moody, and Degauque, to arrive at such a method of MN identification and treatment comprising, generally: (i) identifying a patient as having been previously successfully treated with either immunosuppressive drugs or steroid hormone or both for MN; (ii) identifying the patient as in need of the treating by having an assay carried out, the assay comprising: (a) obtaining a sample from the patient, said sample suspected of containing an anti-PLA2R auto-antibody producing B cell population; (b) isolating peripheral blood mononuclear cells (PBMCs) from the sample, (c) contacting said sample with a first conformational PLA2R epitope bound to a label, wherein the first conformational PLA2R epitope comprises SEQ ID NO: 9; (d) determining the amount of binding of the labeled first conformational PLA2R epitope to cells of the anti-PLA2R auto-antibody producing B cell population within the sample; (e) comparing the amount of binding of the labeled first conformational PLA2R epitope in the sample to the amount of binding expected in a control sample from a subject not having MN; and (f) identifying an increase in the amount of binding of the labeled first conformational PLA2R epitope in the sample relative to the amount of binding expected in the control sample thereby identifying the patient as in need of the treating; and (iii) administering to the patient an agent selected from the group consisting of an immunosuppressant and a steroid hormone, and one of ordinary skill in the art would have had a reasonable expectation of success.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, it is noted that:
(1) Salant discloses: (i) an immunoassay for the identification/diagnosis of MN comprising contacting a sample (e.g., a blood sample) from a subject with a PLA2R or PLA2R fragment thereof, forming an antibody-protein complex between the antibody present in a sample with the PLA2R or PLA2R fragment thereof, washing to remove any unbound antibody, adding a detection antibody that is labeled and is reactive to the antibody from the sample, washing to remove any unbound labeled detection antibody, and converting the label to a detectable signal, wherein the presence of a detectable signal indicates the likelihood of MN in the subject wherein the amount of anti-PLA2R auto-antibodies in a healthy non-MN individual or a population of healthy non-MN individuals can be considered as the background, reference or the control level; (ii) identifying a patient as having been successfully treated with immunosuppressive therapy based on the level of autoantibodies dropping below the detectable level; and (iii) the subsequent administration of immunosuppressive drugs for the treatment of MN.
(2) Kao discloses a conformational epitope that is comprised within instant SEQ ID NO: 9, which is a fragment of PLA2R, wherein said epitope is the immunodominant epitope region in PLA2R and is specifically recognized by anti-PLA2R autoantibodies in human serum.
(3) Moody discloses techniques using antigen-specific reagents for the detection of B cells via the BCR, wherein antigen-specific reagents include (i) haptens on carriers, (ii) labeled proteins or whole virions/organisms, and (iii) epitopes wherein, regardless of the reagent type, the desired interaction is that of the antigen of interest with the cell surface BCR and in each case, a fluorochrome, biotin, or other detection reagent is used to label or capture the cell by using the cell surface bound immune complex.
(4) Degauque teaches methods of measuring interactions (i.e., binding) between B cells, said B cells comprised within PBMCs isolated from a blood sample, and antigen via methods including FACS and ELISPOT assays.
Thus, to one of ordinary skill in the art, it would have been obvious to try the method of MN diagnosis (i.e., identification) and subsequent treatment of Salant wherein an auto-antibody producing B cell was detected instead of auto-antibodies themselves using a conformational epitope of PLA2R because (i) auto-antibody producing B cells would reasonably be expected to be in blood/serum samples (as suggested by Salant and Kao), (ii) Kao identifies the immunodominant epitope of PLA2R, (iii) Moody discloses that auto-antibody producing B cells would reasonably be expected to be detectable by way of antigen-BCR interactions, which can be achieved using label-tagged peptide epitopes (wherein labeled PLA2R fragments are also utilized in the methods disclosed by Salant), and (iv) Deguaque teaches methods of detecting interactions between B cells and antigen, using isolated PBMCs, via FACS and/or ELISA assays. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, (i) identifying a patient as needing treatment for MN by determining the amount of PLA2R fragments bound to auto-antibody producing B cells relative to a control, wherein said patient may have been previously treated successfully with immunosuppressive therapy, and (ii) subsequently administering immunosuppressive therapy to patients identified as needing treatment.
With regard to claim 3, it is noted that Kao teaches a conformational epitope of PLA2R comprised within the 1–3 construct containing CysR, FnII, and CTLD1 domains wherein it is noted that the 1-3 construct corresponds to instant SEQ ID NO: 9 (i.e., residues 1-367 of PLA2R; see Kao Figure 1/instant application Figure 1). It is noted that instant SEQ ID NO: 9 comprises instant SEQ ID NO: 2 (which corresponds to residues 1-364 of SEQ ID NO: 9) and is a 100% match to instant SEQ ID NO: 5. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 4, Salant discloses an immunoassay comprising: contacting a sample from a subject with a PLA2R or PLA2R fragment thereof; forming an antibody- protein complex between the antibody present in a sample with the PLA2R or PLA2R fragment thereof; measuring a light scattering intensity resulting from the formation of the antibody-protein complex wherein the light scattering intensity of at least 10% above a control light scattering intensity indicates the likelihood of MN or relapse of MN in the subject (Paragraph 0078; emphasis added). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 5 and 18-19, Salant discloses an embodiment wherein the subject is a human and the sample from the subject is a blood sample, e.g. serum or plasma (Paragraph 0079). Furthermore, while the invention of Salant focuses on less invasive methods for diagnosing/identifying MN, Salant indicates that the use of tissue samples (i.e., kidney tissue biopsies) to diagnose/identify MN is established in the art (Paragraph 0073). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 6-7, Salant discloses an embodiment wherein the immunoassay described by the invention is performed for a plurality of samples from a subject obtained over a period of time; the pluralities of samples are obtained every two or three months for at least a two year period (Paragraph 0084). The result of immunoassay of each blood sample is recorded and the date of sample noted; the result of immunoassay of each blood sample is compared to that obtained for a previous blood sample taken three months earlier and/or it can also be compared to the results obtained during initial diagnosis before the start of immunosuppressive treatment (Id.). In one embodiment, the detectable signal or light scattering intensity of each immunoassay is compared to the detectable signal or light scattering intensity of a sample
obtained from a prior time point, wherein a reduction of at least 5%, at least 10% or more of detectable signal or light scattering intensity indicates effective treatment of MN in the subject (Paragraph 0085). In other embodiments, there is no decrease in the level of antibodies in the second time point compared to the first time point, wherein instead there can be an increase or a stable level of antibodies; in one embodiment, there is an increase in antibody level in the second time point compared to the first time point and the first time point has no detectable auto-antibodies which indicates that the patient has relapsed and the MN has recurred (Paragraphs 0087-0088). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 9-12, and 20-21, Salant discloses that detection antibodies and PLA2R can be labeled with any of a number of fluorescent compounds such as fluorescein isothiocyanate, europium, lucifer yellow, rhodamine B isothiocyanate for use in immunoassays of the invention (Paragraph 0129). Salant further indicates that radio-immunoassays can also be utilized wherein a radioisotope is used as a label for detection (Id.). Additionally, Salant teaches that the immunoassays can comprise beads coated with native or recombinant PLA2R protein; commonly used are polystyrene beads that are dyed to establish a unique identity and detection is performed by flow cytometry and other types of bead-based immunoassays are well known in the art, e.g., laser bead immunoassays and related magnetic bead assays (Paragraph 0092). Salant also teaches detection methods wherein enzyme-linked assays can be utilized; the detection of auto-antibodies against PLA2R is performed by a serological immunoassay such as an enzyme-linked immunosorbent assays (ELISA) (Paragraph 0106). Additionally, Moody discloses that regardless of the reagent type (i.e., for auto-antibody producing B cell detection), the desired interaction is that of the antigen of interest with the cell surface BCR (Fig. 1) and in each case, a fluorochrome, biotin, or other detection reagent is used to label or capture the cell by using the cell surface bound immune complex (Page 1088, Column 1, Second Full Paragraph; Table 1). Furthermore, Degauque teaches the use of fluorescent Bio-plex COOH beads that contain a fluorescent internal core and can be covalently linked to any protein wherein a broad variety of antigens can be analyzed simultaneously through varying the ratio of two fluorescent molecules within the bead internal core (Page 1, Column 2, Paragraph 2). B cells purified from healthy human blood and immunized individuals were then tested for their ability to interact with various nominal antigens, including viral, vaccine, self and alloantigens, all of which may have some usefulness to the study of various pathological processes (Page 2, Column 1, Paragraph 1); notably, peripheral blood mononuclear cells (PBMCs) were separated on a Ficoll gradient layer and either frozen in DMSO-10% autologous serum or used to purify CD19+ B cells using the human B Cell Isolation Kit (Miltenyi Biotech) according to the manufacturer’s instructions (Page 2, Column 1, Blood Samples and B Cell Isolation). Using a FACS-sorter or antigen-coated on magnetic beads, the authors show that CD19+ cells can be efficiently depleted of CD19+ cells that interact with MOG₁-₁₂₅-coated beads or HLA class I-coated beads and after depletion, the negative fraction did not contain any CD19+ cells able to interact with antigen-coated beads; in contrast, the positive fraction was enriched in CD19+ that interact with either MOG1-125- or HLA class I-coated beads and it was observed that FACS-sorter based strategy was efficient for enrichment when the BBR frequency was higher than 0.8% (initial frequency of HLA class I specific B cells 0.871% and 2.71%; post-sorting frequency 21.1% and 32.6% respectively) (Page 4, Column 2, Paragraph 2; Figure 4). Degauque further teaches that T and B-cell ELISPOT have also been used to measure committed B cell frequency against a given antigen (Page 8, Column 1, Paragraph 1). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 27, Salant further teaches a treatment for MN comprising immunosuppressive drugs, for example, cyclosporin, tacrolimus, azathioprine, infliximab, omalizumab, daclizumab, adalimumab, eculizumab, efalizumab, natalizumab, omalizumab and rapamycin; in a further embodiment, the immunosuppressive treatment for MN additionally includes but is not limited to cyclophosphamide, chlorambucil, and rituximab (Paragraph 0105). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 29, Salant further discloses an embodiment wherein the auto-antibodies detectable at the second and first time points are comparably similar within statistical analysis variances, about 1 %, 2%, 3%, 4%, 5% and all the percentages between 1 %-5% deviation from the level of auto-antibodies from the first time point (i.e., auto-antibody levels are stable; no significant increase or decrease); the stable level of auto-antibody indicates stable disease, wherein the treatment has been of insufficient duration (i.e., that it should be continued if clinically indicated) or is ineffective (Paragraph 0090). Thus, if a patient has stable auto-antibody levels during and after immunosuppressive treatment, the patient is likely indicated to continue treatment and/or a change in treatment; no detectable change (increase or decrease) in auto-antibody levels indicates a patient for continued treatment and/or a change in treatment. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable US 2011/0177534 A1 (previously cited on PTO-892; herein after referred to as "Salant") in view of non-patent literature published by Kao et. al. (J Am Soc Nephrol, 2015, 26, 291-301; previously cited on PTO-892; herein after referred to as "Kao"), non-patent literature by Moody and Haynes (Cytometry Part A, 2008, 73A, 1086-1092; previously cited on PTO-89; herein after referred to as “Moody”), and non-patent literature by Degauque et. al. (PLOS ONE, 2013, 8(12), 1-10; previously cited on PTO-892; herein after referred to as “Degauque”), as applied to claims 1, 3-7, 9-12, 18-21, and 27 above, and in further view of non-patent literature by Daniel Cattran (J. Am. Soc. Nephrol. 2005, 16, 1188-1194; previously cited on PTO-892; herein after referred to as “Cattran”).
The method of claim 1 is rendered obvious by Salant, Kao, Moody, and Deguaque. However, none of the cited references explicitly detail administering a corticosteroid to a patient needing treatment. This deficiency is remedied by Cattran.
Cattran discloses that for idiopathic membranous nephropathy (IMGN), the best accepted responses are improved renal survival and complete remission (CR) of proteinuria, and used an algorithm for predicting outcome to different categories of MN in regards to their risk for progression to chronic renal failure (Page 1190). Cattran grouped patients into the following: (i) low risk, wherein treatment should be conservative only comprising angiotensin-converting enzyme inhibitors with or without angiotensin receptor antagonists; (ii) medium risk, wherein monthly cycling of corticosteroids and cytotoxic drugs (e.g., chlorambucil or cyclophosphamide) on alternate months over 6 months has significantly improved renal survival in this type of patient; and (iii) high risk, wherein cyclosporine has been shown to be effective in a small randomized, controlled trials in patients with IMGN and documented progression and wherein a study that compared conservative therapy in a historical control group with prednisone plus chlorambucil in patients who had IMGN and had shown progression wherein treatment was prednisone 1 mg/kg tapered to 0.5 mg over 6 months plus chlorambucil 0.15 mg/kg for 14 weeks and in a group of 39 patients who were followed for up to 8 year, renal survival was 90% in the treated group compared with only 20% in the historic control group (Pages 1191-1192). A treatment algorithm combining predictive factors and best evidence for treatment is presented in Figure 2 (Page 1191), reproduced below.
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Cattran further discusses the treatment of relapses, wherein re-treatment in 15 patients who had relapsed, with the routine of 1 year of cyclophosphamide plus 6 months of prednisone (as listed under the medium-risk category of patients), and would fit in this high-risk for progression category, i.e., mild to moderate renal insufficiency plus high-grade proteinuria, has been reported to reduce proteinuria and stabilize renal function (Page 1192, Column 1, Treatment of Relapses). Thus, Cattran indicates the use of cytotoxic agents (e.g., cyclophosphamide) and corticosteroids in moderate risk, high risk, and progressive/relapsed patient populations.
It would have been prima facie obvious to one of ordinary skill in the art at the time the instant invention was filed to further modify the method for identifying and treating MN rendered obvious by Salant, Kao, Moody, and Degauque such that the drug administered to a patient indicated as needing treatment is a corticosteroid because Cattran specifically indicates the use of corticosteroids (e.g., prednisone) in the treatment of moderate to high risk MN patients, and in the treatment of relapsed/recurrent MN.
Response to Arguments - 35 USC § 103
Applicant's arguments filed 07/08/2026 (see Pages 5-9; herein after referred to as "Remarks") with regard to the above-listed claim rejections under 35 USC § 103 have been fully considered but they are not persuasive.
Specifically, Applicant argues the following:
The claimed method is fundamentally different from the method disclosed in Salant, wherein the present methods detect PLA2R-memory B cells (MBCs) and treat patients according to PLA2R-MBC levels to prevent relapse, whereas the method as disclosed in Salant detects PLA2R autoantibody titers from serum and treats patients based on these titers.
PLA2R-MBC levels and PLA2R autoantibody titers are not equivalent, and these measurements indicate different levels of risk of relapse in MN. Patients can have a high level of PLA2R-MBCs while the serum autoantibody titer is negative, and these patients have a high risk of relapse if not retreated to eliminate these cells (See Declaration and accompanying publication of Zhu et. al. previously submitted on 08/27/2025). A positive serum PLA2R antibody titer only indicates an active disease but cannot predict disease prognosis, e.g., whether the patient will relapse. Based on the PLA2R-MBC level, one can predict whether a patient has a high risk of relapse and when relapse may occur by regularly monitoring these cells in circulation, guiding treatment to prevent relapse, as described in the instant methods.
Some patients at diagnosis (with proteinuria) can be PLA2R autoantigen-positive on kidney biopsy yet serum PLA2R autoantibody-negative. High levels of PLA2R-MBCs were detected in these patients, and these levels declined as proteinuria improved after treatment. Throughout this process, the PLA2R autoantibody level remained negative. Therefore, autoantibody levels cannot be used to guide treatment for this group of patients. Further, patients treated with B-cell depletion agents, such as Rituximab, can achieve complete immunological remission 6 months post-therapy, meaning the PLA2R autoantibody level becomes negative. Among these patients, some showed high levels of PLA2R-MBC after Rituximab, while their serum PLA2R autoantibodies were negative, even though all had improved proteinuria. It was observed that these patients have a very high risk of relapse if not retreated to eliminate the PLA2R-MBCs; since these patients are already negative for PLA2R autoantibodies, according to the methods of Salant, they would not need further treatment.
Patients negative for serum autoantibodies can develop relapse later on due to the presence of PLA2R-MBCs. An increase in PLA2R-MBC levels was detected in these patients several months before relapse, while their autoantibody levels remained negative. These findings, as described in the Inventor Declaration previously submitted on 08/27/2025, indicate the need for treatment in this population of patients who would not be identified by the methods of Salant.
Patients do not show an increase in antibody levels before the clinical signs of relapse, but rather after the appearance of proteinuria. When relapse occurs, proteinuria typically rises in parallel with serum PLA2R autoantibody levels. Applicant acknowledges that while it is commonly agreed that a decrease in antibody levels indicates disease remission, this does not predict whether the patient will relapse.
Salant proposes delivering therapy to patients based on the detection of PLA2R autoantibodies and never mentions PLA2R-MBCs, or any memory B cells whatsoever, within the application. Kao fails to remedy the deficiencies of Salant and merely identifies a conformational epitope of PLA2R. Kao fails to teach or suggest PLA2R memory B cell detection. Moody fails to remedy the deficiencies of Salant and Kao and provides no teaching or suggestion regarding how antigen-specific B cells associate with autoimmune disease progression, how these cells respond to immunosuppressive therapy, how to deliver treatment based on the level of these cells, or why it may be necessary to deliver treatment based upon antigen-specific B cells rather than antibody titer. Degauque fails to remedy the deficiencies of Salant, Kao, and Moody. Cattran similarly fails to remedy the deficiencies of Salant, Kao, and Moody.
As described in the Inventor Declaration and accompanying publication of Zhu et al. previously submitted on 08/27/2025, antigen-specific B cells can persist in patients after B cell depletion therapy even when the antibody titer is negative. Importantly, these patients showed a high risk of disease relapse, which has never been shown previously and has never been taught, much less described within the cited art. Without this information, one of ordinary skill in the art would not have conceived of delivering therapy based on the level and persistence of PLA2R MBCs as described in the present claims. Accordingly, Applicant respectfully submits that one of skill in the art would not have arrived at the method of Claim 1 absent impermissible hindsight.
One would need to change the principal of operation of the prior art (shifting from detection of PLA2R autoantibody titers and treating patients based on these titers to detection of PLA2R-memory B cells (MBCs) and treating patients according to PLA2R-MBC levels to prevent relapse) to arrive at the claimed invention and the prior art of record provides no guidance to do so.
With regard to the arguments of the cited prior art references, it is noted that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The motivation/rationale for the modification of Salant using the teachings of Kao, Moody, and Deguaque is provided. It would have been obvious to one of ordinary skill in the art to try the method of MN diagnosis (i.e., identification) and subsequent treatment of Salant wherein an auto-antibody producing B cell was detected instead of auto-antibodies themselves using a conformational epitope of PLA2R because (i) auto-antibody producing B cells would reasonably be expected to be in blood/serum samples (as suggested by Salant and Kao), (ii) Kao identifies the immunodominant epitope of PLA2R, (iii) Moody discloses that auto-antibody producing B cells would reasonably be expected to be detectable by way of antigen-BCR interactions, which can be achieved using label-tagged peptide epitopes (wherein labeled PLA2R fragments are also utilized in the methods disclosed by Salant), and (iv) Deguaque teaches methods of detecting interactions between B cells and antigen, using isolated PBMCs, via FACS and/or ELISA assays. Thus, taken together, one of ordinary skill in the art would have a reasonable expectation of, generally, (i) identifying a patient as needing treatment for MN by determining the amount of PLA2R fragments bound to auto-antibody producing B cells relative to a control, wherein said patient may have been previously treated successfully with immunosuppressive therapy, and (ii) subsequently administering immunosuppressive therapy to patients identified as needing treatment. There is no requirement that an “express, written motivation to combine must appear in prior art references before a finding of obviousness.” See Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). Additionally, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Furthermore, the principle operation of the invention of Salant is not changing, as the invention of Salant is, generally, drawn to methods of identifying and treating MN. The modification of Salant is merely a change to the marker relied upon for identifying a need for treatment; Salant relies on measuring antibody titer, whereas the instant method relies on measuring B cell interactions with antigen, wherein such methods are known and established in the art as taught by Moody and Deguaque and wherein the immunogenic antigen implicated in MN is also known, as taught by Kao.
Furthermore, regarding the arguments presented around the Inventor Declaration submitted 08/27/2025 regarding the probability of relapse in the specific patient population argued by Applicant, such arguments are not commensurate in scope with the instant claims. The instant claims are, generally, directed to a method for identifying and treating MN, the active steps of which have been rendered obvious. Applicant is arguing nonobviousness specifically with regard to patients having MN that have elevated anti-PLA2R autoantibody producing B cells without detectable autoantibody production. However, as detailed in the Office Action dated 10/10/2025, any reference to such a patient population is considered new matter and lacks enablement, as it is not disclosed by the specification, and said patient population is not recited in any of the instant claims, nor are the instant claims directed to predicting/identifying the risk of relapse in such a population, and as such arguments directed to said population are not commensurate in scope with the instant claims.
Conclusion
Claims 1, 3-7, 9-12, 18-21, and 27-28 are pending. Claims 1, 3-7, 9-12, 18-21, and 27-28 are rejected. No claims are 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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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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