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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/12/2026 has been entered.
Claim Status
Claims 2, 8, 13-17, and 22-26 have been cancelled and claims 1, 20, and 29 have been amended, as requested in the amendment filed on 01/12/2026. Following the amendment, claims 1, 3-7, 9-12, 18-21, and 27-29 are pending in the instant application.
Claims 1, 3-7, 9-12, 18-21, and 27-29 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1, 3-7, 9-12, 18-21, and 27-29 have an effective filing date of August 12, 2016 corresponding to PRO 63/374,382.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/14/2026 and 03/16/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 1, 3-7, 9-12, 18-21, and 27-29 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. It is noted that claim 25 has been cancelled, rendering the rejection of claim 25 moot. Additionally, Applicant has amended independent claim 1 to remove the limitation of a patient “not having a detectable increase in levels of anti-PLA2R autoantibodies relative to a control sample representative of normal levels of the anti-PLA2R antibodies”. As such, there are no longer conflicting claim limitations. Thus, the rejection of claims 1, 3-7, 9-12, 18-21, and 27-29 under 35 U.S.C. 112(b) as being indefinite is withdrawn.
Claim 20 was further rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for reciting the trademark/trade name ELISPOT. Applicant has amended the claim such that the generic terminology is now recited instead of “ELISPOT”. As such, the rejection of claim 20 under 35 U.S.C. 112(b) as being indefinite is withdrawn.
Claims 1, 3-7, 9-12, 18-21 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. It is noted that claim 25 has been cancelled, rendering the rejection of claim 25 moot. Additionally, as noted above, Applicant has amended independent claim 1 to remove the limitation of a patient “not having a detectable increase in levels of anti-PLA2R autoantibodies relative to a control sample representative of normal levels of the anti-PLA2R antibodies” and instead recites identifying the patient as “having been previously successfully treated with either immunosuppressive drugs or steroid hormone or both”. Applicant has possession of the method of the instantly amended claims. Thus, the rejection of claims 1, 3-7, 9-12, 18-21, 25, and 27-29 under 35 U.S.C. 112(a) for new matter and for failing to comply with the written description requirement is withdrawn.
Claims 1, 3-7, 9-12, 18-21 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, regarding scope of enablement. It is noted that claim 25 has been cancelled, rendering the rejection of claim 25 moot. Additionally, as noted above, Applicant has amended independent claim 1 to remove the limitation of a patient “not having a detectable increase in levels of anti-PLA2R autoantibodies relative to a control sample representative of normal levels of the anti-PLA2R antibodies” and instead recites identifying the patient as “having been previously successfully treated with either immunosuppressive drugs or steroid hormone or both”. The method of the instantly amended claims is considered to be enabled. Thus, the rejection of claims 1, 3-7, 9-12, 18-21, 25, and 27-29 under 35 U.S.C. 112(a) regarding scope of enablement is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 2, 14-15, and 26 were 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. in 2015 (previously cited on PTO-892; herein after referred to as "Kao") and non-patent literature published by Volkman et. al. in 1982 (previously cited on PTO-892; herein after referred to as "Volkman").
Claims 2, 14-15, and 26 have been cancelled rendering their rejection moot. As such, the rejection of claims 2, 14-15, and 26 under 35 U.S.C. 103 as being unpatentable over Salant, Kao, and Volkman is withdrawn.
Claims 16, 22, and 25 were 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"), Kao et. al. in 2015 (previously cited on PTO-892; herein after referred to as "Kao"), and Volkman et. al. in 1982 (previously cited on PTO-892; herein after referred to as "Volkman") and in further view of non-patent literature published by Firer and Gellerman published in 2012 (previously cited on PTO-892; herein after referred to as "Firer").
Claims 16, 22, and 25 have been cancelled rendering their rejection moot. As such, the rejection of claims 16, 22, and 25 under 35 U.S.C. 103 as being unpatentable over Salant, Kao, Volkman, and Frier is withdrawn.
Claims 23-24 were 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"), Kao et. al. in 2015 (previously cited on PTO-892; herein after referred to as "Kao"), and Volkman et. al. in 1982 (previously cited on PTO-892; herein after referred to as "Volkman"), and in further view of non-patent literature published by Lien and Lowman published in 2003 (previously cited on PTO-892; herein after referred to as "Lien").
Claims 23-24 have been cancelled rendering their rejection moot. As such, the rejection of claims 23-24 under 35 U.S.C. 103 as being unpatentable over Salant, Kao, Volkman, and Lien is withdrawn.
Claim Rejections - 35 USC § 112 - New
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 29 is 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
With regard to claim as presently amended, it is noted that the instant specification does not disclose in any capacity a patient population identified as “not having an increased level of anti-PLA2R autoantibodies at diagnosis, during and after immunosuppressive treatment, at immunological remission, and/or relapse.” As such, claim 29 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
With regard to claim 29, the claim is drawn to the method of claim 1 wherein the patient is identified as not having an increased level of anti-PLA2R autoantibodies at diagnosis, during and after immunosuppressive treatment, at immunological remission, and/or relapse. It is noted that there is no support in the instant disclosure for the limitation “not having a detectable increase in the levels of anti-PLA2R autoantibodies”. The only embodiments of the invention provided in the instant specification are drawn to patient samples having detectable increases in anti-epitope (i.e., anti-PLA2R) autoantibodies; a detectable increase in anti-epitope autoantibodies by at least 10% relative to a control sample indicates the presence of an autoimmune disease in the patient (see Paragraphs 0136-0137). As such, the limitation drawn to a patient "identified as not having a detectable increase in the levels of anti-PLA2R autoantibodies" constitutes new matter.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 27-28 are 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.
Each of claims 27-28 recite the limitation "the drug" in line 1. It is noted that the only recitation of a “drug” in claim 1 is with regard to identifying the patient as having previously being successfully treated with an immunosuppressive drug or a steroid hormone or both (emphasis added). As such, it is unclear as to if the recitation of “the drug” is intended to refer to the agents used to successfully treat the patient previously, or if the recitation of “the drug” 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 drug” is being interpreted as referring to the agents administered to the patient identified as needing treatment.
Claim Rejections - 35 USC § 103 - New
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3-7, 9-12, 18-19, and 21 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. in 2015 (herein after referred to as "Kao") and non-patent literature by Moody and Haynes (Cytometry Part A, 2008, 73A, 1086-1092; herein after referred to as “Moody”).
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 been successfully been treated for MN, has no detectable auto-antibodies
against PLA2R in blood circulation and is currently not on 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).
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 and Moody, 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) contacting said sample with a first conformational PLA2R epitope bound to a label, wherein the first conformational PLA2R epitope comprises SEQ ID NO: 9; (c) 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; (d) 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 (e) 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.
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, and (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). 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, 11-12, and 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). 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.
Claims 10 and 20 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. in 2015 (herein after referred to as "Kao") and non-patent literature by Moody and Haynes (Cytometry Part A, 2008, 73A, 1086-1092; herein after referred to as “Moody”), as applied to claims 1, 3-7, 9-12, 18-19, and 21 above, and in further view of 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”).
The methods of claims 9 and 12 are rendered obvious by Salant, Kao, and Moody. However, none of the cited references explicitly detail detecting binding via FACS or fluorescence microscopy (claim 10) nor an enzyme-linked assay that is an ELISPOT (claim 20). 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). 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 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 instant invention was filed to further modify the method for identifying and treating MN rendered obvious by Salant, Kao, and Moody such that the binding of the labeled conformational PLA2R epitope is detected by, for example, FACS and/or an ELISPOT assay with a reasonable expectation of success because Degauque teaches using both FACS and ELISPOT assays for the measurement of interactions (i.e., binding) between B cells (i.e., auto-antibody producing B cells) and respective antigen.
Claim 28 is 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. in 2015 (herein after referred to as "Kao") and non-patent literature by Moody and Haynes (Cytometry Part A, 2008, 73A, 1086-1092; herein after referred to as “Moody”), as applied to claims 1, 3-7, 9-12, 18-19, and 21 above, and in further view of non-patent literature by Daniel Cattran (J. Am. Soc. Nephrol. 2005, 16, 1188-1194; herein after referred to as “Cattran”).
The method of claim 1 is rendered obvious by Salant, Kao, and Moody. 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
PNG
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Figure 2 (Page 1191), reproduced below.
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, and Moody 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
It is noted that on Page 6 of Remarks, Applicant indicates that they do not agree with the characterization and assessment of the dependent claims in the previous Office Action, and asserts that each claim is patentable on its own merits. Applicant submits that the dependent claims incorporate by reference all limitations of the claim to which they refer and include their own patentable features. These arguments have been fully considered, but are deemed not persuasive.
Applicant has amended independent claim 1, such that the claim is now considered to be enabled. As such, art has now been applied under the new grounds of rejection presented in the 103 section above. No specific arguments regarding any previously cited prior art references have been provided.
Conclusion
Claims 1, 3-7, 9-12, 18-21, and 27-29 are pending. Claims 1, 3-7, 9-12, 18-21, and 27-29 are rejected. No claims are allowed.
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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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