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 .
Election/Restrictions
Applicant’s election without traverse of Group I which includes claims 1, 3-7, 9-14 and 18 in the reply filed on 07/31/2025 is acknowledged.
Priority
The present application was filed on 11/15/2022. Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT/EP2021/062960 filed on 05/17/2021 which claims benefit of the foreign Application EPO 20305501.7 filed on 05/15/2020.
Claim status
Claims 1-18 are pending. Claims 2, 8, 15-17 are withdrawn from consideration.
Claims 1, 3-7, 9-14 and 18 are examined herein.
Claim Objections
Claims 1, 3 and 5-6 are objected to because of the following informalities:
Claim 1 has a period put after “a poor prognosis” in line 6.
See MPEP 608.01(m): “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations”.
Claims 5 and 6 recite “according to any one of claim”. They should be “according to claim”.
Claims 1 and 3: the names of biomarkers should be written in full for the first time in the claim set. For example, phospholipase A2 receptor (PLA2R1) or C-type lectin domain 1 (CTLD1) etc.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1, 3-7, 9-14 and 18 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.
Claim 1 recites “a step of determining the nature of the antibody which mostly drives the anti-PLA2R1humoral response…”, “…mostly driven by anti-CTLD1 antibodies…”. The term “mostly” in claim 1 is a relative term which renders the claim indefinite. The term “mostly” is not defined by the claim. While claims are interpreted in light of the specification, the limitations should be clearly recited in the claim itself to ensure they are part of the patent's legal protection. In this case, the claim does not define how to determine if the anti-PLA2R1 humoral response in the patient's sample is mostly or not mostly driven by anti-CTLD1 antibodies.
Claims 3 and 14 depend on claim 1. Claim 3 recites the limitation "wherein step of determining PLA2R1 immunodominance". There is insufficient antecedent basis for this limitation in the claim because this step is not cited in claim 1. Moreover, it is not clear what to be measured in claim 3 using a competition assay with saturating amounts of polypeptide competitors selected among a CysR fragment, a CTLD1 fragment, a CysR-FnII-CTLD1 fragment, or a mixture thereof. The claim recites the competitors but not recite what the analyte is. The analyte has not been cited in the previous claim 1. Claim 14 depends on claim 3 and recites the result of the method in claim 3 but still not define what the analyte is. So the claims fail to particularly point out and distinctly claim the subject matter.
Claims 10 and 18 limit the value of anti-PLA2R1 titer in a sample. It is not apparent what is the consequence of the anti-PLA2R1 titer being lower than the claimed value, or if the measuring of the anti-PLA2R1 titer inevitably would lead to the sample having an anti-PLA2R1 titer lower than the claimed value.
Moreover, claim 1 states if anti-PLA2R1 response is mostly or not mostly driven by anti-CTLD1 antibodies then the patient exhibits a poor or a good prognosis. According to this, it is unclear how to conclude that anti-PLA2R1 response is mostly or not mostly driven by anti-CTLD1 antibodies if anti-PlA2R1 titer is lower than 250RU/mL or lower than 200 RU/mL, and it is unclear if the claimed titer of anti-PlA2R1 is good or not for the prognosis.
Claim 14 defines that “when competition with a CysR-FnII-CTLDI fragment is higher than 50% while competition with a CTLD 1 fragment is lower than 30%, then the patient is immunodominant for CysR (iCR) and is of good prognosis and is a good responder to immunosuppressant”. The claim also defines that “when competition with a CysR-FnII-CTLD1 fragment is higher than 50% while competition with a CTLD 1 fragment is higher than 10% then the patient is immunodominant for CTLD 1 (iCI) and is of bad prognosis and is further a poor responder to immunosuppressant”.
Thus, when competition with a CysR-FnII-CTLD1 fragment is for example 55% and competition with a CTLD1 fragment is for example 20%, then according to claim 14, the patient is immunodominant for CysR (iCR) and also immunodominant for CTLD1 (iC1 ), and the patient is a good responder to immunosuppressant and also at the same time a poor responder to immunosuppressant. Thus claim 14 is unclear due to the overlapping definitions as given in the claim.
Claims 4-7, 9, 11-13 are rejected because they depend on the rejected claim 1.
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 10 and 18 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 10 depends on claim 9. Claim 18 depends on claim 10. Claims 10 and 18 limit the value of anti-PLA2R1 titer in a sample. It is noted that the value of anti-PLA2R1 titer in a sample is determined by using the claimed method to measure the anti-PLA2R1 titer in a sample, so claims 10 and 18 only recite the results of the method of claims 9 and 1.
However, they do not recite an additional step of the claimed method which they depend (claims 1 and 9). So claims 10 and 18 are rejected for failing to further limit the subject matter of the claim upon 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 § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3-7, 9-14 and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed a law of nature without significantly more. Claim 1 recites a method of predicting the prognosis of a patient suffering from membranous nephropathy comprising a step of determining the nature of the antibody which mostly drives the anti-PLA2R1 humoral response in a sample, which is judicial exceptions (law of nature and abstract idea). Claims 6-7 recite using the method of claim 1 to get a ratio and then compare the ratio to a reference value, which is a judicial exception (abstract idea). The judicial exception is not integrated into a practical application because there is no practical application recited in the claims. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional steps amount to mere data gathering that does not go beyond well-understood, routine, and conventional activity; as detailed below.
Step 1 – Whether a claim is to a statutory category - YES
Claims 1, 3-7, 9-14 and 18 are directed a method of predicting the prognosis of a patient suffering from membranous nephropathy. Therefore, the instantly claimed invention falls into one of the four statutory categories.
Step 2A Prong 1 – Whether the claim is directed to a judicial exception (i.e. Does the claim recite an abstract idea, law of nature, or natural phenomenon?) – YES
As explained in MPEP § 2106.04(II), a claim “recites” a judicial exception when the judicial exception is “set forth” or “described” in the claim.
Claim 1 recites a method of predicting the prognosis of a patient suffering from membranous nephropathy comprising the following steps:
determining the nature of the antibody which mostly drives the anti-PLA2R1 humoral response in a sample obtained from said patient, wherein:
- if the anti-PLA2R1humoral response in the patient's sample is mostly driven by anti-CTLD1 antibodies then the patient exhibits a poor prognosis;
- if the anti-PLA2R1 humoral response in the patient's sample is not mostly driven by anti-CTLD1 antibodies then the patient exhibits a good prognosis.
Claims 6-7 recite using the method of claim 1 to get a ratio and then compare the ratio to a reference value.
Claim 14 recite the method of predicting if a patient with membranous nephropathy has a good or bad response to the immunosuppressant based on the results of competition assays are expressed as the percentage of maximal signal measured in the absence of competitor for CysR-FnII-CTLD1 fragment, CysR fragment, CTLD1 fragment, and other PLA2R1 domain.
The broadest reasonable interpretation of the steps of “establishing a ratio”, “comparing”, “determining”, and defining which patient has a good or bad response to the immunosuppressant in claims 1, 6-7 and 14 are abstract ideas, specifically, abstract mental processes. In fact, the step of establishing a ratio is also one way to compare between two values.
Regarding the step of “comparing,” the courts have held similar claims to be abstract mental processes, as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 763, 113 USPQ2d 1241, 1246 (Fed. Cir. 2014) which involved claims to "comparing BRCA sequences and determining the existence of alterations," where the claims cover any way of comparing BRCA sequences such that the comparison steps can practically be performed in the human mind. The claims are also similar to that in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011), which involved a claim to “collecting and comparing known information” (both of these court cases are discussed in MPEP 2106.04(a)(2) (II)(A)).
The step of determining and defining which patient has a good or bad response to the immunosuppressant in claims 1 and 14 also constitute an abstract mental process. Claim 1 involves assessing whether the anti-PLA2R1 humoral response is driven by anti-CTLD1 antibodies, and then making an evaluation or judgment as to the patient exhibits a good or poor prognosis. Claim 14 involves assessing if a patient with membranous nephropathy has a good or bad response to the immunosuppressant based on the results of competition assays, and then making an evaluation or judgment as to the patient exhibits a good or poor prognosis. The judgment step could be performed in the human mind, or by a human using pen and paper, insofar as it reads on drawing conclusion of the prognosis of a patient suffering from membranous nephropathy based on which antibody drives the anti-PLA2R1 humoral response.
The “determining” step in claims 1 and 14 can be regarded as a law of nature, namely, the naturally occurring correlation between the anti-PLA2R1 humoral response and the membranous nephropathy.
Thus, the claims 1, 6-7 and 14 fall into judicial exception.
Step 2A Prong 2 - Does the claim recite additional elements that integrate the judicial exception into a practical application? NO
The Step 2A, Prong 2 analysis requires identifying whether there are any additional elements recited in the claim beyond the judicial exception(s), and evaluating those additional elements to determine whether they integrate the exception into a practical application of the exception.
Claims 1, 3-7, 9-14 and 18 do not recite any additional element that integrate the exception into a practical application of the exception. The additional steps of obtaining a sample and analyzing an expression level are insufficient to integrate the exception into a practical application because the purpose is merely to obtain data.
As in In re Grams, 888 F.2d 835, 839-40; 12 USPQ2d 1824, 1827-28 (Fed. Cir. 1989), such activity involving performing clinical tests on individuals constitutes mere data gathering, and does not go beyond insignificant extra-solution activity. See MPEP §§ MPEP 2106.04(d)(I) and 2106.05(g).
There are no subsequent steps recited after the “determining” step that would practically apply the method depending on the results of the measurements, e.g., treatment or other process steps that are performed after predicting the prognosis of the patient suffering from membranous nephropathy.
Step 2B: Whether the additional elements contribute an “inventive concept”
In the second step it is determined whether the claimed subject matter includes additional elements that amount to significantly more than the judicial exception. See MPEP 2106.05.
Briefly, the claims 1, 3-7, 9-14 and 18 do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the following reasons.
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, has been found to be insufficient to add “significantly more” (MPEP 2106.05(I)(A)).
In claims 11-13, they define what the biological sample is, but the biological sample does not add a meaningful limitation to the instant method as the biological sample would have been routinely used by those of ordinary skill in the art.
In claim 1, 3-7, 9-10, 14 and 18, the method is directed to detect the anti-PLA2R1 humoral response to CTLD1 fragment, CysR fragment, or a mixture thereof, determine the titer of the anti-PLA2R1 antibody and compare the titer to the reference value, and predicting the prognosis to immunosuppressants. These steps do not add a meaningful limitation to the instant method as the steps are well-understood, routine, and conventional. This position is supported by Esnault (US2018203020), Seitz-Polski et al. (Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy, J Am Soc Nephrol. 2015 Nov 13;27(5):1517–1533, which is a non-patent literature version of Esnault US2018203020), and Pan et al. (Serum C3/C4 ratio is a novel predictor of renal prognosis in patients with IgA nephropathy: a retrospective study, Immunologic Research, Volume 66, pages 381–391, 2018).
Esnault discloses a method for assessing the prognosis of idiopathic membranous nephropathy in a subject, based on the analysis of PLA2R1 epitope profile (see Abstract). The method comprises detecting and/or measuring the level, in a biological sample obtained from said subject, of autoantibodies directed against the C-type lectin domain 1 (CTLD1) of PLA2R1; wherein the presence of autoantibodies directed against CTLD1 is indicative of a bad prognosis (see par.14).
The method also comprises determining a level of at least one, preferably two, more preferably three autoantibodies selected from the group consisting of autoantibodies respectively directed against CysR, CTLD1 and CTLD7, which are the extracellular domains of the PLA2R1 (see par.7 and 18).
The method taught by Esnault is also used to predict if the treatment is effective in a patient (see par.18), wherein the treatment is immunosuppressive treatment (see par.50).
Esnault performed competition experiments with the CysR, CTLD1 and CTLD6-7 domains expressed in E. coli against full-length PLA2R1 by ELISA (see Esnault par.141 or Seitz-Polski page 1520 col.2 par.2). The result from the Esnault and Seitz-Polski’s method shows which domain of PLA2R1 contributes the most to the signal measured by ELISA in relative with the full PLA2R1 antigen (see Seitz-Polski’s supplemental figure 3).
Pan teaches the method of prognosing of a patient with nephropathy using a ratio of serum C3 and C4 concentrations (C3/C4 ratio) (see Abstract). The method comprises measuring the concentrations of the two markers and calculating the ratio of the two markers’ concentrations, then the measured value of the ratio is compared to a reference value (see Clinical measures, Statistical analysis: teaching that the C3/C4 ratio was calculated, and then baseline demographic and clinical characteristics and histopathological data of the included patients were separated into four groups according to the C3/C4 ratio and compared using the Kruskal-Wallis test for numerical variables and Pearson’s chi-squared test for categorical variables).
See also detail discussion in the prior art rejections below.
For all of these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception(s).
Therefore, the instantly rejected claims are not drawn to eligible subject matter as they are directed to a law of nature without significantly more. For additional guidance, applicant is directed generally to MPEP § 2106.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 9-13 and 18 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Esnault (US20180203020).
Regarding claim 1, Esnault discloses a method for assessing the prognosis of idiopathic membranous nephropathy in a subject, based on the analysis of PLA2R1 epitope profile (see Abstract). The method comprises detecting and/or measuring the level, in a biological sample obtained from said subject, of autoantibodies directed against the C-type lectin domain 1 (CTLD1) of PLA2R1; wherein the presence of autoantibodies directed against CTLD1 is indicative of a bad prognosis (see par.12 and par.14).
Regarding claims 9-10 and 18, Esnault teaches the invention as discussed above. The method of Esnault allows evaluating the titers of anti- PLA2R1 of the patient (see par.68: titer for autoantibodies directed against CysR, CTLD1 and CTLD7; par.141: performed competition experiments with the CysR, CTLD1 and CTLD6-7 domains expressed in E. coli against full-length PLA2R1 by ELISA).
The anti- PLA2R1 antibody titer ranged from 210-50817 ELISA index value (see Table 1). An ELISA Index value for each antigen was obtained for patients or normal subjects as follows (mean test result−mean domain negative control)/(mean domain positive control−mean domain negative control)×domain correction factor×100 (see par.137). The titer of the anti- PLA2R1 antibody is still displayed in RU/ml (see par.172). Therefore, the method of Esnault can be able to measure the anti- PLA2R1 antibody less than 250 RU/ml.
It appears that the method of Esnault can also be able to measure the anti- PLA2R1 antibody less than 200 RU/ml because Esnault provides the same method of detecting the anti- PLA2R1 antibody titer (see par.135) with the method used in the instant specification (see page 9 par.2), that is standardized and commercially available ELISA.
Regarding claims 11-13, Esnault teaches the invention as discussed above. Esnault discloses that the sample is bodily fluids which may or may not contain cells, e.g., blood (e.g., whole blood, serum or plasma). Such samples also include biopsies (for example kidney biopsy). See paragraph 57.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim(s) 3-5 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Esnault (US2018203020) as evidenced by Seitz-Polski et al. (Epitope Spreading of Autoantibody Response to PLA2R Associates with Poor Prognosis in Membranous Nephropathy, J Am Soc Nephrol. 2015 Nov 13;27(5):1517–1533, which is a non-patent literature version of Esnault US2018203020).
Regarding claims 3-5, Esnault teaches the invention as discussed above. Esnault also teaches that autoantibodies against a mixture of PLA2R1 fragments may be measured by using standard immunodiagnostic techniques, including competitive immunoassay (see par.65-67).
Moreover, the competition assay is used to demonstrate the presence of two different autoantibodies targeting a particular peptide, e.g. CysR or CTLD1 (see par.140). In this assay, serum from patient is pre-absorbed with an excess of a peptide domain (see par.140). So Esnault’s teaching anticipates claims 3 and 4.
Esnault does not teach performing a competition assay with saturating amounts of peptides selected among CysR, CTLD1, CysR-FNII-CTLD1 (triple domain), CTLD7 and CTLD5 as in claim 5.
However, Esnault demonstrates that there are two different autoantibodies targeting CysR or CTLD1, e.g., antibody to CysR domain alone or antibody to several epitopes which is intertwined between CysR and CTLD1 domain (see par.140). The result is also shown in Esnault non-patent literature (see Seitz-Polski Figure 2: depicting that serum from patients 2 and 3 (CTLD1 profile) could recognize constructs containing both the CTLD1 domain and the CysR domains expressed alone as DsbC fusion proteins or as the triple domain, and cleaved or not with thrombin). Interestingly, the relative signals against the two domains were different, likely because of different titers for each anti-CysR and anti-CTLD1 autoantibodies in the two patients’ sera. See Figure 2 of Seitz-Polski.
Also, Esnault demonstrates that CTLD7 is likely another epitope for anti-PLA2R1 (see par.139). This result has illustrated in Figure 1 of Seitz-Polski.
Esnault concludes that analysis of the PLA2R1 epitope profile and spreading during follow-up is a powerful tool to monitor disease severity and stratify patients into subgroups with different renal prognosis (see par.85). “Epitope spreading” refers to the development of immune responses to endogenous epitopes secondary to the release of self-antigens during a chronic autoimmune or inflammatory response. Epitope spreading is thus a phenomenon in which new epitopes, within the same or different molecule, are recognized over time by T or B cells from an original non-cross-reactive antigenic site. As described in many autoimmune diseases intra-molecular epitope spreading is associated with worsening of the disease. See paragraph 87.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Esnault, doing a competition assay with mixture of CysR, CTLD1, CysR-FNII-CTLD1, CTLD2-8, CTLD7, CTLD5, or the mixture thereof because there is anti-PLA2R1 humoral responses to these epitopes and it is a method for monitoring the progression of idiopathic membranous nephropathy based on the analysis of the PLA2R1 epitope spreading as taught by Esnault (see Abstract).
One having an ordinary skill in the art would have had a reasonable expectation of success in predicting the prognosis of a patient suffering from membranous nephropathy because an analysis of the PLA2R1 epitope profile and spreading is a powerful tool for monitoring the progression of idiopathic membranous nephropathy and stratifying patients by renal prognosis (see Esnault and Seitz-Polski ‘s Abstract). As described in many autoimmune diseases intra-molecular epitope spreading is associated with worsening of the disease (see Esnault par.87).
For claim 14, in light of specification pages 4-7, claim 14 is about identifying the immunodominance among antibodies to PLA2R1 fragments in the serum, in other words, defining the proportion of antibodies against PLA2R1 fragments (e.g., CysR, CTLD1, CysR-FNII-CTLD1…etc. fragments). For example, a patient non immunodominant for CTLD1, typically a patient immunodominant for CysR (and/or a patient non-immunodominant if immunodominance is assessed through a competition assay) (see page 6). The applicants determined which PLA2R1 domain contains the major immunodominant epitopes that would contribute the most to the signal measured by ELISA on the full PLA2R1 antigen (see page 12).
Esnault and Seitz-Polski teach the invention as discussed above, which is a competition assay with mixture of PLA2R1 fragments comprising CysR, CTLD1, CysR-FNII-CTLD1…etc. Esnault performed competition experiments with the CysR, CTLD1 and CTLD6-7 domains expressed in E. coli against full-length PLA2R1 by ELISA (see Esnault par.141 or Seitz-Polski page 1520 col.2 par.2). Seitz-Polski clearly shows that the result of the competition experiments are defined by the percentage of max signal (see supplemental figure 3). The figure 3 of Seitz-Polski shows the competition by ELISA with CysR, CTLD1 or CTLD6-7 domains (5 µg each, from E. coli) against the full-length PLA2R1 for two patients with a CysR profile and two patients with a CTLD1 profile. Particularly, serum of patients with a CysR profile, when preincubated with the CysR antigen, induced a total loss of signal but no change with CTLD1 and CTLD6-7. On the other hand, serum of patients with a CTLD1 profile, when competed with CysR or CTLD1 antigens alone induced a partial loss of signal, when competed with CTLD6-7 had no effect, and when competed with all antigens induced a total loss of signal.
This teaching supports that Esnault and Seitz-Polski’s method is analogous with the claimed method in terms of determined which PLA2R1 domain contains the major immunodominant epitopes by competitive immunoassay because the result from the Esnault and Seitz-Polski’s method shows which domain of PLA2R1 contributes the most to the signal measured by ELISA in relative with the full PLA2R1 antigen (see Seitz-Polski’s supplemental figure 3).
Eventually, the method of Esnault and Seitz-Polski also draw to a conclusion that the presence of autoantibodies directed against CTLD1 is indicative of a bad prognosis (see Esnault par.12 and par.14), while the presence of autoantibodies directed against CysR is indicative for good prognosis (see Esnault par.40). See Seitz-Polski page 1525, teaching the comparison of immunosuppressive treatment amongst CysR, CysRC1, and CysRC1C7 groups, wherein the CysR group has a good response to the immunosuppressive in relative to the C1 groups.
Even though Esnault and Seitz-Polski are silent about a particular percentage of maximum signal obtained from the competitive immunoassay to each antigen domain to define the immunodominance domain, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to define which PLA2R1 domain contains the major immunodominant epitopes that would contribute the most to the signal measured by ELISA on the full PLA2R1 antigen based on the teaching of Esnault and Seitz-Polski as discussed above.
This is because Esnault and Seitz-Polski contain a comparable method with the claimed method. One having ordinary skill in the art could have applied the technique and improved it to yield the predictable results, for instant, the presence of autoantibodies directed against CTLD1 is indicative of a bad prognosis for immunosuppressive as taught by Esnault.
Claim(s) 6-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Esnault (US2018203020), as applied in claim 1, in view of Pan et al. (Serum C3/C4 ratio is a novel predictor of renal prognosis in patients with IgA nephropathy: a retrospective study, Immunologic Research, Volume 66, pages 381–391, 2018) and Gong et al. (High serum IgA/C3 ratio better predicts a diagnosis of IgA nephropathy among primary glomerular nephropathy patients with proteinuria ≤ 1 g/d: an observational cross-sectional study, BMC Nephrology, article number 150, 2019).
For claims 6-7, Esnault teaches the invention as discussed above. Esnault does not teach establishing a ratio between the titers of anti-CTLD1 antibodies and anti-CysR antibodies, the measured value of the ratio is compared to a reference value.
On the other hand, Pan teaches the method of prognosing of a patient with nephropathy using a ratio of serum C3 and C4 concentrations (C3/C4 ratio) (see Abstract). The method comprises measuring the concentrations of the two markers and calculating the ratio of the two markers’ concentrations, then the measured value of the ratio is compared to a reference value (see Clinical measures, Statistical analysis: teaching that the C3/C4 ratio was calculated, and then baseline demographic and clinical characteristics and histopathological data of the included patients were separated into four groups according to the C3/C4 ratio and compared using the Kruskal-Wallis test for numerical variables and Pearson’s chi-squared test for categorical variables).
While C3 and C4 are individually associated with poor renal outcomes (see Introduction par.2), Pan shows that compared with the AUCs for C3 and C4 levels, the AUC for the C3/C4 ratio was significantly increased, which indicated that the C3/C4 ratio is superior to C3 and C4 levels in the identification of poor renal outcomes. See page 388 column 2 paragraph 2.
Moreover, Gong teaches a better prediction for diagnosing IgA nephropathy using a ratio of serum immunoglobulin A (IgA)/C3 (see Abstract). The method comprises measuring the concentrations of the two markers and calculating the ratio of the two markers’ concentrations, then the measured value of the ratio is compared to a reference value (see Clinical data collection, Statistical analysis, Fig.2-3).
Gong teaches that both IgA and C3 play an important role in the development and occurrence of IgA nephropathy. Gong suggests the IgA/C3 ratio can be used as a biomarker for IgA nephropathy. In addition, the serum IgA/C3 ratio was of higher predictive value for IgA nephropathy in patients with primary glomerulonephritis than the value of individual IgA or C3. For instant, the AUROC of the IgA/C3 ratio for the diagnosis of IgA nephropathy reached 0.734, while the AUROC of IgA and C3 alone were only 0.696 and 0.621, respectively. See page 9 column 1 paragraph 1.
While Pan and Gong are draw to the different biomarkers in nephropathy field, they are analogous in a method of diagnosing and prognosing a diseases based on measuring concentrations of two markers which each of them is associated with the disease, establishing a ratio between the two markers, comparing the measured value of the ratio with a reference value. Pan and Gong support that the ratio of the two biomarkers is superior to each biomarker alone in the identification of the disease.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try combining the method taught by Pan and Gong with the method of Esnault for improving the prognosis of idiopathic membranous nephropathy in a subject. Since Esnault teaches that three PLA2R1 domains (CysR, CTLD1 and CTLD7) are involved in anti-PLA2R1 activity, which affects the prognosis of idiopathic membranous nephropathy in a subject (see Abstract), establishing the ratio of the parameters, e.g., anti-CTLD1antibodies and anti-CysR antibodies, instead of using the parameter alone, would obtain a higher predictive value for the nephropathy as taught by Pan and Gong.
One of ordinary skill in the art could have pursued the known potential solutions giving by Pan and Gong with a reasonable expectation of success in Esnault’s method because they are directed to a method of diagnosing and prognosing a diseases based on measuring serum concentration of biomarkers.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHAU N.B. TRAN whose telephone number is (571)272-3663. The examiner can normally be reached Mon-Fri 8:30-6:30 CT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy L Nguyen can be reached at 571-272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHAU N.B. TRAN
Examiner
Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 September 29, 2025