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 1-13 have been cancelled as requested in the amendment filed on 03/16/2026. Following the amendment, claims 14-16 are pending in the instant application.
Claims 14-16 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.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Provisional Application No. 62/374,382, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Claims 14-16 are not supported by the above-listed provisional application, as the provisional application does not disclose the administration of a complex comprising a conformational PLA2R epitope linked to a drug to a patient in a state of remission.
Claims 14-16 have an effective filing date of August 11, 2017 corresponding to PCT/US2017/046626.
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Claim Rejections - 35 USC § 103 - Withdrawn
Claims 1, 5-7, and 9 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 by Kao et. al. (J. Am. Soc. Nephrol., 2015, 26, 291-301; previously cited on PTO-892; herein after referred to as “Kao”) and non-patent literature by Volkman et. al. (Journal of Experimental Medicine, 1982, 156, 634-639; previously cited on PTO-892; herein after referred to as "Volkman").
Claims 2-4 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"), non-patent literature by Kao et. al. (J. Am. Soc. Nephrol., 2015, 26, 291-301; previously cited on PTO-892; herein after referred to as “Kao”), and non-patent literature by Volkman et. al. (Journal of Experimental Medicine, 1982, 156, 634-639; previously cited on PTO-892; herein after referred to as "Volkman"), as applied to claims 1, 5-7, and 9 above, and further in view of non-patent literature by Fervenza et. al. (Clin. J. Am. Soc. Nephrol., 2010, 5, 2188-2198; previously cited on PTO-892; herein after referred to as "Fervenza").
Claims 11-12 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"), non-patent literature by Kao et. al. (J. Am. Soc. Nephrol., 2015, 26, 291-301; previously cited on PTO-892; herein after referred to as “Kao”), and non-patent literature by Volkman et. al. (Journal of Experimental Medicine, 1982, 156, 634-639; previously cited on PTO-892; herein after referred to as "Volkman"), as applied to claims 1, 5-7, and 9 above, and further in view of non-patent literature by Lien and Lowman (TRENDS in Biotechnology, 2003, 21(12), 556-562; previously cited on PTO-892; herein after referred to as "Lien").
With regard to the above-listed claim rejections, it is noted that claims 1-13 have been cancelled, rendering their rejection(s) moot. As such, the above listed claim rejections are withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 14-16 stand 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 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 Volkman et. al. (Journal of Experimental Medicine, 1982, 156, 634-639; previously cited on PTO-892; herein after referred to as "Volkman"), non-patent literature by Beck et. al. (J. Am. Soc. Nephrol., 2011, 22, 1543-1550; herein after referred to as "Beck"), non-patent literature by Colucci et. al. (J. Am. Soc. Nephrol., June 2016 (available online Nov. 2015), 27, 1811-1822; herein after referred to as "Colucci"), and non-patent literature by Yoshida et. al. (Immunological Reviews, 2010, 237, 117-139; herein after referred to as "Yoshida").
Response to Arguments
Applicant's arguments filed 03/16/2026 (herein after referred to as “Remarks”) have been fully considered but they are not persuasive.
With regard to the maintained rejection of claims 14-16 under 35 U.S.C. 103 in view of Salant, Kao, Volkman, Beck, Colucci, and Yoshida, Applicant argues the following on Pages 4-5 of Remarks regarding a lack of a prima facie showing of obviousness:
While Beck may suggest that changes in the level of anti-PLA2R antibodies are associated with and precede corresponding changes in the clinical activity of the disease, nothing in Beck suggests a correlation of autoantibody B cells and clinical outcome. Indeed, Beck expressly states the opposite (see Pages 1547-1548; Beck indicates there was no correlation of B cell number or subsets with clinical outcome).
Colucci concluded that "[b ]y multivariate analysis, only the reconstitution of switched memory B cells retained a significant association with the time to relapse." Thus, Colucci concluded that only one subtype of memory B cell was associated with relapse. Applicant further cites Pages 1817-1818 of Colucci, and argues that Colucci suggests that retention of B cells with regulatory function may be important to prevention of relapse, and as such Colucci actually teaches away from the presently claimed method of "eliminating or reducing an anti-PLA2R autoantibody producing B cell population."
Yoshida suggests several then-emerging possibilities to eliminate such autoreactive B cells but provides no teaching regarding reduction of relapse in patients in a state of remission.
Thus, in view of the above, Applicant argues that when the teachings of Beck, Colucci and Yoshida are combined, they do not suggest that eliminating or reducing an anti-PLA2R autoantibody producing B cell population in a patient in a state of remission could be employed to reduce likelihood of remission in the patient. As such, even if the combination of Salant, Kao and Volkman were viewed as suggesting the administration of the recited complex of a conformational PLA2R epitope linked to a drug, the combination of all six references would not have led one having ordinary skill in the art to the presently claimed invention. Therefore, no prima facie showing of obviousness can be established on the basis of the cited references.
With regard to the arguments above, it is specifically noted that the combination of teachings from Beck, Colucci, and Yoshida are relied upon to render obvious the active step of administering a complex comprising a conformational PLA2R epitope linked to a drug to a patient who is in a state of remission. In response to applicant's arguments against the references individually, 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 focus of Beck was monitoring anti-PLA2R levels and correlating said level with clinical response. Beck was relied upon to demonstrate that rituximab (an anti-B cell agent that targets B cells generally via CD20) treatment in patients with IMN generally resulted in a progressive decrease in anti-PLA2R levels after treatment leading to a complete and lasting disappearance of the autoantibodies. The mention of no correlation between B cell number or subsets and clinical outcome, in the context of the cited portion of the reference, is made in reference to the results (i.e., different clinical outcomes) not being due to nonspecific effects of rituximab on B cells; in other words, there were no changes in function, survival, or distribution of B cells that influenced clinical outcomes that were not due to targeted antigen-specific stimulation. Thus, the correlation, or lack thereof, regarding B cell numbers and/or subpopulations was merely to evaluate if rituximab was having nonspecific effects to account for the observed results. Regarding the effects of rituximab directly on B cells and/or the influence of B cells in auto-immune conditions, Colucci and Yoshida are relied upon for their focus on the role of B cells in auto-immune conditions, such as nephrotic syndrome, wherein both references explicitly disclose a relationship between B cells and autoantibodies. Colucci indicates that memory B cell population likely plays an active role in pathogenesis and relapse in nephrotic syndrome, wherein notably the recovery of the memory B cell population correlates with a strongly increased risk of relapse and Yoshida indicates that in auto-immune conditions, B cells mature, get activated, and induce expression of memory, wherein memory PCs secreting autoantibodies, alloantibodies, antibodies to persistent antigens or to allergens, constitute an unmet challenge in the treatment of chronic immune-mediated diseases as they are resistant to irradiation, cytostatic drugs, and conventional immunosuppression aiming at the inhibition of ongoing immune responses, wherein Yoshida specifically suggests that such refractory pathogenic memory PCs could be the reason that those diseases basically cannot be cured. Colucci does not teach away from the instant invention regarding the teaching that retaining B cells with regulatory function may be important to preventing relapse; one of ordinary skill in the art would recognize that there are various subpopulations of B cells with various regulatory roles, wherein said regulatory roles also depend on mechanisms of activation/response to stimuli wherein not all B cells become autoreactive and produce autoantibodies. Colucci specifically implicates the subpopulation of activated, memory B cells as having an active role in pathogenesis and relapse in nephrotic syndrome. Yoshida further supports this conclusion, and explicitly indicates that memory PCs secreting autoantibodies, alloantibodies, antibodies to persistent antigens are likely the reason chronic auto-immune conditions cannot be cured. The combination of Beck, Colucci, and Yoshida together indicate that B cells play critical roles in MN, and more specifically memory B cells are correlated with an enhanced risk of relapse and are likely implicated in why many autoimmune diseases cannot be cured because matured (i.e., memory) self-reactive B cells nor the antigen to which they are reactive are never fully cleared, and a self-perpetuating immune reaction takes place. Thus, it is maintained that it would have been obvious to one of ordinary skill in the art to modify the methods of Salant wherein PLA2R fragments are administered in combination with various drugs for the treatment of MN such that the method comprises (i) identifying a patient as having MN and being in remission, suggested by Salant; (ii) administering a treatment to the patient is identified as being in remission, as suggested by Beck, Colucci, and Yoshida; wherein (iii) said treatment comprises the PLA2R fragment comprising instant SEQ ID NO: 9, which comprises a conformational epitope as suggested by Kao, wherein said fragment is linked/conjugated to a drug useful for the treatment of MN (e.g., cytotoxic agent cyclophosphamide as suggested by Salant) to selectively eliminate autoantibody producing B cells as taught/suggested by Volkman. One of ordinary skill in the art would have recognized that the therapeutic approach of Salant could be modified to incorporate specific PLA2R fragments/epitopes known in the art, such as the conformational epitope specifically identified by Kao, and one of ordinary skill in the art would have been motivated to modify such a therapeutic approach wherein the PLA2R fragments/epitopes could be conjugated to cytotoxic agents (e.g., cyclophosphamide) in order to selectively eliminate autoantibody producing B cells, as suggested by Volkman, wherein such a therapeutic approach would be expected to be successful as Volkman discloses the approach to selective elimination of B cells using conjugates and Salant discloses that cyclophosphamide is useful in the treatment of MN when administered to patients with MN; the conjugation of the PLA2R fragments/epitopes to a cytotoxic drug already useful in the treatment of MN would be expected to be successful, as the drug can be specifically targeted to B cell population of interest (i.e., autoantibody producing B cells). The teachings of Beck, Colucci, and Yoshida suggest that memory B cells are never fully eliminated in autoimmune conditions, and the re-establishment of this population after initial treatment (e.g., after treatment with immunosuppressive drug rituximab wherein remission is achieved) is correlated with a high risk of relapse wherein risk of relapse can be reduced by administration of a therapeutic to prevent additional autoantibody production upon restimulation by self-antigen.
Further with regard to the maintained rejection of claims 14-16 under 35 U.S.C. 103 in view of Salant, Kao, Volkman, Beck, Colucci, and Yoshida, Applicant argues the following on Pages 5-6 of Remarks regarding a lack of the requisite reasonable expectation of success required to demonstrate obviousness:
Beck suggests that reduced levels of autoantibodies corresponds with therapeutic response. Importantly, the presence of these autoantibodies is not directly correlated to the B-cells that produce them. As is well known, B cells must be activated before production of antibodies begins. Thus, antibody producing B cells can be present without the presence of antibodies. Activation is a complex process that is itself part of the complex cellular dynamics underlying a B cell response. Antibodies can be produced by either short-lived plasma cells (SLPCs) or long-lived plasma cells (LLPCs), and several processes are involved with such production. Thus, one having ordinary skill in the art would readily recognize that the connection between autoantibodies and the B cells that produce them involves many distinct steps that may or may not be directly linked. In view of the complexity of these processes, one having ordinary skill in the art will readily discern that the presence of antibodies and the presence of antibody producing B cells are not directly correlated. Thus, while Beck showed a correlation between autoantibody levels and clinical outcome, such correlation cannot be applied to the present invention in which the risk of relapse is significantly reduced by treating patients who have PLA2R autoantibody producing memory B cell levels but are negative for PLA2R autoantibodies. As such, one having ordinary skill in the art would have no reasonable expectation of successfully reducing likelihood of remission even had combining the teachings of the cited references led such a person to attempt to do so.
With regard to the arguments above, it is noted that 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). The combination of Beck, Colucci, and Yoshida together indicate that B cells play critical roles in MN, and more specifically memory B cells are correlated with an enhanced risk of relapse and are likely implicated in why many autoimmune diseases cannot be cured because matured (i.e., memory) self-reactive B cells nor the antigen to which they are reactive are never fully cleared, and a self-perpetuating immune reaction takes place. Salant discloses a method for identifying a patient having MN that is in remission, and the combination of Salant, Kao, and Volkman (no arguments have been presented against any of these references) render obvious a method of treating MN comprising administering a complex comprising a PLA2R epitope linked to a drug, wherein the epitope is comprised within a PLA2R fragment, and the PLA2R fragment comprises SEQ ID NO: 9, thereby eliminating or reducing an anti- PLA2R autoantibody producing B cell population in the patient. Thus, from the teachings of Salant, Kao, and Volkman in view of the additional teachings of Beck, Colucci, and Yoshida, it would have been reasonably expected that the performing the method rendered obvious by Salant, Kao, and Volkman in MN patients currently in remission would serve to specifically target and eliminate memory B cells which would be specifically reactive to PLA2R, and would serve to reduce the likelihood of relapse by prolonging/preventing the recovery/increase in the number of reactive, autoantibody producing memory B cells. Furthermore, independent claim 14 recites functional language; the claim recites that the administration of the claimed complex comprising a PLA2R epitope linked to a drug results in the elimination or reduction of an anti-PLA2R autoantibody producing B cell population thereby reducing the likelihood of relapse in the patient with MN. In the instant case, the act connected to the recited functional language is the administration of the claimed complex comprising a PLA2R epitope linked to a drug to a patient in remission, and the broadest reasonable interpretation of the functional language is that the language is an intended result of the use of the claimed complex comprising a PLA2R epitope linked to a drug. One of ordinary skill in the art would understand that the intended result flows from the administration of the claimed complex comprising a PLA2R epitope linked to a drug, i.e., the administration of the claimed PLA2R epitope linked to a drug would be expected to result in the claimed result of the elimination/reduction of an anti-PLA2R autoantibody producing B cell population thereby reducing the likelihood of relapse in the patient with MN. Considering the active steps of claim 14 (identifying a patient with MN in a state of remission and administering the complex) are rendered obvious, the claimed functional language does not distinguish the instant claims from the combination of Salant, Kao, Volkman, Beck, Colucci, and Yoshida. It is further noted, with regard to Applicant's argument that while Beck showed a correlation between autoantibody levels and clinical outcome, such correlation cannot be applied to the present invention in which the risk of relapse is significantly reduced by treating patients who have PLA2R autoantibody producing memory B cell levels but are negative for PLA2R autoantibodies, it is noted that the instant claims are not specific to a patient population that is negative for PLA2R autoantibodies.
In view of the above, the rejection of claims 14-16 under 35 U.S.C. 103 in view of Salant, Kao, Volkman, Beck, Colucci, and Yoshida is deemed proper and is therefore maintained.
Conclusion
Claims 14-16 are pending. Claims 14-16 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALYSSA RAE STONEBRAKER whose telephone number is (571)270-0863. The examiner can normally be reached Monday-Thursday 7:00 am - 5:00 pm.
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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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