DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
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 CFR1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/19/2025 has been entered.
Claims 1-24 are pending as of the response filed on 12/19/2025. Claims 1-24 are examined herein.
Applicant’s submission of a declaration under 37 C.F.R. 1.132 dated 12/19/2025 is acknowledged. Applicant’s declaration indicating that the biological effect of a biased MC1R/3R agonist, such as AP1189, is distinct from the effects of a MC1R agonist, such as α-MSH and ACTH, was found to be persuasive (section 13 of the declaration dated 12/19/2025). Applicant’s argument indicating Lindskog’s MC1R agonism in reducing proteinuria, does not inform a person of ordinary skill in the art to utilize AP1189 in the treatment of proteinuria, was found to be persuasive (in view of the Qaio teachings contradicting that of Lindskog) (sections 10-11 and 15 of the declaration dated 12/19/2025).
Applicant’s arguments regarding the 35 U.S.C. 103 rejection of record of previous record have been fully considered and was found to be persuasive in light of the declaration.
Therefore, in consideration of the declaration submitted 12/19/2025 and Applicant’s arguments, the 35 U.S.C. 103 rejection of record over the combination of references that include Lindskog are hereby withdrawn.
In view of the pending claims, the following 35 U.S.C. 103 rejections are made. The nonstatutory double patenting rejections of previous record are maintained and updated. Applicant’s arguments regarding the nonstatutory double patenting rejections are addressed below.
Information Disclosure Statement
The information disclosure statement submitted on 12/19/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103 - New
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.
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.
Claim Interpretation : It is reiterated that the scientific literature and state-of-the-art refer to the free base of {3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidine, as AP1189. However, for the purpose of applying prior art, the acetate salt of {3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidine, or a tautomeric form thereof, is referred to as “AP1189” in the Office action (as previously noted in the Office action dated 01/31/2024 and supported by page 3, lines 25-27 of the instant specification).
Claims 1-4 and 12-22 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman), Montero-Mendelez et al. (Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects, 01 April 2015, hereinafter Montero-Mendelez) (in the IDS), Boesen (US 2015/0297672 A1, publication date 22 October 2015) and Ronco et al. (Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care, 16 May 2015, hereinafter Ronco).
Regarding instant claims 1-3, 12-13, Boman teaches a method of treating a mammal having a disease or disorder selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, said method comprising administering to said mammal a therapeutically effective amount of a compound taught by the reference (Pg. 4, Ln. 35 – Pg. 5, Ln. 3). Boman teaches treatment of diseases related to inflammation of the kidney, specifically, glomerulonephritis (Pg. 31, Lns. 14-19). Boman teaches the mammal to include a human being (Pg. 12, Lns. 1-2). Boman teaches an exemplary compound, compound 2 of the invention 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (Pg. 40, Lns. 20-21; Fig. 1, compound 19), shown below.
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Boman teaches the trans isomeric forms, with trans being the preferred configuration (Pg. 14, Lns. 17-30) (Therefore, Boman anticipates AP1189 of the instant claims in trans (E) form). Boman teaches oral administration of compound 2 to male rats at a dose of 10 mg/kg for a single administration (Pg. 6, Lns. 9-12). Boman teaches the dose of the compound can be adjusted based upon the disease, the administration schedule, whether the compound of the reference is administered alone or in conjunction with other therapeutic agents, the general health of the patient and the like. Boman teaches the compound should be administered in a dose of 0.1 to 100 mg body weight per kilo, if administered via the oral route (Pg. 23, Lns. 10-18) (based on an average human adult weight of 60 kg this dose amounts to a about 6-6000 mg, which encompasses the claimed range of about 5-400 mg). Boman teaches a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods (Pg. 24, Lns. 8-10). Boman teaches administering the dose once daily (Pg. 54, Lns. 20-22; Pg. 54, Lns. 30-33). Boman teaches the compounds act on the MC receptors of the melanocortin system (Pg. 25, Lns. 7-11).
Boman do not teach treating proteinuria in a human having membranous nephropathy.
Montero-Mendelez teaches AP1189 to be a biased agonist at the MC1 and MC3 receptors that elicits exceptional anti-inflammatory property with a more favorable safety profile, when administered orally in vivo (Abstract; Pg. 3386, first column, last paragraph). Montero-Mendelez teaches AP1189 to be an exceptional therapeutic devoid of side effects (Pg. 3387, second column, last paragraph).
Boesen teaches melanocyte stimulating hormone (MSH) analogues for use in the treatment of inflammatory conditions (Para. [0002]). Boesen teaches analogues with improved activation of the MC1R and/or MC3R melanocortin receptors (Para. [0012]) and methods of treating an individual with a condition responsive at least in part to MC1R and/or MC3R agonism by administration of such peptides (Para. [0013]). Boesen teaches embodiments wherein the condition being treated includes inflammatory conditions of the kidney, especially a glomerular disease of the kidney, for induction of a remission of proteinuria in patients with nephrotic syndrome (Para. [0302]; Para. [0319]; Paras. [0323]-[0324]). Boesen teaches the anti-inflammatory intervention targeting the melanocortin system would benefit from targeting both the MC1R and MC3R (Para. [0358]). Boesen teaches methods comprising the step of administering a therapeutically effective amount of a peptide according to the present invention to an individual in need thereof (Para. [0300]), wherein the individuals in need thereof is a human (Para. [0296]).
Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults (Abstract). Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome; the remainder present with asymptomatic proteinuria (<3·5 g/24 h) and about 60% of them will progress to full nephrotic syndrome (Pg. 1984, first column, first full paragraph). Ronco teaches 70-80% of the cases are primary or idiopathic membranous nephropathy (without any identified cause) (Pg. 1983, first column, first paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Boman, Montero-Mendelez, Boesen and Ronco, to have arrived at the claimed method of treating proteinuria in a human subject having membranous nephropathy/idiopathic membranous nephropathy (iMN) comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, with a reasonable expectation of success in treating membranous nephropathy/iMN.
Boman teaches a method of treating a mammal having an inflammatory condition, including inflammation of the kidney, say, glomerulonephritis, comprising administering to said mammal a therapeutically effective amount of compound 2 of the invention. Boman teaches compound 2 to be 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate, with the trans isomeric form being the preferred configuration (i.e., AP1189 of the instant claims). Boman teaches a dose of 0.1 to 100 mg body weight per kilo if administered via the oral route (based on an average human adult weight of 60 kg this dose amounts to a dose of 6-6000 mg, which encompasses the claimed range of about 5-400 mg). Boman teaches a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods. Boman teaches administering the dose once daily. Boman teaches the compounds act on the MC receptors of the melanocortin system. Montero-Mendelez teaches AP1189 to be a biased agonist at the MC1 and MC3 receptors that elicits exceptional anti-inflammatory property with a more favorable safety profile, when administered orally in vivo. Montero-Mendelez teaches AP1189 to be an exceptional therapeutic devoid of side effects. Boesen teaches melanocyte stimulating hormone (MSH) analogues for use with improved activation of the MC1R and/or MC3R melanocortin receptors in the treatment of inflammatory conditions. Boesen teaches treating inflammatory conditions of the kidney, especially a glomerular disease of the kidney, for induction of a remission of proteinuria in patients with nephrotic syndrome. Boesen teaches the anti-inflammatory intervention targeting the melanocortin system would benefit from targeting both the MC1R and MC3R. Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome in adults. Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome and the remainder present with asymptomatic proteinuria (<3·5 g/24 h). Ronco teaches 70-80% of the cases are primary or idiopathic membranous nephropathy (without any identified cause).
Summing it up, Boman teaches a method of treating an inflammatory condition of the kidney in a human, comprising orally administering to said human a therapeutically effective amount of AP1189. Montero-Mendelez teaches AP1189 to be a biased agonist at the MC1 and MC3 receptors with a favorable safety profile. Boesen in view of Ronco motivates a person of ordinary skill in the art to explore the use of AP1189 in a method of treating membranous nephropathy (say, iMN) with the activation of melanocortin 1 receptor MC1R and/or MC3R, to effect remission of proteinuria. Therefore, one of ordinary skill in the art would have been motivated to modify the method of treating an inflammatory condition of the kidney comprising orally administering a preferred daily dose of AP1189 as taught by Boman, to treat proteinuria in a human having membranous nephropathy/iMN, as taught by the combined teachings of Montero-Mendelez, Boesen and Ronco, with a reasonable expectation of success in treating such a condition. The motivation being to provide an exceptional anti-inflammatory agent to reduce proteinuria with a favorable safety profile, devoid of side effects (Montero-Mendelez, Pg. 3387, second column, last paragraph).
According to MPEP 2144.05(II)(A), "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Therefore, it would have taken no more than the relative skills of
one of ordinary skill in the art through routine experimentation to have arrived at the
claimed daily dosage range of about 5-400 mg of 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (AP1189), as in instant claim 1 OR the specific optimal doses of 50 mg and 100 mg of 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (AP1189) as in instant claims 12 and 13 respectively, in the absence any criticality of these dosages.
Thus, the limitations of claims 1-3 and 12-13 are rendered prima facie obvious.
Regarding instant claim 4, the combined teachings of Boman, Montero-Mendelez, Boesen and Ronco render the method of instant claim 1, prima facie obvious.
Boman do not teach wherein the human is anti-PLA2-Receptor positive.
Ronco teaches podocyte phospholipase A2 receptor (PLA2R) was reported as an antigenic target in autoimmune adult membranous nephropathy (Abstract; Pg.1988, second column, first full paragraph). Ronco teaches measurement of anti-PLA2R antibodies in serum and detection of PLA2R antigen in glomerular deposits can be done routinely (Abstract; Pg. 1988, first column, first paragraph). Ronco teaches these tests have a major effect on diagnosis and monitoring of treatment (Abstract; Pg. 1988, first column, second paragraph – Pg. 1990, second column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Boman, Montero-Mendelez, Boesen and Ronco, to have tested the presence of anti-PLA2-receptor antibody in the patient being treated. The motivation being to use the antibody profiling of anti-PLA2-receptor antibody as a diagnostic biomarker and for monitoring response to treatment (Ronco, Abstract).
Regarding instant claims 14-22, the combined teachings of Boman, Montero-Mendelez, Boesen and Ronco, renders the method of treating proteinuria in a human subject having membranous nephropathy, comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, in the claimed range of about 5-400 mg, as in instant claim 1, prima facie obvious. Boman teaches orally administering the dose once daily (Pg. 54, Lns. 20-22) and administering the compound for up to 32 days (i.e., about 4 weeks) (Pg. 54, Ln. 23).
According to MPEP 2111.04(I), “However, the court noted that a "‘whereby (here, wherein) clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In the instant case, the limitations herein with respect to claims 14-22, which recite specific efficacy endpoints or clinical effects are related to the intended effect of the agent, (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), in the treatment after 4 weeks of daily administration. The combined teachings of Boman, Montero-Mendelez, Boesen and Ronco render obvious the method of treating proteinuria in a human subject having membranous nephropathy, by administering the same agent, (AP1189) at a dosage that encompasses the claimed range (about 5-400 mg), via the same route of administration (oral), as instantly claimed. In the absence of evidence to the contrary, the method taught by the combined teachings of Boman, Montero-Mendelez, Boesen and Ronco, when practiced in treating proteinuria in a human subject having membranous nephropathy over a period of 4 weeks, would have necessarily produced the same efficacy endpoints and clinical effects. Therefore, the phrase following the “wherein” clause in claims 14-22, are not given patentable weight.
Thus, the limitations of instant claims 14-22, wherein the human’s urinary protein excretion is decreased after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof, as compared to the human’s urinary protein excretion prior to the daily administration; wherein the human’s urinary albumin excretion is decreased after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof, as compared to the human’s urinary albumin excretion prior to the daily administration; wherein the human’s fractional urine excretion of albumin (FEAIb) is decreased after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof, as compared to the human’s FEAIb prior to the daily administration; wherein the human’s plasma albumin is decreased after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof, as compared to the human’s plasma albumin prior to the daily administration; wherein the human’s urinary protein excretion is <0.3 g/d accompanied by a normal P-albumin concentration, and a normal P- creatinine value after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof; wherein the human’s urinary protein excretion is <0.3 g/d and a 50% or greater reduction from peak values accompanied by an improvement or normalization of the human’s P-albumin concentration, and stable O-creatinine value, after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof; wherein the human’s eGFR calculated from both P-creatinine and P-cystatin C is decreased, after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof; wherein the human’s urinary creatinine clearance (Ccr) is decreased, after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof; wherein the human’s cholesterol is decreased, after 4 weeks of daily administration of the AP1189, or the tautomeric form thereof; are held unpatentable.
Claims 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman), Montero-Mendelez et al. (Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects, 01 April 2015, hereinafter Montero-Mendelez) (in the IDS), Boesen (US 2015/0297672 A1, publication date 22 October 2015) and Ronco et al. (Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care, 16 May 2015, hereinafter Ronco) as applied to claims 1-4 and 12-22 above, and further in view of Waldman et al. (Treatment of Idiopathic Membranous Nephropathy, 2012, hereinafter Waldman).
The teachings of Boman, Montero-Mendelez, Boesen and Ronco are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claims 8-11, the combined teachings of Boman, Montero-Mendelez, Boesen and Ronco, renders the method of treating proteinuria in a human subject having membranous nephropathy, comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, in the claimed range of about 5-400 mg, as in instant claim 1, prima facie obvious.
Boman teaches the compounds of the reference may be administered in conjunction with other therapeutic agents. Boman teaches these agents may be administered separately or concurrently with any other acceptable treatment schedule (Pg. 23, Ln. 36 – Pg. 24, Ln. 2).
Boman, Montero-Mendelez, Boesen and Ronco do not teach administering an ACE-inhibitor or angiotensin II receptor blocker.
Waldman teaches a multicenter study (GLOSEN) wherein patients with nephrotic IMN (idiopathic membranous nephropathy) were treated with ACE inhibitors and/or ARBs in addition to their initial immunosuppressive therapy (Pg. 1618, second column, first full paragraph). Waldman teaches the probability of spontaneous remission was higher in patients taking ACE inhibitors or ARBs than those not receiving these agents (P=0.009) (Pg. 1618, third column, last paragraph). Waldman teaches another study which analyzed patients diagnosed with idiopathic membranous nephropathy between 1997 and 2008. The study indicates almost all patients were treated with ACE inhibitors and/or ARBs (Pg. 1618, third column, first full paragraph). Waldman teaches that owing to the proven benefits of treatment with ACE inhibitors and ARBs in other kidney diseases, these agents should remain as part of standard conservative treatment for IMN (idiopathic membranous nephropathy) (Pg. 1618, third column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Boman, Montero-Mendelez, Boesen, Ronco and Waldman, to have included a patient population that were already being concurrently treated with ACE inhibitors or ARBs (angiotensin II receptor blocker) OR further included administration of ACE inhibitors or ARBs in the method taught by the combined teachings of Boman, Montero-Mendelez, Boesen and Ronco, to arrive at the instant method claims, with a reasonable expectation of success in effectively treating symptoms of membranous nephropathy. combined teachings of Boman, Montero-Mendelez, Boesen and Ronco, renders the method of treating proteinuria in a human subject having membranous nephropathy, comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate, or a tautomeric form thereof (AP1189), in the claimed range of about 5-400 mg, as in instant claim 1, prima facie obvious. Waldman teaches wherein patients with nephrotic IMN (idiopathic membranous nephropathy) were treated with ACE inhibitors and/or ARBs in addition to their initial immunosuppressive therapy. Waldman teaches the probability of spontaneous remission was higher in patients taking ACE inhibitors or ARBs than those not receiving these agents (P=0.009). Waldman teaches a study which indicates almost all patients were treated with ACE inhibitors and/or ARBs who were diagnosed with idiopathic membranous nephropathy between 1997 and 2008. Waldman emphasizes treatment with ACE inhibitors and ARBs should remain as part of standard conservative treatment for IMN agents (idiopathic membranous nephropathy), owing to the proven benefits of these agents.
Therefore, one of ordinary skill in the art would have been motivated to include a patient population that were already being treated with ACE inhibitors or ARBs (angiotensin II receptor blocker) OR further administer ACE inhibitors or ARBs to the treatment regimen. The motivation being to effect some improvement in proteinuria, hypoalbuminemia, and hyperlipidemia treatment (Waldman, Pg. 1618, third column, last paragraph).
Claims 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman), Montero-Mendelez et al. (Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects, 01 April 2015, hereinafter Montero-Mendelez) (in the IDS), Boesen (US 2015/0297672 A1, publication date 22 October 2015) and Ronco et al. (Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care, 16 May 2015, hereinafter Ronco) as applied to claims 1-4 and 12-22 above, and further in view of Stoycheff et al. (Nephrotic Syndrome in Diabetic Kidney Disease: An Evaluation and Update of the Definition, 26 June 2009, hereinafter Stoycheff).
The teachings of Boman, Montero-Mendelez, Boesen and Ronco are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claims 5-7, the combined teachings of Boman, Montero-Mendelez, Boesen and Ronco, renders the method of treating proteinuria in a human subject having membranous nephropathy, comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, in the claimed range of about 5-400 mg, as in instant claim 1, prima facie obvious. Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults (Abstract). Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome; the remainder present with asymptomatic proteinuria (<3·5 g/24 h) and about 60% of them will progress to full nephrotic syndrome (Pg. 1984, first column, first full paragraph).
Boman, Montero-Mendelez, Boesen and Ronco do not teach wherein the human has a U-protein/creatinine ratio >3.5 g/g, U-albumin/creatinine ratio >2.2 g/g and eGFR >30 ml/min/1.73m2.
Stoycheff evaluates the threshold values of the U-protein/creatinine ratio and U-albumin/creatinine ratio for defining the nephrotic-range proteinuria and albuminuria for the discrimination of outcomes of kidney disease (Pg. 840, Abstract; Pg. 841, first column, first full paragraph). Stoycheff teaches the threshold value for the definition of nephrotic range U-protein/creatinine ratio to be 3.5 g/g and U-albumin/creatinine ratio to be 2.2 g/g (Pg. 843, Figure 2). Stoycheff teaches patients with U-protein/creatinine ratio >3.5 g/g, U-albumin/creatinine ratio > 2.2 g/g and e GFR (estimated glomerular filtration rate) > 30 ml/min//1.73m2 (Pg. 844, Table 1).
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Stoycheff teaches threshold values (or cutoff values) to categorize continuous variables can aid in medical teaching and practice by simplifying clinical decision making (Pg. 847, first column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Boman, Montero-Mendelez, Boesen, Ronco and Stoycheff to have included patients exhibiting these baseline characteristics with respect to U-protein/creatinine, U-albumin/creatinine ratio and eGFR (as in instant claims 5-7) in the method of treating proteinuria in a human subject having membranous nephropathy, with a reasonable expectation of success in treating such conditions. Boman in view of Montero-Mendelez, Boesen, Ronco, teaches a method of treating proteinuria in a human subject having membranous nephropathy comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof. Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome in adults. Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome; the remainder present with asymptomatic proteinuria (<3·5 g/24 h) and about 60% of them will progress to full nephrotic syndrome. Stoycheff evaluates the threshold values of the U-protein/creatinine ratio and U-albumin/creatinine ratio for defining the nephrotic-range proteinuria and albuminuria for the discrimination of outcomes of kidney disease. Stoycheff teaches threshold values (or cutoff values) to categorize continuous variables can aid in medical teaching and practice by simplifying clinical decision making.
Therefore, one of ordinary skill in the art would have been motivated to develop a method of treating proteinuria in a human subject having membranous nephropathy comprising orally administering to the human a preferred daily dose of (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, wherein the patients exhibit these baseline characteristics with respect to U-protein/creatinine, U-albumin/creatinine ratio and eGFR (as in instant claims 5-7). The motivation being to devise more effective and specific treatments for patients at varying stages of disease progression and to aid clinical decision making (Stoycheff, Pg. 847, first column, last paragraph).
Claims 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman), Montero-Mendelez et al. (Biased Agonism as a Novel Strategy To Harness the Proresolving Properties of Melanocortin Receptors without Eliciting Melanogenic Effects, 01 April 2015, hereinafter Montero-Mendelez) (in the IDS), Boesen (US 2015/0297672 A1, publication date 22 October 2015) and Ronco et al. (Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care, 16 May 2015, hereinafter Ronco) and Waldman et al. (Treatment of Idiopathic Membranous Nephropathy, 2012, hereinafter Waldman).
Regarding instant claims 23-24, Boman teaches a method of treating a mammal having a disease or disorder selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, said method comprising administering to said mammal a therapeutically effective amount of a compound taught by the reference (Pg. 4, Ln. 35 – Pg. 5, Ln. 3). Boman teaches treatment of diseases related to inflammation of the kidney, specifically, glomerulonephritis (Pg. 31, Lns. 14-19). Boman teaches the mammal to include a human being (Pg. 12, Lns. 1-2). Boman teaches an exemplary compound, compound 2 of the invention 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (Pg. 40, Lns. 20-21; Fig. 1, compound 19), shown below.
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Boman teaches the trans isomeric forms, with trans being the preferred configuration (Pg. 14, Lns. 17-30) (Therefore, Boman anticipates AP1189 of the instant claims in trans (E) form). Boman teaches oral administration of compound 2 to male rats at a dose of 10 mg/kg for a single administration (Pg. 6, Lns. 9-12). Boman teaches the dose of the compound can be adjusted based upon the disease, the administration schedule, whether the compound of the reference is administered alone or in conjunction with other therapeutic agents, the general health of the patient and the like. Boman teaches the compound should be administered in a dose of 0.1 to 100 mg body weight per kilo, if administered via the oral route (Pg. 23, Lns. 10-18) (based on an average human adult weight of 60 kg this dose amounts to a about 6-6000 mg, which encompasses the claimed range of about 5-400 mg). Boman teaches a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods (Pg. 24, Lns. 8-10). Boman teaches administering the dose once daily (Pg. 54, Lns. 20-22; Pg. 54, Lns. 30-33). Boman teaches the compounds act on the MC receptors of the melanocortin system (Pg. 25, Lns. 7-11).
Boman do not teach treating proteinuria in a human having membranous nephropathy and wherein the dosage form comprises an angiotensin II receptor blocker (as in instant claim 23) OR an ACE inhibitor (as in instant claim 24).
Montero-Mendelez teaches AP1189 to be a biased agonist at the MC1 and MC3 receptors that elicits exceptional anti-inflammatory property with a more favorable safety profile, when administered orally in vivo (Abstract; Pg. 3386, first column, last paragraph). Montero-Mendelez teaches AP1189 to be an exceptional therapeutic devoid of side effects (Pg. 3387, second column, last paragraph).
Boesen teaches melanocyte stimulating hormone (MSH) analogues for use in the treatment of inflammatory conditions (Para. [0002]). Boesen teaches analogues with improved activation of the MC1R and/or MC3R melanocortin receptors (Para. [0012]) and methods of treating an individual with a condition responsive at least in part to MC1R and/or MC3R agonism by administration of such peptides (Para. [0013]). Boesen teaches embodiments wherein the condition being treated includes inflammatory conditions of the kidney, especially a glomerular disease of the kidney, for induction of a remission of proteinuria in patients with nephrotic syndrome (Para. [0302]; Para. [0319]; Paras. [0323]-[0324]). Boesen teaches the anti-inflammatory intervention targeting the melanocortin system would benefit from targeting both the MC1R and MC3R (Para. [0358]). Boesen teaches methods comprising the step of administering a therapeutically effective amount of a peptide according to the present invention to an individual in need thereof (Para. [0300]), wherein the individuals in need thereof is a human (Para. [0296]).
Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults (Abstract). Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome; the remainder present with asymptomatic proteinuria (<3·5 g/24 h) and about 60% of them will progress to full nephrotic syndrome (Pg. 1984, first column, first full paragraph). Ronco teaches 70-80% of the cases are primary or idiopathic membranous nephropathy (without any identified cause) (Pg. 1983, first column, first paragraph).
Waldman teaches a multicenter study (GLOSEN) wherein patients with nephrotic IMN (idiopathic membranous nephropathy) were treated with ACE inhibitors and/or ARBs in addition to their initial immunosuppressive therapy (Pg. 1618, second column, first full paragraph). Waldman teaches the probability of spontaneous remission was higher in patients taking ACE inhibitors or ARBs than those not receiving these agents (P=0.009) (Pg. 1618, third column, last paragraph). Waldman teaches that owing to the proven benefits of treatment with ACE inhibitors and ARBs in other kidney diseases, these agents should remain as part of standard conservative treatment for IMN (idiopathic membranous nephropathy) (Pg. 1618, third column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the combined teachings of Boman, Montero-Mendelez, Boesen, Ronco and Waldman, to have arrived at the claimed method of treating proteinuria in a human subject having membranous nephropathy in a human comprising administering a dosage form comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, and an angiotensin II receptor blocker (as in instant claim 23) OR an ACE inhibitor (as in instant claim 24), with a reasonable expectation of success in treating such a condition. Boman teaches a method of treating a mammal having an inflammatory condition, including inflammation of the kidney, say, glomerulonephritis, comprising administering to said mammal a therapeutically effective amount of compound 2 of the invention. Boman teaches compound 2 to be 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate, with the trans isomeric form being the preferred configuration (i.e., AP1189 of the instant claims). Boman teaches a dose of 0.1 to 100 mg body weight per kilo if administered via the oral route (based on an average human adult weight of 60 kg this dose amounts to a dose of 6-6000 mg, which encompasses the claimed range of about 5-400 mg). Boman teaches a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods. Boman teaches administering the dose once daily. Boman teaches the compounds act on the MC receptors of the melanocortin system. Montero-Mendelez teaches AP1189 to be a biased agonist at the MC1 and MC3 receptors that elicits exceptional anti-inflammatory property with a more favorable safety profile, when administered orally in vivo. Montero-Mendelez teaches AP1189 to be an exceptional therapeutic devoid of side effects. Boesen teaches melanocyte stimulating hormone (MSH) analogues for use with improved activation of the MC1R and/or MC3R melanocortin receptors in the treatment of inflammatory conditions. Boesen teaches embodiments wherein the condition being treated includes inflammatory conditions of the kidney, especially a glomerular disease of the kidney, for induction of a remission of proteinuria in patients with nephrotic syndrome. Boesen teaches the anti-inflammatory intervention targeting the melanocortin system would benefit from targeting both the MC1R and MC3R. Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome in adults. Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome; the remainder present with asymptomatic proteinuria (<3·5 g/24 h) and about 60% of them will progress to full nephrotic syndrome. Ronco teaches 70-80% of the cases are primary or idiopathic membranous nephropathy (without any identified cause). Waldman teaches patients with nephrotic IMN (idiopathic membranous nephropathy) treated with ACE inhibitors and/or ARBs in addition to their initial immunosuppressive therapy, had higher probability of spontaneous remission than those not receiving these agents. Waldman teaches inclusion of ACE inhibitors and ARBs as part of standard conservative treatment for idiopathic membranous nephropathy.
Therefore, one of ordinary skill in the art would have been motivated to develop a method of treating membranous nephropathy in a human comprising administering a dosage form comprising (E)-N-trans-{3-[1-(2-nitrophenyl)-1H-pyrol-2-yl-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof, and an angiotensin II receptor blocker (as in instant claim 23) OR an ACE inhibitor (as in instant claim 24), with a reasonable expectation of success in treating such a condition. The motivation being to provide an exceptional therapeutic to reduce proteinuria, devoid of side effects (Montero-Mendelez, Pg. 3387, second column, last paragraph; Waldman, Pg. 1618, third column, last paragraph).
Double Patenting – Maintained and modified
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3 and 12-22 are provisionally rejected on the ground of obviousness type nonstatutory double patenting as being unpatentable over claims 2-3 and 7 of co-pending Application No 17/821,500 in view of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman).
Although the claims at issue are not identical, both sets of claims are drawn to a method of treating a kidney disorder in a human, comprising administering to a subject (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino] guanidine acetate (AP1189).
The instant claims are drawn to a method of treating proteinuria in a human having membranous nephropathy comprising orally administering to the human about 5-400 mg daily of (E)-N-trans- {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-amino guanidium acetate (AP1189), or a tautomeric form thereof.
The claims of the co-pending Application No 17/821,500 are drawn to a method of treating a disease or disorder in a subject in need thereof, said method comprising administering the crystalline form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt according to claim 3 to the subject, wherein claim 3 recites the acetate salt (i.e., AP1189). The claims of the co-pending Application No 17/821,500 further recites treating a kidney disease presenting with proteinuria, or wherein the disease is idiopathic membranous nephropathy (claim 7).
The claims of co-pending Application No 17/821,500 do not teach orally administering to a human about 5-400 mg daily of AP1189.
Boman teaches a method of treating a mammal having a disease or disorder selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, said method comprising administering to said mammal a therapeutically effective amount of a compound taught by the reference (Pg. 4, Ln. 35 – Pg. 5, Ln. 3). Boman teaches treatment of diseases related to inflammation of the kidney, specifically, glomerulonephritis (Pg. 31, Lns. 14-19). Boman teaches the mammal to include a human being (Pg. 12, Lns. 1-2). Boman teaches an exemplary compound, compound 2 of the invention 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (Pg. 40, Lns. 20-21; Fig. 1, compound 19). Boman the trans isomeric forms as the preferred configuration, i.e., AP1189 as instantly claimed (Pg. 14, Lns. 17-30). Boman teaches oral administration of compound 2 to male rats at a dose of 10 mg/kg for a single administration (Pg. 6, Lns. 9-12). Boman teaches the dose of the compound can be adjusted based upon the disease, the administration schedule, whether the compound of the reference is administered alone or in conjunction with other therapeutic agents, the general health of the patient and the like. Boman teaches the compound should be administered in a dose of 0.1 to 100 mg body weight per kilo, if administered via the oral route (Pg. 23, Lns. 10-18). Boman teaches a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but can be determined by persons skilled in the art using routine methods (Pg. 24, Lns. 8-10). Boman teaches administering the dose once daily (Pg. 54, Lns. 30-33). Boman teaches the compounds of the reference act on the MC receptors of the melanocortin system (Pg. 25, Lns. 7-11).
The claims of co-pending Application No 17/821,500 render obvious the instant method claims in view of Boman. The limitations herein with respect to claims 14-22, which recite specific efficacy endpoints or clinical effects are related to the intended effect of the agent, an acetate salt of (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino]guanidine, in the treatment. The administration of the same agent, an acetate salt of (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino]guanidine, at the same dosage in the claimed range (5-400 mg), via the same oral route of administration, to the same patient population, i.e., patients diagnosed with membranous nephropathy, would result in the same pharmacological and clinical effects.
Therefore, the instant claims 1-3 and 12-22 and the claims 2-3 and 7 of the co-pending Application No 17/821,500 are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3 and 12-22 are provisionally rejected on the ground of obviousness type nonstatutory double patenting as being unpatentable over claims 99, 102-103, 118 of co-pending Application No 17/906,375 in view of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman), Boesen (US 2015/0297672 A1, publication date 22 October 2015) and Ronco et al. (Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care, 16 May 2015, hereinafter Ronco).
Although the claims at issue are not identical, both sets of claims are drawn to a method of treating a disorder in a human, comprising orally administering to the human a preferred daily dose of (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino] guanidine acetate (AP1189).
The instant claims are drawn to a method of treating proteinuria in a human having membranous nephropathy comprising orally administering to the human about 5-400 mg daily of (E)-N-trans- {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidium acetate (AP1189), or a tautomeric form thereof.
The claims of the co-pending Application No 17/906,375 are drawn to a method of treating a viral disease or disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, wherein the said compound is (E)-N-trans- {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine (AP1189) acetate (claim 102).
The claim of co-pending Application No 17/906,375 do not teach treating proteinuria in a human having membranous nephropathy.
Boman teaches a method of treating a mammal having a disease or disorder selected from the group consisting of inflammatory conditions, e.g. acute or chronic inflammatory conditions, said method comprising administering to said mammal a therapeutically effective amount of a compound taught by the reference (Pg. 4, Ln. 35 – Pg. 5, Ln. 3). Boman teaches treatment of diseases related to inflammation of the kidney, specifically, glomerulonephritis (Pg. 31, Lns. 14-19). Boman teaches the mammal to include a human being (Pg. 12, Lns. 1-2). Boman teaches an exemplary compound, compound 2 of the invention 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (Pg. 40, Lns. 20-21; Fig. 1, compound 19) (AP1189). Boman teaches the dose of the compound can be adjusted based upon the disease, the administration schedule, whether the compound of the reference is administered alone or in conjunction with other therapeutic agents, the general health of the patient and the like. Boman teaches the compounds act on the MC receptors of the melanocortin system (Pg. 25, Lns. 7-11).
Boesen teaches analogues with improved activation of the MC1R and/or MC3R melanocortin receptors (Para. [0012]) and methods of treating an individual with a condition responsive at least in part to MC1R and/or MC3R agonism by administration of such peptides (Para. [0013]). Boesen teaches embodiments wherein the condition being treated includes inflammatory conditions of the kidney, especially a glomerular disease of the kidney, for induction of a remission of proteinuria in patients with nephrotic syndrome (Para. [0302]; Para. [0319]; Paras. [0323]-[0324]). Boesen teaches the anti-inflammatory intervention targeting the melanocortin system would benefit from targeting both the MC1R and MC3R (Para. [0358]).
Ronco teaches membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults (Abstract). Ronco teaches 60–80% of patients with membranous nephropathy present with nephrotic syndrome; the remainder present with asymptomatic proteinuria (<3·5 g/24 h) and about 60% of them will progress to full nephrotic syndrome (Pg. 1984, first column, first full paragraph). Ronco teaches 70-80% of the cases are primary or idiopathic membranous nephropathy (without any identified cause) (Pg. 1983, first column, first paragraph).
Therefore, the teachings of co-pending Application No 17/906,375 in view of Boman, Boesen and Ronco render obvious the oral administration of (E)-N-trans- {3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidine (AP1189) acetate in a method of treating proteinuria in a human having membranous nephropathy, as instantly claimed. The co-pending application teaches a dosage of 1 mg to 1000 mg of the compound administered as a daily oral dosage. The limitations herein with respect to claims 14-22, which recite specific efficacy endpoints or clinical effects are related to the intended effect of the agent, an acetate salt of (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino]guanidine (AP1189), in the treatment. The administration of the same agent, an acetate salt of (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino]guanidine (AP1189), at the same dosage in the claimed range (5-400 mg), via the same oral route of administration, to the same patient population, i.e., patients diagnosed with membranous nephropathy, would result in the same pharmacological and clinical effects.
Therefore, the instant claims 1-3 and 12-22 and the claims 99, 102-103, 118 of the co-pending Application No 17/906,375 are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicants argue on page 9 of the response dated 12/19/2025, that “Applicant has not considered the substance of either provisional rejection because such an analysis is moot. The present application was filed prior to the filing dates of both U.S. 17/821,500 and U.S. 17/906,375. According to USPTO procedures, the provisional rejections over the later-filed applications must be withdrawn so that the earlier-filed application may proceed to grant.”
Applicant's arguments have been fully considered but they are not persuasive.
Withdrawal of the nonstatutory double patenting rejection will be considered when it is the only rejection remaining and the claims are otherwise allowable. Currently, Applicants have not overcome the 103 rejection of record, as discussed above and the claims stand rejected. Therefore, the provisional nonstatutory double patenting rejections are being maintained.
Conclusion
Claims 1-24 are rejected.
No claims are allowed.
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/P.S.R./Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627