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
Claims 1-24 are pending as of the response filed on 05/14/2026. Claims 1-24 are examined herein.
Applicant’s submission of a declaration under 37 C.F.R. 1.132 dated 05/14/2026 is acknowledged. Applicant’s declaration states that at the time of the instant invention, treatment of kidney disease and proteinuria was correlated with increased cAMP generation, not only with respect to melanocortin receptor agonism (Boesen) but also with respect to the use of other agents, such as phosphodiesterase inhibition in the treatment of proteinuria (Omori, Chen) or in the use of prostacyclin analogues in their protective action against renal injury (Yano, Nasrallah). Applicant’s declaration states that while Montero-Mendelez teaches AP1189 to be a biased agonist of the MC1R and/or MC3R, AP1189 does not activate the signaling pathway that results in increased cAMP. Applicant concludes, therefore a PHOSITA would not have had a reasonable expectation of success in treating proteinuria in patients having membranous nephropathy with AP1189. Applicant’s remarks in the declaration was found to be persuasive.
Applicant’s arguments have been carefully considered and were found to be persuasive. Applicant’s emphasis of the fact that at the time of the instant invention, increased cAMP was widely correlated with reduced proteinuria and agents that failed to raise cAMP would not have been predicted to treat proteinuria, was found to be persuasive.
The 35 U.S.C. §103 rejections of previous record is hereby withdrawn in consideration of the submitted declaration and Applicant’s arguments.
In view of the pending claims, the following nonstatutory double patenting rejection is maintained and updated (co-pending Application No 17/821,500 is now, issued patent no US 12,661,336 B2). Since the basis of the nonstatutory double patenting rejection has been changed, this action is non-final.
Information Disclosure Statement
The information disclosure statement submitted on 05/14/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 1-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 6 of US Patent No 12,661,336 B2 in view of Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman, in the IDS), Waldman et al. (Treatment of Idiopathic Membranous Nephropathy, 2012, hereinafter Waldman, of previous record) and Stoycheff et al. (Nephrotic Syndrome in Diabetic Kidney Disease: An Evaluation and Update of the Definition, 26 June 2009, hereinafter Stoycheff, of previous record).
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}-aminoguanidium acetate (AP1189), or a tautomeric form thereof.
The claims of the reference ‘336 patent are drawn to a method of treating a disease or disorder, say a kidney disease (as one option), in a subject in need thereof, said method comprising administering a crystalline form of the N-{3-[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylidene}-aminoguanidinium salt to the subject, wherein the salt is an acetate salt (i.e., AP1189) form A (claims 1-2). The claims of the reference ‘336 patent further recites treating a kidney disease presenting with proteinuria, or wherein the disease is idiopathic membranous nephropathy (claim 6).
The claims of the reference ‘336 patent 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) (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) and administering the compound for up to 32 days (i.e., about 4 weeks) (Pg. 54, Ln. 23). Boman teaches the compounds of the reference act on the MC receptors of the melanocortin system (Pg. 25, Lns. 7-11).
The claims of the reference ‘336 patent render obvious the instant method claims 1-3 and 12-13, 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 over a period of 4 weeks.
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 claims of the reference ‘336 patent in view of Boman 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), as in instant claim 1, prima facie obvious. The administration of the same agent, an acetate salt of (E)-N-[1-(2-nitrophenyl)-1H-pyrrol-2-yl-allylideneamino]guanidine (i.e., AP1189), at a dosage in the claimed range, via the same oral route of administration, to the same patient population, i.e., patients diagnosed with membranous nephropathy, for the same duration (4-weeks), would result in the same pharmacological and clinical effects.
The claims of the reference ‘336 patent do not teach wherein the human is anti-PLAR2-Receptor positive.
Waldman teaches autoantibodies reactive to PLA2R are both sensitive and specific for idiopathic membranous nephropathy, autoantibodies seem to discriminate between primary and secondary forms of membranous disease, and there seems to be a relationship between the titer of circulating anti-PLA2R and clinical disease activity defined by proteinuria (Pg. 1617, second column, last paragraph). Waldman teaches measurement of circulating anti-PLA2R and other antibodies may be used in conjunction with proteinuria to better assess disease activity and provide a more informative definition of clinical remission (Pg. first column, continued paragraph). Therefore, the method of the reference ‘336 patent in view of Waldman, render the patient population wherein the human is anti-PLAR2-Receptor positive, prima facie obvious (instant claim 4).
The claims of the reference ‘336 patent do not teach combination therapy with an ACE-inhibitor or angiotensin II receptor blocker as in instant claims 8-11 and 23-24.
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). 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). Therefore, the method of the reference ‘336 patent in view of Boman and Waldman, render the combination therapy in the treatment of membranous nephropathy, prima facie obvious (instant claims 8-11, 23-24).
The claims of the reference ‘336 patent 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 as in instant claims 5-7.
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). 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). Therefore, the method of the reference ‘336 patent in view of Stoycheff, render the method of treatment of the instant claims wherein the patient exhibits baseline characteristics with respect to U-protein/creatinine, U-albumin/creatinine ratio and eGFR (as in instant claims 5-7), prima facie obvious.
Therefore, instant claims 1-24 and claims 1-2 and 6 of the reference ‘336 patent are not patentably distinct.
This is a nonstatutory double patenting rejection.
Allowable subject matter
Except for the nonstatutory double patenting rejection discussed above, all claims would be allowable.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art of record is Boman et al. (WO 2007/141343 A1, publication date 13 December 2007, hereinafter Boman, in the IDS), 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) and Boesen (US 2015/0297672 A1, publication date 22 October 2015, of previous record).
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 phenyl pyrrole aminoguanidine derivative, with 3-{[1-(2-nitrophenyl)-1H-pyrrol-2-yl]-allylideneamino}guanidinium acetate (i.e., AP1189) exemplified. Boman teaches treatment of diseases related to inflammation of the kidney, specifically, glomerulonephritis.
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. Montero-Mendelez teaches that AP1189 does not provoke canonical cAMP generation but induces alternative pathways of ERK1/2 phosphorylation and Ca2+ mobilization.
Boesen teaches melanocyte stimulating hormone (MSH) analogues for use in the treatment of inflammatory conditions. Boesen teaches analogues with improved activation of the MC1R and/or MC3R melanocortin receptors 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. 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. The MSH analogues of Boesen are taught to elicit their antiproteinuric effects via an increase in intracellular cAMP levels.
The prior art of record does not teach or suggest an antiproteinuric effect driven by melanocortin receptor agonism, with compounds that bind MC1R or MC3R but do not stimulate cAMP signaling. Therefore, the instant method claims are novel and non-obvious over the closest prior art.
Conclusion
Claims 1-24 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PADMAJA S RAO whose telephone number is (571)272-9918. The examiner can normally be reached 9:00-5:30 pm EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PADMAJA S RAO/Examiner, Art Unit 1627
/Kortney L. Klinkel/Supervisory Patent Examiner, Art Unit 1627
Prosecution Insights