PARA-AMINOHIPPURIC ACID (PAH) AS A RENAL PROTECTIVE SUBSTANCE

§103 §112

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 . Acknowledgments and Claim Status The Examiner acknowledges receipt of the amendment filed 8/20/2026 wherein claims 1-30, 32, 33, and 42 were canceled. Note(s): Claims 31, 34-41, and 43-45 are pending. Priority and Priority Document This application is a 371 of PCT/EP2020/062950 filed 5/8/2020 and claims priority to PCT/EP2019/061882 filed 5/8/2019. Note(s): The earliest effective filing date is 5/8/2019 as the parent applications fully support the claimed invention. Once again, receipt of the certified priority document filed 11/4/2021 is acknowledged as required by 37 CFR 1.55. Response to Applicant’s Amendment and/or Arguments The Applicant's arguments and/or amendment filed 8/20/2026 to the rejection of claims 31, 34-41, and 43-45 made by the Examiner under 35 USC 112 have been fully considered and deemed persuasive because Applicant amended the claims to overcome the rejection. Therefore, the said rejection is hereby WITHDRAWN. Applicant’s Invention The pending invention is directed to a method of reducing nephrotoxicity of a radiopharmaceutical in a subject comprising administering a pharmaceutical composition comprising a para-amino hippuric acid (PAH) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent, carrier or a combination thereof, to the subject prior to, during, or after administering the radiopharmaceutical to the subject, wherein the radiopharmaceutical in said subject is a radionuclide containing conjugate molecule comprising a carrier molecule, a chelator, and a radionuclide. Information Disclosure Statements The information disclosure statements filed 7/30/2026 and 9/1/2026 were considered. NEW GROUNDS OF REJECTION 112 Second Paragraph Rejections The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claim 44 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 44: The claim recites the limitation "the therapeutic and/or diagnostic compound(s)" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. 103 Rejection In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. The 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. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 31, 34-41, and 43-45 are rejected under 35 U.S.C. 103 as being unpatentable over Dowling (US 2015/0099270) in view of Lambert et al (Radiation Research, 2004, Vol. 161, pages 607-611). Independent claim 31 is directed to a method of reducing nephrotoxicity of a radiopharmaceutical in a subject comprising administering a pharmaceutical composition comprising a para-amino hippuric acid (PAH) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent, carrier or a combination thereof, to the subject prior to, during, or after administering the radiopharmaceutical to the subject, wherein the radiopharmaceutical in said subject is a radionuclide containing conjugate molecule comprising a carrier molecule, a chelator, and a radionuclide. Claim 34 is directed to the method according to claim 31 wherein the carrier molecule is selected from peptides, peptidomimetics, small molecules, and knottins. Claim 35 is directed to the method according to claim 34 wherein the carrier molecule is selected from somatostatin analogues, prostate-specific membrane antigen (PSMA)-inhibitors, gastrin analogues, integrin binding molecules and folates. Claim 36 is directed to the method according to claim 35 wherein the carrier molecule is selected from Tyr3-octeotride, Tyr3-octreotate, JR11, PSMA-11, Sargastrin, RGD and folate. Claim 37 is directed to the method according to claim 31 wherein the chelator is selected from DOTA, HBED-CC, NOTA, NODAGA, DOTAGA, DOTAM, TRAP, NOPO, PCTA, DFO, DTPA, DO3AP, DO3APrA, DO3APABn, and HYNIC. Claim 38 is directed to the method according to claim 31 wherein the radionuclide is selected from 94Tc, 99mTc,901n,111in,67Ga, 68Ga, 86Y,90Y,177Lu, 186Re, 188Re, 64Cu, 67Cu, 55Co,57Co,43Sc,44Sc,47Sc,225Ac,213Bi,212Bi,212Pb,227Th,153Sm,166Ho, 166Dy, 18F, and 131I. Claim 39 is directed to the method according to claim 38 wherein the radionuclide is selected from177Lu, 225Ac and 68Ga. Claim 40 is directed to the method according to claim 31 wherein the radionuclide containing conjugate molecule is selected from [177Lu-DOTA°-Tyr3]-octreotide, 177Lu-DOTA- JA11, 177Lu-DOTA-RGD, 177Lu-DOTA-Sargastrin, 68Ga-HBED-CC-PSMA-11,177Lu- PSMA I&T and 99mTc-Etarforlatide. Dowling is directed to a method of screening pharmaceuticals for drug interactions and nephrotoxicity. In particular, the invention is directed to a method of determining nephrotoxicity of pharmaceuticals by conducting a metabolite formation study in cells using PAH (see entire document, especially, abstract; page 2, paragraph [0025]; page 10, claims 1, 14, 15, and 19). Determination of in vivo interactions involve two drugs sharing a common metabolic or transporter pathway and that they will have a clinically significant pharmacokinetic interaction when co-administered to a patient (page 3, paragraph [0028]). Thus, the skilled artisan would be motivated to administer PAH in combination with another substance to evaluate nephrotoxicity. The nephrotoxicity may be screened using various classes of substances/drugs including dietary supplements (e.g., vitamins) and amifostine (page 3, paragraphs [0029] and [0030], line 17). Dowling discloses various embodiments wherein PAH is used in combination with a drug/substance (page 7, paragraphs [0058], [0060], 0061], [0063] and [0064]). In one embodiment, nephrotoxicity is determined and comprises PAH and evaluating a control and treatment group (page 7, paragraph [0061]). In another embodiment, PAH and a diagnostic agent are administered to a human and evaluating glomerular infusion rate (page 7, paragraph [0063]). Thus, based on the teachings of Dowling, it would have been obvious to a skilled artisan to administer PAH and a diagnostic agent to a subject to evaluate nephrotoxicity. In Example 3, a cell culture was incubated with 200 µg/ml of PAH for 4, 8, and 18 hours and evaluated (page 8, paragraph [0066]) and PAH metabolism experiments were performed (page 8, paragraph [0092]). In another embodiment, priming doses were administered over 5 minutes at 2 ml (456 mg) and 1 ml (200 mg) for iothalamate and PAH, respectively. While Dowling disclose that it is well known in the art to use PAH to evaluate nephrotoxicity and that PAH may be co-administered with a diagnostic substance, the document does not disclose the multitude of possible diagnostic agents that may be utilized. However, Lambert et al is directed to well-known substances used in the art to evaluate nephrotoxicity after radionuclide therapy. Lambert et al disclose that a variety of radiolabeled monoclonal antibodies, antibody fragments, and low molecular weight oncophilic peptides have been used to deliver radioactivity to targets cells for therapeutic purposes. In particular, radiolabeled peptides such as yttrium-90 labeled synthetic somatostatin analogues are utilized. In general, the toxicity risk seem too dependent on the characteristics of the oncophilic molecules (see entire document, especially abstract). Therapeutic approaches targeting somatostatin receptors involved the use of 90Y conjugated via tetra-azacyclododecane-tetra-acetic acid (DOTA) to Tyr3-octreotide (90Y-DOTATOC) or to lanreotide (90Y-DOTALAN) and 177Lu[Tyr-3]octreotate )177Lu-DOTATATE). However, the substance may induce nephrotoxicity after radionuclide therapy (pages 607-608, bridging paragraph). Lambert et al disclose that in one embodiment 177Lu-DOTA-Tyr3-octreotate was administered concomitant with amino acids to 35 patients (page 609, right column, lines 4-10). Both PAH and the conjugates comprising a carrier molecule, chelator, and radionuclide (e.g., 90Y-DOTATOC, 90Y-DOTALAN, and 177Lu-DOTATATE) are used for evaluating nephrotoxicity in a subject. According to MPEP 2144.06, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third compositions to be used for the very same purpose. Specifically, the idea of combining the two compositions flows logically from their having ben individually taught in the prior art. For the reasons set forth supra, the limitations of claims 31 and 34-40, and 43-45 are met. Claim 41 is directed to the method according to claim 31 further comprising administering a further substance which reduces nephrotoxic side effects of the radiopharmaceutical to the subject wherein the further substance is selected from the group consisting of amino acids, gelatine, amifostine, albumin-derived peptides, prostate-specific membrane antigen (PSMA)-binding molecules, and vitamins. In regard to claim 41, Lambert et al disclose that 177Lu-DOTA-Tyr3-octreotate was administered in combination with an amino acid. Thus, the combination of (1) PAH, (2) a carrier molecule, chelator, and radionuclide complex (e.g., 177Lu-DOTA-Tyr3-octreotate), and (3) an amino acid(s) (see Lambert et al discussion supra), amifostine, and/or vitamins would be optional components that may be present in the composition because those substances are utilized with the PAH or carrier molecule, chelator, and radionuclide complex of Dowling and Lambert, respectively. Claim 43 is directed to the method according to claim 31 wherein PAH or a pharmaceutically acceptable salt is administered in an amount of 5 mg to 500 mg per kilogram of body weight. Claim 44 is directed to the method according to claim 31 wherein the therapeutic and/or diagnostic compound or compounds and PAH or a pharmaceutically acceptable salt are administered in a ratio of from 1/240000 to 1/8000 (w/w). In regard to claim 43, Dowling disclose various embodiments wherein the amounts of PAH utilized varies. In particular, in Example 6 (paragraph [0104]), Dowling disclose that PAH in an amount of 200 mg was administered with iothalamate (a diagnostic) agent. Thus, the limitation of claim 43 is met. In addition, in regard to claims 43 and 44, the skilled artisan would recognize that it would be obvious to optimize the amount of therapeutic or diagnostic compound(s) based on the weight as according to MPEP 2144.05, where 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. Claim 45 is directed to the method according to claim 31 wherein the pharmaceutically acceptable salt of PAH is amino hippurate sodium. In regard to claim 45, it is duly noted that Dowling does not specifically state that one may have the salt of PAH. However, at no point does the reference indicated that it is limited to PAH only and not derivatives (e.g., salts and metabolites) thereof. In particular, Dowling disclose that one may evaluate PAH metabolites (page 2, paragraph [0022]). According to MPEP 2131.02, a reference does not have to expressly spell out the limitation that salts of PAH are included if a person of ordinary skill in the art reading the reference can envisage the presence of PAH substances in general which would include derivatives (salts) of PAH. For the reasons set forth supra, the limitations of claims 41 and 43-45 are met. Comments/Notes In claim 39, line 2, ‘225AC’ should be ‘225Ac’. In claim 34, line 2, the term ‘knotting’ should be ‘knottin’. Conclusion Claims 31, 34-41, and 43-45 are rejected. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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. Note(s): The scope of the pending claims was once again amended. Future Correspondences Any inquiry concerning this communication or earlier communications from the examiner should be directed to D L Jones whose telephone number is (571)272-0617. The examiner can normally be reached M-F. 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, Michael G. Hartley can be reached at (571)272-0616. 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. /D. L. Jones/ Primary Patent Examiner Art Unit 1618 October 6, 2026