DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1, 4, and 7-23 are pending in this application.
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 .
Continued Examination Under 37 CFR 1.114
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 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 27 Oct. 2025 has been entered.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 27 Oct. 2025 has been considered by the examiner.
Response to Amendment
The amendments filed on 27 Oct. 2025 have been entered.
The declaration under 37 CFR 1.132 filed 27 Oct. 2025 is insufficient to overcome the rejection of claims as set forth in the last Office action because of the reasons set forth below.
Dr. Pullen declares that Fig. 1 illustrates 177Lu-PSMA-617 biodistribution across a number of sample tissues including tumor tissue at 1-, 2-, 4-, 24-h, and 7-d timepoints. The tumor uptake (%ID/g) at each these timepoints was approximately 15%, 11%, 16%, 10%, and 2%, respectively. Figure 2 illustrates 177Lu-NG-002 biodistribution across a number of sample tissues at 1-, 4-, 24-, 48-h and 7-d timepoints. The tumor uptake (%ID/g) at each of these timepoints was approximately 20%, 17%, 21%, 8%, and 2%, respectively. NG-002 exhibited a higher and faster tumor accumulation from 1 to 24 h than PSMA-617. The two-fold increase of tumor uptake at 24 h by NG-002 compared to PSMA-617 was unexpected and will likely lead to increased efficacy. This property is particularly important for therapeutic radioisotopes with short half-lives such as 212Pb and 177Lu, as it allows for more irradiation of the tumor before the radioligand is cleared from the patient or decays.
The Dr. Pullen declaration filed 17 Oct. 2025 have been fully considered but it is not persuasive. Wüstemann provides for the 177Lu-PSMA 617 (DOTA) and the 177Lu-PSMA-CHX-A’’-DTPA. The 177Lu-PSMA 617 differs from the claimed invention by omitting a p-SCN-Bn- linker residue. The 177Lu-PSMA-CHX-A’’-DTPA differs from the claimed invention by chelator substitution. Wüstemann describes the PSMA-CHX-A’’-DTPA compound as an improvement over the PSMA 617 because the PSMA-CHX-A’’-DTPA compound demonstrated excellent tumor uptake and retention. Regarding the p-SCN linker residue, at pg. 1092, Wüstemann teaches that the two components known to define the performance of PSMA tracers are the Glu-urea-based binding motif causing receptor binding and the spacer mediating a secondary interaction with the lipophilic surface next to the zinc containing binding pocket. Figure 5 describes the p-SCN-Bn- linker moiety as providing a pharmacokinetic enhancement. Fig. 2D compares a PSMA-DTPA without the p-SCN-Bn- linker moiety with the PSMA-CHX-A’’-DTPA with the p-SCN-Bn where the PSMA-CHX-A’’-DTPA exhibited a superior ratio of internalization. At pg. 1093, Wüstemann teaches that increasing hydrophobicity correlates with higher internalization. This indicates specific interactions of the residues in CHX-A’’-DTPA to the receptor in the process of internalization. Regarding chelator substitution, at for example abstract, Wüstemann teaches conjugation of different chelators did not cause significant difference: all compounds showed nanomolar binding affinity with only minor differences. The Pullen declaration does not contain a comparison with the PSMA-CHX-A’’-DTPA described as the best compound in Wüstemann and as an improvement over the PSMA-617 with respect to tumor uptake. Applicants must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). The test must be sufficient to permit a conclusion respecting the relative effectiveness of applicant’s claimed compounds and the compounds of the closest prior art. See In re Johnson, 747 F.2d 1456, 1461, 223 USPQ 1260, 1264 (Fed. Cir. 1984).
Based on the cited teachings in Wüstemann, a person of ordinary skill in the art would have expected that the incorporation of a hydrophobic p-SCN-Bn linker moiety into the PSMA-617 would lead to an improvement in tumor uptake. Expected beneficial results are evidence of obviousness of the claimed invention. See In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). All of the CHX-A’’DTPA, PCTA, and oxo-DO3A compounds comprising the p-SCN-Bn- linker demonstrated an improved ratio of internalization over PSMA 617 compound without the p-SCN-Bn- linker.
The Pullen declaration only compares 177Lu-NG-002 (p-SCN-Bn-DOTA-ligand 2); however, claim 1 claims a complex of p-SCN-Bn-DOTA-ligand 2 with a radionuclide selected from 212Pb, 212Bi, 213Bi, 225Ac, 227Th, and 177Lu. Claim 13 allows for a complex with any radionuclide. The combination of different claimed radiometals with the claimed ligand would be expected to show significant variations in tumor uptake owing to at least differences in kinetic and thermodynamic stabilities of the complexes. Alpha-emitting radiometals exhibit a well-known recoil energy. In other words, a for example a 227Th-NG-002 cannot exhibit an improved tumor uptake at 24-h or improved PSMA therapy if the 227Th rapidly and/or substantially disassociates from 227Th-NG-002.
Response to Arguments
Claim Rejections - 35 USC § 103
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.
Claim(s) 1, 4, and 7-20 s/are rejected under 35 U.S.C. 103 as being unpatentable over Wüstemann et al. (Theranostics; published 28 Apr. 2016), in view of Larsen (WO 2016/135200 A1; published 1 Sep. 2016) and Ray et al. (WO 2015/171792 A1; published 2015) for the reasons cited in the Office action filed on 25 Apr. 2025.
Claim(s) 21-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wüstemann et al. (Theranostics; published 28 Apr. 2016), in view of Larsen (WO 2016/135200 A1; published 1 Sep. 2016) and Ray et al. (WO 2015/171792 A1; published 2015) for the reasons cited in the Office action filed on 25 Apr. 2025.
Applicants Arguments
Applicants assert that the cited references fail to teach the claimed complex with reasonable expectation of success. Wüstemann does not teach the claimed p-SCN-Bn-DOTA complex because the compounds taught by Wüstemann, 177Lu-PSMA-617, does not contain a p-SCN-Bn-linker. Wüstemann fails to teach that any improvement is due to the substitution of the DOTA moiety with a p-SNC-Bn-DOTA moiety. For the three compounds comprising the p-SCN-Bn moiety, Fig. 5 show that their rate of internalization is completely different. The oxo-DO3A and PCTA derivatives were found to have a ratio of internalization of only ~25% and ~35% respectively, compared to CHX-A’’DTPA which had >60% internalization rate. Wüstemann would not motivate a person of ordinary skill in the art to select the p-SCN-Bn as this group has not been shown to be responsible for the improved internalization of CHX-A’’-DPTA. Larsen would not motivate a person of ordinary skill to select the p-SCN-Bn-DOTA moiety include in a complex. Ray does not teach or suggest the presently claimed complex. While Ray teaches that 86Y-6 (contains a p-SCN-Bn- moiety) demonstrated a desired lower kidney uptake and higher tumor retention required for radiotherapy, Ray teaches that 86Y-6 had a significantly lower binding affinity than 86Y-4 and 86Y-5. Ray does not teach or suggest to a person of ordinary skill in the art to select the p-SCN-Bn linker over other compounds. The claimed complex exhibits unexpected, superior results. As provided in the Pullen declaration, whiled both radioligands displayed rapid tumor accumulation, the NG-002 compound displayed superior tumor retention over 24 h with about 21% tumor uptake at 24 h. In contrast, the PSMA-617 compound exhibited much lower tumor uptake in the first 24 h, with only ~10% uptake in the tumor at 24 h. NG-002 showed unexpectedly high uptake in PSMA expressing tumors, indicating higher PSMA targeting in vivo than PSMA-617.
Applicant’s arguments filed 27 Oct. 2025 have been fully considered but they are not persuasive. The Pullen declaration is ineffective for the reasons discussed above. Wüstemann provides for the PSMA-CHX-A’-DTPA comprising the p-SCN-Bn- linker described as an improvement over PSMA 617 with respect to tumor uptake. Wüstemann describes the PSMA-CHX-A’-DTPA compound as the best compound. At Fig. 5, Wüstemann teaches that that the p-SCN-Bn- linker provides an advantageous pharmacokinetic enhancement. At Fig. 2D, Wüstemann compares the PSMA-CHX-A’-DTPA comprising the p-SCN-Bn- linker with the PSMA-DTPA without the p-SCN-Bn- linker and demonstrated that PSMA-CHX-A’-DTPA exhibited improved internalization. At pg. 1093, Wüstemann teaches that increasing hydrophobicity correlates with higher internalization and this indicates specific interactions of the residues in CHX-A’’-DTPA to the receptor in the process of internalization. A recognized advantage is the strongest reason to combine. When the record establish[ed] such a strong case of obviousness, allegedly unexpectedly superior results are ultimately insufficient to overcome obviousness conclusion. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007). From Wüstemann alone, it would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Wüstemann by incorporating the p-SCN-Bn- linking moiety in PSMA 617 because the incorporating would have been expected to advantageously enable a pharmacokinetic enhancement and an improved tumor uptake and retention. Larsen and Ray were cited for teaching and motivation 212Pb complexation with a reasonable expectation of success. Larsen teaches that 212Pb advantageously enables alpha therapy. Ray teaches and suggests that p-SCN-Bn-DOTA advantageously enables metal complexes where the metal is 177Lu, 225Ac, or 203/212Pb. A purpose and motivation of Wüstemann was provide a PSMA-617 derivative having a chelator capable of stably chelating several radiometals that can be used for diagnostic and therapeutic purposes including alpha therapy. In Wüstemann, chelator substitution of the PSMA 617 did not significantly change binding affinity. It would have been additionally obvious to a person of ordinary skill in the art before the effective filing date to modify Wüstemann by incorporating the p-SCN-Bn- linker in PSMA 617 because the incorporating would have been expected to enable a PSMA 617 chelator derivative advantageously capable of stably chelating several useful radiometals including metals suitable for alpha therapy.
Double Patenting
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 1.321which 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07which and 714.13.
The USPTO Internet website 9ontainns terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 4, and 7-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 12,297,218 B2, in view of Larsen et al. (WO 2016/135200 A1; published 1 Sep. 2016) and Ray et al. (WO 2015/171792 A1; published 2015) for the reasons cited in the Office action filed on 25 Apr. 2025. Note that claims 2-21 of co-pending application No. 18/505,688 issued into the above patent.
Claims 1, 4, and 7-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10,377,778 B2, in view of Larsen et al. (WO 2016/135200 A1; published 1 Sep. 2016) and Ray et al. (WO 2015/171792 A1; published 2015) for the reasons cited in the Office action filed on 25 Apr. 2025.
Applicants Arguments
Applicants request reconsideration in view of the above remarks.
Applicant’s arguments filed 27 Oct. 2025 have been fully considered but they are not persuasive. The Pullen declaration is ineffective for the reasons discussed above. Copending application ‘688 and patent ‘778 each claim the p-SCN-Bn-TCMC PSMA ligand 1. The Pullen declaration does not contain a comparison with the claimed p-SCN-Bn-TCMC PSMA ligand 1. Larsen and Ray are deficient in view of the above remarks.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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 SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618