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 .
Receipt is acknowledged of Applicant’s Request for Continued Examination, Affidavit and Amendment filed on 07/28/2026; and IDS filed on 07/28/2026.
Claims 1, 15, 92-97 have been amended.
Claim 6 has been canceled.
Claims 1-3, 7, 9-18, 92-97 are pending in the instant application.
Claims 13-14, 95-97 have been previously withdrawn from consideration.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/28/2026 has been entered.
Declaration under 37 CFR 1.132
The Declaration under 37 CFR 1.132 filed 07/28/2026 is insufficient to overcome the rejection as set forth in the last Office action because of the reasons discussed below in the Response to Argument section.
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 1.321(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 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 §§ 706.07(e) and 714.13.
The USPTO Internet website contains 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 1-3, 7, 9-12, 15-18, 92-94 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending Application No. 19/538,457 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-application recites a method of treating a PSMA expressing cancer in a subject, comprising administering to the subject a combination of a PD-1 inhibitor, a CTLA-4 inhibitor, and a compound of Formula Ia (Compound Ia) wherein Compound Ia is radiolabeled (see claim 1), wherein the PSMA-expressing cancer is a prostate cancer (see claim 5), wherein Compound Ia is radiolabeled with a radionuclide selected from .sup.177Lu and .sup.225Ac. (see claim 8), wherein the amount of the Compound Ia bound to .sup.177Lu that is administered is from about 6.5 GBq to about 8.5 GB (see claim 13), wherein the amount of the Compound Ia bound to .sup.225Ac that is administered is from about 2 MBq to about 3 MBq (see claim 15).
The difference between instant application and the patented claims is that the patent claims include additional limitations. Thus, the invention of the patent is in effect a “species” of the “generic” invention of the application claims. It has been held that the generic invention is “anticipated” by the “species”, and, therefore, the application claims are not patentably distinct from the claims of the patent and are rejected on the ground of nonstatutory obviousness-type double patenting. See In re Goodman, 29 USPQ2d 2010 (Fed. Cir. 1993).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112, 2nd paragraph
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 1 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.
After Applicant’s amendment, claim 1 still recites a few limitations of "Ia-Lu" and “Ia-Ac. There is insufficient antecedent basis for this limitation in the claim.
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.
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) 1-3, 7, 9-12, 15-18, 92-94 is/are rejected under 35 U.S.C. 103 as being unpatentable over FENDLER et al (177Lu-PSMA Radioligand Therapy for Prostate Cancer. Journal of Nuclear Medicine Aug 2017, 58 (8) 1196-1200) in view of MORGENSTERN et al (WO 2018/108287) and MOKHTARI et al (Combination therapy in combating cancer. Oncotarget, 2017, Vol. 8, (No. 23), pp: 38022-38043).
FENDLER teaches a method of treating metastatic castration-resistant prostate cancer (see abstract) comprised of: administering beta-emitter therapy, such as 177Lu-PSMA (see pg. 1197, 1st col), which reads on Applicant’s 177Lu complexed with Formula I, wherein the dosage is 3.5-7.5 GBq (see pb. 1198, under Safety), which reads on Applicant’s range of about 2-8 GBq. Additional disclosures include: alpha-emitter therapy using 225Ac-PSMA-617 has induced promising response (see pg. 1199, 1st col).
FENDLER does not teach administering 225Ac-PSMA-617 in combination with 177Lu-PSMA-617.
MORGENSTERN teaches the prior art had known of using alpha emitter (see [0022]), such as Ac255-PSMA-617 (see [0013]), which reads on Applicant’s 225Ac complexed with Formula I, wherein the dosage is about 7MBq (see [0055]), which is about 4 MBq.
MOKHTARI teaches the prior art had known of combination therapy, a treatment modality that combines two or more therapeutic agents, is a cornerstone of cancer therapy. The amalgamation of anticancer drugs enhances efficacy compared to the mono-therapy approach because it targets key pathways in a characteristically synergistic or an additive manner (see abstract). A lower therapeutic dosage of each individual drug is required (see pg. 38023, 1st col).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate administering 225Ac-PSMA-617 in combination with 177Lu-PSMA-617. The person of ordinary skill in the art would have been motivated to make those modifications, because it would have an additive effect in treating metastatic castration-resistant prostate cancer, and reasonably would have expected success because both compounds treat metastatic castration-resistant prostate cancer.
The references do not specifically teach the exact amounts of therapeutic agents or administration times as claimed by Applicant. The amount of a therapeutic and administration times in a method of treating prostate cancer is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of active agent and administration times in order to best achieve the desired results, such as effective treatment of the cancer and decrease of adverse effects, especially as discussed above, MOKHTARI teaches lower therapeutic dosage of each individual drug is required (see pg. 38023, 1st col). Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of active agent amounts and administration times would have been obvious at the time of Applicant's invention.
Note, Applicant’s specification provides no experimental data, but only a prophetic example (see Applicant’s only example at [0221]) stating: “Patients with PSMA positive scans will be administered a single dose of Compound Ia-Ac on day 1, cycle 1 of the clinical regimen of 7.4 GBq Compound Ia-Lu, administered 6 weekly for a maximum of 5 cycles. Subjects will be reviewed weekly for assessment of adverse events (onset, duration, grade and relatedness to treatment) during cycle 1 only. DLT will be determined by AE on cycle 1 only”.
Response to Arguments
Applicant argues that a Declaration under 3 7 C.F .R. § 1.132 of Dr. Fatima Rangwala that refers to data from Meyer et al., Widjaja et al., and from Sheikh et al. that provides data corresponding to the claimed treatment methods. In addition, Applicants respectfully assert that the data described in Dr. Rangwala's declaration demonstrates either (1) greater than expected results ( e.g., maintained efficacy with decreased dosage), and/or (2) absence of an expected property (e.g., xerostemia). See MPEP 716.02(a)(I) and (IV). As declared by Dr. Rangwala, Meyer examines the effect of combining 225 Ac and 177Lu. See Declaration, ,i 8. While Meyer notes that 225 Ac is attractive because of its higher energy, "the same radiobiologic features that make 225 Ac attractive against tumors also present a tradeoff at the expense of higher-grade toxicities." (Meyer p. 1773, left column). Further, Meyer states that the "most significant adverse effect of a-particle PSMA-targeted radionuclide therapy with small molecules ... is xerostomia, making the salivary glands a key dose-limiting organ." Id Dr. Rangwala further describes the data in Meyer that is provided by the claimed method of the above-captioned application. See Declaration, ,i 9. According to Dr. Rangwala, Meyer describes the comparison between three different dosing regimens: (1) 177Lu-PSMA-617, (2) 225Ac-PSMA-617, and (3) a combination of 177Lu-PSMA-617 and 225Ac-PSMA-617. For dosing regimen (3), the amount of each of 177Lu-PSMA-617 and 225 Ac-PSMA-617 was half as much as the individual doses from regimen (1) and (2). As shown in Fig. 4 of Meyer, the difference between regimen (2) and regimen (3) was not statistically significant, with a p value of0.108 (left, see also caption for Fig. 4) for the group treated three weeks after inoculation (see caption for Figure 4) and a p value of 0.171 (right, see also caption for Fig. 6) for the group treated five weeks after inoculation. In other words, Meyer provides that combining the two therapies, but administering a lower amount of each, provided a similar therapeutic benefit as administering 225 Ac-PSMA-617 alone. See Declaration ,i 10. However, as noted by Dr. Rangwala, "the treatment of 225 Ac-PSMA-617 alone was known to cause undesirable incidences of xerostomia." Id., (emphasis in original) Dr. Rangwala further describes data for the combination therapy of 177Lu and 225 Ac for treating prostate cancer that was published in Widjaja and Sheikh. See Declaration ,i,i 11-13. As noted in the Declaration, the "PSMA" used in Sheikh and Widjaja was PSMA I&T, which is described along with PSMA-617 in Fendler. See Fendler, p. 1197, left column. As described by Dr. Rangwala, Widjaja discloses that "[t]andem approaches combining [177Lu]Lu-PSMA and Actinium-225 ([225 Ac]Ac)-PSMA may offer safety and efficacy by exploiting both radionuclides." Widjaja at p. 2. To investigate this, Widjaja describes retrospective study of 23 patients that had metastatic castration resistant prostate cancer (mCRPC) and were treated with a tandem therapy of 1.982 ± 1.434 MBq of 177Lu-PSMA and 5.95 ± 1.56 MBq of 225Ac-PSMA. See, id at p. 3. The treated patients experienced a median PSA reduction of -12.35% after two treatment cycles. See id at p. 4. The tandem therapy was also "generally well tolerated." Id As explained by Dr. Rangwala, Widjaja describes that the "dual radiotherapeutic approach may offer a favorable safety profile, while preserving the potent therapeutic efficacy associated with targeted alpha and beta therapy." Id at p. 7 (emphasis added). The increase in tolerability is important because, as noted by Widjaja, "the intensified radiation from Actinium-225 comes at the cost of increased toxicity, including a higher incidence of [chronic kidney disease] and hematological adverse events." Id at 7. Widjaja concludes that "The combined use of the a-emitting Actinium-225 and the ~--emitting Lutetium-177 appears to offer a synergistic therapeutic effect leading to high efficacy and safety of tandem RLT." Id at p. 9, (emphasis added). As declared by Dr. Rangwala, the data in Widjaja of "the combined use of the a-emitting Actinium-225 and the ~-emitting Lutetium-177 indicates a synergistic therapeutic effect." Declaration, ,i 15, (emphasis in original). Dr. Rangwala further declares that this therapeutic effect "is further supported by the data in Meyer, which shows that even while administering half the amount of each of Actinium-225 and Lutetium-177, the efficacy of the therapy was maintained while the side effects were decreased." Id, (emphasis in original). Dr. Rangwala thus concludes that' [t]hese results, from both mice and humans, show that the tandem therapy recited in the claims of the above-captioned application provide a significant and practical advantage over the results provided in the art cited in the Office Action.
The Examiner finds this argument unpersuasive, because the discovery of the alleged synergistic amounts by Meyer et al., Widjaja et al., and Sheikh et al could be allowable for these authors; however, Meyer et al., Widjaja et al., and Sheikh et al are not inventors in the instant application. Additionally, Applicant’s claims are broader in scope of the claimed amounts versus the synergistic amounts disclosed in Meyer et al., Widjaja et al., and Sheikh et al.
Telephonic Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAKE MINH VU whose telephone number is (571)272-8148. The examiner can normally be reached Mon-Fri 9:00am-5:30pm.
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/JAKE M VU/Primary Examiner, Art Unit 1618
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