DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-14, 16, and 19-23 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 .
Status of Claims
Claims 2, 5-6, 9, and 14 are amended. Claims 3, 11, and 20 are withdrawn. Claims 15 and 17-18 are cancelled. Claims 19-23 are new.
Response to Amendment
The amendments filed on 26 Jun. 2025 have been entered.
Response to Arguments
In view of Applicants amendments, the objections to claims 2 and 6 because of minor informalities is withdrawn.
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) 1-2, 4-10, 12-13, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cuthbertson et al. (WO 2021/013978 A1; published 28 Jan. 2021), in view of Pomper et al. (WO 2013/082338 A1; published 6 Jun. 2013) and Wilbur et al. (US 2022/035974 A1; filed 28 Apr. 2021) for the reasons cited in the Office action filed on 3 Apr. 2025.
Applicants Arguments
Applicants assert that only a part of the contents of Wilbur can be considered prior art and used for determining obviousness. Only general formulas (I), (IIA)-(IID), (III) and (IVE)-(IVH) are recorded om the provisional application and can enjoy benefit of the earliest filing date: 28 Apr. 2021. The general formulas (I), (IIA)-(IID), (III) and (IVE)-(IVH) in Wilbur only teach that Y is a trifunctional groups that covalently links L, L1, and L2 but fail to teach that Y could be the specific trivalent linkers such as the cited trivalent linker. Claim 2 is non-obvious over Cuthbertson in view of Pomper and PART of the contents of Wilibur.
The technical field of Wilbur differs significantly from that of the compounds of Claim 1. The molecules of claim 1 specifically target prostate cancer and are intended for treating all subtypes and stages of prostate cancer. In claim 1, X is used to link two PSMA targeting moieties and formula I is Wilbur only discloses a single targeting moiety. The prior art does not teach the claimed compounds specific combination and such excellent tumor growth inhibitory effect. While the effect example 9 in the present application, PSMA-617 is considered a reference compound, and compounds in Claim 1 has much better tumor growth inhibitory effect than the reference compound PSMA 617 according to table 7 demonstrating unexpected better effects compared to the compounds in Cuthbertson.
Applicant's arguments filed 26 Jun. 2025 have been fully considered but they are not persuasive. The cited trivalent linker compounds
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,
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, and
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may be found on pgs 24 and 27 in the specification of the provisional application No. 63/181,126 filed on 28 Apr. 2021. Accordingly, Wilbur is prior art for the cited trivalent linker compounds.
Wilbur provides for the example 1E dimer that links two PSMA-617 targeting moieties to a HOPO chelator while using the HOPO chelator as a chelator and linker moiety. In Wilbur, the HOPO chelator complexes 227Th to form for example a 227Th example 1E dimer. At pg. 7 Cuthbertson teaches 225Ac. Pomper teaches that DOTA is a general chelating agent that may be used with radiometals such as 68Ga and 177Lu for therapy. In addition, Pomper teaches that PSMA dimer compounds are advantageous since PSMA dimer compounds show improved binding affinity. Pomper uses lysine trivalent linker fragments to attach two PSMA binding moieties to a DOTA chelator. However, in the case of the PSMA-617 dimer compounds taught and motivated by Pomper, a lysine trivalent linker fragment is incompatible since lysine contains to amino groups and only one carboxyl. The prior art of Wilbur teaches the above trivalent linker fragments that are compatible for linking two PSMA617 targeting moieties to a DOTA chelator. All of Cuthbertson, Pomper, and Wilbur relate to radiopharmaceuticals. Accordingly, Wilbur is in the same field of endeavor as Curthbertson and a person of ordinary skill in the art would have reasonably considered the teachings of Wilbur and Cuthbertson in combination without the benefit of hindsight analysis. Wilbur provides methods and intermediate trivalent linker precursor compounds suitable for attaching each PSMA 617 to a trivalent linker capable of attaching to DOTA. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify compound of Curthbertson (PSMA 617 dimer) by substituting the HOPO chelator/linker with a DOTA attached to the trifunctional linker in Wilbur with a reasonable expectation of success because the substituting using a trivalent linker compatible with each PSMA 617 would have been expected to enable the use of a general chelating agent that may be used with radiometals such as 68Ga and 177Lu whereby enabling imaging and therapy.
The closest prior art compound is the PSMA 617 dimer in Cuthbertson. The response filed on 26 Jun. 2025 does not point to a section of the specification comprising a comparison with the PSMA 617 dimer in Cuthbertson. The instant specification at pg. 75, table 7 contains a comparison 177Lu-PSMA 617 and asserts that BD-19 exhibited superior tumor growth inhibition on tumor cells. However, a person of ordinary skill in the art would have expected a PSMA dimer such as 177Lu-BD-19 to exhibit improved tumor growth inhibition over a PSMA monomer based on at least the teachings of Pomper discussed above. That is, Pomper teaches that PSMA dimer compounds result in improved binding affinity and tumor inhibition. Applicants’ assertion of superior tumor growth inhibition must be reviewed to determine if the results occur over the entire claim range. Instant claim 1 is broad encompassing a large number of compounds each with different linker moieties including trifunctional linker moieties at instant X. For example instant X of formula I include linker moieties
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and
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. The results at table 7 do not teach or suggest that every claimed compound would exhibit superior tumor growth inhibition over the compound in PSMA 617 dimer in Cuthbertson.
Claim(s) 1-2, 4-10, 12-14, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cuthbertson et al. (WO 2021/013978 A1; published 28 Jan. 2021), in view of Pomper et al. (WO 2013/082338 A1; published 6 Jun. 2013) and Wilbur et al. (US 2022/035974 A1; filed 28 Apr. 2021), in further view of Yu et al. (US 2024/0366813 A1; filed 3 Sep. 2021) for the reasons cited in the Office action filed on 3 Apr. 2025.
Applicants Arguments
Applicants assert that Yu only teaches that L3 could be
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, even when further combined with Yu, the prior art still fails to teach the specific fragments X and the better unexpected effect.
Applicant's arguments filed 26 Jun. 2025 have been fully considered but they are not persuasive. Cuthbertson, Pomper, and Wilber are not deficient for the reasons discussed above. Yu teaches, suggests and motivates replacing the L3 on PSMA 617 that is
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with
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results in an equivalent PSMA inhibitor compound. In addition, Yu teaches better chemical and biological properties for the compounds therein. Instant table 7 does not assert or demonstrate that 177Lu-BD 19 exhibits an unexpected superior tumor inhibition over the cited compound in Yu.
Claim(s) 1-2, 4-10, 12-14, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cuthbertson et al. (WO 2021/013978 A1; published 28 Jan. 2021), in view of Pomper et al. (WO 2013/082338 A1; published 6 Jun. 2013) and Wilbur et al. (US 2022/035974 A1; filed 28 Apr. 2021), in further view of Akaiwa et al. (US 2022/0105194 A1; published 7 Apr. 2022) for the reasons cited in the Office action filed on 3 Apr. 2025.
Applicants Arguments
The compounds in Akaiwa are fragment of antibody and have a molecular weight around 50kDa which is much larger that the compounds in claim 1. One of ordinary skill would not have isolated a specific component from the one compound and applied it to a fundamentally different compound without considering the overall structure, activity and pharmacokinetics. Substituting a fragment with a linker based on an entirely different class of compounds fails to account for the inherent unpredictability of drug discovery. The linkers in Akaiwa and claim 1 share no similarity and are designed to connect fundamentally different biological components: an antibody vs small molecule.
Applicant's arguments filed 26 Jun. 2025 have been fully considered but they are not persuasive. Cuthbertson, Pomper, and Wilbur are not deficient for the reasons discussed above. Akaiwa teaches radiopharmaceutical conjugates using a DOTA chelator, spacer fragments and biomolecule. At for example [0058], Akaiwa teaches the following spacer moieties as equivalent spacer moieties:
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and
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. The selection of a known material based on its suitability for an intended purpose supports prima facie obviousness. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the PSMA 617 dimer in Cutherbertson by replacing the spacer moiety that Cutherbertson teaches is replaceable with the
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spacer moiety or position isomer as taught by Akaiwa because the substituting would have been expected to enable a homobivalent PSMA inhibitor conjugate that provides the same or better chemical and biological properties.
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 1-2, 4-10, 12-13, 16, 19, and 21-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/776,861, in view of Pomper et al. (WO 2013/082338 A1; published 6 Jun. 2013), and Wilbur et al. (US 2022/0354974 A1; provisional filed 28 Apr. 2021) for the reasons cited in the Office action filed on 3 Apr. 2025. Note that claims 19, and 21-23 are included in this rejection because claims 19, and 21-23 read on the elected species optionally complexing 177Lu made obvious by this rejection. This is a provisional nonstatutory double patenting rejection.
Applicants Arguments
Applicants assert that Pomper and Wilbur fail to teach the specific fragment X and the unexpected better effects. As such, the claimed compounds in the present application are non-obvious over the compound in co-pending application No. 18/771,861.
Applicant's arguments filed 26 Jun. 2025 have been fully considered but they are not persuasive. Pomper and Wilbur were found to be not deficient for the reasons discussed above. As discussed above and in the Office action filed on 3 Apr. 2025, Wilbur teaches, suggests and motivates the specific fragment X.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 19, and 21-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Cuthbertson et al. (WO 2021/013978 A1; published 28 Jan. 2021), in view of Pomper et al. (WO 2013/082338 A1; published 6 Jun. 2013) and Wilbur et al. (US 2022/035974 A1; filed 28 Apr. 2021), in further view of Akaiwa et al. (US 2022/0105194 A1; published 7 Apr. 2022).
Cuthbertson et al. teach targeted radiopharmaceuticals for the diagnosis and treatment of prostate cancer (see title). Cuthbertson et al. teach PSMA-617
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(see pgs. 5, 82). Cuthbertson et al. teach the example 1-C-monomer 232Th
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, example 1-E dimer
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and example 1-F dimer-227Th
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(see pgs. 86-88). These compounds read on compounds of instant formula I
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wherein L1= chemical bond, L2 =
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(carbonyl terminal of L2 connected to L1, L3 =
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(carbonyl terminal to L3 connected with L2), and X-R=HOPO chelated radioactive metal (232Th, 227Th). Cuthbertson et al. teach competition and antiproliferation assays for the compounds for the compounds (see pgs. 440-451). Cuthbertson et al. teach 177Lu (see pg. 7). Cuthbertson et al. teach pharmaceutical composition comprising a pharmaceutically acceptable carrier (see pg. 32).
Cuthbertson et al. do not teach a compound of instant formula II wherein X is
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or
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or the compounds
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, and
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Pomper et al. teach homomultivalent and heteromultivalent inhibitors of PSMA and uses thereof (see title). Pomper et al. teach that since DOTA is a general chelating agent, compound 3 may be used with radiometals such as 68Ga (PET) and 177Lu for therapy ([0023]). There was an 11-fold increase to the DOTA-chelated bivalent compound 3 compared to 1 leading to subnanomolar binding affinity for 3 (see [0101]). Pomper et al. teach compound 3
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(see Fig. 1) and [111In]3 (example 9). Pomper et al. teach pharmaceutical composition comprising a pharmaceutically acceptable carrier ([0043]).
Wilbur et al. teach reagents and methods for labeling molecules with astatine isotopes in higher oxidation state (see title). Wilbur et al. teach imaging and therapy of human diseases such as cancer ([0003]). Wilbur et al. teach the trivalent linker moiety 1
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(Fig. 17), and the compound 6
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and compound 9
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(pg. 21). Wilber et al. teach compounds of formula (I)
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wherein Y is trifunctional group that covalently links L, L1, and L2 (see [0008]). Wilbur et al. teach conjugation to targeting agents including large and small molecular weight biomolecules ([0062]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compounds of Cuthbertson et al. (HOPO conjugated PSMA-617dimer above and pharmaceutical composition thereof comprising a pharmaceutically acceptable excipient) by substituting the HOPO based chelating moiety with a trivalent linker that is
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or
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, the trivalent linker further connected to DOTA and then optionally form a 177Lu complex with that the compound to arrive at the compounds
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or
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optionally complexed with 177Lu as taught by Pomper et al. and Wilbur et a. because the substituting and optional complexing would have been expected to advantageously enable bivalent PMSA-617 derivatives, formed from a known compatible trifunctional linker, that enable high sensitivity detection of PSMA cancer, the bivalent PMSA-617 derivatives advantageously conjugated to a general DOTA chelator that forms stable complexes with 68Ga and 177Lu allowing imaging and therapy of cancer.
Cuthbertson et al. do not further teach a compound of instant formula I wherein L3 is
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or the compounds
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and
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.
Akaiwa et al. teach a conjugate comprising ligand, spacer, peptide linker and biomolecule (see title). Akaiwa et al. teach a method for diagnosing and treating cancer. The invention relates to a conjugate comprising DOTA, a spacer, a peptide linker and a biomolecule rapidly excreted by the kidneys ([0057], [0112]). Akaiwa et al. teach spacer moieties of the formulas
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and
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([0058], [0070], [0072]). Akaiwa et al. teach chemical formula 22
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(see pg. 13) and chemical formula 54.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Cuthbertson et al. by further substituting the instant L3 that is
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with
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to arrive at
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as taught by Cuthbertson et al. and Akaiwa et al. because the substituting would have been expected to enable homobivalent PSMA inhibitor conjugates advantageously having a spacer moiety that provides the same or better chemical and biological properties. Position isomers, such as the claimed 1,2,3,5-tetrahydroisoquinoline position isomers, are prima obvious due to a general expectation of similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Conclusion
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.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached on (571)272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
Prosecution Insights