DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 42-61 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 1-41 are cancelled. Claims 42-61 are new. Claims 43-47, 50, 53, 59, 60 and 61 are withdrawn.
Response to Amendment
The amendments filed on 19 Mar. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 11, 16-17, 20, and 24 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 1, 7-11, 20, 26, 30, 33, and 35 under 35 USC 102(a)(1),(2) as being anticipated by Kung et al. (WO 2017/116994 A1; published 6 Jul. 2017) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-2, 7-11, 16-20, 24, 26, 30-31, 33, and 35 under 35 USC 103 as being unpatentable over Kung et al. (WO 2017/116994 A1; published 2017), in view of Lütje et al. (Theranostics; published 2015) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-4, 7-11, 15-20, 24, 26, 28, 30-31, and 33-35 under 35 USC 103 as being unpatentable over Kung et al. (WO 2017/116994 A1; published 2017), in view of Lütje et al. (Theranostics; published 2015), in further view of Abiraj et al. (Chem. Commun.; published 2008) is withdrawn.
New Grounds of Rejection
Claim Objections
Claim 42 is objected to because of the following informalities: in claim 42, “R* is a halogen” would be “R* is a halogen, or”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 42, 48-49, 51-52, and 54-58 are 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. In claim 42, the recitation of A is a bond is indefinite because none of the structures in the claim require an A. The A2 in formulas II-B and III-A are not defined in the claim. In claims 42-43, the squiggly lines such as
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are not defined in the claims or the specification and so the meaning of the squiggly lines in indefinite. Claims 48-49, 51-52, and 54-58 depend to claim 42 and fall therewith.
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.
The following rejection is based upon art which was found incidental to the search for the elected species. This is not indicative that the entire scope of the claims has been examined; however, the following art is being applied in an effort to promote compact prosecution of the case.
Claim(s) 42, 48-49, 54-56, and 58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kung et al. (WO 2017/116994 A1; published 6 Jul. 2017), in view of Lütje et al. (Theranostics; published 2015).
Kung et al. teach urea based prostate specific membrane antigen (PSMA) inhibitors for imaging and therapy (see title). Kung et al. teach compounds of formula IV wherein Z is a chelating moiety ([0014]). Kung et al. teach that the series with the novel phenoxy linker showed equal or better binding affinity that [68Ga]1 ([0027]). Kung et al. teach chelating moieties selected from the group consisting of DOTA, etc ([0038]). Kung et al. teach compounds 5a
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([0127]-[0128]), and [68Ga]5a. The results suggest that specific binding of [68Ga]5b was comparable to that of known compound [68Ga]1 ([0153]).
Kung et al. disclose the compounds 5b
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([0130]-[0131]), and [68Ga]5b having binding affinities of about 11.6±5.2 nM and 16.5±3.1 nM, respectively (see pg. 83).. These compounds read on compounds of instant formula IIIIA
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wherein R37a=Ph; W =
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, R2=H; X2=-O-, A2=bond, and B2=H; D=HBED-CC and -X1-A1-B1= -O-H.
The specific binding of [68Ga]5b was comparable to that of the known compound [68Ga]1a (PSMA 11) ([0153]). The internalized activity was much higher for [68Ga]5b ([0164]-[0165]). Although [68Ga]5a demonstrated lower tumor uptake its kidney retention was the lowest which is desirable for therapeutic drug ([0168]). Only LNCaP tumor was clearly visualized with all tracers with good tumor to background contrasts ([0177]). Kung et al. teach pharmaceutical compositions comprising a pharmaceutically acceptable carrier (abstract, [0050]). Kung et al. teach DOTAGA chelator ([0038]).
Kung et al. do not further teach a compound of instant formula I wherein D=
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, and -X1-A1-B1= bond-H.
Lütje et al. teach PSMA ligands for radionuclide imaging and therapy of prostate cancer (see title). Lütje et al. teach that to improve the pharmacokinetics of the DOTA-coupled PSMA ligands, the hydrophilicity of the ligand was increased by substitution with DOTAGA which can be labeled with both 68Ga and 177Lu and thus used for diagnostic and therapeutic purposes. DOTAGA conjugated ligand complexes showed a significantly increase affinity towards PSMA on PSMA expressing LNCaP cells compared to DOTA-conjugated PSMA ligands (pg. 1398).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compounds of Kung et al. (5a, 5b, and [68Ga]5b and pharmaceutical compositions thereof comprising a pharmaceutically acceptable carrier) by substituting the DOTA or HBED-CC chelator with a DOTAGA chelator as taught by Lütje et al. because the DOTAGA chelator would have been expected to advantageously enable 68Ga and 177Lu complexes for imaging and therapy as well as improved pharmacokinetics, tumor uptake and binding affinity in comparison to the DOTA chelator.
Claim(s) 42, 48-49, 51-52, and 54-58 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kung et al. (WO 2017/116994 A1; published 6 Jul. 2017), in view of Lütje et al. (Theranostics; published 2015), in further view of Abiraj et al. (Chem. Commun.; published 2008).
Kung et al. teach as discussed above.
Kung et al. do not further teach a compound of instant formula I wherein D=
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, and -X1-A1-B1= -O-H or the elected species
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.
Lütje et al. teach as discussed above.
Abiraj et al. teach novel DOTA-based prochelator for divalent peptide vectorization (see title). Abiraj et al. teach that application of multivalent ligands showed markedly increased binding affinity with their respective receptors compared to monovalent ligands (pg. 3248). Abiraj et al. teach that DOTA based prochelators for the multivalent grafting of targeting ligands is of significant interest to develop improved targeting vectors that could find potential application in different imaging modalities (pg. 3248). Abiraj et al. teach prochelator (04)
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containing two free carboxyl groups for divalent vectorization (pg. 3248). Abiraj et al. teach deprotection of the tBu protecting groups (scheme 1). The divalent peptide conjugates showed excellent labeling properties with radiometals of interest such as 177Lu and 68Ga (pg. 3249).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify compounds of Kung et al. (5b and [68Ga]5b and pharmaceutical compositions thereof comprising a pharmaceutically acceptable carrier) by substituting the HBED-CC chelator fragment (instant D) with a DOTA(GA)2 to arrive at the elected species optionally complexed with 68Ga or 177Lu as taught by Lütje et al. and Abiraj et al. because the chelator substitution would have been expected to advantageously enable 68Ga and 177Lu complexation, improved pharmacokinetics and tumor uptake and further enable the formation homo- or hetero- divalent constructs having improved at least improved binding affinity or the enable multimodal imaging.
Applicants Arguments
Applicants assert that Kung discloses twenty different PSMA inhibitors none of which comprising the novel linkers much less the novel linkers attached to the chelating agents as recited in the claims. Nothing in Lütje cures the deficiencies of Kung. Like Kung, Lütje is silent regarding a compound comprising the linkers of formulae II-B, II-C and II-D and III-A as recited in claim 1. Lütje discloses that before a theranostic compound could replace the so far more frequent tested 68Ga-HBED-CC-PSMA-PET/CT, diagnostic accuracy of both agents needs to be directly compared to each other. Nothing in Lütje teaches or suggests the compounds with the linkers in claim 1. The combination of Kung and Lütje fails to teach or suggest a compound having a DOTA(GA)2 chelating agent. A skilled artisan would have had to 1) choose an undisclosed linker and then 2a) choose an undisclosed chelating agent or 2b) replace HBED-CC with DOTAGA to arrive at the claimed compounds. The claimed compounds provide superior properties to the prior art. Especially [177Lu]4 and [177Lu]51 showed much higher uptakes than reference PSMA 11 suggesting that they have superior PSMA binding and retention. Kung discloses that the specific bindings of [68Ga]5b is comparable to PSMA 11. The compounds in the claims demonstrate superior binding and retention than those disclosed in the prior art. A skilled artisan would have expected an unprecedentedly high retention over time due to introducing a 4-(p-iodophenyl) moiety based on Kung and Lütje. A skilled artisan would not have expected the high specific uptake in bone based on the disclosure of Kung and Lütje because 1) neither reference discloses the claimed linkers much less a bisphosphonate group at the position in the claims and none of the references compound disclosed in Kung or Lütje demonstrate high uptake in bone. A skilled artisan would not have expected this faster washout in PIP tumors, kidneys, and spleen based on the disclosure of Kung and Lütje. The claims compounds provide 1) stronger binding affinity; 2) high tumor uptake over time; 3) high specific binding in bone; and 4) significantly faster washout.
Nothing in Abiraj cures the deficiencies of Kung and Lütje with respect to claim 1. Abiraj attributes the improved tumor uptake to divalent compound’s ability to provide two targeting ligands not the chelator itself. The compounds recited in the claims achieved improved tumor uptake while comprising a single PSMA targeting ligand. Nothing in Abiraj teaches or suggests the linkers as recited in the claims.
Applicant's arguments filed 19 Mar. 2026 have been fully considered but they are not persuasive. Kung provides for the compound 5a, 5b and [68Ga]5b having the same linker as the compounds in claim 42 at formula III-A and the elected species but differ only at the chelator moiety where 5a comprises a DOTA chelator and 5b and [68Ga]5b comprise an HBED-CC chelator moiety while formula III-A requires a chelator moiety as defined by D and X1-A1-B1. In addition, Kung teaches and suggests homo- and hetero-bifunctional constructs that link another moiety to the propanoic acid at the terminal arm of the HBED-CC. Lütje teaches, suggests and motivates replacing an HBED-CC of PSMA imaging constructs with the DOTAGA chelator that can be labeled 68Ga and 177Lu (imaging and therapeutic metals) where glutamic acid residue on the DOTAGA enhanced hydrophilicity, pharmacokinetics and tumor uptake while significantly increasing binding towards PSMA on PSMA expressing LNCaP cells compared DOTA conjugated PSMA ligands. Abiraj teaches and suggests DOTAGA chelator derivatives having an additional glutamic acid moiety replacing an acetate on the DOTAGA chelator. Abiraj teaches and suggests that one advantage of this configuration is that added glutamic residue enables multivalent ligands having substantially improved binding affinity. A recognized advantage is the best reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compounds of Kung by substituting the DOTA or HBED-CC chelator with DOTAGA or DOTA(GA)2 as taught by Lütje and Abiraj because those chelator substitution would have been expected to enable to formation of 68Ga and 177Lu complexes for imaging and therapy and improved pharmacokinetics owing to increase hydrophilicity and tumor uptake. In addition, a person of ordinary skill in the art would have been motivated to use the DOTA(GA)2 in order to gain the advantage of multivalent constructs taught, suggested and motivated by Kung and Abiraj.
Regarding Applicants assertions of unexpected results, in order to be effective a showing of unexpected results must comprise a comparison with the closest prior art compounds. In this case, the closest prior art compounds are the 5b and [68Ga]5b in Kung. The Examiner is unable to find in the specification a direct comparison of the 5b and [68Ga]5b in Kung in same experiments. At pg. 64, Table 1 contains a comparison with PSMA-11 and PSMA-617. In one case an IC50 value is derived from LNCaP human PCa cells and [68Ga]PSMA-11. In the other case the IC50 value is derived from PC-3 PIP cells and [125I]MIP-1095. The IC50 values in Kung are derived from LNCaP human cells and [125I]MIP-1095. In addition, Kung at table 1 describes an improved binding affinity of compound 5b over PSMA 11. Based on the teachings of Lütje would have expected the DOTAGA and DOTA(GA)2 chelators to show increased binding affinities, and improved tumor uptake.
A showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. See In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). Instant encompasses thousands of compounds that include widely variant functional and substituent group. The mere substitution of one substituent group for another can substantially alter the in vitro and vivo performance of a compound. Applicants have not shown that all of the claimed compounds would be expected to having increased binding affinity or improved tissue clearance of over the compounds in Kung.
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
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