DETAILED ACTION
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 .
Response to Arguments
Applicants' arguments, filed July 13, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim 1, from which all claims under examination depend, has been amended and the ring structures based on CB-TE2A have been deleted and only cyclam rings remain for the chelator residue A.
Claim Rejections - 35 USC § 103
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) 11, 12, 17 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Eder et al. (WO 2015/055318) in view of Litau et al. (ChemMedChem, 2015), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990) This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed April 14, 2026 and those set forth herein.
Applicants traverse this rejection on the grounds that compounds with the unbridged copper chelators A show excellent pharmaceutical properties. CA003 and CA023 have such rings and the combination of the particular linkers and chelators leads to an unexpected improvement in the pharmacokinetics and tumor targeting properties of the compounds. Figure 3 from the specification as filed is reproduced in the remarks with compounds not according to the invention (CA002, CA005 and CA006) that have different linkers showed lower binding to cells and lower internalization values compared to CA003 and CA023. The biodistribution properties of CA003 are excellent with various data from the specification as filed being reproduced in the remarks and Figure 4A referenced as showing very high tumor uptake in PET scans. PSMA-617, which is identical to MB17 of Eder, was used as a comparative compound, with the presently claimed compounds showing superior tumor-to-liver ratio compared to the PSMA-617/MB17 of Eder et al. and results in significantly improved tumor visualization, rapid clearance from the kidney and liver while maintaining high tumor uptake. Thus the present application demonstrates the unexpected properties of the presently claimed compounds.
These arguments are unpersuasive. The data indicates that PSMA-617, CA003 and CA023 behave differently but given that the compounds are different in structure, differences in their behavior would be expected. The question is whether the differences in behavior are unexpected. Applicants bear the burden of explaining the evidence offered in support of alleged unexpected results which includes an indication of what the expected results would be (please see MPEP 716.02 et seq. for a complete discussion of unexpected results). Without that information as to the expected results, if the differences that are seen are in fact unexpected cannot be determined. Additionally, any evidence must be reasonably commensurate in scope with the claims. CA003 and CA023 include two options of 4 possible options for the chelator residue A, the rest of the molecule is identical between these two compounds and narrower than
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as set forth in claim 1 (see definitions for Z1, Z2, Z3, R6, R7, R8 and R9). Therefore the evidence is also not reasonably commensurate in scope with the claims.
Applicants also argue that, as acknowledged by the Office, there are two structural features that differ between the presently claimed compounds and Eder – the chelator moieties A are different and the phenylene cyclic group Y2. There is no teaching or suggestion in Eder that the specific choice of the combination of the claimed linkers and chelators may lead to improvement of the pharmacokinetics and tumor targeting properties of the claimed compounds that show excellent pharmaceutical properties comprised to PSMA-617.
These arguments are unpersuasive. As discussed in greater detail above, that the compounds behave differently has been established but not if those differences are in fact unexpected as compounds of different structures would not be expected to have identical properties given the difference in structure. The rejection does not rely on Eder et al. to render the claimed complexes obvious as the rejection is made over a combination of references.
Applicants also argue that Litau does not cure the deficiencies of Eder et al. as the chelating moieties are bridged while the claimed chelators are unbridged, with the bridging taught as stabilizing the steric configuration of the donor atoms, teaching away from the unbridged chelators of the instant claims. The structures of the rest of the molecule is also significantly different compared to the PMSA-based compounds of Eder et al. and use a PEG3 (polyethylene glycol 3) linker rather than the glutamate-urea-lysine recognition element of Eder et al. Litau does not teach that the claimed specific linkers and chelator leads to improvement of the pharmacokinetics and tumor targeting properties.
These arguments are unpersuasive. "The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference .... Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 413,425 (CCPA 1981) MPEP 2145(III) The unbridged chelator structure and suitability for copper chelation is taught by Morphy et al., Ruser et al. and the knowledge of one of ordinary skill in the art. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). (MPEP 2123). Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). MPEP 2123, emphasis added. Litau et al. discloses that the targeting ligand, with different chemical structures imparting differential targeting of the radionuclide cargo, can be attached via the ring nitrogen atom rather than the ring carbon atoms as in Morphy et al. and Ruser et al.
Regarding Morphy et al., Applicants disagree about the number of atoms in the ring structure shown and that there are three methylene units between nitrogen atoms in the claimed chelators and only two methylene units in those disclosed by Morphy et al. The phenylene group in the linker of Morphy is flanked by methylene groups and attached to a carbon atom and not having the same structure as required by the instant claims. Given the differences in structure between the compounds of Morphy et al. and the instant claims, the combination of Eder, Litau and Morphy would not arrive at Applicant’s claimed compounds.
These arguments are unpersuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Both Morphy et al. and Ruser et al. discloses radionuclide chelation of unbridged ring systems unlike those in Litau et al. Applicants do not establish that one of ordinary skill in the art would not have a reasonable expectation of success that the differences in the tetraazamacrocyclic ring systems that maintain the nitrogen atoms that coordinate the metal ion amongst the applied references as so different that one of ordinary skill in the art would not have a reasonable expectation that a copper radionuclide containing complex would not form. Only a reasonable and not an absolute expectation of success is required for a prima facie case of obviousness.
Regarding Ruser et al., Applicants argue that Ruser compares 13 or 14 membered rings and the one containing the phenylene substituent has only two methylene substituents between the lower two NH groups. Properties including chelate formation and stability under physiological conditions in ring size dependent with the 14 membered ring being too unstable for in vivo use, teaching away from the presently claimed chelators that are 14-memebred tetra-aza-macrocyclic rings.
These arguments are unpersuasive. The instant claims are drawn to complexes and not to a method of use that required sufficient stability for in vivo studies and complexes could be formed for other purposes such as in vitro use. There only needs to be a reasonable expectation of success that such tetraazamacrocyclic compounds can form chelators with radioactive nuclide of copper for a prima facie case of obviousness. Applicants also do not address that Ruser et al. uses 111In as the radionuclide and the potential differences in chelate stability arising from the different radionuclides between indium and copper particularly in light of Morphy et al. disclosing that similar ring structures complexed with copper gave rise to kinetically stable conjugates in vivo (abstract).
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 11, 12, 17 and 25 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 13 of U.S. Patent No. 10,980,901 in view of Eder et al. (WO 2015/055318), Litau et al. (ChemMedChem, 2015), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed April 14, 2026 and those set forth herein.
Applicants traverse this rejection on the grounds that the radionuclides in the compounds are not the same and the compounds correspond substantially to Eder. In view of the foregoing remarks, the presently claimed compounds are not taught or suggested by Eder nor the’901 patent.
These arguments are unpersuasive. Applicants do not address the fact that the rejection is based on the claims of US’901, Eder et al. and additional references and not just the claims of Us’901 and Eder et al. That combination renders obvious the claimed compounds, including substitution of 225Ac with a copper isotope such as 64Cu, as discussed in greater detail in the Office Action mailed April 14, 2026 and herein.
Regarding the provisional nonstatutory double patenting rejections reiterated below, Applicants argue that the compounds in each application substantially correspond to the compounds including MB17 of Eder et al. The presently claimed compounds are not taught or suggested by Eder, each relevant application and therefore the claims are patentably distinct of the claims of each application.
These arguments are unpersuasive. Applicants do not address the fact that the rejection is based on the claims of each application, Eder et al. and additional references and not just the claims and Eder et al. That combination renders obvious the claimed compounds as discussed in greater detail in the Office Action mailed April 14, 2026 and herein.
Claims 11, 12, 17 and 25 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15 – 29 of copending Application No. 18/440,783 in view of Eder et al. (WO 2015/055318), Litau et al. (ChemMedChem, 2015), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed April 14, 2026 and those set forth herein.
This is a provisional nonstatutory double patenting rejection.
Claims 11, 12, 17 and 25 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15 – 22 of copending Application No. 18/628,570 Eder et al. (WO 2015/055318), Litau et al. (ChemMedChem, 2015), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed April 14, 2026 and those set forth herein.
This is a provisional nonstatutory double patenting rejection.
Claims 11, 12, 17 and 25 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15 - 44 of copending Application No. 19/326,445 in view of Eder et al. (WO 2015/055318), Litau et al. (ChemMedChem, 2015), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990). This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed April 14, 2026 and those set forth herein.
This is a provisional nonstatutory double patenting rejection.
Conclusion
THIS ACTION IS MADE FINAL. 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 Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
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 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.
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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