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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 7, 2025 has been entered.
Response to Arguments
Applicants' arguments, filed August 7, 2025, 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.
The failure of the previous combination of applied references to render obvious compounds with Y2 being phenylene as the new limitation to claim 1 that defines the scope of the compounds complex of claim 11 is remedied by the new grounds of rejection set forth below. The arguments regarding the previous combination of prior art such as Eder failing to teach this feature are moot in light of the new rejection below. The arguments regarding Jeger et al. and Yoo et al. are moot as these references are no longer used in the new grounds of rejection set forth below. Applicants do not present any specific arguments regarding Litau et al. for the Examiner to address herein.
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.
Claims 11, 12, 17 and 25 are rejected under 35 U.S.C. 103 as being obvious over Eder et al. (WO 2015/055318) in view of Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990).
Eder et al. discloses radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and the treatment of various disease states of prostate cancer and the compounds are represented by either formulae (Ia) or (Ib) (whole document, e.g., abstract). As shown on page 8, with definitions of the variables continuing onto the next page, formula (Ia) comports with the formula set forth in instant claim 1:
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with the carbonyl next to the chelator being Y3 of the instant claims although the possible chelator moieties do not fall within the scope of the instant claims. Pharmaceutical preparations with the active ingredient and organic or inorganic solid or liquid pharmaceutically acceptable carriers suited for the intended administration are also disclosed (p 20, ln 3 – 7). Radionuclides complexes of compounds according to formula (Ia) contain one or more radionuclides suitable for use as radioimaging agents or therapeutics for the treatment of rapidly proliferating cells and exemplified radionuclides include 61Cu, 62Cu, 64Cu and 67Cu (p 22, ln 8 – 12). As can be seen in scheme 2 on p 24, the chelator DOTA is conjugated to the PMSA inhibitors with an amide bond to a linker portion to the PMSA recognition element
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.
A chelator with a ring structure of
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and Y2 being a phenylene as required by instant formula (1) is not disclosed.
Morphy et al. discloses macrocyclic-conjugated antibodies are a key feature of radiolabeled tumor-localizing antibodies and macrocyclic ligands tend to undergo very slow acid-dependent decomplexation which makes the labeled antibody stable in vivo over a period of days (p 792). 64Cu and 67Cu can be uses for positron emission tomography (PET) and immunotherapy and copper forms well-defined complexes with 13- and 14-membered tetra-aza-macrocyclic ligands insensitive to decomplexation even at low pH (sentence bridging p 792 and 793). Compounds 1 and 2 shown in the upper left corner of p 793 have rings as required for A-Y2 of instant formula (1). These moieties were conjugated to an antibody using the scheme shown in column 1 on p 793. The conjugated antibodies were radiolabeled with either 64Cu and 67Cu (e.g., p 793, col 2, ¶ 3).
Ruser et al. discloses two new N- and C-functionalized tetraazamacrocyclic ligands intended to be covalently linked to biomolecules such as monoclonal antibodies and to bind to the γ-emitting isotope indium-111 (whole document, e.g., abstract). Compounds L1 and L2 have a phenylene substituent attached to the tetra-aza-macrocyclic ring while compounds L3 and L4 lack that phenylene substituent. Longer incubation times and higher ligand concentration were required for complete complex formation with L3 and L4 compared to L1 and L2 (p 347, col 1, ¶ 2). As shown in Figure 2, there was little if any dissociation from L1 and L2 over 180 minutes while both L3 and L4 showed significant dissociation and stated as too unstable for in vivo use (p 347, col 2, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use tetra-aza-macrocyclic containing moiety of Morphy et al. with a phenylene, the chelator A-Y2 moiety of the instant claims, as the chelator moiety A in the PSMA binding compounds disclosed by Eder et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because different chelator moieties exhibit different metal binding properties based on their different structures and Ruser et al. discloses that the presence of a phenylene ring next to the tetra-aza-macrocyclic ligand influences the rate of metal ion complex formation and dissociation with the presence of such a ring making it easier to form the metal complex and the resultant metal-chelator complex is also more stable. The different kinetics of metal ion binding would motivate one of ordinary skill in the art to use a tetra-aza-macrocyclic ligands-phenylene chelating moiety capable of binding copper disclosed by Morphy et al. as the chelator moiety in the complexes of Eder et al. and would reasonably expect altered metal binding kinetics for the different chelator moieties in view of the teachings of Ruser et al. While the specific compounds of Morphy et al. contain a terminal amine, given the required structure of the carbonyl next to nitrogen containing repeating group in formula (Ia) of Eder et al., one of ordinary skill in the art would use their knowledge of conjugate formation chemistry to prepare suitable fragments that can be reacted form a compound of formula (Ia) of Eder et al. with the para-phenylene- tetra-aza-macrocyclic ligand and phenylene being attached to the carbonyl carbon of the amide and not via the nitrogen atom.
Claims 11, 12, 17 and 25 are rejected under 35 U.S.C. 103 as being obvious over Eder et al., Morphy et al. and Ruser et al. as applied to claims 11, 12, 17 and 25 above, further in view of Litau et al. (ChemMedChem, 2015).
Eder et al., Morphy et al. and Ruser et al. are discussed above.
A chelator with a ring structure of
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is not disclosed.
Litau et al. discloses various chelators for the 64Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agent (whole document, e.g., abstract). Commonly applied chelating agents with hard donor atoms such as oxygen and nitrogen are only of limited applicability in *Cu2+ complexation (p 1220, col 2, ¶ 3) even though it is of great utility in PET imaging with a favorable half-life of 12.7 h that enables successful target visualization even for slowly accumulating target ligands with a mean β+ energy that allows for high resolution PET images (p 1200, col 2, ¶ 2). Among the most potent chelating agents for radiocopper complexation are CB-TE2A and CB-TE1A-GA in figure 1 with structures of
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. The cavity size of these molecules is well suited for the relatively small Cu2+ ion and provides the preferred octahedral complex geometry (p 1201, col 1, ¶ 3). The additional carboxylic acid functionality in CB-TE1A-GA is application for conjugation with a targeting vector meaning that there is no decrease in complex stability from conjugation and the associated amide formation (p 1201, col 1, ¶ 4). Conjugation to a peptide is shown in figures 2 and 3 to obtain a radiolabeled materials that could be administered to animals to study the biodistribution of the conjugates (p 1205, col 2, ¶ 2 onward).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate a phenylene ring between the CB-TE2A and CB-TE1A-GA chelator moiety and the remainder for the conjugate of formula (Ia) disclosed by Eder et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Litau et al. discloses potent radioactive copper chelating motifs suitable for use in PET imaging with a cavity size well suited for Cu2+ that will allow for high resolution PET imaging even for slowly accumulating target ligands. Ruser et al. discloses that the presence of a phenylene ring next to a tetra-aza-macrocyclic ligand can alter the kinetics of metal ion binding, reasonably suggesting to one of ordinary skill in the art that such a change could also improve the kinetics of copper ion binding to the CB-TE2A and CB-TE1A-GA chelator moieties of Litau et al. The choice of radionuclide from those disclosed as suitable in the prior art is within the skill of one of ordinary skill in the art based on the type of imaging and/or therapy being carried out. Pharmaceutical compositions comprising such formulations can be prepared as disclosed by Eder et al. to enable administration to a subject for imaging and/or therapeutic purposes.
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.
Claim 11, 12, 17 and 25 are 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) in view of in view of Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990) optionally further in view of Litau et al. (ChemMedChem, 2015).
The claims of US’901 recite a method requiring the radionuclide Ac-225-containing compounds of formula (A) as in claim 1. Such compounds must be an administered to a patient which requires a pharmaceutical composition of the compounds be prepared as required by instant claim 17.
The presence of radioactive nuclide of copper with a compound of instant claim 1 is not claimed.
Eder et al., Morphy et al., Ruser et al. and Litau et al. are discussed above. Eder et al. lists not only radioactive isotopes of copper as mentioned above but also 225Ac as an illustrative radionuclide (p 22, ln 8 – 13).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the chelator moieties of Morphy et al. or Litau et al. with a phenylene ring connecting that chelator moiety to the compounds of US’901 and to bind a radioactive copper nuclide to that chelator portion as disclosed by Eder et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because different chelator moieties exhibit different metal binding properties based on their different structures. Ruser et al. discloses that the presence of a phenylene ring next to the tetra-aza-macrocyclic ligand influences the rate of metal ion complex formation and dissociation with the presence of such a ring making it easier to form the metal complex and the resultant metal-chelator complex is also more stable. Litau et al. discloses potent radioactive copper chelating motifs suitable for use in PET imaging with a cavity size well suited for Cu2+ that will allow for high resolution PET imaging even for slowly accumulating target ligands. The different kinetics of metal ion binding observed for the addition of a phenylene ring next to the tetra-aza-macrocyclic ligands would motivate one of ordinary skill in the art to use a tetra-aza-macrocyclic ligands-phenylene chelating moiety capable of binding copper disclosed by Morphy et al. or Litau et al. as the chelator moiety in the complexes of US’901. While the specific compounds of Morphy et al. contain a terminal amine, given the required structure of the carbonyl next to nitrogen containing repeating group in formula (Ia) of US’901, one of ordinary skill in the art would use their knowledge of conjugate formation chemistry to prepare suitable fragments that can be reacted form a compound of formula (Ia) of US’901 with the para-phenylene-tetra-aza-macrocyclic ligand and phenylene being attached to the carbonyl carbon of the amide and not via the nitrogen atom.
Claims 11, 12, 17 and 25 are 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), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990) optionally further in view of Litau et al. (ChemMedChem, 2015).
The claims of US’783 recite a 161Tb radiolabeled compound wherein R’ is chelator moiety shown. Pharmaceutical compositions of such metal complexes are recited in claim 11.
Compounds have the chelator moieties are required by formula (I) of instant claim 1 complexed with a copper radionuclide are not claimed.
Eder et al., Morphy et al., Ruser et al. and Litau et al. are discussed above. Note that 161Tb is also taught by Eder et al. along with various copper isotopes (p 22, ln 8 – 14).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the chelator moieties of Morphy et al. or Litau et al. with a phenylene ring connecting that chelator moiety to the compound of US’783 and to bind a radioactive copper nuclide to that chelator portion as disclosed by Eder et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because different chelator moieties exhibit different metal binding properties based on their different structures. Ruser et al. discloses that the presence of a phenylene ring next to the tetra-aza-macrocyclic ligand influences the rate of metal ion complex formation and dissociation with the presence of such a ring making it easier to form the metal complex and the resultant metal-chelator complex is also more stable. Litau et al. discloses potent radioactive copper chelating motifs suitable for use in PET imaging with a cavity size well suited for Cu2+ that will allow for high resolution PET imaging even for slowly accumulating target ligands. The different kinetics of metal ion binding observed for the addition of a phenylene ring next to the tetra-aza-macrocyclic ligands would motivate one of ordinary skill in the art to use a tetra-aza-macrocyclic ligands-phenylene chelating moiety capable of binding copper disclosed by Morphy et al. or Litau et al. as the chelator moiety in the compound of US’783. While the specific compounds of Morphy et al. contain a terminal amine, given the required structure of the carbonyl next to nitrogen in the claimed compound of US’783, one of ordinary skill in the art would use their knowledge of conjugate formation chemistry to prepare suitable fragments that can be reacted form a compound of US’783 with the para-phenylene-tetra-aza-macrocyclic ligand and phenylene being attached to the carbonyl carbon of the amide and not via the nitrogen atom.
This is a provisional nonstatutory double patenting rejection.
Claims 11, 12, 17 and 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 15 – 22 of copending Application No. 18/628,570 in view of Eder et al. (WO 2015/055318), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990) optionally further in view of Litau et al. (ChemMedChem, 2015).
The claims of US’570 recite compositions comprising a means for treating prostate cancer or a metastasis thereof and a pharmaceutically acceptable carrier. No means are claimed but metal complexes such as those of original claim 5 that can be used in a method of treating prostate cancer and/or metastasis are disclosed means for carrying out the claimed function, such that compositions of radiolabeled compounds, such as with 64Cu of a compound of claim 1 (see claims 4 - 6) fall within the scope of claims 15 – 22 even though the specific structures are not recited in these claims.
Compounds that have the chelator moieties are required by formula (I) of instant claim 1 are not disclosed as means for treating prostate cancer or a metastasis thereof and a pharmaceutically acceptable carrier.
Eder et al., Morphy et al., Ruser et al. and Litau et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention use the chelator moieties of Morphy et al. or Litau et al. with a phenylene ring connecting that chelator moiety to the compounds of US’570 and to bind a radioactive copper nuclide to that chelator portion as disclosed by Eder et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because different chelator moieties exhibit different metal binding properties based on their different structures. Ruser et al. discloses that the presence of a phenylene ring next to the tetra-aza-macrocyclic ligand influences the rate of metal ion complex formation and dissociation with the presence of such a ring making it easier to form the metal complex and the resultant metal-chelator complex is also more stable. Litau et al. discloses potent radioactive copper chelating motifs suitable for use in PET imaging with a cavity size well suited for Cu2+ that will allow for high resolution PET imaging even for slowly accumulating target ligands. The different kinetics of metal ion binding observed for the addition of a phenylene ring next to the tetra-aza-macrocyclic ligands would motivate one of ordinary skill in the art to use a tetra-aza-macrocyclic ligands-phenylene chelating moiety capable of binding copper disclosed by Morphy et al. or Litau et al. as the chelator moiety in the complexes of US’570. While the specific compounds of Morphy et al. contain a terminal amine, given the required structure of the carbonyl next to nitrogen containing repeating group in formula (Ia) of US’570, one of ordinary skill in the art would use their knowledge of conjugate formation chemistry to prepare suitable fragments that can be reacted form a compound of formula (Ia) of US’570 with the para-phenylene-tetra-aza-macrocyclic ligand and phenylene being attached to the carbonyl carbon of the amide and not via the nitrogen atom.
This is a provisional nonstatutory double patenting rejection.
Claims 11, 12, 17 and 25 are 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), Morphy et al. (J Chem Soc Chem Commun, 1989) and Ruser et al. (Bioconjugate Chem, 1990) optionally further in view of Litau et al. (ChemMedChem, 2015).
The claims of US’445 recite chelator containing compounds of formula Ia’ (claim 15) that can have a radionuclide such as 64Cu complexed to the chelator (e.g., claims 31 and 33). X can be napthyl (claims 38).
Eder et al., Morphy et al., Ruser et al. and Litau et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention use the chelator moieties of Morphy et al. or Litau et al. with a phenylene ring connecting that chelator moiety to the compounds of formula (Ia’) in US’445 and to bind a radioactive copper nuclide to that chelator portion as disclosed by Eder et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because different chelator moieties exhibit different metal binding properties based on their different structures. Ruser et al. discloses that the presence of a phenylene ring next to the tetra-aza-macrocyclic ligand influences the rate of metal ion complex formation and dissociation with the presence of such a ring making it easier to form the metal complex and the resultant metal-chelator complex is also more stable. Litau et al. discloses potent radioactive copper chelating motifs suitable for use in PET imaging with a cavity size well suited for Cu2+ that will allow for high resolution PET imaging even for slowly accumulating target ligands. The different kinetics of metal ion binding observed for the addition of a phenylene ring next to the tetra-aza-macrocyclic ligands would motivate one of ordinary skill in the art to use a tetra-aza-macrocyclic ligands-phenylene chelating moiety capable of binding copper disclosed by Morphy et al. or Litau et al. as the chelator moiety in the complexes of US’445. While the specific compounds of Morphy et al. contain a terminal amine, given the required structure of the carbonyl next to nitrogen containing repeating group in formula (Ia’) of US’445, one of ordinary skill in the art would use their knowledge of conjugate formation chemistry to prepare suitable fragments that can be reacted form a compound of formula (Ia’) of US’445 with the para-phenylene-tetra-aza-macrocyclic ligand and phenylene being attached to the carbonyl carbon of the amide and not via the nitrogen atom.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/Nissa M Westerberg/Primary Examiner, Art Unit 1618