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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 10/16/2025 has been entered.
Status of Claims
Claims 1, 36, 48, 54 and 55 have been amended. Claim 56-58 are newly added. Claims 1, 5, 12, 16, 23, 25, 30, 33, 36, 40, 42, 45, 48 and 52-58 are pending, of which claims 16, 25, 48, 52 and 56 are withdrawn as being directed to a non-elected invention or species. Claims 1, 5, 12, 23, 30, 33, 36, 40, 42, 45, 53-55, 57 and 58 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below. New grounds for rejection are set forth, necessitated by claim amendment.
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, 5, 12, 23, 30, 33, 36, 40, 42, 45, 53-55, 57 and 58 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/703,086 (reference application), for reasons set forth in the previous Office Action.
Response to arguments
Applicant requests the rejection be held in abeyance.
Applicant’s arguments have been fully considered. The rejection is maintained at this time as a terminal disclaimer has not been received.
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.
Claim 58 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. The claim recites “The metal complex having the structure:
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wherein the metal is Scandium-44 (44Sc), Scandium-47 (47Sc), Scandium-43 (43Sc).” However, the variables Y1, Y2, Z1, L and A are not defined. Is the claim intended to be dependent upon claim 1? Clarification is requested.
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.
Claim(s) 1, 5, 12, 23, 30, 33, 36, 42, 53-55 are rejected under 35 U.S.C. 103 as being unpatentable over Guillou et al. (Eur. J. Inorg. Chem. 2017, 2435–2443) in view of Gasser et al. (Bioconjugate Chem., 2008, 19, 719–730).
Guillou teaches that the different coordination properties of metal ions also facilitate a large choice of sequestrating chelators for the encapsulation of the metallic radioisotope. In addition to the chelating unit, radiopharmaceuticals usually contain an active functional group suitable for conjugation to a targeting biovector such as a peptide or an antibody. The development of such bifunctional chelating agents (BCAs) often requires the cooperation of scientists with different areas of expertise (i.e., coordination chemistry, radiochemistry, and biochemistry).
Among the copper radioisotopes, 64Cu appears to be a particular good candidate for positron emission tomography (PET) imaging owing to its relatively long decay and the possibility to form an interesting theranostic pair with the β- emitter 67Cu isotope.
Among the numerous compounds used as chelators for 64Cu labeling, 1,4,7-triazacyclononane-1,4,7-triacetic acid (H3nota; Scheme 1) has been the subject of intense research efforts, as it forms complexes with in vivo stabilities higher than those of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (H4dota) and 1,4,8,11- tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (H4teta) analogues. Commercially available nota derivatives have been developed owing to the interesting properties of this ligand scaffold for the envisaged applications. As the chelating unit of the BCA plays a crucial role in the properties of the radiopharmaceutical, many ligands have been designed, and their “cold” copper(II) complexation properties have been investigated. An ideal chelator for this specific application should be prepared readily from commercially available materials and show fast complexation kinetics as well as high thermodynamic and kinetic stability in vivo to avoid the release of the toxic metal ion. Given the borderline character of the Cu2+ cation within the Pearson classification, ligands designed for its efficient complexation usually contain oxygen and nitrogen donor atoms, which are often provided by acyclic and cyclic polyamines with pyridyl, acetate, or methylenephosphonate arms. Thus, 1,4,7-triazacyclononane (tacn) derivatives containing methylenephosphonate or picolyl arms to replace pendant carboxylic acids have been reported.
Recently, we described the tacn-based ligand Hno1pa2py, which contains two picolyl and one carboxypicolyl pendant arms for complexation with Cu2+ cations. This complex exhibited fast complexation kinetics, high thermodynamic stability, kinetic inertness in acidic media, and stability under reducing conditions. The 64Cu labeling of Hno1pa2py was also fast and efficient, which opens interesting perspectives for the development of bifunctional agents based on this chelator. Thus, we envisaged that the family of tacn-based ligands containing picolyl and carboxypicolyl pendants could be expanded. To this aim, herein we report the synthesis of no3py, H2no2pa1py, and H3no3pa (Scheme 1), as well as a detailed study of the thermodynamic stabilities of their complexes with Cu2+ and Zn2+ ions. The structures of the complexes in solution were investigated through a combination of electron paramagnetic resonance (EPR) and UV/Vis spectroscopy, cyclic voltammetry, and DFT calculations.
Scheme 1:
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Guillou does not teach wherein at least one of the pyridine arms of the triazacyclononane contains targeting ligand.
Gasser teaches development of improved copper-based radiopharmaceuticals featuring pyridyl derivatives of the tridentate macrocycle 1,4,7-triazacyclononane (TACN) as the chelating agent. Due to its small ring size, TACN coordinates facially to metal ions such as Cu2+, with the metal lying out of the plane defined by the three nitrogen atoms. The donor atoms are oriented in such a way as to maximize orbital overlap and thereby produce complexes with very high thermodynamic stabilities (35). Herein, we report the synthesis and copper coordination chemistry of the TACN derivative, 2-[4,7-bis(2-pyridylmethyl)- 1,4,7-triazacyclononan-1-yl]acetic acid (6) (Scheme 1), that contains two pyridyl pendant groups to increase the stability of the copper complex significantly compared to the parent TACN macrocycle and a carboxylic acid functionality that allows the covalent attachment of 6 to tumor-specific biomolecules via an amide coupling reaction. This possibility for regiospecific coupling is a convincing advantage compared to other previously described pyridine-containing polyamine ligands. To demonstrate the utility of 6 in preparing 64Cu-labeled radiotracers, we chose in the first instance to conjugate it to bombesin (BN), a tetradecapeptide that binds with high affinity to the gastrin-releasing peptide receptor (GRPR). The GRPR is overexpressed on a variety of tumors, including commonly diagnosed breast and prostate cancers, and the less common pancreatic and small-cell lung cancers (page 719).
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Gasser further teaches the conjugation of the TACN derivative 6 to βAla-βAla-[Cha13, Nle14]BN(7–14), resulting in the preparation of the bioconjugate 8 (Figure 1) and present the results of subsequent 64Cu labeling experiments with 6 and 8 to give 64Cu⊂6 and 64Cu⊂8, respectively. In vitro and in vivo stability investigation is taught (page 720).
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Radiopharmacological data support the potential of 64Cu⊂8 for GRPR imaging and indicate that the chelating agent 6 may be an attractive candidate for developing new copper radiopharmaceuticals because it may be efficiently labeled under mild conditions (ambient temperature, aqueous solution) and exhibits fast renal clearance (page 728).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a targeting ligand on a compound taught by Guillou comprising a
tacn-based which contains one or two carboxypicolyl pendant arms for complexation with Cu2+ cations, corresponding to wherein one of Y₁ or Y₂ is alkylheteroaryl-CO₂H according to the instant claims, and including an alkyl or alkamino linker when the teaching of Guillou is taken in view of Gasser. One would have been motivated to do so, with a reasonable expectation of success, because Gasser teaches that doing so
allows the covalent attachment tumor-specific biomolecules via an amide coupling reaction.
Claim(s) 1, 5, 9, 16, 23, 30, 33, 36, 42, 45, 53, 55 and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Caravan et al. (WO 08/098056) in view of Ray (US 2017/0081298).
Caravan teaches modifications of a chelating ligand to enhance the relaxivity of a resultant metal chelate upon metal binding. These modifications include changing the donor groups (functional groups that directly coordinate to the metal ion), introducing groups that organize water in the second coordination sphere (e.g., by hydrogen bonding), and introducing groups that slow down molecular tumbling either by increased molecular weight or by targeting the metal chelate to a macromolecule (e.g., a protein).
Chelating ligands can be used to prepare non-specific metal chelates having high relaxivity, or may be modified to incorporate target binding moieties (TBMs).
Chelating ligands and metal chelates can also be useful as luminescent probes, e.g., fluorescent (or phosphorescent) probes having long fluorescence lifetimes. Finally, chelating ligands may be useful for preparing diagnostic and/or therapeutic compositions of radioactive metal ions (page 2).
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An exemplary compound is compound 42, Table 3.
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Accordingly, the compound is within the scope of the instant claims such that Z is -C(COOH)-, L is a linker and TBM is a targeting ligand; Y2 is alkylheteroaryl-COOH and Y1 and Y3 are alkyl-CO2H.
It is noted that link between the chelator and the TBM may be represented as either:
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(page 15).
Chelating ligands may be modified to incorporate one or more Target Binding Moieties (TBM), as indicated above. TBMs can include peptides, nucleic acids, or small organic molecules. TBMs allow chelating ligands and metal chelates to be bound to targets in vivo.
Caravan does not specifically recite a chelate comprising Cu-44, Cu-47, or Sc-47.
Ray teaches low-molecular weight gadolinium (Gd)-based MR contrast agents for PSMA-specific T1-weighted MR imaging are disclosed. The (Gd)-based MR contrast agents exhibit high binding affinity for PSMA and exhibit specific T1 contrast enhancement at PSMA+ cells. The PSMA-targeted Gd-based MR contrast agents can be used for PSMA-targeted imaging in vivo. 86Y-labeled PSMA-binding ureas also are provided, wherein the PSMA-binding ureas also are suitable for use with other radiotherapeutics (abstract).
Magnetic resonance (MR) imaging is advantageous because it can provide anatomic, functional and molecular information concurrently. MR molecular imaging can combine the ubiquity of this established clinical modality and its high spatial resolution with molecular profiling in vivo. However, due to the intrinsically low sensitivity of MR, high local concentrations of biological targets are required to generate discernable MR contrast.
Without wishing to be bound to any one particular theory, it was thought that PSMA would be good target for MR molecular imaging agents because of the high target concentration per cell (approximately 3 μM/cell volume), as well as the extra-cellular location of the ligand binding site. The presently disclosed approach is directed toward improving the binding affinity (lowest Kd) of contrast agents for a specific molecular or cellular target so that the amount of agent needed for MR-detection will be much lesser. Accordingly, the presently disclosed approach combines a high binding affinity receptor specific ligand with multimeric Gd(III) agents as one possible solution for MR-based molecular imaging.
Previously, successful radiometal-based PET (64Cu) and SPECT (111In and mTc) imaging was demonstrated using radiolabeled, urea-based PSMA inhibitors in mice. A tripartite strategy containing a: (i) PSMA targeting moiety, (ii) linker for pharmacokinetic tuning, and (iii) chelating agent to enable attachment of radionuclides was developed. This strategy included 86Y labeled DOTA conjugated agents for PET imaging and to serve as a model for radiotherapy with corresponding 90Y labeled agents. Because DOTA is a strong chelating agent for many metals the same DOTA conjugates can be used with other radiotherapeutic radionuclides, such as Lu-177, Ac-225, Bi-213, Bi-212, Pb-212, Cu-67, and Sc-47. In the presently disclosed subject matter, the same urea-linker construct was used and the number of Gd-chelates (mono-, di- and trimeric Gd) was increased to optimize relaxometric behavior or MR sensitivity as high field contrast agents as well as their binding affinity to investigate systematically the possibility of PSMA-based MR imaging of PCa (paragraph 0050-53).
In some embodiments, the metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc, and Y. In particular embodiments, the metal or the radiometal is selected from the group consisting of Gd-157, Lu-177, Ac-225, Bi-212, Bi-213, Pb-203/Pb-212, Cu-67, In-111, Sc-44/Sc-47, and Y-90. In yet more particular embodiments, for MRI applications, the nonradioactive metal is Gd-157 (stable isotope); for radiotherapy applications, the radiometal is selected from the group consisting of Lu-177, Ac-225, Bi-203, Pb-210, Cu-67, In-111, Sc-47, and Y-90; for PET imaging, the radiometal is selected from the group consisting of Y-86 and Sc-44; and for SPECT application, the radiometal is selected from the group consisting of Lu-177 and In-111 (paragraph 0061).
See also exemplified compounds and compounds in claim 11 bearing PSMA targeting ligands.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide Cu-64, Cu-67, Sc-47 or Sc-44 as a radioisotope in the compounds taught by Caravan when the teaching of Caravan is taken in view of Ray. While Caravan exemplifies gadolinium complexes, rather than radioactive copper or scandium, Ray further teaches that the chelating ligands may be useful for preparing diagnostic and/or therapeutic compositions of radioactive metal ions. One would have been motivated to provide Cu-64, Cu-67, Sc-47 or Sc-44 with a reasonable expectation of success because it is known from Ray that a given chelate, e.g. DOTA, may be used for magnetic resonance imaging when gadolinium is complexed, but DOTA conjugates can be used with other radiotherapeutic radionuclides, such as Cu-64, Lu-177, Ac-225, Bi-213, Bi-212, Pb-212, Cu-67, and Sc-47 or for PET imaging, the radiometal is selected from the group consisting of Y-86 and Sc-44.
It would have been further obvious to provide -CH2-C(=O)NH- equivalent to position Z1 of the instant claims, as Caravan readily teaches that a DOTA chelator can be conjugated to a targeting ligand by -CH2-C(=O)NH- or -C(COOH)- and a linker at the stated position (page 15).
It would have been further obvious to provide a DUPA ligand for targeting PSMA because Caravan teaches conjugation of chelating agents to target binding moieties, and Ray teaches that the prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of prostate and other forms of cancer (paragraph 0003), and urea-based metal/radiometal-based agents to maintain high binding affinity for PSMA. Consequently, metal or radiometal conjugated carbamate scaffold can also be utilized for imaging and therapy of PSMA-expressing cells and tissues (paragraph 0008).
Response to arguments
Applicant argues that compound 42 from Caravan does not fall within the scope of amended claim 1 because it does not have -C(COOH)- directly linked to the rest of the molecule. Applicant further argues that because compound 42 has a picolinate arm and a carboxyl arm, a POSA would not have considered that having both a picolinate arm and a carboxyl arm would contribute to a higher relaxivity and would not have been motivated to select compound 42 for further modification. Applicant asserts that compound 42 has a much lower relaxivity than compound 29, and also that many compounds in Tables 4 and 5 have a higher relaxivity than compound 29. Applicant submits that the Examiner’s assertion that “it would have been obvious to one of ordinary skill in the art .. to provide Sc-47 or Sc-44 as a radioisotope in the compounds taught by Caravan when the teaching of Caravan is taken in view of Ray” constitutes unreasonably hindsight. A POSA would not have been motivated to select compounds 29 or 42 from Caravan to arrive at the compounds recited in amended claim 1 in the first place.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Caravan teaches that the DOTA chelate may be functionally conjugated to a targeting ligand by either C(=O)NH- or -C(COOH)- and a linker at the stated position (page 15). With regard to arguments directed to relaxivity, it is respectfully submitted that in addition to MR imaging, Caravan teaches that the chelating ligands may be useful for preparing diagnostic and/or therapeutic compositions of radioactive metal ions (page 2), it is considered that one of ordinary skill desiring to provide radiopharmaceuticals with radioactive metal ions would not be concerned with relaxivity.
Applicant further argues that because MR imaging and PET imaging are different imaging technologies, a contrast agent that is suitable for MR imaging is not necessarily suitable for PET imaging. Therefore, A POSA would not have a reasonable expectation of success that by simply replacing gadolinium with Sc-47 or Sc-44 in the compounds taught by Caravan, that compound would successfully be used for PET imaging.
Applicant’s arguments have been fully considered but are not considered to be persuasive. It is respectfully submitted that Ray readily teaches that “Because DOTA is a strong chelating agent for many metals the same DOTA conjugates can be used with other radiotherapeutic radionuclides (paragraph 0052), including reference to gadolinium and radionuclides.
Applicant further argues that Caravan and Ray do not prepare complexes with Sc. Applicant asserts that the subject application surprisingly found that that "the uptake achieved with 4'Sc-picaga-DUPA was 6 times greater than what was observed for the corresponding DOTA conjugate, citing Fig. 7. Applicant asserts that the subject application surprisingly found that ⁶⁴Cu(DO2Apic)-DUPA, and ⁶⁴Cu(NOpic-DUPA) shows "rapid renal clearance and liver uptake”.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that with regard to allegations of unexpected results, differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 716.02(d). Unexpected results should be commensurate in scope with the claimed invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also MPEP 716.02(e), an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). In the instant case, it is noted that the claims are directed to a very large number of potential compounds and are not commensurate in scope with the results which are alleged to be unexpected and the response does not provide a comparison with the closest prior art. The rejections are maintained at this time.
Claim(s) 1, 5, 9, 12, 23, 30, 33, 36, 40, 42, 45, 53-55 and 57-58 are rejected under 35 U.S.C. 103 as being unpatentable over Babich et al. (US 2015/0078998) in view of Gateau (US 2010/0247448) and Ray (US 2017/0081298).
Babich teaches compounds according to Formula I and Formula II are potent inhibitors of PSMA activity.
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The chelator D includes any linear, branched, cyclic, or alicyclic, aliphatic polyaza/polycarboxylic acid moiety that is capable of forming a metal complex with a radionuclide (paragraph 0024). Various chelators are shown in paragraph 0033.
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An exemplary synthetic scheme is set forth in Scheme 1 as an illustration of the general synthetic route for GUL-HEX-EDTA-DOTA and GUG-HEX-EDTA-DOTA analogs.
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In one aspect, the synthesis and methods for using PSMA selective
Indium, Ytterbium, Gallium, Copper and Lutetium, Gadolinium and Iron complexes
of Formula I compounds or Formula II compounds as novel radiopharmaceuticals
for the treatment and imaging of cancer cells is provided (paragraph 0041).
Pharmaceutically acceptable carriers are taught (paragraph 0060).
Metal complexes of any of the compounds of Formula II may also be provided. Specifically provided are radionuclide complexes of Formula II compounds. Illustrative radionuclides are moieties selected from the group consisting of 111In, 90Y, 68Ga, 64Cu, 153Gd, 155Gd, 157Gd, Fe and 177Lu (paragraph 0017).
The term radionuclide refers to an atom with an unstable nucleus, which is a nucleus characterized by excess energy available to be imparted either to a newly created radiation particle within the nucleus or to an atomic electron. The radionuclide can undergo radioactive decay and in the process emit subatomic ionizing particles. Illustrative of subatomic ionizing particles without limitation are alpha (.alpha.) particles, beta (.beta.) particle and gamma (.gamma.) rays. Illustrative radionuclides may include, but are not limited to 111In, 90Y, 68Ga, 64Cu, 171Lu, 153/157/158Gd, or Fe. However, the term is not limited to these four radionuclides (paragraph 0054).
Babich does not specifically teach wherein the chelator is a picolinate-pendant triazacylononane complexing scandium.
Gateau teaches ligand for metals, in particular lanthanides, of the general formula (I). The invention relates moreover to the ligands and the complexes grafted to a molecule of biological interest, as well the contrast agents and the pharmaceutical compositions including at least one of these molecules.
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Exemplary compounds are shown:
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The favorable electronic relaxation properties observed for the gadolinium complex by NMR and PER indicate that, after grafting to a macromolecule, relaxivity greater than that of the commercial contrast agents might be reached (paragraph 0086).
Preferable metal ions include gadolinium, terbium, europium, neodymium, erbium and ytterbium (paragraph 0062). Development of radiotracers is also contemplated (paragraph 0077). The invention also corresponds to the pharmaceutical compositions, including at least one ligand and/or one complex, grafted or not to a molecule of interest and/or a contrast agent as defined previously, useable in a diagnostic method and in particular a medical imaging method (paragraph 0078).
In another particular embodiment of the present invention, the ligands and/or the complexes as described in the present application may moreover be grafted to a molecule of biological interest.
The molecules of interest according to the invention correspond in particular to the biomolecules such as the nucleotides, the polypeptides, the deoxyribonucleic (DNA) and ribonucleic (RNA) acids, the antibodies or any other active molecule of biological and/or medicinal interest. It may be any molecule which an experimenter wishes to detect inside a living system, using in vivo or in vitro techniques, and using the magnetic properties of the metal and the intrinsic optical properties of the metal or the possible fluorescence conferred by the ligand (paragraph 0063-0064).
An additional grafting step to a molecule of interest is advantageous. The molecule of interest may be grafted at numerous points on the ligand or the complex by any suitable reaction from available functions arranged on the complex and in particular from alkyl or aryl radicals present on the structure and as shown above (paragraph 0071).
Ray teaches low-molecular weight gadolinium (Gd)-based MR contrast agents for PSMA-specific T1-weighted MR imaging are disclosed. The (Gd)-based MR contrast agents exhibit high binding affinity for PSMA and exhibit specific T1 contrast enhancement at PSMA+ cells. The PSMA-targeted Gd-based MR contrast agents can be used for PSMA-targeted imaging in vivo. 86Y-labeled PSMA-binding ureas also are provided, wherein the PSMA-binding ureas also are suitable for use with other radiotherapeutics (abstract). Magnetic resonance (MR) imaging is advantageous because it can provide anatomic, functional and molecular information concurrently. MR molecular imaging can combine the ubiquity of this established clinical modality and its high spatial resolution with molecular profiling in vivo. However, due to the intrinsically low sensitivity of MR, high local concentrations of biological targets are required to generate discernable MR contrast.
Without wishing to be bound to any one particular theory, it was thought that PSMA would be good target for MR molecular imaging agents because of the high target concentration per cell (approximately 3 μM/cell volume), as well as the extra-cellular location of the ligand binding site. The presently disclosed approach is directed toward improving the binding affinity (lowest Kd) of contrast agents for a specific molecular or cellular target so that the amount of agent needed for MR-detection will be much lesser. Accordingly, the presently disclosed approach combines a high binding affinity receptor specific ligand with multimeric Gd(III) agents as one possible solution for MR-based molecular imaging.
Previously, successful radiometal-based PET (64Cu) and SPECT (111In and mTc) imaging was demonstrated using radiolabeled, urea-based PSMA inhibitors in mice. A tripartite strategy containing a: (i) PSMA targeting moiety, (ii) linker for pharmacokinetic tuning, and (iii) chelating agent to enable attachment of radionuclides was developed. This strategy included 86Y labeled DOTA conjugated agents for PET imaging and to serve as a model for radiotherapy with corresponding 90Y labeled agents. Because DOTA is a strong chelating agent for many metals the same DOTA conjugates can be used with other radiotherapeutic radionuclides, such as Lu-177, Ac-225, Bi-213, Bi-212, Pb-212, Cu-67, and Sc-47. In the presently disclosed subject matter, the same urea-linker construct was used and the number of Gd-chelates (mono-, di- and trimeric Gd) was increased to optimize relaxometric behavior or MR sensitivity as high field contrast agents as well as their binding affinity to investigate systematically the possibility of PSMA-based MR imaging of PCa (paragraph 0050-53).
In some embodiments, the metal is selected from the group consisting of Gd, Lu, Ac, Bi, Pb, Cu, In, Sc, and Y. In particular embodiments, the metal or the radiometal is selected from the group consisting of Gd-157, Lu-177, Ac-225, Bi-212, Bi-213, Pb-203/Pb-212, Cu-67, In-111, Sc-44/Sc-47, and Y-90. In yet more particular embodiments, for MRI applications, the nonradioactive metal is Gd-157 (stable isotope); for radiotherapy applications, the radiometal is selected from the group consisting of Lu-177, Ac-225, Bi-203, Pb-210, Cu-67, In-111, Sc-47, and Y-90; for PET imaging, the radiometal is selected from the group consisting of Y-86 and Sc-44; and for SPECT application, the radiometal is selected from the group consisting of Lu-177 and In-111 (paragraph 0061).
See also exemplified compounds and compounds in claim 11 bearing PSMA targeting ligands.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a dota/tacn chelator having one or two picolinate arms such as bpatcn or Hno1pa2py as a functionally equivalent ligand which is conjugated to a
compounds according to Formula I and Formula II as potent inhibitors of PSMA activity taught by Babich when the teaching of Babich is taken in view of Gateau and Ray. For example, Babich teaches the following targeting moiety-linker for conjugation to a chelator.
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While Babich does not specifically recite a picolinate pendant tacn/dota chelator, it would have been obvious to one of ordinary skill in the art at the time of the instant invention to substitute such a chelator as bpatcn or Hno1pa2py as a functionally equivalent chelator to those set forth in Babich. Upon conjugation of bpatcn or Hno1pa2py to the targeting moiety-linker of Babich above, one would arrive at an amide bond linked conjugate of the instant claims.
The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143.
In the instant case, the substituted components (chelators) and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known chelator for another, and the results of the substitution would have been predictable, that is conjugation of the chelator to targeting agent for use as a PSMA targeted contrast agent. Further Gateau teaches the benefit of favorable relaxation properties with picolinate pendant chelates, and may be used as radiotracers, and each of Babich, Gateau and Ray teach macrocyclic chelators for radionuclides.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide Sc-47 or Sc-44 or Cu-67 as a radioisotope in the compounds taught by Babich and Gateau when the teachings of Babich and Gateau are taken in view of Ray. While Babich and Gateau do not specifically recite scandium, one would have been motivated to provide Sc-47 or Sc-44 with a reasonable expectation of success because it is known from Ray that a given chelate, e.g. DOTA, may be used for magnetic resonance imaging when gadolinium is complexed, but DOTA conjugates can be used with other radiotherapeutic radionuclides, such as Lu-177, Ac-225, Bi-213, Bi-212, Pb-212, Cu-67, and Sc-47 or for PET imaging, the radiometal is selected from the group consisting of Y-86 and Sc-44. Further Babich teaches that the radionuclide can undergo radioactive decay and in the process emit subatomic ionizing particles, including alpha, beta or gamma radiation and is not particularly limited. Each of Babich, Gateau and Ray are directed to targeted bifunctional chelators, including for radioactive metal, which may include scandium as taught by Ray. With regard to the length of the alkyl chain in the linker taught by Babich, see MPEP 2144. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Response to arguments
Applicant argues that Babich did not specifically teach wherein the chelator is a picolinate-pendant triazacylononane complexing scandium and that Gateau exemplified Ln complex having picolinate. Applicant asserts that Gateau did not test the relaxivity of Ln complex as shown, however, as indicated in the preceding remarks, Caravan showed compounds having a picolinate arm and a carboxyl arm have relatively poor relaxivity compared to compounds not having picolinate arms. Applicant argues that a POSA would not have considered that having both a picolinate arm and a carboxyl arm would contribute to a higher relaxivity and therefore, would not have been motivated to combine Gateau with Babich.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to arguments directed to relaxivity, it is respectfully submitted that in addition to MR imaging, Caravan teaches that the chelating ligands may be useful for preparing diagnostic and/or therapeutic compositions of radioactive metal ions (page 2), it is considered that one of ordinary skill desiring to provide radiopharmaceuticals with radioactive metal ions would not be concerned with relaxivity.
Applicant further argues that Ray did not conduct experiments on Sc complex. In fact, none of Babich, Gateau and Roger conducted experiments on Sc complex. Therefore, a POSA could not and would not have predicted the superior properties possessed by 44Sc-picaga-DUPA in view of a combination of Babich, Gateau, Ray and Roger. Similarly, none of Babich, Gateau and Roger conducted PET imaging using Cooper complex, and that one would not have predicted the superior properties possessed by 64Cu(DO2Apic)-DUPA, and 64Cu (NOpic-DUPA) in view of a combination of Babich, Gateau, Ray, and Roger.
Applicant’s arguments have been fully considered but are not found to be persuasive. See MPEP 716.01. It is respectfully submitted that objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984) ("It is well settled that unexpected results must be established by factual evidence." "[A]ppellants have not presented any experimental data showing that prior heat-shrinkable articles split. Due to the absence of tests comparing appellant’s heat shrinkable articles with those of the closest prior art, we conclude that appellant’s assertions of unexpected results constitute mere argument."). See also In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parte George, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that with regard to allegations of unexpected results, differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). See MPEP 716.02(d). Unexpected results should be commensurate in scope with the claimed invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). See also MPEP 716.02(e), an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). In the instant case, it is noted that the claims are directed to a very large number of potential compounds and are not commensurate in scope with the results which are alleged to be unexpected and the response does not provide a comparison with the closest prior art.
Applicant further argues that the scope of the claimed metal complex is a reasonable extrapolation from the exemplified metal complex in the subject application.
Applicant’s arguments have been fully considered but are not found to be persuasive. The allegations of unexpected results are directed to copper or scandium DO2Apic-DUPA or NOpic-DUPA, the claims include a large number of complexes to include triaza or tetraaza-based backbone, multiple variables for Y1 and Y2 including H, heteroaryl, alkyl-CO2H, etc., which allow for differing metal coordination, as well as a large number of variables directed to Z-L-A, as such it is considered that the claims are not commensurate in scope with the allegations of unexpected results directed to a single complex. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618