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 .
Acknowledgement of Receipt
Applicant’s Response, filed 1/2/2026, in reply to the Office Action mailed 10/2/2025, is acknowledged and has been entered. Claim 1 has been amended. Claims 1, 2, 4-6 and 10-31 are pending, of which claims 2 and 18-31 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1, 4-6 and 10-17 are readable upon 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 Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds of rejection are set forth herein, 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, 4-6 and 10-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 17/749,763, for reasons set forth in the previous Office Action. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
Applicant argues that the claims have been amended such that Q+³ is a trivalent radioactive isotope ion of Ac+3 submits that the amended claims of the present application are patentably distinct over the claims of the '763 application. Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the trivalent Ac radioactive isotope is encompassed by the trivalent radioactive isotope ion of the ‘763 Application, see MPEP 804. Accordingly the claims are overlapping in scope and are obvious variants of one another.
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, 4-6, 10, 11 and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Kovacs et al. (US 8,198,101) in view of Cooper et al. (Bioconjugate Chem., 2012, 23, p. 1029−1039), in further view Frank (US 2004/0067924).
Kovacs teaches bifunctional polyazamacrocyclic chelating agents, to complexes of these chelating agents with metal ions, and to conjugates of these complexes with a biological carrier. Bifunctional polyazamacrocyclic chelating agents of Formula XI are taught:
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, including variables R1 which may be H or an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof, and R may be hydrogen (column 3 and 10).
Exemplary compounds include XXXVII (column 27):
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And L-p-NCS-Bz-PCTA (column 34).
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.
The invention provides a conjugate comprising the bifunctional polyazamacrocyclic chelating agent of one of formulas (I), (II), (III), (IV), (IV), (VI), (VIa-f), (VII), (VIIa-c), (VIII), (VIIIa-c), (IX), (IXa-c), (X), (Xa-c), (XI), (XIa-c), (XII), (XIIa-c), (XIII), (XIIIa-c), (XIV), (XIVa-c), (XV), (XVa-c), (XVI), and (XVIa-c), defined above, covalently attached to a biological carrier, such as a. protein, antibody, antibody fragment, hormone, peptide, growth factor, antigen or hapten.
The metal ion may be 177Lu, 212Bi, etc. (column 15).
The term "antibody" refers to a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a heteroantibody, or a fragment thereof. Antibodies used in the present invention may be directed against, for example, cancer, tumors, bacteria, fungi, leukemias, lymphomas, autoimmune disorders involving cells of the immune system, normal cells that need to be ablated such as bone marrow and prostate tissue, virus infected cells including HIV, parasites, mycoplasma, differentiation and other cell membrane antigens, pathogen surface antigens, toxins, enzymes, allergens, drugs and any biologically active molecules. Some examples of antibodies are HuM195 (anti-CD33), etc.
Kovacs does not specifically recite wherein g is from 1 to about 12, and wherein the radionuclide is 225Ac.
Cooper teaches that high radiolabeling efficiency, preferably to high specific activity, and good stability of the radioimmunoconjugate are essential features for a successful immunoconjugate for imaging or therapy. In this study, the radiolabeling efficiency, in vitro stability, and biodistribution of immunoconjugates with eight different bifunctional chelators labeled with 64Cu were compared. The anti-CD20 antibody, rituximab, was conjugated to four macrocyclic bifunctional chelators (p-SCN-Bn-DOTA, p-SCN-Bn-Oxo-DO3A, p-SCN-NOTA, and p-SCN-PCTA), three DTPA derivatives (p-SCN-Bn-DTPA, p-SCN-CHX-A″- DTPA, and ITC-2B3M-DTPA), and a macrobicyclic hexamine (sarcophagine) chelator (sar-CO2H) = (1-NH2-8-NHCO- (CH2)3CO2H)sar where sar = sarcophagine = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane). Radiolabeling efficiency under various conditions, in vitro stability in serum at 37 °C, and in vivo biodistribution and imaging in normal mice over 48 h were studied. All chelators except sar-CO2H were conjugated to rituximab by thiourea bond formation with an average of 4.9 ± 0.9 chelators per antibody molecule.
Figure 1 shows the structure of p-SCN-Bn-PCTA, and Table 1 shows the average number of bifunctional chelators per antibody molecule to be 4.9 ± 1.2 for p-SCN-Bn-PCTA.
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64Curituximab immunoconjugates containing a macrocyclic BFC (pSCN-Bn-DOTA, p-SCN-Bn-NOTA, p-SCN-Bn-oxo-DO3A, pSCN-Bn-PCTA, or sar-CO2H) demonstrated greater radiochemical stability than immunoconjugates containing DTPA BFC derivatives. All macrocyclic conjugated immunoconjugates showed high stability in serum over 48 h with 64Cu-NOTArituximab showing the greatest stability (97.5% ± 0.3%) at 48 h (page 1033).
Frank teaches that specific cytotoxic effects of "alpha particle-emitting radioimmunoconjugates" have been demonstrated in several experimental systems. Specific in vitro cell-killing has been demonstrated against a human epidermoid cell line using 213Bi- and 225Ac-containing immunoconjugates.
Potential for use of 225Ac in radiotherapy of cancer has also been recognized due to its favorable properties. This isotope decays with a radioactive half-life of 10 days into a cascade of short lived alpha- and beta-emitting isotopes (paragraph 0004+).
It would also be desirable to provide conjugates of such 225Ac complexes with a biological carrier. The biological carrier in these conjugates would provide the tumor specificity and the 225Ac isotope would provide potent cytotoxicity.
Another desirable property of these conjugates includes physiological compatibility which would permit the 225Ac complex, if separated from its targeting, conjugated biological carrier in vivo, to be soluble in physiological fluids and thus be rapidly eliminated from the body.
The present invention is directed to 225Ac complexes and their conjugates with a biological carrier. The 225Ac complexes and conjugates of the present invention are useful for the treatment of cancer in mammals, especially humans.
More specifically, the present invention is directed to 225Ac complexes comprising a functionalized polyazamacrocyclic chelant compound of the formula I hereinbelow
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(paragraph 0012-6).
Exemplary compounds include compound 4.
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While Kovacs does not specifically teach the average number of PCTA chelates per antibody on the pSCN-Bn-PCTA antibody conjugate complexes, it would have been obvious to one of ordinary skill in the art at the time of the invention to provide an average number of chelating agents per antibody within the claimed range when the teaching of Kovacs is taken in view of Cooper. Each of Kovacs and Cooper are directed to radiolabeled chelate complexes conjugated to an antibody, wherein the antibody is linked to the chelator via a thiourea bond. One would have been motivated to provide approximately 5 chelates per antibody because Cooper teaches as such to be suitable for conjugation of PCTA to antibody for use as a successful immunoconjugate for imaging or therapy. One would have had a reasonable expectation of success in doing so because both Kovacs and Cooper teach conjugation of p-SCN-Bn-PCTA to an antibody.
It would have been further obvious to provide a radioactive isotope of Ac3+, such as 225Ac, in order to provide a suitable metal for use in radiotherapy when the teachings of Kovacs and Cooper are taken in view of Frank. One would have been motivated to do so, with a reasonable expectation of success, because Frank teaches that both 212Bi and 225Ac-containing immunoconjugates have demonstrated in vitro cell killing, and that 225Ac has favorable properties, such as decays with a radioactive half-life of 10 days into a cascade of short lived alpha- and beta-emitting isotopes. Kovacs teaches 225Ac PCTA-based complexes and conjugates useful for the treatment of cancer in mammals, especially humans.
Claim(s) 1, 4-6 and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Kovacs et al. (US 8,198,101) in view of Cooper et al. (Bioconjugate Chem., 2012, 23, p. 1029−1039) and Frank (US 2004/0067924), in further view of Parry et al. (US 2009/0180952).
The rejection over Kovacs in view of Cooper and Frank is applied as above.
With regard to claims 12, Kovacs does not specifically teach wherein the antibody is ATN-658.
Parry teaches antibodies or other ligands specific for the binary uPA-uPAR complexes, for ternary complexes comprising uPA-uPAR and for complexes of uPAR and proteins other than uPA such as integrins inhibit the interaction of uPA and uPAR with additional molecules with which the complexed interact. Such antibodies or other ligands are used in diagnostic and therapeutic methods, particularly against cancer (abstract).
The present inventors have produced and studied two mabs, ATN-615 and ATN-658, that specifically bind ligand-occupied uPAR and thus serve as exemplary molecules that can bind uPAR regardless of the presence of ligand. The mAbs can detect both occupied and unoccupied uPAR in a tumor or other diseased tissue where the uPA system plays a role in the pathobiology. Preferred Abs or other non-Ab ligands are those that do not bind to the uPA-binding site of uPAR (paragraph 0021).
The present invention provides antibodies, both polyclonal and monoclonal, reactive with uPA/uPAR complexes that inhibit interactions of uPAR with integrins or other downstream targets. The antibodies may be xenogeneic, allogeneic, syngeneic, or modified forms thereof, such as humanized or chimeric antibodies (paragraph 0119).
For in vivo diagnosis or therapy, radionuclides may be bound to the Ab either directly or indirectly using a chelating agent such as DTPA and DOTA. Examples of such radionuclides are 99Tc, 123I, 125I, 131I, 111In, 97Ru, 67Cu, 67Ga, 68Ga, 72As, 89Zr, 90Y and 201Tl. Generally, the amount of labeled Ab needed for detectability in diagnostic use will vary depending on considerations such as age, condition, sex, and extent of disease in the patient, contraindications, if any, and other variables, and is to be adjusted by the individual physician or diagnostician. Dosage can vary from 0.001 mg/kg to 100 mg/kg (paragraph 0181).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide ATN-658 as the antibody to be conjugated to a chelating agent for complexation of a radionuclide when the teachings of Kovacs, Cooper and Frank are taken in view of Parry. While Kovacs and Cooper do not specifically recite ATN-658 as the antibody, Kovacs teaches that the antibody may be directed against cancer, tumors, etc., and Parry teaches that ATN-658 specifically binds ligand-occupied uPAR, and such antibodies or other ligands, including humanized antibodies, etc., are used in diagnostic and therapeutic methods, particularly against cancer. One would have had a reasonable expectation of success in doing so because Parry teaches that for in vivo diagnosis or therapy, radionuclides may be bound to the Ab either directly or indirectly using a chelating agent.
Claim(s) 1, 4-6, 10, 11 and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Kovacs et al. (US 8,198,101) in view of Cooper et al. (Bioconjugate Chem., 2012, 23, p. 1029−1039) and Frank (US 2004/0067924)), in further view of Benesova (US 2021/0009715).
The rejection over Kovacs in view of Cooper and Frank is applied as above.
Kovacs and Cooper do not specifically recite that the composition is isotonic to the blood of the intended host.
Benesova teaches conjugates by covalently cupling a PSMA-peptidomimetic urea-based binding entity via suitable spacers and linkers to a chelator capable of complexing therapeutic/diagnostic radionuclides on the one hand, and a human serum albumin (HSA) binding entity on the other hand (paragraph 0034). The chelator may be PCTA.
For (pharmaceutical) compositions in liquid form, useful pharmaceutically acceptable excipients in general include solvents, diluents or carriers such as (pyrogen-free) water, (isotonic) saline solutions such phosphate or citrate buffered saline, fixed oils, vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, corn oil, ethanol, polyols (for example, glycerol, propylene glycol, polyetheylene glycol, and the like); lecithin; surfactants; preservatives such as benzyl alcohol, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like; isotonic agents such as sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride; aluminum monostearate or gelatin; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Buffers may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e. the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the aforementioned salts may be used, which do not lead to damage of cells due to osmosis or other concentration effects. Reference media are e.g. liquids occurring in in vivo methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in in vitro methods, such as common buffers or liquids. Such common buffers or liquids are known to a skilled person.
Liquid (pharmaceutical) compositions administered via injection and in particular via i.v. injection should preferably be sterile and stable under the conditions of manufacture and storage. Such compositions are typically formulated as parenterally acceptable aqueous solutions that are pyrogen-free, have suitable pH, are isotonic and maintain stability of the active ingredient(s) (paragraph 0283-4). Administration to human subjects is taught (paragraph 0299, 306, 310+).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide the radioactive immunoconjugates taught by Kovacs, Cooper and Frank in isotonic solution for administration to human patients when the teachings of Kovacs and Cooper are taken in view of Benesova. One would have been motivated to do so, with a reasonable expectation of success, because Benesova teaches that the immunoconjugates are useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent, and Benesova teaches that targeted radioactive chelate complexes are typically formulated as parenterally acceptable aqueous solutions that are pyrogen-free, have suitable pH, are isotonic and maintain stability of the active ingredient(s).
Response to arguments
Applicant argues that Claim 1 has been amended to be directed to a targeted radiopharmaceutical that comprises a targeting species thiourea-bonded to PCTA-chelated Q+³ radioactive isotope ion wherein Q3+ is a trivalent radioisotope of Ac3+. Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the Frank reference is included to show that it would have been an obvious modification from Kovacs to provide a radioactive isotope of Ac3+, such as 225Ac, in order to provide a suitable metal for use in radio therapy when the teachings of Kovacs and Cooper are taken in view of Frank. One would have been motivated to do so, with a reasonable expectation of success, because Frank teaches that both 212Bi an 225Ac-containing immunoconjugates have demonstrated in vitro cell killing, and that 225Ac has favorable properties, such as decays with a radioactive half-life of 10 days into a cascade of short lived alpha- and beta-emitting isotopes. Kovacs teaches 225Ac PCTA-based complexes and conjugates useful for the treatment of cancer in mammals, especially humans.
Conclusion
No claims are allowed at this time.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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