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 .
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 10/28/2025 is acknowledged. Claims 1-14, 18 and 21-26 are pending, of which claims 14 and 18 are withdrawn as being directed to a non-elected invention. Claims 1-13 and 21-26 encompass the elected invention and examined herein on the merits for patentability.
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 1-13 and 21-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 35 of copending Application No. 17/749,763 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a radioconjugate comprising a chelating linker that binds to a radioactive metal and links the radioactive metal to a monoclonal antibody (mAb) specific for human urokinase plasminogen activator receptor (UPAR), including MNPR-101 in the dependent claims. The claims of the ’763 Application are directed to a targeted radiopharmaceutical of Formula 1, which includes a PCTA chelate conjugated to MNPR-101 and a radioisotope. Accordingly, the claims are overlapping in scope and are obvious variants of one another. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-13 and 21-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12 of copending Application No. 17/749,574 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a radioconjugate comprising a chelating linker that binds to a radioactive metal and links the radioactive metal to a monoclonal antibody (mAb) specific for human urokinase plasminogen activator receptor (UPAR), including MNPR-101 in the dependent claims. The claims of the ’763 Application are directed to a targeted radiopharmaceutical of Formula 1, which includes a PCTA chelate conjugated to targeting ligand and a radioisotope, and wherein the targeting ligand is a mAb designated ATN- 658 produced by hybridoma having ATCC Accession #PTA-8191 or paratope-containing portion of ATN-658, i.e. which is specific for human urokinase plasminogen activator receptor (UPAR). Accordingly, the claims are overlapping in scope and are obvious variants of one another. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-13 and 21-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-12 of U.S. Patent No. 8,121,726 in view of Babich (US 2020/0157087). Although the claims at issue are not identical, they are not patentably distinct from each other. The instant claims are directed to a radioconjugate comprising a chelating linker that binds to a radioactive metal and links the radioactive metal to a monoclonal antibody (mAb) specific for human urokinase plasminogen activator receptor (UPAR), including MNPR-101 in the dependent claims. The claims of the ’726 patent are directed to an antibody ligand or an antigen-binding fragment thereof that binds to a binary uPA-uPAR complex and to a ternary complex of uPA-uPAR with an additional molecule X, which ligand is further characterized by properties a-c, including a mAb designated ATN- 658 produced by hybridoma having ATCC Accession #PTA-8191 or paratope-containing portion of ATN-658, i.e. which is specific for human urokinase plasminogen activator receptor (UPAR); and wherein the antibody ligand is labeled with (a) one of the following radionuclides: 3H, 14C, 35S, 67Ga, 68Ga, 72As, 89Zr, 97Ru, 99Tc, 111In, 123I, 125I, 131I, 169Yb or 201Tl. While the claims of the ‘726 patent do not recite a chelator such as Macropa-NCS to label the antibody, it would have been obvious to provide the radionuclides such as 99mTc, 89Zr, etc. in chelated form because doing so is known on the art for labeling an antibody with the stated radiolabels including to UPAR targeting ligands, see paragraph 0152. Accordingly, the claims are overlapping in scope and are obvious variants of one another.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, 5, 8, 11 and 22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Craik et al. (US 2013/0052128).
Craik discloses binding agents (e.g. antibodies) that bind to and/or modulate the activity of a urokinase plasminogen activator receptor (uPAR/CD87), compositions comprising the antibodies, and methods involving use of the antibodies (abstract).
Figure 5 shows detection of HEK cell surface uPAR with human anti-uPAR antibodies. (Panels A-D), white profiles represent staining with control whole human IgG, shaded profiles represent staining with human anti-uPAR antibody. The identity of the human anti-uPAR antibody is indicated within the shaded profile (paragraph 0012).
UPAR-binding agents may also be detectably labeled, either directly or indirectly. Direct labels include radioisotopes (e.g., 125I; 35S, 111In, 99mTc, and the like): enzymes whose products generate a signal (e.g., luciferase, B-galactosidase, horse radish peroxidase, alkaline phos phatase, and the like); fluorescent labels (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g., 152Eu, or others of the lanthanide series, attached to the antibody through metal chelating groups such as EDTA, etc. (paragraph 0073). Radionuclides may be e.g. 90Y, 131I, 177L (paragraph 0105).
Example 14 shows radiolabeling DOTA-2G10 IGG with 111In and in vivo SPECT/CT imaging. A processed image of the MDA-MB-321 xenouraph labeled with 111In-DOTA-2G10 IgG is shown in Figure 14 with four different views. As indicated by regions that are dark gray, 2G10 specifically labeled uPAR-expressing tumors.
Accordingly, a radioconjugate comprising a chelating linker that binds to a radioactive metal and links the radioactive metal to a monoclonal antibody (mAb) specific for human urokinase plasminogen activator receptor (uPAR) is disclosed.
Claim(s) 1-5, 13, 21 and 26 are rejected under 35 U.S.C. 102 as being anticipated by Boonstra et al. (Oncotarget, 2015, 6(16), p. 14260-14273).
Boonstra discloses the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity (abstract).
The urokinase-type plasminogen activator receptor (uPAR) is implicated in many aspects of tumor growth and (micro) metastasis. The levels of uPAR are undetectable in normal tissues except for occasional macrophages and granulocytes in the uterus, thymus, kidneys and spleen. Enhanced tumor levels of uPAR and its circulating form (suPAR) are independent prognostic markers for overall survival in colorectal cancer patients. The relatively selective and high overexpression of uPAR in a wide range of human cancers including colorectal, breast, and pancreas nominate uPAR as a widely applicable and potent molecular target. The current study aims to develop a clinically relevant uPAR-specific multimodal agent that can be used to visualize tumors pre- and intraoperatively after a single injection. We combined the 111Indium isotope with NIR fluorophore ZW800-1 using a hybrid linker to an uPAR specific monoclonal antibody (ATN-658) and evaluated its performance using a pre-clinical SPECT system (U-SPECT-II) and a clinically-applied NIR fluorescence camera system (FLARE™) (page 14261).
ATN-658 and isotype antibody control MOPC-21 were conjugated to the hybrid label (DTPA-Lys(ZW800)- Cys-NHS) in mean ratios (dye:antibody) of 1.7:1 and 2.2:1 respectively (page 14261).
Mice were injected with 150 μg (1 nmol) hybrid ATN-658 conjugated to 111In with activities for mice measured and sacrificed at 6 h post injection of 32.6 ± 0.1, at 24 h 33.1 ± 0.7, at 48 h 32.8 ± 0.9 and at 72 h 34.0 ± 1.2 (MBq, mean ± SD). The biodistribution study using SPECT and gamma-counter confirmed accumulation of hybrid ATN658 in subcutaneous colorectal tumors and metabolizing organs.
The antibody recognizes human uPAR (page 14266).
ATN-658 and MOPC-21 were conjugated to the zwitterionic fluorophore ZW800-1 (λex=773 nm, λem= 790 nm) and radiolabeled with 111In using a hybrid label called MSAP (multifunctional single attachment point) [59, 63]. The hybrid label (DTPA-Lys(ZW800)-CysNHS) was synthesized according to previously described procedures [59] with the following deviations: Pyridine and DMSO were used to conjugate ZW800-NHS. A stock solution (DMSO) with a concentration of 5.14 mM was prepared (page 14268).
As evidenced by the instant specification at published paragraph 0106, it is noted that MNPR-101 is formerly ATN-658. Regarding claim 21 directed to half-life, it is noted that the construct taught by Boonstra meets the physical limitations of the instant claims, “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
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) 1-6, 8, 11, 13, 21, 22 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Parry et al (US 2009/0180952) in view of McGinness (US 2021/0332334).
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 developed a method to identify Abs that mimic the characteristics of ATN-615 and ATN-658. This method can be used to develop humanized or fully human mAbs that recognize and bind to the same epitopes as those bound by ATN-615 and ATN-658. Such mimics of ATN-615 and ATN-658, the latter of which has particularly robust anti-tumor activity, are included herein as therapeutic and/or diagnostic agents (paragraph 0023).
The consensus amino acid sequence (single-letter code) of the light chain variable region (VL) and heavy chain variable region (VH) polypeptides of mAb ATN-658 are shown below. cDNA was prepared from total RNA extracted from the hybridoma expressing ATN-658 and the variable regions were cloned, amplified and sequenced using standard techniques (paragraph 0099).
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For in vivo use, particularly for injection into humans, it is desirable to decrease the immunogenicity of the mAb by making mouse-human (or rodent-human) chimeric Abs as above, or by humanizing the Abs using methods known in the art. The humanized Ab may be the product of an animal having transgenic human Ig Constant region genes. Alternatively, the Ab of interest may be genetically engineered to substitute the CH1, CH2, CH3, hinge domains, and/or the framework domain with the corresponding human sequence (paragraph 0172).
The Ab of the invention can also be labeled for detection using fluorescence-emitting metals such as 152Eu, or others of the lanthanide series. These metals can be attached to the peptide using such metal chelating groups as diethylenetriaminepentaacetic acid (DTPA) or ethylene-diaminetetraacetic acid (EDTA). DTPA, for example, is available as the anhydride, which can readily modify the NH2-containing peptides of this invention (paragraph 0180).
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).
See also claim 17, wherein a mAb designated ATN-658 produced by hybridoma having ATCC Accession #PTA-8191.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide a humanized mAb designated ATN-658 produced by hybridoma having ATCC Accession #PTA-8191 and having polypeptides according to SEQ ID 3-8 of mAb ATN-658, i.e. corresponding to MNPR-101, and having a radionuclide conjugated thereto in view of Parry and McGinness. One would have been motivated to do so because Parry teaches that humanized or fully human mAbs that recognize and bind to the same epitopes as those bound by ATN-615 and ATN-658 and mimics of ATN-658 have particularly robust anti-tumor activity, are included herein as therapeutic and/or diagnostic agents. One would have had a reasonable expectation of success in doing so because McGinness teaches that MNPR-101 is known in the art to be an exemplary antibody for targeting the urokinase receptor (Table 3). It is further noted that the instant specification at published paragraph 0106, it is noted that MNPR-101 is formerly ATN-658. One would have been further motivated to provide a radionuclide for as a diagnostic agent because Parry teaches that for in vivo diagnosis or therapy, radionuclides such as 99mTc, 111In, and 89Zr may be bound to the Ab either directly or indirectly using a chelating agent such as DTPA and DOTA.
Regarding claim 21 directed to half-life, it is noted that “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure or composition as that which is claimed, the properties applicant discloses and/or claims are necessarily present. See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). The “discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” See Atlas Power Co. v. Ireco Inc., 51 USPQ 2d 1943, 1947 (Fed. Cir. 1999). Therefore, merely claiming a new use, new function, or new property, which is inherently present in the prior art does not make the claim patentable. See In re Best, 195 USPQ 430, 433 (CCPA 1977), and MPEP § 2112.
Claim(s) 1-13, 21-23 and 25 rejected under 35 U.S.C. 103 as being unpatentable over Parry et al (US 2009/0180952) in view of McGinness (US 2021/0332334), in further view of Babich (US 2020/
The rejection over Parry in view of McGinness is applied as above.
With regard to claims 7, 9 and 10, Parry does not teach 225Ac or Macropa as the radionuclide and chelator.
Babich teaches macrocyclic complexes of alpha-emitting radionuclides, as well as compositions including such compounds and methods of use (paragraph 0003). In an aspect, compounds of Formula I and Ia provided (paragraphs 0004+), including wherein M1 is an alpha-emitting radionuclide, and variables L3, L4, L5, and L6 are independently at each occurrence a bond or a linker group; and R22, R24, R26, and R28 each independently comprises an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide, etc. (paragraph 0031+). In a further related aspect, a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula I or pharmaceutically acceptable salt thereof, with an antibody, antibody fragment, or binding peptide. In a related aspect, a modified antibody, modified antibody fragment, or modified binding peptide is provided that includes a linkage arising from conjugation of a compound of Formula IA or a pharmaceutically acceptable salt thereof, with an antibody, antibody fragment, or binding peptide.
In any embodiment disclosed herein, it may be that M1 is actinium-225 radium-223, bismuth-213, etc. (paragraph 0119).
With regard to claim a person of ordinary skill in the art will recognize that cysteine coupling reactions may be employed to conjugate prosthetic molecules with thiol-reactive termini to protein surfaces through exposed thiol side chains on cysteine residues on the protein (e.g., antibody) surface
Although targeted radiotherapy has been practiced for some time using macrocyclic complexes of radionuclides, the macrocycles currently in use (e.g., DOTA) generally form complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium, radium, bismuth, and lead isotopes. Such instability results in dissociation of the radionuclide from the macrocycle, and this results in a lack of selectivity to targeted tissue, which also results in toxicity to non-targeted tissue.
The present technology provides new macrocyclic complexes that are substantially more stable than those of the conventional art. Thus, these new complexes can advantageously target cancer cells more effectively, with substantially less toxicity to non-targeted tissue than complexes of the art. Moreover, the new complexes can advantageously be produced at room temperature, in contrast to DOTA-type complexes, which generally require elevated temperatures (e.g., at least 80° C.) for complexation with the radionuclide. The present technology also specifically employs alpha-emitting radionuclides instead of beta radionuclides. Alpha-emitting radionuclides are of much higher energy, and thus substantially more potent, than beta-emitting radionuclides (paragraph 0099).
Preparation of Macropa-(OCH2CH2)-Ph-NCS is taught at paragraph 0246, which teaches a schematic overview of the synthesis of an alternative embodiment of , having improved stability is provided in FIG. 3. This compound is evaluated as described below, and useful in Macropa-NCS the chelation of radionuclides for their conjunction to antibodies, antibody fragments (e.g., antigen-binding fragments), and peptides, and their consequent use in the manufacture of therapeutic compounds and targeted delivery of therapeutic radiation (paragraph 0246).
The compounds of any embodiment and aspect herein of the present technology may be a tripartite compound. However, such tripartite compounds are not restricted to compositions including Formulas I, IA, or II. Thus, in an aspect, a tripartite compound is provided that includes a first domain that has relatively low but still specific affinity for serum albumin (e.g., 0.5 to 50×10−6M), a second domain including a chelating moiety such as but not limited to those described herein, and a third domain that includes tumor targeting moiety (TTT) having relatively high affinity for a tumor antigen (e.g., 0.5 to 50×10−9M). The following exemplary peptide receptors, enzymes, cell adhesion molecules, tumor associated antigens, growth factor receptors and cluster of differentiation antigens are useful targets for constructing the TTT domain: somatostatin peptide receptor-2 (SSTR2), gastrin-releasing peptide receptor…uPAR, etc. Other such targets will be apparent to those of skill in the art, and compounds that bind these can be incorporated in the TTT to produce a tripartite radiotherapeutic compound (paragraph 0150).
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide Macropa-NCS as a functionally equivalent chelating ligand and 225Ac as a radionuclide when the teaching of Parry and McGinness are taken in view of Babich. While Parry teaches that the conjugated antibodies may be used in therapy and that radionuclides may be bound to the Ab either directly or indirectly using a chelating agent such as DTPA and DOTA, Macropa-NCS is not specifically taught. However, one would have been motivated to substitute Macropa-NCS as a macrocyclic ligand, with a reasonable expectation of success, because Babich teaches that DOTA generally forms complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium (i.e. 225), resulting in dissociation of the radionuclide from the macrocycle, and this results in a lack of selectivity to targeted tissue, which also results in toxicity to non-targeted tissue; and that macrocycle complexes taught therein substantially more stable than those of the conventional art. Upar is further taught as a targeting ligand in Babich.
Regarding claim 12, Parry teaches that the radionuclides may be bound to the Ab either directly or indirectly using a chelating agent such as DTPA and DOTA. It is known from Babich that macrocycles can be conjugated at cysteine sites. A person of ordinary skill in the art will recognize that cysteine coupling reactions may be employed to conjugate prosthetic molecules with thiol-reactive termini to protein surfaces through exposed thiol side chains on cysteine residues on the protein (e.g., antibody) surface (paragraph 0147). Accordingly, it would have been obvious to one of ordinary skill in the art to provide site specific conjugation of the chelates on the antibody.
Claim(s) 1-6, 8, 11, 13, 21, 22, 24 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Parry et al (US 2009/0180952) in view of McGinness (US 2021/0332334), in further view of Piwnica-Worms (US 2023/0014398).
The rejection over Parry in view of McGinness is applied as above.
With regard to claim 24, Parry does not teach DFO as the chelator.
Piwnica-Worms teaches that radioactively labeled monoclonal antibodies and antibody fragments may be produced according to well-known methods in the art. For instance, monoclonal antibodies can be iodinated by contact with sodium and/or potassium iodide and a chemical oxidizing agent such as sodium hypochlorite, or an enzymatic oxidizing agent, such as lactoperoxidase. Monoclonal antibodies according to the disclosure may be labeled with technetium-99m by ligand exchange process, for example, by reducing pertechnate with stannous solution, chelating the reduced technetium onto a Sephadex column and applying the antibody to this column. Alternatively, direct labeling techniques may be used, e.g., by incubating pertechnate, a reducing agent such as SNCl2, a buffer solution such as sodium-potassium phthalate solution, and the antibody. Intermediary functional groups that incorporate chelators, which are often used to bind radioisotopes that exist as metallic ions to an antibody are diethylene-triamine-pentaacetic acid (DTPA), ethylene diamine-tetraacetic acid (EDTA), monomeric or dendrimeric 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), deferoxamine (DFO), or 1-hydroxy-2(1H)-pyridinone derivatives (e.g., 3,4,3-LI(1,2-HOPO) or HOPO).
It would have been obvious to one of ordinary skill in the art at the time of the instant invention to substitute DFO as a functional equivalent to the chelators including DTPA and DOTA disclosed by Parry when the teaching of Parry is taken in view of Piwnica-Worms. 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 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 complexation of a radionuclide and conjugation to an antibody.
Claim(s) 1, 2, 4, 5, 8, 11, 22 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Craik et al. (US 2013/0052128) in view of Lopez et al. (US 2021/0324104).
Craik teaches binding agents (e.g. antibodies) that bind to and/or modulate the activity of a urokinase plasminogen activator receptor (uPAR/CD87), compositions comprising the antibodies, and methods involving use of the antibodies (abstract).
Figure 5 shows detection of HEK cell surface uPAR with human anti-uPAR antibodies. (Panels A-D), white profiles represent staining with control whole human IgG, shaded profiles represent staining with human anti-uPAR antibody. The identity of the human anti-uPAR antibody is indicated within the shaded profile (paragraph 0012).
UPAR-binding agents may also be detectably labeled, either directly or indirectly. Direct labels include radioisotopes (e.g., 125I; 35S, 111In, 99mTc, and the like): enzymes whose products generate a signal (e.g., luciferase, B-galactosidase, horse radish peroxidase, alkaline phos phatase, and the like); fluorescent labels (e.g., fluorescein isothiocyanate, rhodamine, phycoerythrin, and the like); fluorescence emitting metals, e.g., 152Eu, or others of the lanthanide series, attached to the antibody through metal chelating groups such as EDTA, etc. (paragraph 0073). Radionuclides may be e.g. 90Y, 131I, 177L (paragraph 0105).
Example 14 shows radiolabeling DOTA-2G10 IGG with 111In and in vivo SPECT/CT imaging. A processed image of the MDA-MB-321 xenouraph labeled with 111In-DOTA-2G10 IgG is shown in Figure 14 with four different views. As indicated by regions that are dark gray, 2G10 specifically labeled uPAR-expressing tumors.
Accordingly, a radioconjugate comprising a chelating linker that binds to a radioactive metal and links the radioactive metal to a monoclonal antibody (mAb) specific for human urokinase plasminogen activator receptor (uPAR) is disclosed.
Craik does not specifically teach wherein a radionuclide is 225Ac.
Lopez teaches an antibody is conjugated to a radioisotope or to a radioisotope-containing chelate. For example, the antibody can be conjugated to a chelator linker, e.g. DOTA, DTPA or tiuxetan, which allows for the antibody to be complexed with a radioisotope. The antibody may also or alternatively comprise or be conjugated to one or more radiolabeled amino acids or other radiolabeled molecules. Non-limiting examples of radioisotopes include, a radioisotope emitting beta- or alpha-particle radiation can be used, e.g., 1311, 90Y, 211At, 212Bi, 67Cu, 186Re, 188Re, and 212Pb. 3H, 14C, 15N, 35S, 90Y, 99Tc, 1251, 1311, 186Re, 213Bi, 225Ac and 227Th.
A further aspect of the invention relates to the anti-Nectin-4 antibody of the invention for diagnosing and/or monitoring and/or staging a cancer and particularly a cancer in which Nectin-4 is overexpressed.
It would have been obvious to one of ordinary skill in the art at the time of the invention to substitute 225Ac as a functionally equivalent radioisotope in Craik when the teaching of Craik is taken in view of Lopez. One would have been motivated to do so, with a reasonable expectation of success, because Wu teaches that various radioisotopes including 90Y, etc. are suitable, and Lopez teaches that 90Y, 99Tc, 1251, 1311, 225Ac are desirable isotopes for use radionuclides which are conjugated to antibody for use in radioimaging or therapy.
Claim(s) 1-6, 8, 11-13, 21, 22, 24 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Parry et al (US 2009/0180952) in view of McGinness (US 2021/0332334), in further view of Ahn et al. (Journal of Nuclear Medicine, 2019, 60(supplement 1), 66).
The rejection over Parry in view of McGinness is applied as above.
Parry does not specifically recite site-specific conjugation of the chelating ligand or DFO as the chelator.
Ahn teaches that classical antibody bioconjugation techniques rely on non-site specific conjugation to amino acids, typically accessible lysines or reduced cysteines; however, stochastic conjugation can alter targeting affinity and pharmacokinetics of the antibody. ImmunoPET requires favorable in vivo pharmacokinetics and high binding affinity to the target for clinical applicability. Here, we describe the preparation and in vivo application of site-specifically functionalized immunoconjugates with chelators designed for diagnostic and therapeutic radiometals. The on-target uptake of site-specific immunoconjugates is compared to the uptake of classical stochastic conjugates via nuclear imaging and biodistribution in a murine xenograft model.
Dibenzocyclooctyne (DBCO) functionalized radiometal chelators desferrioxamine (DFO) and 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthesized and conjugated to site-specifically incorporated para-azido phenylalanine of glycan-free variants of the antibody trastuzumab. Clinical trastuzumab was conjugated to isothiocyanate-functionalized chelators via lysine residues in a non-site-specific fashion. ESI-TOF MS/MS was employed to characterize the corresponding immunoconjugates and radiolabeling was carried out with 89Zr and 111In.
ESI-TOF MS/MS analyses show that site-specific, copper-free click chemistry results in predominantly one immunoconjugate product with 4 chelators appended, whereas stochastically labeled conjugate ranges from 0 to 6 chelators per antibody. Both DFO-functionalized immunoconjugates were efficiently radiolabeled with yields of 82±5% for stochastic 89Zr-DFO-trastuzumab and 78±6% for site-specific 89Zr-DFO-DBCO-trastuzumab, with specific activity of 0.85±0.15 mCi/mg and 0.79±0.05 mCi/mg respectively.
We have successfully prepared site-specifically radiolabeled immunoconjugates and assessed their performance in vivo. Site-specific functionalization using copper-free click chemistry produces immunoPET and immunoSPECT probes with retained high targeting affinity and favorable in vivo performance. The efficient click reaction between azide-functionalized antibody and DBCO linker provides a modular platform for preparing site-guaranteeing minimal batch variation and consistent in vivo performance.
It would have been obvious to one of ordinary skill in the art at the time of the invention to provide site-specific labeling of the antibodies taught by Parry and McGinness in view of Ahn. One would have been motivated to do so, with a reasonable expectation of success, because Parry teaches conjugation of DTPA or DOTA to antibody for radionuclide labeling, and Ahn teaches that site-specific conjugation allows for retained high targeting affinity and favorable in vivo performance and allows for a modular platform for preparing site-guaranteeing minimal batch variation and consistent in vivo performance. It would have been further obvious to substitute DFO as a functionally equivalent chelator to DTPA or DOTA. 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 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 complexation of a radionuclide and conjugation to an antibody.
Conclusion
No claims are allowed at this time.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618