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 4/24/2026, in reply to the Office Action mailed 11/25/2025, is acknowledged and has been entered. Claims 1 and 11 have been amended. Claims 1, 3-14, 18 and 21-25 are pending, of which claims 14 and 18 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1, 3-13 and 21-25 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment.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 of rejection are set forth herein, necessitated by claim amendment.
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 4 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 is dependent on cancelled claim.
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, 3-13 and 21-25 are rejected under the doctrine of obviousness-type double patenting in view of claims 1-11 and 35 in co-owned U.S. Patent Application No. 17/749,763, for reasons set forth in the previous Office Action. Applicant acknowledges the provisional double patenting rejection. However, the present application is earlier filed compared to the reference application. Should this be the last remining rejection prior to allowance, this rejection should be withdrawn to allow the earlier filed application to proceed to allowance (MPEP 804).
Claims 1, 3-13 and 21-25 are rejected under the doctrine of obviousness-type double patenting in view of claims issued in co-owned U.S. Patent No. 8,101,726 in view of Fonge (US 2021/0236667).
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), wherein the antibody does not bind to the uPA-binding site of uPAR and does not inhibit binding of uPA to uPAR, and wherein there are < 2 chelating linkers per antibody. 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 201TI. While the claims of the '726 patent do not recite a chelator such as Macropa-NCS, DFO, etc. 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 as taught by Fonge. Further it would have been obvious to provide the stated number of chelators because Fonge teaches an antibody is coupled to 1-3 scaffolds, for an antibody: radionuclide ratio of 1:1 to 1:3. The number of scaffolds per antibody may be controlled for example by adjusting the pH of the reaction, the reaction time and the # of fold excess of the chelator to antibody (paragraph 0182, 198).
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, 3-5, 13 and 21 are rejected under 35 U.S.C. 102 as being anticipated by Boonstra et al. (Oncotarget, 2015, 6(16), p. 14260-14273), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that Boonstra describes an anti-uPAR antibody linked to a fluorescent dye and indicates the ratio of the dye to antibody is 1.7:1 or 2.2:1. Applicant submits that a dye is not the same as a radioactive metal and the ratio for the chelating linker to the different agents on an antibody is not necessarily the same or interchangeable as the metal and dye have different properties. Applicant argues that the conjugate of Boonstra does not have the linker directly attached to the antibody and the fluorescent moiety, and asserts that the construct in Boonstra has the structure "DTPA-Lys(ZW800)-Cys-ATN-658" indicating that the antibody is either directly connected to the dye or at least connected by a cysteine residue between the dye and the antibody. Applicant contends that this construct does not have the structural order of metal-linker-antibody as recited in the claims.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the hybrid label DTPA-Lys(ZW800)-Cys-NHS was provided in Boonstra, as such there are an equivalent number of DTPA and dye, as such a dye to antibody ratio of 1.7:1 is within the scope of the instant claims. The dye or lysine is interpreted to be encompassed within the scope of a linker, as in a metal-linker-antibody of the instant claims. Applicant’s arguments have been fully considered but the rejection is maintained.
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, 3-13 and 21-25 are rejected under 35 U.S.C. 103 as being unpatentable over Parry et al (US 2009/0180952) in view of Fonge (US 2021/0236667).
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 201TI. 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.
Parry does not specifically recite the number of chelators per antibody.
Fonge teaches radiolabeled and/or cytotoxin labelled antibodies and methods and uses of these antibodies. In one embodiment, provided is a cytotoxic agent comprising an antibody that specifically binds a target disease cell surface receptor, a cytotoxin, and a radiolabel, wherein the cytotoxin is linked directly or indirectly to the antibody, and wherein the radiolabel comprises a radionuclide and optionally a scaffold, wherein the scaffold is directly or indirectly coupled to the antibody. Also provided are methods of preparing the cytotoxic agent and methods of treating disease using the cytotoxic agent (abstract).
A scaffold is required for conjugation to the antibody for some radionuclides.
For example, where the radionuclide is 211At or 131I, the radionuclide may be directly coupled to the antibody.
A radionuclide may be coupled directly to an antibody … or by directly radiolabelling tyrosine residues on the antibody with isotopes such as 211At or 131I.
Where the radionuclide is 225Ac, the radionuclide will be present in a scaffold such that the radionuclide is indirectly coupled to the antibody.
The scaffold can comprise a chelator which chelates the radionuclide and has a moiety that is or can be coupled to an antibody. For example, the term “derived from a chelator or derived from a bifunctional chelator” refers to a chelator that prior to coupling is bifunctional and which been coupled to an antibody.
Chelators for radionuclides are known in the art. The chelator is typically a bifunctional chelator. As used herein, the term “bifunctional chelator” refers to a chelator that has a metal binding function as well as a chemically reactive functional group that provides the requisite chemistry for coupling to the antibody.
In another embodiment, the chelator is isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (NCS-DTPA), isothiocyanatobenzyl-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid) (p-NCS-DOTP) and Macropa-NCS (6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4-isothiocyanatopicolinic acid).
[0195] The chelator can also be DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid; tetraxetan), and derivatives thereof such as p-SCN-Bn-DOTA and Meo-DOTA-NCS or DOTP (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic) acid).
Other examples of chelators that can be used include 1,4,7,10-Tetraazacyclododecane-1,4,7-tris(acetic acid)-10-(2-thioethyl)acetamide (DO3A), [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-DTPA), 2-S-(4-lsothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-NOTA), 1,4,7-Triazacyclononane-1,4-bis-acetic acid-7-maleimidoethylacetamide (maleimide-NOTA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) (CB-TE2A) and Triethylenetetramine (TETA) derivatives.
The scaffold may be directly or indirectly coupled to the antibody. For example, the scaffold may be coupled to the antibody by any chemical reaction that will bind the scaffold and the antibody, so long as these retain their respective activities/characteristics for the intended use thereof. This coupling can include chemical mechanisms including for instance covalent binding, affinity binding, intercalation, coordinate binding and complexation. In one embodiment, the scaffold is attached to the antibody by an isopeptide linkage with an amino group of the antibody.
In one embodiment, each scaffold carries one radionuclide. Optionally, each antibody is coupled to 1-3 scaffolds, for an antibody: radionuclide ratio of 1:1 to 1:3. The number of scaffolds per antibody may be controlled for example by adjusting the pH of the reaction, the reaction time and the # of fold excess of the chelator to antibody.
The radionuclide is optionally an alpha emitter (a radionuclide that emits alpha particles) or a beta emitter (a radionuclide that emits beta particles) (paragraph 0188-0193).
FIG. 1F is a schematic of 225Ac-antibody using macropa-NHS to chelate the 225Ac (paragraph 0084).
DFO-8709-scFv-Fc was radiolabeled with 89Zr (paragraph 0343).
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 via a chelator in view of Parry and Fonge. 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 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.
It is noted that the instant specification at published paragraph 0106, that MNPR-101 is formerly ATN-658.
It would have been further obvious to provide the claimed number of chelators per antibody when the teaching of Parry is taken in view of Fonge. One would have been motivated to select from among a known value of chelators (scaffolds) per antibody, as shown by Fonge to be an antibody: radionuclide ratio of 1:1 to 1:3. One would have had a reasonable expectation of success in doing so because Fonge teaches that the number of scaffolds per antibody may be controlled for example by adjusting the pH of the reaction, the reaction time and the # of fold excess of the chelator to antibody.
It would have been further obvious to substitute DOTA, DTPA, macropa-NCS, DFO, etc. as taught by Fonge as functionally equivalent chelators by which to conjugate a radionuclide to the antibody. 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. 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 a chelator for complexing radionuclide to an antibody.
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.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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