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 .
Information Disclosure Statement
The information disclosure statements filed January 16, 2024 and February 4, 2026 are acknowledged and have been considered by the examiner.
Drawings
The drawings are objected to because of the following informalities:
Figures 54 and 55 are of low resolution and are blurry. It is difficult to interpret the labels and values of the graphs. Furthermore, it is not possible to discern which curves on the plots correspond to which concentration of ligand. Therefore, these drawings are not able to be interpreted by the examiner.
Figure 56 is of inadequate resolution. It is difficult to discern the labels and values on the axes of the plot. Therefore, the drawing is not in a state in which the examiner can interpret.
In Figure 57, the x-axis labels of the two biodistribution plots are formatted in a way in which the characters of the labels have shifted in a way that makes them difficult to read and discern what words are written. Furthermore, in the Uptake graph, it is not possible to distinguish between the Surface Uptake and Self-block data being presented on the graph, as these look identical in the key of the graph.
Appropriate correction is required.
Claim Objections
Claims 21, 29, 32, 35, 38, and 41 are objected to because of the following informalities:
In claim 21, several of the provided images of the FAP-targeted conjugate structures lack clarity in a way that makes it difficult to discern the atoms and bonds in portions of the structures. This especially applies to the first, fourth, fifth, eleventh, twelfth, and fourteenth provided structures in the order in which they are presented.
In claims 29, 35, and 41, both glycerol and glycerine are listed as optional components in the pharmaceutical composition. To the examiner’s understanding, glycerol and glycerine are the same thing. Therefore, this is a duplication of items in the lists and one should be removed from each list.
In claim 29, “a syntheticsolvents” appears to contain typographical and grammatical errors. The examiner suggests this phrase be amended to “a synthetic solvent” instead.
In claims 32 and 38, head and neck cancer appears in the lists of cancers twice. One instance should be removed from each list.
In claims 35 and 41, “a synthetic solvents” contains a grammatical error. The examiner suggests the phrase be amended to “a synthetic solvent” instead in both instances.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 35 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.
Claim 35 recites the limitation “The method according to claim 11” in the first line. There is insufficient antecedent basis for this limitation in the claim. In the set of claims being examined, there is no claim 11, as claim 11 was previously canceled by the applicant on August 25, 2025. For the purpose of examination, the examiner will interpret claim 35 to depend on claim 30 and include the limitation of the method according to claim 30 instead.
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 21-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 12,514,938 in view of Jo (Jo, H.; et al., J. Am. Chem. Soc., 2012).
The claims of U.S. Patent No. 12,514,938 (henceforth referred to as the ‘938 patent) are drawn to fibroblast activation protein (FAP)-targeted conjugate compounds. These compounds are characterized by the structure comprising a cyclic peptide, a chelating moiety, and a linking group. The conjugates may be labeled with radionuclides. The conjugates may also be part of a pharmaceutical composition further comprising pharmaceutically acceptable carriers and other agents.
The claims of the ‘938 patent are not drawn to FAP targeting conjugate compounds possessing identical structures to those of instant claim 21.
Jo teaches the preparation of cyclic peptides using various crosslinking reagents that react with and connect two cysteine residues in a peptide (pg. 17,706, Scheme 1; and pg. 17,710, Cross-Linker Screen). Among the crosslinking reagents tested by Jo are 1,2-bis(bromomethyl) benzene (c14), 1,3-bis(bromomethyl) benzene (c15), and 1-4-bis(bromomethyl) benzene (pg. 17,706, Scheme 1). Jo found that the 1,3-bis(bromomethyl) benzene crosslinking reagent was one of the two best crosslinking agents for producing the cleanest formation of the desired macrocyclic peptide (pg. 17,706, right column, third paragraph). Jo describes these cyclic peptides as inhibitors of a protease (pg. 17,710, left column, second and third paragraphs).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the FAP-targeted conjugates of the ‘938 patent with the use of the 1,3-bis(bromomethyl) benzene crosslinking agent in the synthesis of the cyclic peptide as taught by Jo because this amounts to a simple substitution of one known element for another to obtain the predictable result of a cyclic peptide wherein the cysteines are connected by a xylene-like cyclization moiety wherein the aryl core of the cyclization group is meta functionalized rather than in the ortho form (MPEP § 2143(I)(B)).
A person of ordinary skill in the art would have had a reasonable expectation of success in making this substitution because both the ‘938 patent and Jo are drawn to or teach cyclic peptides that are crosslinked using bifunctionalized benzyl groups that react to connect two cysteine residues in a peptide. The methods of Jo indicate that ortho, meta, and para functionalized aryl cyclization moiety cores are known in the art of cysteine-cysteine peptide crosslinkers. The use of each of these forms in the methods of Jo indicate that these crosslinking agents perform the same function as each other and that changing one for another results in predictable similar results of crosslinked peptides.
The skilled artisan would have been motivated to make this substitution as crosslinker optimization enables the selection of the best form of a cyclic peptide without needing to change the peptide sequence. Changing between the ortho, meta, and para forms of the bifunctionalized benzyl groups results in slightly different distances between the cysteine residues, which may influence the structure or stability of the cyclic peptide product.
Regarding instant claim 21, conflicting claim 1 of the ‘938 patent is drawn to FAP-targeted conjugates comprising a cyclic peptide of sequence CTPWEQWWC, DOTA- or NOTA-like derivative chelating groups, and PEG-based linking groups. Both FAP-targeted conjugates are crosslinked by an ortho-functionalized benzyl cyclization moiety connecting two cysteine residues. Additionally, Jo teaches crosslinking cysteines of a peptide using a meta-functionalized benzyl cyclization moiety to produce a cyclic peptide (pg. 17,706, Scheme 1; and pg. 17,710, Cross-Linker Screen). The modification of the second compound of conflicting claim 1 of the ‘938 patent with the substitution to the meta-functionalized cyclization moiety would result in a molecule that reads on the fourth compound of instant claim 21 (PSC-PEG2-[C(mXdB)TPWEQWWC]-NH2), rendering instant claim 21 obvious.
Regarding instant claims 22-25, conflicting claim 4 of the ‘938 patent is drawn to embodiments wherein the conjugate is labeled with a radionuclide. Conflicting claims 5 and 6 further specify the radionuclides included in the claimed embodiments, including Pb-203 and Pb-212.
Regarding instant claim 26, conflicting claim 7 of the ‘938 patent is drawn to pharmaceutical compositions comprising the FAP-targeted conjugate and a pharmaceutically acceptable carrier, wherein the conjugate is labeled with a radionuclide.
Regarding instant claim 27, conflicting claim 8 of the ‘938 patent is drawn to pharmaceutical compositions comprising an injectable or infusible aqueous formulation.
Regarding instant claim 28, conflicting claim 9 of the ‘938 patent is drawn to pharmaceutical compositions further comprising any one or more of a sterile diluent for injection, a saline solution, an oil, a polyol, glycerol, a solvent, an antibacterial or antifungal agent, an antioxidant, a chelating agent, a buffer, and an agent for the adjustment of tonicity.
Regarding instant claim 29, conflicting claim 10 of the ‘938 patent is drawn to pharmaceutical compositions further comprising any of saline, phosphate buffered saline, glycerol, propylene glycol, liquid polyethylene glycol, glycerine, a syntheticsolvents, a paraben, chlorobutanol, phenol, ascorbic acid, thimerosal, gentisic acid, sodium bisulfite, EDTA, DTPA, DMSA, DMPS, acetates, citrates, phosphates, sodium chloride, mannitol, sorbitol, lecithin, and dextrose.
Claims 30-41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-36 of copending Application No. 18/767,232 in view of Jo (Jo, H.; et al., J. Am. Chem. Soc., 2012).
The claims of copending Application No. 18/767,232 (henceforth referred to as the ‘232 application) are drawn to methods of using fibroblast activation protein (FAP)-targeted conjugate compounds for imaging or treating cancer. These compounds are characterized by the structure comprising a cyclic peptide, a chelating moiety, and a linking group. The conjugates may be labeled with radionuclides. The conjugates may also be part of a pharmaceutical composition further comprising pharmaceutically acceptable carriers and other agents.
The claims of the copending ‘232 application are not drawn to methods of using FAP targeting conjugate compounds possessing identical structures to those of instant claim 21.
As described above, Jo teaches the preparation of cyclic peptides using various crosslinking reagents that react with and connect two cysteine residues in a peptide (pg. 17,706, Scheme 1; and pg. 17,710, Cross-Linker Screen). Among the crosslinking reagents tested by Jo are 1,2-bis(bromomethyl) benzene (c14), 1,3-bis(bromomethyl) benzene (c15), and 1-4-bis(bromomethyl) benzene (pg. 17,706, Scheme 1). Jo found that the 1,3-bis(bromomethyl) benzene crosslinking reagent was one of the two best crosslinking agents for producing the cleanest formation of the desired macrocyclic peptide (pg. 17,706, right column, third paragraph). Jo describes these cyclic peptides as inhibitors of a protease (pg. 17,710, left column, second and third paragraphs).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of using FAP-targeted conjugates for imaging and treating cancer of the copending ‘232 application by modifying the FAP-targeted conjugates to be used with the use of the 1,3-bis(bromomethyl) benzene crosslinking agent in the synthesis of the cyclic peptide as taught by Jo because this amounts to a simple substitution of one known element for another to obtain the predictable result of a cyclic peptide wherein the cysteines are connected by a xylene-like cyclization moiety wherein the aryl core of the cyclization group is meta functionalized rather than in the ortho form (MPEP § 2143(I)(B)).
A person of ordinary skill in the art would have had a reasonable expectation of success in making this substitution because both the copending ‘232 application and Jo relate to cyclic peptides that are crosslinked using bifunctionalized benzyl groups that react to connect two cysteine residues in a peptide. The methods of Jo indicate that ortho, meta, and para functionalized aryl cyclization moiety cores are known in the art of cysteine-cysteine peptide crosslinkers. The use of each of these forms in the methods of Jo indicate that these crosslinking agents perform the same function as each other and that changing one for another results in predictable similar results of crosslinked peptides.
The skilled artisan would have been motivated to make this substitution as crosslinker optimization enables the selection of the best form of a cyclic peptide without needing to change the peptide sequence. Changing between the ortho, meta, and para forms of the bifunctionalized benzyl groups results in slightly different distances between the cysteine residues, which may influence the structure or stability of the cyclic peptide product.
Regarding instant claim 30, conflicting claim 21 of the copending ‘232 application is drawn to a method of imaging or diagnosing a cancer associated with overexpression of FAP in a patient, the method comprising administering a FAP-targeted conjugate wherein the conjugate is labeled with a radionuclide, and imaging the patient. Additionally, Jo teaches crosslinking cysteines of a peptide using a meta-functionalized benzyl cyclization moiety to produce a cyclic peptide (pg. 17,706, Scheme 1; and pg. 17,710, Cross-Linker Screen). The modification of the second compound of conflicting claim 21 of the copending ‘232 application with the substitution to the meta-functionalized cyclization moiety would result in a molecule that reads on the fourth compound of instant claim 21 (PSC-PEG2-[C(mXdB)TPWEQWWC]-NH2), rendering instant claim 30 obvious.
Regarding instant claim 31, conflicting claim 24 of the copending ‘232 application is drawn to embodiments wherein the radionuclide is selected from the group consisting of In-111, Pb-203, Cu-64, Ga-68, and Zr-89.
Regarding instant claim 32, conflicting claim 25 of the copending ‘232 application is drawn to embodiments wherein the cancer comprises any selected from the group consisting of sarcoma, head and neck cancer, esophageal cancer, glioma, cholangiocarcinoma, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thymus cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma, differentiated thyroid cancer, insulinoma, kidney cancer, and skin cancer.
Regarding instant claim 33, conflicting claim 26 of the copending ‘232 application is drawn to embodiments in which the FAP-targeted conjugate is administered intravenously or intraperitoneally.
Regarding instant claim 34, conflicting claim 27 of the copending ‘232 application is drawn to embodiments in which the FAP-targeted conjugate is administered as part of a pharmaceutical composition comprising any one or more of a sterile diluent for injection, a saline solution, an oil, a polyol, glycerol, a solvent, an antibacterial or antifungal agent, an antioxidant, a chelating agent, a buffer, and an agent for the adjustment of tonicity.
Regarding instant claim 35, conflicting claim 28 of the copending ‘232 application is drawn to embodiments in which the FAP-targeted conjugate is administered as part of a pharmaceutical composition comprising any of saline, phosphate buffered saline, glycerol, propylene glycol, liquid polyethylene glycol, glycerine, a synthetic solvents, a paraben, chlorobutanol, phenol, ascorbic acid, thimerosal, gentisic acid, sodium bisulfite, EDTA, DTPA, DMSA, DMPS, acetates, citrates, phosphates, sodium chloride, mannitol, sorbitol, lecithin, and dextrose.
Regarding instant claim 36, conflicting claim 29 of the copending ‘232 application is drawn to a method of treating a cancer associated with the overexpression of FAP in a patient, the method comprising administering a FAP-targeted conjugate wherein the conjugate is labeled with a radionuclide. Additionally, Jo teaches crosslinking cysteines of a peptide using a meta-functionalized benzyl cyclization moiety to produce a cyclic peptide (pg. 17,706, Scheme 1; and pg. 17,710, Cross-Linker Screen). The modification of the second compound of conflicting claim 21 of the copending ‘232 application with the substitution to the meta-functionalized cyclization moiety would result in a molecule that reads on the fourth compound of instant claim 21 (PSC-PEG2-[C(mXdB)TPWEQWWC]-NH2), rendering instant claim 36 obvious.
Regarding instant claim 37, conflicting claim 32 of the copending ‘232 application is drawn to embodiments wherein the radionuclide is selected from the group consisting of Y-90, Pb-212, Bi-212, Bi-213, At-211, Ac-225, and Lu-177.
Regarding instant claim 38, conflicting claim 33 of the copending ‘232 application is drawn to embodiments wherein the cancer comprises any selected from the group consisting of sarcoma, head and neck cancer, esophageal cancer, glioma, cholangiocarcinoma, breast cancer, lung cancer, prostate cancer, pancreatic cancer, thymus cancer, ovarian cancer, desmoid tumor, chordoma, colorectal cancer, anal cancer, neuroendocrine tumor, small intestine cancer, medullary thyroid cancer, cervical cancer, endometrial cancer, hepatocellular cancer, gastric cancer, adenoid cystic cancer, pheochromocytoma, differentiated thyroid cancer, insulinoma, kidney cancer, and skin cancer.
Regarding instant claim 39, conflicting claim 34 of the copending ‘232 application is drawn to embodiments in which the FAP-targeted conjugate is administered intravenously or intraperitoneally.
Regarding instant claim 40, conflicting claim 35 of the copending ‘232 application is drawn to embodiments in which the FAP-targeted conjugate is administered as part of a pharmaceutical composition comprising any one or more of a sterile diluent for injection, a saline solution, an oil, a polyol, glycerol, a solvent, an antibacterial or antifungal agent, an antioxidant, a chelating agent, a buffer, and an agent for the adjustment of tonicity.
Regarding instant claim 41, conflicting claim 36 of the copending ‘232 application is drawn to embodiments in which the FAP-targeted conjugate is administered as part of a pharmaceutical composition comprising any of saline, phosphate buffered saline, glycerol, propylene glycol, liquid polyethylene glycol, glycerine, a synthetic solvents, a paraben, chlorobutanol, phenol, ascorbic acid, thimerosal, gentisic acid, sodium bisulfite, EDTA, DTPA, DMSA, DMPS, acetates, citrates, phosphates, sodium chloride, mannitol, sorbitol, lecithin, and dextrose.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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