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 statement filed September 26, 2025 is acknowledged and has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The abstract of the disclosure is objected to because it is too short (30 words). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
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.
Claims 6-7, 10-11, and 13-14 are 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.
Each of claims 6-7, 10-11, and 13-14 are drawn to methods of treating or ameliorating cancer using a combination of a radiopharmaceutical and a DNA damage response inhibitor. Each of claims 6-7, 10-11, and 13-14 provide limitations specifying options of DNA damage response inhibitor compounds to be used in the claimed methods. However, in each of these claims, the specific DNA damage response inhibitor compound names are followed by the phrase “or an analog thereof.” This phrase renders the claims indefinite. It is not clear what structures the inhibitor analogs may possess and how different the analog may be from the parent compounds. Therefore, the scopes of these claims are indefinite.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 15, and 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over Osterkamp (WO 2014/086499 A1 – provided by applicant in IDS filed September 26, 2025) in view of Golan (Golan, T.; et al., N. Engl. J. Med., 2019) and Baum (Baum, R. P.; et al., J. Nucl. Med., 2018).
Osterkamp teaches a neurotensin receptor binding ligand of formula (I) (pg. 9), which is reads on formula (I) in the instant application. Osterkamp also teaches the specific embodiment of formula (IIIa) (pg. 35). Osterkamp teaches specific examples of labeling the compound of formula (IIIa) with indium, gallium, yttrium, and lutetium (pg. 99-100, Examples 6B-E). Osterkamp teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the compound of formula (IIIa) binds to NTR1 at a high affinity (pg. 49, last paragraph). Osterkamp also teaches that NTR1 is highly expressed in pancreatic ductal adenocarcinoma, colorectal carcinoma, lung cancer, breast cancer, and head and neck cancer (pg. 3-5, Table). Osterkamp teaches that the disclosed compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Osterkamp also teaches that dosing of the NTR1-binding compound can be administered at several timepoints over a time period; for example, over a period of 1 to 3 weeks or longer and that dosing can be 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). Osterkamp further teaches that the targeted radiotherapy using the disclosed NTR1-binding compounds may be used in combination with chemotherapy (pg. 73, fourth paragraph) such as with targeted agents (pg. 80, second paragraph).
Osterkamp does not teach a method of treating cancer wherein both a neurotensin receptor targeting radiopharmaceutical and a DNA damage response inhibitor that is a PARP inhibitor are administered.
Golan teaches a method of treating pancreatic cancer using olaparib (pg. 317, Abstract). More specifically, Golan teaches administration of 300 mg olaparib tablets twice daily to patients with pancreatic adenocarcinoma (pg. 318-319, Patients; and Trial Design and Interventions). Golan teaches that olaparib administration significantly improved median progression-free survival (pg. 320, Efficacy, first paragraph; and pg. 323, Figure 2A). Golan describes olaparib as a PARP inhibitor and as an agent that prevents repair of single-strand breaks in DNA (pg. 318, left column, second paragraph).
Baum teaches a method of administering a 177Lu-radiolabeled neurotensin receptor 1 binding compound, 177Lu-3BP-227, to human patients with ductal pancreatic adenocarcinoma (pg. 809, Abstract). Baum teaches administration of the radiopharmaceutical resulted in a significant decrease in primary pancreatic tumor size in Patient 3 (pg. 811, right column, fourth paragraph, lines 1-3; and pg. 814, Figure 4). Baum also teaches that the radiopharmaceutical reduced metabolic activity in the supra- and retroclavicular lymph node metastases in this patient and had the effect that liver metastases were no longer detectable (pg. 811, right column, fourth paragraph, lines 3-7).
A person of ordinary skill in the art would recognize that Osterkamp, Golan, and Baum all teach anti-cancer pharmaceuticals and methods of treating cancer. It would be recognized that Baum teaches the use of a specific embodiment of the radiopharmaceutical of Osterkamp (formula (IIIa) bound to 177Lu). It would also be recognized that both Baum and Golan teach methods of treating pancreatic cancer.
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 cancer treatment method of Osterkamp (and the more specific embodiment taught by Baum) with the olaparib administration of Golan because these cancer therapies were known in the art to both be useful for the treatment of pancreatic cancer and one of skill in the art could have combined these elements by known methods and achieve the predictable result of an effective combination therapy (MPEP § 2143(I)(A)). Additionally, per MPEP § 2144.06(I), the combination of two compositions each taught to be useful for the same purpose is prima facie obvious.
A person of ordinary skill in the art would have had a reasonable expectation of success in adding the administration of olaparib to the radiopharmaceutical cancer treatment method because Golan teaches olaparib to be a safe and effective cancer therapy.
The skilled artisan would have been motivated to incorporate the olaparib administration of Golan in pursuit of a potentially more effective cancer treatment than the radiopharmaceutical agent as a monotherapy.
Regarding claim 1, Osterkamp teaches a radiopharmaceutical compound of formula (I) (pg. 9), which reads on formula (I) of claim 1. Osterkamp also teaches a specific embodiment of formula (IIIa) (pg. 35), which reads on the structure of claim 1 wherein R1 is methyl, AA-COOH is 2-amino-2-adamantane carboxylic acid, R2 is C3 alkyl, R3 and R4 are C1 alkyl, L1 and L2 are C3 alkylidene, and W is DOTA. Osterkamp also teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the disclosed compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Furthermore, Baum teaches a method of treating pancreatic cancer using a 177Lu labeled radiopharmaceutical (3BP-227) that has the same structure of formula (IIIa) of Osterkamp (thus reading on formula (I) of claim 1 in the same ways) (pg. 809, Radiopharmaceuticals, first paragraph). Golan teaches a method of treating pancreatic cancer comprising the administration of olaparib (pg. 318-319, Trial Design and Interventions), which is described as a PARP inhibitor and an agent that prevents repair of DNA damage (pg. 318, left column, second paragraph). The examiner interprets this to mean that olaparib is a DNA damage response inhibitor (DDRi). Osterkamp teaches that the disclosed radiopharmaceuticals may be administered to humans (pg. 81, first paragraph). Furthermore, Baum teaches administration of a similar neurotensin receptor-targeting radiopharmaceutical to humans (pg. 809, Patients and Regulatory Issues; and pg. 810, Treatment Procedure) and Golan teaches administration of olaparib to humans (pg. 318, Patients).
For the reasons stated above, providing a combination therapy method wherein both olaparib and a neurotensin receptor-targeting radiopharmaceutical are administered to treat or ameliorate pancreatic cancer is prima facie obvious. The examiner notes that the limitations (i), (ii), and (iii) of claim 1 relate to the timing of such combination therapy, reciting options wherein either the DDRi is administered first, the radiopharmaceutical is administered first, or that both agents are administered at the same time. As the scope of the claim includes all of these options, any combination therapy must read on these alternative limitations as a whole because they cover all possible arrangements for such a combination therapy. In a combination therapy using a DDRi and a neurotensin receptor-targeting radiopharmaceutical, it must be the case that one of the agents is administered first or that both agents are administered at the same time. Therefore, any combination therapy reads on the scope of this aspect of the claim.
Therefore, the combined teachings of Osterkamp, Golan, and Baum render claim 1 obvious.
Regarding claim 2, for the reasons described above a method in which both olaparib and a neurotensin receptor-targeting radiopharmaceutical that reads on formula (I) of claim 1 is prima facie obvious. Furthermore, the examiner considers the selection of administering a DDRi after a mammal has already received or is receiving a radiopharmaceutical to amount to a change in sequence of steps in a procedure, which is prima facie obvious, per MPEP § 2144.04(IV). Therefore, the combined teachings of Osterkamp, Golan, and Baum render claim 2 obvious.
Regarding claim 3, Osterkamp also teaches that the atom chelated in the radiopharmaceutical can be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). This list includes 225Ac. Furthermore, formula (IIIa) of Osterkamp (pg. 35) is identical to the structure of claim 3. Therefore, the combined teachings of Osterkamp, Golan, and Baum render claim 3 obvious.
Regarding claims 4-7, Golan teaches administration of olaparib (pg. 318-319, Trial Design and Interventions). Golan also describes that olaparib is a PARP inhibitor and an agent that prevents repair of DNA damage (pg. 318, left column, second paragraph). Therefore, the combined teachings of Osterkamp, Golan, and Baum render claims 4-7 obvious.
Regarding claim 15, Osterkamp teaches that the disclosed radiopharmaceuticals may be administered to humans (pg. 81, first paragraph). Furthermore, Baum teaches administration of a similar neurotensin receptor-targeting radiopharmaceutical to humans (pg. 809, Patients and Regulatory Issues; and pg. 810, Treatment Procedure) and Golan teaches administration of olaparib to humans (pg. 318, Patients). Therefore, the combined teachings of Osterkamp, Golan, and Baum render claim 15 obvious.
Regarding claims 19-21, Osterkamp teaches that the radiopharmaceutical compound can be administered at doses ranging from 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). These ranges overlap with the claimed ranges, rendering the claimed ranges obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Osterkamp, Golan, and Baum render claims 19-21 obvious.
Regarding claims 22 and 23, Osterkamp teaches that the disclosed radiopharmaceutical compounds that read on the structure of formula (I) of claim 1 can be used for the treatment of pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Additionally, Baum teaches the use of a 177Lu-radiolabeled compound that reads on formula (IIIa) of Osterkamp, 177Lu-3BP-227 in the treatment of pancreatic adenocarcinoma (pg. 809, Patients and Regulatory Issues; and pg. 810, Treatment Procedure). Furthermore, Golan teaches a method of treating pancreatic cancer with olaparib (pg. 318-319, Patients; and Trial Design and Interventions). Therefore, the combined teachings of Osterkamp, Golan, and Baum render claims 22 and 23 obvious.
Regarding claim 24, Baum teaches that the 177Lu radiopharmaceutical significantly decreased the size of the primary pancreatic tumor of one subject (pg. 811, right column, fourth paragraph, lines 1-3; and pg. 814, Figure 4). The examiner interprets this to teach a decrease in tumor volume. Therefore, the combined teachings of Osterkamp, Golan, and Baum render claim 24 obvious.
Regarding claim 25, Baum teaches that the 177Lu radiopharmaceutical reduced metabolic activity in the supra- and retroclavicular lymph node metastases in a patient and had the effect that liver metastases were no longer detectable (pg. 811, right column, fourth paragraph, lines 3-7). The examiner interprets the teaching of liver metastases no longer being detectable to read on the limitation of a decreased incidence of metastasis. Therefore, the combined teachings of Osterkamp, Golan, and Baum render claim 25 obvious.
Claims 1-3, 8-11, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Osterkamp (WO 2014/086499 A1 – provided by applicant in IDS filed September 26, 2025) in view of Wengner (Wengner, A. M.; et al., Mol. Cancer Ther., 2020).
As described above, Osterkamp teaches a neurotensin receptor binding ligand of formula (I) (pg. 9), which is reads on formula (I) in the instant application. Osterkamp also teaches the specific embodiment of formula (IIIa) (pg. 35). Osterkamp teaches specific examples of labeling the compound of formula (IIIa) with indium, gallium, yttrium, and lutetium (pg. 99-100, Examples 6B-E). Osterkamp teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the compound of formula (IIIa) binds to NTR1 at a high affinity (pg. 49, last paragraph). Osterkamp also teaches that NTR1 is highly expressed in pancreatic ductal adenocarcinoma, colorectal carcinoma, lung cancer, breast cancer, and head and neck cancer (pg. 3-5, Table). Osterkamp teaches that the disclosed compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Osterkamp also teaches that dosing of the NTR1-binding compound can be administered at several timepoints over a time period; for example, over a period of 1 to 3 weeks or longer and that dosing can be 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). Osterkamp teaches that radionuclide therapy preferably works by damaging the DNA of cells (pg. 74, second paragraph). Osterkamp further teaches that the targeted radiotherapy using the disclosed NTR1-binding compounds may be used in combination with chemotherapy (pg. 73, fourth paragraph) such as with targeted agents (pg. 80, second paragraph).
Osterkamp does not teach a method of treating cancer wherein both a neurotensin receptor targeting radiopharmaceutical and a DNA damage response inhibitor that is an ATR or ATM inhibitor are administered.
Wengner teaches the efficacy of the ATR inhibitor compound BAY 1895344 in the treatment of cancer in xenograft tumor models (pg. 26, Abstract). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph). Wengner also states that ATR plays a key role in DNA damage repair (pg. 26, Introduction, second paragraph). Wengner teaches that BAY 1895344 exhibits antitumor activity as a single agent in xenograft tumor models of prostate cancer and colon cancer (pg. 29, right column, last paragraph; and pg. 30, Figure 2). Wengner also teaches that BAY 1895344 exhibits synergy with chemotherapy and radiation therapy in xenograft models of colorectal cancer (pg. 33, left column, paragraphs 4, 6, and 7). Wengner also teaches that BAY 1895344 has single agent efficacy in a breast cancer model (pg. 34, Figure 5E). Wengner suggests that the cancer-killing activity of radiation may be increased by the inhibition of ATR (pg. 26, right column, last paragraph through pg. 27, left column, first paragraph). Wengner concludes that BAY 1895344 displays synergy when used in combination with DNA damage-inducing therapies.
A person of ordinary skill in the art would recognize that Osterkamp and Wengner teach anti-cancer pharmaceuticals and methods of treating cancer. It would be recognized that Osterkamp teaches that radiopharmaceuticals work by damaging DNA and that Wengner suggests that BAY 1895344 exhibits synergy with DNA damaging therapies. It would also be recognized that Osterkamp teaches that the radiopharmaceutical may be used for the treatment of colorectal carcinoma, prostate cancer, and breast cancer; and that Wengner demonstrates efficacy of BAY 1895344 in preclinical models of these cancers.
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 cancer treatment method of Osterkamp with the BAY 1895344 administration of Wengner because these cancer therapies were known in the art to both be useful for the treatment of the same cancers and one of skill in the art could have combined these elements by known methods and achieve the predictable result of an effective combination therapy (MPEP § 2143(I)(A)). Additionally, per MPEP § 2144.06(I), the combination of two compositions each taught to be useful for the same purpose is prima facie obvious. Furthermore, it would also have been prima facie obvious to combine these methods because Osterkamp teaches that radiopharmaceuticals work by damaging DNA and Wengner suggests that BAY1895344 exhibits synergy with DNA damaging therapies (MPEP § 2143(I)(G)).
A person of ordinary skill in the art would have had a reasonable expectation of success in adding the administration of BAY 1895344 to the radiopharmaceutical cancer treatment method because Wengner demonstrates efficacy in cancer therapy. Wengner also teaches combination of BAY 1895344 with other agents (chemotherapeutics and radiation), indicating that BAY 1895344 is suitable for use in combination therapies.
The skilled artisan would have been motivated to incorporate the BAY 1895344 administration of Wengner in pursuit of a potentially more effective, synergistic cancer treatment than the radiopharmaceutical agent as a monotherapy.
Regarding claim 1, Osterkamp teaches a radiopharmaceutical compound of formula (I) (pg. 9), which reads on formula (I) of claim 1. Osterkamp also teaches a specific embodiment of formula (IIIa) (pg. 35), which reads on the structure of claim 1 wherein R1 is methyl, AA-COOH is 2-amino-2-adamantane carboxylic acid, R2 is C3 alkyl, R3 and R4 are C1 alkyl, L1 and L2 are C3 alkylidene, and W is DOTA. Osterkamp also teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the disclosed compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Additionally, Wengner teaches a method of treating cancer in xenograft tumor models using BAY 1895344, which is an inhibitor of ATR, a protein involved in DNA damage repair (pg. 26, Introduction, second paragraph). The examiner interprets BAY 1895344 to be a DDRi. Osterkamp teaches that the disclosed radiopharmaceuticals may be administered to a mammal (pg. 44, third paragraph). Wengner teaches administration of BAY 1895344 to mice possessing xenograft tumors derived from human cell lines (pg. 27, In vivo studies in CDX models).
For the reasons stated above, providing a combination therapy method wherein both BAY 1895344 and a neurotensin receptor-targeting radiopharmaceutical are administered to treat or ameliorate pancreatic cancer is prima facie obvious. The examiner notes that the limitations (i), (ii), and (iii) of claim 1 relate to the timing of such combination therapy, reciting options wherein either the DDRi is administered first, the radiopharmaceutical is administered first, or that both agents are administered at the same time. As the scope of the claim includes all of these options, any combination therapy must read on these alternative limitations as a whole because they cover all possible arrangements for such a combination therapy. Furthermore, Wengner teaches administration of BAY 1895344 in combination with other therapies in which BAY 1895344 is administered first before radiation therapy or at the same time as other chemotherapies (pg. 27 and 29, In vivo studies in CDX models).
Therefore, the combined teachings of Osterkamp and Wengner render claim 1 obvious.
Regarding claim 2, for the reasons described above a method in which both BAY 1895344 and a neurotensin receptor-targeting radiopharmaceutical that reads on formula (I) of claim 1 is prima facie obvious. Furthermore, the examiner considers the selection of administering a DDRi after a mammal has already received or is receiving a radiopharmaceutical to amount to a change in sequence of steps in a procedure, which is prima facie obvious, per MPEP § 2144.04(IV). Additionally and separately, Wengner teaches administration of BAY 1895344 twice daily 2on/5off in combination with external beam radiation therapy once daily on days 12 and 27 (pg. 27, right column, last paragraph, lines 19-21). In such a method, BAY 1895344 would be dosed on days 15 and 16, which is administration of a DDRi after the mammal has received a radiation-based therapy. As Osterkamp teaches that the radiopharmaceutical is effective due to inducing DNA damage (pg. 74, second paragraph) and Wengner suggests combining BAY 1895344 with DNA damaging therapies (pg. 36, right column, last paragraph), this would suggest to the skilled artisan to administer the radiopharmaceutical of Osterkamp in combination with the BAY 1895344 of Wengner with a similar regimen. Therefore, the combined teachings of Osterkamp and Wengner render claim 2 obvious.
Regarding claim 3, Osterkamp also teaches that the atom chelated in the radiopharmaceutical can be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). This list includes 225Ac. Furthermore, formula (IIIa) of Osterkamp (pg. 35) is identical to the structure of claim 3. Therefore, the combined teachings of Osterkamp and Wengner render claim 3 obvious.
Regarding claims 8-11, Wengner teaches administration of BAY 1895344 (pg. 27, In vivo studies in CDX models). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph). Therefore, the combined teachings of Osterkamp and Wengner render claims 8-11 obvious.
Regarding claims 19-21, Osterkamp teaches that the radiopharmaceutical compound can be administered at doses ranging from 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). These ranges overlap with the claimed ranges, rendering the claimed ranges obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Osterkamp and Wengner render claims 19-21 obvious.
Regarding claims 22 and 23, Osterkamp teaches that the disclosed radiopharmaceutical compounds that read on the structure of formula (I) of claim 1 can be used for the treatment of pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, prostate cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Additionally, Wengner teaches that BAY 1895344 exhibits antitumor activity as a single agent in xenograft tumor models of prostate cancer and colon cancer (pg. 29, right column, last paragraph; and pg. 30, Figure 2). Wengner also teaches that BAY 1895344 exhibits synergy with chemotherapy and radiation therapy in xenograft models of colorectal cancer (pg. 33, left column, paragraphs 4, 6, and 7). Wengner also teaches that BAY 1895344 has single agent efficacy in a breast cancer model (pg. 34, Figure 5E). Wengner suggests that the cancer-killing activity of radiation may be increased by the inhibition of ATR (pg. 26, right column, last paragraph through pg. 27, left column, first paragraph). Therefore, the combined teachings of Osterkamp and Wengner render claims 22 and 23 obvious.
Claims 1-3, 8-11, and 19-23 are rejected under 35 U.S.C. 103 as being unpatentable over Osterkamp (WO 2014/086499 A1 – provided by applicant in IDS filed September 26, 2025) in view of Fok (Fok, J. H. L.; et al., Nat. Commun., 2019).
As described above, Osterkamp teaches a neurotensin receptor binding ligand of formula (I) (pg. 9), which is reads on formula (I) in the instant application. Osterkamp also teaches the specific embodiment of formula (IIIa) (pg. 35). Osterkamp teaches specific examples of labeling the compound of formula (IIIa) with indium, gallium, yttrium, and lutetium (pg. 99-100, Examples 6B-E). Osterkamp teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the compound of formula (IIIa) binds to NTR1 at a high affinity (pg. 49, last paragraph). Osterkamp also teaches that NTR1 is highly expressed in pancreatic ductal adenocarcinoma, colorectal carcinoma, lung cancer, breast cancer, and head and neck cancer (pg. 3-5, Table). Osterkamp teaches that the disclosed compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Osterkamp also teaches that dosing of the NTR1-binding compound can be administered at several timepoints over a time period; for example, over a period of 1 to 3 weeks or longer and that dosing can be 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). Osterkamp teaches that radionuclide therapy preferably works by damaging the DNA of cells (pg. 74, second paragraph). Osterkamp further teaches that the targeted radiotherapy using the disclosed NTR1-binding compounds may be used in combination with chemotherapy (pg. 73, fourth paragraph) such as with targeted agents (pg. 80, second paragraph).
Osterkamp does not teach a method of treating cancer wherein both a neurotensin receptor targeting radiopharmaceutical and a DNA damage response inhibitor that is a DNA-PK inhibitor are administered.
Fok teaches a method of using AZD7648 to treat cancer (pg. 1, Abstract). Fok describes AZD7648 as a DNA-PK (DNA-dependent protein kinase) inhibitor (pg. 2, right column, second paragraph). Fok describes that DNA-PK is an important protein in repairing DNA damage (pg. 2, left column, paragraphs 2 and 3). Fok teaches administration of AZD7648 to mice with xenograft tumors as a single agent, in combination with targeted irradiation, and in combination with chemotherapeutic agents (pg. 13, In vivo studies). Fok teaches that AZD7648 increases the anticancer effect of radiation therapy in a xenograft lung cancer model (pg. 5, Figure 2 a and b). Fok also teaches that AZD7648 displays moderate efficacy in slowing tumor volume growth in xenograft breast cancer models and that AZD7648 exhibits significantly increased efficacy in combination with another chemotherapeutic agent in the same models (pg. 7, Figure 4 a and b). Fok further teaches that AZD7648 reduces cell growth in ATM knockout head and neck cancer cells and that it exhibits moderate tumor growth suppression in a xenograft model as a solo agent and significant efficacy in combination with another agent in the same model (pg. 9, Figure 5 b and c). Fok also teaches efficacy of AZD7648 as a single agent and in combination in patient-derived xenograft models of breast, ovarian, and lung cancers (pg. 10, Figure 6). Fok states that the potential for combination of radiation and DNA-PK inhibitors is well-established (pg. 2, fourth paragraph, first sentence). Fok also describes AZD7648 a potent radiosensitizer in both in vivo and in vitro models (pg. 2, right column, last paragraph). Fok describes AZD7648 as an anticancer agent that can act as a sensitizer to a range of DNA damage inducing agents (pg. 13, left column, last paragraph).
A person of ordinary skill in the art would recognize that Osterkamp and Fok teach anti-cancer pharmaceuticals and methods of treating cancer. It would be recognized that Osterkamp teaches that radiopharmaceuticals work by damaging DNA and that Fok teaches that AZD7648 is a radiosensitizer and suggests using AZD7648 in combination with DNA damaging therapies. It would also be recognized that Osterkamp teaches that the radiopharmaceutical may be used for the treatment of lung cancer, head and neck cancer, and breast cancer; and that Fok demonstrates efficacy of AZD7648 as a single agent or in combination in preclinical models of these cancers.
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 cancer treatment method of Osterkamp with the AZD7648 administration of Fok because these cancer therapies were known in the art to both be useful for the treatment of the same cancers and one of skill in the art could have combined these elements by known methods and achieve the predictable result of an effective combination therapy (MPEP § 2143(I)(A)). Additionally, per MPEP § 2144.06(I), the combination of two compositions each taught to be useful for the same purpose is prima facie obvious. Furthermore, it would also have been prima facie obvious to combine these methods because Osterkamp teaches that radiopharmaceuticals work by damaging DNA and Fok suggests that AZD7648 is a radiosensitizer and should be used in combination with DNA damaging therapies (MPEP § 2143(I)(G)).
A person of ordinary skill in the art would have had a reasonable expectation of success in adding the administration of AZD7648 to the radiopharmaceutical cancer treatment method because Fok demonstrates efficacy in cancer therapy. Fok also teaches combination of AZD7648 with other agents (chemotherapeutics and radiation), indicating that AZD7648 is suitable for use in combination therapies.
The skilled artisan would have been motivated to incorporate the AZD7648 administration of Fok in pursuit of a potentially more effective cancer treatment than the radiopharmaceutical agent as a monotherapy.
Regarding claim 1, Osterkamp teaches a radiopharmaceutical compound of formula (I) (pg. 9), which reads on formula (I) of claim 1. Osterkamp also teaches a specific embodiment of formula (IIIa) (pg. 35), which reads on the structure of claim 1 wherein R1 is methyl, AA-COOH is 2-amino-2-adamantane carboxylic acid, R2 is C3 alkyl, R3 and R4 are C1 alkyl, L1 and L2 are C3 alkylidene, and W is DOTA. Osterkamp also teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the disclosed compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Additionally, Fok teaches a method of treating cancer in xenograft tumor models using AZD7648, which is an inhibitor of DNA-PK, a protein involved in DNA damage repair (pg. 2, left column, paragraphs 2 and 3; and right column, second paragraph). The examiner thus interprets AZD7648 to be a DDRi. Osterkamp teaches that the disclosed radiopharmaceuticals may be administered to a mammal (pg. 44, third paragraph). Fok teaches administration of AZD7648 to mice possessing xenograft tumors derived from human cell lines or patient tumors (pg. 13, In vivo studies).
For the reasons stated above, providing a combination therapy method wherein both AZD7648 and the neurotensin receptor-targeting radiopharmaceutical of Osterkamp are administered to treat or ameliorate pancreatic cancer is prima facie obvious. The examiner notes that the limitations (i), (ii), and (iii) of claim 1 relate to the timing of such combination therapy, reciting options wherein either the DDRi is administered first, the radiopharmaceutical is administered first, or that both agents are administered at the same time. As the scope of the claim includes all of these options, any combination therapy must read on these alternative limitations as a whole because they cover all possible arrangements for such a combination therapy. Furthermore, Fok teaches administration of AZD7648 in combination with other therapies in which AZD7648 is administered at the same time or before or after radiation or other chemotherapies (pg. 13, In vivo studies).
Therefore, the combined teachings of Osterkamp and Fok render claim 1 obvious.
Regarding claim 2, for the reasons described above a method in which both AZD7648 and a neurotensin receptor-targeting radiopharmaceutical that reads on formula (I) of claim 1 is prima facie obvious. Furthermore, the examiner considers the selection of administering a DDRi after a mammal has already received or is receiving a radiopharmaceutical to amount to a change in sequence of steps in a procedure, which is prima facie obvious, per MPEP § 2144.04(IV). Additionally and separately, Fok teaches administration of AZD7648 twice daily in combination with external beam radiation therapy on the same days and with further AZD7648 administration after radiation therapy is complete (pg. 5, Figure 2 a and b). In the latter method, AZD7648 dosed in the early phase while the animal is receiving radiation therapy and in the later phase is dosed after the mammal has received a radiation-based therapy. As Osterkamp teaches that the radiopharmaceutical is effective due to inducing DNA damage (pg. 74, second paragraph) and Fok suggests combining AZD with DNA damaging therapies (pg. 13, left column, last paragraph), this would suggest to the skilled artisan to administer the radiopharmaceutical of Osterkamp in combination with the AZD7648 of Fok with a similar regimen. Therefore, the combined teachings of Osterkamp and Fok render claim 2 obvious.
Regarding claim 3, Osterkamp also teaches that the atom chelated in the radiopharmaceutical can be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). This list includes 225Ac. Furthermore, formula (IIIa) of Osterkamp (pg. 35) is identical to the structure of claim 3. Therefore, the combined teachings of Osterkamp and Fok render claim 3 obvious.
Regarding claims 12-14, Fok describes AZD7648 as a DNA-PK inhibitor (pg. 2, right column, second paragraph). Fok describes that DNA-PK is an important protein in repairing DNA damage (pg. 2, left column, paragraphs 2 and 3). Therefore, the combined teachings of Osterkamp and Fok render claims 12-14 obvious.
Regarding claims 19-21, Osterkamp teaches that the radiopharmaceutical compound can be administered at doses ranging from 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). These ranges overlap with the claimed ranges, rendering the claimed ranges obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Osterkamp and Fok render claims 19-21 obvious.
Regarding claims 22 and 23, Osterkamp teaches that the disclosed radiopharmaceutical compounds that read on the structure of formula (I) of claim 1 can be used for the treatment of pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, prostate cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Additionally, Fok teaches the use of AZD7648 to treat breast, lung, and head and neck cancers as a single agent and in a combination therapy (Figures 2, 4, 5, and 6). Therefore, the combined teachings of Osterkamp and Fok render claims 22 and 23 obvious.
Claims 16-18 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Osterkamp and Wengner as applied to claims 1-3, 8-11, and 19-23 above, and further in view of Kratochwil (Kratochwil, C.; et al., J. Nucl. Med., 2017).
As described above, Osterkamp and Wengner combine to teach a method of treating cancer using a combination of a neurotensin receptor-targeting radiopharmaceutical and BAY 1895344, an ATR inhibitor. Specifically, Osterkamp teaches a neurotensin receptor binding ligand of formula (I) (pg. 9), which is reads on formula (I) in the instant application. Osterkamp also teaches the specific embodiment of formula (IIIa) (pg. 35). Osterkamp teaches that the chelated atom can be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the disclosed radiopharmaceutical compounds can be used for the treatment of disease involving neurotensin receptor, including pancreatic ductal adenocarcinoma, colorectal cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Osterkamp also teaches that dosing of the NTR1-binding compound can be administered at several timepoints over a time period; for example, over a period of 1 to 3 weeks or longer and that dosing can be 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). Additionally, Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph). Wengner teaches that BAY 1895344 exhibits antitumor activity as a single agent in xenograft tumor models of prostate cancer and colon cancer (pg. 29, right column, last paragraph; and pg. 30, Figure 2). Wengner also teaches that BAY 1895344 exhibits synergy with chemotherapy and radiation therapy in xenograft models of colorectal cancer (pg. 33, left column, paragraphs 4, 6, and 7). Wengner suggests that the cancer-killing activity of radiation may be increased by the inhibition of ATR (pg. 26, right column, last paragraph through pg. 27, left column, first paragraph). Wengner concludes that BAY 1895344 displays synergy when used in combination with DNA damage-inducing therapies.
The combined teachings of Osterkamp and Wengner do not teach a method of treating cancer wherein the radiopharmaceutical is administered at specific doses in the units of kBq/kg.
Kratochwil teaches targeted alpha therapy using a 225Ac containing radiopharmaceutical in the treatment of prostate cancer in humans (pg. 1624, Abstract). Kratochwil suggests that alpha therapy with 225Ac radiopharmaceuticals can overcome resistance to beta emitting therapy (such as with 177Lu) and increase efficacy and reduce toxicity (pg. 1624, Introduction, second paragraph). Specifically, Kratochwil teaches administration of 225Ac-PSMA-617 to patients with prostate cancer (pg. 1624-1625, Patients). Kratochwil teaches administering the 225Ac-labeled targeted radiopharmaceutical at doses of 50, 100, 150, and 200 kBq/kg as a single agent and in combination with other therapies (pg. 1625, Table 1). Kratochwil also teaches that the first cycle of the 225Ac-labeled targeted radiopharmaceutical was provided as a unitary dose of 3.3-19.1 MBq (pg. 1626, Table 2) (*The examiner notes that while Table 2 does not explicitly state that the unit is MBq, pg. 1629, right column, last paragraph describes that a patient who received 177Lu-PSMA-617 also received 13.4 MBq of the 225Ac-labeled radiopharmaceutical. Table 1 demonstrates that only Patient 10 received a 177Lu radiopharmaceutical and Table 2 describes the activity of the 225Ac radiopharmaceutical administered in the first cycle to this patient to be 13.4 of a unit, which the examiner interprets to be MBq). Kratochwil concludes that of these doses, 100 kBq/kg was considered the treatment with the highest therapeutic range (pg. 1628, left column, third paragraph).
A person of ordinary skill in the art would recognize that each of Osterkamp, Wengner, and Kratochwil teach anti-cancer pharmaceuticals and methods of treating cancer. It would be recognized that both Osterkamp and Kratochwil teach tumor antigen targeting radiopharmaceutical agents. It would also be recognized that Wengner suggests that BAY 1895344 exhibits synergy with DNA damaging therapies. It would also be recognized that Osterkamp teaches that the radiopharmaceutical may be used for the treatment of colorectal carcinoma, prostate cancer, and breast cancer; that Wengner demonstrates efficacy of BAY 1895344 in preclinical models of these cancers; and that Kratochwil teaches dosing of a 225Ac-labeled radiopharmaceutical compound in prostate cancer.
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 cancer treatment method of the combination of Osterkamp and Wengner with the specific dosing of a 225Ac-labeled radiopharmaceutical at 50-200 kBq/kg as taught by Kratochwil because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods and achieve the predictable result of an effective combination therapy of a 225Ac-labeled radiopharmaceutical and a DDRi (MPEP § 2143(I)(A)).
A person of ordinary skill in the art would have had a reasonable expectation of success in applying the 225Ac radiopharmaceutical dosing of Kratochwil to the method of the combination of Osterkamp and Wengner because Osterkamp teaches that dosing of the radiopharmaceutical can change depending on the type of emission exhibited by the radionuclide bound to the radiopharmaceutical. There would also be a reasonable expectation of success because Kratochwil describes that the selection of radionuclide is a key factor for determining efficacy, toxicity, and dose. Thus, it would be expected that the dose used in a 225Ac-based targeted radiotherapy of prostate cancer using one targeting agent could translate to other targeting radiopharmaceuticals using the same radionuclide.
The skilled artisan would have been motivated to incorporate the dosing of Kratochwil in pursuit of a more effective or less toxic cancer treatment.
Regarding claims 16-18, as described above, the combined teachings of Osterkamp and Wengner render the method of claim 3 obvious. Osterkamp teaches that the chelated atom can be 225Ac (pg. 66, last paragraph). Osterkamp teaches that the radiopharmaceutical compound can be administered at unitary doses ranging from 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). Additionally, Kratochwil teaches administration of a 225Ac-labeled radiopharmaceutical at doses of 50, 100, 150, and 200 kBq/kg (pg. 1625, Table 1). These values fall within the claimed ranges, rendering the claimed ranges obvious (MPEP § 2144.05(I)).
Additionally and separately, the examiner considers administering the radiopharmaceutical at a different dose to amount to administration of a composition with a different concentration of radiopharmaceutical. Per MPEP § 2144(II)(A) , changes in concentration amount to routine optimization and are prima facie obvious. The skilled artisan in the practice of methods of treating cancer would be motivated to optimize the dose amount to balance the maximization of efficacy with the minimization of toxicity in this combination therapy. Furthermore, as Wengner describes BAY 1895344 to be a radiosensitizer pg. 36, left column, fourth paragraph), this suggests a lower dose of a radiopharmaceutical would be able to produce a similar effect when used in combination with BAY 1895344 compared to radiopharmaceutical monotherapy, providing a motivation to decrease the amount of the radiopharmaceutical dosed and an expectation of success and efficacy in such a modification.
Therefore, the combined teachings of Osterkamp, Wengner, and Kratochwil render claims 16-18 obvious.
Regarding claim 26, as described above, the combined teachings of Osterkamp and Wengner render claim 1 obvious. Additionally, Osterkamp teaches that the chelated atom can be 225Ac (pg. 66, last paragraph) and formula (IIIa) of Osterkamp reads on the claimed structure of the radiopharmaceutical (pg. 35). Furthermore, Wengner teaches administration of BAY 1895344 (pg. 27, In vivo studies in CDX models). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph). Additionally, Kratochwil teaches administration of a 225Ac-labeled radiopharmaceutical at doses of 50, 100, 150, and 200 kBq/kg of body weight (pg. 1625, Table 1). The latter three values fall within the claimed ranges, rendering the claimed ranges obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Osterkamp, Wengner, and Kratochwil render claim 26 obvious.
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 1-2 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/541,604 in view of Wengner (Wengner, A. M.; et al., Mol. Cancer Ther., 2020).
Claims 1-2 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/541,618 in view of Wengner (Wengner, A. M.; et al., Mol. Cancer Ther., 2020).
Claims 1-2 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/541,584 in view of Wengner (Wengner, A. M.; et al., Mol. Cancer Ther., 2020).
Claims 1-2 and 8-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 7 of copending Application No. 18/541,534 in view of Wengner (Wengner, A. M.; et al., Mol. Cancer Ther., 2020).
The claims of copending applications 18/541,604; 18/541,618; 18/541,584; and 18/541,534 are drawn to methods of treating cancer comprising administering a neurotensin receptor targeting radiopharmaceutical in combination with other chemotherapeutic agents. The chemotherapy in copending application 18/541,604 is gemcitabine and nab-paclitaxel. The chemotherapy in copending application 18/541,618 is folinic acid, fluorouracil, liposomal irinotecan, and oxaliplatin. The chemotherapy in copending application 18/541,584 is folinic acid, fluorouracil, irinotecan, and oxaliplatin. The chemotherapy in copending application 18/541,534 is folinic acid, fluorouracil, and liposomal irinotecan.
The copending applications do not teach a combination therapy in which the chemotherapy is a DDRi.
As described above, Wengner teaches the efficacy of the ATR inhibitor compound BAY 1895344 in the treatment of cancer in xenograft tumor models (pg. 26, Abstract). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph). Wengner also states that ATR plays a key role in DNA damage repair (pg. 26, Introduction, second paragraph). Wengner teaches that BAY 1895344 exhibits antitumor activity as a single agent in xenograft tumor models of prostate cancer and colon cancer (pg. 29, right column, last paragraph; and pg. 30, Figure 2). Wengner also teaches that BAY 1895344 exhibits synergy with chemotherapy and radiation therapy in xenograft models of colorectal cancer (pg. 33, left column, paragraphs 4, 6, and 7). Wengner also teaches that BAY 1895344 has single agent efficacy in a breast cancer model (pg. 34, Figure 5E). Wengner suggests that the cancer-killing activity of radiation may be increased by the inhibition of ATR (pg. 26, right column, last paragraph through pg. 27, left column, first paragraph). Wengner concludes that BAY 1895344 displays synergy when used in combination with DNA damage-inducing therapies.
A person of ordinary skill in the art would recognize that Wengner describes BAY 1895344 as an effective anti-cancer drug that is suitable for use in combination with therapies that damage DNA, such as radiopharmaceuticals.
Therefore, 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 chemotherapy-targeted radiotherapy combinations claimed by the copending applications 18/541,604; 18/541,618; 18/541,584; and 18/541,534 by substituting the chemotherapeutic agents of the conflicting claims with the BAY1895344 chemotherapeutic agent taught by Wengner. This would predictably result in an effective cancer treatment combination.
Regarding instant claim 1, the radiopharmaceutical compound of conflicting claim 7 in each of the aforementioned copending applications reads on the structure of claim 1 wherein R1 is methyl, AA-COOH is 2-amino-2-adamantane carboxylic acid, R2 is C3 alkyl, R3 and R4 are C1 alkyl, L1 and L2 are C3 alkylidene, W is DOTA, and the compound is labeled with the radionuclide 177Lu. Additionally, Wengner teaches a method of treating cancer in xenograft tumor models using BAY 1895344, which is an inhibitor of ATR, a protein involved in DNA damage repair (pg. 26, Introduction, second paragraph). The examiner interprets BAY 1895344 to be a DDRi.
For the reasons stated above, providing a combination therapy method wherein both BAY 1895344 and a neurotensin receptor-targeting radiopharmaceutical are administered to treat or ameliorate cancer is prima facie obvious. The examiner notes that the limitations (i), (ii), and (iii) of claim 1 relate to the timing of such combination therapy, reciting options wherein either the DDRi is administered first, the radiopharmaceutical is administered first, or that both agents are administered at the same time. As the scope of the claim includes all of these options, any combination therapy must read on these alternative limitations as a whole because they cover all possible arrangements for such a combination therapy. Furthermore, Wengner teaches administration of BAY 1895344 in combination with other therapies in which BAY 1895344 is administered first before radiation therapy or at the same time as other chemotherapies (pg. 27 and 29, In vivo studies in CDX models).
Regarding instant claim 2, for the reasons described above a method in which both BAY 1895344 and a neurotensin receptor-targeting radiopharmaceutical that reads on formula (I) of claim 1 is prima facie obvious. Furthermore, the examiner considers the selection of administering a DDRi after a mammal has already received or is receiving a radiopharmaceutical to amount to a change in sequence of steps in a procedure, which is prima facie obvious, per MPEP § 2144.04(IV). Additionally and separately, Wengner teaches administration of BAY 1895344 twice daily 2on/5off in combination with external beam radiation therapy once daily on days 12 and 27 (pg. 27, right column, last paragraph, lines 19-21). In such a method, BAY 1895344 would be dosed on days 15 and 16, which is administration of a DDRi after the mammal has received a radiation-based therapy. As radiopharmaceuticals are effective due to inducing DNA damage and Wengner suggests combining BAY 1895344 with DNA damaging therapies (pg. 36, right column, last paragraph), this would suggest to the skilled artisan to administer the radiopharmaceutical of the copending applications in combination with the BAY 1895344 of Wengner with a similar regimen.
Regarding instant claims 8-11, Wengner teaches administration of BAY 1895344 (pg. 27, In vivo studies in CDX models). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph).
This is a provisional nonstatutory double patenting rejection.
Claims 1-3, 8-11, and 15-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 9-20 of copending Application No. 18/833,848 in view of Wengner.
The claims of copending application 18/833,849 are drawn to a method of treating cancer comprising administering a neurotensin receptor targeting radiopharmaceutical in combination with checkpoint inhibitors. The combination can be dosed in different orders and different doses of radiopharmaceutical and it can be used in the treatment of several specific cancers.
Copending application 18/833,848 does not teach a combination therapy in which the chemotherapy is a DDRi.
As described above, Wengner teaches the efficacy of the ATR inhibitor compound BAY 1895344 in the treatment of cancer in xenograft tumor models (pg. 26, Abstract). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph). Wengner also states that ATR plays a key role in DNA damage repair (pg. 26, Introduction, second paragraph). Wengner teaches that BAY 1895344 exhibits antitumor activity as a single agent in xenograft tumor models of prostate cancer and colon cancer (pg. 29, right column, last paragraph; and pg. 30, Figure 2). Wengner also teaches that BAY 1895344 exhibits synergy with chemotherapy and radiation therapy in xenograft models of colorectal cancer (pg. 33, left column, paragraphs 4, 6, and 7). Wengner also teaches that BAY 1895344 has single agent efficacy in a breast cancer model (pg. 34, Figure 5E). Wengner suggests that the cancer-killing activity of radiation may be increased by the inhibition of ATR (pg. 26, right column, last paragraph through pg. 27, left column, first paragraph). Wengner concludes that BAY 1895344 displays synergy when used in combination with DNA damage-inducing therapies.
A person of ordinary skill in the art would recognize that Wengner describes BAY 1895344 as an effective anti-cancer drug that is suitable for use in combination with therapies that damage DNA, such as radiopharmaceuticals.
Therefore, 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 chemotherapy-targeted radiotherapy combinations claimed by copending application 18/833,848 by substituting the checkpoint inhibitor chemotherapeutic agents of the conflicting claims with the BAY1895344 chemotherapeutic agent taught by Wengner. This would predictably result in an effective cancer treatment combination.
Regarding instant claim 1, the radiopharmaceutical compound of conflicting claim 1 of the reference application is identical to that of formula (I) of instant claim 1. Additionally, the dosing order combinations are also the same as instant claim 1. Additionally, Wengner teaches a method of treating cancer in xenograft tumor models using BAY 1895344, which is an inhibitor of ATR, a protein involved in DNA damage repair (pg. 26, Introduction, second paragraph). The examiner interprets BAY 1895344 to be a DDRi.
Regarding instant claim 2, conflicting claim 2 of the reference application specifies administering the chemotherapeutic agent where a mammal has received or is receiving a radiopharmaceutical.
Regarding instant claim 3, conflicting claim 3 of the reference application is drawn to a method of using the same structure of radiopharmaceutical as instant claim 3, also labeled with 225Ac.
Regarding instant claims 8-11, Wengner teaches administration of BAY 1895344 (pg. 27, In vivo studies in CDX models). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph).
Regarding instant claim 15, conflicting claim 9 of the reference copending application is drawn to a method wherein the mammal is a human.
Regarding instant claims 16-18, conflicting claims 10-12 of the reference application are drawn to methods wherein the same 225Ac-labeled radiopharmaceutical is dosed at less than 1 MBq/kg, 250 kBq/kg, or 100 kBq/kg of body weight of a mammal.
Regarding instant claims 19-21, conflicting claims 13-15 of the reference copending application are drawn to methods wherein the same 225Ac-labeled radiopharmaceutical is dosed in a unitary dosage of less than 15, 10, or 5 MBq.
Regarding instant claims 22 and 23, conflicting claims 16 and 17 of the reference copending application are drawn to methods in which the cancer is a list that includes colorectal cancer and ductal pancreatic adenocarcinoma.
Regarding instant claim 24, conflicting claim 18 of the reference copending application is drawn to a method wherein the administration of the combination therapy results in a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume.
Regarding instant claim 25, conflicting claim 19 of the reference copending application is drawn to a method wherein the administration of the combination therapy results in a decreased incidence of recurrence or metastasis.
Regarding instant claim 26, conflicting claim 20 of the reference copending application is drawn to a method using the same 225Ac-labeled radiopharmaceutical at a dosage of 100-600 kBq/kg of body weight of a mammal. Additionally, Wengner teaches administration of BAY 1895344 (pg. 27, In vivo studies in CDX models). Wengner describes BAY 1895344 to be an ATR inhibitor (pg. 27, left column, second paragraph).
This is a provisional nonstatutory double patenting rejection.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10, 12-13, 16, 19, and 22-25 of copending Application No. 19/474,981 in view of Osterkamp (WO 2014/086499 A1 – provided by applicant in IDS filed September 26, 2025).
The claims of copending application 19/474,981 are drawn to a method of treating cancer comprising administering a targeted radiopharmaceutical compound in combination with DNA damage response inhibitors. The combination can be dosed in different orders and different doses of radiopharmaceutical and it can be used in the treatment of several specific cancers.
Copending application 19/474,981 does not teach a combination therapy in which the radiopharmaceutical is a neurotensin receptor targeting compound having the structure of formula (I) of instant claim 1.
As described above, Osterkamp teaches a neurotensin receptor binding ligand of formula (I) (pg. 9), which is reads on formula (I) in the instant application. Osterkamp also teaches the specific embodiment of formula (IIIa) (pg. 35). Osterkamp teaches specific examples of labeling the compound of formula (IIIa) with indium, gallium, yttrium, and lutetium (pg. 99-100, Examples 6B-E). Osterkamp teaches that the chelated atom can alternatively be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). Osterkamp teaches that the disclosed compounds can be used for the treatment of pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Osterkamp also teaches that dosing of the radiopharmaceutical can be administered at several timepoints over a time period; for example, over a period of 1 to 3 weeks or longer and that dosing can be 1 to 200 MBq, 1 to 400 MBq, or 10 to 5,000 MBq depending on the radionuclide identity and the organism to which the compound is administered (pg. 80, last paragraph through pg. 81, first paragraph). Osterkamp further teaches that the targeted radiotherapy using the disclosed compounds may be used in combination with chemotherapy (pg. 73, fourth paragraph) such as with targeted agents (pg. 80, second paragraph).
A person of ordinary skill in the art would recognize that Osterkamp describes anti-cancer targeted radiopharmaceutical compounds that may be labeled with 225Ac that are suitable for use in combination with chemotherapeutic compounds.
Therefore, 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 DDRi chemotherapy-targeted 225Ac radiotherapy combinations claimed by copending application 19/474,981 by substituting the PSMA-targeting radiopharmaceutical of the conflicting claims with the neurotensin receptor targeting radiopharmaceutical compound taught by Osterkamp. This would predictably result in an effective cancer treatment combination.
Regarding instant claim 1, Osterkamp teaches a radiopharmaceutical compound of formula (I) (pg. 9), which reads on formula (I) of claim 1. Osterkamp also teaches a specific embodiment of formula (IIIa) (pg. 35), which reads on the structure of claim 1 wherein R1 is methyl, AA-COOH is 2-amino-2-adamantane carboxylic acid, R2 is C3 alkyl, R3 and R4 are C1 alkyl, L1 and L2 are C3 alkylidene, and W is DOTA. Osterkamp also teaches that the chelated atom can be 225Ac (pg. 66, last paragraph). Osterkamp teaches that the disclosed compounds can be used for the treatment of diseases including pancreatic ductal adenocarcinoma, colorectal cancer, lung cancer, head and neck cancer, breast cancer, and prostate cancer (pg. 43, last paragraph through pg. 44 first paragraph). Additionally, conflicting claim 1 of the copending reference application teaches administration of DDRi in combination with a targeted radiopharmaceutical compound. Conflicting claim 1 is also drawn to combinations of the same order of administration of the DDRi and the targeted 225Ac radiopharmaceutical.
Regarding instant claim 2, conflicting claim 2 of the reference copending application is drawn to a method wherein the DDRi is administered to a mammal that has received or is receiving a targeted 225Ac radiopharmaceutical.
Regarding instant claim 3, Osterkamp teaches that the atom chelated in the radiopharmaceutical can be a therapeutic radionuclide selected from a list including 177Lu, 90Y, 67Cu, 64Cu, 68Ga, 131I, 153Sm, 186Re, 188Re, 211At, 212Pb, 213Bi, 225Ac, and 227Th (pg. 66, last paragraph). This list includes 225Ac. Furthermore, formula (IIIa) of Osterkamp (pg. 35) is identical to the structure of instant claim 3.
Regarding instant claims 4-7, conflicting claims 4-7 of the copending reference application are drawn to methods wherein the DDRi is a PARP inhibitor, including olaparib.
Regarding instant claims 8-11, conflicting claims 8-10 of the copending reference application are drawn to methods wherein the DDRi is an inhibitor of ATR or ATM, including AZ20.
Regarding instant claims 12-14, conflicting claims 12-13 of the copending reference application are drawn to methods wherein the DDRi is an inhibitor of DNA-PK, WEE1, Chk1, or Chk2; including AZD7648.
Regarding instant claim 15, conflicting claims 16 and 19 of the copending reference application are drawn to methods wherein the mammal is a human.
Regarding instant claims 16-18, conflicting claim 16 of the copending reference application is drawn to methods wherein the 225Ac targeted radiopharmaceutical compound is administered at a dose of less than 2 MBq/kg, 250 kBq/kg, or 100 kBq/kg of body weight of the subject.
Regarding instant claims 19-21, conflicting claim 19 of the copending reference application is drawn to methods wherein the 225Ac targeted radiopharmaceutical compound is administered at a dose of less than 15, 10, or 5 MBq as a unitary dosage to the subject.
Regarding instant claims 22 and 23, conflicting claim 22 of the copending reference application is drawn to a method of treating cancers including prostate cancer, breast cancer, and colorectal cancer.
Regarding instant claim 24, conflicting claim 24 of the reference copending application is drawn to a method wherein the administration of the combination therapy results in a decrease in tumor volume, a stable tumor volume, or a reduced rate of increase in tumor volume.
Regarding instant claim 25, conflicting claim 25 of the reference copending application is drawn to a method wherein the administration of the combination therapy results in a decreased incidence of recurrence or metastasis.
Regarding instant claim 26, as described above, Osterkamp renders obvious a method of using the 225Ac-labeled radiopharmaceutical of instant claim 3, which is the same as that of instant claim 26. Additionally, conflicting claims 4-10 of the reference copending application are drawn to methods wherein the DDRi is a PARP inhibitor or an inhibitor of ATR or ATM. Furthermore, conflicting claim 16 of the copending reference application is drawn to methods wherein the 225Ac targeted radiopharmaceutical compound is administered at a dose of less than 2 MBq/kg, 250 kBq/kg, or 100 kBq/kg of body weight of the subject.
This is a provisional nonstatutory double patenting rejection.
Pertinent Art
As pertinent art, the examiner cites Nonnekens (Nonnekens, J.; et al., Theranostics, 2016). Nonnekens teaches combination of targeted radionuclide therapy and the PARP inhibitor olaparib (pg. 1821, Abstract). More specifically, Nonnekens teaches that the combination of 177Lu-DOTA-TATE and olaparib results in more effective killing of cultured cells than either agent as a monotherapy (pg. 1825, Figure 1). Nonnekens concludes that the PARP inhibitor olaparib sensitizes cells to targeted radionuclide therapy, suggesting it useful to combine such therapies (pg. 1832, Conclusion). The examiner notes that this suggests to the skilled artisan to combine PARP inhibitors with other targeted radionuclide therapies in methods of treating cancers.
As pertinent art, the examiner cites Li (Li, D.; et al., Cancer Biother. Radiopharm., 2021). Li teaches a dose-response study of a 225Ac-labeled neurotensin receptor targeting radiopharmaceutical in a cancer model (pg. 651, Abstract). More specifically, Li teaches administering 18.5, 37, or 74 kBq of 225Ac-di-DOTA-α,ε-Lys-NT(6-13) to mice bearing xenograft tumors (pg. 653, Therapy studies). The xenograft tumors were a model for prostate cancer (pg. 653, Animal studies). Li teaches that the 225Ac-labeled neurotensin receptor targeting radiopharmaceutical effectively slowed the growth of tumors in the mice and increased survival at some doses (pg. 658, Figure 7). Li describes that alpha emitting radionuclides, such as 225Ac, exhibit higher linear energy transfer than beta emitters (such as 177Lu), resulting in higher therapeutic efficacy and lower toxicity (pg. 653, left column, second paragraph). Li describes that beta emitter radiopharmaceuticals tend to be administered at higher doses, such as 110-165 MBq to a mouse, whereas alpha emitters can be administered on the scale of 18.5-74 kBq to a mouse (pg. 659, fifth paragraph). Li concludes that further studies are required to determine an optimal therapeutic dose of such 225Ac-labeled neurotensin receptor targeting radiopharmaceuticals. The examiner notes that Li suggests continued optimization of radiopharmaceutical dose even after observing some efficacy. Li also indicates that radiopharmaceuticals labeled with 225Ac can be administered at kBq-level doses to mice and achieve efficacy.
As pertinent art, the examiner cites Burak (WO 2020/115,548 A1 – provided by applicant in IDS filed September 26, 2025). Burak teaches combination therapies comprising administering radiopharmaceuticals and DDRi compounds (Abstract). More specifically, Burak teaches combinations of radionuclide-labeled IGF1-R targeting antibodies and DDRi compounds such as PARP inhibitors, ATR inhibitors, WEE1 inhibitors, Chk1 inhibitors, Chk2 inhibitors, and DNA-PK inhibitors (pg. 2, line 3 through pg. 3, line 15). Burak specifically teaches that combination of BAY 1895344 (an ATR inhibitor) and a radiopharmaceutical has a greater anticancer effect in a xenograft model of colon cancer (Figure 4). Burak also teaches that combination of olaparib (a PARP inhibitor) and a radiopharmaceutical has a greater anticancer effect in a xenograft model of colon cancer (Figure 10). In these studies, the radiopharmaceutical was labeled with 225Ac (pg. 44-46, Examples). Burak teaches that synergy was observed between olaparib and the 225Ac-labeled targeted radiopharmaceutical (pg. 46, third paragraph). The examiner notes that these results would suggest to the skilled artisan to combine ATR inhibitors or PARP inhibitors with targeted 225Ac-labeled radiopharmaceuticals in methods of treating cancer.
Conclusion
No claim is allowed.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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