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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 31, 2025 has been entered.
Applicants' arguments, filed July 31, 2025, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Response to Amendment
The 9 page declaration by Nonnekens labeled “Replacement Declaration” under 37 CFR 1.132 filed July 31, 2025 is insufficient to overcome the rejection of the pending claims based upon Nonnekens et al. (Theranostics, 2016) alone or further in view of additional references as set forth in the last Office action because: the contents of the declaration are substantially the same as that filed May 6, 2025 with the addition of larger versions of panels A – C from Figure 1 attached at the end of the declaration. While these larger versions present clearer text, the data corresponding to the different conditions still cannot be discerned as the various shades of gray, similar symbols and or line styles are not readily discernible from one another even though the overall quality is higher for the larger versions of the figures.
The 4 page declaration by Nonnekens under 37 CFR 1.132 filed July 31, 2025 is insufficient to overcome the rejection of the pending claims based upon Nonnekens et al. (Theranostics, 2016) alone or further in view of additional references as set forth in the last Office action because: the expected results are not clearly established and the evidence in support of unexpected results does not outweigh the prima facie case of obviousness.
In the discussion set forth in the Office Action mailed May ,16, 2025 as to why the declaration filed May 6, 2025 was not persuasive, the Examiner indicated that the expected results were not established and Applicants bear the burden of establishing the expected results as part of explaining the evidence offered in support of alleged unexpected results. Without establishing what the expected results would be, it cannot be determined if any differences observed were in fact unexpected. The Examiner cited art, Venere et al. (Cell Death Diff, 2014), indicating that the expected results could be the administration of the poly ADP ribose polymerase (PARP) inhibitor (PARPi) prior to radiation exposure can lead to greater effects by compromising the ability of the cells to respond to DNA damage, driving the cells to undergo apoptosis (e.g., p 265, col 2, ¶ 2). In various in vitro and in vivo experiments, PARP inhibitors such as olaparib have been shown to act as radiosensitizers to enhance radiation therapy (p 259, col 1, ¶ 2). While in a different type of cancer from that claimed, damage DNA from ionizing radiation (IR) was resolved after 24 hours while PARPi compromised repair kinetics and/or contributed to continual formation of DNA breaks as unrepaired ROS (reactive oxygen species)-induced damage can be converted to double-stranded breaks (p 261, col 1, ¶ 2). This is addressed in section 5 of the declaration stating that there are substantial differences between the external radiation therapy in Venere et al. and PRRT therapy as claimed which must accumulate at the tumor sire whereas external radiation therapy causes an immediate localized effect. Section 6 of the declaration states that “[o]nly after confirming [tumor] accumulation of PRRT radionuclides might a person of ordinary skill in the art desire to maximize PAPR inhibition to coincide with maximal PRRT radionuclide concentration in the targeted tumor, with the intention of minimizing potential damage to healthy tissues within the patient from PARP inhibition.” This still does not establish what the expected results would be and both external radiation and the 177Lu deliver ionizing radiation to cells and while the amount of such radiation delivered to the tumor would depend on the amount of 177Lu-oxodotreotide (177Lu-DOTA-TATE) localized at the tumor, even small amounts of 177Lu-DOTA-TATE would begin to cause damage to the DNA of the cells. Citing of this art was an attempt by the Examiner to establish what the expected results could be but the statements in this declaration still do not clearly establish what the expected results would be. While the statements indicate a difference in outcome based on olaparib beginning administration 2 days prior compared to 3 days after 177Lu-DOTA-TATE administration and continuing olaparib administration for 14 days, without knowing if such a difference is in fact unexpected, the evidence of record in support of unexpected results does not outweigh the prima facie case of obviousness reiterated below.
The declaration also states that it would logical to administer the PARP at day 3 post-PRRT when the tumor/kidney ratio indicating tumor localization is high as indicated by the initial studies of the declarant but this regimen schema did not initially demonstrate efficacy. Those results would not have motivated a person of ordinary skill in the art to expect that administering PARP inhibitors prior to PRRT would provide better results especially in view of the therapeutic windows of PARP inhibition and PRRT individually. It is surprising to those of ordinary skill in the art that the claimed administration of PARP inhibitors prior to PRRT demonstrated such efficacy.
These statements are unpersuasive. The therapeutic windows of the PARP inhibition and PRRT are not given that in part forms the basis for the conclusion. But as discussed previously, documents such as Venere et al. would be available to those of ordinary skill in the art and while the radiation exposure in that study was a single dose rather than more continuous delivery of radiation as with PRRT, improved efficacy was clearly demonstrated when the PARPi radiosensitizer was administered prior to radiation damage and DNA damage was resolved at 24 hours after IR exposure in the absence of such inhibition (p 2651, col 1, ¶ 2). While maximal DNA damage might occur with maximal tumor localization of the 177Lu-DOTA-TATE, 177Lu continually emits ionizing radiation and will cause damage in the vicinity of the 177Lu-DOTA-TATE, whether that is the tumor or elsewhere in the body. While the exact source and method of radiation delivery differ between Venere et al. and the instant claims, the declaration still fails to establish what the expected results of the claimed method would be to show that the differences observed would in fact be unexpected. That the opposite order of administration failed to show efficacy does not necessarily establish that one would reasonably expect the same lack of efficacy when the PARPi is administered prior to the onset of radiation exposure particularly light of prior art such as Venere et al.
The declaration also states disagreement with the assertion by the Examiner that the data of record is not commensurate scope in part because the somatostatin receptor state of the tested cell line was not given. It was unnecessary to explicitly state the somatostatin receptor status of the CS20948 rat pancreatic tumor cells used since they are known to those of skill to express SST2 receptor [Examiner note: SST2 stands for somatostatin receptor type 2].
These statements are unpersuasive. Based on the name, it appears that there are more than one type of somatostatin receptor and the cell line used only expresses one. Only dependent claim 33 requires the neuroendocrine tumor to express at least one somatostatin receptor, meaning that the neuroendocrine tumors of independent claim 19 and any claim not depending from claim 33 need not express any somatostatin receptor. No data or explanation as been given as to why it would reasonably be expected that the data for SST2-expressing neuroendocrine tumor would extrapolate to all neuroendocrine tumors including those that are somatostatin receptor negative. Claim 19 encompasses a single administration of olaparib 2 days prior to 177Lu-DOTA-TATE administration with only claim 49 clearly requiring administration for 14 days as in the experiments reported in the previously filed declaration. No data or explanation as been given as to why it would reasonably be expected that a single dose would have the same effect as a two week dosing regimen has been set forth. While it is not necessary to provide data for every embodiment within the scope of the claims, some explanation as to how the data given would be expected to occur for the full scope (e.g., neuroendocrine tumors that are somatostatin receptor positive) is required. That burden has not been met.
When the totality of the evidence of record is considered, the evidence of record in support of the alleged unexpected results does not outweigh the prima facie case of obviousness reiterated below.
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.
Claim(s) 19, 37, 48 and 49 were rejected under 35 U.S.C. 103 as being unpatentable over Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS). This rejection is MAINTAINED for the reasons of record set forth herein.
Nonnekens et al. discloses that neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) are targeted for treatment with radiolabeled peptides in peptide receptor radionuclide therapy (PRRT; p 1821, col 1). 177Lu coupled to the somatostatin analogue DOTA-[Tyr3]octreotate (177Lu-DOTA-TATE) is applied as a third line treatment with clinical trials showing high tumor response rates, low toxicity, extended progression free survival and improved quality of life (p 1821, col 2). While most tumors initially respond well to such treatment, there will eventually be relapse and potential damage to healthy tissue could result from simply administering a higher radionuclide dose (p 1822, col 1, ¶ 1). The cell killing effect of 177Lu is likely due to double stranded DNA breaks caused by the emitted ionizing beta particles (p 1822, col 1, ¶ 2). The use of poly-[ADP-ribose]-polymerase 1 (PARP-1) inhibitors has been used to kill cells with homologous recombination defects and PARP inhibitors can be used as single agents but also in new strategies to enhance the efficacy of radiation (p 1822, col 1, ¶ 2). Monotherapy with PARP inhibitors in the clinic is associated with relatively mild side effects and therefore are ideal candidates for use as combination agents (p 1830). Synergistic sensitization to PPRT using the PARP inhibitor olaparib was demonstrated from SSTR2-positive human osteosarcoma cells and ex vivo cultured human NET slices that was caused by increased genome instability leading to cell death (p 1822, col 1, ¶ 3). Increased cell death and reduced cellular proliferation was seen with the combination treatment compared to the PRRT alone (abstract).
Administration of this combination treatment to a subject with cancer was not disclosed.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to administer the combination of 177Lu-DOTA-TATE and olaparib taught by Nonnekens et al. to a subject having a NET tumor overexpressing SSTR2 and vary the order of administration of the two agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because both agents are used individually in subjects to treat cancer and Nonnekens et al. showed with in vitro and ex vivo experiments that the combination treatment showed synergistic sensitization to PPRT with 177Lu-DOTA-TATE and the PARP inhibitor olaparib. Thus the 177Lu-DOTA-TATE and olaparib can be administered to human subjects and one of ordinary skill in the art would reasonably expect that the enhanced efficacy seen in the experiments of Nonnekens et al. would also be seen in vivo when administered to a subject. Absent evidence of unexpected results [see above for a discussion of the Declaration filed July 31, 2025), it is prima facie obvious to vary the order of administration of the 177Lu-DOTA-TATE and olaparib (see MPEP 2144.04 IV). Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent when used as a monotherapy) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims.
As to claim 37, this claim reflects the effects of the administered combination therapy. As agents as claimed are administered to cancer subjects, the same effects would necessarily occur and explicit recitation of such effects does not patentably distinguish the claims over the applied prior art.
Applicants traverse this rejection on the grounds summarize the statements made by the Examiner in the previous Office Action and indicate that the Examiner has broadly and improperly conflated the claimed PRRT with radiation in general. The precise ongoing durations and frequencies of olaparib and 177Lu-DOTA-TATE with respect to the regime is immaterial to the regimen features demonstrated in the study data and claimed with olaparib first administered 2 days prior to the first administration of 177Lu-DOTA-TATE. Unexpected efficacy was demonstrated for a single-cycle treatment alone with no statistically significant different in median survival and tumor growth between the PRRT alone and PRRT+olaparib(+3d) groups, surprising results demonstrating the important of administering the first PARPi 2 days prior to the first PRRT.
These arguments are unpersuasive. The concurrently filed declarations were discussed in greater detail above. Without establishing what the expected results of administration of olaparib 2 days before 177Lu-DOTA-TATE administration compared to administration 3 days after 177Lu-DOTA-TATE administration, if the differences seen are in fact unexpected cannot be determined. The data presented compare administration of olaparib either 2 days before or 3 days after 177Lu-DOTA-TATE administration to treat a SST2-receptor expressing neuroendocrine tumor, with the olaparib being administered for 14 days. While independent claim 19 has been amended to limit the olaparib administration to just 2 days prior to 177Lu-DOTA-TATE administration, the neuroendocrine tumor need not be positive for somatostatin receptors (see claim 33) and need not be administered for 14 days (see claim 49). The effects of a single dose of olaparib compared to continuous administration not only until the time of 177Lu-DOTA-TATE administration but for many days after may not have the same results. Therefore even if the expected results had been established and the data for the claimed treatment condition could be discerned in the evidence of record, that evidence would not be reasonably commensurate in scope with the claims.
Claim(s) 32 – 36, 44 and 45 were rejected under 35 U.S.C. 103 as being unpatentable over Nonnekens et al. as applied to claims 19, 37, 48 and 49 above, and further in view of Strosberg et al. (NEJM, January 12, 2017). This rejection is MAINTAINED for the reasons of record set forth herein.
Nonnekens et al. is discussed above.
An in vivo dosing protocol for the 177Lu-DOTA-TATE is not disclosed.
Strosberg et al. discloses results from a phase 3 trial of 177Lu-DOTA-TATE (177Lu-dotatate) for midgut neuroendocrine tumors in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors (whole document, e.g., title and background section of abstract). The patients had metastasized or locally advanced inoperable tumors with grading of the tumor based on the percentage of cells positive for the Ki67 (p 126, col 2, ¶ 1). The treatment groups were balanced with respect to tumor grade and the groups contained at least low- and high-grade tumors (p 128, col 2, ¶ 2). In the 177Lu-DOTA-TATE group, 7.4 GBq (200 mCi) of 177Lu-DOTA-TATE was infused intravenously over a period of 30 minutes with patients receiving 4 infusions (4 doses) every 8 weeks for a cumulative radioactivity of 29.6 GBq (p 127, col 1, ¶ 3). For the 177Lu-DOTA-TATE group, the estimated rate of progression free survival at month 20 was 65.2% and the median progression free survival had not been reached while the control group receiving octreotide long-acting repeatable (LAR) had an estimated rate of progression free survival of 10.8% and the median progression free survival was 8.4 months (methods section of abstract and p 129, col 1). A subgroup analysis showed consistent benefit across major subgroups with the 18% response rate in the 177Lu-DOTA-TATE group compared to the 3% rate in the control being notable given that response rates above 5% have not been observed in large randomized trials of others systemic therapies in this patient population (p 133, col 2, ¶ 1). 177Lu-DOTA-TATE treatment resulted in markedly longer progression free survival than high dose octreotide and was associated with limited acute toxic effects in patients with progressive neuroendocrine tumors that originated in the midgut (p 133, col 2, ¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the 177Lu-DOTA-TATE dosing regimen of 7.4 GBq of 177Lu-DOTA-TATE infused intravenously every 8 weeks for 4 infusions in the phase 3 trial of Strosberg et al. for subjects treated with the combination therapy of 177Lu-DOTA-TATE and olaparib disclosed by Nonnekens et al. such as those with varying grades and/or inoperable neuroendocrine tumors. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Strosberg et al. provides a dosing regimen for the radiolabeled portion of the combination therapy in Nonnekens et al. that showed markedly longer progression free survival with limited acute toxic effects on midgut neuroendocrine tumors in a phase 3 trial. Thus, one of ordinary skill in the art would reasonably expect that 7.4 GBq of 177Lu-DOTA-TATE infused intravenously every 8 weeks for 4 infusions would have a reasonable expectation of success in treating the cancer given the phase 3 trial results of Strosberg et al., and that even better results could be observed due to the further enhancements in anti-cancer activity disclosed by Nonnekens et al. for the combination therapy of 177Lu-DOTA-TATE and olaparib.
Applicants do not present any arguments regarding this rejection for the Examiner to address herein.
Claim(s) 46 was rejected under 35 U.S.C. 103 as being unpatentable over Nonnekens et al. and Strosberg et al. as applied to claims 19, 32 – 36, 37, 44, 45, 48 and 49 above, and further in view of Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
Nonnekens et al. and Strosberg et al. are discussed above.
While mention is made that the cancer cells were somatostatin-receptor (SSTR) positive (e.g., p 1821, col 1 of Nonnekens et al. and p 126, col 1, ¶ 2 of Strosberg et al.), the manner in which this was determined is not set forth.
Koch et al. investigated the use of Ga-68-DOTA-Tyr3-octreotate (Ga-68-DOTA-TATE) positron emission tomography (PET) to predict the effectiveness of octreotide acetate treatment (whole document, e.g., abstract). PET offers higher resolution than planar scintigraphy and single-photon emission computer tomography (SPECT) and the ability to quantify radiotracer uptake in tumor lesions (p 1, col 1, ¶ 2). Ga-68-DOTA-TATE is among the PET imaging radiopeptides developed, with different compounds having slightly different affinities for SSTR subtypes 1 – 5 (p 1, col 2, ¶ 1). While less useful on an individual basis, information from radiotracer uptake using Ga-68-DOTA-TATE PET is an important prognostic index for predicting the response to therapy with octreotide acetate (abstract).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use PET scanning with Ga-68-DOTA-TATE to assess the SSTR state of tumor cells and the amount of uptake by such tumor cells when gathering information about the neuroendocrine tumor prior to treatment with protocols used to treat SSTR positive tumor cells. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because reference is made in the art such as Strosberg et al. as to the SSTR status of the tumors but explicit mention of how such information can be determined is not set forth. Koch et al. discloses that PET imaging with peptides such Ga-68-DOTA-TATE can be used to determine uptake by cancer, requiring the presence of SSTR on the cells and particularly in aggregate, such information can be used to predict the response to therapy using compounds such as octreotide, which forms part of the therapeutic agents used in Nonnekens et al. and Strosberg et al.
Applicants do not present any arguments regarding this rejection for the Examiner to address herein.
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.
Applicants request that the double patenting rejections be held in abeyance until such time that otherwise allowable subject matter is identified.
As set forth herein, the claims are otherwise not in condition for allowance. Additionally, Applicant' s failure to argue the rejection on the grounds of non-statutory double patenting over US Patent Nos. 10,596,276; 10,596,278; 11,904,027; 12,151,003; 12,168,063 and 12,415,003 is noncompliant with the regulations under 37 C.F.R. 1.111. The instant rejections are not a provisional rejection as the claims of US Patent Nos. 10,596,276; 10,596,278; 11,904,027; 12,151,003; 12,168,063 and 12,415,003 have been issued. In the interest of compact prosecution, the Examiner has examined the instant application. However, in order for the response to the instant Office Action to be fully responsive and in compliance with the regulations under 37 C.F.R. 1.111, the Applicant should either file a terminal disclosure or traverse the rejection based on US Patent Nos. 10,596,276; 10,596,278; 11,904,027; 12,151,003; 12,168,063 and 12,415,003. Because applicant did not distinctly and specifically point out the supposed errors in the instant non-statutory double patenting rejection based on US Patent Nos. 10,596,276; 10,596,278; 11,904,027; 12,151,003; 12,168,063 and 12,415,003 and no Terminal Disclaimer has been filed, the rejections are maintained for the reasons set forth herein.
The provisional nonstatutory double patenting rejection over Application No. 17/290,337 has been withdrawn due to the abandonment of US’337 since the mailing of the previous Office Action.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 24 of U.S. Patent No. 10,596,276 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’276 recite methods of preparation and pharmaceutical compositions for a complex of the radionuclide 177Lu and a somatostatin receptor binding peptide linked to the chelating agent DOTA such as 177Lu-DOTA-TATE and at least one stabilizer against radiolytic degradation (e.g., claims 1 and 17).
The use of the claimed product in any methods of use is not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’276 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’276 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims. Strosberg et al. provides detailed information on a dosing and administration regimen shown in a phase 3 trial to show markedly longer progression free survival in patients with various grades and inoperable neuroendocrine tumors with limited acute toxic effects on midgut neuroendocrine tumors that would provide additional information for treatment protocols involving the compounds prepared and claimed in US’276. Koch et al. discloses the use of PET imaging with 68-Gd-DOTA-TATE to gather information about the SSTR state of tumor cells which can be used to predict the response to octreotide therapy.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 25 of U.S. Patent No. 10,596,278 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’278 recite pharmaceutical compositions of a complex of 177Lu, a somatostatin receptor binding peptide linked to the chelating agent DOTA, gentisic acid and ascorbic acid (claim 1). The somatostatin receptor binding peptide linked to the chelating agent DOTA can be DOTA-TATE or DOTA-TOC (claim 19)
The use of the claimed product in any methods of use is not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’278 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’278 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims. Strosberg et al. provides detailed information on a dosing and administration regimen shown in a phase 3 trial to show markedly longer progression free survival in patients with various grades and inoperable neuroendocrine tumors with limited acute toxic effects on midgut neuroendocrine tumors that would provide additional information for treatment protocols involving the compounds prepared and claimed in US’278. Koch et al. discloses the use of PET imaging with 68-Gd-DOTA-TATE to gather information about the SSTR state of tumor cells which can be used to predict the response to octreotide therapy.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 16 of U.S. Patent No. 11,904,027 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’027 recite a process for making a complex of 177Lu with a somatostatin receptor binding peptide linked to the chelating agent DOTA and at least one stabilizer (claim 1) or pharmaceutical compositions of the prepared product (e.g., claims 20 and 21). The somatostatin receptor binding peptide linked to DOTA can be DOTA-TATE or DOTA-TOC (claim 17).
The use of the claimed product in any methods of use is not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’027 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’027 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims. Strosberg et al. provides detailed information on a dosing and administration regimen shown in a phase 3 trial to show markedly longer progression free survival in patients with various grades and inoperable neuroendocrine tumors with limited acute toxic effects on midgut neuroendocrine tumors that would provide additional information for treatment protocols involving the compounds prepared and claimed in US’027. Koch et al. discloses the use of PET imaging with 68-Gd-DOTA-TATE to gather information about the SSTR state of tumor cells which can be used to predict the response to octreotide therapy.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 30 of U.S. Patent No. 12,151,003 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’003 recite a composition of 177Lu labeled somatostatin receptor binding peptide-chelator containing compositions such as DOTA-TATE (e.g., claims 1 and 7). Methods of treating tumors with the prepared compositions are also claimed (e.g., claim 23) and the tumor can be a neuroendocrine tumor (claims 25, 26 and 30).
The use of olaparib to also treat such tumors or particulars of the 177Lu-DOTA-TATE administration are not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’003 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’003 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims. Strosberg et al. provides detailed information on a dosing and administration regimen shown in a phase 3 trial to show markedly longer progression free survival in patients with various grades and inoperable neuroendocrine tumors with limited acute toxic effects on midgut neuroendocrine tumors that would provide additional information for treatment protocols involving the compounds prepared and claimed in US’003. Koch et al. discloses the use of PET imaging with 68-Gd-DOTA-TATE to gather information about the SSTR state of tumor cells which can be used to predict the response to octreotide therapy.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 30 of U.S. Patent No. 12,168,063 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’063 recite a process for making compositions of 177Lu labeled somatostatin receptor binding peptide-chelator containing compositions such as DOTA-TATE (e.g., claims 1 and 6). Methods of treating tumors with the prepared compositions are also claimed (e.g., claim 21) and the tumor can be a neuroendocrine tumor (claims 23 - 25).
The use of olaparib to also treat such tumors or particulars of the 177Lu-DOTA-TATE administration are not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’063 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’063 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims. Strosberg et al. provides detailed information on a dosing and administration regimen shown in a phase 3 trial to show markedly longer progression free survival in patients with various grades and inoperable neuroendocrine tumors with limited acute toxic effects on midgut neuroendocrine tumors that would provide additional information for treatment protocols involving the compounds prepared and claimed in US’063. Koch et al. discloses the use of PET imaging with 68-Gd-DOTA-TATE to gather information about the SSTR state of tumor cells which can be used to predict the response to octreotide therapy.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 - 30 of U.S. Patent No. 12,415,003 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014).
Note that since the mailing of the previous Office Action, Application No. 18/927,047 issued as U.S. Patent No. 12,415,003 so the nonstatutory double patenting rejection is no longer a provisional rejection. This rejection is maintained for the reasons of record set forth herein.
The claims of US’003 recite a process for making a complex of 177Lu with a somatostatin receptor binding peptide linked to the chelating agent DOTA-TATE and at least one stabilizer (claim 1). Methods of treating a tumor in a patient with the compositions are also claimed (claims 13 - 30) and the tumor can be a gastroenteropancreatic neuroendocrine tumor (claims 17 and 18).
The use of olaparib to also treat such tumors or those that are inoperable or particulars of the 177Lu-DOTA-TATE administration are not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’003 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’003 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of ordinary skill in the art would routinely optimize the dose of each therapeutic agent based on their knowledge (e.g., known dosing for each agent) and teachings of the prior art as to the concentrations used for the studies carried out and that combination treatment can require additional optimization of the dose. Optimization of the therapeutic dose is well within the skill of one of ordinary skill in the art and the evidence of record does not establish evidence of unexpected results that is reasonably commensurate in scope with the claims. Strosberg et al. provides detailed information on a dosing and administration regimen shown in a phase 3 trial to show markedly longer progression free survival in patients with various grades and inoperable neuroendocrine tumors with limited acute toxic effects on midgut neuroendocrine tumors that would provide additional information for treatment protocols involving the compounds prepared and claimed in US’003. Koch et al. discloses the use of PET imaging with 68-Gd-DOTA-TATE to gather information about the SSTR state of tumor cells which can be used to predict the response to octreotide therapy.
Claims 19, 32 – 37, 44 – 46, 48 and 49 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 26 - 48 of copending Application No. 17/331,927 in view of Nonnekens et al. (Theranostics, 2016; cited on May 21, 2021 IDS) and optionally further in view of Strosberg et al. (NEJM, January 12, 2017) and Koch et al. (Mol Imaging, 2014). This rejection is MAINTAINED for the reasons of record set forth herein.
The claims of US’927 are product-by-process claims for pharmaceutical compositions of 177Lu-DOTA-TATE along with additional required ingredients (e.g., claim 26).
The use of the claimed product in any methods of use is not claimed.
Nonnekens et al., Strosberg et al. and Koch et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use the material prepared by US’927 combined with a PARP inhibitor for the treatment of cancer such as neuroendocrine tumors (NET) overexpressing the somatostatin receptor subtype 2 (SSTR2) and to vary the order of administration of therapeutic agents. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Nonnekens et al. discloses that the combination of 177Lu-DOTA-TATE and olaparib is better than treatment with just 177Lu-DOTA-TATE for the treatment of such cancers. Thus, it would have been obvious to one of ordinary skill to the pharmaceutical composition resulting from the claimed method of preparation and the claimed pharmaceutical formulations of US’927 to be administered to a subject in combination with olaparib to treat cancer. Both agents can be administered starting at the same time or one agent can be administered before the other for a finite number of possible dosing regimens. One of