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 .
Summary
Claims 1, 3, 6-16, 18-20, and 25-29 are pending in this office action. Claims 2, 4-5, 17, and 21-24 are cancelled. All pending claims are under examination in this application.
Priority
The current application was filed on May 9, 2024 is a 371 of PCT/IB2022/060840 filed on November 10, 2022, which in turn claims domestic priority to provisional patent application 63/278,621 filed on November 12, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on May 9, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Claim Objections
Claims 1, 3, 6-16, 18-20, and 25-29 are objected to because of the following informalities:
Claim 1: Please define C-S-P. Also, please define the acronyms associated with DOTA and PD in full. Once defined the acronym can be used in subsequent claims. Furthermore, the text “inibitor” should be “inhibitor,” and “admistered” should be “administered.” Instead of the text, “one or more chemotherapeutic agents” please amend this to read, “two or more chemotherapeutic agents,” because the limitation requires at least carboplatin and etopside.
Dependent claims 3, 6-16, 18-20, and 25-28 are included here because they fail to cure the defect of claim 1.
Claims 6-7, 10-11, 18-20, 25, and 28-29: These claims all list acronyms similar to claim 1. They need to be defined or if they were defined earlier in the claim set, then they can remain within acronym form.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 3 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 3 uses the term “preferably.” The term "preferably" renders the claim indefinite because it is unclear whether the limitations following the term are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 non-obviousness.
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, 3, 6-16, 18-20, and 25-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lewin et al. (Eur. J. Nucl. Med. Mol. Imaging, 2015) in view of Buono et al. (WO2020/021465A1), and Zargoulidis et al. (Lung Cancer, 2012).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims.]
1. Lewin et al.
Lewin et al. is the closest prior art to the present invention as it teaches peptide receptor chemoradionuclide therapy in small cell carcinoma: from bench to bedside (see title). Additionally, Lewin et al. disclose the following abstract:
Purpose: Small cell cancers (SmCC), whether pulmonary (SCLC) or extrapulmonary have a poor prognosis unless localised at diagnosis. Given a proportion of these cancers express somatostatin receptor subtype 2 (SSTR2), we aimed to investigate the efficacy of targeted peptide receptor chernoradionuclide therapy (PRCRT).
Methods: In this preclinical study, we used a SCLC xenograft mouse model with high expression of SSTR2 to investigate the effect of peptide receptor radionuclide therapy (PRRT) with chemotherapy compared to either alone. We subsequently explored the clinical utility in a patient with SmCC with high SSTR expression treated with PRCRT.
Results: Robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by 68Ga-DOTA-octreotate (GaTate) (tumour to background update ratio=35). The combination of PRRT using 177Lu-DOTA-octreotate (LuTate) with carboplatin/etoposide (C/E) chemotherapy was more effective than either LuTate or C/E alone for regression of the NCI-H69 model (p value<0.05). PRCRT was associated with significantly
prolonged survival versus PRRT (p value=0.0001) or chemotherapy alone (p value=0.0058). In the subsequent case study, a patient with relapsed SmCC with high SSTR2 expression on GaTate PET underwent PRCRT with radiosensitising etoposide with evidence of a complete metabolic response for 4 months.
Conclusion: Given the limited treatment options in this setting, PRCRT is a promising therapeutic option for SSTR2-expressing SmCC (see abstract).
2. Buono et al.
Buono et al. teach method of treatment of neuroendocrine tumors (see title). In addition, Buono et al. disclose that the present invention relates to methods of treating cancers that overexpress somatostatin receptors, e.g. neuroendocrine tumors (NET). In particular, the invention provides novel therapies based on the combination of a peptide receptor radionuclide therapeutic (PRRT) agent and immuno-oncology (I-O) therapeutic agents, wherein said I-O therapeutic agents are selected from the group consisting of LAG-3 inhibitors, TIM-3 inhibitors, GITR angonists, TGF-β inhibitors, IL15/IL-15RA complex, and selected PD-1 inhibitors (see abstract).
3. Zarogoulidis et al.
Zarogoulidis et al. teach long-acting somatostatin analogues in combination to antineoplastic agents in the treatment of small cell lung cancer patients (see title). Furthermore, Zarogoulidis et al. disclose the following abstract:
Background: Long-acting somatostatin analogues combined with platinum analogues have demonstrated an antiproliferative effect on growth of human SCLC xenographs.
Method: 130 previously untreated SCLC patients - 54 with limited disease (LD) and positive somatostatin receptors were included in the study. All patients performed 111In-Octreotide scanning before chemotherapy (CHT), every 3 months and up to 4 times. All patients were treated with paclitaxel 190mg/m2 + carboplatin AUC = 5.5 for up to 6 cycles. 47 / 130 patients (Group A, control group) received only CHT. Forty-eight hours after each CHT 43 / 130 patients (Group B) were also administered 30 mg somatuline® (lanreotide) by a single subcutaneous (s.c.) injection to stimulate somatostatin receptors (SSTRS) for 2 weeks. 40 / 130 patients (Group C) received 60 mg somatuline® autogel to stimulate SSTRS for 4 weeks. Patients in Groups A and B after the completion of the CHT continued maintenance therapy with somatuline. NSE, IGF1, VEGFA, VEGFC, VEGFR2, and HER2 levels were monitored. In histological samples Bcl-2 and VEGF were also explored by immunohistochemistry.
Results: No statistically significant differences were observed between the 3 Groups regarding LD and extensive disease (ED) patient ratios, age and PS. Group B had a survival benefit in comparison to Groups A and C (p =0.029). LD patients of Group B had a significant benefit compared to Groups A and C (p =0.012, Breslow test). In LD Group B had a significant longer TIP (p =0.02) in comparison to Groups A and C.
Adverse effects had no statistically significant difference between the Groups and toxicity was well managed.
Interpretation: Long-acting somatostatin analogues could be used as an additive therapy in combination to antineoplastic agents in patients positive for somatostatin receptors. A dose of 30 mg improved survival only in LD SCLC patients (see abstract).
Combination of Lewin et al., Buono et al., and Zarogoulidis et al.
Regarding instant claim 1, Lewin et al., Buono et al., and Zarogoulidis et al. teach a method for treating small cell lung cancer (SCLC). The necessary citations within Lewin et al., Buono et al., and Zarogoulidis et al. that pertain to instant claim 1 are presented in Table I.
Table I
Instant Claim 1
Lewin et al., Buono et al., and Zarogoulidis et al. Citations
A method for treating small cell lung cancer (SCLC), in a human subject in need thereof, said method comprising administering to said subject, a therapeutically efficient amount of a radiopharmaceutical compound of formula M-C-S-P,
Lewin et al. is considered to be the closest prior art to the claimed subject matter and describes in the abstract the combination of 177Lu-DOTA-octreotate with carboplatin and etoposide chemotherapy for use in treating SCLC in an SCLC xenograft mouse model.
Lewin et al. does not describe the treatment of SCLC in a human patient.
[The solution of transitioning from the mouse model in Lewin et al. to treating human patients would have been obvious for the skilled person, because this is the common way of clinical development of treatments: first animal models are used for a study, and when these are successful, in the next step the treatment is tested in human patients.]
[Related disclosure]
Zarogoulidis et al. (see abstract within Zarogoulidis et al.) describes the combination of 111ln-octreotide scanning (i.e. radiopharmaceutical compound comprising a somatostatin receptor binding molecule) and chemotherapy with paclitaxel and carboplatin in (previously untreated) human patients suffering from SCLC. Even though 111ln-octreotide is used as a tracer, de facto the combination of 111In-octreotide and paclitaxel and carboplatin leads to treatment of SCLC (see abstract within Zarogoulidis et al.). 111In-octreotide is of Octreoscan (page 85, column, 3rd paragraph), which is 111ln-DTPA-octreotide.
wherein M is a radionuclide, and C-S-P is selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), satoreotide tetraxetan, DOTA-LAN, and DOTA-VAP, and
Lewin et al. indeed teach that the combination of 177Lu-DOTA-octreotate with carboplatin and etoposide chemotherapy was successful, as it was the most effective of the regimens tested and Lewin et al. concluded that it is a promising therapeutic option for SCLC (see abstract within Lewin et al.; also see PTO-892 NPL W). The skilled person seeking to develop an alternative SCLC treatment would therefore be motivated to use the treatment of 177Lu-DOTA-octreotate with carboplatin and etoposide of Lewin et al. in human patients instead of the animal models of Lewin et al. with a reasonable expectation of success, because Lewin et al. already notes that said treatment was effective and promising.
wherein the radiopharmaceutical compound is administered in combination with i) one or more chemotherapeutic agents comprising at least carboplatin and etoposide, and ii) a PD-1 inhibitor or a PD-L1 inhibitor.
Lewin et al. does co-administer both carboplatin and etoposide. Lewin et al. does not co-administer either a PD-1 inhibitor or a PD-L1 inhibitor.
However, Buono et al. is within the neuroendocrine radionuclide arts and allows for the co-administration of PD-1 inhibitors (see abstract and page 1, lines 9-14; both within Buono et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Lewin et al. with the teachings of both Buono et al. and Zarogoulidis et al. to create a treatment protocol that comprises a radiopharmaceutical composition, two or more chemotherapeutic agents, and a PD-1 inhibitor for SCLC treatment in human subjects. The motivation for doing so would have been to develop a therapeutic option for patients with SCLC not currently disclosed within the art.
Regarding instant claims 3 and 26, Lewin et al., Buono et al., and Zarogoulidis et al. teach the appropriate radionuclide, 177Lu.
Lewin et al. disclose the use of 177Lu (see abstract within Lewin et al.). Also, please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claims 6 and 7, Lewin et al., Buono et al., and Zarogoulidis et al. teach the appropriate M-C-S-P formulation.
Lewin et al. disclose the combination of 177Lu-DOTA-octreotate with carboplatin and etoposide chemotherapy for use in treating SCLC in an SCLC xenograft mouse model (see abstract within Lewin et al.; also see PTO-892 NPL W). Additionally, please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claims 8-11, Lewin et al., Buono et al., and Zarogoulidis et al. teach wherein said subject has not received prior chemotherapy for treating SCLC.
A skilled artisan (POSITA; person having ordinary skill in the art) would be able to design an administration experiment with the desired patient parameters. For example, Zarogoulidis et al. disclose an administration experiment within human subjects (see both abstract and page 85, left column, 2. Patients and methods; both within Zarogoulidis et al.).
Furthermore, a hybrid human administration experiment using both Zarogoulidis et al. and Lewin et al. parameters would be an option to a skilled artisan (POSITA). Lewin et al. disclose robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by 68Ga-DOTA-octreotate [GaTate; identical organic compound but with a radiometal suitable for imaging] (tumour to background uptake ratio=35) [see abstract; and see Fig. 1 and Fig. 3 (PET/CT); also see page 29, right column, paragraph 1 (lesions); all within Lewin et al.].
Regarding instant claim 12, Lewin et al., Buono et al., and Zarogoulidis et al. teach wherein said one or more chemotherapeutic agents are carboplatin and etoposide.
Please see the discussion and citations within instant claim 1 for the necessary rejection text.
Regarding instant claims 13-16, Lewin et al., Buono et al., and Zarogoulidis et al. teach wherein said radiopharmaceutical compound is administered 1 to 8 times.
A skilled artisan (POSITA) could modify the dosing protocol (for example the induction period) of the drug administration to the human patient in order to meet the instant claim limitations. Zarogoulidis et al. and Lewin et al. disclose human and mammal administration experiments, respectively. Please see the discussion and citations within instant claims 8-11 for the necessary rejection text.
Regarding instant claims 18-19, Lewin et al., Buono et al., and Zarogoulidis et al. teach the appropriate modified administration protocol.
A skilled artisan (POSITA) could modify the dosing protocol (for example the induction period) of the drug administration to the human patient in order to meet the instant claim limitations. Please see the discussion and citations within instant claims 1, 8-11, and 13-16 for the necessary rejection text.
Regarding instant claims 20 and 28, Lewin et al., Buono et al., and Zarogoulidis et al. teach wherein said PD-1 or PD-L1 inhibitor is an anti-PD1 or anti-PD-L1 antibody.
Buono et al. disclose the anti-PD-1 antibody molecule is Durvalomab (PD-1 inhibitor, see page 24, lines 14-19; anti-PD-1 antibody, see page 33, line 33; both within Buono et al.; also see PTO-892 NPL X).
Regarding instant claim 25, Lewin et al., Buono et al., and Zarogoulidis et al. teach wherein said radiopharmaceutical compound is administered at a dose (i.e. daily dose, dose for each administration, non-cumulative dose) ranging between 0.925 GBq and 29.6 GBq.
Buono et al. disclose the delivery of 7.4 GBq [177Lu DOTA (Lutathera); see page 100, lines 21-27 and page 101, lines 1-15 within Buono et al.).
Regarding instant claim 27, Lewin et al., Buono et al., and Zarogoulidis et al. teach wherein the SCLC is extensive stage small cell lung cancer (ES-SCLC).
Buono et al. disclose the following criteria to be included in the administration study: Patients must have cytologically or histologically confirmed relapsed or refractory extensive-disease small-cell lung cancer (ES-SCLC) or non-progressing ES-SCLC after first line chemotherapy, or advanced or inoperable grade I-II pulmonary NETs (see page 107, lines 15-17 within Buono et al.).
Regarding instant claim 29, Lewin et al., Buono et al., and Zarogoulidis et al. teach a ready-to-use solution for infusion containing [177Lu] Lu-DOTA-TATE with a volumetric activity of 370 MBq/mL at reference date and time, wherein the total amount of radioactivity per single dose vial is 7,400 MBq/7.4 GBq (200 mCi)+10% at the time and date of infusion.
Buono et al. disclose the following information for 177Lu-DOTA0-Tyr3-Octreotate: the product is manufactured and supplied to the clinical sites in monodose vials. One vial, for one administration, contains 7.4 GBq (200 mCi) of 177Lu-DOTA0-Tyr3-Octreotate at calibration time (the time of infusion) in a formulation solution of 22 to 25 mL. The variability of the volume depends on the time between the calibration date and the production date. The product will be shipped and calibrated for use at 24 h or 48h after production in a centralized GMP facility. The calibration time of a dose depends on the distance from the manufacturing facility to the clinical sites. The amount of
administered radioactivity, 7.4 GBq（±10%), is specified at the time of infusion (370 MBq/mL; see Example 1 within Buono et al.).
Analogous Art
The Lewin et al., Buono et al., and Zarogoulidis et al. references are directed to the same field of endeavor as the instant claims, that is, a method for treating SCLC within a human subject, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the PRRT and chemotherapy administration protocol disclosed by Lewin et al., using the teachings of Buono et al. and Zarogoulidis et al. in order to arrive at the subject matter of the instant claims.
The Lewin et al., Buono et al., and Zarogoulidis et al. references all have considerable overlap in the radionuclide arts. In this instance, Lewin et al. supplies the template for the PRRT and chemotherapeutic agents, Buono et al. supplies the co-administration of a PD-1 inhibitor, while Zarogoulidis et al. supplies the support for the human subject administration. All references are directed to radionuclides and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the three references when seeking to develop a PRRT, chemotherapy, and PD-1 inhibitor protocol to treat SCLC.
Given these teachings, a POSITA would have been motivated to combine the template for the PRRT and chemotherapeutic agents as disclosed by Lewin et al., the administration of a PD-1 inhibitor supplied by Buono et al., and the support for human subject administration disclosed by Zarogoulidis et al.
The modification constitutes a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar composition in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the template for the PRRT and chemotherapeutic agents taught by Lewin et al. along with the use of the necessary claim limitations taught by Buono et al. and Zarogoulidis et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Buono et al. and Zarogoulidis et al. would have been viewed by a POSITA as routine design optimizations or known modifications for PRRT and chemotherapeutic agents. The motivation for doing so would have been to develop a therapeutic option for patients with SCLC. Implementing these features in Lewin et al.’s PRRT and chemotherapeutic agents would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Lewin et al., Buono et al., and Zarogoulidis et al. provides all the elements of the claimed invention. The resulting method for treating SCLC in human subjects comprising PRRT, chemotherapeutic agents, and a PD-1 inhibitor, constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 6-7, and 13-16 are provisionally rejected on the ground of non-statutory double patenting as being unpatentable over claims 19-25, 27-30, and 34-38 of co-pending Application No. 17/273,820 (reference application) in view of Nonnekens et al. (Theranostics, 2016).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and that of Application ‘820 encompass a radiopharmaceutical compound of formula M-C-S-P.
The difference between the instant claims and that of Application ‘820 is the co-administration of a PARP inhibitor.
However, Nonnekens et al. teach potentiation of peptide receptor radionuclide therapy by the PARP inhibitor Olaparib (see title). Furthermore, Nonnekens et al. disclose metastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumours (NETs) can be treated with radiolabeled somatostatin analogues, resulting in strongly increased progression-free survival and quality of life. There is nevertheless still room for improvement, as very few patients can be cured at this stage of disease. We aimed to specifically sensitize replicating tumor cells without further damage to healthy tissues. Thereto we investigated the DNA damaging effects of PRRT with the purpose to enhance these effects through modulation of the DNA damage response. Although PRRT induces DNA double strand breaks (DSBs) a larger fraction of the induced lesions are single strand breaks (expected to be similar to those induced by external beam radiotherapy) that require poly-[ADP-ribose]-polymerase I (PARP-I) activity for repair. If these breaks cannot be repaired, they will cause replication fork arrest and DSB formation during replication. Therefore, we used the PARP-I inhibitor Olaparib to increase the number of cytotoxic DSBs. Here we show chat this new combination strategy synergistically sensitized somatostatin receptor expressing cells to PRRT. We observed increased cell death and reduced cellular proliferation compared to the PRRT alone. The enhanced cell death was caused by increased numbers of DSBs that are repaired with remarkably slow kinetics, leading to genome instability. Furthermore, we validated the increased DSB induction after PARP inhibitor addition in the clinically relevant model of living human NET slices. We expect that this combined regimen can thus augment current PRRT outcomes.
It would have been prima facie obvious to provide a PARP inhibitor as suggested by Nonnekens et al. There would have been a reasonable expectation of success in doing so as both Nonnekens et al. and Application ‘820 both use PRRT and radionuclide therapy.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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