Detailed Action
The present office action is in response to the reply filed on 26 Sep 2025.
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 .
Status
Claims 1-2, 9-15, 17, 21, and 28-30 of the pending application have been examined on the merits. Claims 18-20 remain withdrawn. Acknowledgement is made of the cancellation of claims 3-8, 16, 22-27, and 31-68.
Priority
The instant application, App. No. 17/599,188 filed 11/07/2024, is a National Stage Entry of International App. No. PCT/US2020/025693, filed 03/30/2020, which claims priority of Provisional App. No. 62/825,173, filed 03/28/2019.
Response to Applicant Arguments
Examiner acknowledges applicant amendments filed 26 Sep 2025.
The rejection of claim 10 under 35 U.S.C. § 112(a) is rendered moot following applicant amendments.
The rejections of claims 3 and 5 are rendered moot following the cancellation of claims 3 and 5.
Regarding the rejection of claims 1-2, 9-15, 17, and 21 under 35 U.S.C. § 103 over Dinavahi et al. (Mol Pharm Fast Forward, 2017, MOL #110759; provided in the office action mailed 28 May 2025), hereinafter Dinavahi (2017), further in view of ClinicalTrials.gov ID NCT03002376 (https://clinicaltrials.gov/study/NCT03002376?a=4&tab=history, version from 2017-08-16, accessed
December 3, 2024; provided in the office action mailed 28 May 2025), hereinafter '376, Najem et al. (Anticancer Res, 2017, 37:5941-5953; provided in the office action mailed 28 May 2025), hereinafter Najem, Moreno et al. (Semin Oncol, 2015, 42:466-473; provided in the office action mailed 28 May 2025), hereinafter Moreno, Wang et al. (Cancer Res, 2018, 78:5560; provided in the office action mailed 28 May 2025), hereinafter Wang, and Rudolph et al. (Cancer Res, 2018, 78:4866; provided in the office action mailed 28 May 2025), hereinafter Rudolph, in light of September 8, 2017 Regeneron Press Briefing (http://www.prnewswire.com/news-releases/regeneron-and-sanofi-announce-cemiplimab-regn2810-has-received-fda-breakthrough-therapy-designation-for-advanced-cutaneous-squamous-cell-carcinoma-300516208.html, accessed December 9, 2024; cited for evidentiary purposes, provided in the office action mailed 28 May 2025), hereinafter Regeneron, Ji et al. (J Invest Dermatol, 2012, 132:356-364; cited for evidentiary purposes, provided in the office action mailed 28 May 2025), hereinafter Ji, Dinavahi et al. (Cancer Immunol Res, 2022, 10:757-769; cited for evidentiary purposes, provided in the office action mailed 28 May 2025), hereinafter Dinavahi (2022), and Panka et al. (Clin Cancer Res, 2006, 12:2371s-2375s; cited for evidentiary purposes, provided in the office action mailed 28 May 2025), hereinafter Panka; applicant arguments on pgs. 10-13 of the remarks filed 26 Sep 2025 have been considered but are not persuasive.
Applicant argues that the only combinatorically relevant discussion in any of the cited references is a combination of MDM2 inhibitors with PD-1 checkpoint inhibitors such as in Wang and Rudolph. Applicant argues that the claims recite a stimulator of p53 levels and/or p53 activity comprising an inhibitor of AKT and an inhibitor of WEE1 and thus the claims recite a mechanism of stimulating p53 activity that is entirely distinguishable from the teaching of the references.
This is not persuasive. MPEP § 2145(IV) states, "one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references." The teachings of Wang and Rudolph are relied on to teach that PD-1 blockades enhance the effect of small molecules which have effects on the p53 pathway and that the artisan would have an expectation of such a result.
Applicant argues that the office makes an unfounded lead that regulation of MDM2 is functionally equivalent to stimulation of p53 and disagrees that inhibition of MDM2 is at all equivalent to stimulation of p53. Applicant argues that MDM2 does not stimulate p53 levels or activity.
This is not persuasive. MPEP § 2145(I) states, "An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection." Applicant has not provided an admission for the arguments submitted in the remarks.
Applicant argues that the claimed combination of an anti-cancer immune therapeutic agent and a stimulator of p53 levels and/or p53 activity possesses unique properties and efficacy that is far greater than that expected for any such combination taught by the cited references. Applicant notes that the specification provides comparative results to the combination of an AKT inhibitor and WEE1 inhibitor taught by Dinavahi (2017) and '376. Applicant points to Fig. 6 which applicant argues shows that the combination of an anti-PD-1 antibody, an AKT inhibitor, and a WEE1 inhibitor dramatically reduces tumor volume when compared to the combination of an AKT inhibitor and a WEE1 inhibitor.
This is not considered persuasive. Dinavahi (2017) teaches that AKT inhibitors and WEE1 inhibitors exhibit synergy, and Wang, Moreno, and Rudolph teach that PD-1 blockades combined with other therapies result in enhanced effects, including enhancing the effects of treatments which increase p53 activity.
Applicant argues that claim 10 is directed to a synergistic combination of an anticancer immune therapeutic agent and a stimulator of p53 activity, not just to the combination of two compounds which stimulate p53 activity as taught by Dinavahi (2017).
This is not persuasive. The claim recites a method of treating cancer by administering a combination of an anti-PD-1 antibody, an AKT inhibitor, and a WEE1 inhibitor, "wherein administration of the combination provides a synergistic effect…" As stated in the office action mailed 28 May 2025, because the combination of the AKT inhibitor and WEE1 inhibitor already provides a synergistic effect, the combination including an anti-PD-1 antibody, such as REGN2810, would be expected to maintain the synergism of the AKT/WEE1 inhibitor combination and thus the combination would exhibit synergism.
In light of the discussion above, the rejection of claims 1-2, 9-15, 17, and 21 under 35 U.S.C. § 103 as obvious over Dinavahi (2017), ‘376, Najem, Moreno, Wang, Rudolph, Regeneron, Ji, Dinavahi (2022), and Panka is maintained for the reasons of record and restated below.
Regarding the rejection of claims 1-2, 9-15, 17, 21, and 28-30 under 35 U.S.C. § 103 over Dinavahi (2017), '376, Najem, Moreno, Wang, and Rudolph, in light of Regeneron, Panka, Dinavahi (2022), and Ji, further in view of Lee et al. (Cell, 2012, 149:780-794; provided in the office action mailed 28 May 2025), applicant arguments on pgs. 13-14 of the remarks filed 26 Sep 2025 have been fully considered but are not persuasive.
Applicant argues that Lee fails to provide any teaching or suggestion that the claimed combination would or could dramatically improve reduction in tumor volume or survival over administration of either anti-PD-1 or AKT/WEE1 inhibitors alone. Applicant argues that Lee is nothing more than a naked invitation to experiment with no guidance as to what would have any effect on outcome. Applicant argues that Lee in combination with the other references fails to provide any reasonable expectation of success of achieving the resulting dramatically improved survival and reduction in tumor volume as is achieved by the claimed combination of an anti-cancer immune therapeutic agent, an AKT inhibitor, and a WEE1 inhibitor.
This is not persuasive. MPEP § 2145(IV) states, "one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references." Lee is not relied on to teach or suggest the claimed combination of an anti-PD-1 antibody, an AKT inhibitor, and a WEE1 inhibitor. Lee is relied on for teaching that a person would find it obvious to vary the drug presentation, dosage, and scheduling to achieve optimal results for the combination of an anti-PD-1 antibody, an AKT inhibitor, and a WEE1 inhibitor as taught by Dinavahi (2017), '376, Najem, Moreno, Wang, and Rudolph, in light of Regeneron, Panka, Dinavahi (2022), and Ji.
In light of the discussion above, the rejection of claims 1-2, 9-15, 17, 21, and 28-30 under 35 U.S.C. § 103 as obvious over Dinavahi (2017), ‘376, Najem, Moreno, Wang, Rudolph, Regeneron, Ji, Dinavahi (2022), Panka, and Lee is maintained for the reasons of record and restated below.
Regarding the obviousness-type nonstatutory double-patenting rejection of claims 1, 9, and 13-15 over claims 10-13, 18, 25, and 26 of copending Application No. 18/517,746, hereinafter '746 in view of '376, Najem, Moreno, Wang, Rudolph, in light of Regeneron, applicant arguments on pgs. 14-15 of the remarks filed 26 Sep 2025 have been fully considered but are not persuasive.
Applicant arguments have been answered above and the non-statutory double-patenting rejection stands.
In light of the discussion above, the rejection of claims 1, 9, and 13-15 under obviousness-type non-statutory double patenting as obvious over ‘746, ‘376, Najem, Moreno, Wang, Rudolph, and Regeneron is maintained for the reasons of record and restated below.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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 1-2, 9-15, 17, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Dinavahi (2017), and further in view of ‘376, Najem, Moreno, Wang, and Rudolph, in light of Regeneron, Ji, Dinavahi (2022), and Panka.
Regarding claims 1, 9, 13-15, and 21, Dinavahi (2017) teaches the treatment of melanoma cell lines (UACC903, 1205 Lu, SK-MEL-28, and WM 164 cells (pg. 7)) with AKT inhibitor AZD5363 and WEE1 inhibitor AZD1775 using simultaneous and sequential dosing schedules (pg. 3). Dinavahi (2017) further teaches that combinations of AZD1775 and AZD5363 in a simultaneous treatment act synergistically to decrease tumor size when treating UACC 903 xenograft mice (pg. 11). Dinavahi (2017) also teaches simultaneous treatment of AZD5363 and AZD1775 led to a 7.5-fold increase in p53 levels in melanoma cells and concludes that p53 activity is essential for synergy between AKT and WEE1 inhibitors (pg. 12 and Fig. 3). The instant specification recognizes AZD1775 as another name for MK1775 (paragraph [00166]). However, Dinavahi (2017) does not teach using the anti-PD-1 antibody, cemiplimab, in combination with an AKT and WEE1 inhibitor to treat melanoma.
‘376 teaches a study to understand the relationship between biomarkers and indicators of clinical response in immunomodulatory treatment-naïve unresectable stage III/IV melanoma patients receiving the anti-PD-1 antibody REGN2810 (pg. 4). ‘376 teaches as part of the inclusion criteria, histologically confirmed diagnosis of stage III or stage IV melanoma accessible for biopsies (pg. 10). Additionally, ‘376 teaches the only intervention as part of this study as REGN2810 (pg. 8). Regeneron, cited for evidence, teaches the assignment of Breakthrough Therapy designation status for cemiplimab (REGN2810) for the treatment of adults with metastatic cutaneous squamous cell carcinoma (pg. 1, paragraph 1). Thus, REGN2810 is cemiplimab.
Najem teaches the discovery of either targeted therapies or immunotherapies has led to dramatic improvements to the standard-of-care treatment of melanoma (pg. 5945, column 1). Najem teaches dual immune and molecular therapy together can lead to early and robust antitumor responses with long-term benefit for patients (pg. 5945, column 2). Najem teaches several examples where treatment of melanoma using anti-PD-1 antibodies and various targeted molecular therapies combine to produce synergy (pg. 5945, column 2 and Fig. 2). Najem teaches monotherapy for melanoma is unlikely to yield a long-term benefit due to drug resistance and rationale-based combinatorial strategies are the key to overcome resistance and obtain a long-term response (pg. 5948, column 1). Najem teaches the key issues for combinatorial approaches are the ideal timing and sequences of combination regimens that can give the higher efficacy, durable response, and lower toxicity (pg. 5948, column 1).
Moreno teaches antibodies blocking PD-1 and PD-L1 have revolutionized the management of metastatic melanoma (pg. 471, column 2). Moreno further teaches there is emerging evidence that combining the PD-1 blocking therapies with other immunotherapies will result in improved results compared to single-agent activity (pg. 471, column 2).
Wang teaches that p53 is a transcription factor and participates in the regulation of tumor immunity homeostatic regulation of immune responses (pg. 1). Wang teaches that a PD-1 and PD-1 blockade enhanced HDM201, an MDM2 inhibitor, activity in p53 wild-type cells, but not in p53 mutated models and the rate of complete tumor regressions was significantly increased with combination treatment as compared to either treatment alone (pg. 1). Wang teaches the results demonstrate that the activation of the p53 pathway by inhibition of MDM2 triggered adaptive immunity which was enhanced by blockade of the PD-1/PD-L1 pathway (pg. 1-2). Wang teaches this provides a rationale to combine MDM2 inhibitors and checkpoint blocking antibodies in cancer patients with wild-type p53.
Rudolph teaches that MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors (pg. 1). Rudolph teaches that a novel MDM2 inhibitor, BI 907828, shows synergistic efficacy in combination with a PD-1 checkpoint inhibitor in a Colon-26 syngeneic mouse model (pg. 1).
MPEP § 716.02(a)(I) teaches that evidence of a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected.
Dinavahi (2017) teaches a combination of AZD1775 and AZD5363 is useful for treating melanoma cells. ‘376 teaches that REGN2810 is useful for treating melanoma cells too. It would be therefore be prima facie obvious for a person of ordinary skill in the art to combine the composition of AZD1775 and AZD5363 with the composition of REGN2810 to create a third composition for the treatment of the melanoma cell line UACC903 with a reasonable expectation of success. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). The artisan would further be motivated to combine targeted molecular therapy of AZD1775 and AZD5363 with the immunotherapy of REGN2810 because, as taught by Najem, combinatorial strategies are key to overcoming resistance and obtaining a long-term response for melanoma treatment.
It would further be obvious to an artisan that there is an expectation of enhancement when combining anti-PD-1 antibodies with targeted molecular therapies as taught by Najem and Moreno. Furthermore, it would be obvious to the artisan that targeting the p53 pathway with molecular therapies benefits from enhanced effect when combined with anti-PD-1 antibodies as taught by Wang and Rudolph. Thus, the artisan would have an expectation of enhanced or greater than additive effect when combining the use of an AKT inhibitor and WEE1 inhibitor (which increases p53 protein in melanoma models) with the anti-PD-1 antibody REGN2810.
Regarding claim 2, Ji, cited here for evidence, teaches that the gene for p53, TP53, is wild type in the melanoma cell line UACC903 (Table 1). Thus, treating a UACC903 cell xenograft inherently treats melanoma with wild-type p53. It would therefore be obvious that treating UACC903 cell xenografts with a combination of REGN2810, AZD5363, and AZD1775 as taught by Dinavahi and Lee would treat melanoma cells with the wild-type p53 genotype.
Regarding claim 10, Dinavahi (2017) teaches that AZD5363 and AZD1775 act synergistically to reduce tumor size (vide supra). Therefore, because there is a synergistic effect when AZD5363 and AZD1775 are used to treat melanoma cells, a person having ordinary skill in the art would expect that the composition of AZD5363, AZD1775, and REGN2810 would maintain the synergism taught by Dinavahi (2017) and further expected as taught by Najem, Moreno, Wang, and Rudolph. Thus, by treating melanoma cells with AZD5363, AZD1775, and REGN2810 it would be obvious to one of ordinary skill in the art that the composition would have supraadditive effects. See In re Diamond, 360 F. 2d 214, 218 ( CCPA 1966). (“What section 103 requires is ‘unexpected synergism’ ... “ (pg. 216, n.7); “we attribute no magic status to synergism per se since it may be expected or unexpected"” (pg. 218)).
Regarding claims 11-12, Dinavahi (2022), cited for evidence, teaches that using AZD5363 and MK1775 led to increased calreticulin signals indicative of immunogenic cell death which further increased NK-cell ligand expression on melanoma and enhanced recognition, leading to NK-cell activation and cytotoxicity (pg. 758, column 1, final paragraph). Thus treating with a combination of AZD5363 and MK1775 in melanoma cells inherently increases NK-cell ligand expression and leads to NK-cell activation and cytotoxicity. One having ordinary skill in the art would thus find it prima facie obvious that treating melanoma with a composition of AZD5363, MK1775, and REGN2810 would also increase NK-cell ligand expression and led to NK-cell activation and cytotoxicity.
Regarding claim 17, Panka, cited here for evidence, teaches that the mitogen-activated protein kinase (MAPK) pathway is activated in virtually all melanomas (pg. 2371s, column 1). Panka also teaches that an activating mutation in the catalytic domain of the serine-threonine kinase B-raf can result in a V600E amino acid mutation which renders the BRAF kinase and the MAPK pathway constitutively active (pg. 2371s, columns 1-2). Ji, cited for evidence, teaches that UACC903 cells contain a BRAF V600E. Therefore, UACC903 cells contain a BRAF mutation that renders serine-threonine kinase B-raf constitutively active which in turn constitutively activates the MAPK pathway. Thus, it would be obvious to a person having ordinary skill in the art that treating UACC903 melanoma cells with a composition of AZD5363, AZD1775, and REGN2810 would treat melanoma characterized by constitutive activation of a MAPK-signaling pathway.
In summary, Dinavahi (2017) teaches a method of treating melanoma cancer cells (the UACC903 cell line which contains the wild-type p53 genotype, as evidenced by Ji, and contains a BRAF mutation which constitutively activates the MAPK-signaling pathway, as evidenced by Panka) with AZD5363 and MK1775 administered as a combination formulation or separately. This composition has a synergistic effect and, as evidenced by Dinavahi (2022), causes immunogenic tumor cell death by activating NK cells. Lee teaches treatment of melanoma cancer patients with REGN2810. It is prima facie obvious for a person having ordinary skill in the art to combine two compositions known in the art to be useful for the same thing, in this case melanoma treatment, to create a third composition to perform the same task. Therefore, claims 1-2, 9-15, 17, and 21 are rejected.
Claim(s) 1-2, 9-15, 17, 21, and 28-30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dinavahi (2017), ‘376, Najem, Moreno, Wang, and Rudolph in light of Regeneron, Panka, Dinavahi (2022), and Ji, cited for evidence, as applied to claims 1-2, 9-15, 17, and 21 above, and further in view of Lee.
Claims 1-2, 9-15, 17, 21, and 28-30 are rejected by Dinavahi (2017), ‘376, Najem, Moreno, Wang, and Rudolph in light of Regeneron, Panka, Dinavahi (2022), and Ji. Dinavahi (2017) teaches a method of treating UACC903 melanoma cells (having a constitutively activated MAPK-signaling pathway and a wild-type p53 genotype) with AZD5363 and MK1775 administered separately or as a combination formulation. ‘376 teaches a method of treating melanoma with REGN2810 (cemiplimab). Najem teaches the key issues for combinatorial approaches are the ideal timing and sequences of combination regimens that can give the higher efficacy, durable response, and lower toxicity. However, Dinavahi only varies the sequence of AZD5363 and AZD1775 and does not teach varying the AKT/WEE1 inhibitor treatment with the immune therapeutic treatment.
Lee teaches that emerging understanding of the complex nonlinear and time-dependent interplay between signaling networks argues that a more systematic assessment exploring not only dosage but also the order of drug presentation, scheduling, and dose duration might uncover cross-pathway effects and efficacious interactions (pg. 781, column 1).
One having ordinary skill in the art would find it obvious to combine the teachings of Dinavahi and ‘376 for the reasons above, and further find it obvious to use the method of Najem Lee to vary the order of drug presentation, scheduling, and dose duration to achieve optimal results for the combination therapy. A person having ordinary skill in the art would be motivated to vary the drug presentation, scheduling, and dose durations of AZD5363, AZD1775, and REGN2810 to uncover cross-pathway effects and efficacious interactions. Furthermore, the selection of any order of performing process steps would be prima facie obvious to a person of ordinary skill in the art in the absence of new or unexpected results. See In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946).
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, 9, and 13-15 are provisionally rejected on the ground of an obviousness-type nonstatutory double patenting as being unpatentable over claims 10-13 and 18 of ‘746, in view of ‘376, Najem, Moreno, Wang, and Rudolph in light of Regeneron.
‘746 claims a method of treating cancer in a subject in need thereof, comprising: administering a combination of an AKT inhibitor and a WEE1 inhibitor as a combination formulation or separately, wherein the AKT inhibitor and WEE1 inhibitor are administered in a 3:1 ratio (reference claim 10) where the combination provides a synergistic effect (reference claim 12) and the inhibitors can be administered sequentially or simultaneously. ‘746 also claims the AKT inhibitor can be AZD5363 (reference claim 12) and the WEE1 inhibitor can be MK1775 (reference claim 13). Furthermore, ‘746 claims the cancer can be melanoma (claim 18). However, ‘746 does not claim combining AZD5636 and MK1775 with cemiplimab.
‘376 teaches a study to understand the relationship between biomarkers and indicators of clinical response in immunomodulatory treatment-naïve unresectable stage III/IV melanoma patients receiving the anti-PD-1 antibody REGN2810 (pg. 4). ‘376 teaches as part of the inclusion criteria, histologically confirmed diagnosis of stage III or stage IV melanoma accessible for biopsies (pg. 10). Additionally, ‘376 teaches the only intervention as part of this study as REGN2810 (pg. 8). Regeneron, cited for evidence, teaches the assignment of Breakthrough Therapy designation status for cemiplimab (REGN2810) for the treatment of adults with metastatic cutaneous squamous cell carcinoma (pg. 1, paragraph 1). Thus, REGN2810 is cemiplimab.
Najem teaches the discovery of either targeted therapies or immunotherapies has led to dramatic improvements to the standard-of-care treatment of melanoma (pg. 5945, column 1). Najem teaches dual immune and molecular therapy together can lead to early and robust antitumor responses with long-term benefit for patients (pg. 5945, column 2). Najem teaches several examples where treatment of melanoma using anti-PD-1 antibodies and various targeted molecular therapies combine to produce synergy (pg. 5945, column 2 and Fig. 2). Najem teaches monotherapy for melanoma is unlikely to yield a long-term benefit due to drug resistance and rationale-based combinatorial strategies are the key to overcome resistance and obtain a long-term response (pg. 5948, column 1). Najem teaches the key issues for combinatorial approaches are the ideal timing and sequences of combination regimens that can give the higher efficacy, durable response, and lower toxicity (pg. 5948, column 1).
Moreno teaches antibodies blocking PD-1 and PD-L1 have revolutionized the management of metastatic melanoma (pg. 471, column 2). Moreno further teaches there is emerging evidence that combining the PD-1 blocking therapies with other immunotherapies will result in improved results compared to single-agent activity (pg. 471, column 2).
Wang teaches that p53 is a transcription factor and participates in the regulation of tumor immunity homeostatic regulation of immune responses (pg. 1). Wang teaches that a PD-1 and PD-1 blockade enhanced HDM201, an MDM2 inhibitor, activity in p53 wild-type cells, but not in p53 mutated models and the rate of complete tumor regressions was significantly increased with combination treatment as compared to either treatment alone (pg. 1). Wang teaches the results demonstrate that the activation of the p53 pathway by inhibition of MDM2 triggered adaptive immunity which was enhanced by blockade of the PD-1/PD-L1 pathway (pg. 1-2). Wang teaches this provides a rationale to combine MDM2 inhibitors and checkpoint blocking antibodies in cancer patients with wild-type p53.
Rudolph teaches that MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors (pg. 1). Rudolph teaches that a novel MDM2 inhibitor, BI 907828, shows synergistic efficacy in combination with a PD-1 checkpoint inhibitor in a Colon-26 syngeneic mouse model (pg. 1).
MPEP § 716.02(a)(I) teaches that evidence of a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected.
‘746 teaches a combination of AZD1775 and AZD5363 is useful for treating melanoma cells. ‘376 teaches that REGN2810 is useful for treating melanoma. It would be therefore be prima facie obvious for a person of ordinary skill in the art to combine the composition of AZD1775 and AZD5363 with the composition of REGN2810 to create a third composition for the treatment of the melanoma cells with a reasonable expectation of success. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
It would further be obvious to an artisan that there is an expectation of enhancement when combining anti-PD-1 antibodies with targeted molecular therapies as taught by Najem and Moreno. Furthermore, it would be obvious to the artisan that targeting the p53 pathway with molecular therapies benefits from enhanced effect when combined with anti-PD-1 antibodies as taught by Wang and Rudolph. Thus, the artisan would have an expectation of enhanced or greater than additive effect when combining the use of an AKT inhibitor and WEE1 inhibitor (which increases p53 protein in melanoma models) with the anti-PD-1 antibody REGN2810.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/J.D.M./Examiner, Art Unit 1625
/Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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