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 .
Claim Status
Claims 1-3, 6-7, 9, 16-17 and 20-24 are pending. Claims 24 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species. Therefore, Claims 1-3, 6-7, 9, 16-17 and 20-23 are presented for examination.
Election/Restrictions
Applicant elected without traverse the following in the reply filed on 6/3/2025:
Type of cancer—breast cancer, particularly triple negative breast cancer (TNBC),
Neuropilin antagonist- = NRPa-47 (N-[5-(1H-benzimidazol-2-yl)-2-methylphenyl]-N'-(2,3-dihydro-1,4-benzodioxin-6-ylcarbonyl)thiourea), and
P38αkinase inhibitor- Ralimetinib.
Claim 24 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6/3/2025.
Therefore, Claims 1-3, 6-7, 9, 16-17, and 20-23 are presented for examination limited to the scope of the elected species.
Priority
This application is a 371 national phase application of PCT/EP2020/065369, filed 06/03/2020, which claims priority to foreign application EP19305719.7, filed 06/04/2019. The claim to priority is acknowledged.
Information Disclosure Statement
No Information Disclosure Statement was filed with the Applicant’s recent remarks.
Withdrawn Claim Rejections
Claims 8 and 12 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. The rejection is rendered moot due to cancellation of the claims. Therefore, the rejection is withdrawn.
Claim Rejections - 35 USC § 103
Maintained
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 6-7, 9, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Borriello et al. (Cancer Letters 349 (2014) 120–127 – cited in 11/26/2021 IDS) in view of Tate et al. (The Journal of Biological Chemistry; VOL. 288, NO. 9, pp. 6743–6753, March 1, 2013) and Campbell et al. (Mol. Cancer Ther. 2014 Feb;13(2):364-74. doi: 10.1158/1535-7163.MCT-13-0513. Epub 2013 Dec 19. PMID: 24356814– cited in 11/26/2021 IDS.)
Claimed invention
A method to synergistically enhance the effect of a p38α kinase (pK) inhibitor (pKi) in breast cancer cells (e.g., triple negative breast cancer – TNBC) comprising administering a combination comprising ralimetinib and at least one p38a-kinase inhibitor selected from one of NRPa-47 or NRPa-48, and wherein down-modulation of pK with a pKi results in a synergistic anti-tumoral effect when combined with the ralimetinib.
Prior art
Borriello teaches that compound-1
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(i.e., NRPa-47) is effective for treating MDA-MB-231 cancer (i.e., triple negative breast cancer – TNBC) in vitro and in vivo. See Fig. 2D,2F and Fig. 5B,5C,5F and the captions of Fig. 2 and Fig. 5; see also p. 126, especially ‘Discussion’ section. Borriello teaches compound 1 inhibited proliferation of MDA-MB-231 cancer in vitro and reduces growth of tumor size and increase survival of human MDA-MB-231-xenografted mice.
While Borriello teaches the use of NRPa-47 for treating TNBC, Borriello does not expressly teach ralimetinib.
However, ralimetinib, like NRPa-47, was known to be effective for treating MDA-MB-231 cancer (i.e., TNBC). For example, Tate teaches LY2228820 dimesylate (“ralimetinib”) shows both in vitro and in vivo anti-angiogenesis and antitumor activity using MDA-MB-231 cancer (i.e., TNBC). LY2228820 significantly reduced tumor-driven cord formation and smooth muscle actin expression from a range of tumor histologies, including MDA-MB-231 cancer. See pp. 6747, 6751; see also Fig. 3 and its caption.
Campbell also teaches LY2228820 treats cancers including breast cancer and that it interacts with p38α MAPK by binding to its ATP-binding site and reduces its activity. See Campbell, abstract, Fig. 1 and caption; see also Table 1.
A person of ordinary skill in the art (POSA) would have found it obvious to co-administer NRPa-47 and ralimetinib for breast cancer cells, including TNBC, because Borriello teaches that NRPa-47 is effective against TNBC cells and Tate teaches ralimetinib is effective against TNBC cells. The POSA would have recognized that NRPa-47 and ralimetinib co-administration for breast cancer cells, including TNBC, would reasonably combine their known anticancer effects against TNBC cells. The artisan would have reasonably expected the agents to provide their known anticancer effect against TNBC.
The POSA would have reasonably expected that combining a neuropilin antagonist with a pKi would result in at least a beneficial combined effect on breast cancer cell proliferation.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed, notwithstanding Applicant’s recitation of a synergistic antitumor effect, as the claims do not recite structural or procedural limitations other than the combination of known agents used for their known anticancer activities.
Claim 2 limits claim 1 wherein the subject is a human. Claim 3 limits claim 1 wherein the subject is a non-human mammal. While both references teach administration of the drugs to a mouse model for TNBC, i.e., MDA-MB-231, the POSA would understand that the drugs are being testing in the models for human use because Borriello states that NRPs fulfill criteria of a promising pharmacological target in cancer after mentioning NRP over-expression correlates with poor prognosis in different cancer types clinically (Borriello, p. 120) and Tate teaches ralimetinib is already used in clinical trials, thus indicating their suitability for use in humans.
Claim 6 limits claim 1, wherein the cancer is triple-negative breast cancer. Both references teach anticancer effects against TNBC (triple negative breast cancer) of each drug, which is a non-hematopoietic cancer.
Claim 7 limits claim 1, wherein the cancer is neuropilin positive. Claim 9 limits claim, 1 wherein the ralimetinib inhibits interaction between a neuropilin protein and a binding partner of the neuropilin protein. Borriello teaches compound-1 a small molecule VEGF-A165/NRP antagonist and binds to NRP-1 (neurolipin). See p. 126, ‘Discussion’; see also Fig. 4 and its caption. The use of the antagonist of NRP-1 in cancers is predicated on the cancer expressing NRP-1. The POSA would recognize that the administration of compound-1 would cause reduction of NRP-1 activity because it binds to and antagonizes NRP-1. Thus, the limitations of Claim 16, Claim 17, and Claim 20 are met.
Claim 21 limits claim 17, wherein the ralimetinib inhibits the binding of the neuropilin protein and VEGF-A₁₆₅. Claim 22 limits claim 1, wherein the ralimetinib specifically binds to a neuropilin protein and neutralizes its activity to activate a neuropilin signaling pathway. These limitations are construed as being functions of the compound ralimetinib and tare therefore met by the prior art because it teaches the use of ramlimetinib in the same cancer cell population claimed.
Claim 23 limits claim 1, wherein the at least one p38α-kinase inhibitor is NRPa-47. Borriello teaches NRPa-47.
Response to rejections
Applicant argues that the combination of ralimetinib and neuropilin antagonist produces synergistic anticancer effect and that such synergistic effect and its underlying mechanism were allegedly not known in the prior art. Applicant's arguments have been fully considered but have not been found to be persuasive. The rejection is not predicated on a requirement that the prior art expressly teach or predict synergy, nor does it rely on an understanding of the precise mechanism of action. Rather, the rejection is based on the combination of known anticancer agents – a neuropilin antagonist and a pKi – taught to provide anticancer effect against TNBC separately. The discovery mechanism does not negate a reasonable expectation of beneficial therapeutic effect from such combination, especially given the known synergistic studies surrounding ralimetinib in combination anticancer treatment around p38 kinase inhibition. In this regard, the art – particularly, US PG-PUB 2023/0190717 at 0911 (filing date 4/9/2018) – already demonstrated that synergistic effects were involving pK pathway inhibition were routinely investigated, including the use of ralimetinib as a p38 inhibitor in combination studies. This evidence that synergy was a known and expected subject of empirical evaluation, and not an unforeseeable outcome as asserted by Applicant.
Applicant’s reliance on in vitro data to support synergy is further insufficient to overcome the rejection, as the claims broadly recite a synergistic effect without limitation as to experimental conditions, dose ranges, comparative baselines, or synergy metrics. Accordingly, the evidence is not commensurate in scope with the claims as required by MPEP §716.02.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622