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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/3/2026 has been entered.
Claim Status
Claims 1-3, 6-7, and 25 are pending and under 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.
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.
Claim Objections
Claim 1 is objected to because of the following informalities: the term “ralimetinib” at the second line should be deleted and the term “a” should be added before the term “combination” at that line. Appropriate correction is required.
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, and 25 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.
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. 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.
Claim 25 limits claim 1, wherein doses of ralimetinib are in the range of 0.1 to 100 mg/kg, and doses of NRPa-47 or NRPa-48 are in the range of 0.1 to 100 mg/kg. Borriello teaches administration of 10 mg/kg and 50 mg/kg. See p. 121, right column.
Response to rejections and declaration filed 6/3/2026
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here, only information gleaned from the prior art was used to arrive at the claimed invention.
Again, 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. Applicant asserts that the above argument is moot because the prior art did not show synergy with the specific combination. However, in order to be probative, a showing of synergy must demonstrate results that are unexpected – that are different in kind, not in degree from what a POSA would have reasonably predicted. MPEP 716.02. The burden is on Applicant to establish that the asserted results are both unexpected and significant. MPEP 716.02(b). 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 sufficient 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.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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
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