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 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.
Claim(s) 21-37 and 40-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over Semko, WO2018204416 and Wang, Scientific Reports | 6:18987, 2016, 1-12; O’Bryan, Pharmacological Research, Volume 139, January 2019, Pages 503-511, Knickelbein, Genes & Diseases, Volume 2, Issue 1, March 2015, Pages 4-12; Mann, Pharmacology & Therapeutics, Volume 168, December 2016, Pages 29-42; and McDaid, , Molecular Cancer (2024) 23:253, not in the rejection statement
WO2018204416 Applicant provided (and has US provisional priority date 2017-05-02) not included herewith.
Semko teaches mTOR inhibitors useful for the treatment of cancer, immune-mediated diseases and age related conditions.. Claim 42 of Semko 483 teaches large number of mTOR inhibitors (linking two ligands, more on this later) that is consistent with the instant definition of the claim term ‘bi-steric’ at page 11 [0031] of specification. At page 220, Semko explicitly teaches the two pharmacophores. Semko compounds are close analogs of instant dependent claim 28.
RAS inhibitors as being useful for treatment is also not Applicants invention as explained below.
Wang is a Review article teaches state of the art on the subject matter of mTOR inhibitors for cancer treatment
Note that a scientific review publication is a scholarly article that synthesizes and critically evaluates existing research on a specific topic, rather than presenting new experimental data
Wang teaches Discovering new mTOR inhibitors for cancer treatment through
virtual screening methods and in vitro assays
According to Wang, the mammalian target of rapamycin (mTOR) plays a critical role in several signaling pathways, controlling cell growth, proliferation, angiogenesis, protein translation, energy homeostasis, and lipid metabolism Rapamycin and its analogs (rapalogs) have been successfully applied to treat specific cancers in the clinic, suggesting that mTOR is a promising anticancer drug target.
Review article of O’Bryan, titled ‘Pharmacological targeting of RAS: Recent success with direct inhibitors’ teaches page 503 that he recent success with mutation-specific inhibitors that exploit the unique biochemistry of the RAS(G12C) mutant. Although this mutation in KRAS accounts for 11% of all KRAS mutations in cancer, it is the most prominent KRAS mutant in lung cancer suggesting that G12C-specific inhibitors may provide a new approach for treating the subset of lung cancer patients harboring this mutant allele. Knickelbein titled, “Mutant KRAS as a critical determinant of the therapeutic response” is a Review article teaches state of the art on the subject matter of targeting mutant KRAS for anti-cancer therapy, see page 7 column B. Likewise, Mann is concerned with KRAS-related proteins in pancreatic cancer. Mann teaches (Abstract) that genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance.
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit since each is well known in the art for treating cancer. Limitations of the dependent claims with respect to specific cancer being treated, compounds and mutations as well as ‘acquired resistance’ (of claim 42) are known in in the many Review articles cited. For the treatment of NSCLC (elected disease state) with mTOR inhibitor and Ras inhibitors see McDaid, The PI3K-AKT-mTOR axis persists as a therapeutic dependency in KRASG12D-driven non-small cell lung cancer, Molecular Cancer (2024) 23:253.. This rejection is based on the well-established proposition of patent law that no invention resides in combining old ingredients of known properties where the results obtained thereby are no more than the additive effect of the ingredients, In re Sussman, 136 F.2d 715, 718, 58 USPQ 262, 264 (CCPA 1943). Accordingly, the instant claims, in the range of proportions where no unexpected results are observed, would have been obvious to one of ordinary skill having the above cited references before him.
Claim(s) 21-37 and 40-42 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/055761, WO 2019/212990 and WO 2019/212991.
The above references are Applicant cited and provided references (see IDS 09/09/2025, not the IDS that has three hundred sixty two NPL documents) and theretofore not provided herewith.
055761 discloses combinations of mTOR inhibitors including mTORC1 inhibitors and a KRASG12c inhibitor of Formula (I) and their use in the treatment of various cancers including colorectal cancer or lung cancer such as NSCLC [055761, par.8-40, 169]. Tumours having a mutation at G12C are considered as RAS-resistant tumours according to the present patent application. Given the fact that the feature "bi-steric" is an expression which does not structurally delimit the known mTOR inhibitors from those claimed nor is it functionally/pharmacologically clear what this term refers to (see also item VIII below), the term "bi-steric" is disregarded as a distinguishing feature for the assessment of novelty.
Individualized mTOR inhibitors according to 055761 include among others everolimus, rapamycin, zotarolimus, idaforolimus, deforolimus, sapanisertib, buparlisib or vistusertib [055761, par.38]. Example A of 055761 shows synergy in KRASG12c lung cancer treatment in vitro [055761, par.183-193] and Example B demonstrates synergy in vivo in several mouse models for different cancers having the KRASG12c mutation e.g. NSCLC [055761, par. 194-204]. In these examples the mTOR inhibitors are Vistusertib and Everolimus and the RAS inhibitor used in these examples corresponds to MRTX-849 [055761, page 102, example 478], which is one of the preferred RAS inhibitors according to the present patent application. 055761 anticipates the subject matter of present claims 1-8, 13, 14, 16, 18-26, 31, 33 and 35-39.
212990 describes mTOR inhibitors as presently described/claimed such as for instance example compound 12 (=RMC-5552) and their use in the treatment of various cancers including the claimed ones.
RMC-5552 is one of the preferred mTOR inhibitors according to the patent application.
212991 discloses mTOR inhibitors as claimed/described and their use in the treatment of various cancers.
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As a first point it is remarked that the scope of the claims is extremely broad compared to what is experimentally shown in the patent application on file. An extrapolation from the experimental data to the actual scope of claims is not allowable, as it is not plausible that any drug combination claimed will credibly result in an effective therapy against RAS-resistant cancers. Moreover, the presently claimed subject matter concerns drug combinations. When combining drugs it can never be predicted whether such combination will ultimately result in additive effects, synergy or even antagonism - with the consequence of possible negative side effects. This is particularly the case in cancer therapy, where an effective treatment is often highly dependent on the cancer type to be treated, as many cancer types have different mechanisms of action. A predictability on the efficacy on a given drug combination is thus not given.
The patent application itself confirms at least part of this argument, as it says for example on page 372, line 15-20:
Not all eel! lines with a given RAS mutation may be equally sensitive to a RAS inhibitor targeting that mutation, due to differential expression of efflux transporters, varying dependencies on RAS pathway activation for growth, or other reasons. This has been exemplified by the cell line KYSE-410 which, despite having a KRAS G12C mutation, is insensitive to the KRAS G12C (OFF) inhibitor MRTX-849 (Hallin et al., Cancer Discovery 10:54-71 (2020)), and the cell line SW1573, which is insensitive to the KRAS G12C (OFF) inhibitor AMG510 (Canon et al., Nature 575:217-223 (2019)).
Secondly, the prior art is insofar close as combinations of mTOR inhibitors (including mTORC1 inhibitors) and RAS inhibitors are already known for treating tumours being resistant to RAS inhibitors (see 055761 ), which is also evidenced by in vivo data. The contribution of the prior art is thus comparable to what is shown in the patent application on file and the applicant is not the first in showing synergistic effects between mTORC1 inhibitors and RAS inhibitors for treating RAS-resistant cancers (which may justify, broader scope of protection). Accordingly, an inventive step can only be acknowledged for drug combinations, for which actually experimental data is available and where an over- additive effect can be observed.
For the remaining subject matter when starting from 055761 as closest prior art the problem of effectively treating RAS resistant cancer would be rendered obvious in view of 055761 alone or in combination with 212990 -212991 as the latter two documents refer to mTOR inhibitors as presently preferred.
Having regard to experiments involving combinations with compound A and compound B (see for instance example 8-10 on pages 129-132) it is remarked that this Authority was not able to find out which compounds concretely where actually used for these experiments, i.e. what their respective structure is. Without this information these experiments do not provide an added value to the claimed subject matter.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625