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 .
Amended claims 21-37 are pending.
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 are rejected under 35 U.S.C. 103 as being unpatentable over Pitzen US20190336609; Lanman US20180334454; Liang, Oncogene 38, 622–636 (2019);
and previously cited Semko, O’Bryan, Knickelbein; Mann references.
Applicant’s arguments are not persuasive.
Applicant’s arguments focus on the following:
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According to Applicant the Review articles
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Applicant points out McDaid has post filing date.
Response:
Reference to McDaid was not relied upon. It is removed the instant write-up.
What the term ‘Review’ means is noted at page 3 of the previous action.
Applicant is reminded of the following commonly understood by one of skill in the art:
A review article is a journal article that summarizes the current state of understanding on a topic within a certain discipline. A review article is generally considered a secondary source since it may analyze and discuss the method and conclusions in previously published studies.
Applicant overlooks the earliest priority date is 06/18/2020.
None of the cited references is post-filing dated:
Claim 1 method of treating cancer requires the combination of two agents:
mTor Inhibitor Plus KRas inhibitor
mTor Inhibitor (for RMC 5552 and RMC 6272) cancer is taught at page 659 Example 9 of Pitzen.
KRas inhibitor AMG 510 for cancer is taught at page 53 of Lanman.
The exactamente combination is found in the Figures of the instant Application
Liang titled “mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer” teaches the combination of mTor inhibitor and KRas inhibitor.
According to MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-01.2024].
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
The term ‘combination’ appears 40 times in Liang document. Applicant is encouraged to use the Ctrl + F (Windows) or Cmd + F (Mac) shortcut to instantly find a specific word in Liang documentThis brings up a search bar where you can type your keyword; the application will highlight every matching instance and allow you to jump between them. Applicant is encouraged to use this technique for word teaching with respect to the limitations of the claim. For example, searching for NSLC returns 17 hits (including in the references cited by Liang ) corresponds to instant claim 33 and so on.
Accordingly, the claims do not recite an unobvious distinction over the prior art. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103.
From previous action on the teachings of Semko, O’Bryan, Knickelbein; Mann references:
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 rejected under 35 U.S.C. 103 as being unpatentable over WO 2020/055761, WO 2019/212990 and WO 2019/212991, further in view of Pitzen US20190336609; Lanman US20180334454; Liang, Oncogene 38, 622–636 (2019).
Applicant’s arguments are not persuasive.
Applicant’s arguments focus on the amendments to base claim with respect to the the inhibitors. These are prior art compounds. For example as noted below instant claim 28 pictures and thus there is no ambiguity with respect to what the active agents are. Similarly, previous action did address now added claim language ‘developed resistance’ and ‘resistance’.
Claim 1 method of treating cancer requires the combination of two agents:
mTor Inhibitor Plus KRas inhibitor
mTor Inhibitor (for RMC 5552 and RMC 6272) cancer is taught at page 659 Example 9 of Pitzen.
KRas inhibitor AMG 510 for cancer is taught at page 53 of Lanman.
The exactamente combination is found in the Figures of the instant Application
Liang titled “mTOR mediates a mechanism of resistance to chemotherapy and defines a rational combination strategy to treat KRAS-mutant lung cancer” teaches the combination of mTor inhibitor and KRas inhibitor.
According to MPEP 2144.06 Art Recognized Equivalence for the Same Purpose [R-01.2024].
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
The term ‘combination’ appears 40 times in Liang document. Applicant is encouraged to use the Ctrl + F (Windows) or Cmd + F (Mac) shortcut to instantly find a specific word in Liang documentThis brings up a search bar where you can type your keyword; the application will highlight every matching instance and allow you to jump between them. Applicant is encouraged to use this technique for word teaching with respect to the limitations of the claim. For example, searching for NSLC returns 17 hits (including in the references cited by Liang ) corresponds to instant claim 33 and so on.
Form previous action on the teachings of WO 2020/055761, WO 2019/212990 and WO 2019/212991:
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.
Accordingly, the claims do not recite an unobvious distinction over the prior art. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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