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 .
Election/Restrictions
Applicant’s election without traverse of Group (I) with the addition of compound
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as the elected compound in the reply filed on 05/13/2026 is acknowledged.
Claims 25-26, 31-32, and 34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/13/2026.
Priority
This application is a U.S. National Stage under 35 U.S.C. § 371 of International Patent Application number PCT/EP2022/025396 filed August 26, 2022, which depends from and claims priority to European Application No: 21020437.6 filed September 1, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/27/2024 & 02/11/2026 has been considered by the examiner.
Status of Claims
Claims 1, 3-11, 21-23, 25-26, 29, 31-32, and 34 are pending. Claims 2, 12-20, 24, 27-28, 30, and 33 are canceled. Claims 25-26, 31-32, and 34 are withdrawn. Claims 1, 3-11, 21-23, and 29 are examined in accordance to the elected species.
Claim Objections
Claim 21 is objected to because of the following informalities: the phrase “selected from formulae (Ia), (Ia’) (Ib), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V) according to claim 1” improperly refers to formulae (Ia) and (a’), which are not recited in claim 1 Appropriate correction is required.
Claim 29 is objected to because of the following informalities: the phrase “selected from formulae (Ia), (Ia’), (Ib), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V) according to claim 1” improperly refers to formulae (Ia) and (a’), which are not recited in claim 1 Appropriate correction is required.
Claim 7 is objected to under 37 CFR 1.75(c), as being of improper dependent form for failing to further limit the subject matter of a previous claim. Applicant is required to cancel the claim(s), or amend the claim(s) to place the claim(s) in proper dependent form, or rewrite the claim(s) in independent form
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 22 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 22 is directed to a pharmaceutical composition comprising a compound according to claim 21 and additional active substance selected from chemotherapeutic agents, radiotherapeutic agents, immune-oncology agents, and combinations thereof. Claims 23 is directed to the pharmaceutical composition of claim 21 for use in the prophylaxis and/or treatment of proliferative disorders.
The specification discloses synthesis of compounds and presents biochemical and cell-based assays measuring inhibition of KRAS G12V and eIF4A1 activity. However, the specification does not disclose any in vivo studies, tumor regression studies, prophylaxis studies, pharmacokinetic studies, toxicity studies, dosage regimens, therapeutic indices, or evidence demonstrating efficacy in animal models of proliferative disorders. Furthermore, no examples are provided for combinations with chemotherapeutic agents, radiotherapeutic agents, immuno-oncology agents, or combinations thereof encompassed by claim 22.
The claims encompass a large number of structurally distinct compounds, pharmaceutical compositions, and therapeutic combinations and further encompass prophylaxis and treatment of proliferative disorders include numerous diseases having distinct etiologies and treatment mechanisms. The specification provides little guidance as to which compounds, doses, schedules, combinations, or disease indications would be effective.
The state of the art further demonstrates that the development of eIF4A inhibitors remain unpredictable. Kayastha et al. (Blood, 67th Annual Meeting abstract, 2025) report that eIF4A inhibitors, including rocaglamide analogs, have shown preclinical efficacy but development has been hampered by challenges. Likewise, Steel et al. (Cancer Prevention Research, 2010) explains that efficacy in animal models is central to chemoprevention and anticancer development. Thus, the art recognizes that promising in vivo activity alone does not reliably predict therapeutic efficacy.
Applying the factors set forth in re Wands, 858 F2d 731, 8USPQ2d 1400 (Fed. Cir. 1988), the quantity of experimentation necessary to identify therapeutically effective compounds, doses, regimens. Combinations, and indications throughout the full scope of claims 22-23 would be substantial. The specification provides only limited guidance and few working examples directed to therapeutically efficacy. Furthermore, the predictability of the art is low, as evidenced by the continued challenges associated with translating eIF4A inhibition into successful therapies. Consequently, a person of ordinary skill in the art would have required to engage in undue experimentation to practice the full scope of the claims 22-23.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 7-9, 11, 21, and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the , subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 5 recites that “the enantiomer excess (ee) of the enantiomer of formula (Ia) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.” The terms “preferably”, “in particular”, and “especially” fail to positively define the scope of the claim and render unclear values constitute limitations of the claim.
Claim 7 recites that “Ra, Rb, Rc, Rd, Re, Rf, and Rg have one of the meanings as defined in claim 2 has been canceled and no longer defines any meanings for these substituents. Therefore, it is unclear whether the scope of claim 7 includes meanings previously cited in canceled claim 2, thereby rendering the metes and bounds uncertain.
Claim 8 recites, inter alia, “preferably R2 and R3 independently from each other are selected from hydrogen, C2-C3-alkyl…” and “preferably R2 and R3 together with the nitrogen atom …” The term “preferably” does not positively define the scope of the claim and renders unclear whether the recited preferred embodiment constitutes claim limitations.
Claim 9 recites that “preferably R1 is selected from pyrrolidinyl and piperidinyl.” The term “preferably” fails to positively define the metes and bounds of the claim and renders unclear whether the recited groups are limitations of the claim.
Claim 11 recites “the mixture of each compound A to V with its respective enantiomer” and further recites “mixtures selected from two or more compounds (A) to (V) and the enantiomers thereof.” It is unclear whether the claim encompasses individual racemic mixtures corresponding to compounds A-V, a single mixture containing all compounds A-V and their respective enantiomers, or mixtures containing selected compounds and their corresponding enantiomers. Therefore, the scope of the claim is ambiguous.
Claim 21 recites “an enantiomeric mixture thereof.” It is unclear whether “thereof” refers to formula (I), formulae (Ia) and (a’), compounds (A)-(V), or all recited compounds collectively. Accordingly, the metes and bounds of the claim are unclear.
Claim 22 recites “a further active substance, preferably selected from chemotherapeutic agents, radiotherapeutic agents, immune-oncology agents, and combinations thereof.” The term “preferably” fails to positively define the scope of the claim and renders unclear whether the recited classes of active substances are limitations of the claim.
Claim 29 recites “an enantiomeric mixture thereof.: It is unclear whether “thereof” refers to formula (I), formulae (Ia) and (Ia’), compounds (A)-(V), or all recited compounds collectively. Therefore, the scope of the claim is uncertain.
Further, claims 29 recites “a1) …. Or a2) …. and b) instructions….” It is unclear whether the Kit must contain component a1), component a2), or both components. Therefore, the metes and bounds of the claim are not reasonably certain.
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 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.
Claims 1, 3-6, 8-11, 21-23 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Rajalingam et al. (WO2020/078975 A1) in view of Ernst et al. (WO2017/091585 A1).
Rajalingam teaches an inhibitor of KRAS oncogene activation, which is a flavagline derivative having the general formula (I) and a pharmaceutical composition comprising a compound, which is a flagaline derivative having the general formula (I)
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and a pharmaceutically acceptable vehicle, diluent, adjuvant, or excipient for use in the prevention or treatment of a KRAS-mutated proliferative disorder or genetic disorder, wherein the disease is a neoproliferative disease, cancer, RASOpathy or craniofacial syndrome. (See claims 1, 9, and 11.) Moreover, Rajalingam teaches flavaglines: potent anticancer drugs that target prohibitins and the helicase elF4A. (See third paragraph of page 4.) Rajalinkgam further expressly teaches compound FL-40 having the following structure:
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and FL-42
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. (See claims 2 and 10.)
Rajalinkgam does not expressly teach the elected compound
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and an additional active substance selected from chemotherapeutic agents.
Ernst teaches Formula (I) compounds are inhibitors of eIF4A and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers where the compound
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. (See claim 1 and Abstract.) Moreover, Ernst expressly teaches Ra and Rb which can be heterocyclyl and the heterocyclyl can be morpholinyl among others and R1 can be CN. (See paragraph [054].) In fact, Ernst teaches compound 9F having a CN group at the
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and compound 199F having a morpholino group at position of Ra/Rb
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, (See paragraph [0779].) Ernst expressly exemplifies compounds 9F and 199F possessing the cyano and morpholino substituents, respectively, and disclose formula I compounds are eIF4 inhibitors useful for treatment of cancer. Thus, a person of ordinary skill in the art would have understood those substituents as suitable alternatives within the disclosed genus.
One of ordinary skill in the art looking at compound Fl-40 would understand that CN and morpholino moieties are particularly preferred substituents because such substituents are expressly exemplified by Ernst in compound 9F and 199F, respectively. It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to select compound FL-42 of Rajalingam and replace the para-bromo substituent with a cyano group and replace dimethylamino amide substituent with a morpholino group in view of the teachings of Ernst because Ernst teaches that compounds bearing substituents and morpholino moieties retain eIF4A inhibitory activity and are useful in the treatment of cancer and other proliferative diseases. A person of ordinary skill in the art would have reasonably expected success because both references are directed to flavagline derivative acting through inhibition of eIF4A and disclosed closely related scaffolds and therapeutic utilities.
Accordingly, it would have been obvious to modify compound FL-42 of Rajalingam to obtain the elected compound having a para-cyano substituent and a morpholine carboxamide moiety with a reasonable expectation of success.
With respect to claim 22, Rajalingam further teaches pharmaceutical composition for use in the treatment of KRAS-mutated proliferative disorders and expressly contemplate administration in combination with additional therapeutic agents. Ernst likewise teach administration of eIF4A inhibitors for the treatment of cancers and proliferative disorders. Therefore, it would have been prima facie obvious for a person of ordinary skill in the art at the time of the invention was made to combine the obvious compound FL-42 taught by Rajalingam and Ernst with compound 9F set forth by Ernst because each is taught by the prior art to be useful for the same purpose (i.e., treating cancer and proliferative diseases). See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Further, a person of ordinary skill in the art would reasonably have expected to be successful because both compositions were shown to be useful separately for the exact same purpose and thus would be expected to be similarly useful when used together.
Conclusion
Claims 1, 3-6, 8-11, 21-23 and 29 are not allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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