DETAILED ACTION
Claims 32-38, 40-43, and 46-54, submitted 27 October 2025, are pending in the application. Claim 35 has been withdrawn. Claims 32-34, 36-38, 40-43, and 46-54 are under examination in the instant Office 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 the specifically disclosed species of KRAS G12C inhibitor, AMG-510, and the specifically disclosed species of cancer, non-small cell lung cancer, in the reply filed on 27 October 2025 is acknowledged.
Claim 35 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 27 October 2025.
Claim Objections
Claim 48 is objected to because of the following informalities: Claim 48 currently reads “wherein the dual RAF/MEK Currently Amended is administered...”. The claim should read as “wherein the dual RAF/MEK inhibitor is administered…”. Appropriate correction is required.
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 32-34, 36-38, 40-43, and 46-54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating non-small cell lung cancer and colorectal cancer, does not reasonably provide enablement for the treatment of all cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Breadth of the Claims
Independent claim 1 recites “A method of treating a cancer in a subject…”. Claim 1 is not drawn to any particular cancer and thus can be interpreted to encompass all cancers.
Nature of the Invention
The nature of the invention is within the pharmaceutical arts with regards to the treatment of cancer in a subject in need, the method comprising administering to the subject an effective amount of a KRAS G12C inhibitor and an effective amount of a dual RAF/MEK inhibitor.
State of the Prior Art
The state of the prior art is what one skilled in the art would have known, at the
time the application was filed, about the subject matter to which the claimed invention
pertains. The relative skill of those in the art refers to the skill of those in the art at the
time the application was filed. See MPEP 2164.05(b). See Pac. Bioscience of Cal., Inc.
v. Oxford Nanopore Techs., Inc., 996 F.3d 1342, 1352, 2021 USPQ2d 519 (Fed. Cir.
2021).
The state of the prior art provides evidence for the degree of predictability in the
art and is related to the amount of direction or guidance needed in the specification as
filed to meet the enablement requirement. The state of the prior art is also related to the
need for working examples in the specification. See MPEP 2165.05(a).
The prior art teaches a variety of G12 mutations, some of which are not sensitive to inhibitors of the G12C mutations. As taught by Yang et al. ("KRAS mutations in solid tumors: characteristics, current therapeutic strategy, and potential treatment exploration." Journal of clinical medicine 12.2 (2023): 709.), it has been found that the G13D, R68M, A59S, and A59T mutations are resistant to AMG-510, a KRAS G12C inhibitor (pg. 15, Section “Acquired Resistance”, 2nd paragraph). Yang also teaches wherein the KRAS Y96D mutation in patients is resistant to the KRAS G12C inhibitor, MRTX849, which affects the Switch-II pocket and can lead to resistance of all current KRAS G12C inhibitors (pg. 15, Section “Acquired Resistance”, 2nd paragraph). This leads to unpredictability in the treatment of all cancers with a KRAS G12C inhibitor in combination with a dual RAF/MEK inhibitor.
Further, Coma et al. ("The RAF/MEK clamp VS-6766 shows strong anti-tumor activity across multiple MAPK pathway alterations, with a preferential effect on KRAS G12V." European Journal of Cancer 174 (2022): S18.) teaches wherein VS-6766, also known as CH5126766, has shown strong anti-proliferative potency across tumor cell lines carrying KRAS, BRAF, CRAF, NRAS or NF1 alterations. Coma also mentions VS-6766 varied in potency dependent on the KRAS variant, with the greatest potency in G12V, G12C, and had the least potency in G12D mutated cells (pg. S18, Section “Results”, Right Col., 1st paragraph). Thus, this would further the notion of unpredictability of the treatment of cancers that do not exhibit the aforementioned mutations.
Level of Skill in the Art
The person of ordinary skill in the art is a person who is presumed to have known
the relevant art at the relevant time. Factors that may be considered in determining the
level of ordinary skill in the art may include: (A) “type of problems encountered in the
art;” (B) “prior art solutions to those problems;” (C) “rapidity with which innovations are
made;” (D) “sophistication of the technology; and” I “educational level of active workers
in the field. In a given case, every factor may not be present, and one or more factors
may predominate.” In re GPAC, 57 F.3d 1573, 1579, 35 USPQ2d 1116, 1121 (Fed. Cir.
1995); Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962, 1
USPQ2d 1196, 1201 (Fed. Cir. 1986); Environmental Designs, Ltd. V. Union Oil Co.,
713 F.2d 693, 696, 218 USPQ 865, 868 (Fed. Cir. 1983). See MPEP 2141.03 (I).
The invention described pertains to the medical or pharmaceutical arts. One of
ordinary skill would be trained in pharmacology, biochemistry, medicine, or a related art
with a Ph. D or other advanced degree in these or other related fields.
Level of Predictability in the Art
The amount of guidance or direction needed to enable the invention is inversely
related to the amount of knowledge in the state of the art as well as the predictability of
the art. In re Fisher, 427, F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount
of guidance or direction” refers to that information in the application, as originally filed,
that teaches exactly how to make or use the invention. The more that is known in the
prior art about the nature of the invention, how to make, and how to use the invention,
and the more predictable the art is, the less information needs to be explicitly stated in
the specification. In contrast, if little is known in the prior art about the nature of the
invention and the art in unpredictable, the specification would need more detail as to
how to make and use the invention in order to be enabling. The scope of the required
enablement varies inversely with the degree of predictability involved, but even in
unpredictable art, a disclosure of every operable species is not required. A single
embodiment may provide broad enablement in cases involving predictable factors, such
as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ
122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA
1971). However, in applications directed to inventions in arts where the results are
unpredictable, the disclosure of a single species usually does not provide an adequate
basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA
1938). In cases involving unpredictable factors, such as most chemical reactions and
physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166
USPQ 18, 24 (CCPA 1970). See MPEP 2164.03. The applicant would need to provide
more objective evidence to support the enablement of the aforementioned claims to
contrast the unpredictability of the subject matter art.
There is unpredictability in the field of endeavor regarding the currently claimed method of treating a cancer comprising administering a KRAS G12C inhibitor and a dual RAF/MEK inhibitor as there is no prior art to suggest that all cancers can be treated with mutation specific drugs.
Amount of Direction Provided by the Inventor
The amount of direction provided by the inventor is correlated by the nature of
the unpredictability of the art. Given the context and scope of the claims mentioned
above, the inventor failed to provide the necessary amount of direction for one skilled in
the art to adequately use the invention across all suggested utility in the broadly stated
disease and disorders disclosed above. (See: Section (A) Breadth of the Claims).
Applicant provided guidance for certain aspects of the invention through in vitro 3D proliferation assays encompassing four KRAS G12C mutant NSCLC cell lines (H2122, H358, H2030, and H1373) as well as two colorectal cancer cell lines (SW873 and SW1463). Additionally, the Applicant provided guidance in the form of xenograft tumor mouse studies using VS-6766, AMG-510, VS-4718, and trametinib in monotherapy and in combination therapy on pages 32-34 of the instant specification. Finally, the Applicant provided guidance on the combination of VS-6766, AMG-510, and the FAK inhibitor, defactinib.
Existence of Working Examples
The provided working examples focused on the combination therapy of VS-6766, AMG-510, and defactinib on the xenograft tumor mouse model on the above mentioned KRAS G12C mutant NSCLC cell lines and colorectal cancer cell lines. It does not appear, however, that the combination therapy of VS-6766, AMG-510, and defactinib would be applicable to all cancers and thus would not be applicable to encompass the breadth of the claim. One skilled in the art would be unable to adequately use the invention without unduly experimentation, which would require the practitioner to discover that which the Applicant has failed to disclose.
Quantity of Experimentation Needed to Make or Use the Invention Based on the Content of the Disclosure
As previously stated, the amount of experimentation depends on the art, the
predictability of the art, and the direction provided by the inventor. For one skilled in the
art to practice the invention as disclosed, the applicant would be required, but not
limited to providing:
Experimentation to show functional application to all of the disclosed cancers.
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 32-34, 36-38, 40-43, and 46-54 are rejected under 35 U.S.C. 103 as being unpatentable over Canon et al. ("The clinical KRAS (G12C) inhibitor AMG 510 drives anti-tumour immunity." Nature 575.7781 (2019): 217-223.) in view of Wada et al. ("The dual RAF/MEK inhibitor CH5126766/RO5126766 may be a potential therapy for RAS-mutated tumor cells." PloS one 9.11 (2014): e113217.), Akinleye et al. ("MEK and the inhibitors: from bench to bedside." Journal of hematology & oncology 6.1 (2013): 27.), and Bhattacharya et al. ("KRAS mutant lung cancer: progress thus far on an elusive therapeutic target." Clinical and translational medicine 4.1 (2015): 35.).
Canon discloses a method of treating a KRAS mutant cancer in a subject in need thereof by administering an effective amount of a KRAS G12C inhibitor, AMG-510 (Abstract, pg. 217, Section “Introduction”, Right Col., 2nd paragraph), thereby treating the subject.
Canon does not teach wherein the KRAS G12C inhibitor is administered in combination with a dual RAF/MEK inhibitor. Wada cures the deficiency of the dual RAF/MEK inhibitor by teaching the compound CH5126766, which is can be used in the suppression of tumor growth of KRAS mutated cancers (Abstract).
A person having ordinary skill in the art would have been motivated to modify the teachings of Canon with the teachings of Wada to treat a cancer with the combination of a KRAS G12C inhibitor and a dual RAF/MEK inhibitor because Canon discloses the combination of AMG-510 with an inhibitor of the MEK pathway (Figure 4a, pg. 220, Section “AMG 510 improves efficacy of targeted agents”, Right Col., 1st paragraph). Additionally, an oridnary skilled artisan would have had a reasonable expectation of success because Canon states the combination with a MEK inhibitor was synergistic in multiple settings and significantly enhanced anti-tumour activity was also observed in vivo with a minimally efficacious dose of AMG 510 in combination with a MEK inhibitor (pg. 220, Section “AMG 510 improves efficacy of targeted agents”, Right Col., 1st paragraph). Therefore, it would have been prima facie obvious for a person having ordinary skill, prior to the effective filing date of the instantly claimed invention, to modify the teachings of Canon with the teachings of Wada, to arrive at the instantly claimed invention. Additionally, it would have been prima facie obvious for an ordinary skilled artisan to try to treat a cancer with the combination of a KRAS G12C inhibitor and a dual RAF/MEK inhibitor because both classes of treatment individually have been used in the treatment of certain KRAS mutated cancers prompting a skilled artisan to have at least a reasonable expectation of success in treating certain KRAS mutated cancers.
With respect to claim 33, Canon teaches wherein the KRAS G12C inhibitor is selected from AMG-510 or ARS-1620 (pg. 218, Section “Enhanced binding and potency of AMG 510”, Left Col., 1st paragraph). This also reads on the limitation of claim 34 wherein the KRAS G12C inhibitor is AMG-510.
With respect to claim 36, Wada teaches wherein the dual RAF/MEK inhibitor is CH5126766 (Abstract, pg. 3, Section “Reagents”, 1st paragraph, pg. 5, Section “In vitro activity of MEK and RAF inhibitors”, 1st paragraph)
Regarding claim 37, Canon teaches wherein AMG-510 was administered to cohorts in doses of 180 mg, 360 mg, 720 mg, and 960 mg in patients with non-small cell lung carcinoma (pg. 220, Section “Evidence of clinical activity”, Left Col., 1st paragraph, Figure 3a-c).
Regarding claim 38, Canon teaches wherein the KRAS G12C inhibitor is administered orally and once daily (pg. 220, Section “Evidence of clinical activity”, Left Col., 1st paragraph). This also reads on claim 40 which recites the limitation wherein the KRAS G12C inhibitor is administered orally.
With respect to claim 41, Wada discloses wherein the dual RAF/MEK inhibitor is administered orally once a day (pg. 4, Section “Mouse xenograft models”, 1st paragraph). This also reads on the limitation of instant claim 47 which recites wherein the RAF/MEK inhibitor is administered orally.
Regarding claim 42, Wada does not teach wherein the dual RAF/MEK inhibitor is administered once a week. However, it can be reasoned that one having ordinary skill in the art would acknowledge that there are limitations with respect to dose limitations, absorption limitations, patient compliance, and dose adjustments when managing large concentrations. Thus, a skilled artisan would experiment with varying formulation concentrations to achieve the desired effect of the administered composition.
Regarding claim 43, Wada does not teach wherein the dual RAF/MEK inhibitor is administered twice a week. However, it can be reasoned that one having ordinary skill in the art would acknowledge that there are limitations with respect to dose limitations, absorption limitations, patient compliance, and dose adjustments when managing large concentrations. Thus, a skilled artisan would experiment with varying formulation concentrations to achieve the desired effect of the administered composition.
Regarding claim 46, Wada does not teach wherein the dual RAF/MEK inhibitor is administered in a dose at about 0.1 mg to about 100 mg. However, Akinleye teaches the data of a clinical study involving the administration of RO5126766, also known as CH5126766 and VS-6766, in patients with advanced cancers. Akinleye discloses the dose recommended for phase II of the clinical study at 2.7 mg (pg. 7, Section “RO5126766”, Left Col., 2nd paragraph).
With regards to claim 48, Canon nor Wada teach wherein the dual RAF/MEK inhibitor is administered before the KRAS G12C inhibitor is administered. However, through routine optimization, one skilled in the art would have experimented with the order of administration to find the optimal administration of the dual RAF/MEK inhibitor and the KRAS G12C inhibitor.
With respect to claim 49, Canon nor Wada teach wherein the dual RAF/MEK inhibitor is administered after the KRAS G12C inhibitor is administered. However, through routine optimization, one skilled in the art would have experimented with the order of administration to find the optimal administration of the dual RAF/MEK inhibitor and the KRAS G12C inhibitor.
With respect to claim 50, Canon nor Wada teach wherein the dual RAF/MEK inhibitor is administered concurrently with the KRAS G12C inhibitor is administered. However, through routine optimization, one skilled in the art would have experimented with the order of administration to find the optimal administration of the dual RAF/MEK inhibitor and the KRAS G12C inhibitor.
Regarding claim 51, Canon teaches wherein in two KRAS G12C cell lines, AMG-510 almost completely inhibited p-ERK (pg. 218, Section “AMG 510 inhibits signaling and growth”, Right Col., 1st paragraph).
Regarding claim 52, Canon teaches wherein four patients with non-small cell lung carcinoma received AMG 510 treatment in which two patients received objective partial response and stable disease in two patients (pg. 220, Section “Evidence of clinical activity”, Left Col., 1st paragraph).
With respect to claim 53, Canon, Wada, nor Akinleye fail to teach the combinatory treatment of a KRAS G12C inhibitor, a dual RAF/MEK inhibitor, and an effective amount of a FAK inhibitor. Bhattacharya et al cures this deficiency by teaching the use of the FAK inhibitor, defactinib, in the treatment of KRAS mutant non-small cell lung cancer (pg. 7, Section “Focal adhesion kinase (FAK) inhibitors”, Left Col., 1st paragraph).
A person having ordinary skill in the art would have been motivated to modify the teachings of Canon with the teachings of Wada, Akinleye, and Bhattacharya to treat a cancer with the combination of a KRAS G12C inhibitor and a dual RAF/MEK inhibitor because Canon discloses the combination of AMG-510 with an inhibitor of the MEK pathway (Figure 4a, pg. 220, Section “AMG 510 improves efficacy of targeted agents”, Right Col., 1st paragraph). Additionally, a skilled artisan would have had a reasonable expectation of success because Canon states the combination with a MEK inhibitor was synergistic in multiple settings and significantly enhanced anti-tumour activity was also observed in vivo with a minimally efficacious dose of AMG 510 in combination with a MEK inhibitor (pg. 220, Section “AMG 510 improves efficacy of targeted agents”, Right Col., 1st paragraph). Therefore, it would have been prima facie obvious for a person having ordinary skill, prior to the effective filing date of the instantly claimed invention, to modify the teachings of Canon with the teachings of Wada, Akinleye, and Bhattacharya, to arrive at the instantly claimed invention.
Conclusion
No claims are allowed.
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JUSTIN CHRISTOPHER. SANCHEZ
Examiner
Art Unit 1622
/J.C.S./ Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622