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 .
Status of the Claims
Applicant’s election without traverse of:
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in the reply filed on 12/1/25 was previously acknowledged.
In the reply filed 6/23/26, Applicants canceled claims 73-92 and added new claims 97-115.
Claims 97-115 are pending.
Claims 104,110-115 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. Please note that the Applicants elected the combination of ITGB4/PXN pathway and KRAS pathway inhibitor. Applicants did not elect the combination of ITGB4/PXN pathway inhibitor, Wnt/beta-catenin pathway inhibitor (i.e. tegatrabetan) and KRAS pathway inhibitor. Therefore, claims 104, 110-115 are withdrawn.
Claims 97-103 and 105-109 read on the elected species and are under consideration.
Claim Rejections - Withdrawn
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 rejection of claims 73-78, 81-82, 84, 86, 89 and 90-91 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), paragraph (scope of enablement) is withdrawn due to cancelation of the claims.
The rejection of claims 73-78, 81-82, 84, 86, 89-91 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn due to cancelation of the claims.
The rejection of claims 73-76, 78, 81-82, 84, 86-92 under 35 U.S.C. 103 as being unpatentable over Nagasaka et al. (Cancer Treat Rev. 2020 March:84, cited on IDS) in view of Verma et al. (WO2016/081281,cited on IDS) is withdrawn due to cancelation of the claims.
The rejection of claims 73-78, 81, 82, 84 and 86-92 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 , 5-6, 8-9, 13-14, 16-17, 21-22 and 24-25 of copending Application No. 18/653,869 (reference application) in view of Nagasaka et al. and Wu et al. is withdrawn due to cancelation of the claims.
Claim Rejections - 35 USC § 103-NEW
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.
New claims 97-103 and 105-107 are rejected under 35 U.S.C. 103 as being unpatentable over Nagasaka et al. (Cancer Treat Rev. 2020 March:84, cited on IDS) in view of Verma et al. (WO2016/081281,cited on IDS).
Nagasaka et al. teach that KRAS mutation are among the most common aberration in cancer, including NSCLC. Nagasaka et al. teach that despite efforts, KRAS remains a challenging therapeutic target (Abstract). Nagasaka et al. teach that among the different known mutations of KRAS, G12C is considered potentially “druggable” (Abstract). Nagasaka et al. teach that AMG510 (sotorasib) and MRTX849 (adagrasib) covalently bind to KRASG12C at the cysteine residue at 12, keeping KRAS in its inactive GDP-bound state and inhibiting KRAS dependent signaling. Nagasaka et al. teach both compounds are being studied alone and in combination with other targets (Abstract). Nagasaka et al. teach efforts to evaluate KRA G12C inhibitors in combination with other agents are ongoing (p. 4, 2nd col.). Nagasaka et al. teach evaluating AMG510 (sotorasib) in NSCLC (p. 5, 1st col.). Nagasaka et al. also teach MRTX849 (adagrasib) is orally available mutation selective small molecule inhibitor of KRAS G12C. Nagasaka et al. teach that NRTX849 displayed broad spectrum anti-tumor activity KRASG12C in pancreatic and lung cancer achieving reasonable tumor regression in most models which was most pronounced in lung cancer (p. 1, 2nd col). Nagasaka et al. teach that sotorasib and adagrasib are promising for treating of NSCLC with KRASG12C mutations (conclusions).
Nagasaka et al. does not teach administering an effective amount of an ITGB/PXN pathway inhibitor, such as carfilzomib in combination with the KRAS pathway inhibitor. However, the teachings of Verma et al. cure this deficiency.
Verma et al. teach compounds used for treating cancer with KRAS mutations, such as lung cancer (NSCLC) (Abstract). Verma et al. teach the KRAS mutation G12C (p. 16). Verma et al. teach a combination for treatment of the KRAS mutation cancers including carfilzomib (claim 19).
With respect to claims 97-103, It would have been obvious to a person of ordinary skill in the art to treat NSCLC with a G12C mutation with a combination of KRAS pathway inhibitor, such as sotorasib or adagrasib, as taught by Nagasaka et al. and carfilzomib as taught by Verma et al. in a single composition or separately administered because both references teach treatment of NSCLC. A person of ordinary skill in the art would have a motivation to include a combination of agents because both references teach the compounds in combination with other agents. Furthermore, MPEP 2144.06 states: “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 the instant case, Nagasaka et al. teach the KRAS pathway inhibitors for treatment of NSCLC with a KRASG12C mutation and Verma et al. teach carfilzomib for treatment of NSCLC with KRASG12C mutation, therefore the prior art teaches the compositions useful for the same purpose. A reasonable expectation of success is expected given that the component are all potential treatments of NSCLC with KRAS G12C mutation.
With respect to claim 105, the references do not teach the KRAS mutation is a homozygous KRAS mutation, however the prior art teaches treatment of cancers comprising KRAS mutations. KRAS mutations will necessarily occur in both heterozygous and homozygous forms. A person of ordinary skill in the art would understand that the therapeutic approach made obvious by Nagasaka et al. and Verma et al. would be applicable to KRAS mutant cancer that are both homozygous and heterozygous. Selecting or identifying cancer with homozygous KRAS mutation would constitute routine optimization or patient stratification. There is a reasonable expectation of success given that method of assessing the alleles of KRAS are well known in the art.
With respect to claims 106-107, the references do not explicitly teach the step of identifying a homozygous mutation in a biological sample obtained from the subject, however the references are suggestive of the limitation. The references teach methods of treating cancers comprising the specific KRAS mutations which necessarily requires analyzing a biological sample to identify the presence of those mutations. Such identification inherently involves characterization of the KRAS gene using routine techniques. With respect to the homozygous status, as indicated above, KRAS mutations will necessarily occur in both heterozygous and homozygous forms. A person of ordinary skill in the art would understand that the therapeutic approach made obvious by Nagasaka et al. and Verma et al. would be applicable to KRAS mutant cancer that are both homozygous and heterozygous. Selecting or identifying cancer with homozygous KRAS mutation from a tumor sample or blood samples would constitute routine optimization or patient stratification. There is a reasonable expectation of success given that method of assessing the alleles of KRAS are well known in the art.
New claim 108 is rejected under 35 U.S.C. 103 as being unpatentable over Nagasaka et al. (Cancer Treat Rev. 2020 March:84, cited on IDS) and Verma et al. (WO2016/081281, cited on IDS) as applied to claims 97-103 and 105-107 above, and further in view of Wu et al. (PeerJ. 2019 Dec 20; 7, previously cited).
The teachings of Nagasaka et al. and Verma et al. are presented above in detail. The references do not teach measuring the elevated expression level of ITGB4. However, the teachings of Wu et al. cure this deficiency.
Wu et al. teach that integrins play a crucial role in the regulation process of cell proliferation, migration, differentiation and metastasis. Wu et al. teach that ITGB4 encodes an integrin (Background). Wu et al. teach that evidence shows that abnormal expression of ITGB4 is common in different malignancies (Background). Wu et al. teach that higher ITGB4 expression was detected in tumors than adjacent non tumor tissue in patients and silencing of ITGB4 could repress cell proliferation and invasiveness. Wu et al. teach that ITGB4 is a candidate biomarker and therapeutic target (Introduction). Wu et al. teach that ITGB4 was overexpressed in NSCLC compared to normal samples (Results and Fig. 1-2, Table 1).
With respect to claim 108, it would have been obvious to a person of ordinary skill in the art to measure the expression level of ITGB4 in a biological sample from a NSCLC patient in order to inform treatment decisions. There is a reasonable expectation of success given that measuring cancer biomarkers is routine and well-established practice in the art.
New claim 109 is rejected under 35 U.S.C. 103 as being unpatentable over Nagasaka et al. (Cancer Treat Rev. 2020 March:84, cited on IDS) and Verma et al. (WO2016/081281, cited on IDS) as applied to claims 97-103 and 105-107 above, and further in view of Mackinnon et al. (J Clin Pathol 2011;64:16-24).
The teachings of Nagasaka et al. and Verma et al. are presented above in detail. The references do not teach measuring the elevated expression level of PXN. However, the teachings of Mackinnon et al. cure this deficiency.
Mackinnon et al. teach paxillin is a modular protein that localizes to cell adhesion sites where it facilitates bidirectional communication between the intracellular actin cytoskeleton and the extracellular matrix and is overexpressed in lung cancer tissues (Abstract). Mackinnon et al. teach that paxillin overexpression occurs during the earliest stages of lung cancer development (Abstract).
With respect to claim 109, it would have been obvious to a person of ordinary skill in the art to measure the expression level of PXN in a biological sample from a NSCLC patient in order to inform treatment decisions. There is a reasonable expectation of success given that measuring cancer biomarkers is routine and well-established practice in the art.
Response to Arguments
Applicant's arguments filed 6/23/26 have been fully considered but they are not persuasive. Applicants argue unexpected and synergistic properties of the combination of agents. In particular, applicants argue that the data in the specification demonstrates that the claimed combination of carfilzomib and sotorasib produce synergistic results applicants point to the specification at paragraph 0255, 0268, 0290 and Fig. 4E. The applicants also argue that the data in the specification demonstrates that the presently claimed combination of carfilzomib and adagrasib produced synergistic results. Applicants points to the specification at paragraph 0270 and Fig. 20B. Applicants further argue synergistic results for carfilzomib and point to paragraphs 0302 and 0304 of the specification. Applicants argue that tegatrabetan and sotorasib also had synergistic results. Applicants argue that the unexpected and synergistic effects shown in the specification and figures overcome the obvious rejection of Nagasaki in view of Verma.
These arguments and results were considered in detail but are not persuasive. Applicant’s evidence of synergistic activity is insufficient to overcome the prima facie case of obviousness because the asserted unexpected results are not commensurate in scope with the claims. MPEP 716.02(d) states: Unexpected Results Commensurate in Scope With Claimed Invention. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In the instant case, the claims recite administration of an effective amount of the agents without requiring the particular concentration, dose or relative amounts which Applicants report had a synergistic effect. The evidence demonstrates synergy only under a particular tested concentration or combination of concentrations. Applicants’ own results demonstrate that the synergistic effect is concentration dependent. At other tested concentrations the combination produced no significant effect or merely an additive effect (for example see Fig. 4E, 20A). Thus, the evidence does not establish that synergism is a property of the claimed combination generally. Therefore, the prima facie case of obviousness is maintained. MPEP 2144.06 states: “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 the instant case, Nagasaka et al. teach the KRAS pathway inhibitors for treatment of NSCLC with a KRASG12C mutation and Verma et al. teach carfilzomib for treatment of NSCLC with KRASG12C mutation, therefore the prior art teaches the compositions useful for the same purpose. Accordingly, because the claims are not limited to the particular concentration or ratio demonstrated to provide synergy, applicants narrowly demonstrated synergistic effect does not outweigh the evidence supporting the prima facie conclusion of obviousness. It should be noted that the evidence would be more appropriately commensurate in scope with the claims, if the claims were limited to the concentration, concentration range, or ratio for which the asserted unexpected synergistic effect has been adequately demonstrated. Merely claiming “a synergistic amount” is not adequate because the specifications limited testing does not provide sufficient basis to conclude the synergistic amount.
Conclusion
No claims are allowed.
Applicants’ 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 TARA L MARTINEZ whose telephone number is (571)270-1470. The examiner can normally be reached Mon-Fri 8:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached at (571)270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TARA L MARTINEZ/Primary Examiner, Art Unit 1654
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