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:
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in the reply filed on 12/1/25 is acknowledged.
Claims 73-92 are pending.
Claims 79-80, 83 and 85 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim.
Claims 73-78, 81, 82, 84 and 86-92 read on the elected species and are under consideration.
Drawings
The drawings are objected to because Fig 10B is unclear. The figure is faded and it is impossible to determine the different groups. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 73-78, 81-82, 84, 86, 89 and 90-91 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), paragraph, because the specification, while being enabling for treatment of NSCLC with the KRAS mutation G12C with the ITGB4/PXN pathway inhibitor carfilzomib and the KRAS pathway inhibitor sotorasib or adagrasib, does not reasonably provide enablement for treatment of all cancers with KRAS mutations. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
As stated in MPEP 2164.01(a), “there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
The factors to be considered when determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, were described in In re Wands, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) as:
1. the nature of the invention;
2. the breadth of the claims;
3. the state of the prior art;
4. the relative skill of those in the art;
5. the predictability or unpredictability of the art;
6. the amount of direction or guidance presented [by the inventor];
7. the presence or absence of working examples; and
8. the quantity of experimentation necessary [to make and/or use the invention.
(1) The nature of the invention and (5) The breadth of the claims:
The claims are drawn to a method of treating cancer, comprising administering to a subject an effective amount of an ITGB4/PXN pathway inhibitor and an effective amount of a KRAS pathway inhibitor. The claims are extremely broad because it covers any KRAS mutant cancer, across all tissue and across all mutation subtypes. KRAS mutations represent a diverse class of variants with differing biochemical and therapeutic response properties.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regard to treating all cancer is non-existent including cancers with KRAS mutations. There is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific cancers with specific agents, it has long been underdeveloped with regard to the treatment of cancers broadly.
The lack of significant guidance from the present specification or prior art with regard to treatment of all cancers with KRAS mutations with ITGB4/PXN pathway inhibitor and the KRAS pathway inhibitor makes practicing the claimed invention unpredictable. Thus, the specification or the art does not provide enablement for treatment of all cancers with KRAS mutations with the claimed combination.
The state of the art is that some cancers with specific KRAS mutations are treatable with specific compounds. The Medical Advisor (Jan 13, 2026) teaches KRAS mutations drive approximately 20-30% of all cancers with high prevalence in NSCLC (30%), colorectal cancer (40%) and pancreatic cancer (90%) with the most common mutation a G12C. The Medical advisor teaches that the pioneering inhibitors sotorasib and adagrasib were approved for KRAS G12C mutations in NSCLC. The Medical advisor states that despite these advances, resistance limits durability. Nagasaka et al. (Cancer Treat Rev. 2020 March:84) 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). Therefore, there is unpredictability for treating all cancers with KRAS mutations.
(3) The relative skill of those in the art:
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). Taken as a whole, the skill level in oncology must be considered as low. “It should be noted that oncology has the lowest success rates of any therapeutic area.” Cancer Drug Design and Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008) page 431.
Specifically, the prior art knows that there never has been a compound or combination of compounds capable of treating cancers, including cancers with KRAS mutations. Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. The skill thus depends on the particular cancer involved. There are some cancers where the chemotherapy skill level is high and there are multiple successful chemotherapeutic treatments. The mechanism in these situations, however, is not necessarily the same as is alleged for these compounds.
(6) The amount of direction or guidance presented and (7) The presence or absence of working examples:
The specification does not enable any person skilled in the art to which it pertains to make or use the invention commensurate in scope with the claims. The lack of adequate guidance from the specification or prior art with regard to the actual treatment of all cancers with mutations with any ITGB4/PXN pathway inhibitor and any KRAS pathway inhibitor, fails to rebut the presumption of unpredictability existent in this art. Applicants fail to provide the guidance and information required to ascertain which particular type of cancer the claimed pathway inhibitors will be effective against without resorting to undue experimentation. Applicant's limited disclosure is noted but is not sufficient to justify claiming treating of cancers with KRAS mutations. An undue amount of experimentation would be required to practice the invention as it is claimed in its current scope, because the specification provides inadequate guidance to do otherwise.
The amount of direction or guidance presented in the specification is very limited. The specification provided examples of zebrafish larvae with KRAS G12C mutation with sotorasib +carfilzomib and adagrasib + carfilzomib (Fig. 10). Fig. 11 discloses treating of mice SW1573 xenografts with sotorasib +carfilzomib and adagrasib + carfilzomib. Fig. 16 discloses the signaling response to KRAS inhibition in various cells lines with the IC50 dose of sotorasib and adagrasib. Fig. 20 discloses the combined effects of carfilzomib and adagrasib on cell proliferation. Fig. 23 disclose combination of sotorasib and carfilzomib inhibited proliferation of SW1573 cells (NSCLC cell line).
Therefore, the direction provided and the working examples provided in the specification, support treating NSCLC with a G12C KRAS mutation with sotorasib +carfilzomib and adagrasib + carfilzomib. The instant specification does not support treating all cancers with any KRAS mutation with any ITGB4/PXN pathway inhibitor and the KRAS pathway inhibitor.
8) The quantity of experimentation necessary:
Due to the large quantity of experimentation necessary, the lack of direction/guidance presented in the specification regarding treatment of all cancers with KRAS mutations, the complex nature of the invention, the state of the prior art which establishes the unpredictability, and the breadth of the claims which are very broad, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
In conclusion, the instant specification is enabling for treating NSCLC with a G12C KRAS mutation with sotorasib +carfilzomib and adagrasib + carfilzomib. The instant specification does not support treating all cancers with any KRAS mutation with any ITGB4/PXN pathway inhibitor and the KRAS pathway inhibitor.
Claims 73-78, 81-82, 84, 86, 89-91 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
Scope of the claimed genus
The claims are drawn to a method of treating cancer, comprising administering to a subject an effective amount of an ITGB4/PXN pathway inhibitor and an effective amount of a KRAS pathway inhibitor. The USPTO provides claim terms with broadest reasonable interpretation in light of the specification.
The instant specification defines “ITGB4/PXN pathway inhibitor” and “KRAS pathway inhibitor” [PGPUB 0048, 0052]:
The term “ITGB4/PXN inhibitor” refers to therapeutic agents that perturb the interaction between integrin (ITGB4) and paxillin (PXN), e.g., by inhibiting the expression of ITGB4, by inhibiting the expression of PXN, by inhibiting the expression of both ITGB4 and PXN. In aspects, the ITGB4/PXN inhibitor inhibits the expression of ITGB4. In aspects, the ITGB4/PXN inhibitor inhibits the expression of PXN. In aspects, the ITGB4/PXN inhibitor inhibits the expression of ITGB4 and PXN. In aspects, the ITGB4/PXN inhibitor inhibits an interaction between ITGB4 and PXN. In aspects, the ITGB4/PXN inhibitor is an anti-ITGB4 antibody, an RNA (e.g., siRNA) that inhibits the expression of ITGB4, a small molecule that inhibits the expression of ITGB4, an anti-PXN antibody, an RNA (e.g., siRNA) that inhibits the expression of PXN, or a small molecule that inhibits the expression of PXN. Exemplary ITGB4/PXN inhibitors include, without limitation, carfilzomib, tozasertib, dasatinib, afatinib, dacomitinib, poziotinib, pacritinib, ixazomib, osimertinib, CUDC-101 (i.e., 7-((4-((3-ethynylphenyl)amino)-7-methoxyquinazolin-6-yl)oxy)-N-hydroxyheptanamide), and cerdulatinib. Carfilzomib is commercially available as KYPROLIS® from Amgen, Inc. Carfilzomib can alternatively be referred to as CFZ.
In aspects, the “KRAS inhibitor” is a “KRAS pathway inhibitor.” In aspects, a KRAS pathway inhibitor refers to a therapeutic agent (e.g., compound, antibody, RNA) capable of detectably lowering expression of or activity level of the KRAS signaling pathway compared to a control. The inhibited expression or activity of the KRAS signaling pathway can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or less than that in a control. In aspects, the inhibition is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, or more in comparison to a control. A KRAS pathway inhibitor is capable of inhibiting the KRAS signaling pathway, e.g., by binding, partially or totally blocking stimulation of the KRAS signaling pathway; decrease, prevent, or delay activation of the KRAS signaling pathway; or inactivate, desensitize, or down-regulate signal transduction, gene expression, or enzymatic activity of the KRAS signaling pathway.
Therefore, the ITGB4/PXN pathway inhibitor can be any agent that perturbs the interaction between ITGB4 and PXN. The agent can inhibit expression of ITGB4 or PXN or inhibit interaction between ITGB4 and PXN. Agents include antibodies, RNAs (e.g. siRNA), small molecules. The KRAS pathway inhibitor can refers to a therapeutic agent (e.g., compound, antibody, RNA) capable of detectably lowering expression of or activity level of the KRAS signaling pathway compared to a control. Therefore, the inhibitors can be any agent including antibodies, small molecules or RNAs.
Assessment of whether species are support in the original specification
Two embodiment of the invention of claims were reduced to practice at the time of filing. Applicants disclosed with sotorasib +carfilzomib and adagrasib + carfilzomib.
In addition, the instant specification lists the ITGB4/PXN pathway inhibitors and KRAS pathway inhibitors of claim 79.
There was no disclosure of other small molecules, antibodies or RNA that were capable of the claimed use.
In summary, for these reasons, the skilled artisan would reasonably conclude that the inventor(s), at the time the application was filed, had possession of KRAS inhibitors sotorasib and adagrasib and the ITGB4/PXN pathway inhibitor carfilzomib at the time the invention was filed.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, the disclosure of sotorasib, adagrasib and carfilzomib are not representative of the genus. The disclosure of the specific small molecules are not representative of the entire genus encompassed by ITGB4/PXN pathway inhibitors and KRAS pathway inhibitors because the genus is large.
Identifying characteristics and structure/function correlation
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe the structural, physical and/or chemical properties of ITGB4/PXN pathway inhibitors and KRAS pathway inhibitors that lead to the claimed function of treating a cancer with a KRAS mutation.
In conclusion, for the reasons presented above, the skilled artisan would reasonably conclude that the inventors, at the time the application was filed had full possession of the , had possession of KRAS inhibitors sotorasib and adagrasib and the ITGB4/PXN pathway inhibitor carfilzomib.
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 73-76, 78, 81-82, 84, 86-92 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 studies 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 73-76, 81, 82, 86-88, 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. 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 78, Nagasaka et al. that due to the specific features of the molecular structure of KRAS, it has shown its high resistance to small molecule modulation. Nagasaka et al. teach that combination screening in order to enhance the response of the compound MRTX849 and overcome potential resistance. It would have been obvious to a person of ordinary skill in the art to treat the subject with NSCLC KRASG12C mutation that is resistant with a combination of compounds because Nagasaka et al. teach the combination treatment enhances the response of the compounds to overcome resistance. There is a reasonable expectation of success given that the combination treatment is suggested by both Nagasaka et al. and Verma et al.
With respect to claim 84, 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 claim 89, the references do not explicitly teach the step of identifying a homozygous mutation in a biological sample obtains 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 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 90-92, It would have been obvious to a person of ordinary skill in the art to treat NSCLC with homozygous 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. 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.
Claims 73-78, 81-82, 84, 86-92 are 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) in view of Wu et al. (PeerJ. 2019 Dec 20; 7).
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 or PXN. 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 77, 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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 73-78, 81, 82, 84 and 86-92 are provisionally 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. Although the claims at issue are not identical, they are not patentably distinct from each other. The copending Application claims a method of alleviating resistance to a platinum based chemotherapy comprising administering to a subject the composition comprising a therapeutic agent comprising an siRNA that inhibitos ITGB4 and an siRNA that inhibits PXN or carfilzomib. The copending application also claims the cancer is lung cancer such as NSCLC. The copending application does not teach the ITGB4 inhibitor in combination with a KRAS pathway inhibitor. However, the teachings of Nagasaka et al. cures this deficiency.
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 studies 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).
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 the copending application 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 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 the copending application teach carfilzomib for treatment of NSCLC, 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 78, Nagasaka et al. that due to the specific features of the molecular structure of KRAS, it has shown its high resistance to small molecule modulation. Nagasaka et al. teach that combination screening in order to enhance the response of the compound MRTX849 and overcome potential resistance. It would have been obvious to a person of ordinary skill in the art to treat the subject with NSCLC KRASG12C mutation that is resistant with a combination of compounds because Nagasaka et al. teach the combination treatment enhances the response of the compounds to overcome resistance. There is a reasonable expectation of success given that the combination treatment is suggested by both Nagasaka et al. and Verma et al.
With respect to claim 84, 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 the copending application 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 claim 89, the references do not explicitly teach the step of identifying a homozygous mutation in a biological sample obtains 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 the copending application 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 90-92, It would have been obvious to a person of ordinary skill in the art to treat NSCLC with homozygous 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 the copending application 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 the copending teach carfilzomib for treatment of NSCLC, 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.
The references do not teach measuring the elevated expression level of ITGB4 or PXN. 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 77, 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654