DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 44-52 are pending in the application.
Applicant’s claim listing filed July 6, 2026 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Election/Restrictions
Applicant’s election of:
Species A1), active KRAS protein is a KRAS4A protein (corresponding to claims 46, 47, and 49), and
Species B2), kinase binding moiety is of the formula:
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in the reply filed on July 6, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 July 6, 2026.
Claims 44-47 and 49-52 are being examined on the merits with claim 50 being examined only to the extent the claim reads on the elected subject matter. In the interest of clarity, it is noted that at least one of the following rejections is directed in-part to a non-elected species in claim 50. However, the non-elected species has yet to be searched and examined on the merits as the cited prior art was identified during a search of the elected species in claim 50.
Priority
This application is filed under 35 U.S.C. 120 as a continuation application of U.S. non-provisional application no. 17/327,319, filed May 21, 2021, now abandoned, which claims domestic priority under 35 U.S.C. 119(e) to U.S. provisional applications 63/028,729 and 63/109,103, filed May 22, 2020 and November 3, 2020, respectively.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 63/028,729, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application.
Application No. 63/028,729 fails to provide adequate descriptive support for “KRAS4A” in claims 46 and 47 and “the active KRAS protein comprises a substitution at position 12 relative to SEQ ID NO: 2” in claim 49. In the absence of descriptive support for the noted limitations in application No. 63/028,729, the effective filing date for claims 46, 47, and 49 is November 3, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 22, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Specification/Informalities
Applicant is requested to update the status of application no. 17/327,319 at p. 1, lines 4-5 of the specification. According to USPTO records, application no. 17/327,319 is now abandoned.
The specification is objected to in the disclosure of “a luciferase with at least 70% sequence identity with SEQ ID NO: 4” (e.g., specification at p. 3, lines 13-14 and p. 5, lines 6-7) because the specification discloses that SEQ ID NO: 4 is the amino acid sequence of KRAS4AG12C (p. 15, line 15 and p. 49, lines 12-15). KRAS4AG12C is not a luciferase. Appropriate correction is required.
The use of trade names or marks used in commerce, has been noted in this application at p. 24, lines 26-31 and p. 29, lines 10-15. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 51 is objected to in the recitation of “a luciferase with at least 70% sequence identity to the sequence of SEQ ID NO: 18” and in the interest of improving claim form, it is suggested that the noted phrase be amended to recite “a luciferase comprising an amino acid sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 18.”
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
A. The following two rejections are based on the interpretation of “an active KRAS protein from a vector that has been introduced into the cell” in part (c) of claim 44 as a product-by-process limitation.
Claims 44, 45, and 49-52 are rejected under 35 U.S.C. 103 as being unpatentable over Vasta et al. (Cell Chemical Biology 25:206-214.e1-e11, 2018; cited on the attached Form PTO-892; hereafter “Vasta”) in view of Supplementary Table S1 (obtained from https://ars.els-cdn.com/content/image/1-s2.0-S2451945617303914-mmc2.xlsx, February 2018, 6 pages; cited on the attached Form PTO-892; hereafter “Table S1”) and dos Santos et al. (Molecular Cancer 15:12, 2016, 14 pages; cited on the IDS filed August 22, 2024; hereafter “dos Santos”), and as evidenced by Nano-Glo® Live Cell Assay System Quick Protocol (December 2017, 2 pages; cited on the attached Form PTO-892; hereafter “Quick Protocol”).
The claims are drawn to a method of detecting or quantifying a kinase in a sample, comprising:
(a) expressing a fusion of the kinase and a bioluminescent reporter within a cell in the sample;
(b) contacting the sample with (i) a substrate for the bioluminescent reporter and (ii) a kinase binding agent comprising a kinase binding moiety and a fluorophore;
(c) expressing an active KRAS protein from a vector that has been introduced into the cell; and
(d) detecting or quantifying a bioluminescence resonance energy transfer (BRET) signal from the bioluminescent reporter to the fluorophore.
Regarding claim 44, Vasta teaches that for kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism (p. 206, Summary). Vasta teaches various challenges of selectively modulating individual kinases (p. 206, column 2, middle) and teaches that acellular approaches to measure kinase binding or enzymatic inhibition can fail to accurately predict engagement in cells (p. 206, Summary and column 2, bottom). Vasta teaches that a growing need has emerged for methods capable of quantifying kinase inhibitor occupancy, selectivity, and affinity within the cellular environment where engagement would naturally occur (p. 206, column 2, middle). Vasta generally teaches an energy-transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells (p. 206, Summary). Vasta’s method uses an expressed kinase fused to Nanoluc luciferase (p. 207, column 2; p. 208, column 1) and a fluorescent energy transfer probe (p. 208, Figure 2). Vasta teaches that to measure BRET, NanoBRET NanoGlo Substrate was added to the cells (p. e3, middle). Vasta explains that compound binding results in competitive displacement of the probe and a loss of energy transfer in live cells (p. 207, column 2). Vasta’s method is illustrated below (re-copied from p. 207, Figure 1):
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The energy transfer probes of Vasta (p. 208, Figure 2) are considered to comprise a kinase binding moiety and a fluorophore.
Regarding claim 45, Vasta teaches expression vectors encoding the NanoLuc/Kinase fusions and teaches that for the BRET target engagement experiments, HEK-293 or HeLa cells were transfected with the fusion constructs (p. e3 under the heading “Cell Transfections and BRET Measurements).
Regarding claim 50, the structure of energy transfer probe 5 (recopied below) comprises a structure recited in claim 50.
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Regarding claim 51, as stated above, Vasta’s method uses an expressed kinase fused to Nanoluc. Given that SEQ ID NO: 18 is the amino acid sequence of NanoLuc, it follows that Vasta’s Nanoluc has an amino acid sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 18.
Regarding claim 52, while Vasta teaches bioluminescence imaging was performed using NanoGlo Live Cell Reagent (paragraph bridging pp. e4-e5), Vasta does not teach the substrate furimazine. However, evidentiary reference Quick Protocol teaches that Nano-Glo Live Cell Reagent comprises the substrate furimazine (p. 1, top).
The difference between Vasta and the claimed invention is that Vasta does not teach expressing active KRAS protein from a vector that has been introduced into the cell as recited in claims 44 and 49.
Table S1 shows the 178 full-length kinases that can be queried in the method of Vasta including AURKA and AURKB (see Vasta at p. 208, column 1, top). One of ordinary skill in the art would have recognized AURKA and AURKB are abbreviations for Aurora kinase A and Aurora kinase B, respectively.
The reference of dos Santos teaches that activation of KRAS by mutation is a very common event in human malignancies, yet, in spite of intensive investigation, KRAS-related malignancies currently lack effective therapies. The reference of dos Santos teaches that Aurora kinase pharmacological inhibition preferentially targets lung cancer cells expressing KRASG12V and supports the hypothesis that AURKA and AURKB are promising targets for KRAS-induced lung cancer therapy (p. 10, column 1, bottom). As stated above, the recitation of “from a vector that has been introduced into the cell” in part (c) of claim 44 is interpreted as a product-by-process limitation and in this case, the recitation of “from a vector that has been introduced into the cell” does not distinguish the recited “active KRAS protein” in claims 44 and 49 from KRASG12V expressed in lung cancer cells of dos Santos.
In view of the combined teachings of Vasta, Table S1, and dos Santos, it would have been obvious to one of ordinary skill in the art before the effective filing date to query AURKA or AURKB in Vasta’s method and to modify Vasta’s method to use lung cancer cells expressing KRASG12V. One would have been motivated for AURKA or AURKB to be the queried kinase in Vasta’s method because Table S1 shows AURKA or AURKB as kinases that can be queried in the method of Vasta. One would have been motivated to modify Vasta’s method to use lung cancer cells expressing KRASG12V because dos Santos teaches that Aurora kinase pharmacological inhibition preferentially targets lung cancer cells expressing KRASG12V and that Aurora kinase A and Aurora kinase B are promising targets for KRAS-induced lung cancer therapy. One would have had a reasonable expectation of success for the cells and kinase of Vasta’s method to be lung cancer cells expressing KRASG12V and Aurora kinase A or Aurora kinase B, respectively, because Table S1 teaches that Aurora kinase A and Aurora kinase B can be queried using Vasta’s method and dos Santos teaches lung cancer cells expressing KRASG12V.
Therefore, the method of claims 44, 45, and 49-52 would have been obvious to one of ordinary skill in the art before the effective filing date.
In the interest of clarity, it is noted that the instant rejection is directed in-part to a non-elected species in claim 50. However, the non-elected species has yet to be searched and examined on the merits as the cited prior art was identified during a search of the elected species in claim 50.
Claims 46 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Vasta in view of Table S1 and dos Santos and as evidenced by Quick Protocol as applied to claims 44, 45, and 49-52 above, and further in view of Westcott et al. (Chin. J. Cancer 32:63-70, 2013; cited on the attached Form PTO-892; hereafter “Westcott”) and Xue et al. (Nature 577:421-425.Article pp. 1-15, January 2020; cited on the attached Form PTO-892; hereafter “Xue”).
The relevant teachings of Vasta, Table S1 and dos Santos as applied to claims 44, 45, and 49-52 are set forth above.
The combination of Vasta, Table S1 and dos Santos does not teach or suggest a KRAS4A protein including KRAS4AG12C as recited in claims 46 and 47.
Westcott teaches that as a result of alternative splicing, the human Kras loci encodes two highly similar proteins, Kras4A and Kras4B, that are jointly affected by activating mutations commonly found in cancer (p. 67, column 1, top). Westcott teaches that studies have suggested that Kras4A is essential for lung carcinogenesis and that Kras4A is an essential component of mutant Kras-driven lung tumors (p. 67, column 1, middle).
Xue teaches that KRASG12C is one of the most common activating alterations in lung adenocarcinoma (p. 421, Abstract). Xue teaches that the effect of KRASG12C inhibition is bypassed by the production of new KRASG12C, which is due in-part to reactivation by AURKA (p. 421, Abstract; p. 423, column 2, middle). Xue teaches that a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antiproliferative effect as compared to KRASG12C inhibition alone (p. 423, column 2).
In view of the additional teachings of Westcott and Xue, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine Vasta, Table S1, dos Santos, Westcott, and Xue for the cells and kinase of Vasta’s method to be lung cancer cells expressing KRAS4AG12C and AURKA, respectively. As stated above, the recitation of “from a vector that has been introduced into the cell” in part (c) of claim 44 is interpreted as a product-by-process limitation and in this case, the recitation of “from a vector that has been introduced into the cell” does not distinguish the recited “active KRAS” from KRAS4AG12V expressed in lung cancer cells. One would have been motivated for the cells and kinase of Vasta to be lung cancer cells expressing KRAS4AG12C and AURKA because Westcott teaches that Kras4A is essential for lung carcinogenesis and is an essential component of mutant Kras-driven lung tumors, and Xue teaches KRASG12C is one of the most common activating alterations in lung adenocarcinoma and a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antitumor effect as compared to KRASG12C inhibition alone. One would have had a reasonable expectation of success for the cells and kinase of Vasta to be lung cancer cells expressing KRAS4AG12C and AURKA because Vasta and Table S1 teach that AURKA can be queried using Vasta’s method, Westcott teaches Kras4A is an essential component of mutant Kras-driven lung tumors, and Xue teaches lung cancer cells expressing KRASG12C.
Therefore, the method of claims 46 and 47 would have been obvious to one of ordinary skill in the art before the effective filing date.
B. The following two rejections are based on the interpretation of “an active KRAS protein from a vector that has been introduced into the cell” in part (c) of claim 44 as requiring that a vector expressing the active KRAS protein has been introduced into the cell.
Claims 44, 45, and 49-52 are rejected under 35 U.S.C. 103 as being unpatentable over Vasta in view of Table S1 and dos Santos and as evidenced by Quick Protocol.
Regarding claim 44, Vasta teaches that for kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism (p. 206, Summary). Vasta teaches various challenges of selectively modulating individual kinases (p. 206, column 2, middle) and teaches that acellular approaches to measure kinase binding or enzymatic inhibition can fail to accurately predict engagement in cells (p. 206, Summary and column 2, bottom). Vasta teaches that a growing need has emerged for methods capable of quantifying kinase inhibitor occupancy, selectivity, and affinity within the cellular environment where engagement would naturally occur (p. 206, column 2, middle). Vasta generally teaches an energy-transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells (p. 206, Summary). Vasta’s method uses an expressed kinase fused to Nanoluc luciferase (p. 207, column 2; p. 208, column 1) and a fluorescent energy transfer probe (p. 208, Figure 2). Vasta teaches that to measure BRET, NanoBRET NanoGlo Substrate was added to the cells (p. e3, middle). Vasta explains that compound binding results in competitive displacement of the probe and a loss of energy transfer in live cells (p. 207, column 2). Vasta’s method is illustrated below (re-copied from p. 207, Figure 1):
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The energy transfer probes of Vasta (p. 208, Figure 2) are considered to comprise a kinase binding moiety and a fluorophore.
Regarding claim 45, Vasta teaches expression vectors encoding the NanoLuc/Kinase fusions and teaches that for the BRET target engagement experiments, HEK-293 or HeLa cells were transfected with the fusion constructs (p. e3 under the heading “Cell Transfections and BRET Measurements).
Regarding claim 50, the structure of energy transfer probe 5 (recopied below) comprises a structure recited in claim 50.
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Regarding claim 51, as stated above, Vasta’s method uses an expressed kinase fused to Nanoluc. Given that SEQ ID NO: 18 is the amino acid sequence of NanoLuc, it follows that Vasta’s Nanoluc has an amino acid sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 18.
Regarding claim 52, while Vasta teaches bioluminescence imaging was performed using NanoGlo Live Cell Reagent (paragraph bridging pp. e4-e5), Vasta does not teach the substrate furimazine. However, evidentiary reference Quick Protocol teaches that Nano-Glo Live Cell Reagent comprises the substrate furimazine (p. 1, top).
The difference between Vasta and the claimed invention is that Vasta does not teach expressing active KRAS protein from a vector that has been introduced into the cell as recited in claims 44 and 49.
Table S1 shows the 178 full-length kinases that can be queried in the method of Vasta including AURKA and AURKB (see Vasta at p. 208, column 1, top). One of ordinary skill in the art would have recognized AURKA and AURKB are abbreviations for Aurora kinase A and Aurora kinase B, respectively.
The reference of dos Santos teaches that activation of KRAS by mutation is a very common event in human malignancies, yet, in spite of intensive investigation, KRAS-related malignancies currently lack effective therapies. dos Santos teaches a cell line that is genetically modified to inducibly express KRASG12V from a vector (p. 10, column 2, top). dos Santos teaches that induced expression of KRASG12V in the cell enhanced growth and ability to form colonies, which was abrogated in the presence of a AURKA/AURKB dual inhibitor, however, the dual inhibitor had little effect in uninduced cells (p. 5, column 2, middle). According to dos Santos, these results show that Aurora kinase inhibition primarily exerts anti-tumor effects in the presence of KRASG12V , having little to no effect on normal cells or tumorigenic cells without KRAS mutations (p. 5, column 2, bottom).
In view of the combined teachings of Vasta, Table S1, and dos Santos, it would have been obvious to one of ordinary skill in the art before the effective filing date to query AURKA or AURKB in Vasta’s method and to modify Vasta’s method to express KRASG12V from a vector. One would have been motivated to and would have expected success to use AURKA or AURKB as the kinase for Vasta’s method because Table S1 teaches that AURKA and AURKB can be queried using Vasta’s method. One would have been motivated to modify the cells of Vasta’s method to express KRASG12V from a vector because, while Table S1 teaches that Aurora kinase A and Aurora kinase B can be queried using Vasta’s method, the cells of Vasta’s method are not described as having and do not require a KRAS mutation, and dos Santos teaches that Aurora inhibition primarily exerts anti-tumor effects in the presence of KRASG12V , having little to no effect on normal cells or tumorigenic cells without KRAS mutations, and that AURKA and AURKB are promising targets for KRAS-induced lung cancer therapy. One would have had a reasonable expectation of success to modify the cells of Vasta’s method to express KRASG12V from a vector because dos Santos teaches a method to express KRASG12V from a vector.
Therefore, the method of claims 44, 45, and 49-52 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 46 and 47 are rejected under 35 U.S.C. 103 as being unpatentable over Vasta in view of Table S1 and dos Santos and as evidenced by Quick Protocol as applied to claims 44, 45, and 49-52 above, and further in view of Westcott and Xue.
The relevant teachings of Vasta, Table S1, and dos Santos as applied to claims 44, 45, and 49-52 are set forth above.
The combination of cited prior art does not teach or suggest a KRAS4A protein including KRAS4AG12C as recited in claims 46 and 47.
Westcott teaches that as a result of alternative splicing, the human Kras loci encodes two highly similar proteins, Kras4A and Kras4B, that are jointly affected by activating mutations commonly found in cancer (p. 67, column 1, top). Westcott teaches that studies have suggested that Kras4A is essential for lung carcinogenesis and that Kras4A is an essential component of mutant Kras-driven lung tumors (p. 67, column 1, middle).
Xue teaches that KRASG12C is one of the most common activating alterations in lung adenocarcinoma (p. 421, Abstract). Xue teaches that the effect of KRASG12C inhibition is bypassed by the production of new KRASG12C, which is due in-part to reactivation by AURKA (p. 421, Abstract; p. 423, column 2, middle). Xue teaches that a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antiproliferative effect as compared to KRASG12C inhibition alone (p. 423, column 2). Xue teaches a cell engineered to stably express an inducible KRASG12C (Methods, p. 4, column 2, bottom), which was used in the inhibitor studies (e.g., p. 424, Figure 4f; Extended Data Fig. 9).
In view of the additional teachings of Westcott and Xue, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine Vasta, Table S1, dos Santos, Westcott, and Xue to use AURKA as the queried kinase and to modify the cells of Vasta’s method to express KRAS4AG12C from a vector. One would have been motivated to and would have expected success to use AURKA as the kinase for Vasta’s method because Table S1 teaches that AURKA can be queried using Vasta’s method. One would have been motivated to modify the cells of Vasta’s method to express KRAS4AG12C from a vector because the cells of Vasta’s method are not described as having a KRAS mutation, dos Santos teaches that Aurora inhibition primarily exerts anti-tumor effects in the presence of a KRAS mutation, having little to no effect on normal cells or tumorigenic cells without KRAS mutations, Westcott teaches that Kras4A is essential for lung carcinogenesis and is an essential component of mutant Kras-driven lung tumors, and Xue teaches KRASG12C is one of the most common activating alterations in lung adenocarcinoma and a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antitumor effect as compared to KRASG12C inhibition alone. One would have had a reasonable expectation of success to modify the cells of Vasta’s method to express KRAS4AG12C from a vector because Westcott teaches Kras4A and Xue teaches a method to express KRASG12C from a vector.
Therefore, the method of claims 46 and 47 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant’s remarks filed February 28, 2025 argue that the obviousness rationale mischaracterizes the present technology, noting that the presently claimed method detects BRET from a kinase/reporter fusion to a fluorophore tethered to a kinase binding moiety and the BRET signal is increased upon increased binding of the kinase binding moiety to the kinase in the presence of an active KRAS protein.
Applicant’s arguments are not found persuasive. At least for the reasons set forth above, the combination of cited references teaches all claim limitations and provides a motivation and reasonable expectation of success to practice the claimed method.
Applicant’s remarks filed February 28, 2025 further argue that the obviousness rationale mischaracterizes the teachings of dos Santos, noting that while dos Santos teaches Aurora kinase expression is upregulated by the presence of KRASG12V, dos Santos does not identify any effect of KRASG12V on the function of Aurora kinase and one of ordinary skill in the art would not expect any relationship between increased Aurora kinase protein levels and binding to a kinase binding moiety. Thus, according to applicant, one would not have been motivated to modify the method of Vasta to include an active KRAS protein.
Applicant’s arguments are not found persuasive. As stated above, Table S1 teaches that Aurora kinase A and Aurora kinase B can be queried using Vasta’s method and dos Santos taught that AURKA and AURKB are promising targets for KRAS-induced lung cancer therapy. However, dos Santos teaches Aurora kinase inhibition primarily exerts anti-tumor effects in the presence of KRASG12V, having little to no effect on normal cells or tumorigenic cells without KRAS mutations, and the cells of Vasta’s method are not described as having a KRAS mutation, one would have been motivated to modify Vasta’s method to use lung cancer cells expressing KRASG12V or cells expressing KRASG12V from a vector as physiologically relevant cells for querying Aurora kinase A and Aurora kinase B.
For these reasons, it is the examiner’s position that the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Claim Rejections - 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.
A. The following two rejections are based on the interpretation of “an active KRAS protein from a vector that has been introduced into the cell” in part (c) of claim 44 as a product-by-process limitation.
Claims 44, 45, and 49-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 17, and 20 of U.S. Patent No. 11,442,063 B2 (cited on the attached Form PTO-892) in view of Vasta, Table S1, and dos Santos, and as evidenced by Quick Protocol.
Claim 17 of the patent recites a method of detecting or quantifying kinases in a sample, comprising contacting the sample with a composition of claim 3 and detecting or quantifying the functional element of a signal produced thereby.
Claim 20 of the patent recites a method of monitoring interactions between kinases and unmodified biomolecules comprising contacting the sample with a broad-spectrum kinase binding agent of claim 3.
Claim 13 of the patent limit the broad-spectrum kinase binding agent of claim 3 of the patent to comprising the structure of
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The claims of the patent do not recite all limitations of instant claims 44, 45, and 49-52.
Regarding instant claim 44, Vasta teaches that for kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism (p. 206, Summary). Vasta teaches various challenges of selectively modulating individual kinases (p. 206, column 2, middle) and teaches that acellular approaches to measure kinase binding or enzymatic inhibition can fail to accurately predict engagement in cells (p. 206, Summary and column 2, bottom). Vasta teaches that a growing need has emerged for methods capable of quantifying kinase inhibitor occupancy, selectivity, and affinity within the cellular environment where engagement would naturally occur (p. 206, column 2, middle). Vasta generally teaches an energy-transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells (p. 206, Summary). Vasta’s method uses an expressed kinase fused to Nanoluc luciferase (p. 207, column 2; p. 208, column 1) and a fluorescent energy transfer probe (p. 208, Figure 2). Vasta teaches that to measure BRET, NanoBRET NanoGlo Substrate was added to the cells (p. e3, middle). Vasta explains that compound binding results in competitive displacement of the probe and a loss of energy transfer in live cells (p. 207, column 2). Vasta’s method is illustrated below (re-copied from p. 207, Figure 1):
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The energy transfer probes of Vasta (p. 208, Figure 2) are considered to comprise a kinase binding moiety and a fluorophore.
Table S1 shows the 178 full-length kinases that can be queried in the method of Vasta including AURKA and AURKB (see Vasta at p. 208, column 1, top). One of ordinary skill in the art would have recognized AURKA and AURKB are abbreviations for Aurora kinase A and Aurora kinase B, respectively.
The reference of dos Santos teaches that activation of KRAS by mutation is a very common event in human malignancies, yet, in spite of intensive investigation, KRAS-related malignancies currently lack effective therapies. The reference of dos Santos teaches that Aurora kinase pharmacological inhibition preferentially targets lung cancer cells expressing KRASG12V and supports the hypothesis that AURKA and AURKB are promising targets for KRAS-induced lung cancer therapy (p. 10, column 1, bottom). As stated above, the recitation of “from a vector that has been introduced into the cell” in part (c) of claim 1 is interpreted as a product-by-process limitation and in this case, the recitation of “from a vector that has been introduced into the cell” does not distinguish the recited “active KRAS” from KRASG12V expressed in lung cancer cells.
In view of the teachings of Vasta, Table S1, and dos Santos, it would have been obvious to one of ordinary skill in the art before the effective filing date for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRASG12V and AURKA or AURKB as the kinase. One would have recognized that claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRASG12V and AURKA or AURKB because claims 17 and 20 of the patent recite broad method steps of “contacting the sample with a composition of claim 3 and detecting or quantifying the functional element of a signal produced thereby” and “comprising contacting the sample with a broad-spectrum kinase binding agent of claim 3”, respectively, Vasta’s method uses an energy transfer probe nearly identical in structure to the broad-spectrum kinase binding agent of claim 13 of the patent, dos Santos teaches that Aurora kinase pharmacological inhibition preferentially targets lung cancer cells expressing KRASG12V and that AURKA and AURKB are promising targets for KRAS-induced lung cancer therapy. One would have had a reasonable expectation of success for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRASG12V and AURKA or AURKB because Vasta and Table S1 teach that AURKA and AURKB can be queried using Vasta’s method and dos Santos teaches lung cancer cells expressing KRASG12V.
Regarding instant claim 45, Vasta teaches expression vectors encoding the NanoLuc/Kinase fusions and teaches that for the BRET target engagement experiments, HEK-293 or HeLa cells were transfected with the fusion constructs (p. e3 under the heading “Cell Transfections and BRET Measurements).
Regarding instant claim 50, the structure of energy transfer probe 5 (recopied below) comprises a structure recited in claim 50.
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Regarding instant claim 51, as stated above, Vasta’s method uses an expressed kinase fused to Nanoluc. Given that SEQ ID NO: 18 is the amino acid sequence of NanoLuc, it follows that Vasta’s Nanoluc has an amino acid sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 18.
Regarding instant claim 52, while Vasta teaches bioluminescence imaging was performed using NanoGlo Live Cell Reagent (paragraph bridging pp. e4-e5), Vasta does not teach the substrate furimazine. However, evidentiary reference Quick Protocol teaches that Nano-Glo Live Cell Reagent comprises the substrate furimazine (p. 1, top).
Therefore, claims 44, 45, and 49-52 of this application are unpatentable over the claims of the patent in view of Vasta, Table S1, and dos Santos.
Claims 46 and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 17, and 20 of U.S. Patent No. 11,442,063 B2 in view of Vasta, Table S1, and dos Santos, and as evidenced by Quick Protocol as applied to claims 44, 45, and 49-52 above, and further in view of Westcott and Xue.
The claims of the patent do not recite a KRAS4A protein and/or a KRAS4AG12C protein as recited in claims 46 and 47.
Westcott teaches that as a result of alternative splicing, the human Kras loci encodes two highly similar proteins, Kras4A and Kras4B, that are jointly affected by activating mutations commonly found in cancer (p. 67, column 1, top). Westcott teaches that studies have suggested that Kras4A is essential for lung carcinogenesis and that Kras4A is an essential component of mutant Kras-driven lung tumors (p. 67, column 1, middle).
Xue teaches that KRASG12C is one of the most common activating alterations in lung adenocarcinoma (p. 421, Abstract). Xue teaches that the effect of KRASG12C inhibition is bypassed by the production of new KRASG12C, which is maintained in-part by aurora kinase signaling (p. 421, Abstract). Xue teaches that a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antitumor effect as compared to KRASG12C inhibition alone (p. 423, column 2).
In view of the additional teachings of Westcott and Xue, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine Vasta, Table S1, dos Santos, Westcott, and Xue for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRAS4AG12C and AURKA. As stated above, the recitation of “from a vector that has been introduced into the cell” in part (c) of claim 44 is interpreted as a product-by-process limitation and in this case, the recitation of “from a vector that has been introduced into the cell” does not distinguish the recited “active KRAS” from KRAS4AG12C expressed in lung cancer cells. One would have recognized that claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRAS4AG12C and AURKA because claims 17 and 20 of the patent recite broad method steps of “contacting the sample with a composition of claim 3 and detecting or quantifying the functional element of a signal produced thereby” and “comprising contacting the sample with a broad-spectrum kinase binding agent of claim 3”, respectively, Vasta’s method uses an energy transfer probe nearly identical in structure to the broad-spectrum kinase binding agent of claim 13 of the patent, Westcott teaches that Kras4A is essential for lung carcinogenesis and that Kras4A is an essential component of mutant Kras-driven lung tumors and Xue teaches KRASG12C is one of the most common activating alterations in lung adenocarcinoma and a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antitumor effect as compared to KRASG12C inhibition alone. One would have had a reasonable expectation of success for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRAS4AG12C and AURKA because Vasta and Table S1 teach that AURKA can be queried using Vasta’s method, Westcott teaches Kras4A is an essential component of mutant Kras-driven lung tumors, and Xue teaches lung cancer cells expressing KRASG12C.
Therefore, claims 46 and 47 of this application are unpatentable over the claims of the patent in view of Vasta, Table S1, dos Santos, Westcott, and Xue.
B. The following two rejections are based on the interpretation of “an active KRAS protein from a vector that has been introduced into the cell” in part (c) of claim 44 as requiring that a vector expressing the active KRAS protein has been introduced into the cell.
Claims 44, 45, and 49-52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 17, and 20 of U.S. Patent No. 11,442,063 B2 (cited on Form PTO-892 mailed on July 26, 2023) in view of Vasta, Table S1, and dos Santos, and as evidenced by Quick Protocol.
Claim 17 of the patent recites a method of detecting or quantifying kinases in a sample, comprising contacting the sample with a composition of claim 3 and detecting or quantifying the functional element of a signal produced thereby.
Claim 20 of the patent recites a method of monitoring interactions between kinases and unmodified biomolecules comprising contacting the sample with a broad-spectrum kinase binding agent of claim 3.
Claim 13 of the patent limit the broad-spectrum kinase binding agent of claim 3 of the patent to comprising the structure of
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The claims of the patent do not recite all limitations of instant claims 44, 45, and 49-52.
Regarding instant claim 44, Vasta teaches that for kinase inhibitors, intracellular target selectivity is fundamental to pharmacological mechanism (p. 206, Summary). Vasta teaches various challenges of selectively modulating individual kinases (p. 206, column 2, middle) and teaches that acellular approaches to measure kinase binding or enzymatic inhibition can fail to accurately predict engagement in cells (p. 206, Summary and column 2, bottom). Vasta teaches that a growing need has emerged for methods capable of quantifying kinase inhibitor occupancy, selectivity, and affinity within the cellular environment where engagement would naturally occur (p. 206, column 2, middle). Vasta generally teaches an energy-transfer technique that enabled the first broad-spectrum, equilibrium-based approach to quantitatively profile target occupancy and compound affinity in live cells (p. 206, Summary). Vasta’s method uses an expressed kinase fused to Nanoluc luciferase (p. 207, column 2; p. 208, column 1) and a fluorescent energy transfer probe (p. 208, Figure 2). Vasta teaches that to measure BRET, NanoBRET NanoGlo Substrate was added to the cells (p. e3, middle). Vasta explains that compound binding results in competitive displacement of the probe and a loss of energy transfer in live cells (p. 207, column 2). Vasta’s method is illustrated below (re-copied from p. 207, Figure 1):
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The energy transfer probes of Vasta (p. 208, Figure 2) are considered to comprise a kinase binding moiety and a fluorophore.
Table S1 shows the 178 full-length kinases that can be queried in the method of Vasta including AURKA and AURKB (see Vasta at p. 208, column 1, top).
The reference of dos Santos teaches that activation of KRAS by mutation is a very common event in human malignancies, yet, in spite of intensive investigation, KRAS-related malignancies currently lack effective therapies. dos Santos teaches a cell line that is genetically modified to inducibly express KRASG12V from a vector (p. 10, column 2, top). dos Santos teaches that induced expression of KRASG12V in the cell enhanced growth and ability to form colonies, which was abrogated in the presence of a AURKA/AURKB dual inhibitor, however, the dual inhibitor had little effect in uninduced cells (p. 5, column 2, middle). According to dos Santos, these results show that Aurora inhibition primarily exerts anti-tumor effects in the presence of KRASG12V , having little to no effect on normal cells or tumorigenic cells without KRAS mutations (p. 5, column 2, bottom).
In view of the teachings of Vasta, Table S1, and dos Santos, it would have been obvious to one of ordinary skill in the art before the effective filing date for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling modified to use AURKA or AURKB as the kinase and to express KRASG12V from a vector. One would have recognized that claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling modified to use AURKA or AURKB as the kinase because Vasta and Table S1 teach that AURKA and AURKB can be queried using Vasta’s method. One would have recognized that claims 17 and 20 of the patent encompass Vasta’s method of inhibitor profiling modified to express KRASG12V from a vector because the cells of Vasta’s method are not described as having and do not require a KRAS mutation, dos Santos teaches that Aurora inhibition primarily exerts anti-tumor effects in the presence of KRASG12V , having little to no effect on normal cells or tumorigenic cells without KRAS mutations, and that AURKA and AURKB are promising targets for KRAS-induced lung cancer therapy. One would have had a reasonable expectation of success to modify the cells of Vasta’s method to express KRASG12V from a vector because dos Santos teaches a method to express KRASG12V from a vector.
Regarding instant claim 45, Vasta teaches expression vectors encoding the NanoLuc/Kinase fusions and teaches that for the BRET target engagement experiments, HEK-293 or HeLa cells were transfected with the fusion constructs (p. e3 under the heading “Cell Transfections and BRET Measurements).
Regarding instant claim 50, the structure of energy transfer probe 5 (recopied below) comprises a structure recited in claim 50.
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Regarding instant claim 51, as stated above, Vasta’s method uses an expressed kinase fused to Nanoluc. Given that SEQ ID NO: 18 is the amino acid sequence of NanoLuc, it follows that Vasta’s Nanoluc has an amino acid sequence with at least 70% sequence identity to the sequence of SEQ ID NO: 18.
Regarding instant claim 52, while Vasta teaches bioluminescence imaging was performed using NanoGlo Live Cell Reagent (paragraph bridging pp. e4-e5), Vasta does not teach the substrate furimazine. However, evidentiary reference Quick Protocol teaches that Nano-Glo Live Cell Reagent comprises the substrate furimazine (p. 1, top).
Therefore, claims 44, 45, and 49-52 of this application are unpatentable over the claims of the patent in view of Vasta, Table S1, and dos Santos.
Claims 46 and 47 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13, 17, and 20 of U.S. Patent No. 11,442,063 B2 (cited on Form PTO-892 mailed on July 26, 2023) in view of Vasta, Table S1, and dos Santos, and as evidenced by Quick Protocol as applied to claims 44, 45, and 49-52 above, and further in view of Westcott and Xue.
The claims of the patent do not recite a KRAS4A protein and/or a KRAS4AG12C protein as recited in claims 46 and 47.
Westcott teaches that as a result of alternative splicing, the human Kras loci encodes two highly similar proteins, Kras4A and Kras4B, that are jointly affected by activating mutations commonly found in cancer (p. 67, column 1, top). Westcott teaches that studies have suggested that Kras4A is essential for lung carcinogenesis and that Kras4A is an essential component of mutant Kras-driven lung tumors (p. 67, column 1, middle).
Xue teaches that KRASG12C is one of the most common activating alterations in lung adenocarcinoma (p. 421, Abstract). Xue teaches that the effect of KRASG12C inhibition is bypassed by the production of new KRASG12C, which is maintained in-part by aurora kinase signaling (p. 421, Abstract). Xue teaches that a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antitumor effect as compared to KRASG12C inhibition alone (p. 423, column 2).
In view of the additional teachings of Westcott and Xue, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine Vasta, Table S1, dos Santos, Westcott, and Xue for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling modified to use AURKA as the kinase and to express KRASG12C from a vector. One would have recognized that claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling using lung cancer cells expressing KRAS4AG12C and AURKA because claims 17 and 20 of the patent recite broad method steps of “contacting the sample with a composition of claim 3 and detecting or quantifying the functional element of a signal produced thereby” and “comprising contacting the sample with a broad-spectrum kinase binding agent of claim 3”, respectively, Vasta’s method uses an energy transfer probe nearly identical in structure to the broad-spectrum kinase binding agent of claim 13 of the patent, Westcott teaches that Kras4A is essential for lung carcinogenesis and that Kras4A is an essential component of mutant Kras-driven lung tumors and Xue teaches KRASG12C is one of the most common activating alterations in lung adenocarcinoma and a combination of AURKA inhibition and KRASG12C inhibition resulted in a stronger and synergistic antitumor effect as compared to KRASG12C inhibition alone. One would have had a reasonable expectation of success for claims 17 and 20 of the patent to encompass Vasta’s method of inhibitor profiling modified to use cells expressing KRAS4AG12C from a vector and AURKA because Vasta and Table S1 teach that AURKA can be queried using Vasta’s method, Westcott teaches Kras4A is an essential component of mutant Kras-driven lung tumors, and Xue teaches lung cancer cells expressing KRASG12C.
Therefore, claims 46 and 47 of this application are unpatentable over the claims of the patent in view of Vasta, Table S1, dos Santos, Westcott, and Xue.
Conclusion
Status of the claims:
Claims 44-52 are pending.
Claim 48 is withdrawn from consideration.
Claims 44-47 and 49-52 are rejected.
No claim is in condition for allowance.
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/David Steadman/Primary Examiner, Art Unit 1656
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