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 .
Information Disclosure Statement
The information disclosure statement filed May 27, 2025 is acknowledged and has been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
In [156], there appears to be a formatting error in the example polymethacrylate name “EUDRAGIT(r).”
Appropriate correction is required.
The use of the terms ZELBORAF, TAFINLAR, BRAFTOVI, and AVICEL, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term 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.
The abstract of the disclosure is objected to because it is too short (41 words). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 8 objected to because of the following informality: there should be an article (such as “a” or “the”) in between “wherein” and “KRAS” in the first line of the claim. The examiner notes that as claim 8 depends upon claim 7, which recites “a KRAS mutant,” there would be no antecedent basis if inserting the article “the” into claim 8 at this position. Appropriate correction is required.
Claim Interpretation
Claims 1-17 and 39 are interpreted to be drawn to a tangible product. These claims can be described as fitting either the article of manufacture or composition of matter statutory categories of 35 U.S.C. 101. While the preamble phrase “pharmaceutical combination” could potentially be interpreted to either be a tangible product or a method, in view of the disclosure as a whole and the claim limitations, the examiner interprets the scope of these claims as belonging in the categories of article of manufacture or composition of matter. Such support includes the limitations of claim 1 being drawn to the identity and amount of a composition of matter. As these are structural limitations, this supports this interpretation of the claim. Additionally, independent claim 18 is drawn to a method and is clearly requires and is limited by actions to be performed. In contrast, independent claim 1 does not require any procedural actions be performed. Therefore, claims 1 and 2-27 and 39 (which depend upon claim 1) are interpreted to be claims drawn to a tangible product. See MPEP § 2106.03(I).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 13-14 and 16-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 13 recites the broad recitation "about 200 mg to about 2000 mg,” and the claim also recites “about 400 mg to about 1000 mg” and “about 500 mg to about 700 mg” which are narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For the purpose of examination, the examiner will interpret the scope of this limitation to be that of the broadest range (about 200 mg to about 2000 mg). Additionally, as claim 14 depends upon claim 13, it is also rejected due to said dependence.
Claim 13 recites the limitation "the dosage amount" in the first line. There is insufficient antecedent basis for this limitation in the claim. No claim from which claim 13 depends (directly or indirectly) recites or describes a “dosage amount” or even a “dose.” Additionally, as claim 14 depends upon claim 13, it is also rejected due to said dependence.
Claim 14 recites the limitation "the dos" in the first line. There is insufficient antecedent basis for this limitation in the claim. No claim from which claim 14 depends (directly or indirectly) recites or describes a “dose.”
Regarding claims 13-14 and 16-17, as described above, the pharmaceutical combination of claim 1 (upon which these claims depend) is interpreted to be drawn to a tangible product such as an article of manufacture or a composition of matter (see Claim Interpretation). However, claims 13-14 and 16-17 are interpreted by the examiner to recite limitations drawn to modifying the action of administering pharmaceutical combination of claim 1. Such limitations do not alter the structure of the tangible product itself. Per MPEP 2173.05(p)(II), a single claim which claims both a product and the method steps of using the product is indefinite. For the purpose of examination, the examiner will interpret the action limitations to not narrow the scope of the structure of the pharmaceutical combination product.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 15-18, and 39 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Hamdy (US 2017/0224819 A1).
Hamdy teaches therapeutic combinations (Abstract). More specifically, teaches pharmaceutical compositions comprising either a Bruton’s tyrosine kinase (BTK) inhibitor with a CDK4/6 inhibitor or a BTK inhibitor, a CDK4/6 inhibitor, and a PI3K inhibitor (pg. 2, [0014]-[0015]). Alternative embodiments further comprise anti-CD20 antibodies and/or JAK2 inhibitors (pg. 2-3, [0017]-[0025]). Hamdy teaches various BTK inhibitor structures including that of Formula (XVIII) (pg. 61, [0685]). Hamdy teaches that the BTK inhibitor of Formula (XVIII) covalently binds BTK (pg. 205, [2525], right column, lines 24-27). Hamdy teaches that the BTK inhibitor may be in a pharmaceutical composition with the PI3K inhibitor and at least one pharmaceutically acceptable excipient (pg. 149, [2224]).
Regarding claim 1, Hamdy teaches a pharmaceutical combination comprising the BTK inhibitor of Formula (XVIII) and gemcitabine (pg. 189, [2412]). Hamdy teaches that the compound of Formula (XVIII) covalently binds to Bruton’s tyrosine kinase (pg. 205, [2525]). Thus, the examiner interprets the compound of Formula XVIII to be a compound that forms a covalent bond with a kinase. The examiner also interprets gemcitabine to be at least one additional therapeutically active agent. Hamdy teaches that the Formula (XVIII) administered is therapeutically effective at shrinking tumor size both on its own and in combination with gemcitabine (Figure 116). The examiner interprets this to read on the “therapeutically effective amount” limitation of claim 1.
Regarding claim 15, Hamdy teaches administering the BTK inhibitor of Formula (XVIII) orally and the gemcitabine by IV administration (pg. 189, [2412]). The examiner interprets this to mean that the compound that forms a covalent bond with a kinase and the at least one additional therapeutically active agent are in separate dosage forms.
Regarding claim 16, Hamdy teaches administering the BTK inhibitor of Formula (XVIII) orally and the gemcitabine by IV administration (pg. 189, [2412]). The examiner interprets this to mean that the separate dosage forms were administered by different modes of administration.
Regarding claim 17, Hamdy teaches administering the BTK inhibitor of Formula (XVIII) BID orally together with gemcitabine given by IV every 4 days (pg. 189, [2412]). On the days that both Formula (XVIII) and gemcitabine are dosed, they must be dosed either at the same time or at different times. The examiner interprets this to read on simultaneous administration or sequential administration. It could also further include overlapping administration, interval administration, or a combination thereof. As claim 17 permits a combination of such administration methods, the examiner interprets the coadministration of Hamdy to read on this limitation.
Regarding claim 18, Hamdy teaches a method of treating a xenograft tumor in an animal model by administering the BTK inhibitor of Formula (XVIII) and gemcitabine by IV administration (pg. 189, [2412]). Hamdy teaches that the compound of Formula (XVIII) covalently binds to Bruton’s tyrosine kinase (pg. 205, [2525]). Thus, the examiner interprets the compound of Formula XVIII to be a compound that forms a covalent bond with a kinase. The examiner also interprets gemcitabine to be at least one additional therapeutically active agent. Hamdy teaches that the Formula (XVIII) administered is therapeutically effective at shrinking tumor size both on its own and in combination with gemcitabine (Figure 116). The examiner interprets this to read on the “therapeutically effective amount” limitation of claim 18. Hamdy also teaches that the compound of Formula (XVIII) is given orally BID and gemcitabine is given by IV every 4 days for a total of 3 doses (pg. 189, [2412]). The examiner interprets this to mean that if administration starts on day 0; on day 3, Formula (XVIII) is administered; on day 4, both Formula (XVIII) and gemcitabine are administered; and on day 5, Formula (XVIII) is administered. In this sequence of events the gemcitabine is understood to be administered both before and after the compound that forms a covalent bond with a kinase (and could possibly be dosed at the same time on day 4).
Regarding claim 39, Hamdy teaches that the BTK inhibitor may be provided in a pharmaceutical composition comprising the BTK inhibitor, a PI3K inhibitor, and a pharmaceutically acceptable excipient (pg. 149, 2224]). Hamdy teaches that the compound of Formula (XVIII) is a BTK inhibitor that covalently binds to Bruton’s tyrosine kinase (pg. 205, [2525]). Thus, the examiner interprets the compound of Formula XVIII to be a compound that forms a covalent bond with a kinase. The examiner also interprets the PI3K inhibitor in this embodiment to be at least one additional therapeutically active agent. Therefore, this is a pharmaceutical combination that reads on claim 1 provided as a pharmaceutical formulation.
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 6-14 are rejected under 35 U.S.C. 103 as being unpatentable over Niu (US 2011/023476 A1 – provided by applicant in IDS filed May 27, 2025) in view of Johnson (Johnson, M. L.; et al., Eur. J. Cancer, 2020) and Misale (Misale, S.; et al., Clin. Cancer Res., 2019).
Niu teaches irreversible inhibitors of PI3 Kinases (pg. 2, [0026]). Niu teaches that such irreversible inhibitors covalently bond to PI3K (pg. 7, [0054]). Niu teaches several structures of such compounds (Tables 5-17, pg. 109-196). Niu teaches that these inhibitors may be provided as a pharmaceutical composition comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle (pg. 203, [0662]). Niu teaches that such compounds may be used for treating proliferative disorders (pg. 211, [0724]). Niu teaches that the covalent PI3K inhibitors may be used in combination with other antiproliferative compounds, including inhibitors of oncogenic Ras isoforms (pg. 217, [0760]). Niu teaches that the oncogenic Ras isoforms includes K-Ras (pg. 218, [0777]). Niu teaches that the PI3K inhibitor compounds may be mixed with other drug substances in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with, or after the other drug substances (pg. 219, [0793]; and pg. 220, [0799]-[0800]).
Niu does not teach a pharmaceutical combination comprising a therapeutically effective amount of a compound that forms a covalent bond with a kinase or pseudokinase and at least one additional therapeutically active agent wherein the additional agent is a KRAS inhibitor.
Johnson teaches adagrasib (MRTX849) (slide 3). Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that adagrasib may be dosed at doses of 150-1200 mg once or twice a day (slide 4). Johnson teaches that adagrasib may be used in combination with other therapeutic agents to treat cancer (slide 4). Johnson teaches that adagrasib can effectively be used to treat cancer (slide 7).
Misale teaches the use of a KRAS G12C inhibitor ARS1620 (pg. 796, Abstract). Misale also teaches screening drugs able to sensitize cell lines to ARS1620 (pg. 798, left column, paragraph 3). Misale teaches that three PI3K inhibitors provided synergy in combination with ARS1620 in the screening method (pg. 801, Figure 3; and pg. 803, left column, paragraph 2). Misale teaches that a combination of ARS1620 and GDC0941 (a PI3K inhibitor) is more effective at blocking tumor growth than either therapeutic as a single agent (pg. 804, Figure 5; and pg. 805, Figure 6). Misale teaches that the data suggests that combining KRAS G12C and PI3K inhibition may be a broadly effective strategy to increase the efficacy of KRAS G12C inhibitors (pg. 805, right column, first paragraph).
A person of ordinary skill in the art would have recognized that each of Niu, Johnson, and Misale teach anti-cancer pharmaceutical agents. Furthermore, it would be recognized that each teach that the pharmaceutical agents disclosed may be used in combination with other therapeutically active agents. It would be recognized that Niu teaches PI3K inhibitors and Johnson teaches a KRAS G12C inhibitor. It would be further recognized that Misale teaches synergy between a PI3K inhibitor and a KRAS G12C inhibitor.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the irreversible PI3K inhibitor of Niu by providing it in combination with the KRAS G12C inhibitor adagrasib of Johnson because Misale teaches that combining a PI3K inhibitor and a KRAS G12C inhibitor can result in a more effective combination than either agent alone (MPEP § 2143(I)(C) and 2143(I)(G)) and because combining two therapeutically active agents useful for the same purpose (treating cancer) is prima facie obvious (MPEP § 2144.06(I)). The resulting combination would have predictably resulted in a pharmaceutical combination of a covalent inhibitor of PI3K and a KRAS G12C inhibitor.
A person of ordinary skill in the art would have had a reasonable expectation of success because both Niu and Johnson teach that the PI3K inhibitor and KRAS G12C inhibitor, respectively, can be used in combination with other therapeutic agents. Additionally, Misale demonstrates that such a combination of inhibitors of these proteins is feasible and tolerated. Furthermore, Niu specifically teaches that the PI3K inhibitors may be combined with inhibitors of KRAS (pg. 217, [0760]; and pg. 218, [0777]).
The skilled artisan would have been motivated to make this modification because combining two agents known to be useful for the same purpose can alone serve as a motivation to combine (MPEP § 2144.06(I)). Additionally, Misale teaches that a combination of a PI3K inhibitor with a KRAS G12C inhibitor is more effective than the single agents alone and that the combination displays synergy.
Regarding claim 1, Niu teaches irreversible inhibitors of PI3 Kinases (pg. 2, [0026]). Niu teaches that such irreversible inhibitors covalently bond to PI3K (pg. 7, [0054]). Niu teaches several structures of such compounds (Tables 5-17, pg. 109-196). Niu teaches that the covalent PI3K inhibitors may be used in combination with other antiproliferative compounds, including inhibitors of oncogenic Ras isoforms (pg. 217, [0760]). Niu teaches that the oncogenic Ras isoforms includes K-Ras (pg. 218, [0777]). Niu teaches that the PI3K inhibitor compounds may be mixed with other drug substances in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with, or after the other drug substances (pg. 219, [0793]; and pg. 220, [0799]-[0800]). Additionally, Johnson teaches adagrasib, a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that adagrasib may be used in combination with other drugs (slide 4). Furthermore, Misale teaches combining a PI3K inhibitor and a KRAS G12C inhibitor to treat cancer and that the combination is more effective than either monotherapy (Figures 5 and 6). For the reasons set forth above, it would have been prima facie obvious to combine the PI3K inhibitors of Niu with the adagrasib of Johnson. As Niu teaches that the irreversible inhibitors covalently bond to PI3 Kinase (pg. 7, [0054]), the examiner interprets these compounds to be compounds that form a covalent bond with a kinase or pseudokinase. Additionally, as Johnson teaches adagrasib can treat cancer, the examiner interprets this to be an additional therapeutically active agent. Furthermore, Niu teaches that the amount of PI3K inhibitor in the pharmaceutical compositions is an amount such that it is effective to measurably inhibit a PI3 Kinase, which the examiner interprets to be therapeutically effective. Additionally, Misale teaches including both a PI3K inhibitor and a KRAS G12C inhibitor in a combination using amounts that are therapeutically effective as monotherapies (Figures 5 and 6). Therefore, the combined teachings of Niu, Johnson, and Misale render claim 1 obvious.
Regarding claim 2, Niu teaches that the disclosed compounds are irreversible inhibitors of PI3 Kinases (pg. 2, [0026]). Niu teaches that such irreversible inhibitors covalently bond to PI3K (pg. 7, [0054]). Therefore, the combined teachings of Niu, Johnson, and Misale render claim 2 obvious.
Regarding claim 6, Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Thus, in this pharmaceutical combination, the additional therapeutically active agent is a KRAS inhibitor. Therefore, the combined teachings of Niu, Johnson, and Misale render claim 6 obvious.
Regarding claim 7, Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that this is a KRAS mutant (slide 3). Therefore, the combined teachings of Niu, Johnson, and Misale render claim 7 obvious.
Regarding claims 8 and 9, Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Therefore, the combined teachings of Niu, Johnson, and Misale render claims 8 and 9 obvious.
Regarding claims 10-12, Johnson teaches the KRAS inhibitor adagrasib (slide 3). Therefore, the combined teachings of Niu, Johnson, and Misale render claims 10-12 obvious.
Regarding claim 13, Johnson teaches that adagrasib can be dosed at 150, 300, 600, or 1200 mg dosage amounts (slide 4). The 300, 600, and 1200 mg dosage amounts are within the claimed range and thus render it obvious (MPEP § 2144.05(I)). Therefore, the combined teachings of Niu, Johnson, and Misale render claim 13 obvious.
Regarding claim 14, Johnson teaches that adagrasib can be dosed once or twice daily (slide 4). Therefore, the combined teachings of Niu, Johnson, and Misale render claim 14 obvious.
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 1-18 and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-45 of copending Application No. 19/122,219 in view of Johnson and Misale.
The conflicting claims of copending Application No. 19/122,219 (the copending ‘219 application) are drawn to methods of treating cancer. Conflicting claims 19-45 are drawn to methods of treating cancer using a compound that forms a covalent bond with a kinase or pseudokinase wherein the kinase is PI3-Kinase. Conflicting claim 22 is drawn to a method wherein the compound that forms a covalent bond with PI3K is Compound 1.
The conflicting claims of copending Application No. 19/122,219 do not teach a pharmaceutical combination comprising a therapeutically effective amount of a compound that forms a covalent bond with a kinase or pseudokinase and at least one additional therapeutically active agent.
As described above, Johnson teaches adagrasib (MRTX849) (slide 3). Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that adagrasib may be dosed at doses of 150-1200 mg once or twice a day (slide 4). Johnson teaches that adagrasib may be used in combination with other therapeutic agents to treat cancer (slide 4). Johnson teaches that adagrasib can effectively be used to treat cancer (slide 7).
As described above, Misale teaches the use of a KRAS G12C inhibitor ARS1620 (pg. 796, Abstract). Misale also teaches screening drugs able to sensitize cell lines to ARS1620 (pg. 798, left column, paragraph 3). Misale teaches that three PI3K inhibitors provided synergy in combination with ARS1620 in the screening method (pg. 801, Figure 3; and pg. 803, left column, paragraph 2). Misale teaches that a combination of ARS1620 and GDC0941 (a PI3K inhibitor) is more effective at blocking tumor growth than either therapeutic as a single agent (pg. 804, Figure 5; and pg. 805, Figure 6). Misale teaches that the data suggests that combining KRAS G12C and PI3K inhibition may be a broadly effective strategy to increase the efficacy of KRAS G12C inhibitors (pg. 805, right column, first paragraph).
A person of ordinary skill in the art would have recognized that each of Johnson, Misale, and the conflicting claims of the ‘219 application teach methods of treating cancer using anti-cancer pharmaceutical agents. Furthermore, it would be recognized that Johnson and Misale teach that the pharmaceutical agents disclosed may be used in combination with other therapeutically active agents. It would be recognized that the ‘219 application is drawn to uses of compounds that covalently bind PI3K and Johnson teaches a KRAS G12C inhibitor. It would be further recognized that Misale teaches synergy between a PI3K inhibitor and a KRAS G12C inhibitor.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the use of the irreversible PI3K inhibitor of copending Application No. 19/122,219 by combining it with the KRAS G12C inhibitor adagrasib of Johnson because Misale teaches that combining a PI3K inhibitor and a KRAS G12C inhibitor can result in a more effective combination than either agent alone (MPEP § 2143(I)(C) and 2143(I)(G)) and because combining two therapeutically active agents useful for the same purpose (treating cancer) is prima facie obvious (MPEP § 2144.06(I)). The resulting combination would have predictably resulted in a pharmaceutical combination of a covalent inhibitor of PI3K and a KRAS G12C inhibitor.
A person of ordinary skill in the art would have had a reasonable expectation of success because Johnson teaches that the KRAS G12C inhibitor can be used in combination with other therapeutic agents. Additionally, Misale demonstrates that such a combination of inhibitors of these proteins (PI3K and KRAS G12C) is feasible and tolerated.
The skilled artisan would have been motivated to make this modification because combining two agents known to be useful for the same purpose can alone serve as a motivation to combine (MPEP § 2144.06(I)). Additionally, Misale teaches that a combination of a PI3K inhibitor with a KRAS G12C inhibitor is more effective than the single agents alone and that the combination displays synergy.
Regarding instant claim 1, conflicting claim 19 of the copending ‘219 application is drawn to a method of using a compound that forms a covalent bond with PI3K. Additionally, Johnson teaches adagrasib, a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that adagrasib may be used in combination with other drugs (slide 4). Furthermore, Misale teaches combining a PI3K inhibitor and a KRAS G12C inhibitor to treat cancer and that the combination is more effective than either monotherapy (Figures 5 and 6). For the reasons set forth above, it would have been prima facie obvious to combine the covalent PI3K inhibitor of the copending ‘219 application with the adagrasib of Johnson. As Johnson teaches adagrasib can treat cancer, the examiner interprets this to be an additional therapeutically active agent. Additionally, Misale teaches including both a PI3K inhibitor and a KRAS G12C inhibitor in a combination using amounts that are therapeutically effective as monotherapies (Figures 5 and 6). Therefore, the examiner interprets this combination therapy to utilize a pharmaceutical combination that reads on instant claim 1.
Regarding instant claim 2, conflicting claim 19 of the copending ‘219 application is drawn to the use of a compound that covalently bonds with PI3K.
Regarding instant claim 3, conflicting claim 20 of the copending ‘219 application is drawn to the use of a compound having the same (FCB)a-(L)b-(CLM)c structure.
Regarding instant claim 4, conflicting claim 21 of the copending ‘219 application is drawn to the use of a compound having the same FCB structure.
Regarding instant claim 5, conflicting claim 22 of the copending ‘219 application is drawn to the use of a compound wherein the compound is Compound 1.
Regarding instant claim 6, Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Thus, this treatment combination uses a pharmaceutical combination in which the additional therapeutically active agent is a KRAS inhibitor.
Regarding instant claim 7, Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that this is a KRAS mutant (slide 3).
Regarding instant claims 8 and 9, Johnson teaches that adagrasib is a covalent inhibitor of KRAS G12C (slide 3).
Regarding instant claims 10-12, Johnson teaches the KRAS inhibitor adagrasib (slide 3).
Regarding instant claim 13, Johnson teaches that adagrasib can be dosed at 150, 300, 600, or 1200 mg dosage amounts (slide 4). The 300, 600, and 1200 mg dosage amounts are within the claimed range.
Regarding instant claim 14, Johnson teaches that adagrasib can be dosed once or twice daily (slide 4).
Regarding instant claim 15, Misale teaches administering a KRAS G12C inhibitor and PI3K inhibitor in separate dosage forms (pg. 798, right column, paragraph 2).
Regarding instant claim 16, Misale teaches administering a KRAS G12C inhibitor and PI3K inhibitor by the same mode of administration (oral gavage) (pg. 798, right column, paragraph 2).
Regarding instant claim 17, Misale teaches administering a KRAS G12C inhibitor and PI3K inhibitor on the same days (pg. 798, right column, paragraph 2). The examiner interprets administration on the same day to require that the inhibitors were either dosed at the same time (which reads on simultaneous and overlapping administration) or at different times on the same day (which reads on sequential administration). As at least one of the administration means is read on by this teaching, it reads on the claim as a whole.
Regarding instant claim 18, conflicting claim 19 of the copending ‘219 application is drawn to a method of treating or ameliorating cell proliferation disorder in a subject using a compound that forms a covalent bond with PI3K. Additionally, Johnson teaches adagrasib, a covalent inhibitor of KRAS G12C (slide 3). Johnson teaches that adagrasib may be used in combination with other drugs (slide 4). Furthermore, Misale teaches combining a PI3K inhibitor and a KRAS G12C inhibitor to treat cancer and that the combination is more effective than either monotherapy (Figures 5 and 6). For the reasons set forth above, it would have been prima facie obvious to combine the covalent PI3K inhibitor of the copending ‘219 application with the adagrasib of Johnson. As Johnson teaches adagrasib can treat cancer, the examiner interprets this to be an additional therapeutically active agent. Additionally, Misale teaches including both a PI3K inhibitor and a KRAS G12C inhibitor in a combination using amounts that are therapeutically effective as monotherapies (Figures 5 and 6). Furthermore, Misale teaches administering a PI3K inhibitor and KRAS G12C inhibitor on the same day (pg. 798, right column, paragraph 2). The examiner interprets this to mean that the KRAS inhibitor was administered either before, during, or after the subject had been administered the PI3K inhibitor.
Regarding instant claim 22, conflicting claim 22 of the copending ‘219 application is drawn to the method wherein the compound that forms a covalent bond with PI3K is Compound 1.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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