DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-7, 9, 12-14, 17-18, 24-26, 37-42 and 45-54 are pending. Claims 13-14, 40-42 and 45 are withdrawn. Claims 1-7, 9, 12, 17-18, 24-26, 37-39 and 46-54 are rejected.
Election/Restrictions
Applicant's election of the elected species of non-small cell lung cancer and pembrolizumab without traverse in the reply filed on July 21, 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)).
Claims 1-7, 9, 12, 17-18, 24-26, 37-39 and 46-54 read on Applicant’s species election of non-small cell lung cancer and pembrolizumab. Examination of the elected invention was conducted in accordance with the MPEP 803.02.
The elected species is not allowable in view of the prior art; therefore, examination of the Markush-type claim has not been extended.
Since art was found on the elected species, subject matter not embraced by the elected embodiment is therefore withdrawn from further consideration. Claims 13-14, 40-42 and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be amended in compliance with 37 CFR 1.48(b) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. Any amendment of inventorship must be accompanied by a request under 37 CFR 1.48(b) and by the fee required under 37 CFR 1.17(i).
Priority
This application claims benefit to PRO 63/496,447 filed 04/17/2023, PRO 63/486,785 filed 02/24/2023, and PRO 63/357,227 filed 06/30/2022.
Information Disclosure Statement
The information disclosure statement(s) (IDS) dated 06/29/2023, 11/14/2023, and 08/15/2025 have been considered.
Claim Objections
Claims 38 and 47 are objected to because of the following informalities:
Claim 38 is objected to for being written in improper Markush format. The claim should be amended such that the phrase “or pharmaceutically acceptable salts thereof” in the last line of the claim is changed to “or a pharmaceutically acceptable salt thereof”.
Claim 47 should be amended to state “wherein the compound of Formula I is administered” so as not to be confused with pembrolizumab.
Appropriate correction is required.
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.
Claims 1, 3-7, 9, 12, 17-18, 24-26, 37-39, 46-48, 51-54 are rejected under 35 U.S.C. 112(b) being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The term “about” in claims 1, 3-7, 18, 25-26, 37, 46-48, 51 and 53 is a relative term which renders the claims indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Page 60, lines 13-28 adequately defines “dose” with several examples of possible doses, but does not adequately describe what range might be considered “about” any given dose amount. Therefore, the metes and bounds of the claims are unclear.
Dependent claims 9, 12, 17, 24, 38-39, 52 and 54 are rejected as indefinite for the same reason since they do not correct the indefiniteness issue of their parent claims.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 18 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Per claim 1, a dose is at least about 50 mg of a compound of Formula I. Per claim 17, the dose is in a capsule. Accordingly, the capsule of claim 17 would need to have at minimum about 50 mg of a compound of Formula I. Since claim 18 recites the limitation wherein the capsule contains about 25 mg, the claim does not properly limit its parent claims. Applicant may amend the claim, for example, by deleting the limitation “about 25 mg”.
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.
(1 of 3) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Boulet et al. teach the compound Example 35,
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, see top of Table 22, page 142. The reference indicates that Example 35 and its analogs exist as atropisomers and in the case of Example 35, the diastereomeric atropisomers of its precursor Preparation 168 may be separated via column chromatography. See top of page 115 which states “The desired diastereomer is eluted after the undesired one to give the title compound” and top of Table 18 on the same page which discloses Preparation 168.
Boulet et al. disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Ascertaining the differences between the prior art and the claims at issue. (See MPEP § 2141.02)
The difference between the teaching of Boulet et al. in ‘877 and the instant claims is in the dosage amount and/or number of administration(s) in a day. The reference teaches either administering 1) 12.5, 25, 50 or 100 mg/kg once daily or 2) 30 mg/kg twice daily. The instant claims are drawn to a twice daily administration of between 50 mg and 200 mg. However, it would have been obvious to a person having ordinary skill in the art to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily. See page 22, lines 16-21.
Considering objective evidence present in the application indicating obviousness or nonobviousness. (See MPEP § 2142-2144)
Although the reference does not teach a single example using the precise dose amounts and number of administration(s) as the instant claims, it would have been obvious to a person having ordinary skill in the art to combine the two teachings from Boulet et al. In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious.
(2 of 3) Claims 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 9. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 11.
Ascertaining the differences between the prior art and the claims at issue. (See MPEP § 2141.02)
Boulet et al. do not teach a method involving monitoring dose limiting toxicity (DLT) or adjusting a second dose amount based on DLT, as recited in instant claims 24-26.
Considering objective evidence present in the application indicating obviousness or nonobviousness. (See MPEP § 2142-2144)
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious.
(3 of 3) Claims 48 and 51-54 are rejected under 35 U.S.C. 103 as being unpatentable over Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Ascertaining the differences between the prior art and the claims at issue. (See MPEP § 2141.02)
Boulet et al. do not teach a method wherein the compound of Formula I is administered in combination with a specific dosage for pembrolizumab, as recited in instant claim 48.
Boulet et al. do not teach a method wherein the compound of Formula I is administered with pembrolizumab, pemetrexed and cisplatin, as recited in claims 51 and 52, nor do they teach a similar method with carboplatin in place of cisplatin, as recited in claims 53 and 54.
Considering objective evidence present in the application indicating obviousness or nonobviousness. (See MPEP § 2142-2144)
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(1 of 18) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,731,984 in view of Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘984 patent is directed to the compound of the instant claims and methods of use thereof.
Claims 1-16 of the ‘984 patent disclose the compound
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, see claim 16 for instance, which is identical to the compound of the instant claims. With respect to the fact that claims 1-16 of the ‘984 patent are drawn to compounds while the instant claims are drawn to methods of treating a KRAS G12C mutant cancer, Applicant is directed to Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. 95 USPQ2d 1797, Geneva Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373 [68 USPQ2d 1865] (Fed. Cir. 2003), and Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353 [86 USPQ2d 1001] (Fed. Cir. 2008) for analogous situations. The patent discloses the instantly claimed utilities in, for instance method claims 17-23 and column 12, lines 16-40.
Since claims 17-18 of patent ‘984 teaches methods for treating a patient for cancer and specifically a non-small cell lung cancer, a person having ordinary skill in the art would be motivated to optimize the method with specific dosage ranges, modes of administration, etc. and in doing so would use the teachings of Boulet et al. as described in the rejection under USC 103 above.
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious over the patented claims.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, claim 23 of patent ‘984 discloses that the patient is also administered a PD-1 inhibitor. Moreover, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious over the patented claims.
(2 of 18) Claims 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,731,984 in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘984 patent is directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of patent ‘984 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 9. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 11.
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious over the patented claims.
(3 of 12) Claims 48 and 51-54 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,731,984 in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘984 patent is directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of patent ‘984 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious in view of the patented claims.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are obvious in view of the patented claims.
(4 of 18) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 18-21 and 24-36 of copending Application No. 18/853,699 (reference application) in view of Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘699 reference is directed to the compound of the instant claims and methods of use thereof.
Claim 5 of the ‘699 reference application discloses the compound
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, which is identical to the compound of the instant claims. With respect to the fact that claims 5 and 33-36 of the ‘699 reference are drawn to compounds while the instant claims are drawn to methods of treating a KRAS G12C mutant cancer, Applicant is directed to Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. 95 USPQ2d 1797, Geneva Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373 [68 USPQ2d 1865] (Fed. Cir. 2003), and Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353 [86 USPQ2d 1001] (Fed. Cir. 2008) for analogous situations. The copending application discloses the instantly claimed utilities in, for instance method claims 18-21 and 24-32 and at least on page 20, lines 8-19 of the specification.
Since claims 18-21 of reference ‘699 teaches methods for treating a patient for cancer and specifically a non-small cell lung cancer, a person having ordinary skill in the art would be motivated to optimize the method with specific dosage ranges, modes of administration, etc. and in doing so would use the teachings of Boulet et al. as described in the rejection under USC 103 above.
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious over the reference claims.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(5 of 18) Claims 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 18-21 and 24-36 of copending Application No. 18/853,699 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘699 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘699 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 9. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 11.
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious over the reference claims.
(6 of 18) Claims 48 and 51-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5, 18-21 and 24-36 of copending Application No. 18/853,699 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘699 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of patent ‘984 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious in view of the reference claims.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are obvious in view of the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(7 of 18) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-10, 12-14, 16-26, 34-35 and 40-54 of copending Application No. 18/854,022 (reference application) in view of Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘022 reference is directed to the compound of the instant claims and methods of use thereof.
Claim 35 of the ‘022 reference application discloses a method of treating a patient for cancer wherein one or more cells express KRas G12C mutant protein using the compound
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, which is identical to the compound of the instant claims.
Since claims 1, 5-7, 9-10, 12-14, 16-26, 34-35 and 40-54 of reference ‘022 teach a method for treating a patient for cancer that has a KRas G12C mutant protein using the cited compound, a person having ordinary skill in the art would be motivated to optimize the method with specific dosage ranges, modes of administration, etc. and in doing so would use the teachings of Boulet et al. as described in the rejection under USC 103 above.
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious over the reference claims.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(8 of 18) Claims 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-10, 12-14, 16-26, 34-35 and 40-54 of copending Application No. 18/854,022 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘022 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘022 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 9. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 11.
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious over the reference claims.
(9 of 18) Claims 48 and 51-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-10, 12-14, 16-26, 34-35 and 40-54 of copending Application No. 18/854,022 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘022 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘022 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious in view of the reference claims.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are obvious in view of the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(10 of 18) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-19, 39-40 and 49 of copending Application No. 19/526,716 (reference application) in view of Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘716 reference is directed to the compound of the instant claims and methods of use thereof.
Claim 16 of the ‘716 reference application discloses the compound
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, which is identical to the compound of the instant claims. With respect to the fact that claims 16-17 and 19 of the ‘716 reference are drawn to compounds or compositions while the instant claims are drawn to methods of treating a KRAS G12C mutant cancer, Applicant is directed to Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. 95 USPQ2d 1797, Geneva Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373 [68 USPQ2d 1865] (Fed. Cir. 2003), and Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353 [86 USPQ2d 1001] (Fed. Cir. 2008) for analogous situations. The copending application discloses the instantly claimed utilities in, for instance method claims 18, 39-40 and 49 and at least page 5 line 12 through page 6 line 30 of the specification.
Since claims 18, 39-40 and 49 of reference ‘716 teaches methods for treating a patient for cancer, a person having ordinary skill in the art would be motivated to optimize the method with specific dosage ranges, modes of administration, etc. and in doing so would use the teachings of Boulet et al. as described in the rejection under USC 103 above.
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious over the reference claims.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(11 of 18) Claims 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-19, 39-40 and 49 of copending Application No. 19/526,716 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘716 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘716 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 2. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 4.
The clinical trial also recites in the Inclusion Criteria section the following: “For untreated patients in the arm with LY3537982 in combination with pembrolizumab noted above, a single cycle of pembrolizumab may be initiated within 21 days prior to enrollment. For untreated patients in the arm of LY3537982 in combination with pembrolizumab, pemetrexed, and platinum therapy, a single cycle of any or all of the drugs other than LY3537982 may be initiated within 21 days prior to enrollment.” See bottom of page 7. The study also specifies cisplatin and carboplatin as investigational agents in the “Arms and Interventions” Table on page 4.
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious over the reference claims.
(12 of 18) Claims 48 and 51-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-19, 39-40 and 49 of copending Application No. 19/526,716 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘716 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘716 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious in view of the reference claims.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are obvious in view of the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(13 of 18) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-39 of copending Application No. 19/542,276 (reference application) in view of Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘276 reference is directed to the compound of the instant claims and methods of use thereof.
Claim 24 of the ‘276 reference application discloses the compound
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, which is identical to the compound of the instant claims. With respect to the fact that claims 24-29 of the ‘276 reference are drawn to compounds or compositions while the instant claims are drawn to methods of treating a KRAS G12C mutant cancer, Applicant is directed to Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co. 95 USPQ2d 1797, Geneva Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, 349 F.3d 1373 [68 USPQ2d 1865] (Fed. Cir. 2003), and Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353 [86 USPQ2d 1001] (Fed. Cir. 2008) for analogous situations. The copending application discloses the instantly claimed utilities in, for instance method claims 30-39 and at least page 15 line 24 through page 16 line 9 of the specification.
Since claims 30-39 of reference ‘276 teaches methods for treating a patient for cancer and specifically non-small cell lung cancer in claim 31, a person having ordinary skill in the art would be motivated to optimize the method with specific dosage ranges, modes of administration, etc. and in doing so would use the teachings of Boulet et al. as described in the rejection under USC 103 above.
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious over the reference claims.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(14 of 18) Claims 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-39 of copending Application No. 19/542,276 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘276 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘276 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 9. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 11.
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious over the reference claims.
(15 of 18) Claims 48 and 51-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-39 of copending Application No. 19/542,276 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘276 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘276 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious in view of the reference claims.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are obvious in view of the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(16 of 18) Claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-10, 12-14, 16-19 and 20-37 of copending Application No. 18/842,544 (reference application) in view of Boulet et al. in WO 2021/118877 A1, as cited in the IDS dated 06/29/2023. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘022 reference is directed to the compound of the instant claims and methods of use thereof.
Claim 22 of the ‘544 reference application discloses a method of treating a patient for cancer using the compound
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, which is identical to the compound of the instant claims.
Since claims 1, 5-7, 9-10, 12-14, 16-19 and 20-37 of reference ‘022 teach a method for treating a patient for cancer that has a KRas G12C mutant protein using the cited compound, and specifically for non-small cell lung cancer wherein KRas G12C mutant protein is expressed per reference claim 28, a person having ordinary skill in the art would be motivated to optimize the method with specific dosage ranges, modes of administration, etc. and in doing so would use the teachings of Boulet et al. as described in the rejection under USC 103 above.
Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
In particular, the skilled artisan would have been motivated to adjust the twice daily dosage amount given that Boulet et al. teach dose amounts ranging from 1 mg to 1000 mg and preferable dose amounts ranging from 100 to 900 mg once or twice daily and that a skilled artisan, such as an attending physician, would be able to determine the effective amount for the dose. See page 22, lines 16-21. Accordingly, a skilled artisan would have had a reasonable expectation of success by administering 30 mg of the drug twice daily and adjusting the dosage to, for instance, 50 mg or 100 mg or even up to 900 mg given the preferred embodiment taught by Boulet et al. Per MPEP 2144.05, “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”. In the instant case, the claimed range of 50 to 200 mg lies entirely inside the prior art range of 1 to 1000 mg and overlaps with the preferred range of 100 mg to 900 mg. Thus, claims 1-7, 9, 12 and 49-50 are obvious.
Regarding instant claims 17-18, drawn to the method of claim 1 wherein the dose is in a capsule and the capsule contains 25 or 50 mg, Boulet et al. teach a capsule for oral administration. See page 22, line 28 - page 23, line 2. Thus, claims 17 and 18 are obvious over the reference claims.
Regarding instant claims 37-39 and 46-47 drawn to a method of administering the compound of Formula (I) in simultaneous, separate or sequential combination with pembrolizumab as a second therapeutic agent, Boulet et al. teach a preferred embodiment wherein a PD-1 or PD-L1 inhibitor is used in combination with the instantly claimed compound and said PD-1 or PD-L1 inhibitor is pembrolizumab on page 17, lines 14-22. Thus, claims 37-39 and 46-47 are obvious over the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(17 of 18) Claims 24-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-10, 12-14, 16-19 and 20-37 of copending Application No. 18/842,544 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above, and further in view of National Library of Medicine, “Study of LY3537982 in Cancer Patients with a Specific Genetic Mutation (KRAS-G12C),” NCT 04956640, version 9, posted 03/18/2022. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘544 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘544 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
The clinical trial NCT 04956640 describes a study wherein LY3537982, the same compound of the instant claims and Boulet’s Example 35, is administered to cancer patients with KRAS-G12C-mutant solid tumors in two different study phases. See Detailed Description on page 9. In the phase 1A dose escalation portion of the study, the recited outcome measure to “determine the recommended phase 2 dose (RP2D) of LY 3537982 monotherapy” is “measured by the number of patients with dose limiting toxicities (DLTs)”. See Primary Outcome Measures section on page 11.
Regarding claims 24-26 drawn to a method of claim 1 comprising monitoring a patient for a dose limiting toxicity and administering a reduced second dose of the compound of Formula I, a person having ordinary skill in the art would have been motivated to optimize the method taught by Boulet et al. In particular, the method “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” disclosed on pages 162-163 served the purpose of evaluating efficacy and signs of toxicity, per page 162, line 16. Since no significant animal body weight loss was observed in this model at 30 mg/kg, the skilled artisan would be motivated to optimize the method to achieve improved efficacy without increasing toxicity. The artisan would therefore identify the clinical trial NCT 04956640 which discloses measuring a patient’s DLT to determine a patient’s dose in the next phase. Thus, claims 24-26 are obvious over the reference claims.
(18 of 18) Claims 48 and 51-54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5-7, 9-10, 12-14, 16-19 and 20-37 of copending Application No. 18/842,544 (reference application) in view of Boulet et al. in WO 2021/118877 A1 as applied to claims 1-7, 9, 12, 17-18, 37-39, 46-47 and 49-50 above and further in view of Reck et al. in “Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer” N. Eng. J Med. (2016); 375: 1823-33 and the appended supplemental protocol. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘544 reference claims are directed to the compound of the instant claims and methods of use thereof.
As discussed above, the claims of reference application ‘544 disclose the identical compound as the instant claims, including methods of use for treating a patient for a KRAS G12C mutant cancer such as non-small cell lung cancer. Boulet et al. teach the compound Example 35, see top of Table 22, page 142, and disclose several in vitro and in vivo biological assays utilizing Example 35, such as the “Dose Dependent In Vivo Target Inhibition And Pharmacodynamic Effects in Lung Cancer H388 Xenograft Model” described on page 159 wherein Example 35 is administered in a single dose to H358 xenograft mouse models in a single dose of 12.5 to 100 mg/kg. Boulet additionally teaches, for example, an assay titled “Anti-tumor Growth Activity in Lung Cancer H358 Xenograft Mouse Model” wherein Example 35 is orally administered twice daily to H358 xenograft mouse models at a dose of 30 mg/kg. See pages 162-163, including Table 29.
Reck et al. teach a study wherein outcomes for patients with NSCLC receiving pembrolizumab at a dose of 200 mg once every three weeks are compared with those receiving chemotherapy such as pemetrexed and cisplatin or pemetrexed and carboplatin. See abstract and page 1824, right column, second paragraph.
Regarding claim 48, drawn to a method of claim 46 wherein pembrolizumab is administered at a dose of about 200 mg once every three weeks, a person having ordinary skill in the art would have been motivated to identify a dosage amount/regimen when administering pembrolizumab with Example 35 in the method taught by Boulet et al. Said artisan would have relied on the teaching from Reck et al. that disclosed an administration of 200 mg of pembrolizumab every three weeks. See page 1824, right column, second paragraph. Thus, the claim is obvious in view of the reference claims.
Regarding instant claims 51-54, drawn to a method of treating KRAS G12C mutant NSCLC comprising administering the compound of Formula I, pembrolizumab, pemetrexed, and cisplatin (per claims 51 and 52) or carboplatin (per claims 53 and 54), Reck et al. disclose treatment methods wherein patients received chemotherapy, specifically either carboplatin plus pemetrexed or cisplatin plus pemetrexed. See page 1824, right column, second paragraph. Additionally, Reck et al. disclose methods wherein patients in one of the chemotherapy groups “crossed over” to the pembrolizumab treatment group. See supplemental protocol page 71-72. Therefore, it would have been obvious to a person having ordinary skill in the art to administer Example 35 and pembrolizumab as taught by Boulet et al. to a patient that had received pemetrexed and cisplatin or carboplatin for the treatment of KRAS G12C NSCLC. Since the instant claims are directed to separate or sequential combination therapy, claims 51-54 are obvious in view of the reference claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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/J.H.F./Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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