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 .
DETAILED ACTION
Status of claims
The amendment filed on June 25, 2025 is acknowledged. Claims 3-7, 12-13, 17-18, 21, 24, 26-31, 34-38, 40-47, 50-76, and 78-81 have been canceled and claims 14-16, 19-20, 22-23, 49, 77, and 82-83 have been withdrawn. Claims 1-2, 8-11, 25, 32-33, 39, 48 and 84 are under examination in the instant office action.
Applicants' arguments, filed on June 25, 2025, have been fully considered but they are moot in view of new ground of rejections. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 of this title, 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.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-2, 8-11, 25, 32, 39, 48, and 84 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190275049 (hereafter, GOLDBERG) in view of US2015/0056193 (hereafter, Crosby) in further view of US 2014/0121126 (hereafter, Bivona, prior art of record) and US 2019/0134044 (hereafter, SHAILUBHAI).
GOLDBERG teaches a method of treating non-small cell lung cancer (NSCLC) by administering an EGFR T790M inhibitor in combination with a CDK inhibitor to a patient in need thereof wherein the non-small cell lung cancer is EGFR-mutant non-small cell lung cancer (abstract, [0032], and claims 1-2). GOLDBERG discloses that in embodiments of the method or use of the present invention, the EGFR-mutant non-small cell lung cancer includes a mutation selected from the group consisting of del 19 and L858R ([0044]).
GOLDBERG discloses that EGFR mutations include del 19, L858R, exon 18 insertions, exon 19 insertions, E709X, G719X, A763_Y764insFQEA, S768I, L861Q, exon 20 insertions, T790M, C797X, EGFR-KDD, EGFR-RAS51 and EGFR-PURB ([0135]).
GOLDBERG discloses that CDK inhibitors include pan-CDK inhibitors that target a broad spectrum of CDKs or selective CDK inhibitors that target specific CDK(s) and CDK inhibitors include abemaciclib, alvocidib, dinaciclib, palbociclib, ribociclib, roscovitine, AT7519, AZD5438, BMS-265246, BMS-387032, BS-181, JNJ-7706621, K03861, MK-8776, P276-00, PHA-793887, R547, RO-3306 and SU 9516 ([0114]). Examples of Pan-CDK inhibitors include alvocidib, dinaciclib, roscovitine, AT7519, AZD5438, BMS-387032, P276-00, PHA-793887, R547 and SU 9516; a non-limiting example of a CDK1 inhibitor is RO-3306; examples of CDK2 inhibitors include, K03861 and MK-8776; and examples of CDK1/2 inhibitors include BMS-265246 and JNJ-7706621 ([0114]). As to claim 84, GOLDBERG discloses dinaciclib as one of CDK inhibitors in use ([0114]). Dinaciclib is not CDK4 or CDK6 inhibitor as evidenced by the instant specification (see [0008]).
GOLDBERG discloses that the cancer is resistant to one or more tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and PF-06747775 (example 1 and [0204]).
GOLDBERG discloses that the EGFR inhibitors are tyrosine kinase inhibitors (TKI) a ([0108] and [0109]). In addition, GOLDBERG teaches that in an embodiment, EGFR-mutant NSCLC includes the EGFR double-mutant, del 19/T790M or L858R/T790M ([0135]).
Further, GOLDBERG specifically discloses the treatment of a CDK inhibitor such as palbociclib to HCC827 cell line (example 5 and Table 4).
While GOLDBERG teaches the use of CDK inhibitors for treating cancer such as NSCLC associated with an exon 19 deletion mutation, GOLDBERG does not specifically disclose an embodiment of administering the CDK inhibitor to a subject for treating a cancer having a specific subtype of the exon 19 deletion mutation such as E746-A750 deletion, L747-E749 deletion, and A750P. However, GOLDBERG disclosed that the most common activating mutations associated with good response to EGFR tyrosine kinase inhibitors (TKIs) are deletions within exon 19 (e.g., del E746-A750, del 19) ([0003]). Also, it was well known in the art that the exon 19 deletion includes del E746-A750, del L747-E749 and A750P as evidenced by Crosby ([0067]). Crosby further teaches that the most common EGFR mutations are deletions within exon 19 (e.g., a 15-bp nucleotide in-frame deletion in exon 19 (Del E746-A750) and a point mutation replacing leucine with arginine at codon 858 in exon 21 (L858R) and these two classes of EGFR mutants account for 85-90% of activating EGFR mutations ([0067]). This is further evidenced by the instant specification, which discloses the del 19 comprises an E746-A750 deletion, L747-E749 deletion, and A750P (see [0006]).
Bivona teaches that human NSCLCs with activating mutations in EGFR frequently respond to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib but responses are not durable as tumors acquire resistance ([0193]). Bivona further teaches that increased activation of AXL and evidence of epithelial-to-mesenchymal transition (EMT) are found in multiple in vitro and in vivo EGFR-mutant lung cancer models with erlotinib acquired resistance in the absence of EGFR T790M or MET activation ([00193]). Bivona discloses new in vivo and in vitro models of acquired resistance to the EGFR TKI erlotinib using EGFR exon 19 deletion mutant (delE746-A750) HCC827 human NSCLC cells, wherein erlotinib resistant subclone of HCC827 cells (HCC827 ER) are established from the parental HCC827 cells by the treatments of erlotinib and they express increased levels of AXL ([0194] and [0197]). Bivona also teaches that AXL overexpression is necessary for erlotinib resistance in H3255 EGFR-mutant NSCLC cells with acquired resistance to erlotinib and increased expression of the EMT marker vimentin was also noted in conjunction with AXL overexpression ([0028] and Fig. 23-24). In addition, Bivona teaches that AXL upregulation promotes erlotinib acquired resistance in the setting of EMT in EGFR-mutant NSCLC tumor models and that combined inhibition of AXL and EGFR overcomes acquired resistance to erlotinib in these models ([204]). Thus, one of ordinary skill in the art would have recognized that EGFR-mutant NSCLC with acquired resistance to TKI such as erlotinib would have EMT.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the CDK inhibitor for treating EGFR-mutant non-small cell lung cancer having E746-A750 deletion, L747-E749 deletion, or A750P with or without a second mutation such as L858R because of the following reasons. GOLDBERG already teach and suggest that a CDK inhibitor in combination with TKI is effective for treating EGFR-mutant NSCLC cells with L858R or exon 19 deletion. Also, one of ordinary skill in the art would have recognized that the exon 19 deletion disclosed in GOLDBERG encompasses E746-A750 deletion, and A750P and the exon 19 deletion usually refers to E746-A750 deletion because it is the most common mutation in the exon 19 as evidenced by GOLDBERG and Crosby. In addition, GOLDBERG specifically discloses the treatment of a CDK inhibitor such as palbociclib to HCC827 cell line, which is a human NSCLC cell line harboring a mutation (delE746-A750) as evidenced by Bivona ([0194]). Thus, the skilled artisan would have reasonably expected that the therapy effective for treating EGFR-mutant NSCLC with exon 19 deletion disclosed in GOLDBERG would be also useful for treating a NSCLC subject with E746-A750 deletion, L747-E749 deletion, A750P, or their combination, which is included by the exon 19 deletion mutation, in the absence of evidence to the contrary.
As to the limitation, “the cancer has undergone epithelial to mesenchymal transition (EMT)”, it was known in the art that NSCLC cells can undergo EMT due to acquired resistance to TKI such as erlotinib as evidenced by Bivona. Also, the invasive potential of cancer cells is dependent on losing epithelial characteristics and acquiring a migratory mesenchymal property referred to as Epithelial to Mesenchymal Transition (EMT) as evidenced by SHAILUBHAI ([0303]). In addition, SHAILUBHAI discloses the use of a CDK inhibitor for the treatment of cancers such as NSCLC and discloses that the CDK inhibitor is effective for inhibiting EMT, thereby reducing the invasion potential (abstract and Example 6). SHAILUBHAI further disclose that the “CDK inhibitor include milciclib, palbociclib, dinaciclib, P276-00, roniciclib, ribociclib, P1446A-05, AT7519M, SNS-032, SCH 727965, AG-024322, hygrolidin, fascaplysin, abemaciclib, arcyriaflavin A, CINK4, AM-5992, CDK4 Inhibitor (CAS #546102-60-7), CDK4 Inhibitor III (CAS #265312-55-8), Cdk4/6 Inhibitor IV (CAS #359886-84-3), MM-D37K, NSC 625987, ON-123300, or any pharmaceutically acceptable salt thereof and in one embodiment, the CDK inhibitor is milciclib which is a small molecule inhibitor of multiple CDKs, including CDK1, CDK2, CDK4, CDK5, CDK7, and CDK9 ([0154] and [0004]).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the CDK inhibitor for treating EGFR-mutant NSCLC which has undergone EMT because the CDK inhibitor is taught to be useful for treating NSCLC with claimed EGFR activating mutation and resistant to TKI as taught by GOLDBERG and for inhibiting EMT as evidenced by SHAILUBHAI. The skilled artisan would have recognized that NSCLC with claimed EGFR activating mutation and resistant to TKI as taught by GOLDBERG would encompass those which have undergone EMT because EMT is found in multiple in vitro and in vivo EGFR-mutant lung cancer models with TKI-acquired resistance as evidenced by Bivona. Accordingly, the skilled artisan would have been motivated to use the therapy of GOLDBERG comprising a CDK inhibitor for NSCLS with EMT on the reasonable expectation that it would be effective for inhibiting EMT, thereby reducing the invasion potential as taught by SHAILUBHAI.
As to claim 32, Bivona teaches that Axl overexpression is necessary for erlotinib resistance in H3255 EGFR-mutant NSCLC cells with acquired resistance to erlotinib and increased expression of epithelial-to-mesenchymal transition (EMT) markers such as vimentin and Axl are detected in EGFR-mutant NSCLC cells as stated above (see [0028], [0193], and Fig. 23-24). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use known markers for EMT such as vimentin and Axl taught by Bivona for demonstrating EMT in the treatment of EGFR-mutant non-small cell lung cancer because the EMT markers are taught be associated with resistance to EGFR therapy in EGFR-mutant NSCLC cells as evidenced by Bivona.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over US 20190275049 (hereafter, GOLDBERG) in view of US2015/0056193 (hereafter, Crosby) in further view of US 2014/0121126 (hereafter, Bivona, prior art of record) and US 2019/0134044 (hereafter, SHAILUBHAI), in further view of Chen et al. (Journal of Thoracic Oncology Vol. 12 No. 6: e65-e68, available online- 14 Jan. 2017).
GOLDBERG, Crosby, Bivona, and SHAILUBHAI as applied supra are herein applied for the same teachings in their entirety.
GOLDBERG does not specifically disclose that the subject is further determined to comprises a secondary mutation comprising C797S resistance mutation or L792H resistance mutation recited in claim 33.
However, it was known in the art that C797S and L792H resistance mutations occur in NSCLC after the treatment of TKI such as Osimertinib as evidenced by Chen et al. (Title, abstract, and e67, col 2, Discussion section). Thus, one of ordinary skill in the art would have recognized that the NSCLC patient would encompass those with a secondary mutation comprising C797S or L792H resistance mutation. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the CDK inhibitor in combination with TKI as taught by GOLDBERG or treating those NSCLC patients with a secondary mutation comprising C797S or L792H because GOLDBERG already teach and suggest that a CDK inhibitor in combination with TKI is effective for treating NSCLC cells harboring various EGFR-mutations. One of ordinary skill in the art would have reasonably expected that the same treatment would be similarly useful for treating EGFR-mutant NSCLC with the secondary mutation in the absence of evidence to the contrary.
Examiner’s note
The Examiner tried to contact Applicant’s attorney, Monica Mann Shah, and left message multiple times to discuss the case. However, the Examiner was unable to reach her and did not receive a return call from her.
Conclusion
No claims are allowed.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611