DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Claims 11-19 are pending and presently examined.
Election/Restrictions
The claims are directed to pharmaceutical compositions comprising “gilteritibib” as an active ingredient” and a screening method. Accordingly, an election/restriction requirement has not been set forth on record at this time. However, Applicant is directed to MPEP §§ 818, 818.02(a), 819, and 821.
Priority
The priority claim to PCT/JP2022/005499 (filed 2/11/2022) is acknowledged.
Examiner notes that no certified translation of the Foreign Application JP2021-020640 (filed 2/12/2021) has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file. See 37 CFR 41.154(b).
Information Disclosure Statement
The IDS filed 9/21/2023 and 4/07/2025 are each acknowledged and presently considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 11 is representative of the pending claim scope. Applicable claim interpretation is set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
The transitional phrase of “containing” is used at claims 11 and 18. Per MPEP § 2111.03(IV), transitional phrases other than those discussed at MPEP §§ 2111.03(I)-(III) “must be interpreted in light of the specification to determine whether open or claimed claim language is intended” (see, e.g., MPEP § 2111.03(IV)). In the absence of clear guidance to the contrary, the transition phrase “containing” has been interpreted as equivalent to “comprising” and is open-ended (see, e.g., MPEP § 2111, noting that the broadest reasonable interpretation is given during prosecution). This interpretation is reasonable because a pharmaceutical composition is understood to contain excipients, which would otherwise be excluded from the claim scope. If Applicant disagrees, Applicant should identify if the transitional phrase is intended to be open-ended or closed and direct Examiner to disclosures in the originally filed disclosure that support the Applicant’s position. Alternatively, Examiner notes that the issue could be clarified by simply amending the claim to use common transitional phrases set forth at MPEP §§ 2111.03(I)-(III).
Regarding recitations of intended use or expected/intended results at pending claims 11-18 (see, e.g., instant claim 11 reciting “for treating an ALK fusion gene positive tumor”; claim 11 reciting “as an active ingredient”; claim 12 reciting “wherein the ALK fusion gene-positive tumor is a tumor having a wild type ALK kinase domain or acquired resistance to a first generation, a second-generation of ALK-TKls or lorlatinib”; claim 13 reciting “wherein the ALK fusion gene-positive tumor is compound mutations with I1171N, I1171S, V1180L, L1196M or C1156Y”; claim 14 reciting “wherein the ALK fusion gene-positive tumor is an ALK fusion gene having at least two compound mutations including mutations: I1171N/S/T, F1174I/L, L1196M, L1198F/H, G1202R, D1203N, F1245V, L1256F and G1269A”; claim 15 reciting “wherein the ALK fusion gene-positive tumor has at least one ALK mutation of T1151K, C1156Y, I1171N, I1171T, I1171S, F1174I, F1174V, V1180L, L1196M, L11960, L1198F, D1203N, F1245V, L1256F or G1269A”; claim 16 reciting “wherein the ALK fusion gene-positive tumor is a non-small cell lung cancer”; claim 17 reciting “for use as a primary therapy or a secondary therapy of non-small cell lung cancer”; claim 18 reciting “for treating a tumor caused by activation of AXL, an NTRK fusion gene, an LTK fusion gene and/or a ROS1 fusion gene”), per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the recitations of intended use or expected results (e.g., “for use” or “wherein” clauses) do not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore such phrases are not reasonably understood to be a functional limitation further limiting the claimed product, which is a pharmaceutical composition comprising gilteritinib (see, e.g., instant claim 1 and 18). Rather, the “wherein” and “for use” clauses are understood to merely recite an intended or expected result fully satisfied by the positively recited structures set forth in the body of claim 11 and 18, namely a pharmaceutical composition comprising gilteritinib. Therefore, the “wherein” and “for use” clauses at claims 11-18 are understood to be fully satisfied by all prior art embodiments that satisfy the structural limitations of the claimed product, namely a pharmaceutical composition that comprises some amount of gilteritinib.
At claims 11 and 18, the phrase “gilteritnib as an active ingredient” is not limiting because "A chemical composition and its properties are inseparable”, therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.” See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Accordingly, claims 11 and 18 are understood to be directed to products, namely pharmaceutical compositions comprising gilteritinib.
At claim 19 the method recites
A method for examining whether gilteritnib exerts an effect on a patient with an ALK fusion-gene positive tumor, including: examining whether a kinase domain of ALK is a wild type or has at least one ALK mutation of T1151K, C1156Y, I1171N, I1171T, I1171S, F1174I, F1174V, V1180L, L1196M, L1196Q, L1198F, D1203N, F1245V, L1256F or G1269A; and determining that gilteritinib is effective when any one of the above present
Accordingly, the claim is understood to require consideration of “an effect on a patient” and be an in vivo or ex vivo screening method. The method is understood to require two steps, namely an “examining” step (i.e., a genetic screen for ALK mutations) and a “determining” step.
At claim 19 the phrase “patient with an ALK fusion-gene positive tumor” is understood to refer to a subset of cancers driven by a specific genetic rearrangement where the ALK gene fuses with another gene (see, e.g., Spec. filed 8/02/2023 at ¶[0004]).
At claim 19 the phrase “determining that gilteritinib is effective when any one of the above present” is not equivalent to “determining if gilteritinib is effective when any one of the above present” or “determining whether or not gilteritinib is effective when any one of the above present”. “Determining that” is a factive construction wherein “that” introduces a complement clause asserting a known, presupposed outcome (i.e., it concludes that a single, known outcome exists; i.e., here the diagnostic outcome is already known). This is distinct from “Determining if”, which is an interrogative or conditional construction that leaves the outcome open (i.e., the outcome is unknown; i.e., here the diagnostic outcome unknown, and a step of actually administering and testing is required to know the outcome). Accordingly, the phrase is understood to be a determination that is made “when any one of the above [mutations are] present”. Therefore, claim 19 is understood to require that an Applicant screen a patient for an enumerated mutation at claim 19, and conclude or otherwise be aware that gilteritinib is effective.
Additional claim interpretations are discussed below.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show described details because they are illegible at the current resolution (see, e.g., Drawings filed 8/02/2023 at Fig. 1A, 1C, 3A, and 3C, noting that labels, axes, or other information is not fully legible). Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
At claim 11, the acronym “ALK” should be completely spelled out at least once in the claim scope.
Claims 11 and 18 are objected to under 37 CFR 1.75 as being a substantial duplicate of claim 1, as all such claims are directed to the same structure, namely a product, and more specifically a pharmaceutical composition comprising gilteritinib. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim 19 is objected to for reciting “when any one of the above present” at the last two lines, which is grammatically incorrect. Claim 19 should read “when any one of the above are present”.
Claim Rejections
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 13 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 recites “is effective” at the final two lines, which renders the claim scope indefinite. The term “effective” in claim 19 is a relative term which renders the claim indefinite. The term “effective” 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. For purposes of applying prior art, any level of “effectiveness” is deemed sufficient, and is understood to exist if prior art expressly teachings that the compound may be administered to such patients for treating the condition.
Claim 13 recites “…wherein the ALK fusion gene-positive tumor is compound mutations with….”, which renders the claim scope indefinite because it is unclear what this phrase is meant to state, and appears to comprise one or more grammatical errors. Accordingly, it is unknown what claim scope is intended. For purposes of applying prior art, the “wherein” clause at claim 13 is understood to further limit a recitation of intended use or expected results at claim 11, which does not further limit the scope of the product claimed per MPEP § 2111.04(I).
Accordingly, claims 13 and 19 are rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 11-18 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Lee et al.1
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 11-18 and a pharmaceutical composition comprising gilteritinib, Lee teaches and discloses pharmaceutical compositions comprising gilteritinib (see, e.g., Lee at 257 at col I-II at bridging ¶, referring to pharmaceutical testing done using composition comprising 120 mg of gilteritinib, Fig. 1 on 258, disclosing pharmaceutical assays resulting in determinations of IC50 values of Gilteritinib for different FLT3 receptor subtypes). Regarding recitation of intended use and expected results, Claims 12-17 depend directly or indirectly from instant claim 11, and are understood to differ from the claim 11 only by the recitation of intended or expected results that do not further structurally limit the claimed product of instant claim 11 (i.e., specifically a pharmaceutical composition comprising gilteritinib). Per MPEP § 2111.04(I), phrases that do not further limit the claim scope to a particular structure do not limit the claim scope (see also MPEP § 2111.02(I)-(II), noting that “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction” and “If a prior art structure is capable of performing the intended use as recited in the preamble, then it meets the claim”). Here, the recitations at claims 11-18 do not correspond to any structure/function limitation on record further limiting the structure of a pharmaceutical composition comprising gilteritinib as set forth in the body of instant claim 11. Accordingly, these claims are understood to necessarily and inherently be satisfied by all products satisfying the structural limitations set forth at claims 11 and 18, namely any pharmaceutical composition comprising Gilteritinib.
Accordingly, claims 11-18 are anticipated by the prior art.
Claims 11-18 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by US2019/0262328 (Aug. 29, 2019).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 11-18 and a pharmaceutical composition comprising gilteritinib, the primary reference teaches and discloses that gilteritinib was a known prior art element, CYP3A4 substrate drug, and identifies data evidencing that pharmaceutical compositions comprising gilteritinib were previously reduced to practice and analyzed for pharmaceutical parmaters, and explicitly taught for use at 40, 80, and 120 mg daily (see, e.g., US’328 at ¶¶[0012], [0301], Table 1 at col. 35, claims 1-2 and 16). Regarding recitations of intended use and expected results, the applicable claim interpretation has been set forth above in a separate section, and that interpretation is incorporated herein with respect to “wherein”, “for use”, and similar phrases that do not further limit the claimed product (see, e.g., MPEP § 2111.04(I)). Per MPEP § 2111.04(I), phrases that do not further limit the claim scope to a particular structure do not limit the claim scope (see also MPEP § 2111.02(I)-(II), noting that “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction” and “If a prior art structure is capable of performing the intended use as recited in the preamble, then it meets the claim”). Here, the recitations at claims 11-18 do not correspond to any structure/function limitation on record further limiting the structure of a pharmaceutical composition comprising gilteritinib as set forth in the body of instant claims 11 and 18.
These recitations do not correspond to any structure/function limitation on record further limiting the structures actually claimed. Accordingly, these claims are understood to necessarily and inherently be satisfied by all products satisfying the structural limitations set forth at claims 11 and 18, namely any pharmaceutical composition comprising Gilteritinib.
Accordingly, claims 11-18 are anticipated by the prior art.
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.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over US2019/0262328 (Aug. 29, 2019) as applied to claims 11-18 above, and further in view of Katayama et al.2
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of US’328 as applied to claims 11-18 have been set forth above, and those teachings are incorporated into the instant rejection. In sum, pharmaceutical compositions comprising gilteritinib are prior art elements (see, e.g., US’328 at ¶¶[0012], [0301], Table 1 at col. 35, claims 1-2 and 16). Regarding instant claim 19, US’328 explicitly teaches and claims methods directing artisans to treat patients in need thereof with a CYP3A4 substrate drug (see, e.g., US’328 at claim 1), wherein the CYP3A4 substrate drug may be gilteritinib (see, e.g., US’328 at claim 2), and wherein the “patients in need thereof” expressly include patients “with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on” either crizotinib and/or alectinib (see, e.g., US’328 at claim 16, ¶[0317] at 76 at col I). Accordingly, an artisan would have already known, expected, predicted, and concluded that gilteritinib administration would be an “effective” treatment for all such patients having (ALK)-positive NSCLC in view of US’328 because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)), absent objective evidence to the contrary.
US’328 differs from the scope of instant claim 19 as follows: Although US’328 claims and renders obvious methods of administering gilteritinib to treat patients (ALK)-positive NSCLC (i.e., guidance to determine that gilteritinib would be effective in all such patients), US’328 does not teach a step requiring “examining whether a kinase domain of ALK is a wild type or has at least one ALK mutation of I1171T, V1180L, and L1196M.
However, Katayama identifies that, it was already known, circa 2014, that although crizotinib was a standard therapy for patients with ALK-rearranged NSCLC, that patients could relapse and become crizotinib-resistance (see, e.g., Katayama at title, abs, 5687 at box). Katayama also tests models of alectinib resistance (see id.). Katayama identifies that mutations in ALK cause patients to “eventually develop resistance to next-generation inhibitors” (see id. at 5686 at col II at 1st full ¶), and identifies that the mutations of V1180L, L1196M, and I1171T mediate resistance to alectinib and crizotinib (see id. at 5686 at col II at 1st full ¶, 5690 at col I at 1st full ¶ to col II at 1st partial ¶). Katayama identifies that ALK-rearranged NSCLC patients were identified as having a I1171T mutation during a course of alectinib treatment and following a durable response to crizotinib (see, e.g., Katayama at 5695 at col I at 1st full ¶ to col II at 1st partial ¶).
Accordingly, the patient population of patients with ALK-positive NSCLC “who had progressed on or are intolerant to crizotinib” and (ALK)-positive NSCLC “whose disease has progressed on crizotinib and and at least one other ALK inhibitor” as disclosed by the primary reference (see, e.g., US’328 at claim 16, ¶[0317] at 76 at col I) were known in the prior art, and understood to include patients having at least a I1171T mutation (see, e.g., Katayama at 5695 at col I at 1st full ¶ to col II at 1st partial ¶).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): The claimed invention is obvious because it is the application or combination of known patient screening techniques for I1171T mutations in ALK-positive NSCLC patients, with the treatment of such patients with gilteritinib as taught by the primary reference, wherein administration of gilteritinib would be predicted and expected to successfully treat such ALK-positive NSCLC (i.e., it would be “determined” to be “effective” to some extent); such a combination would predictably help patients obtain more effective treatments once a mutation associated with resistance to alectinib and crizotinib was detected (see, e.g., MPEP §§ 2143(I)(A), (C), (D), (F), and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to screen patients for known mutations and to perform a known method on a known patient population by administering a known compound to the patients to achieve a known outcome.
Accordingly, claim 19 is rejected.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Takahashi et al.3 pertains to known mutations in ALK positive cancers that cause resistance to cancer therapeutics (see, e.g., Takahashi at title, abs). Takahashi explicitly identifies known ALK mutations causing resistance (see, e.g., Takahashi at title, abs, 582 at col I at 1st ¶). Accordingly, screening ALK patients for known mutations associated with drug resistance would be apparent to one of skill in the art to facilitate individualized and effective treatments.
Holla et al.4 pertains to known mutations in ALK-positive cancers associated with drug resistance (see, e.g., Holla at title, abs, passim). Accordingly, screening ALK patients for known mutations associated with drug resistance would be apparent to one of skill in the art to facilitate individualized and effective treatments.
Kuravi et al.5, pertains to the treatment of NPM1-ALK-driven ALCL with Gilteritinib (see, e.g., Kuravi at title, abs, passim).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 Lee et al., Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood. 2017 Jan 12;129(2):257-260. doi: 10.1182/blood-2016-10-745133. Epub 2016 Dec 1. PMID: 27908881; PMCID: PMC5234222; hereafter “Lee”.
2 Katayama et al., Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin Cancer Res. 2014 Nov 15;20(22):5686-96. doi: 10.1158/1078-0432.CCR-14-1511. Epub 2014 Sep 16. PMID: 25228534; PMCID: PMC4233168; hereafter Katayama.
3 Takahashi et al., Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non-small cell lung cancer. Thorac Cancer. 2020 Mar;11(3):581-587. doi: 10.1111/1759-7714.13299. Epub 2020 Jan 13. PMID: 31943796; PMCID: PMC7049522; hereafter “Takahashi”.
4 Holla et al., ALK: a tyrosine kinase target for cancer therapy. Cold Spring Harb Mol Case Stud. 2017 Jan;3(1):a001115. doi: 10.1101/mcs.a001115. PMID: 28050598; PMCID: PMC5171696; hereafter “Holla”.
5 Kuravi et al., Preclinical Evaluation of Gilteritinib on NPM1-ALK-Driven Anaplastic Large Cell Lymphoma Cells. Mol Cancer Res. 2021 May;19(5):913-920. doi: 10.1158/1541-7786.MCR-20-0738. Epub 2021 Jan 29. PMID: 33514657; PMCID: PMC9135172; hereafter Kuravi.