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 .
Priority
This Application is a 371 of PCT/CN2021/120260, filed Sept. 24, 2021 and claims foreign priority to PCT/CN2020/117895, filed Sept. 25, 2020.
Claim Status
Claims 1, 3, 8-9, 28-31, 35 and 44-52 are pending.
Applicant’s election without traverse of Group II, claim(s) 29-31 and 35, and compounds 5 (ALK inhibitor) and 34 (BCR-ABL inhibitor) as the species, in the reply filed on Nov. 12, 2025 is acknowledged.
Claims 29-31, 35 and 44-52 are currently active and subject to examination.
Claims 1, 3, 8-9 and 28 are withdrawn.
Withdrawn Rejections – Overcome by Amendment
The rejection of claims 30-31 and 35 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn.
The rejection of claim(s) 29-31 and 35 under 35 U.S.C. 102(a)(1) as being anticipated by Wood et al. (Clin Cancer Res (2017) 23 (11): 2856–2868) (of record, cited in the Restriction/ Election requirement dated Aug. 12, 2025) is withdrawn.
The rejection of claim(s) 29-31 and 35 under 35 U.S.C. 102(a)(1) as being anticipated by Geng et al. (WO 2019141235 A1, published July 25, 2019) is withdrawn.
The above rejections were overcome by Applicant’s amendments to the claims.
Claim Rejections – 35 USC § 112(b) – New Grounds of Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(b):
“(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.”
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
“The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.”
Claims 35 and 47 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 35 recites the limitation "the one or more anticancer reagents" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 47 recites the limitation "the one or more anticancer reagents" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections – 35 USC § 103 – New Grounds of Rejection Necessitated by Amendment
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(s) 29-31, 35 and 44-52 is/are rejected under 35 U.S.C. 103 as being unpatentable over Recondo et al. (Clinical Cancer Research, Vol. 26, Issue 1, January 1, 2020, p. 242-255) in view of Wang & Chen (US20190175595A1) and Ren et al. (Journal of Medicinal Chemistry, Vol. 52, Issue 3, January 9, 2013, p. 879-894).
Claim 29 is directed towards a method of treating or suppressing a cancer, reducing its severity, lowering its risk or inhibiting its metastasis in an individual, comprising administering to the individual a therapeutically effective amount of an ALK inhibitor and a therapeutically effective amount of a BCR-ABL inhibitor, wherein:
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And
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Recondo teaches a combination of an ALK inhibitor (lorlatinib) and a BCR-ABL inhibitor (ponatinib) for the treatment of ALK inhibitor-resistant lung cancer. Recondo isolated cancer cells from a patient, MR 135, with lung adenocarcinoma (a form of non-small cell lung cancer (NSCLC)) who had been previously treated with the ALK inhibitors ceritinib and lorlatinib and acquired resistance to ALK inhibitors (Table 1). Recondo found that treatment with a combination of ponatinib and lorlatinib was synergistic and decreased the viability of these cancer cells:
NF2 encodes the merlin protein, a key tumor suppressor implied in the regulation of the PI3K–AKT–mTOR pathway through mTOR inhibition (22). We performed a drug screen in the MR135-R1 identifying the selective dual mTOR1-2 inhibitor, vistusertib (AZD2014, AstraZeneca), and the multikinase inhibitor, ponatinib, as hits in this cell line.
Both MR135-R1 and MR135-R2 cell lines were highly sensitive to vistusertib and the combination of vistusertib and lorlatinib (Fig. 4B, MR135-R1; Supplementary Fig. S3C, MR135-R2). The activity of an mTOR inhibitor was confirmed by using the clinically available rapamycin analogue everolimus (Supplementary Fig. S3D). Ponatinib, a multikinase inhibitor targeting ABL, VEGR, FGFR3, PDGFRA, and RET, showed an important synergistic effect with lorlatinib in this cell line with a 57- to 80-fold IC50 reduction with the combination compared with lorlatinib single agent (Supplementary Fig. S3E)…
Similarly, the combination of lorlatinib and ponatinib reduced AKT, ERK, and S6 phosphorylation, and increased apoptosis as compared with either treatment alone (Fig. 4C).
Recondo, p. 28-29 (emphasis added);
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Recondo, Supp. Fig. 3E.
While Recondo does not teach that the ALK inhibitor is a compound of formula I or that the BCR-ABL inhibitor is compound 34, one of ordinary skill in the art would have a reasonable expectation of success to substitute a compound of formula I for lorlatinib and compound 34 for ponatinib because compounds of formula I and compound 34 are known in the art as ALK and BCR-ABL inhibitors respectively, which have comparable activity to other members of their classes.
The Applicant has done nothing more than substitute equivalents known for the same purpose: “the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent” (MPEP § 2144.05(II)(A) (quoting In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929)).
For example, Wang teaches compounds of formula I as ALK inhibitors, specifically compound 5, which has similar activity anticancer activity to ceritinib (LDK378):
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Wang, Specification, p. 1;
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Wang, Specification, p. 5;
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Wang, Fig. 1.
For example, Ren teaches that compound 34 (compound 10a) is BCR-ABL inhibitor, designed based on ponatinib, and has comparable activity to ponatinib:
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Ren, p. 880, Figs. 1-2;
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Ren, p. 883, Table 1.
Therefore, claim 29 was prima facie obvious at the time of filing.
Claim 30 is directed towards the method of claim 29, wherein the ALK inhibitor is administrated in an amount from about 0.0005 mg/day to about 5000 mg/day.
Recondo teaches that a daily dose of the ALK inhibitor lorlatinib is 75 mg daily (Ren, p. 18). While Recondo does not teach the dose of the ALK inhibitor of formula I, one of ordinary skill in the art would have a reasonable expectation of success to administer the ALK inhibitor in an amount from about 0.0005 mg/day to about 5000 mg/day because these amounts are commonly known in the art for ALK inhibitors of formula I.
For example, Wang teaches that the compound of formula I can be administered in an amount of about 0.005 mg to about 500 mg per dose (Wang, Specification, para. [0089]), and the desired dose can be administered as a single dose or as multiple doses administered at appropriate intervals, for example, as one two three four or more subdoses per day (id., para. [0088]). As these amounts overlap with the claimed range, a prima facie case of obviousness exists (MPEP § 2144.05).
Therefore, claim 30 was prima facie obvious at the time of filing.
Claim 31 is directed towards the method of claim 29, wherein the ALK inhibitor is administrated in an amount from about 1 ng/kg to about 200 mg/kg, about 1 µg/kg to about 100 mg/kg or about 1 mg/kg to about 50 mg/kg per unit dose.
While Recondo does not teach the above amounts, one of ordinary skill in the art would have a reasonable expectation of success to administer the ALK inhibitor in these amounts because they are commonly known in the art.
For example, Wang teaches that “The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, can be from about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg.” (Wang, Specification, para. [0090]).
Therefore, claim 31 was prima facie obvious at the time of filing.
Claim 35 recites: “The method according to claim 29, wherein the ALK inhibitor and the one or more cancer reagents are administered for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days.”
One of ordinary skill in the art would have a reasonable expectation of success to administer the ALK inhibitor and the one or more anticancer reagents for at least 3-50 days because Recondo teaches that the cells were treated with the combination of ponatinib and lorlatinib for 7 days (Recondo, Supplementary Fig. 3 legend) and that typical ALK inhibitor treatment occurs over the course of months (E.g. Figure 4A, showing certinib treatment for 14.3 months and lorlatinib treatment for 15.1 months).
Therefore, claim 35 was prima facie obvious at the time of filing.
Claims 44-46 read on compound 5 and are therefore rejected for the reasons given in the rejection of claim 29.
Claim 47 is directed towards the method of claim 29, wherein the weight ratio between the ALK inhibitor and the one or more anticancer reagents is 0.005-5000:0.005-5000.
One of ordinary skill in the art would have a reasonable expectation of success to administer the ALK inhibitor and one or more anticancer reagents in a weight ratio from 0.005-5000:0.005-5000 because it is commonly known in the art to administer ALK inhibitors with additional anticancer reagents in weight ratios that fall within this range.
For example, Recondo teaches that vistusertib and lorlatinib have similar effects on MR135-R1 cells in culture as the combination of lorlatinib and ponatinib and to administer vistusertib and lorlatinib in a weight ratio of 1:1 in a mouse model for tumor growth inhibition:
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Rotando, Fig. 4.
Therefore, claim 47 was prima facie obvious at the time of filing.
Claims 48-51 read on treating non-small cell lung cancer and lung adenocarcinoma with the combination of compound 5 and compound 34. The rejection of claim 29 is incorporated herein by reference, which shows that the combination of compound 5 and compound 34 is obvious for the treatment of lung adenocarcinoma, which is a form of non-small cell lung cancer.
Therefore, claims 48-51 were prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing. The Applicant has only demonstrated that “the combination of compound 5 with compound 34 enhances inhibition effect on the proliferation of NCI-H228 tumor cells” in culture (Specification, p. 3, Fig. 1 legend). This is predictable based on the teachings of Recondo in view of Wang and Ren. Recondo teaches that there is a synergistic effect between ALK inhibitors and BCR-ABL inhibitors. Wang and Ren teach that compound 5 and compound 34 would be expected to behave similarly to other members of their classes. The Applicant has done nothing more than substitute equivalents doing the same thing as in the prior art by substantially the same means (MPEP §§ 2144.05(II)(A); 2144.06(II)). As such, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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