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 .
Application Status
2. Applicant's amendment and response, filed on January 27, 2026, has been reviewed by the examiner and entered of record in the file.
3. Claims 19 and 33 are amended. Claim 25 is canceled.
4. Claims 27-30 remain withdrawn from consideration withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
5. In view of the amendment to claim 19, the scope of the examined invention is as follows:
A method for treating a subject with CML, wherein the subject is resistant to treatment with imatinib, dasatinib, nilotinib, bosutinib and/or ponatinib, comprising administering to the subject a composition comprising an FLT3 inhibitor, wherein the FLT3 inhibitor is quizartinib, and further administering to the subject a tyrosine kinase inhibitor selected from the group consisting of imatinib, dasatinib, nilotinib, bosutinib and/or ponatinib.
6. The non-elected FLT3 inhibitors and non-elected tyrosine kinase inhibitors are withdrawn from consideration as directed to non-elected subject matter.
7. Claims 19, 21, 26 and 31-33 are under examination with the elected species and are the subject of this office action.
Previous Claim Rejections - 35 USC § 103
8. Claims 19, 21, 26 and 31-33 were previously rejected under 35 U.S.C. 103 as being unpatentable over Komarova et al., PLOS ONE 2009, further in view of Halbach, Cell Communication and Signaling 2016.
9. In view of Applicant’s amendment to claim 19, the previous obviousness rejection is withdrawn. However, upon further consideration, a new ground of rejection is made over Komarova et al., PLOS ONE (2009), in view of Halbach, Cell Communication and Signaling (2016), and further in view of Galanis and Levis, Haematologica (2015), please see below.
10. Claim 25 was previously rejected under 35 U.S.C. 103 as being unpatentable over Komarova et al., PLOS ONE 2009, in view of Halbach, Cell Communication and Signaling 2016, applied to claims 19, 21, 26, and 31-33, above, and further in view of Galanis and Levis, Haematologica 2015.
11. In view of Applicant’s cancellation of claim 25, the previous obviousness rejection is withdrawn.
New Claim Rejections - 35 USC § 103
12. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
13. Claims 19, 26 and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Halbach, Cell Communication and Signaling (2016), in view of Galanis and Levis, Haematologica (2015), and further in view of
Komarova et al., PLOS ONE 2009.
This rejection is newly applied as necessitated by Applicant’s amendment to claim 19.
Claim 19, as amended, is drawn to a method for treating a subject with chronic myelogenous leukemia (CML) comprising administering to the subject a composition comprising an FLT3 inhibitor (more specifically, quizartinib), and
further administering to the subject a tyrosine kinase inhibitor (more specifically, dasatinib, nilotinib, bosutinib (claims 26 and 31) and/or ponatinib
wherein the subject is resistant to treatment with imatinib, dasatinib, nilotinib, bosutinib and/or ponatinib.
Claim 32 is drawn to claim 19 and limits wherein the subject is resistant to treatment with imatinib, dasatinib, and/or nilotinib.
Claim 33, as amended, is drawn to claim 19, wherein the subject is resistant to imatinib and wherein the tyrosine kinase inhibitor is imatinib.
14. Halbach et al. suggest the administration of sorafenib (SF) for treating drug resistant CML, wherein SF is sensitive to all TKI resistances in CML including the TKI resistant Bcr-Abl mutation (page 4, Figure 2, G). In particular, Halbach et al. demonstrate that SF shows potency in various and mechanistically distinct scenarios of TKI resistance, specifically the T315I mutant (Bcr-AblT315I), i.e.: “SF effectively kills Bcr-Ablwt and Bcr-AblT315I expressing cells (Fig. 1b/c),” [emphasis added] (page 3, right column, first paragraph and Figure 1). Halbach et al. do not teach the administration of quizartinib.
15. Yet, Galanis teach FLT3 inhibitors as a class of tyrosine kinase inhibitors in the treatment of hematological cancers, in particular that quizartinib is a potent FLT3 inhibitor that demonstrates superior myelosuppressive effects over sorafenib. In an in vitro assay of human leukemia cells Galanis teaches that quizartinib has an FLT3 IC50 value in human plasma of 18 nM while sorafenib has an FLT3 IC50 value in plasma of 484 nM (see Table 1 at page 1).
16. Thus, one of skill in the art would have been motivated before the effective filing date of the claimed invention to substitute the more potent FLT3 inhibitor quizartinib for sorafenib, as taught by Halbach, in a method of treating drug resistant CML, and the results of the substitution would have been predictable, i.e., a reasonable expectation of success in the treatment of drug resistant CML in a patient in need thereof.
17. Halbach et al. do not teach the administration of a tyrosine kinase inhibitor.
18. Yet, Komarova et al. disclose the treatment of drug resistant CML in a subject in need thereof, wherein the combined administration of two or more tyrosine kinase inhibitors (TKI) improves treatment success in said subject, wherein the TKIs are imatinib, dasatinib, and/or nilotinib (see abstract). Komarova et al. are aware that CML expressing the T315I mutation confers resistance against each of imatinib, dasatinib, and nilotinib, which meets the limitation of claim 19, (see page 1, left column, last three sentences), and to overcome said resistance, Komarova et al. suggest that the most effective treatment strategy is to combine a drug effective against T315I mutants with two of the three TKIs: imatinib, dasatinib, and/or nilotinib (page 4, left column, last paragraph- right column, first two lines).
19. As such, one of skill in the art would have been motivated before the effective filing date of the claimed invention to treat a subject suffering from CML and having the T315I mutation, such that said subject is resistant to imatinib, dasatinib, and/or nilotinib, comprising administering quizartinib (a drug effective against the T315I mutant) and at least two of the TKIs selected from imatinib, dasatinib, and/or nilotinib, with a reasonable expectation of success.
20. And, one of skill in the art would reasonably consider that known compounds which individually demonstrate anticancer activity in the treatment of drug resistant CML could be combined in order to achieve an additive effect for treatment of drug resistant CML in a subject in need thereof.
21. MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.
22. Please refer to MPEP 2144.06 “I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE” wherein Kerkhoven is specifically referenced:
“It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
23. As stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined.
As such, claims 19, 26, 31-33 are prima facie obvious.
24. Claim 21 is rejected under 35 U.S.C. 103 as being unpatentable over Halbach, Cell Communication and Signaling (2016), in view of Galanis and Levis, Haematologica (2015), and further in view of Komarova et al., PLOS ONE 2009, as applied to claims 19, 26 and 31-33, above, and further in view of Zhu et al., Acta Haematol (2012).
Claim 19 is addressed in detail, above.
Claim 21 is drawn to claim 19, and limits wherein the CML is blast crisis CML.
25. Halbach et al. in view of Galanis and further in view of Komorova et al. suggest the
26. Yet, Zhu et al. suggest that suggest that the treatment of drug resistant CML (specifically imatinib-resistant) with imatinib and nilotinib in combination improves the outcome of imatinib-resistant CML patients in the blast phase (see abstract and page 155, right column, first paragraph).
27. Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to treat CML that is resistant to treatment with imatinib comprising administering the FLT3 inhibitor quizartinib together with the combination of tyrosine kinase inhibitors comprising at least imatinib and nilotinib, wherein said combination treatment would be successful in the treatment of said resistant CML that is in the blast crisis phase.
As such, claim 21 is prima facie obvious.
Response to Arguments
28. Applicant traverses the obviousness rejection over Komarova in view of Halbach, wherein claim 25 is further rejected over Galanis, and argues the following points:
(i) Applicant alleges that in view of the amendments to claim 19 to limit the FLT3 inhibitor to one or more selected from the group consisting of quizartinib, midostaurin, gilteritinib, and crenolanib, Halbach does not disclose or suggest any of said FLT3 inhibitors. Applicant argues that the instant Specification (Example 5 and shown in Figs. 8a- 8c) demonstrates that the tested FLT3 inhibitors (quizaritinib, midostaurin, gilteritinib, and crenolanib) each synergize with the tyrosine kinase inhibitor imatinib to kill FLT3-transformed K562 cells, mimicking the blast crisis of chronic myelogenous leukemia.
29. Applicant’s arguments have been fully considered but they are not persuasive. Komarova specifically suggests the combination therapy of at least two TKIs selected from imatinib, dasatinib, and/or nilotinib with a drug that is effective against T315I mutants for the “most effective treatment strategy” for drug resistant CML (page 4, last paragraph). And, in view of the combined teachings of Halbach and Galanis, nothing unobvious is seen in substituting quizartinib in the method of treating CML suggested by Halbach. Therefore one skilled in the art would have reasonably considered administering the combination of the TKIs imatinib, dasatinib, and/or nilotinib together with the FLT3 inhibitor quizartinib for the treatment of drug resistant CML in a subject in need thereof.
30. Regarding Applicant’s allegation of synergism, although the Specification demonstrates synergistic results, Applicant is reminded that: “the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support,” (In re Clemens, 622 F.2d 1029 (CCPA 1980)). And, in In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003), factual evidence demonstrating a greater than expected result from the addition of 2% of an ingredient did not evidence unexpected results for the entire claimed range of about 1-3% of the ingredient. Rather, the nonobviousness of a broader range or genus can only be established by evidence based on unexpected results of a narrower range or genus when one of ordinary skill in the art would be able to determine a trend in the exemplified data allowing said artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48 (CCPA 1979).
In the instant case, the claims are not drafted commensurate in scope with the unexpected results to overcome the prima facie case of obviousness, because the synergism demonstrated by Applicant in Example 5 and Figs. 8a- 8c of the Specification is limited to the combined effect of each of the recited FLT3 inhibitors (quizaritinib, midostaurin, gilteritinib, and crenolanib) with just one of the recited tyrosine kinase inhibitors, i.e., imatinib. It is recommended that the claimed method of treatment is limited to the synergistic results demonstrated by Applicant in Figures 8a-8c. See MPEP 716.02(d).
Conclusion
30. Claims 19, 21, and 26-33 are present in the application. Claims 27-30 are presently withdrawn from consideration. Claims 19, 21, 26 and 31-33 are rejected. No claim is presently allowable.
31. 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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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