DETAILED ACTION
This office action is in response to the Applicant’s filing dated November 11th, 2025.
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 Claims
Claims 1, 5, 8-13 and 69-70 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed on November 11th, 2025. Acknowledgement is made of Applicant's amendment of claim 1; and cancelation of claims 2-4, 6-7, and 14-68.
Priority
This application is a 371 of PCT/CN2021/091169 filed on April 29th, 2021; and has a PRO 63/019,508 filed on May 4th, 2020.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Maintained Objections and/or Rejections
Claim Rejections - 35 USC § 103
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 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.
Claims 1, 5, 8-13 and 69-70 are rejected under 35 U.S.C. 103 as being unpatentable over Bai et al. (Journal of Medicinal Chemistry, (2013), 56(3), 879-894), cited in a previous Office action; in view of Nabavi et al. (Archives of Medical Science, (April 14th, 2020) 16(3), 519-521), cited in a previous Office action.
Regarding claims 1, 5 and 8-10, Bai teaches compound GZD824 (Compound 10a), which is Compound 1 of instant claim 1. Bai states “GZD824 tightly bound to Bcr-AblWT and Bcr-AblT315I with Kd values of 0.32 and 0.71 nM (addressing claim 9), respectively, and strongly inhibited the kinase functions with nanomolar IC50 values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC50 values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h)” (page 879, Abstract). Bai further states, “The selectivity profile of GZD824 against a panel of 442 kinases was also investigated at a concentration of 10 nM which was about 33 times of its Kd values on native Abl. The results clearly revealed that compound GZD824 also exhibited strong binding with b-RAF, DDR1, FGFR, Flt3, Kit, PDGFRα, PDGFRβ, RET, Src, Tie1, and Tie2 and several other kinases” (page 885, left column, first paragraph). Moreover, Bai teaches that GZD824 overcomes the Bcr-Abl mutations that result in clinically required resistance to imatinib (FDA approved drug 1), stating “Highly consistent with its potent biochemical kinase inhibition and tight protein binding affinity, GZD824 also strongly inhibited the proliferation of Ba/F3 cells that stably expressed the most refractory Bcr-AblT315I mutant, with an IC50 value of 7.1 nM. All three FDA-approved drugs (1−3) did not inhibit the proliferation of these cells. Furthermore, GZD824 displayed a similar potency of inhibition against Ba/F3 cells expressing 14 other resistance-relevant Bcr-Abl mutants. (page 885, left column third paragraph).
Bai does not teach the use of Compound 1 to treat SARS-CoV-2.
Nabavi teaches that Abl kinase activity has been shown to be involved in the coronavirus fusion step with endosomal membrane as well as the cell-cell fusion that occurs late in infection (page 520 left column, first paragraph); further stating that “Upon binding of SARS-CoV-2 spike protein to ACE2, the action of proteases at the cell membrane and in the endosomal compartment is required to complete the subsequent fusion steps of the virus. Abl kinase inhibitors act on proteases required for the completion of these steps by blocking their activity in SARS-CoV and MERS-CoV infection in vitro (addressing claims 8 and 10), and a similar activity of proteases is seen in SARS-CoV-2 (addressing claims 2-3 and 5). Taken together, repurposing the FDA-approved Abl2 inhibitors imatinib and saracatinib should be clinically tested for their antiviral effects in the early stage of SARS-CoV-2 infection, either alone or in combination with current antiviral drugs” (page 520, Figure 1; right column, last paragraph).
It would have been prima facie obvious to a person of ordinary skill in the art to use the known potent, orally bioavailable inhibitor of Bcr/Abl and related kinases, showing strong activity in human CML cell lines (e.g. K562 and Ku812), and effective inhibition across a panel of kinases including Abl2 inhibitor GZD824 taught by Bai, in a method of treating SARS-CoV-2 infection, in view of the rationale taught by Navabi that Abl kinase activity is required for endosomal fusion during SARS-CoV-2 infection and further repurposing known Abl2 inhibitors to block viral replication. The combination of these references suggests that GZD824 would reasonably be expected to exhibit antiviral efficacy via the same mechanism. A person of ordinary skill in the art would have been motivated to combine these teachings to arrive at the claimed method, with a reasonable expectation of success, in order to block a known host-virus entry pathway using a known, potent kinase inhibitor. The result constitutes the predictable outcome of combining known elements for an expected therapeutic application, and the claimed invention does not reflect an unexpected result or synergistic effect.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Regarding claims 11-13, The prior art is silent regarding "inhibiting serine/threonine-protein kinase 1 and the production of cytokines in a cytokine storm". However: "inhibiting serine/threonine-protein kinase 1 and the production of cytokines in a cytokine storm" will naturally flow from the method made obvious by the prior art (see above rejection), since the same Compound 1 (GZD824) is being administered to the same subjects, patients with COVID-19. In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
In other words, even though the prior art is silent regarding "inhibiting serine/threonine-protein kinase 1 and the production of cytokines in a cytokine storm", by practicing the method made obvious by the prior art: repurposing GZD824 (Compound 1) to treat COVID-19, one will also be "inhibiting serine/threonine-protein kinase 1 and the production of cytokines in a cytokine storm", even though the prior art was not aware of it.
Apparently, Applicant has discovered a new property or advantage ("inhibiting serine/threonine-protein kinase 1 and the production of cytokines in a cytokine storm") of the method made obvious by the prior art (repurposing GZD824 (Compound 1) to treat COVID-19).
MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
MPEP 2112.01 states:
"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). 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.
Regarding claims 69-70, it is obvious to vary and/or optimize the amount and dosing regimen of Compound 1, according to the guidance established by both Bai and Navabi logically administering at least once per day, to provide a therapeutically effective amount of a compound, combination or composition having the desired properties such as the desired ratios and concentrations. It is noted that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Taken together, all this would result in the method of instant claims 1, 5, 8-13 and 69-70 with a reasonable expectation of success.
Applicant argues:
Applicant contends Bai does not disclose or suggest the use of Compound 1 to treat viral infections caused by SARS-CoV-2. Nabavi only provides scientific conjecture to use Compound 1 to treat viral infections caused by SARS-CoV-2.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner acknowledges that Bai does not acknowledge the use of Compound 1 to treat viral infections caused by SARS-CoV-2.
Bai explicitly teaches that GZD824 (Compound 10a), which is instantly claimed Compound 1, is a potent Bcr-Abl kinase inhibitor that consistently overcomes the Bcr-Abl mutations that result in clinically required resistance to imatinib and other commonly used Bcr-Abl inhibitors, exhibiting a tight protein binding affinity.
Nabavi teaches Abl kinase activity has been shown to be involved in the coronavirus fusion step with endosomal membrane as well as the cell-cell fusion that occurs late in infection. Navabi further teaches that upon binding of SARS-CoV-2 spike protein to ACE2, the action of proteases at the cell membrane and in the endosomal compartment is required to complete the subsequent fusion steps of the virus; and that Abl kinase inhibitors act on proteases required for the fusion completion by blocking their activity. Navabi then explicitly suggests the repurposing of imatinib, an FDA approved Abl inhibitor, for the treatment of viral infection caused by SARS-CoV-2.
This mechanistic teaching and repurposing suggestion would have given a person of ordinary skill in the art a reasonable expectation of success in employing another potent Abl inhibitor, namely GZD824 of Bai, in the same therapeutic context; as it has been shown by Bai to outperform imatinib in every aspect of Abl inhibition, especially in situations where there have been mutations where imatinib is no longer effective.
Applicant argues:
Applicant contends Compound 1 demonstrated unexpected activity against viral infections caused by SARS-CoV-2, seen in Example 1 (pages 32-33, paragraphs [0228-0231] and Table 3), specifically much lower IC50 values in comparison with imatinib.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
It is acknowledged that the data produced from Example 1 and disclosed in Table 3 shows that Compound 1 outperformed imatinib. However, this is not unexpected in light of the teaching of the prior art. Bai teaches that GZD824 (Compound 10a), which is instantly claimed Compound 1, is a potent Abl kinase inhibitor exhibiting nanomolar IC50 values. Bai further teaches that GZD824 overcomes the Abl mutations that result in clinically required resistance to imatinib (FDA approved drug 1), stating “Highly consistent with its potent biochemical kinase inhibition and tight protein binding affinity, GZD824 also strongly inhibited the proliferation of Ba/F3 cells that stably expressed the most refractory Bcr-AblT315I mutant, with an IC50 value of 7.1 nM. All three FDA-approved Abl kinase inhibitors (1−3) did not inhibit the proliferation of these cells. Because antiviral efficacy in this context is predicated on inhibition of Abl kinase activity (see Navabi), and Bai teaches that GZD824 exhibits superior Abl inhibition relative to imatinib, improved IC50 values against SARS-CoV-2 would have been reasonably expected, particularly given Bai’s teaching that GZD824 overcomes clinically relevant Abl resistance mutations.
Conclusion
Claims 1, 5, 8-13 and 69-70 are rejected.
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691