DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on January 7, 2026 has been entered.
Priority
The present Application, filed July 28, 2022, is a national stage entry under 35 U.S.C. § 371 of International Patent Application No. PCT/US2021/015592 filed January 29, 2021, which claims priority to U.S. Provisional Patent Application No. 62/967,271, filed January 29, 2020.
Status of the Claims
In the amendment filed January 7, 2026, claims 2-3 have been canceled and claims 1, 14, 44, 48, and 86 have been amended. 4-8, 10, 12-13, 15-17, 19, 21, 22, 24, 26-27, 29-36-43, 45- 47, and 49-84 were previously canceled. Claims 1, 9, 11, 14, 18, 20, 23, 25, 28, 34-35, 44, 48, and 85-86 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 8, 2026 is acknowledged.
Previous Rejections and/or Objections
Claim objections:
As noted in Applicant’s Remarks, Applicant properly responded via the amendment of July 24, 2025 to the objection to claim 1. That objection was erroneously restated in the Office Action of October 7, 2025. The objection is withdrawn.
Rejection for indefiniteness:
The previous rejection of claim 14 for indefiniteness under 35 U.S.C. § 112(b) is obviated by Applicant’s amendment to claim 14. That rejection is therefore withdrawn.
Rejection for obviousness:
The previous rejections of the claims for obviousness under 35 U.S.C. § 103 are obviated by Applicant’s amendment to claim 1. All previous obviousness rejections are therefore withdrawn, and are replaced by the new obviousness rejections, described below.
Note on claim interpretation:
Claim 1 recites a method of treating leukemia or lymphoma, the method comprising: administrating a B-cell lymphoma 2 (BCL-2) inhibitor and a Polo-like kinase 1 (PLK1) inhibitor to a subject with leukemia or lymphoma, thereby inhibiting progression of the leukemia or lymphoma.
The thereby clause (thereby inhibiting progression of the leukemia or lymphoma) is regarded as an intended result that cannot be given patentable weight in this instance. “A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Minton v. Nat'l Ass'n. of Sec. Dealers, 336 F.3d 1373, 1381 (Fed. Cir. 2003). The “thereby” clause of instant claim 1 is functionally equivalent to such a “whereby” clause, i.e. “thereby inhibiting progression of the leukemia or lymphoma” is functionally equivalent to “whereby progression of the leukemia or lymphoma is inhibited.” Because this clause is not afforded patentable weight, for the purpose of examination against the prior art, claim 1 is construed as reciting a method of a method of treating leukemia or lymphoma, the method comprising: administrating a B-cell lymphoma 2 (BCL-2) inhibitor and a Polo-like kinase 1 (PLK1) inhibitor to a subject with leukemia or lymphoma.
Similarly, the limitation of claim 14 recites an intended result that is not entitled to patentable weight. The body of claim 14 recites “wherein the subject achieves a morphologic leukemia-free state.” Also similarly to claim 1, this “wherein” clause is functionally equivalent to the type of “thereby” clause described in Minton. The “wherein” clause of claim 14 does not appear to be clearly connected to the manner of performing the method (e.g. there is no direction as to what manner of performing the method, beyond the broadest manner described in claim 1, will effectuate the recited outcome of claim 14). As a consequence, this intended result recited in claim 14 does not carry patentable weight.
Claim Rejections - 35 USC § 103 – 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.
Claims 1, 9, 14, 28, 44, and 86 are obvious over Shah and Weiss:
Claims 1-3, 9, 14, 28, and 44 are rejected under 35 U.S.C. § 103 as obvious over the non-patent publication, Identification of a New Targeted Therapy for T-Cell Acute Lymphoblastic Leukemia and Studies on Its Mechanism of Action, blood, 134 (Supplement_1), pg. 2752 (2018) by Shah et al. (hereinafter, “Shah”), in view of the non-patent publication, Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors, Invest. New Drugs, 36, pgs. 85-95 (2018) by Weiss et al. (hereinafter, “Weiss”).
Amended claim 1 recites a method of treating leukemia, the method comprising: administrating a B-cell lymphoma 2 (BCL-2) inhibitor and a Polo-like kinase 1 (PLK1) inhibitor to a subject with leukemia, thereby inhibiting progression of the leukemia or lymphoma. Amended claim 1 further specifies that the PLK1 inhibitor is onvansertib and the leukemia is acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, or chronic myelomonocytic leukemia.. As noted above, the “thereby” clause is not afforded patentable weight.
Shah teaches that T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive subset of acute lymphoblastic leukemia (ALL) in which immature early progenitor leukemia cells rely on Bcl-2 for their survival (Background), and that Bcl-2 inhibitors have shown promising antitumor activity against early T cell progenitor ALL, a subgroup with a high risk of relapse (Background). It is to be noted that ALL is the same as the acute lymphocytic leukemia recited in instant claim 1 (see, for example, the non-patent publication, Acute lymphocytic leukemia, a page at the Mayo Clinic website, obtained at the url www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/symptoms-causes/syc-20369077, which states that, “[a]cute lymphocytic leukemia is also known as acute lymphoblastic leukemia.”
Shah discloses a screen of ten T-ALL cell lines with a combination of a Bcl-2 inhibitor and a panel of 378 protein kinase inhibitors, resulting in the identification of PLK1 inhibitors as good candidates for combination therapy with Bcl-2 inhibitors in the treatment of ALL (Methodology). Shah further teaches cell viability testing of 14 T-ALL cell lines with a PLK1 inhibitor, BI-6727 (volasertib) and a Bcl-2 inhibitor, ABT-199 (venetoclax), with all lines being sensitive to the PLK1 inhibitor but only some to the Bcl-2 inhibitor (Results). Shah notes that, in the cell lines susceptible to Bcl-2 inhibition, synergy was observed with the combination therapy, and that a higher degree of apoptosis was observed with the combination therapy than with a single drug (Results).
While the study of Shah is preclinical, Shah, by showing in cellulo synergy of a Bcl-2/PLK1 inhibitor combination, renders obvious a method of treating acute lymphocytic leukemia, the method comprising administrating venetoclax (a Bcl-2 inhibitor) and volasertib (a PLK1 inhibitor) to a subject having such a leukemia.
Mechanistically, Shah teaches that ABT-199 (venetoclax) has been shown to be initially effective as a lone agent against DHL, but the tumors tend to become resistant due to compensatory induction of MCL-1. Shah states that the synergistic combinatorial effect of BI-6727 and ABT-199 in treating ALL is mediated through the pharmacological inhibition of both BCL2 and PLK1, and as such, one would have expected that other PLK1 inhibitors, aside from BI-6727, could be effective in tandem with ABT-199 to treat ALL. While Shah does not explicitly teach the use of onvansertib, one of skill in the art would thus have had a reasonable expectation of success in using a PLK1 inhibitor such as onvansertib in place of volasertib, because onvansertib was known in the art as a PLK1 inhibitor. See, for example, Weiss.
Weiss teaches a Phase I, dose-escalation trial of NMS-1286937 in patients with advanced solid tumors (Summary, Methods). Weiss teaches that NMS-1286937 is an ATP-competitive (same mechanism as volasertib), highly potent and selective inhibitor of PLK1 (pg. 86, right column, first full paragraph, with reference to volasertib in preceding paragraph). NMS-1286937 is onvansertib (see, for example, MedChemExpress catalog page for onvansertib, available at the time of this writing at the url www.medchemexpress.com/NMS-1286937.html; first web capture in 2015). Given onvansertib’s known properties as a potent, selective inhibitor of PLK1 with the same general mechanism of action as volasertib, one would have had a reasonable expectation of success in using the onvansertib of Weiss as a PLK1 inhibitor, in place of the volasertib of Shah, for the treatment of acute lymphocytic leukemia.
With respect to claim 9, Shah is silent as to the sequence of administration of the two drugs, however with respect to simultaneous vs sequential administration, there are only two possibilities. The selection of one of the only two possibilities (simultaneous administration of the two drugs or sequential administration of the two drugs) is prima facie obvious, particularly where, as here, there is no evidence of any particular benefit or difference in selecting the recited simultaneous administration.. With respect to claim 14, as noted above, the “wherein” clause of this claim is afforded no patentable weight as reciting a mere intended result. As a consequence, claim 14 is obvious for the same reason as is claim 1, from which it depends.
With respect to claim 28, Shah teaches that the BCL-2 inhibitor is venetoclax. With respect to claim 34, Weiss teaches that patients were administered onvansertib at daily dose levels of 6, 12, 24, 36, and 48 mg/m2 (Summary, Methods). While not utilized by Weiss in conjunction with a BCL-2 inhibitor, it would have been obvious to administer onvansertib at a dose within the range recited in claim 34. Furthermore, Weiss plainly recognizes onvansertib dose as a result-effective variable in the treatment of cancer and, as such, it would have been obvious to one of skill in the art to optimize the onvansertib dose, whether in a monotherapy or combination therapy context, as a matter of routine experimentation. This is particularly true where, as here, there is no evidence of criticality of the recited dose range.
With respect to claim 35, Weiss teaches that all doses examined resulted in Cmax, AUC, Tmax, and T1/2 of onvansertib in the blood within the recited ranges. With respect to claim 86, Shah teaches the leukemia is acute lymphocytic leukemia.
Claims 11, 18, 20, and 25 are obvious over Shah, Weiss, and Venclexta:
Claims 11, 18, 20, and 25 are rejected under 35 U.S.C. § 103 as being unpatentable over Shah and Weiss, in view of the non-patent publication, Venclexta prescribing information, version 233, published in 2019, and obtained online at the URL dailymed.nlm.nih.gov/dailymed/getArchivalFile.cfm?archive_id=438680 (referred to hereinafter as “Venclexta”). A newer version of this documentation, revised in 2024, is also appended to the present Action, because the newer revision (referred to hereinafter as “Venclexta2024”) is presented in an easier-to-read format.
Claim 11 recites that the administration of the PLK1 inhibitor, the BCL-2 inhibitor, or both is oral administration. The element is not explicitly taught by Shah or Weiss, however it would have been obvious to administer the venetoclax of Shah and Weiss as an oral administration because oral venetoclax administration was well-known in the art. See, for example, Venclexta.
Venclexta discloses venetoclax tablets for oral use (pg. 1, subtitle information, see pg. 1 of Venclexta2024, left column near the top). As noted above with respect to claim 1, it would have been obvious to administer the combination therapy of Shah and Weiss to a human subject having double-hit lymphoma. Given the teaching of Venclexta described above, it would have been obvious to administer this combination therapy to a human subject wherein the BCL-2 inhibitor is oral venetoclax.
With respect to claims 18, 20, and 25 Venclexta teaches various cycles of venetoclax in combination with different drugs (beginning at pg. 4 of Venclexta2024). For example, in combination with Obinutuzumab, venetoclax is administered in 28 day cycles, including a ramp of period with daily administration beginning at day 22 of cycle 1. This describes a cycle where venetoclax (the BCL-2 inhibitor) is administered to the subject in a cycle of at least twice within a week (claim 18); where the BCL-2 inhibitor is administered in a cycle of at least 7 days (claim 20); and wherein the BCL-2 inhibitor is administered daily (claim 25). While Venclexta doesn’t teach co-therapy with a PLK1 inhibitor, it would have been obvious to administer venetoclax, as part of the method of Shah and Weiss, within the parameters recited in claims 18, 20, and 25. Furthermore, Venclexta plainly recognizes venetoclax cycle administration as a result-effective variable in the treatment of cancer and, as such, it would have been obvious to one of skill in the art to optimize the combination therapy cycle as a matter of routine experimentation. This is particularly true where, as here, there is no evidence of criticality of the recited cycle parameters, or even evidence that the recited parameters had been empirically tested as of the priority date.
Claim 44 is obvious over Shah, Weiss, and Hoelzer:
Claims 48 and 85 are rejected under 35 U.S.C. § 103 as being unpatentable over Shah and Weiss, in view of the non-patent publication, Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Annal. Oncol., 27 (suppl. 5), pgs. v69-v82 (2018) by Hoelzer et al. (hereinafter, “Hoelzer”).
Claim 44 recites the method of claim 1, further comprising a step of determining leukemia status of the subject and/or responsiveness of the subject to a PLKl inhibitor treatment.
Neither Shah nor Weiss expressly teaches inclusion of such a diagnostic step, it would have been obvious to determine the leukemia status of the subject as part of the method of Shah and Weiss, because it was well-known in the art that one must determine that a subject has leukemia prior to treating the subject for leukemia. See, for example, Hoelzer.
Hoelzer provides guidelines for diagnosing and treating acute lymphoblastic leukemia (i.e. acute lymphocytic leukemia) in patients, and states that initial diagnostic work-up must be carried out expeditiously and before any chemotherapy to confirm ALL diagnosis (pg. v69, left column, final 5 lines).
Claims 48 and 85 are obvious over Shah, Weiss, and Deng:
Claims 48 and 85 are rejected under 35 U.S.C. § 103 as being unpatentable over Shah and Weiss, in view of U.S. Patent Application Publication No. 2019/0070183 to Deng et al. (hereinafter, “Deng”).
Claim 48 recites a kit comprising: a PLK1 inhibitor; and a manual providing instructions for co-administrating the PLK1 inhibitor with a B-cell lymphoma 2 (BCL-2) inhibitor to a subject for treating leukemia and lymphoma.
Shah and Weiss are applied to claim 48 as to claim 1, above, but do not explicitly teach the recited kit having instructions for co-administration of the co-therapeutics, onvansertib and venetoclax. It would have been obvious to supply such a kit, however, because kits for combination therapy in cancer, including instructions for co-administering the combination therapeutics, were well-known in the art. See, for example, Deng.
Deng teaches combination therapy for treating c-Myc-overexpressing cancers (paragraph [0103]), including lymphocytic leukemias (paragraph [0121]). Notably, Shah also provides proof-of-concept via in cellulo treatment tests on T-ALL cells and in T-ALL mouse models (paragraph [0079] and [0381]). Deng further teaches kits for administering such combination therapy, the kits having the two therapeutic compounds and instructions for use of the contents of the kit (claim 84 and paragraph [0071]). It thus would have been obvious to utilize a kit of the type described in Deng, having the onvansertib and venetoclax of Shah and Weiss for the treatment of ALL, along with instructions for administering the two drugs, as taught by Deng. Such a kit would have the elements of claim 48, and the elements of claim 85, which requires the BCL-2 inhibitor be present in the kit along with the PLK1 inhibitor.
Conclusion
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629