DETAILED ACTION
This Office Action is in response to Applicant’s Amendment and Remarks filed on 19 February 2026 in which claims 8, 12, 48-50 were canceled, claims 1, 3, 4, 9-11, 13, 17, 21, 25, 32, 33 and 45 were amended to change the scope and breadth of the claims, and claim 51 was newly added.
Claims 1, 3, 4, 9-11, 13, 17, 21, 25, 29, 30, 32, 33, 45 and 51 are pending in the current application and are examined on the merits herein.
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 .
Claim Interpretation
The recitation “wherein the anthracene derivative is administered with or after administration of the two or more pyrimidine analog antimetabolites” in claim 1 is broadly and reasonably interpreted to mean “the anthracene derivative is administered with two or more pyrimidine analog antimebaolites”, or in the case when it is administered after the two or more pyrimidine analog antimetabolites, it encompasses treating a patient clearly identified as being a patient that has at some point been treated with two or more pyrimidine analog antimetabolites.
Withdrawn Rejections
Applicant’s amendment, filed 19 February 2026, with respect to the rejection of claims 4, 13, 17, 21, 25 and 33 under 35 U.S.C. § 112, second paragraph, for indefiniteness, has been fully considered and is persuasive. The claims have been amended to recite “milligrams per square meter body surface area”.
It is noted, this is only needed in the first instance of the recitation “mg/m2”.
The rejection is hereby withdrawn.
Applicant’s amendment, filed 19 February 2026, with respect to the rejection of claims 1, 3, 4, 8-13, 17, 21, 25, 29-30, 32, 45 and 48-50 under 35 U.S.C. § 102(a)(1)/(a)(2) as being anticipated by Levy et a., has been fully considered and is persuasive because the claims have been amended to recite “comprise fludarabine and clofarabine”. The rejection is hereby withdrawn.
Response to Arguments
Applicant's arguments filed 19 February 2026 have been fully considered but they are not persuasive.
To overcome some of the rejection under 35 U.S.C. §112(b), second paragraph (namely the rejection over the term “pyrimidine analog antimetabolite” and the recitation “wherein the two or more pyrimidine analog antimetabolite comprise fludarabine and clofarabine”, claim 1 could be amended to recite “pyrimidine analog metabolites are selected from the group consisting of fludarabine, clofarabine, cytarabine, cladribine, 5-azacytidine, gemcitabine, floxuridine, 5-fluorouracil, capecitabine, 6-azauracil, troxacitabine, thiarabine, sapacitabine, 2’-C-cyano’-2’-deoxy-β-arabinofuranosylcytosine, 2’-deoxy-2’methylidenecytidine, 2’-deoxy-2’-fluoromethylidenecytidine, 2’-deoxy-2’-methylidene-5-fluorocytidine, 2’-deoxy-2’,2’-difluorocyitidine, and at least include fludarabine and clofarabine”.
The above suggestion limits the structures encompassed by “analog metabolites”.
The rejection is hereby maintained
New & Modified Rejections
The following are new ground(s) or modified rejections necessitated by Applicant's amendment, filed on 19 February 2026, where the limitations in pending claims 1, 3, 4, 9-11, 13, 17, 21, 25, 32, 33 and 45 as amended now have been changed and claim 51 has been newly added. Therefore, rejections from the previous Office Action, dated 20 November 2025, have been modified and are listed below.
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.
Claims 1, 3, 4, 8-13, 17, 21, 25, 29-30, 32-33, 45 and 48-51 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.
The recitation “pyrimidine analog antimetabolites” in claim 1; render the claims and dependent claims 4, 8-13, 17, 21, 25, 29-30, 32, 33, 45 and 48-50 herein indefinite.
The term “pyrimidine analog antimetabolites” is not clearly defined in the present Specification. Thus, these compounds could also deviate from the parent structure. While the claims recite examples of pyrimidine analog antimetabolites, no claim clearly defines and limits these compounds. Thus, the term is held indefinite.
Claim 1 further includes fludarabine and clofarabine as types of pyrimidine analog antimetabolites. However, as noted by Zhenchuk, these are actually purine antimetabolites.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “pyrimidine analog antimetabolite” in claim 1 is used by the claim to mean “a compound having a pyrimidine nucleobase,” while the compounds included contain purine nucleobases (not pyrimidine nucleobases). The term is indefinite because the specification does not clearly redefine the term.
The recitation “wherein the two or more pyrimidine analog antimetabolites comprise fludarabine and clofarabine” in claim 1 renders the claim herein indefinite. It is unclear if the claim is directed towards an improper Markush, or if the claim should clearly indicate the requirement of two antimetabolites.
MPEP 2173.05(h) states “If a claim is intended to encompass combinations or mixtures of the alternatives set forth in the Markush grouping, the claim may include qualifying language preceding the recited alternatives (such as "at least one member" selected from the group), or within the list of alternatives (such as "or mixtures thereof")”.
While not required, the claims would be clearer if they adopted the language suggested by the MPEP.
The recitation “The method of claim 8” in claim 11 renders the claim herein indefinite, because claim 8 has been canceled.
The recitation “wherein the two or more pyrimidine analog antimetabolites comprise cytarabine, and wherein the cytarabine is administered at a dose of…” in claim 13 (and similar language in claim 21) renders the claim herein indefinite. Claim 13 depends from claim 10, and claim 10 depends from claim 9, and claim 1. Claim 1 already recites “two or more pyrimidine analogs comprise fludarabine and clofarabine”. Thus, the limitation of claim 13 is confusing. Claim 13 could be amended to clearly require cytarabine by reciting “further comprising cytarabine”.
Response to Arguments
Applicant's arguments filed 19 February 2026 have been fully considered but they are not persuasive.
Applicant contends Levy discloses many potential agents, resulting in hundreds of possible permutations without any guidance towards the specific three-agent regimen recited in amended claim 1.
The above argument is not found persuasive. Claim 1 is drawn towards requiring any anthracene derivative, and multiple pyrimidine antimetabolites, so long as they at least include fludarabine and clofarabine.
Levy is primarily concerned with treating cancers including leukemia with bisantrene dihydrochloride, an anthracene derivative. While Levy et al. teach a variety of additional agents that can be administered with the anthracene derivative, it is still relevant for teaching anthracene derivatives can be combined with the class of drugs known as pyrimidine antimetabolites.
Applicant contends Zhenchuk teaches clofarabine and fludarabine are purine analogs, not pyrimidine analogs.
The above arguments are not found persuasive to overcome the obviousness to combine an anthracene derivative with fludarabine and clofarabine, because Zhenchuk also teaches “although clofarabine is a purine analogue (as is fludarabine), its effects on lymphocyte subsets more closely resemble those of gemcitabine, a pyrimidine analog, in having a selective detrimental effect on the B-lymphocyte subset. This observation should be considered when developing appropriate combination regimens involving clofarabine” (p.1356, section 3.3).
The ordinary artisan would have been motivated to include the combination of fludarabine and clofarabine, because Zhenchuk found “cells resistant to fludarabine exhibited cross-resistance to cladribine, but not clofarabine.”. Thus, administering the combination increases the likelihood of successful treatment, because while some cancer cells may be resistant to fludarabine, they will be affected by clofarabine.
Applicant contends the amended claims no longer require cytarabine.
The above argument is not found persuasive, because the claims do not exclude cytarabine. Additionally, claim 13 is still directed towards cytarabine.
Applicant contends the specification provides evidence showing the claimed combination demonstrates unexpected synergy.
The above arguments are not found persuasive, because none of the text in the drawings are legible. Without legible drawings, a determination of unexpected results cannot be determined.
On 07 May 2026, a phone call was made to Applicant’s representative requesting submission of a file/digital copy of the drawings with better resolution. A follow-up call was made on the 18 May 2026. However, Applicant’s representative, was unable to provide a copy at the time of the call.
For the above stated reasons, said claims are properly rejected under 35 U.S.C. 103(a). Thus, the rejection is hereby maintained.
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.
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) 1, 3, 4, 9-11, 13, 17, 21, 25, 29-30, 32, 45 and 48-51 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. (WO2020/072948, cited in IDS submitted 03 May 2024) in view of Zhenchuk et al. (Biochemical Pharmacology, 2009, vol. 78, pp. 1351-1359, cited in previous Office Action).
Levy et al. disclose delivering bisantrene dihydrochloride to a patient in need of treatment (claim 28). The bisantrene is administered intravenously at a dosage of from about 200 mg/m2 to about 300 mg/m2 (abstract, claim 53). The bisantrene is used to treat acute lymphocytic leukemia of childhood and acute myelocytic leukemia (claims 57, 61 and 62). The method further comprises administering to the patient a therapeutically effective amount of an additional therapeutic agent (claims 56, 60, 61). The additional therapeutic agent is a pyrimidine antimetabolite selected from the group consisting of cytarabine, 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine, and 6-azauracil (claims 134-137). Additional therapeutic agents include fludarabine, and venetoclax (i.e. ABT-199), (claims 63, 69). In particular, fludarabine and venetoclax is indicated as useful for treating chronic lymphocytic leukemia (para [0097]). When two or more additional therapeutic agents are administered, each agent can be administered in its own composition, or if compatible they can be administered in a single composition (para [0105]).
While Levy et al. teach administering two or more additional therapeutic agents including one or more pyrimidine antimetabolites, Levy et al. do not expressly disclose administering two or more additional pyrimidine antimetabolites (present claim 1). Levy et al. do not expressly disclose “fludarabine and clofarabine” (present claim 1). Levy et al. do not expressly disclose the dose of clofarabine (present claim 25).
Zhenchuk et al. teach clofarabine was developed as a more efficacious and less toxic alternative to cladribine and fludarabine (abstract). While it’s a purine analogue, its effects on lymphocyte subsets show it functions more like a pyrimidine analog (p.1356, right col., section 3.3). A maximum tolerated dose for clofarabine for treating solid tumors was determined at 2 mg/m2 (p.1356, section 4). In another trial where patients were diagnosed with refractory acute leukemia and myelodysplastic syndrome, a good response rate was observed at 40 mg/m2 IV (p.1356, last para). It also showed promising results in elderly refractory AML patients at doses of 30 mg/m2/day for 5 days (p.1357, first para). In a trial with pediatric patients with ALL and AML, the maximum tolerated dose was 52 mg/m2. Another study involves a combination of clofarabine (30-40 mg/m2/day) with cytarabine (AraC; 20-100 mg/m2/day) was more effective in patients with AML and MDS than single agent treatment (p.1357, fourth para). Cells resistant to fludarabine did not exhibit cross-resistance to clofarabine (p.1354, section 2.4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer bisantrene in combination with two or more pyrimidine antimetabolites.
According to MPEP 2144.06: “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).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, the combination of bisantrene with one or more pyrimidine antimetabolites and venetoclax was suggested and encompassed by the teaching of Levy et al.. Furthermore, Levy et al. discuss how to formulate and administer more than one additional therapeutic agent. Thus, the skilled artisan would have been motivated to combine the two or more pyrimidine antimetabolites with bisantrene wherein they each produce different effects for the treatment of cancer.
While Levy et al. do not expressly disclose administering bisantrene within 12 hours after administration of the one or more pyrimidine analog antimetabolites, Levy et al. teach they both can be administered to treat AML. Thus, it would have been obvious to optimize the order of drug administration.
It would have been obvious to administer a combination of clofarabine and fludarabine, because cells resistant to fludarabine were susceptible to treatment with clofarabine. Thus, the combination increases the likelihood of successful treatment.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer 30-40 mg/m2 clofarabine with 20-100 mg/m2 cytarabine, because Zhenchuk et al. teach it was more effective in treating patients with AML and MDS than single agent treatment.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 33 is rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. and Zhenchuk et al. as applied to claims 1, 3, 4, 9-11, 13, 17, 21, 25, 29-30, 32, 45 and 48-50 above, and further in view of Itchaki et al. (Therapeutic Advances in Hematology, 2016, vol. 7, issue no. 5, pp.270-287, cited inprevious Office Action).
Levy et al. teach as discussed above.
Levy et al. do not expressly the dose of BH3 mimetic (present claim 33).
Zenchuk et al. teach as discussed above.
Itchaki et al. teach the use of venetoclax (ABT-199) as an orally bioavailable BH3-mimetic for treating chronic lymphocytic leukemia (CLL), (abstract). Itchaki et al. teach venetoclax has been administered at doses of 100 mg or 200 mg to patients with refractory CLL (p.275, second para). The final recommended dose of 400 mg is achieved in time (Table 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer 100-400 mg venetoclax to patients with ACL, because Levy et al. teach it can be used for treating lymphocytic leukemia or acute myelocytic leukemia. The ordinary artisan would have looked to Itchaki et al. for teaching recommended doses. The skilled artisan would have been motivated to administer 1.6 mg/kg to 6.6 mg/kg body weight, because Itchaki et al. teach administering 100 mg, 200 mg or 400 mg of venetoclax to patients in various clinical trials of treating patients with CLL. An average person weighing 60-70 kg would result in a dose of 1.6-6.6 mg/kg body weight.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 9, 10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. and Zenchuk et al. teach as discussed above as applied to claims 1, 3, 4, 9-11, 13, 17, 21, 25, 29-30, 32, 45 and 48-50 above, and further in view of Lowenberg et al. (N. Engl. J. Med., 2011, vol. 364, no. 11, pp. 1027-1036, cited in previous Office Action).
Levy et al. teach as discussed above.
Levy et al. do not expressly the dose of cytarabine (present claim 13).
Zenchuk et al. teach as discussed above.
Lowenberg et al. teach administering 200 mg/m2 as an intermediate dose of cytarabine per body surface area for treating acute myeloid leukemia (abstract). Like the high-dose group, it resulted in the same remission rate, probability of relapse, event-free survival at 5 years, and overall survival. The intermediate dose has the same therapeutic efficacy as the high-dose treatment without the toxic side effects.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer 200 mg/m2 cytarabine for treating acute myeloid leukemia, because it had the maximal therapeutic efficacy and minimal toxic side effects as taught by Lowenburg et al.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 9 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. and Zenchuk et al. as applied to claims 1, 3, 4, 9-11, 13, 17, 21, 25, 29-30, 32, 45 and 48-50 above, and further in view of Ricci et al. (Therapeutic and Clinical Risk Management, 2009, vol. 5, pp. 187-207, cited in previous Office Action).
Levy et al. teach as discussed above.
Levy et al. do not expressly the dose of fludarabine (present claim 17).
Zenchuk et al. teach as discussed above.
Ricci et al. teach the use of fludarabine for the treatment of chronic lymphocytic leukemia (CLL), (title). Efficacy of fludarabine can be increased by combining this agent with other chemotherapeutic and non-chemotherapeutic agent (abstract). Other nucleoside analogs useful for treating leukemia and lymphoma include cytarabine (ara-C) and cladribine (2CdA). Studies have shown cytarabine and cladribine have similar activity in treating B-cell chronic lymphocytic leukemia. Fludarabine can be infused at 25-30 mg/m2, or orally given at a dosage of 40 mg/m2 (p.188, Pharmacokinetics).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer fludarabine at a dose of 25-30 mg/m2 by infusion or 40 mg/m2 orally for the treatment of AML, because these are well known efficacious doses of the agent as taught by Ricci et al. for the treatment of CLL, wherein Levy et al. teach pyrimidine antimetabolites like fludarabine and cytarabine are effective in treating AML or CLL, alternative forms of leukemia.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 9-11, 13 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. and Zenchuk as applied to claims 1, 3, 4, 9-11, 13, 17, 21, 25, 29-30, 32, 45 and 48-50 above, and further in view of Mayer et al. (Eur. J. Haematol., 2020, vol. 104, pp. 538-545, cited in previous Office Action).
Levy et al. teach as discussed above.
Levy et al. do not expressly disclose the dose of cytarabine (present claim 13) or cladribine (present claim 21).
Mayer et al. teach administering a cycle of cladribine (5 mg/m2/12 h, d1-3), cytarabine (1000 mg/m2/12 h, d1-5) and idarubicin (12 mg/m2/d over 3 h, d1-3) for patients with acute myeloid leukemia (Table 1 and p.539, 2.2 Study design). The overall protocol showed encourage response rates, particularly for relapsed AML (p.544, last para).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer 5 mg/m2 cladribine and 1000 mg/m2 cytarabine, because Mayer et al. found this combination of doses was effective in treating relapse AML.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
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