DETAILED ACTION
The present application is a national stage entry of PCT/US2022/012989, filed 19 January 2022, which claims priority to US Provisional Application No. 63/139,683, filed 20 January 2021.
The preliminary amendment filed 28 March 2024 is acknowledged. Claims 1, 3, 4, 8-13, 17, 21, 25, 29-30, 32-33, 45 and 48-50 are pending in the current application.
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 subject has been treated with or will be treated with one or more pyrimidine analog antimetabolites” in claim 1 includes an alternative subject population which is not required to have received a pyrimidine analog antimetabolite.
Specifically, the recitation “will be treated” is not an active step, and does not require the subject to be treated with one or more pyrimidine analog antimetabolites.
The recitation “wherein the one or more pyrimidine analog antimetabolites…”in claim 8 is not an active step, and does not require a pyrimidine analog antimetabolite to be administered.
The same rational applies to present claims 9-13, 17, 21, 25, 45 and 48-50.
To advance prosecution, these claims have been addressed under 35 U.S.C. §103 as if they were required steps.
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 48-50 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; and the recitation “bisantrene or a derivative or analog thereof” in claim 3 render the claims and dependent claims 4, 8-13, 17, 21, 25, 29-30, 32, 33, 45 and 48-50 herein indefinite.
According to the Specification “derivative” applied to the term bisantrene includes compounds having the same carbon skeleton as bisantrene, including the tricyclic aromatic nucleus and the two side chains attached to the tricyclic aromatic nucleus but has one or more substituents that replace at least one hydrogen present with another moiety (para [0081] of the present PGPub). Thus, the same parent compound is structurally present in a derivative of bisantrene.
The term “analog” includes compounds that are structurally related to bisantrene, but “having one or more of the tricyclic aromatic nucleus or one or more of the side chains altered, for example, by replacing one or more carbons in the tricyclic aromatic nucleus with nitrogens or by removing one or both of the side chains” (para [0081] of the present PGPub). Thus, the same parent compound is not necessarily present in an analog of bisantrene.
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.
The recitation “CNDAC” in claim9 renders the claim herein indefinite. Acronyms or abbreviations can be interpreted differently depending on the context and the art. The term “CNDAC” is not defined in the Specification. To render the claim definite, it is respectfully suggested that Applicants spell out what they intend to claim or clearly identify the claimed agents, rather than use acronyms or abbreviations. If Applicants intend to use acronyms or abbreviations in the claims, it is respectfully suggested that the acronym or abbreviation first be spelled out along with the acronym where it is first used in a claim before use of the acronym or abbreviation in subsequent claims.
Clarification is required.
The recitation “mg/kg” and “mg/m2” throughout claims 4, 13, 17, 21, 25 and 33 render the claims herein indefinite. There is no indication as to what “kg” and “m2” define. Clarification is required.
The recitation “wherein the one or more pyrimidine analog antimetabolites comprise fludarabine and clofarabine” in claim 12 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.
Claim Rejections – 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3, 4, 8-13, 17, 21, 25, 29-30, 32, 45 and 48-50 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Levy et al. (WO2020/072948, cited in IDS submitted 03 May 2024).
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]).
Thus, Levy et al. disclose administering bisantrene dihydrochloride (a derivative or analog of bisantrene), at least one or more pyrimidine antimetabolite analogs including cytarabine, and a BH3 mimetic to treat cancer including acute lymphocytic leukemia of childhood and acute myelocytic leukemia.
Thus, the disclosure of Levy et al. anticipates claims 1, 3, 4, 8-13, 17, 21, 25, 29-30, 32, 45 and 48-50 of the present application.
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, 8-13, 17, 21, 25, 29-30, 32, 45 and 48-50 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. (cited above).
Levy et al. teach as discussed above.
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 claims 8, 11, 12).
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.
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. as applied to claims 1, 3, 4, 8-13, 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 in PTO-892).
Levy et al. teach as discussed above.
Levy et al. do not expressly the dose of BH3 mimetic (present claim 33).
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 CLL, because Itchaki et al. teach these amounts were administered 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 mg/kg to 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. as applied to claims 1, 3, 4, 8-13, 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 PTO-892).
Levy et al. teach as discussed above.
Levy et al. do not expressly the dose of cytarabine (present claim 13).
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, 10 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. as applied to claims 1, 3, 4, 8-13, 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 PTO-892).
Levy et al. teach as discussed above.
Levy et al. do not expressly the dose of fludarabine (present claim 17).
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 CLL, because these are well known efficacious doses of the agent as taught by Ricci et al.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Claim(s) 8-11, 13 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. as applied to claims 1, 3, 4, 8-13, 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 PTO-892).
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.
Claim(s) 8-13 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Levy et al. as applied to claims 1, 3, 4, 8-13, 17, 21, 25, 29-30, 32, 45 and 48-50 above, and further in view of Zhenchuk et al. (Biochemical Pharmacology, 2009, vol. 78, pp. 1351-1359, cited in PTO-892).
Levy et al. teach as discussed above.
Levy et al. do not expressly disclose “fludarabine and clofarabine” (present claim 12). 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 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.
Additionally, 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 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.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
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