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
The Preliminary Amendment filed on 8/07/2023 is acknowledged. Claims 1-16 are currently pending and under consideration.
Information Disclosure Statement
The information disclosure statement filed on 8/14/2023 has been considered except where lined through.
Specification
The disclosure is objected to because of the following informalities: The specification at page 2, line 5 references US Patent No 8,053,422 as disclosing the compound referred to as KAE609 which appears to be incorrect. The correct US Patent No appears to be 8,053,442 B2..
Appropriate correction is required.
Claim Interpretation
Claim 1 is drawn to a composition comprising N, N’-bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester (KAE609). However, there is no support in the specification for any formulations comprising this compound, nor for its use in treating malaria. A review of the prior art indicates that the claimed compound is not referred to as KAE609. Instead, the compound is referred to as Evofosfamide having the structure:
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, which is a compound being evaluated for the treatment of multiple tumors. The specification does teach a compound referred to as KAE609 which is a spiroindolone having the structure:
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which is consistent with the CAS registry numbers associated with this application. Accordingly, for prior purposes, the compound recognized in the art as KAE609 will be searched for prior art purposes.
Claim Rejections - 35 USC § 112
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.
Claims 1-16 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.
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 “N, N’-bis(2-bromoethyl)phosphorodiamidic acid (1-methyl-2-nitro-1H-imidazol-5-yl)methyl ester” in claim 1 is used by the claim to mean “KAE609,” while the accepted meaning is “1’R,3’S)-5,7’-dicholoro-6’-fluoro-3’-methyl-2’,3’,4’,9’-tetrahydrospiro[indoline-3-1’-pyrido[3’-4-b]indo]-2-one.” The term is indefinite because the specification does not clearly redefine the term.
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.
Claim(s) 1-5 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lakshminarayana et al. (Antimicrobial Agents and Chemotherapy (2015), 59(2), 1200-1210) in view of Magee et al. (Drug Development and Industrial Pharmacy (2003), 29(6), 441-450, IDS).
Lakshminarayana et al. teach pharmacokinetic-pharmacodynamic analysis of spiroindolone analogs and KAE609 in a murine malaria model (Title). With regards to the pharmacokinetic studies, Lakshminarayana et al. teach that the compounds were formulated at a concentration of 1mg/ml for a dose of 5 mg/kg given intravenously, wherein the solution formulation for i.v. dosing contained 10% ethanol, 30% PEG 400 and 60% 10% vitamin E TPGS (page 1202, 1st column, lines 3-6).
While Lakshminarayana et al. teach that the composition comprises PEG 400 and vitamin E TPGS, the prior art does not specifically teach that the composition comprises mixed micelles comprising the first and second surfactant or micelle forming agents.
Magee et al. teach that bile salts and lecithin combine physiologically to form mixed micelles which aid in the solubilization and absorption of dietary fats and drug molecules (abstract). Moreover, Magee et al. teach that when administered parentally as a vehicle incorporating amphotericin B, a bile salt mixed micelle system was seen to be nontoxic at doses of up to 100 mg.kg, and more effective in treating murine candidal infections than the non-mixed micelle formulation (page 442, 1st paragraph). Furthermore, Magee et al. teach that the solubility of Taxol was improved substantially by incorporating it into a bile salt/phosphatidylcholine mixed micellar system (page 442, 1st paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the formulation taught by Lakshminarayana et al. to include mixed micelles such as bile salt and lecithin in view of the teachings of Magee et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Magee et al. teach that bile salt/lecithin mixed micelles aid in the solubility of drug molecules and, has been shown to increase the effectiveness of drug molecules compared to non-mixed micelles.
Claim(s) 6, 8-9 and 11-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Lakshminarayana et al. (Antimicrobial Agents and Chemotherapy (2015), 59(2), 1200-1210) in view of Magee et al. (Drug Development and Industrial Pharmacy (2003), 29(6), 441-450, IDS), as applied above to claim 1-5 and 7, in further view of White et al. N. Engl. J. Med. (2014) 371:5, 403-410, IDS)
The combination of Lakshminarayana et al. and Magee et al. have been described above and incorporated herein. In short, the combination of Lakshminarayana et al. and Magee et al. teach a composition comprising KAE609, lecithin and a bile salt, wherein the composition was intravenously administered to mice at a KAE609 concentration of 1mg/ml for a dose of 5 mg/kg.
The combination does not teach a method of treating malaria in a human comprising administering said composition. Moreover, the combination does not teach that KAE609 was administered in an amount of 10mg/ml to about 40 mg/ml for at least 5 days.
White et al. teach a phase 2 open-label study to assess the antimalarial efficacy, safety and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days in patients with P. vivax malaria or P.falciparum malaria (Abstract, Methods). Specifically, the reference teaches that 10 mg capsule of KAE609, for a total dose of 30 mg was administered orally with water once daily for 3 days (page 404, 2nd column, Treatment and Procedures). White et al. further teaches that KAE609, at a dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax malaria or P.falciparum malaria (Abstract, Conclusion).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to utilize the composition taught by the combination of Lakshminarayana et al. and Magee et al. for the treatment of malaria in a human in view of the teachings of White et al. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-White teaches that KAE609, at a dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax malaria or P.falciparum malaria.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the amounts of KAE609 in the composition taught by the combination of Lakshminarayana et al. and Magee et al. for humans as well as optimize the frequency and duration of administration. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-White teaches that KAE609, at a dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax malaria or P.falciparum malaria and,
-the combination of Lakshminarayana et al. and Magee et al. teach that the composition was intravenously administered to mice at a KAE609 concentration of 1mg/ml for a dose of 5 mg/kg..
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[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) .
Claim(s) 10 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Lakshminarayana et al. (Antimicrobial Agents and Chemotherapy (2015), 59(2), 1200-1210) in view of Magee et al. (Drug Development and Industrial Pharmacy (2003), 29(6), 441-450, IDS) and White et al. N. Engl. J. Med. (2014) 371:5, 403-410, IDS), as applied above to claim 1-9, 11-14, in further view of Burrows et al. (Malar. J. (2017) 16:26, 1-29).
The combination of Lakshminarayana et al., Magee et al. and White et al. as set forth above teach a method of treating malaria in a human, comprising administering a composition comprising KAE609, lecithin and a bile salt.
The combination does not teach a method of treating severe malaria in a human comprising administering said composition.
Burrows et al. reviews the new developments in anti-malarial target candidates and product profiles (Title). In particular, Burrows et al. teach that in severe malaria, patients are often unconscious or otherwise to sick to take oral medications (page 11, 2nd column, 2nd full paragraph). Burrows et al. further teach that because artesunate resistance has been a concern for almost a decade, ultimately a new fast acting compound may be needed to treat severe malaria (page 13, 1st column, 1st full paragraph). Moreover, Burrows et al. teach that amongst the current portfolio of TCP-1 molecules, KAE609 clears parasites more rapidly than artesunate and could have value in severe malaria if a parental formulation were available (page 13, 1st column, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to include a patient with severe malaria in the method taught by the combination of Lakshminarayana et al., Magee et al. and White et al. in view of the teachings of Burrows. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-the combination of Lakshminarayana et al., Magee et al. and White et al. teach a parenteral formulation comprising KAE609.
-Burrow et al. acknowledges the value of KAE609 for treating severe malaria because it clears parasites more rapidly than artesunate.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Lakshminarayana et al. (Antimicrobial Agents and Chemotherapy (2015), 59(2), 1200-1210) in view of Magee et al. (Drug Development and Industrial Pharmacy (2003), 29(6), 441-450, IDS) and White et al. N. Engl. J. Med. (2014) 371:5, 403-410, IDS), as applied above to claim 1-9, 11-14, in further view of Alven and Aberibigbe (Molecules 2019, 24, 3601, 1-26).
The combination of Lakshminarayana et al., Magee et al. and White et al. as set forth above teach a method of treating malaria in a human, comprising administering a composition comprising KAE609, lecithin and a bile salt.
The combination does not teach a method of treating malaria in a human comprising administering said composition in combination with another antimalarial drug.
Alven and Aberibigbe teach that the major reason for the great mortality caused by malaria infections globally is drug resistance, wherein combination therapy is a promising approach that is currently employed to overcome drug resistance (page 1, Introduction, 2nd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the methods taught by the combination of Lakshminarayana et al., Magee et al. and White et al. to include another antimalarial agent in view of the teachings of Alven and Aberibigbe. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Alven and Aberibigbe teach that combination therapy is a promising approach that is currently employed to overcome drug resistance.
Conclusion
Therefore, No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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/BRANDON J FETTEROLF/ Primary Examiner, Art Unit 1626