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 .
Status of the Application
Claims 38-59 are pending
Claims 38-59 are under consideration in the instant office action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/30/2024 comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application claims benefit of U.S. Provisional Application No. 62/430,758 filed on 12/06/2016, PCT Application No. PCT/US2017/064589 filed on 12/05/2017, and U.S. Application No. 16/466,931 filed on 06/05/2019.16/466,931 filed on 06/05/2019.
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 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.
Claims 38-41, 48-54, and 57-59 are rejected under 35 U.S.C. 103 as being unpatentable over Castro et al. (In vitro and in vivo evaluation of anti-Trypanosoma cruzi activity of derivates of vitamin K, Sociedade Brasileira de Medicina Tropical, 2012, pg. 1, as disclosed in IDS), in view of Marim et al. (EFFECTS OF VITAMIN C SUPPLEMENTATION ON ACUTE PHASE CHAGAS DISEASE IN EXPERIMENTALLY INFECTED MICE WITH Trypanosoma cruzi QM1 STRAIN, Rev. Inst. Med. Trop. Sao Paulo, 2012, 54(6), pp. 319-323, as disclosed in IDS).
Castro is drawn towards the activity of Vitamin K derivatives against Trypanosoma cruzi, the etiologic agent of Chagas disease (pg. 1). Castro teaches that Vitamin K3 (which is a quinone compound recited in instant claims 38 and 49-54) provided effective inhibition of T. cruzi, and discloses benznidazole as a standard treatment against T. cruzi (pg. 1).
Castro does not teach inhibiting parasitic growth by further administering ascorbic acid.
Marim et al. is drawn towards the effects of vitamin C (i.e. L-ascorbic acid) supplementation on acute phase Chagas disease (see title). Marim et al teaches in the abstract that “The tissue changes that occur in Chagas disease are related to the degree of oxidative stress and antioxidant capacity of affected tissue. Studies with vitamin C supplementation did not develop oxidative damage caused by Chagas disease in the host, but other studies cite the use of peroxiredoxins ascorbate - dependent on T. cruzi to offer protection against immune reaction. Based on these propositions, thirty “Swiss” mice were infected with T. cruzi QM1 strain and treated with two different vitamin C doses in order to study the parasitemia evolution, histopathological changes and lipid peroxidation biomarkers during the acute phase of Chagas disease. The results showed that the parasite clearance was greater in animals fed with vitamin C overdose. There were no significant differences regarding the biomarkers of lipid peroxidation and inflammatory process or the increase of myocardium in animals treated with the recommended dosage. The largest amount of parasite growth towards the end of the acute phase suggests the benefit of high doses of vitamin C for trypomastigotes. The supplementation doesn’t influence the production of free radicals or the number of amastigote nests in the acute phase of Chagas disease.” Marim et al. further teaches that “group S parasitemia was lower than in groups P and R from the 10th to the 43rd day, suggesting that the vitamin C overdose orally administered to this group possibly allowed the immune system to temporarily take control of parasitic multiplication in the blood” (pg. 322, left column, fourth paragraph), and thus that the parasite clearance was greater in animals fed with vitamin C overdose (see abstract).
It would have been obvious to one of ordinary skill in the art to inhibit parasitic growth by further administering ascorbic acid and in the recited dosage forms and amounts with Vitamin K3, as suggested by Marim et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since Castro teaches that Vitamin K3 provided effective inhibition of T. cruzi, and discloses benznidazole as a standard treatment against T. cruzi (pg. 1). Marim et al. teaches that “group S parasitemia was lower than in groups P and R from the 10th to the 43rd day, suggesting that the vitamin C overdose orally administered to this group possibly allowed the immune system to temporarily take control of parasitic multiplication in the blood” (pg. 322, left column, fourth paragraph), and thus that the parasite clearance was greater in animals fed with vitamin C overdose (see abstract). Therefore, it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the particular formulation. Additionally, “[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).
Therefore, it would have been prima facie obvious to combine Vitamin C, benznidazole, and Vitamin K3 in a composition cojointly to inhibit T. cruzi.
Claims 55-56 are rejected under 35 U.S.C. 103 as being unpatentable over Castro et al. (In vitro and in vivo evaluation of anti-Trypanosoma cruzi activity of derivates of vitamin K, Sociedade Brasileira de Medicina Tropical, 2012, pg. 1, as disclosed in IDS) and Marim et al. (EFFECTS OF VITAMIN C SUPPLEMENTATION ON ACUTE PHASE CHAGAS DISEASE IN EXPERIMENTALLY INFECTED MICE WITH Trypanosoma cruzi QM1 STRAIN, Rev. Inst. Med. Trop. Sao Paulo, 2012, 54(6), pp. 319-323, as disclosed in IDS) as applied to claims 38-41, 48-54, and 57-59 above, and further in view of Jakobsen (WO 2009/063044, as disclosed in IDS).
The teachings of Castro et al. and Marim et al. are presented above.
Castro et al. and Marim et al. do not teach administering ascorbic acid and the quinone compound in the recited molar ratios.
Jakobsen is drawn towards the treatment of parasitic diseases, including Trypanosoma sp. (page 29 lines 7-8 and page 115 line 29), by administering compositions comprising Vitamin K3 (see abstract). Jakobsen teaches such compositions further comprising vitamins such as Vitamin C (claim 8; pg. 39, lines 4-11). Jakobsen teaches a dosage amount of about 1.0 mg to about 1000 mg, which can be administered one to six times daily (pg. 49, lines 25-31). Given that the molecular weight of Vitamin C is 176.12 g/mol and the molecular weight of Vitamin K3 is 172.18 g/mol, the dosage range for Vitamin C is about 5.68 x 10-6 mol to about 5.68 x 10-3 mol and about 5.81 x 10-6 mol to about 5.81 x 10-3 mol, which results in molar ratios of about 1:1022 to about 977:1.
It would have been obvious to one of ordinary skill in the art to administer ascorbic acid and the quinone compound in the recited molar ratios, as suggested by Jakobsen, and produce the instant invention.
Regarding the limitation of wherein the molar ratio of the ascorbic acid to the quinone compound ranges from about 50 to about 500, wherein the molar ratio of the ascorbic acid to the quinone compound is about 100, about 200, or about 400, Jakobsen teaches a dosage amount of about 1.0 mg to about 1000 mg, which can be administered one to six times daily (pg. 49, lines 25-31). Given that the molecular weight of Vitamin C is 176.12 g/mol and the molecular weight of Vitamin K3 is 172.18 g/mol, the dosage range for Vitamin C is about 5.68 x 10-6 mol to about 5.68 x 10-3 mol and about 5.81 x 10-6 mol to about 5.81 x 10-3 mol, which results in molar ratios of about 1:1022 to about 977:1.
Even though the range for dosages as taught by Jakobsen is not the same as the claimed dosages, Jakobsen does teach an overlapping range of dosages, and it has been held that in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP § 2144.05(I). Furthermore, the determination of dosages is well within the purview of those skilled in the art through routine experimentation, and it has been held that “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). See MPEP § 2144.05(II). It would have been obvious to one of ordinary skill in the art to optimize the dosage in order to increase the efficacy of the composition against Chagas disease. The amounts of active agents to be used, the pharmaceutical forms, e.g., tablets, etc; mode of administration, flavors, surfactant are all deemed obvious since they are all within the knowledge of the skilled pharmacologist and represent conventional formulations and modes of administration.
Furthermore, no unobviousness is seen in the ratio claimed because once the usefulness of a compound is known to treat a condition, it is within the skill of the artisan to determine the optimum ratio.
Claims 42-44 are rejected under 35 U.S.C. 103 as being unpatentable over Castro et al. (In vitro and in vivo evaluation of anti-Trypanosoma cruzi activity of derivates of vitamin K, Sociedade Brasileira de Medicina Tropical, 2012, pg. 1, as disclosed in IDS) and Marim et al. (EFFECTS OF VITAMIN C SUPPLEMENTATION ON ACUTE PHASE CHAGAS DISEASE IN EXPERIMENTALLY INFECTED MICE WITH Trypanosoma cruzi QM1 STRAIN, Rev. Inst. Med. Trop. Sao Paulo, 2012, 54(6), pp. 319-323, as disclosed in IDS) as applied to claims 38-41, 48-54, and 57-59 above and further in view of Docampo (Enhancement of the cytotoxicity of crystal violet against Trypanosoma cruzi in the blood by ascorbate, Molecular Biochemical Parasitology, 1988, 27(2-3), pp. 241-247, as disclosed in IDS).
The teachings of Castro, Marim et al., and Jakobsen are presented above.
Castro, Marim et al., and Jakobsen do not teach ascorbic acid in the form of sodium ascorbate for the inhibition of parasitic growth.
Docampo is drawn towards the use of ascorbate against Trypanosoma cruzi in the blood (see abstract). Docampo teaches that photoirradiation and addition of sodium ascorbate reduces significantly the effective dose and time of contact of crystal violet with T. cruzi-infected blood (see abstract).
It would have been obvious to one of ordinary skill in the art to administer ascorbic acid in the form of sodium ascorbate for the inhibition of parasitic growth, as suggested by Docampo, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since formulating ascorbic acid in the form of sodium ascorbate is conventionally practiced in the treatment against Trypanosoma cruzi as taught by Docampo, with a reasonable expectation of success absent evidence of criticality of the particular steps.
Claims 45-47 are rejected under 35 U.S.C. 103 as being unpatentable over Castro et al. (In vitro and in vivo evaluation of anti-Trypanosoma cruzi activity of derivates of vitamin K, Sociedade Brasileira de Medicina Tropical, 2012, pg. 1, as disclosed in IDS) and Marim et al. (EFFECTS OF VITAMIN C SUPPLEMENTATION ON ACUTE PHASE CHAGAS DISEASE IN EXPERIMENTALLY INFECTED MICE WITH Trypanosoma cruzi QM1 STRAIN, Rev. Inst. Med. Trop. Sao Paulo, 2012, 54(6), pp. 319-323, as disclosed in IDS) as applied to claims 38-41, 48-54, and 57-59 above and further in view of Aguilar et al. (Calcium ascorbate, magnesium ascorbate and zinc ascorbate added for nutritional purposes in food supplements, The EFSA Journal, 2009, 7(3): 994, pp. 1-22).
The teachings of Castro, Marim et al., and Jakobsen are presented above.
Castro, Marim et al., and Jakobsen do not teach the potassium, calcium, or magnesium salt of ascorbic acid for the inhibition of parasitic growth.
Aguilar et al. is drawn towards “the safety of calcium ascorbate, magnesium ascorbate and zinc ascorbate added for nutritional purposes to food supplements as sources of calcium, magnesium, zinc and vitamin C, and on the bioavailability of the nutrient cations from these sources as well as the vitamin C bioavailability from magnesium ascorbate and zinc ascorbate.” (pg. 1, 1st paragraph). Aguilar et al. teaches that the potassium, calcium, and magnesium salts of ascorbic acid are safe and approved for human use (pg. 9, paragraphs 5-7).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to formulate the potassium, calcium, or magnesium salt of ascorbic acid for the inhibition of parasitic growth, as suggested by Aguilar et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since the potassium, calcium, and magnesium salts of ascorbic acid are conventionally formulated in such forms since they are safe and approved for human use as taught by Aguilar et al., with a reasonable expectation of success absent evidence of criticality of the particular formulations.
Conclusion
Claims 38-59 are rejected.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
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