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 .
Claims 1-5 are presented for examination on the merits.
For purposes of examination the claims are given their broadest reasonable interpretation (BRI) in light of the specification. Since the specification at paragraph [0028] states that, the supercritical fluid may be selected from the group consisting of supercritical carbon dioxide (CO2), water (H2O), methanol, and ethanol, the composition employed in the claims can contain any product of Agaricus blazei Murrill extracted with any of these solvents.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-5 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for inhibiting inhibiting the growth of the lung adenocarcinoma cells, gastric adenocarcinoma cells, liver cancer cells, colorectal cancer cells, and breast cancer cells with to a supercritical CO2 extract Agaricus blazei Murrill prepared as specified in paragraph [0051] of the instant specification, does not reasonably provide enablement for inhibiting any and all cancer cell growth by any and all supercritical fluid-extracted products of Agaricus blazei Murrill. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
Undue experimentation would be required to practice the invention as claimed due to the quantity of experimentation necessary; limited amount of guidance and limited number of working examples provided in the specification; nature of the invention; state of the prior art; relative skill level of those in the art; predictability or unpredictability in the art; and breadth of the claims. In re Wands, 8USPQ2d 1400, 1404 (Fed. Cir. 1988).
Applicant’s claims are drawn to a method of inhibiting the growth of any cancer cells by a administering a composition containing any supercritical fluid-extracted product of Agaricus blazei Murrill, which means any product of Agaricus blazei Murrill extracted with any of the solvents of supercritical carbon dioxide (CO2), water (H2O), methanol, and ethanol.
Regarding the extraction solvent used to obtain the claims product with anti-inflammatory properties, it is well known in the art that polarity of solvents plays a key role in determining the final product obtained by an extraction. However, because many phytochemicals remain undiscovered, the skilled artisan has to make his/her best educated guess as to what types of phytochemicals will be successfully extracted with a solvent of a particular polarity. Oftentimes, unless the constituents in a particular natural product extract have been well evaluated and documented in the literature, the skilled artisan must adhere to trial and error protocols in order to quantitatively determine phytochemical constituents present in samples obtained from respective extraction procedures. These procedures are common when, for example, a natural product or part thereof has been documented in the literature as possessing some medicinal quality. The skilled artisan will attempt numerous extraction protocols in an attempt to isolate particular ingredient(s) that have medicinal efficacy. Typically, beginning with the first crude extraction, it is a guess as to whether or not the extract will possess certain phytochemical constituents. For example, unpredictability with regard to natural extracts due to their highly complex nature has been well documented. Revilla et al. (J. Agric. Food Chem. (1998), vol. 46, pp. 4592-4597) showed that the slightest variations in polarity of solvent and reaction time upon grape extraction provided respective products with unique characteristic properties (See tables 1, 2, 4, 5, 6 and 7 in Revilla). In turn, each product would possess varying pharmacological properties based upon their respective methods of extraction.
There is well-known unpredictability regarding natural product extracts and their e.g., pharmaceutical capabilities. The resulting compositions and thus functional properties of an extraction process are highly dependent on the particular steps of the extraction and the extraction solvent employed
Raskin et al. clearly establish the grave unpredictability of elucidating active ingredients from natural sources:
Multi-component botanical therapeutics also present unique challenges in identifying their active ingredients and in validating their clinical effects. Activity-guided fractionation and reconstitution experiments currently used to characterize compound interferences within a mixture are cumbersome and time consuming…..While chromatographic analysis is often employed to produce biochemical fingerprints used for product comparison…..in the absence of information about the identity of active ingredients, such analysis is hardly reliable, since chromatography provides an incomplete picture of the qualitative and quantitative comparison of a complex extract (p. 3426, col. 2 – p. 3427, col. 1) emphasis added.
Thus, the functional property of an extract of is not considered to be predictable because the type of extraction used to produce the extract would have a significant impact on the chemical characteristics of the extract.
See e.g., In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970), held that "Inventor should be allowed to dominate future patentable inventions of others where those inventions were based in some way on his teachings, since such improvements while unobvious from his teachings, are still within his contribution, since improvement was made possible by his work; however, he must not be permitted to achieve this dominance by claims which are insufficiently supported and, hence, not in compliance with first paragraph of 35 U.S.C. 112; that paragraph requires that scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; in cases involving predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific law; in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved."
The specification does not provide any specific guidance to show that any and all supercritical fluid-extracted products of Agaricus blazei Murrill (that is – as defined by Applicant) have the claimed functionality. An artisan would have to test every potential extraction technique with a number of solvents as well as well as modify the various extraction conditions to determine if it is able to inhibit cancer cell growth. This degree of experimentation clearly places an undue burden on the artisan of ordinary skill. The specification only provides testing data that a supercritical CO2 extract Agaricus blazei Murrill prepared as specified in paragraph [0051]. Given the wide range of possible resulting extracts that could potentially result from various extraction methods, the presence of a single example of an extract that possesses anti-cancer properties provides insufficient guidance to the person to practice the invention.
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) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
It was known at the time of the date of filing the instant Application that products extracted from Agaricus blazei Murrill could inhibit the growth of cancer cells.
For example, Bertollo et al. provides an extensive review of the anti-cancer effects of Agaricus blazei Murrill.
Kim et al. (2009) [cited by Applicant in IDS filed 4/15/24] beneficially disclose that an hydro-ethanolic extract product of Agaricus blazei Murrill could inhibit the growth of cancer cells in nude mice bearing xenogenic human promyelocytic leukemia NB-4 cells.
It was further known that supercritical fluid extraction (SFE) of Agaricus blazei Murrill could extract beneficial phytochemicals. For example,
Mazzutti S. et al. (2012) [cited by Applicant in IDS filed 4/15/24] beneficially disclose that Agaricus brasiliensis is mushroom that reached the top ranking of the best medicinal and culinary mushrooms. This mushroom has been widely studied in the areas of food science, medicine, biotechnology and pharmacology and concerning medical aspects, many works have reported that A. brasiliensis presents antibacterial, antioxidant, antidiabetic, antiangiogenic, and anticancer activities. The reference further discloses that extracts from the mushroom Agaricus brasiliensis using super critical fluid extraction (SFE) with pure CO2 and with CO2plus 2.5%, 5.0% and 10.0% (w/w) of ethanol as co-solvent. In order to evaluate the high-pressure method in terms of process yield, extract composition and biological activity, low-pressure methods, such as maceration with ethanol (Mac), Soxhlet (Sox) with different organic solvents, and hydrodistillation (HD), were also applied to obtain extracts. The SFE conditions were temperatures of 313.15 K, 323.15 K and 333.15 K and pressures from 10 to 30 MPa. The SFE kinetics was investigated through the overall extraction curve (OEC). The extracts obtained by Sox with water and ethanol showed the best results for the global extraction yield. The best conditions in the studied range to obtain high yields using pure CO2resulted to be 30.0 MPa and 323.15 K. The antioxidant potential of the extracts was evaluated by the DPPH method and by the Folin–Ciocalteau method. Maceration extract presented low yield, but good results of antioxidant activity by DPPH assays and total phenolic. The antimicrobial activity of the extracts was also studied. The main identified compounds in the extracts were linoleic and palmitic acids.
Matsushita et al. (2018) beneficially teach that the hot water extract of A. blazei significantly inhibited the proliferation of cultured pancreatic cancer cells through the induction of G0/G1 cell cycle arrest and caspase-dependent apoptosis; the effect was the smallest in HPDE cells. Furthermore, significant alterations in the global gene expression profiles of pancreatic cancer cells occurred following treatment with the hot water extract of A. blazei. Genes associated with kinetochore function, spindle formation, and centromere maintenance were particularly affected, as well as cyclins and cyclin-dependent kinases that are essential for cell cycle progression. In addition, proapoptotic genes were upregulated.
Misgiati et al. (2017) beneficially teach that ABM (Agaricus blazei Murill) is used by people for the treatment of diabetes, antihypertention, anticholesterol, anticancer, and immunostimulant. ABM contains terpene, steroids, agaritine, vitamin C, vitamin E, and betaglucane. In this research, ABM extract was tested as an anti-breast cancer in vitro using MCF-7 breast cancer cells. The extract was obtained from the multistage extraction process of several solvents in turn, the solvent used, among others, n-hexane, dichloromethane (DCM), chloroform, ethyl acetate, butanol, and water. The results of the research were the obtained IC50 value from n-hexane extract 247.17 μg/mL; extract DCM 227μg/mL; chloroform extract 215.64 μg/mL; extract of ethyl acetate 234.9 μg/mL; butanol extract 500,78 μg/mL; while the water extract was inactive. Based on these results can be considered for further research to fractionate in order to know which class compounds have the potency as anticancer within the extracts.
Furthermore, it was known in the prior art that extracts of Cucuma longa and Ganoderma lucidum have anticancer effects. For example:
Naama et al. (2010) beneficially teach Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice, derived from the rhizome of the plant Curcuma longa. In India and Southeast Asia, turmeric has long been used as a treatment for inflammation, skin wounds and tumors. Curcumin has broad spectrum cancer chemo preventive activity in preclinical animal models. The extract of the herb curcumin, from Iraqi curcumin, was done by using of 95% ethanol as a solvent, then isolation of curcumin from the ethanolic extract by column chromatography, curcumin was characterized by Uvvisible, FT-IR and proton NMR spectroscopy. The study of anticancer activity of the curcumin and ethanolic extract were done in vivo on mice and in vitro on cell line. The extract showed a considerable anticancer activity against the cell line of human hepato cellular liver carcinoma.
Zhu et al. (2020) beneficially disclose that Ganoderma lucidum (G. lucidum) has been reported to have a number of pharmacological effects such as anti-tumor and liver protection. Compared with the common ethanol reflux method, supercritical CO2 extraction has obvious advantages in obtaining antitumor extracts from G. lucidum fruiting body such as short extraction time, low temperature and no solvent residue. However, using high pressure supercritical CO2 without entrainer to obtain the antitumor extracts from G. lucidum and studying their anti-hepatoma effect have not been reported. In this study, high-pressure supercritical CO2 extracts obtained under 65, 85, and 105 MPa pressure named as G65, G85, G105 respectively and ethanol reflux extract (GLE) were used to investigate their antihepatoma activity and the underlying molecularmechanism. The total triterpenoid content of G85 was significantly higher than that of G65 and GLE, but did not differ significantly from that of G105 by UV and high-performance liquid chromatography. GLE, G65, andG85 could inhibit cell proliferation, arrest cell cycle in G2/M phase, and induce apoptosis in two liver cancer cell lines (QGY7703 and SK-Hep1), of which G85 had the strongest effect. The results showed that the potency of their cytotoxicity of the high-pressure supercritical CO2 extracts on human hepatoma carcinoma cells in vitro was consistent with their total
triterpenoid content. G85 exhibited significant anti-hepatoma effect with low toxicity In vivo. Further mechanistic investigation revealed that the anti-tumor effect of these extracts was associated with their inhibition of Ras/Raf/MEK/ERK signaling pathway. Our findings suggest that the high-pressure supercritical CO2 extraction of G. lucidum fruiting body can be used to obtain a triterpenoid-rich anti-tumor agent, which may have potential clinical significance for the treatment of human hepatoma.
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to combine the instant ingredients for their known benefit since each is well known in the art for the same purpose and for the following reasons: each of the extracts of Agaricus blazei Murrill, Curcuma longa and Ganoderma lucidum are known individually to possess anticancer properties. In KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court reaffirmed "the conclusion that when a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273,282 (1976)). The Supreme Court also emphasized a flexible approach to the obviousness question, stating that the analysis under 35 U.S.C. § 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418; see also id. at 421 ("A person of ordinary skill is... a person of ordinary creativity, not an automaton."). The Supreme Court thus implicitly endorsed the principle, stated in In re Kerkhoven, 626 F.2d 846, 850 (CCPA 1980) (citations omitted), that: 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 which is 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.
[0028] According to the present disclosure, the supercritical fluid may be selected from the group consisting of supercritical carbon dioxide (CO2), water (H2O), methanol, and ethanol. In certain embodiments, the supercritical fluid is supercritical CO2.
The adjustment of particular conventional working conditions is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. V. Biocraft Labs. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989) As both dosages, routes of administration, dosage frequency and timing are known to the ordinary artisan, it would have been obvious to optimize the mode of administration as well as dosage amounts and frequency. It also would have been prima facie obvious to optimize the dosage regimen for an additive or synergistic therapeutic result because the general conditions of the dosages are disclosed in the prior art and it is not inventive to discover the optimum or workable ranges by routine experimentation and the art expects that dosages of the invention will vary depending upon such factors as the subject's age, weight, height, sex, general medical conditions and previous medical conditions.
Accordingly, the instant claims, in the range of proportions where no unexpected results are observed, would have been obvious to one of ordinary skill having the above cited references before him/her.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUSSELL G FIEBIG whose telephone number is (571)270-5366. The examiner can normally be reached M-F 8-4.
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/RUSSELL G FIEBIG/ Examiner, Art Unit 1655
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