Technological prospection: the genus Mikania in therapeutic use

The genus Mikania (Asteraceae) comprises about 450 species of these, 203 are found in Brazil and present several chemical and biological activities. Considering the variety of species and their therapeutic properties, the present study aimed to perform technological prospecting of this genus, since this approach aims to contribute to technological, scientific and innovation research. For this purpose, the patent documents were analyzed, regarding the applicant countries, year of filing and the international classification of patents of the genus Mikania. The search was conducted in the databases World Intellectual Property Organization (WIPO), European Patent Office (EPO) and the National Institute of Industrial Property (INPI) in October 2020, using the descriptor “Mikania”; present in the title and/or abstract in addition, documents that included medicinal approaches were selected. Thus, taking into consideration the filing countries, Japan, Brazil and the United States led the patent deposits, with the first document filed in 1991 and the largest number of applications in the years 2000 and 2010. The data concerning the international patent classification are concentrated in subclass A61K, which deals with preparations for medical, dental or hygienic purposes. These results demonstrated the therapeutic and technological potential of the Mikania species and thus which can be evidenced the potential of this study.

Some secondary metabolites that present pharmacological activities have already been identified in several parts of Mikania. Among the main chemical classes present in this genus, the following stand out coumarins and derivatives, sesquiterpenes, sesquiterpene lactones, diterpenes, phytosterols/terpenoids and flavonoids (Rufatto, Gower, Schwambach, & Moura, 2012).
Pharmacological studies show that Mikania species have activities in the respiratory tract, anti-inflammatory, hypoglycemic, antioxidant, antiallergic, analgesic (Coutinho et al., 2020;Silva et al., 2018). The proof of the therapeutic potential of the genus facilitates research strategies and investigation of applicability in the areas of innovation and biotechnology. The survey of patents and publications enables the direction of knowledge for production and technological, scientific and economic development, in addition to issues that facilitate decision making (Correia, Júnior, Spósito, & Pungartnik, 2020;Pires, Ribeiro, & Quintella, 2020).
In this context, the objective of this study was to carry out a technological prospection on the Mikania genus, in order to verify the market trends of pharmaceutical products developed from its species, as well as to relate the patent deposits found with other scientific productions on this genus.

Methodology
The search was conducted in the databases of the World Intellectual Property Organization (WIPO), the European Patent Office (EPO) and the Brazilian National Institute of Industrial Property (INPI), considering all patent filings until October 2020. The term "Mikania" was used as a descriptor, and the patents that presented the descriptor in the title or abstract were analyzed. In order to refine the search results, only patents with a medicinal approach were included, as well as pharmaceuticals and cosmetics. Duplicate patents within the same database were excluded (Silva et al., 2015).
The patents obtained were analyzed according to the country of origin, year of publication, International Patent Classification (IPC) and the Mikania species used. The data obtained were presented in graphs and figures processed in the Origin ® software, version 8.0.

Results and Discussion
Using the descriptor "Mikania" and the preliminary criteria established, 234 patents were identified, 108 patents in WIPO, 119 in EPO and 07 in INPI. After analyzing the patents found and including only those with a medicinal approach, 34 patents were selected for this technological prospection study (WIPO -21 patents; EPO -10 patents; and INPI -03 patents).

Analysis of the WIPO database data
Of the 21 selected patents, it was observed that one patent was duplicated, but with different CIP and filing countries.
For the purposes of this technological prospection, only the patent with the oldest filing date was considered, resulting in 20 patents found in WIPO. Thus, Table 1 describes the title, identification number, a brief description of the patents and the Mikania species analyzed in each patent found in WIPO. Research, Society and Development, v. 10, n. 14, e333101422076, 2021 (CC BY 4.0)

Title a Patent Description b Species
Aerosol cosmetic Cosmetic suppression in aerosol with vegetal extracts and with excellent stability. Mikania sp.

Antioxidative stress agent
Antirust stressing agent derived from the natural product that accelerates the improvement activities of the Antioxidant Response Element (ARE) in a path Erythroid-2 Nrf2/ARE related nuclear factor participating in the oxidative stress, thus inducing the expression of an antioxidative enzyme to mitigate the oxidative stress.

M. glomerata
Composicion farmaceutica y metodo de tratamento utilizando dicha composicion Extract derived from plants that have active components capable of inhibiting the lethal effects of a poisonous animal poison, the extracts being combined with an acceptable pharmaceutical vehicle and combined in an effective proportion to inhibit the lethal effects of the poison.

M. guaco
Composition for suppressing emission of odor Odor emission suppressive composition is formulated with plants of several genres.

M. lindleyana
Formulações farmacêuticas a partir do extrato etanólico das folhas de Mikania glomerata Sprengel Production of an anxiolytic agent and central nervous system depressant, obtained from the ethanolic extract of the leaves of the plant M. glomerata Sprengel.

M. glomerata
Fremgangsmåde til fremstilling af mikania-ekstrakter, som indeholder mikanolid og dihydromikanolid, og anvendelse i behandlingen af prolifererende sygdomme Inhibitors of DNA polymerase, extracts enriched with mikanolide and dihydromikanolide or mixtures that can be used for the preparation of drugs for the treatment of proliferative diseases, particularly cancer, viral diseases, or parasitic diseases caused by protozoa or protists.

M. scandens
Herbal compositions for management of bone disorders and methods thereof Pharmaceutical phytotherapic preparation to natural treatment and management of metabolic bone disorders with antiosteotetotic potential composed of M. micrantha and Zinziber officinale as active ingredient and at least one acceptable pharmaceutical excipient. The herbal preparation of this publication is economical and exhibits minimal side effects. The neuritis growth agent comprises compounds of various plants. A preventive/therapeutic agent for neurodegenerative diseases, a preventive/therapeutic agent for Alzheimer's and dementia diseases and food are provided, each comprising the neuritis growth agent.

M. glomerata
New 11-membered ring compound New 11-member ring compound expressed by a specific and useful structural formula as a carcinostatic agent, among others. The compound can be produced by extracting the dry leaf and stalk of M. hirsutissima with ethanol, concentrating the extract under reduced pressure and purifying the concentrate by column chromatography.

M. hirsutisima
Un nouveau medicament, le dihydromikanolide, son obtention par extraction de la plante Mikania micrantha et son utilisation comme agent antiproliferatif Anti-proliferative agent, from dihydromikanolide-enriched extracts as well as dihydromikanolide. It is also intended to obtain them by extraction of the plant M. micrantha.

M. micrantha
Research, Society and Development, v. 10, n. 14, e333101422076, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i14.22076 5 Pharmaceutical composition and method of treatment utilizing the composition An antivenom composition composed of extracts of active components of the plants combined in effective proportions; the method of elaboration of this composition; the pharmaceutical products derived from these extracts of active components; and a method of treatment of snake bites, scorpion bites and similar using this composition.

M. guaco
Procedimiento de preparacion de extractos de Mikania que contienen mikanolida y dihidromikanolida y utilizacion en el tratamiento de enfermedades proliferativas Drugs as antiproliferative agents, extracts enriched with dihydromikanolide, obtained by extraction of M. micrantha. The effects of a treatment using the compounds of the invention in the incorporation of cytosine marked with 32P to a presence of DNA of DNA polymerase (acellular system); the incorporation of tritiated thymidine in the DNA of the tumor cells in division for a short period of time (cellular system); proliferation of two human cellular lines Mia-Paca2 and Du145.

M. cordata M. micrantha M. scandens
Process for preparing Mikania extracts containing mikanolide and dihydromikanolide and use in the treatment of proliferative disorders Polymeric DNA inhibitors, i.e., mikanolide, dihydromikanolide and dihydromikanolide-enriched extracts. These compounds or mixtures can be used to prepare drugs for the treatment of proliferative diseases such as cancer, viral diseases, or parasitic diseases caused by protozoa or prothesisists.

M. cordata M. micrantha M. scandens
Verfahren zur herstellung von Mikania extrakten enthaltend mikanolide und dihydromikanolide und verwendung in der behandlung proliferativer erkrankungen Dihydromikanolide-enriched extracts in the form of drugs and, in particular, in the form of antiproliferative agents from preparation by extraction of the plant M. micrantha.

M. cordata M. micrantha M. scandens
Processo de preparação de extratos secos padronizados de Mikania sp., Asteraceae (Guaco), extratos secos padronizados assim obtidos e aplicações Standardized dry vegetal extract in coumarin and o-cumaric acid, elaborated from the extraction, characterization, standardization, and drying of a guaco extract. The dry extract showed antiulcerogenic activity in the model and Indometacin-induced ulcers. The production of dry extracts by spray drying from the leaves of Mikania sp. can be an interesting and promising alternative to obtain this raw material.
Processo para extração de frações do extrato hidroalcoólico da Mikania glomerata; fração MG1 obtida pelo processo; composição farmacêutica contendo a dita fração e uso terapêutico da composição em doenças respiratórias em geral Obtaining fractions from the hydro-alcoholic extract of M. glomerata leaves with dilating activity of the respiratory smooth, anti-edema and anti-allergic musculature. The organic fraction presented great dilating activity of the respiratory smooth muscle much more intense than the dry residue of the hydro-alcoholic extract. The inorganic fraction also presented anti-edema activity in mice and anti-allergic action in rats. From the inorganic fraction, gelatinous capsules containing this fraction were prepared and when tested in chronic asthmatic patients it showed anti-asmatic activity.

M. glomerata
Sirompas para (Mikania micrantha) sebagai salah satu alternatif obat ramuan pada pengobatan malaria Plants that have the potential to be developed as antimalarial alternatives: M. micrantha leaf ethanol extract shows no significant signs of poisoning and death until the highest dose of the test is 5000 mg/kg. M. micrantha Kunth ethanol extract is categorized as practically non-toxic or mild toxicity. From these results, it can be affirmed that the treatment with doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg has potential for antimalarial activity.

M. micrantha
Legend: a.The titles are presented in the language in which they were published; b.The descriptions were translated into English; Source: Authors (2021).
Analyzing the distribution of patents per country, Japan and Brazil stand out as the largest holders of registered patents involving the genus Mikania for medicinal application with 5 and 3 patents, respectively ( Figure 1). Brazil has the largest plant biodiversity on the planet, with more than 20% of the total number of species on planet Earth (Brazil & Environment, 2021). Thus, the country presents a great innovative potential in the areas of natural products and biotechnology, and can promote innovation in different areas, such as biopharmaceuticals (Bittencourt et al., 2020;Dutta et al., 2019).
In Considering the year of patent filing (Figure 2), patent filings were observed in the period from 1991 to 2019. The year 2000 presented the highest number of patents filed, with 5 patents. In the following years there was a decrease in deposits, followed by stability until the year 2019, where a brief increase in deposits was observed, with 2 patents. With respect to IPC, section A (Human needs) had the largest number of patents filed, followed by section C (Chemistry; metallurgy) and B (Processing operations; transportation). It is worth noting that the 20 patents included in the survey presented more than one classification, with 55 assigned to subclass A61K (Preparations for medical, dental or hygienic purposes), and 44 patents appearing in subclass A61P (Specific therapeutic activity of chemical compounds or medicinal preparations), these two subclasses containing 86% of all patents filed (Figure 3). Research, Society and Development, v. 10, n. 14, e333101422076, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i14.22076 8 The remaining deposits, in smaller numbers, were observed in subsections C07D (heterocyclic compounds), B01D (separation), C12N (microorganisms or enzymes; compositions thereof; propagating, preserving or maintaining microorganisms; mutation or genetic engineering culture media), A23L (food, foodstuffs or non-alcoholic beverages), A61Q (specific use of cosmetics or toilet preparations or the like) and A01N (preservation of bodies of humans or animals or plants or parts thereof).

Analysis of the EPO database data
After analysis and application of the inclusion criteria of the results obtained from the EPO database using the term "Mikania", 10 patents were selected (Table 2).

Antioxidative stress agent
Antioxidative stressing agent derived from the natural product that accelerates the improvement activities of the Antioxidant Response Element (ARE) in a path Erythroid-2 Nrf2/ARE related nuclear factor participating in the oxidative stress, thus inducing the expression of an antioxidative enzyme to mitigate the oxidative stress.

M. glomerata
Composition for suppressing emission of odor Odor emission suppressive composition is formulated with plants of several genera M. lindleyana Heatoproblective activity of Mikania scandens (L) Willd. against thisaccta mide induced hepato toxicity Composition of synergistic herbs for the hepatoprotective activity. More particularly, the present invention concerns the preparation process of 4-(l-Carboxy-ethyl)-8-9-dimethyl-cyclodeca-2, carboxylic acid of 5 diene from M. scandens (L.) Willd.

Medicament for treating cancer and preparation method thereof
The medicament is made from a formula with plants of several genera. The drug disseminated by the invention has the functions of cleaning heat, detoxifying, eliminating stagnation, relieving water retention, dispersing blood stasis, inducing diuresis, expelling wet wind, cleaning lung heat, expelling pus, detoxifying, stimulating menstrual flow, eliminating stagnant blood, regulating vital energy, reducing swelling, and treating multiple cancers. In addition, the raw material used in the invention drug is based on pure Chinese plants, so that the drug has low cost; and clinical applications indicate that the drug has a good treatment effect on breast cancer, liver cancer, lung cancer, and the like.

Neurite outgrowth agent
The neuritis growth agent comprises compounds of various plants. A preventive/therapeutic agent for neurodegenerative diseases, a preventive/therapeutic agent for Alzheimer's and dementia diseases, and a food are also provided, each comprising the neuritis growth agent.

M. glomerata
Methods

M. guaco
Mikanolide and dihydromikanolide as inhibitors of DNA-polymerases Mikanolide and dihydromikanolide are used to treat proliferative and parasitic diseases. They are used as antiproliferative, antiviral and antiparasitic drugs, mikanolide, dihydromikanolide and extracts enriched with dihydromikanolide. The invention also refers to a method for its preparation by extraction from the M. micrantha plant. Besides, the dihydromikanolide and the mikanolide inhibit the replication of the DNA by inhibiting the enzymes of the polymerase of the DNA necessary for the reproduction of eukaryots.

M. cordata M. micrantha M. scandens
New 11-membered ring compound Composed of an 11-member ring expressed by a specific structural formula and useful as a carcinostatic agent, among others. The compound can be produced by extracting the dry leaf and stalk of M. hirsutissima with ethanol, concentrating the extract under reduced pressure and purifying the concentrate by column chromatography.

M. hirsutissima
Pharmaceutical composition and method of treatment utilizing the composition An antivenom composition composed of extracts of active components of the plants combined in effective proportions; the method of elaboration of this composition; the pharmaceutical products derived from these extracts of active components; and a method of treatment of snake bites, scorpion bites, and the like using this composition.

M. guaco
Legend: a.The titles are presented in the language in which they were published; b. The descriptions were translated into English. Source: Authors (2021).
Regarding the depositing countries, Japan was the largest patent holder with 5 patents followed by the United States with 2 patents. The other countries such as China, Russia and India each have only one patent filed (Figure 4).  According to the distribution of patents by IPC, it was possible to verify that the subclasses A61K (Preparations for medical, dental or hygienic purposes), A61P (Specific therapeutic activity of chemical compounds or medicinal preparations) and A61Q (Specific use of cosmetics or toilet preparations or similar) represented 90% of all patents filed, with emphasis on the A61K subclass that had the highest number of patents.

Analysis of the data referring to the INPI database
A total of 3 patent deposits were obtained in the INPI database (Table 3) after applying the inclusion criteria. Production of an anxiolytic agent and central nervous system depressor. Process of obtaining an agent with central action, used as an anxiolytic and central nervous system depressant obtained from the ethanolic extract of the leaves of the plant M. glomerata Sprengel.

M. glomerata
Processo de preparação de extratos secos padronizados de Mikania sp., Asteraceae (guaco), extratos secos padronizados assim obtidos e aplicações Standardized dry vegetal extract in coumarin and o-cumaric acid, elaborated from the extraction, characterization, standardization and drying of a guaco extract. The extract was dried by nebulization (spray drying), using different adjuvants. This dry extract showed antiulcerogenic activity in the model and indomethacin induced ulcers.
Processo para extração de frações do extrato hidro-alcoólico da Mikania glomerata; fração MG1 obtida pelo processo; composição farmacêutica contendo a dita fração e uso terapêutico da composição em doenças respiratórias em geral Obtaining fractions from the hydro-alcoholic extract of M. glomerata leaves with dilating activity of the respiratory smooth, anti-edema, and anti-allergic musculature. The organic fraction presented great dilating activity of the respiratory smooth muscle much more intense than the dry residue of the hydro-alcoholic extract. The inorganic fraction also presented anti-edema activity in mice and anti-allergic action in rats. From the inorganic fraction, gelatinous capsules containing this fraction were prepared and when tested in chronic asthmatic patients it showed anti-asmatic activity.

M. glomerata
Legend: a. The titles are presented in the language in which they were published; b. The descriptions were translated into English. Source: Authors (2021).
Research, Society andDevelopment, v. 10, n. 14, e333101422076, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i14.22076 13 The INPI is responsible for the filing and publication of patents in the Brazilian territory. Thus, the three patents found originated in Brazil, with two of these publications using M. glomerata.  Regarding IPC, it can be seen in Figure 8 that the only subclasses present were A61K and A61P, and these may have more than one group to characterize. In Table 4 you can see all the meanings of the IPCs highlighted in Figure 8.  From the analysis of the deposits in the INPI database it was possible to observe low expressiveness, which can be justified by the lack of incentive and practice of patenting among Brazilian researchers (Sampaio et al., 2018). In developing countries, as is the case of Brazil, educational institutions, especially universities, are responsible for scientific and technological knowledge (Perucchi & Mueller, 2014).
Patenting research conducted at universities or that had public funding is seen as controversial, since the role of universities is to create and disseminate knowledge and not charge for it, however, the junction between scientific knowledge, generated by universities, and applied knowledge, provided by companies, is important for technological and scientific advancement and allows them to offer a return to society in the form of an innovative product (Pojo, 2014;Póvoa, 2010).

Analysis of the Mikania species cited in the patents
From the analysis of the patents accepted in the investigated databases, a compilation of the most cited species was made (Figura 9). When analyzing the species of Mikania cited in the selected patents, during this review, it was observed the occurrence of 7 species of this genus, as well as in some cases there was no specification of the species used (Mikania sp.).
Also, in some patents, more than one species was cited.
The two most cited species were M. micrantha and M. scandens, with 7 and 5 citations, respectively. M. micrantha Kunth, is an invasive vine that causes economic losses related to sunlight blockage (Liu et al., 2020). However, M. micrantha also has several studies proving its medicinal use for its antibacterial, antitumor, antimicrobial, cytotoxic, and phytotoxic activities (Dou, Zhang, Sun, Wu, & Li, 2014). According to the study by Dong et al. (2017) (Dong et al., 2017) it was also proven that M. micrantha has phenolic compounds with antioxidant activity.
M. scandens (L.) Willd. is characterized as a fast-growing invasive weed. However, aqueous extracts of the leaves are used for medicinal purposes in the Indian subcontinent to treat stomach ulcers, gastric problems, and a variety of other ailments. The species has several constituents, including mykanolide and dihydromikanolide. The species has analgesic and antioxidant activity and preliminary studies have proven antinociceptive effects and central nervous system depressant action (Dey, Chandra, Chatterjee, & Bhattacharya, 2011;Piyasena & Dharmaratne, 2013;Siddiqui et al., 2017). Secretariat for Science, Technology, 2020).
The species M. guaco Humb. et Bonpl. has been cited 3 times and is noted for its anti-inflammatory activity in traditional Central American medicine (Rüngeler, Brecht, Tamayo-Castillo, & Merfort, 2001). The species is also indicated for snake bites, cholera and respiratory diseases described in the "Medical Form and Guide" published in 1874 (Ricardo, Paula-Souza, Andrade, & Brandão, 2017).
Such pharmacological properties described for these species related to the number of patents found, demonstrate the potential of plants of the genus Mikania in innovative pharmacological development.

Conclusion
The publication of patents is a resource that aims to register the innovation and protection of an invention with the purpose of producing it commercially. Thus, the study of technological prospection carried out in this work from the research in WIPO, EPO and INPI, ratified the therapeutic potential the species of the genus Mikania.
Furthermore, it was possible to evidence that although Brazil has a great diversity of flora, it is still necessary that research be encouraged. Another relevant point is the innovation of patenting natural products, since the use of technological prospecting as a tool for strategic planning provides a forecast of scientific advances and thus the direction of new technologies.
Therefore, due to the relevance of technology prospecting for the development of new research projects and the potential of the genus Mikania in medicinal properties, this technology mapping assisted in understanding the state of the art of Mikania-related inventions and the results presented can assist researchers in finding collaborators for new technologies.
The data presented reinforce the importance of Brazilian companies investing in the production of scientific studies involving natural products, by applying financial resources to strengthen and boost the research, technology, and innovation sector.