Patenting Bioactive Molecules from Biodiversity: the Brazilian Experience

Expert Opinion on Therapeutic Patents

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Patenting bioactive molecules from biodiversity: the Brazilian experience

Renata Campos Nogueira, Harley Ferreira de Cerqueira & Milena Botelho Pereira Soares

To cite this article: Renata Campos Nogueira, Harley Ferreira de Cerqueira & Milena Botelho Pereira Soares (2010) Patenting bioactive molecules from biodiversity: the Brazilian experience, Expert Opinion on Therapeutic Patents, 20:2, 145-157, DOI: 10.1517/13543770903555221 To link to this article: https://doi.org/10.1517/13543770903555221

Published online: 25 Jan 2010.

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Patenting bioactive molecules from biodiversity: the Brazilian experience

† 1. Introduction Renata Campos Nogueira , Harley Ferreira de Cerqueira & 2. The potential of Brazilian Milena Botelho Pereira Soares † biodiversity as a source Fundaçaõ Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz, Laborato´rio de Engenharia Tecidual e of new drugs Imunofarmacologia, Rua Waldemar Falcaõ, 121-Candeal, Salvador, 40296-750, Bahia, Brazil 3. Natural products in drug The use of natural compounds from biodiversity, as well as ethnobotanical discovery process using emerging technologies knowledge, for the development of new drugs is the gate leading to support the conservation of natural resources in developing countries. Recent tech- 4. Intellectual property and nological advances and the development of new methods are revolutionizing biodiversity access under the screening of natural products and offer a unique opportunity to replace Brazilian legislation natural products as major source of drug leads. Over the past decades, the 5. Patent and trade mark cases Brazilian government established a legislation aiming to grant patent pro- 6. Conclusion tection in all technological fields. The Convention on Biological Diversity, an 7. Expert opinion international agreement that recognizes the sovereign rights of States over their natural resources, and the Brazilian legislation (Decreto n 2186-12/01) set for legislative, administrative or policy measures regarding the share of research and product development benefits could be the key for progress in issues related to rational employment of the Brazilian biodiversity and economy, but are far from being effective. Based on literature review, this article provides a brief description of the Brazilian legislation policy regarding intellectual property and biodiversity access, places natural drug discovery in context, analyzes patent cases and highlights critical key issues responsible for the drawback of the whole process that has a direct impact on industrial and research development, nature protection and benefit share with our society.

Keywords: biodiversity, Brazilian legislation, chemical diversity, drug development

Expert Opin. Ther. Patents (2010) 20(2):145-157

1. Introduction

The contribution of natural products in pharmaceutical discovery and development process is unquestionable. Over the last 25 years, 77.8% of the non-biological anticancer drugs were either natural products (per se or based thereon) or mimicked natural products in one form or other [1]. In the 1990s, about 80% of the drugs were either natural products or analogues inspired by them. Antibiotics (e.g., penicillin, tetracycline and erythromycin), antiparasitics (e.g., avermectin), antimalarials (e.g., quinine and artemisinin), lipid control agents (e.g., lovastatin and analogues), immunosuppressants (e.g., cyclosporine and rapamycins) and anticancer drugs (e.g., taxol and doxorubicin) have revolutionized medical treatment [2]. Despite this successful record, many pharmaceutical companies have scaled back their natural product research in the past 2 decades. In part, this could be explained by the development of high-throughput screening (HTS) technologies combined with the introduction of combinatorial chemistry. The development of these technologies has led the pharmaceutical companies to believe that their combined use would boost the discovery of novel drug leads. Due to the extreme complexity of natural products libraries, they were incompatible with HTS technologies in the late

10.1517/13543770903555221 © 2010 Informa UK Ltd ISSN 1354-3776 145 All rights reserved: reproduction in whole or in part not permitted Patenting bioactive molecules from biodiversity: the Brazilian experience

1980s. Although no conclusive data exist, it is possible that the Mexico, Peru and Democratic Republic of Congo [11]. The decreased emphasis on natural products in drug discovery tropical forests of the world are believed to contain > 50% of contributed to the decline in the number of new chemical the plant species on earth. The Amazonian forest, however, is entities (NCE) launched in recent years [3]. not the only place with high biodiversity in South America. Difficulties with ongoing legislation for biodiversity and Brazil has two additional biodiversity hotspots, the Atlantic traditional knowledge access may also have contributed to the Forest in the Coast and the Cerrado in Central Brazil decline of natural product research in private sectors [4,5]. (Figure 1). A biodiversity hotspot is defined as an area contain- A while ago, genetic resources were considered to be a ing at least 0.5% of the world’s 300,000 known plant species common heritage of humanity, but the United Nations as endemics [11]. In addition, the Caatinga region, located in Convention on Biodiversity and the meetings in Rio de the Northeastern region, is characterized by high temperatures Janeiro in 1992 changed the rules and redefined biodiversity and low average humidity, with an annual rainfall of ownership. Since then, biodiversity belongs to the country of 250 – 500 mm. The name ‘Caatinga’ is a Tupi (indigenous origin. To address such issues, initially the US National language) word meaning ‘white forest’ or ‘white vegetation’ Cancer Institute, then other institutes within the National (kaa = forest, vegetation; tıńga = white). It covers between Institutes of Health and other agencies of the US government, 700,000 and 1,000,000 km2 (depending on the source), collaborated in the establishment of the International Co- > 10% of the Brazilian territory. On the other hand, the operative Biodiversity groups, modeled on successful, but US Araucaria forest located in the South of Brazil is characterized oriented, National Cooperative Natural Product Drug by a regular distribution of rainfall, in contrast to other Discovery groups in order to aid in biodiversity oriented country parts, and wide differences among the seasons, projects with the first awards in 1992 [6,7]. After this legal temperatures and photoperiods (Figure 1). mark, all patents from bioactive molecules generated from A large country with different soil types and a wide range of Brazilian biodiversity would have to clearly state the origin of climates provides a unique set of selective pressures for the its source. However, when the European Patent Office and the adaptations of life. The biodiversity and the struggle for life in Brazilian National Institute of Industrial Property (INPI) these different ecosystems provoke the generation of an databases were reviewed, most of the applications involving incredible chemical diversity in living organisms. Plants living Brazilian native plants published in the 2003 – 2008 period under stress develop and survive under intense competition for belonged to Brazilian research centers and universities [8]. resources and nutrients. They also need to develop an extra- However, it should be noted that by stating that the bioactive ordinary array of defenses, most of which are chemical molecule was synthesized instead of bioprospected or derived compounds, to protect themselves from viral, bacterial and from pharmacophore groups based on structures isolated from fungal pathogens, insects and mammalian predators. The Brazilian biodiversity, an inventor can avoid the problems combination of biodiversity with a rich traditional medicine with benefit share brought up with ongoing legislation. places Brazil in a strategic and privileged position for drug Considering that 95% of the patent deposits in the world discovery programs. belong to developed countries, this is a potential problem [9]. The Brazilian biodiversity has been a source of compounds Nowadays, the advent of new tools for screening predicts a for drug development. Many compounds commercialized revival of drug discovery inspired by natural sources [2,3,10]. nowadays by pharmaceutical companies had an origin in Pharmaceutical companies have reconsidered the role of plants and animals growing in tropical forests. One of the natural products in drug discovery. In this context, a revision main drugs used for the treatment of glaucoma is pilocarpine, of the Brazilian legislation is mandatory in order to assure which is extracted from the plant leaves of genus Pilocarpus, public and private sectors access to biodiversity, as well as mainly Pilocarpus jaborandi Holmes (Rutaceae) (Figure 2). patent protection, of the discoveries generated. This will Pilocarpine has been used in the treatment of chronic contribute to enhancing product development in the country, open-angle glaucoma and acute angle-closure glaucoma for leading to a sustainable use of our resources. > 100 years [12]. Pilocarpine is also used to treat dry mouth In this paper, we discuss Brazilian biodiversity potential and (xerostomia), a side effect of radiation therapy for head and ethnobotanical knowledge as a source of new drugs, update neck cancers. Pilocarpine stimulates the secretion of large the technologies applied in screening of natural products and amounts of saliva and sweat. It is interesting to observe critically review intellectual property and biodiversity access that this last indication was described by the American natives under Brazilian legislation. centuries ago; in fact ‘jaborandi’ is the indigenous way of saying ‘slobber-mouth plant’. 2. The potential of Brazilian biodiversity as a Another important drug discovered from a Brazilian trop- source of new drugs ical plant was d-tubocurarin. The compound was first isolated from the ‘curare’, a common name for various arrow poisons According to Myers et al. (2000), ~ 70% of the world’s plant in South America. In the 1930s, Squibb, Inc. of New Jersey species are found in only 11 countries: Australia, Brazil, (USA) introduced in the market the first drug based on a China, Colombia, Ecuador, India, Indonesia, Madagascar, curare extract called Intocostrin . The extract was made with

146 Expert Opin. Ther. Patents (2010) 20(2) Nogueira, de Cerqueira & Soares

Brazilian ecosystems Emetine, an alkaloid with emetic properties, was isolated from Psychotria ipecacuanha (Brot. Stokes) or Cephaelis ipecacuanha, plants belonging to the Rubiaceae family. The name of the plant is the Portuguese form of the native word, Amazon i-pe-kaa-gueńe, which is said to mean ‘road-side sick-making Caatinga plant’. Emetine was used as a drug to induce vomiting [18,19]. Dehydroemetine is a synthetically produced drug similar to emetine in its anti-amoebic properties [20]. In the US and Europe, it is manufactured by Roche (Figure 2). Cerrado The poison of the Brazilian snake Bothrops jararaca was the source of a major discovery, the ACE inhibitors used for Pantanal Atlantic forest the treatment of hypertension and some types of congestive heart failure. In the 1960s, the Brazilian scientist Se´rgio Ferreira et al. described a peptide isolated from the snake poison that inhibits the ACE [21-23]. In 1977, based on this Pampa discovery, the pharmaceutical company Squibb (now Bristol- N Myers Squibb) developed captopril [24]. Captopril was among the earliest successes of the revolutionary concept of structure- based drug design. The peptide described by Ferreira’s group Figure 1. The Brazilian ecosystems. was used as a base for the development of a much simpler compound with the same properties (Figure 3). The benefits that these examples brought to humanity are enormous. It is impossible to estimate the profit for the Chondrodendron tomentosum Ruiz & Pav. (Menispermaceae), companies who patented those compounds. The country of one of the 26 different species of liana collected by Richard Brazil has not received any economic return with these Gill in Ecuador [13]. Because the extract contains a mixture of discoveries. The above mentioned episodes happened before different quaternary alkaloids, each batch was standardized by the convention of biodiversity when natural resources were the biological rabbit head-drop test, but different batches were considered a common heritage of humanity, and before the later shown to vary widely in their content of the main active patent law of Brazil [25]. Therefore, they are not legally compound d-tubocurarin. Intocostrin was first used to modify considered misappropriation of traditional knowledge drug-induced convulsions [14]. Eventually, the use of this drug or biopiracy. would be replaced by electroshock, which was easy to stan- Natural product chemical libraries can be constructed based dardize and control. The Intocostrin (curare) was introduced on ethnobotany information, random selection and field into anesthesiology by Harold Randall Griffith and Enid observations [26]. Random screening is classified as low rational Johnson in the early 1940s as a muscle relaxant for surgery, search process in which the discovery of new hits occurs at and this methodology was considered a revolution in surgical lower probability when compared to ethnobotanical selection. anesthesia [15]. D-tubocurarin was isolated in 1935 by Harold Plants collected on an ethnobotanical basis depending upon King (1887 – 1956) in London, working in Sir Henry Dale’s the disease(s) studied may give higher hit rates than the laboratory. He also established its chemical structure [16]. random approach [27]. Fabricant and Farnsworth identified D-tubocurarin is an antagonist of nicotinic neuromuscular 122 compounds of defined structure obtained from only 94 acetylcholine receptors and is used to paralyze patients under- species of plants, used globally as drugs, and found that 80% going anesthesia. Curares are active (i.e., toxic or muscle of these plants have had an ethnomedical use identical or relaxing, dependent on the intention of their use) only if related to the current use of the active elements of the given/applied parenterally, that is, by an injection, or direct plant [28]. wound contamination by poisoned dart/arrow tips. It is harmless if taken orally because curare compounds are too large and too highly charged to pass through the lining of the 3. Natural products in drug discovery process digestive tract to get absorbed into the blood [16]. This is using emerging technologies crucial, because the native tribes use curares mainly for hunting purposes, and thus the curare-poisoned prey The importance of natural products in modern medicine is remained safe to eat. Currently, D-tubocurarin has been evident when we analyze the rate of NCE derived from this replaced by other muscle relaxants. Most of them, such as source introduced in the market. Including the compounds Atracurium , however, are in fact developed from the struc- serving as templates for semi-synthetic and total synthetic tural information of compounds isolated from plants used for modification, it represents nearly 50% of all small molecules centuries as arrow poisons (Figure 2) [17]. launched in the years 2000 – 2006 [1]. The high amount of

Expert Opin. Ther. Patents (2010) 20(2) 147 148 experience Brazilian the biodiversity: from molecules bioactive Patenting

H3CO H3CO OCH3

OH +N NH O O NH + + O H3CO OCH3 H O O

O H3CO OCH3

OH OCH OCH 3 Atracurium 3 N+ D-tubocurarin xetOi.Te.Patents Ther. Opin. Expert OCH3

H CO 3 H3CO

N N N H CO 3 H3CO

(2010) O H H N O 20 (2) H H Pilocarpin N N

H H

OCH3 OCH3

OCH 3 OCH3

Emetin Dehydroemetin

Figure 2. Some important compounds identiﬁed from Brazilian biodiversity. Nogueira, de Cerqueira & Soares

HO O O

O OH HS N NH Captopril ® HO O O O H H N N

H2N N N H O O HO O O H N N BPF NH2

O O Enalapril ®

Figure 3. BPF, the peptide isolated from Bothrops jararaca snake and the synthetic compounds Captopril and Enalapril. BPF: Bradykinin potentiating factor. bioactive compounds isolated from natural products may be automated. The last years have witnessed major developments explained by the evolutionary selective pressure of chemical in fermentation technology process, purification, derepli- structures able to interact with a wide variety of proteins and cation and structural elucidation of natural products, biological targets for specific purposes [29]. Historically, screen- accounting for sufficient amounts of pure compounds for ing of natural materials for biological activity has worked well. drug development [29,35-37]. Considering only polyketide metabolites, just > 7000 known The recent development of hyphenated techniques with structures have led to > 20 commercial drugs with a ‘hit rate’ of combined separation technologies, such as high pressure 0.3%, which is much better than the < 0.001% hit rate for liquid chromatography (HPLC) with UV detection (LC- HTS of synthetic compound libraries [30]. UV), mass spectrometry (LC-MS) and NMR (LC-NMR), A successful drug is a combination of drug-like properties provided plenty of structural information, leading to a partial and biological activity with tolerable toxicity. Poor pharma- or a complete online de novo structure determination of the ceutical properties due to poor solubility, permeability and natural products of interest. The combination of metabolite metabolic stability account for about 40% of compounds profiling and LC/bioassays gives the possibility of distinguish- that fail to reach the market [31-33]. During the hit ing between already known bioactive compounds and new identification stage, chemical libraries from different origins molecules directly in crude plant extracts (dereplication). can be screened over a defined target using high-through Thus, the tedious isolation of compounds of low interest put methods. can be avoided and replaced for a targeted isolation of new A series of studies reveals that natural products have a bioactive products [26,38,39]. greater number of oxygen-containing substituents and chiral A great range of methods are widely used in predictive and centers increasing the steric complexity than either synthetic multi-mechanisms screens based on chemical libraries in drugs or combinatorial libraries [34]. Moreover, the active search for drugs with therapeutic potential [33,40,41]. The compounds are present sometimes in very small amounts goal of those procedures is to evaluate, with reasonable in natural matrices, representing a challenge for scientists accuracy, the potential of a compound to become a drug. working on isolation and structure elucidation. This slows A hit compound is a structure identified by an in vitro the identification process and contributes to the problems of biological activity screening of a chemical library. In the hit supply and manufacture. identification stage, compounds with demonstrated initial Recent technological advances and the development of new feasibility of interaction with a target are selected [42]. Based methods are revolutionizing the screening of natural products on the affinity to a given target, it is possible to explore the and offer a unique opportunity to re-establish natural products structure–activity-relationship of a chemical structure. After as a major source of drug leads [3]. The process of natural the process of properties optimization of pharmacokinetic/ screening has been streamlined. The methodology of extract toxicity and before it has reached the drug candidate status, the preparation and bioassay-guided fractionation are increasingly compound is at lead stage [32].

Expert Opin. Ther. Patents (2010) 20(2) 149 Patenting bioactive molecules from biodiversity: the Brazilian experience

The lead discovery process can be improved by rational and transfer of technology derived from (Article 16-1 ) [43]. drug design using the pharmacophores of compounds from In this regard, the Article 15 of the CBD indicates that the ethnobotanical information or hits identified with auto- sharing of benefits and results should be given by mutual mated HTS of natural products. A drug can be chemically agreement between the parties through terms established by designed, enabling the construction of libraries of new lead the contract of access and benefit sharing. active compounds. When the discovery project is focused on Brazil, aiming to regularize items 1,8 (j), 10 (c), 15, orally bioavailable drugs, physicochemical parameters and 16 (3) and (4) of the CBD, issued a law (Provisional that benefit drug-like properties are enhanced during the Measure No 2186-16, 2001) which regulates access to genetic lead stage development. This whole process requires heritage of Brazil, both with regard to components as well as very little amount of natural sample using the new associated traditional knowledge. It is worthy to note that, technological advances. even before the CBD, since 1988, Brazil has launched its commitment to the protection of biological diversity, inserted 4. Intellectual property and biodiversity access into the federal constitution [44]. The Provisional Measure No under Brazilian legislation 2186-16/01 adopted the term ‘genetic heritage’ instead of ‘genetic resources’, as did the CBD, aiming at strengthening It was the signing of the international environmental law the economic nature of the genetic susceptible monetary entitled ‘Convention on Biological Diversity’ (CBD) on 5 valuation as well as any other goods. Moreover, it entered June 1992 by 156 countries except the US, in a meeting held the dimension of conservation through sustainable use, in Rio de Janeiro, known as ECO ’92, which placed a coupled with the idea of sharing benefits derived from this significant milestone in the settlement of the contemporary use of biodiversity [45]. ideal of biological diversity protection. The legal definition given to the Genetic Heritage (Item I, The attention given by the CBD extended beyond the Article 7) of the Provisional Measure No 2186-16/01 is the legitimate and necessary protection and biodiversity conser- genetic information contained in samples of all or part of vation, concerning the sustainable use of natural resources and plant, fungal, microbial or animal in the form of molecules fair equitable sharing of benefits arising from their use. This is and substances from the metabolism of the organisms and because biodiversity, besides having intrinsic and intangible from the extracts of live or dead organisms, found in situ, value, such as life maintenance, has also a tangible nature, as including domesticated, or kept in ex situ collections. This they hold genetic resources as containing the genetic material piece of legislation also establishes the conditions for use, of actual or potential value. marketing and utilization of genetic resources in order to It is noticeable that the CBD brought changes of para- ensure fair and equitable sharing of benefits. In order to do so, digms. The first was about the concept of conservation, which it establishes the terms on which will be given the legal earlier faced a strong preservationist view, that is, conservation relationships, focusing on the following vectors: i) required of biodiversity would be limited to the creation of protected previous authorization to have access to genetic resources areas. The CBD incorporated the dimension of conservation (components or associated traditional knowledge); ii) the through sustainable use of biodiversity, coupled with the idea formalization of Contract for Use of Genetic Heritage and of sharing benefits derived from its use. In this respect, the Benefit-Sharing, as a way to ensure fair and equitable sharing model of sustainability is the creation of a system to reconcile of benefits derived from exploitation of the genetic resource and balance the economic development, environmental pro- and iii) access to the technological development, the obliga- tection and welfare of the community. The second grants the tion to facilitate access to and transfer of technology as a means States sovereign rights over their biological resources, includ- of conservation and use of biological diversity of the country. ing the traditional knowledge of local communities and Indeed, any practice that seeks to access (more specifically, indigenous people, in present or potential use or value for collect, identify and use) samples of genetic heritage compo- humanity. In other words, the genetic resources are no longer nents, alive or dead, in their natural habitat (in situ)or considered patrimony of humanity, that is, with free access information from traditional knowledge, for industrial or and use. Thus, the access to a genetic resource, aiming at its commercial application, or for any other purpose, except application, in industry or not, is subject to authorization by with regard to human genetic resources (Article 3), is con- the country holding the genetic resource. ditional upon the authorization of the Board of Management In addition to ensuring the need to seek previous autho- of Genetic Resources (Article 2 ) [46]. rization from the country holding the resources, the CBD also It is noteworthy that the Provisional Measure No 2186-16/ guarantees the fair and equitable sharing of benefits arising 01 only allow foreign companies to bioprospect the Brazilian from the utilization of genetic resources. In other words, in genetic patrimony if the activities occur in conjunction and exchange for providing access to genetic components, the under the coordination of a national public institution (§.6, donor country should benefit by participating in research Article 16), being assigned to duty in charge of state (§.1, (Article 15-6) or in the search results and benefits of Article 16) and deposit sub-samples of (§. 3, Article 16) the commercial exploitation (Article 15-7 ), or in the access genetic components in accessible ex situ condition [47].

150 Expert Opin. Ther. Patents (2010) 20(2) Nogueira, de Cerqueira & Soares

Also, under the Brazilian law, the granting of industrial However, the Brazilian Industrial Law Property (Article 10 of property rights of a process or product obtained from Law 9279/96) does not consider biological material found in samples of genetic heritage components is contingent on nature as inventions and discoveries, even if it is a molecule or evidence that it has met the requirements of Provisional a new substance, or even if the product has a feature not No 2186-16/01, and the applicant must inform the source attainable by the species under natural conditions and has a of genetic material and associated traditional knowledge used, new functional purpose, and if it holds the ability to promote a when appropriate. new state of the art, they are not patentable [25]. Thus, the INPI, in Brazil, became critical to achieving the What is permitted in Brazil is solely the patenting of objectives of the Provisional Measure No 2186-16, establish- processes used for the isolation of natural components, ing an instrument of control of the distribution of benefits only if the process by which the substances and extracts from the use of genetic resources and other requirements obtained is new. Regarding this point, the INPI has developed imposed by the above mentioned legislation. At this point, the a general guideline entitled Guidelines for Examination of CBD has recognized that patents and other intellectual Patent Applications in Areas of Biotechnology and Pharma- property rights may affect the implementation of this con- ceuticals, which the examiners of INPI use for the examination vention and shall cooperate in this regard subject to national of the most common cases of patent applications using legislation and international law to ensure that such rights are biological materials [49]. supportive and not contrary to the purposes of this convention In a superficial reading of the Federal Constitution articles, (Article 15-5). it appears that there are no limits to industrial protection to The meeting of this specific requirement, determined by the any technological field. The opposite is also true: there is no above mentioned resolution, shall be checked only and solely obligation to grant it without restriction to all fields. Indeed, in Brazilian territory, an issue being particularly discussed, in the Brazilian Federal Constitution assigned to a supplemental addition to the CBD, at the World Trade Organization and law the limits of industrial property of each technological field, the World Intellectual Property Organization. the Law 9279 of 14 May 1996 [25]. However, this law, which Another important point that needs to be raised is the fact governs all matters of patents, was restrictive to the point that the Brazilian patent law, unlike almost all other legisla- that the use of biological material isolated from its natural tion, including the North American, does not allow the environment or produced by a technical process, especially patenting of isolated molecules from biodiversity with a those that pre-determined in nature, are not recognized particular application. The patenting is restricted to the as inventions. process of obtaining the given molecule and its application, leaving the document extremely fragile. With the arrival of 5. Patent and trade mark cases new technologies explained in the previous section, and re- interest of corporations in the natural sources for the devel- There are many extracts from plants such as copaı´ba (Copaifera opment of new drugs, there is a clear need for an immediate officinalis L., Fabaceae), andiroba (Carapa guianensis Aubl., review of intellectual property laws in order to prepare the Meliaceae), cupuaçu (Theobroma grandiflorum (Willd. ex country to be more competitive. Spreng.) K. Schum, Sterculiaceae) and acerola (Malpighia As previously mentioned, the pharmacologically active glabra L. Malpighiaceae) being patented in cosmetic ingredients derived from biodiversity, such as extracts and preparations around the world [50-56]. chemicals, are of paramount importance for the development The use of a popular name as a trademark is not acceptable. of many innovative products and processes. It seems that The name of cupuaçu fruit, Theobroma grandiflorum (Willd. the largest number of patents that use biodiversity elements ex Spreng.) K. Schum, Sterculiaceae, native to the Amazon comes from developed countries such as the US and Japan region, was registered as a trademark by a Japanese company and from the European Community. In these countries, in Japan, the US and Europe. Brazilian products composed of the laws allow almost unrestrictedly the patenting of products cupuaçu ended up being denied entry in those markets. This and processes that have material which is isolated from trademark campaign that begun in 2002 attracted a great its natural environment or derivatives, even pre-existing deal of attention, launched by the Acre State-based non- in nature. governmental organization (NGO) Amazonlink.org, and As an example, the article 3, item ‘2’ Directive 98/44/EC pushed many NGO groups to join the fight against biopiracy of the European parliament and of the council on the legal in Brazil [57,58]. In addition, these groups discovered that a protection of biotechnological inventions can be mentioned. series of patents on the production and use of fatty material It states that a biological material isolated from its natural from cupuaçu seeds were under the Japanese Patent Office environment or produced by a technical process may be the (JPO) analysis, despite the processing of cupuaçu seed subject of an invention even if it pre-exists in nature [48].In being used by traditional communities in Amazonia [53-56]. practice, the Directive 98/44/EC applies the same criteria used On 1 March 2004, the JPO in Tokyo decided to cancel the for chemical molecules to support the patenting of products trademark Cupuaçu and rejected a patent request for the that contain natural ingredients (substances, extracts, etc.). production of Cupuaçu chocolate [59].

Expert Opin. Ther. Patents (2010) 20(2) 151 Patenting bioactive molecules from biodiversity: the Brazilian experience

OCH3 H3CO

N N

R OCH3

OH HO

R = H or CH3

Figure 4. Rupununine derivatives isolated from Ocotea rodiaei.

To avoid foreign companies from registering the names from biodiversity, as previously mentioned, are not patentable popularly used in Brazil, a list with the scientific and according to Brazilian Patent Law (1996). After the CBD customary names of about 3000 species of Brazilian flora convention in 1992, the biodiversity resources were nation- was delivered to foreign patent offices and international alized, the whole society begun to refer to such bioprospecting organizations, such as the World Intellectual Property research as ‘biopiracy’. Brazilian and Guyanese Wapishanas Organization, which deal with these matters [60]. Indians prepared a lawsuit in the European court against When bioactive molecules bioprospected with ethno- Gorinsky, accusing him of biopiracy. Those episodes led to botanical/ethnomedical studies or screened from biodiversity the banishment of researchers from entering Indian even when they were used as scaffolds for synthetic or semi- villages [61]. synthetic derivatives are patented, this represents a misappropriation of traditional knowledge or biological resources. 5.2 Peptides isolated from skin secretions of the South Unless a previous agreement to follow the new rules on American frog Phyllomedusa bicolor (Hylidae) informed consent and benefit sharing is set up, this procedure Recently, the research and development of compounds from is illegal. It is very difficult, or nearly impossible, to monitor Phyllomedusa bicolor, a small Amazonian frog used for bioactive molecules derived from biodiversity when its origin ‘hunting magic’ by several groups of Panoan-speaking Indians is not given in the patent document. Two cases are being in the borderline between Brazil and Peru, is opening a debate discussed in Brazilian media and are worth mentioning. regarding intellectual property rights [66]. Evolutionarily, frogs have developed the production of 5.1 Rupununine: a bioactive compound isolated from powerful substances to defend themselves due to the lack Ocotea rodiaei (R. H. Schomb.) Mez (Lauraceae) of physical strength and sharp teeth, making them a great Conrad Gorinsky grew up in Rupununi, a village in southern source of new therapeutics [67]. Based on the indigenous Guyana rainforest on the northern edge of the Amazon basin. people’s knowledge and traditions, scientists had begun to He completed a Ph.D. program at Barts Hospital in London, research the active compounds present in the frogs responsible studying the natural drugs and poisons of the forest. At that for the pharmacological activities observed. time, he was considered a campaigner for the rights of The skin secretion of P. bicolor, which is rich in peptides, indigenous peoples and founded the UK-based Foundation includes vasoactive and opioid peptides, and a new peptide for Ethnobiology. One of his studies was about the constitu- named adenoregulin [68,69]. Skin secretion, previously scraped ents of greenheart tree (Ocotea rodiaei). For centuries, local from a live frog and stored dry on a stick, is mixed with saliva women used the tree’s nuts as a contraceptive to control and introduced into fresh burns on the arms or chest. This menstruation and made infusions of the bark to prevent induces, within minutes, violent illness, including rapid malaria fevers [61,62]. His research led to the isolation of active pulse, incontinence and vomiting, after which the recipient bisbenzylisoquinoline alkaloids that were named rupununine lapses into a state of listlessness and, finally, into a state (Figure 4). The purified compound and its derivatives are the perhaps to be described as euphoric; the subject later claims claims of a patent named ‘biologically active rupununines’ to be a better hunter, with improved stamina and keener deposited in 1994 followed by another deposit in 1996 senses [68]. claiming the treatment of lung tumors using these substances, Based on this discovery, some companies have already both under his name [63-65]. patented the peptides from P. bicolor. The main applications It is regrettable that this same patent request would never be of these patents are the use of dermorphin and deltorphin granted in Brazil, because living beings and molecules isolated in preventing cerebral ischemia and as a method for

152 Expert Opin. Ther. Patents (2010) 20(2) Nogueira, de Cerqueira & Soares

treating cytokine-mediated hepatic injury [70-74]. It does not by the American ethnobotanist Professor Paul Cox, in the appear that any group signed the share of profits they might village of Falealupo used by the healers to treat a disease called derive from Phyllomedusa with Brazil, Peru or with the locally as ‘Fiva Sama Sama’, a form of hepatitis. Later on, it indigenous tribes from which the frog-based effects was discovered that this compound holds enormous thera- were identified. peutic potential as an anti-AIDS drug and it was patented. An Despite this, Brazilian newspapers report that at least eight agreement between ARA and the Samoan government was of the international patents on dermorphin and deltorphin signed with Professor Cox’s support. It was negotiated that have been questioned because they had been granted after the 20% of any profits made from prostatin will go directly to declaration of the United Nation’s CBD, which states the Samoa. In 2004, in order to ensure the plentiful supply of ‘sovereign right to exploit their own resources’ [75]. However, prostatin without depending directly from the mamala’s tree according to Cooper and Plotkin, the US patents remain bark, the cloning of the prostatin genes was achieved aiming at legitimate because the US has not ratified the convention [66]. its synthesis in the UC Berkeley lab. An agreement was signed In 2006, The New York Times published an article about this establishing that any royalties from the sale of a gene-derived situation: an Indian chief says that ‘Kampoˆ’s use is nothing less drug would be equally shared with the people of Samoa [66,80]. than biopiracy; if economic gain is generated by the remedy, Once more, Samoa’s sovereignty over its natural resources and the Katukina tribe should get a cut’ [76]. In 2004, the Brazilian the contributions of Samoan healers were recognized. national agency of health monitoring (Anvisa), prohibited all This collaboration provides opportunities for all the parts publicity of therapeutic use of Phyllomedusa secretions ‘Vacina involved, and humanity will benefit from this discovery. The do sapo Kampoˆ’ and considered its exploitation an environ- lessons from native collective knowledge can and should be mental crime [77]. However, it is important to point out that used, as long as there is respect for their rights and by honoring the original discovery was reported in 1992 [68] and this may their cultures and ensuring prosperity for all stakeholders. represent an example where materials were collected before the CBD convention. 6. Conclusion In 2003, the Brazil’s Ministry of Environment launched a project named kampoˆ, in order to identify, in the secretion of The country of Brazil is in a unique position to explore its the frog, molecules or active principles for the development of natural potential resources. However, it currently assumes the pharmaceuticals and cosmetics and to study the biology and insignificant role of a raw material supplier. Biodiversity’s legal ecology of the frog, giving support to analyze the sustainability access regulations and patent protection comprise a huge of economic use and management plan for the species and to problem for the scientific and technological development of finally perform an anthropological study of indigenous knowl- the national pharmaceutical industry. edge related to the use of Kampoˆ [78,79]. The project, by While an atmosphere of anxiety surrounding the notion of integrating the traditional use of biodiversity, scientific biopiracy remains, few researchers are out there actually research and technological development, is intended to be studying Brazilian biodiversity. Important science research developed within an integrated approach, seeking to build the is lost out to bureaucracy, while many species are disappearing paths of promoting sustainable use of biodiversity resources, from earth before we can protect and study them. At the while ensuring fair and equitable sharing of benefits due to the deeper level, there are many different ideas about what is use of such knowledge, promoting respect and appreciation classifiable as biopiracy and, instead of controlling biopiracy, for cultural diversity, and thus generating benefits to the government and NGOs are undermining local and foreign structuring of environmental public policies more inclusive biodiversity research. and in accordance with the demands of society. Because it is very time consuming to collect plants The examples presented above show that much work with ethnomedical history, random collection followed by remains to be done to ensure that developing countries are HTS in vitro assays may be the future in pharmaceutical treated as equal partners in the research and development of industries [81]. However, ethnobotanical studies in research traditional knowledge and biological resources. centers and universities will remain major contributors to drug discovery process [82]. Therefore, the search for 5.3 The Samoan traditional knowledge and the bioactive compounds from biodiversity that will serve as a discovery of prostratin: an example to be followed scaffold for lead synthetic or semi-synthetic development, The prostatin case, one of the few ethnobotanical discoveries assuring patent protection with the new tools available, that led directly to an active agent, is a rare example of effective will evolve. compensation mechanism established between Aids Research Alliance (ARA), the University of California at Berkeley and 7. Expert opinion the Samoan government. In 1991, the National Cancer Institute isolated prostatin, a Due to the many examples of biodiversity exploration without chemical compound present in the bark of the mamala tree economic return to Brazil, very negative views concerning such (Homalanthus nutans), from samples identified and collected efforts are widely distributed among many levels of Brazilian

Expert Opin. Ther. Patents (2010) 20(2) 153 Patenting bioactive molecules from biodiversity: the Brazilian experience society, NGOs and decision makers. Strict laws governing patenting of living biological material was justified. Nowa- the way Brazil’s biodiversity is used for research and edu- days, when Brazil has proved efficiency in the development of cation discourage suitable collaborative relationships among innovative technologies capable of patenting, the social and universities, research institutes and private sectors. economic loss is greater. We are convinced that to overcome the problems posed by It is worth noting that the absence of an effective universal patents of bioactive molecules from biodiversity outside the system of patents on inventions that use biodiversity has national boundaries, it is necessary to invest in the country’s created conflicts. There were discoveries made pre-CBD, research, human resources and particularly to reformulate patents issued after 1992 that might well have been in the our legislation. respective patent office years before the CBD and cases of Extensive investment in research will provide conditions patents granted on products or processes derived from bio- for more Brazilians scientists to study the potential of diversity without any authorization for access. These are very biodiversity. There are more plant species collections of distinct situations but are being considered the same. Brazilian flora outside our boundaries than in our In order to avoid misappropriation or unfair use of genetic museums. The three biggest herbarium collections in Ama- resources or associated traditional knowledge, the solution zonia represent only 6% of what is found in the National would be the harmonization between the access system of Museum of Natural History of Paris in France [58].Thissole distribution and intellectual property system by implementing Amazonian vegetal species example illustrates that there is international rules. In this context, the TRIPS agreement still a lot to be prospected from biodiversity. Human itself, the World Trade Organization could incorporate resources well trained in scientific matters, intellectual prop- such rules, conditioning the granting of patents to verify erty and able to transfer the benefit of this research for private the legality of access and benefit sharing, as Brazil has done sectors are key points for the industrial development. internally in its legal framework. A recent example of a native species that has been taken This will bring security for companies willing to invest up as an economic opportunity outside the country is the in drug screening of natural products without being branded Brazilian guava (Acca sellowiana O. Berg, Myrtaceae), a fruit as ‘biopirates’. Also, researchers will no longer suffer from a from southern Brazil. It was introduced into New Zealand in bad reputation caused by over-reaction of uninformed groups. 1908, where it serves as the raw material for > 20 products, The fewer the research projects, the fewer the patents regis- including champagne, as well as preserves, juices and essen- tered, which leads to underdevelopment of the segment. tial oils [83]. Massive education may provide a realistic Without the active involvement of government, this approach definition of which are the benefits of research with sustain- is bound to fail. On the other hand, efforts at the international able use of biodiversity, and this will lead to the conservation level must be reinforced. It requires strong political will and a of natural resources. dedicated team of specialists able to recognize similarities As already mentioned, the Brazilian Law of Industrial between novel chemical structures patented and bioactive Property (Law 9279/96) does not allow the patenting of molecules from biodiversity, or even pharmacophore groups, living biological material found in nature, even if isolated in addition to being capable of deeply understanding the or modified by human intervention (e.g., plants, animals, patent legislation. This is not easy to achieve and depends on extracts or substances), with the exception of microorganisms the efforts made at the national level: investments on research, that are genetically modified. This restriction was motivated training of human resources and reformulation of our patent by the Brazilian fear, at the time the Industrial Property Law legislation. We cannot expect the world to change, but was prepared, that by allowing the patenting of products and campaigns are necessary to provide information worldwide processes of living beings and their derivatives, the country about the causes and consequences of biopiracy for would be legitimizing and recognizing the many existing developing countries. patents abroad course patented by other countries, which There is no question that inventions related to elements of have elements of Brazilian biodiversity. It was feared that their genetic heritage, as those using pharmacologically active the recognition of these kinds of patents would cause a duty ingredients, such as extracts and chemicals, are of upmost to respect (by the phenomenon of the extension of patents) importance for the development of many innovative products the monopoly of the foreign market for an asset that is and processes. Extremely promising fields of technology rightfully Brazilian. During the 1990s the idea that genetic that could boost scientific progress and the development of resources were regarded as a world heritage was very the national and regional production based on knowledge strong. Although the CBD has recognized in that decade and innovation are being neglected without the right of the sovereign right of each country over its biological patent protection. resources, such fear still shows to be latent and justified, Considering that the benefits of exploitation of biodiversity as some countries have not acceded to the CBD so far, are enormous, opposing the patenting of such inventions including the US, who also have patents containing elements would represent a delay in the progress of science and of Brazilian diversity. One can even understand that, at that technology in Brazil, which are also contemplated, explicitly, historical moment, the option of not permitting the in its constitution (Articles 218 and 219). It also reinforces

154 Expert Opin. Ther. Patents (2010) 20(2) Nogueira, de Cerqueira & Soares the dependence of foreign technology and discourages the Declaration of interest development of industrial inventions in this field [84]. Finally, a positive contribution from all entities involved, The authors state no conflict of interest and have received no especially the government, is mandatory to ensure the rights of payment in preparation of this manuscript. RC Nogueira Brazilian scientists to research Brazilian biodiversity and had a fellowship from Fundaçaõ de Amparo a Pesquisa do proper procedures for those who want to bioprospect the Estado da Bahia (FAPESB). MBP Soares holds a senior country’s biodiversity giving the world a chance to develop researcher fellowship from the Brazilian National Council effective new medicines. of Research (CNPq).

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