Abstract:

Since 1996, when antiretroviral (ARV) treatments started being guaranteed to people living with HIV in Brazil, the government has faced the challenge of ensuring sustainability of this policy within a context of incorporating patented medicines. This article sought to analyze the historical series of the price of lopinavir/ritonavir (LPV/r) in Brazil and in the international market also considering the initiatives to challenge patent barriers between 2001 and 2012. The methods used were mapping initiatives to challenge LPV/r patent barriers and the analysis of historical series of its price in Brazil and in the international market. Results show that, between 2001 and 2003, there were efforts to use compulsory licensing as a threat. From 2005 to 2007, initiatives by different satkeholders were identified: declaration of public interest, pre-grant opposition ("support to examination") and civil action. From 2006 to 2008, compulsory licensing initiatives in other countries resulted in a price reduction in Brazil. Between 2009 and 2012, there was a 30% reduction in the Brazilian purchasing price.

Keywords:
Intellectual Property of Pharmaceutic Products and Process; Drug Price; Anti-Retroviral Agents

Introduction

The first cases of AIDS in the world were reported in the late 1970s but they were only diagnosed in 1982. In the beginning of the 1980s, the number of AIDS cases in Brazil followed a trend of growth, and from 1998 and 2006 achieved a relative stabilization. In 2012, there were an estimate of 718,000 people living with HIV in Brazil. Of these, 80% had been diagnosed ¹1. Departamento de DST, Aids e Hepatites Virais, Secretaria de Vigilância em Saúde, Ministério da Saúde. Boletim Epidemiológico Aids e DST 2013; Ano II, nº 1..

Brazil was one the first developing countries to guarantee an integral response to the AIDS epidemic, establishing initiatives for prevention, diagnosis, treatment and care. The Brazilian response was built with the involvement of and the commitment from several stakeholders: users, health care workers, government, private sector and others ²2. Oliveira MA, Esher A. Acesso universal ao tratamento para as pessoas vivendo com HIV e Aids no Brasil. In: Bermudez JAZ, Oliveira MA, Esher A, organizadores. Acceso a medicamentos: derecho fundamental, papel del estado. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 233-50.^{), (3}3. Berkman A, Garcia J, Muñoz-Laboy M, Paiva V, Parker R. A critical analysis of the Brazilian response to HIV/AIDS: lessons learned for controlling and mitigating the epidemic in developing countries. Am J Public Health 2005; 95:1162-72..

Antiretroviral (ARV) treatments started being offered by the government in 1991, but it was only in 1996 that free distribution of the medicines to people living with HIV was established. This allowed that the guarantee of access to treatment could be more structured ²2. Oliveira MA, Esher A. Acesso universal ao tratamento para as pessoas vivendo com HIV e Aids no Brasil. In: Bermudez JAZ, Oliveira MA, Esher A, organizadores. Acceso a medicamentos: derecho fundamental, papel del estado. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 233-50.^{), (4}4. Brasil. Lei nº 9.313, de 13 de novembro de 1996. Dispõe sobre a distribuição gratuita de medicamentos aos portadores do HIV e doentes de AIDS. Diário Oficial da União 1996; 14 nov.. The implementation of free ARV distribution to people living with HIV was set within the formulation of the National Medicines Policy, established in 1998, which consolidated pharmaceutical services as a political commitment by the Brazilian government ²2. Oliveira MA, Esher A. Acesso universal ao tratamento para as pessoas vivendo com HIV e Aids no Brasil. In: Bermudez JAZ, Oliveira MA, Esher A, organizadores. Acceso a medicamentos: derecho fundamental, papel del estado. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 233-50.^{), (5}5. Scheffer M. Coquetel: a incrível história dos antirretrovirais e do tratamento da Aids no Brasil. São Paulo: Editora Hucitec/Sobravime; 2012.^{), (6}6. Ministério da Saúde. Portaria GM nº 3.916, de 30 de outubro de 1998. Aprova a Política Nacional de Medicamentos, cuja íntegra consta no anexo desta portaria. Diário Oficial da União 1998; 10 nov..

Currently, the Brazilian Unified National Health System (SUS) provides 21 ARV, nine of which are produced locally. In the 1990s, with the development of protease inhibitors, among them, the fixed-dose combination lopinavir/ritonavir (LPV/r), there was a considerable improvement in AIDS treatments, including the highly active antiretroviral therapy (HAART) and association of medicines. Since its incorporation into the national treatment guideline, in 2002, LPV/r has an increased role in therapeutic schemes in Brazil ³3. Berkman A, Garcia J, Muñoz-Laboy M, Paiva V, Parker R. A critical analysis of the Brazilian response to HIV/AIDS: lessons learned for controlling and mitigating the epidemic in developing countries. Am J Public Health 2005; 95:1162-72.^{), (7}7. Orsi F, D'Almeida C, Hasenclever L, Câmara M, Tigre P, Coriat B. TRIPS post-2005 and access to new antiretroviral treatments in Southern countries: issues and challenges. AIDS 2007; 21:1997-2003.. It is currently being indicated as a part of a second line scheme ⁸8. Departamento de DST, Aids e Hepatites Virais, Secretaria de Vigilância em Saúde, Ministério da Saúde. Protocolo clínico e diretrizes terapêuticas para manejo da infecção pelo HIV em adultos. Brasília: Ministério da Saúde; 2013..

The first efforts to respond to the AIDS epidemic aimed at ensuring access to treatment. The next challenge was to ensure the sustainability of this response, progressively increasing the number of people in treatment and dealing with the incorporation of new medicines into the therapeutic arsenal.

Internationally, the Agreement on Trade-Related Aspects of Intellectual Property Rights (Trips) came into effect in 1995. All members of the World Trade Organization had to adapt their industrial property to became compliant with the new legal framework, which meant granting patents in the pharmaceutical sector.

The monopoly situation created by the grant of patents or the expectation that a patent application will be granted enables companies to set high prices by restricting production, commercialization of generics and competition. This monopoly is deepened because, in the pharmaceutical sector, there is a overlap of patent applications for medicines, that can indefinitely extend the monopoly of those medicines - a practice known as evergreening ⁹9. Correa C. Guidelines for the examination of pharmaceutical patents: developing a public health perspective. Geneva: International Centre for Trade and Sustainable Development/International Environment House/World Health Organization; 2007..

The AIDS epidemic made explicit the conflict between access and intellectual property. Several ARV are or have been under patent protection, leading to high prices offered to governments. The analysis of LPV/r case allows to draw an outline of the economic barriers created for the access to patented medicines in the context of the implementation of the international system of intellectual property ⁷7. Orsi F, D'Almeida C, Hasenclever L, Câmara M, Tigre P, Coriat B. TRIPS post-2005 and access to new antiretroviral treatments in Southern countries: issues and challenges. AIDS 2007; 21:1997-2003..

Thus, by mapping the initiatives that aim at to overcoming LPV/r's patent barrier, it might de possible to highlight explanatory elements of the evolution of its price in Brazil. A patent barrier is the monopoly that arises from, at least, one pending patent application or, at least, one granted patent. Initiatives to challenge this barrier are those which seek to reduce this monopoly. We assume that even if these initiatives do not lead to the patent's rejection, revocation or licencing, they may have effects on the dynamics of medicines price.

The outline of this path seeks to analyze the historical series of LPV/r prices in Brazil and in the international market in light of the initiatives to challenge patent barriers. In order to do so, we assume that there is a relationship between these initiatives and the medicines price, suggesting a possible effect of the former on the latter.

Methods

This is a longitudinal case study covering the period from 2001 to 2012. It investigates initiatives to challenge patent barriers as explanatory elements of the evolution of LPV/r's treatment cost.

The study comprised the following methodological steps: non-exhaustive literature review, identification of Brazilian initiatives to challenge patent barriers for LPV/r, comparison between the historical series of LPV/r's price in Brazil and in the international market.

The initiatives to challenge patent barriers for LPV/r in Brazil were mapped out and systematized chronologically, as well as classified according to their proponents: the government, national public and private manufactures and civil society organizations.

We obtained unit prices in US dollars (US$) for LPV/r in Brazil from the STI, AIDS and Viral Hepatitis Department of the Ministry of Health through the Access to Information Law. The cost of one treatment per year was calculated by multiplying the number of daily pills by 365 days. In order to compare Brazilian and international prices, prices for the brand (Abbott) and international generic alternatives were obtained from the documents Accessing ARVs: Untangling the Web of Price Reductions for Developing Countries from 2001 to 2012 ¹⁰10. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2001.^{), (11}11. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2002.^{), (12}12. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2003.^{), (13}13. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2004.^{), (14}14. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2005.^{), (15}15. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2006.^{), (16}16. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2007.^{), (17}17. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2008.^{), (18}18. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2009.^{), (19}19. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2010.^{), (20}20. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2011.^{), (21}21. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2012..

The information was systematized in electronic spreadsheets. We constructed a graph with the estimates of cost per treatment per year. Between 2001 and 2006, the adopted dosage form was 133/33mg of LPV/r capsules six times a day. From 2007 on, the adopted dosage form became 200/50mg LPV/r tablets four times a day. Therefore, in order to estimate and compare costs over different years, we calculated treatment costs per individual based on the recommended dosage form daopted by the Brazilian government in each year.

Results and discussion

In Brazil, the Industrial Property Law (LPI; Law 9,279/96) was approved to become compliant to Trips Agreement and also included provisions that went beyond the minimum requirements of the agreement, having negative consequences such as high prices for the ARV adopted by SUS ²²22. Bermudez JAZ, Oliveira MA, Chaves GC. Intellectual property in the context of the WTO Trips agreement: what is at stake? In: Bermudez JAZ, Oliveira MA, editors. Intellectual property in the context of the WTO Trips agreement: challenges for public health. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 23-61.^{), (23}23. Meiners CMMA. Patentes farmacêuticas e saúde pública: desafios à política brasileira de acesso ao tratamento antirretroviral. Cad Saúde Pública 2008; 24:1467-78.^{), (24}24. Chaves GC, Oliveira MA. A proposal for measuring the degree of public health-sensitivity of patent legislation in the context of the WTO Trips agreement. Bull World Health Organ 2007; 85:49-56.^{), (25}25. Oliveira MA, Bermudez JAZ, Epsztejn R, Chaves GC, Ferreira RL, Oliveira MT. Pharmaceutical patent protection in Brazil: who is benefiting? In: Bermudez JAZ, Oliveira MA, editores. Intellectual property in the context of the WTO Trips agreement: challenges for public health. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 161-75.. The first medicines that inaugurated the adoption of patented products were efavirenz, nelfinavir and LPV/r ²⁶26. Grangeiro A, Teixeira L, Bastos FI, Teixeira P. Sustentabilidade da política de acesso a medicamentos antirretrovirais no Brasil. Rev Saúde Pública 2006; 40 Suppl:60-9..

These products were protected through pipeline patents or revalidation patents, considered a Trips-plus provision. This allowed the retroactive patent protection of pharmaceutical products and processes whose patent applications were filed in other countries, as long as there were no local efforts to explore the invention. Additionally, there was no technical examination in Brazil and applications could be field even after the priority period. Thus, even though the invention was already in the public domain, a patent monopoly was granted in Brazil ²⁷27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.^{), (28}28. Hasenclever L, Lopes R, Chaves GC, Reis R, Vieira MF. O instituto de patentes Pipeline e o acesso a medicamentos: aspectos econômicos e jurídicos deletérios à economia da saúde. Rev Direito Sanit 2010; 11:164-88..

When the LPI came into effect in Brazil, it had an immediate effect on medicine costs and on the sustainability of the programs due to its direct impact on the public budget ²⁶26. Grangeiro A, Teixeira L, Bastos FI, Teixeira P. Sustentabilidade da política de acesso a medicamentos antirretrovirais no Brasil. Rev Saúde Pública 2006; 40 Suppl:60-9.. Studies comparing prices of some medicines in Brazil with generic versions in the international market show a large discrepancy in the price offered by the patent holder ²⁹29. Chaves GC, Vieira MF, Reis R. Acesso a medicamentos e propriedade intelectual no Brasil: reflexões e estratégias da sociedade civil. Sur Rev Int Direitos Human 2008; 5:170-98..

Another Trips-plus provision that was included in the LPI was the sole paragraph of article 40, which ensures a minimum patent term of ten years from the time it is granted. If the examination is delayed by more than ten years, the term of the patent will be greater than twenty years. In some countries, high prices of ARV have been a limiting factor for access to treatment, while in Brazil it threats the sustainability of the medicines' supply by SUS ²⁶26. Grangeiro A, Teixeira L, Bastos FI, Teixeira P. Sustentabilidade da política de acesso a medicamentos antirretrovirais no Brasil. Rev Saúde Pública 2006; 40 Suppl:60-9.. In Brazil, users do not directly pay for the treatments. Medicines are provided through the SUS, according to the treatment guideline.

Some safeguards were included in the Trips agreement, from a public health perspective, in order to minimize the negative impacts of patent protection on health policies. It was up to each country to incorporate them into their legislations ²²22. Bermudez JAZ, Oliveira MA, Chaves GC. Intellectual property in the context of the WTO Trips agreement: what is at stake? In: Bermudez JAZ, Oliveira MA, editors. Intellectual property in the context of the WTO Trips agreement: challenges for public health. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 23-61.^{), (23}23. Meiners CMMA. Patentes farmacêuticas e saúde pública: desafios à política brasileira de acesso ao tratamento antirretroviral. Cad Saúde Pública 2008; 24:1467-78.. These safeguards seek to enable the entry of generic versions into the market and to promote competition as a means for reducing prices and enabling access in the context of a monopoly.

These safeguards may act at different moments: if the product is already patented, there are instruments that make it possible to obtain generic alternatives during the term of patent (compulsory licensing and parallel importation); if a patent application has been filed, but not yet granted, it may possible to technically challeng (oppositions); and to adopt guidelines to ensure a restrictive examination of the patentability requirements. Lastly, there is also the possibility of developing research with patented product and process, including carrying out necessary tests for obtaining market approval by country's drug regulatory authorities (experimental use and Bolar exception).

Government and civil society strategies: from price negotiations to demands for compulsory licensing

Between 2001 and 2003, initiatives were mostly governmental, such as the use of threats to issue compulsory license in order to achieve price reduction during negotiations with patent holders and in changes in the Brazilian legislation.

The possibility of issuing a compulsory license was used as an important instrument for price negotiation in Brazil. Between 2001 and 2003, the Brazilian government negotiated a discount for several patented medicines ³⁰30. Bermudez J, Oliveira MA, Chaves GC. O acordo Trips da OMC e os desafios para a saúde pública. In: Bermudez JAZ, Oliveira MA, Esher A, organizadores. Acceso a medicamentos: derecho fundamental, papel del estado. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 69-89.. About launched LPV/r in 2000 and, in 2001, there were no generic versions available in the market. That year, the cost per treatment paid by Brazil was more than five times higher than the cost per treatment with prices offered to least developed countries (Figure 1).

In 2001, as a result of the negotiation, there was a considerable reduction in the price for some medicines, among them LPV/r, which had a 46% price reduction, according to the literature (Figure 2). In addition the the reduction in LPV/r's price, other measures were identified in that period: changes in the Brazilian legislation in order to include the Bolar exception and the prior consent of the Brazilian Health Regulatory Agency (Anvisa) for examining pharmaceutical patents application ³⁰30. Bermudez J, Oliveira MA, Chaves GC. O acordo Trips da OMC e os desafios para a saúde pública. In: Bermudez JAZ, Oliveira MA, Esher A, organizadores. Acceso a medicamentos: derecho fundamental, papel del estado. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 69-89.. According to the analysis of the historical series of cost per treatment (Figure 1), there was a 35% reduction between 2001 and 2002.

In 2002, a generic version of LPV/r was launched. However, the price charged by the company that year was higher than what was sold by Abbott in Brazil.

As shown in Figure 2, in 2003, another negotiation process between the Brazilian Ministry of Health and patent holders was necessary due to the high cost of the medicines. The threat to issue compulsory licensing was once again used as a strategy and a reduction in price was agreed upon that led to a 37% reduction in total spending for ARV ³⁰30. Bermudez J, Oliveira MA, Chaves GC. O acordo Trips da OMC e os desafios para a saúde pública. In: Bermudez JAZ, Oliveira MA, Esher A, organizadores. Acceso a medicamentos: derecho fundamental, papel del estado. Rio de Janeiro: Escola Nacional de Saúde Pública Sergio Arouca, Fundação Oswaldo Cruz; 2004. p. 69-89..

Additionally, another normative change was proposed in 2003 with the decree that detailed the used of compulsory licensing for public interest and national emergency cases ³¹31. Brasil. Decreto nº 4.830, de 4 de setembro de 2003. Dá nova redação aos arts. 1º, 2º, 5º, 9º e 10º do Decreto nº 3.201, de 6 de outubro de 1999, que dispõe sobre a concessão, de ofício, de licença compulsória nos casos de emergência nacional e de interesse público de que trata o art. 71 da Lei nº 9.279, de 14 de maio de 1996. Diário Oficial da União 2003; 5 set.. That change established the possibility of importing products from producers other than the patent holder, if a compulsory license were issued.

Between 2003 and 2004, the price of the Indian generic version had a near 50% reduction, ending up well below the purchasing cost in Brazil, which had been slowly decreasing since 2002, as can be seen in Figure 1. In that same period, the protease inhibitor atazanavir was introduced in Brazil and quickly became LPV/r's main competitor as a therapeutic substitute ⁵5. Scheffer M. Coquetel: a incrível história dos antirretrovirais e do tratamento da Aids no Brasil. São Paulo: Editora Hucitec/Sobravime; 2012.. However, these two events seem not to have had an immediate impact on the price of LPV/r in Brazil. There was a increase in the cost of LPV/r purchased by Brazil between 2004 and 2005 (Figure 1).

In the period between 2005 and 2007, there were also a series of initiatives led mainly by civil society. There were also government initiatives and one initiative by a national public manufacturer.

As we have already discussed (Figure 2), until 2005, Brazil used the threat of compulsory licensing in order to successfully negotiate price reductions for several patented drugs. Giving into Brazilian threats of compulsory licensing, the pharmaceutical industry preferred to reduce prices than have their patents compulsorily licensed. But, over time, that negotiation tactic began to lose credibility and became inefficient, so that the prices reached were unsatisfactory ²⁶26. Grangeiro A, Teixeira L, Bastos FI, Teixeira P. Sustentabilidade da política de acesso a medicamentos antirretrovirais no Brasil. Rev Saúde Pública 2006; 40 Suppl:60-9.^{), (27}27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.^{), (29}29. Chaves GC, Vieira MF, Reis R. Acesso a medicamentos e propriedade intelectual no Brasil: reflexões e estratégias da sociedade civil. Sur Rev Int Direitos Human 2008; 5:170-98..

According to Grangeiro et al. ²⁶26. Grangeiro A, Teixeira L, Bastos FI, Teixeira P. Sustentabilidade da política de acesso a medicamentos antirretrovirais no Brasil. Rev Saúde Pública 2006; 40 Suppl:60-9., during that time, it was announced that the sustainability of the ARV supply in Brazil would be at risk if costs continued to rise in the same proportion. In 2005, LPV/r accounted for around 30% of governmental ARV expenditures of R$ 1 billion ³²32. Conselho Nacional de Saúde. Resolução nº 352, de 11 de agosto de 2005. Delibera sobre a emissão de licenças compulsórias dos medicamentos Efavirenz, Lopinavir e Tenofovir, bem como de outros anti-retrovirais patenteados e a fabricação local dos medicamentos. http://conselho.saude.gov.br/resolucoes/reso_05.htm (acessado em 05/Mai/2014).
http://conselho.saude.gov.br/resolucoes/... . That year, there was a 66% increase in ARV expenditures, according to the literature, breaking the reduction tendency observed between 2000 and 2004. Some factors associated with the increase were: the weakened national pharmaceutical industry and negotiations with unsatisfactory results ²⁶26. Grangeiro A, Teixeira L, Bastos FI, Teixeira P. Sustentabilidade da política de acesso a medicamentos antirretrovirais no Brasil. Rev Saúde Pública 2006; 40 Suppl:60-9..

In 2005, there were four initiatives to challenge patent barrier (Figure 2). In March of that year, Brazil announced its intention to issue a compulsory license for three medicines if producers did not provide a voluntary license. In June of that year, during negotiations with Abbott to reduce LPV/r's price, the Brazilian government declared it to be of public interest - the first step for issuing a compulsory license - and gave Abbott a deadline to offer a reasonable price ⁷7. Orsi F, D'Almeida C, Hasenclever L, Câmara M, Tigre P, Coriat B. TRIPS post-2005 and access to new antiretroviral treatments in Southern countries: issues and challenges. AIDS 2007; 21:1997-2003.^{), (27}27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.^{), (29}29. Chaves GC, Vieira MF, Reis R. Acesso a medicamentos e propriedade intelectual no Brasil: reflexões e estratégias da sociedade civil. Sur Rev Int Direitos Human 2008; 5:170-98.^{), (33}33. Brasil. Portaria MS/GM nº 985, de 24 de junho de 2005. Declara, para fins de sustentabilidade social do programa brasileiro de combate à AIDS, interesse público relativamente aos medicamentos advindos da associação dos princípios ativos Lopinavir e Ritonavir, com vistas à composição do rol dos inibidores de protease que devem compor o arsenal terapêutico para o tratamento da infecção por HIV/AIDS no Brasil. Diário Oficial da União 2005; 24 jun.^{), (34}34. Instituto Brasileiro de Altos Estudos de Direito Público. Remédio para AIDS: portaria histórica. 2007. http://www.altosestudos.com.br/?p=46539 (acessado em 07/Jul/2015).
http://www.altosestudos.com.br/?p=46539... .

The issue of high medication prices threatening the sustainability of the ARV supply was also discussed in a meeting of the Brazilian National Health Council (CNS) in August 2005. Based on considerations made by council members, CNS unanimously approved a resolution in favor of issuing a compulsory license and local production of LPV/r and other patented medicines, given the lack of satisfactory negotiations for reducing prices ³²32. Conselho Nacional de Saúde. Resolução nº 352, de 11 de agosto de 2005. Delibera sobre a emissão de licenças compulsórias dos medicamentos Efavirenz, Lopinavir e Tenofovir, bem como de outros anti-retrovirais patenteados e a fabricação local dos medicamentos. http://conselho.saude.gov.br/resolucoes/reso_05.htm (acessado em 05/Mai/2014).
http://conselho.saude.gov.br/resolucoes/... ^{), (35}35. Conselho Nacional de Saúde. Ata da centésima quinquagésima sétima reunião ordinária. http://conselho.saude.gov.br/atas/atas_05.htm (acessado em 05/Mai/2014).
http://conselho.saude.gov.br/atas/atas_0... .

However, after four months of negotiations, in October 2005, a deal was signed between the Ministry of Health and Abbott ensuring a 46% price reduction. Even with this discount, the price of the medicine was still much higher than the lowest price offered internationally by Abbott and than the estimated production cost. There were other restrictions in the agreement ⁷7. Orsi F, D'Almeida C, Hasenclever L, Câmara M, Tigre P, Coriat B. TRIPS post-2005 and access to new antiretroviral treatments in Southern countries: issues and challenges. AIDS 2007; 21:1997-2003.^{), (27}27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.. Despite the CNS initiative, the Ministry of Health did not issue a compulsory license for LPV/r and opted instead for an agreement with the pharmaceutical company ³⁶36. Vieira MF, Reis R. Litigância estratégica em direitos humanos - a atuação da sociedade civil no acesso a medicamentos no Brasil. In: Frigo D, Prioste F, Escrivão Filho AS, organizadores. Justiça e direitos humanos: experiências de assessoria jurídica popular. Curitiba: Terra de Direitos; 2010. p. 61-83..

In December 2005, due to the lack of a compulsory license, the Working Group on Intellectual Property of the Brazilian Network for the Integration of Peoples (GTPI/Rebrip), along with the Federal Prosecutor, filed a civil action against the Brazilian government and Abbott, demanding that a compulsory license be issued for LPV/r. However, the initial judicial response was negative, due to fear of retaliation from developed countries, possible medicine shortages and doubts regarding local production capacity. The authors of the civil action appealed against the decision. The appeal is still pending ²⁷27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.^{), (29}29. Chaves GC, Vieira MF, Reis R. Acesso a medicamentos e propriedade intelectual no Brasil: reflexões e estratégias da sociedade civil. Sur Rev Int Direitos Human 2008; 5:170-98.. In this case, there is a clear reproduction of pharmaceutical companies and developed countries' discourse by the Brazilian judiciary, with no critical analysis of the topic ³⁶36. Vieira MF, Reis R. Litigância estratégica em direitos humanos - a atuação da sociedade civil no acesso a medicamentos no Brasil. In: Frigo D, Prioste F, Escrivão Filho AS, organizadores. Justiça e direitos humanos: experiências de assessoria jurídica popular. Curitiba: Terra de Direitos; 2010. p. 61-83..

Between 2005 and 2006, with LPV/r having been declared of public interest, CNS's recommendation that a compulsory license be issued and the collective action, even after an agreement was reached with Abbott, LPV/r's cost dropped once again, by more than 51% (Figure 1). Dhamija et al. ³⁷37. Dhamija P, Bansal D, Medhi B. Trends and economic stress: a challenge to universal access to antiretroviral treatment in India. Curr HIV Res 2009; 7:410-7. state that, after 2006, there was a stabilization in the prices of several medicines, which is reflected in the price of LPV/r.

New stakeholders and new strategies to challenge patent barriers

Starting in 2006, in addition to government and civil society initiatives, there were efforts to confront the LPV/r patent barrier by other stakeholders: public and private national manufacturers and the Attorney General.

In 2006, the Institute of Drug Technology (Farmanguinhos), a unit of Oswaldo Cruz Foundation (Fiocruz), presented a pre-grant opposition (support to examination) for one of the patent applications for LPV/r. That same year, on World AIDS Day, GTPI/Rebrip presented another pre-grant opposition contesting the same patent application (Figure 2). As a result of these initiatives, that application was rejected by the Brazilian National Institute of Industrial Property (INPI) in 2010 (INPI. Base de dados do INPI. https://gru.inpi.gov.br/pPI/jsp/patentes/PatenteSearchBasico.jsp, accessed on 01/May/2014) ³⁸38. Barroso WBG. Contribuição ao estudo do subsídio ao exame de pedido de patente no Brasil. In: Corrêa MCDV, Cassier M, organizadores. Aids e saúde pública: contribuições à reflexão sobre uma nova economia política do medicamento no Brasil. Rio de Janeiro: EdUerj; 2010. p. 1-244.. However, the large number of patent applications field in Brazil generates uncertainties regarding whether the rejection of this application does put the medicine in the public domain.

The LPI establishes the possibility of presenting pre-grant opposition (support to examination), before they are granted, or nullity, after they are granted (post-grant opposition). This strategy is internationally known as patent opposition. Up to the end of the period of patent examination, interested parties could submit technical informations to the INPI. This procedure seeks to prevent that monopolies be granted if the requirements for patentability are not met - novelty, inventiveness and industrial application ⁷7. Orsi F, D'Almeida C, Hasenclever L, Câmara M, Tigre P, Coriat B. TRIPS post-2005 and access to new antiretroviral treatments in Southern countries: issues and challenges. AIDS 2007; 21:1997-2003.^{), (27}27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9., preventing the emergency strategy.

At least twelve patent requests related to LPV/r were deposited in Brazil. With the last request being granted, the monopoly will be extended by nine more years beyond the expiration of the first patent request in Brazil - until 2025 (INPI. Base de dados do INPI. https://gru.inpi.gov.br/pPI/jsp/patentes/PatenteSearchBasico.jsp, accessed on 01/May/2014) ³⁹39. Villardi P. Panorama do status patentário e registro sanitário dos medicamentos antirretrovirais no Brasil - implicações para o acesso e a política industrial no Brasil. Rio de Janeiro: Associação Brasileira Interdisciplinar de Aids; 2012..

In 2007, GTPI/Rebrip, through the National Pharmacist Federation (Fenafar) filed a representation requesting that the Attorney General file a Direct Action of Unconstitutionality (ADIn, in Portuguese) against the pipeline mechanism at the Federal Supreme Court. The ADIn is a mechanism that enables stakeholders to contest the constitutionality of a given law ²⁹29. Chaves GC, Vieira MF, Reis R. Acesso a medicamentos e propriedade intelectual no Brasil: reflexões e estratégias da sociedade civil. Sur Rev Int Direitos Human 2008; 5:170-98..

The representation sought to show that pipeline patents are unconstitutional. It is worth noting that the inventions that were meant to be protected by this mechanism were already in the public domain and therefore did not meet the novelty requirement ³⁶36. Vieira MF, Reis R. Litigância estratégica em direitos humanos - a atuação da sociedade civil no acesso a medicamentos no Brasil. In: Frigo D, Prioste F, Escrivão Filho AS, organizadores. Justiça e direitos humanos: experiências de assessoria jurídica popular. Curitiba: Terra de Direitos; 2010. p. 61-83.. It is estimated that 340 medicines have been protected through pipeline patents, including ritonavir and lopinavir ²⁷27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.^{), (28}28. Hasenclever L, Lopes R, Chaves GC, Reis R, Vieira MF. O instituto de patentes Pipeline e o acesso a medicamentos: aspectos econômicos e jurídicos deletérios à economia da saúde. Rev Direito Sanit 2010; 11:164-88.^{), (40}40. Miranda PHMV. Perguntas e respostas sobre patentes pipeline: como afetam sua saúde? Rio de Janeiro: Associação Brasileira Interdisciplinar de Aids; 2009..

This initiative did not address LPV/r specifically, but sought to annul the article of the LPI that made this form of patenting possible. This way, other patent applications could also be annulled. Other medicines for which a patent was granted through pipeline are: atorvastatin, imatinib and olanzapine. Between 2009 and 2010, it is estimated that Brazil paid between 704% and 5,622% more for these medicines than it would have spent on equivalent generic medicines ⁴¹41. Grupo de Trabalho sobre Propriedade Intelectual. Cálculo estimado do prejuízo monetário causado pela compra de quatro medicamentos selecionados protegidos por patentes pipeline. http://www.deolhonaspatentes.org.br/media/file/Notas%20GTPI%20-%202011/GTPI%20-%20calculo%20pipeline%20(final).pdf (acessado em 25/Set/2014).
http://www.deolhonaspatentes.org.br/medi... .

There is another study on the effect of pipeline patents on the prices of five ARV: abacavir, nelfinavir, efavirenz, amprenavir and LPV/r. The prices of generic versions available internationally were compared with the value paid by the Ministry of Health between 2001 and 2007. It was estimated that, in that period, Brazil paid between US$ 420 and US$ 519 million more, when compared with the reference prices from World Health Organization or Doctors without Borders, respectively ²⁸28. Hasenclever L, Lopes R, Chaves GC, Reis R, Vieira MF. O instituto de patentes Pipeline e o acesso a medicamentos: aspectos econômicos e jurídicos deletérios à economia da saúde. Rev Direito Sanit 2010; 11:164-88..

In May 2009, in response to Fenafar's representation on behalf of GTPI/Rebrip, the Attorney General presented the ADIn 4,234 to the Supreme Court, questioning the validity of pipeline patents. Several amici curiae were presented both in favor and against the ADIn ²⁸28. Hasenclever L, Lopes R, Chaves GC, Reis R, Vieira MF. O instituto de patentes Pipeline e o acesso a medicamentos: aspectos econômicos e jurídicos deletérios à economia da saúde. Rev Direito Sanit 2010; 11:164-88..

The Court's decision is still pending. This delay may weaken the effect of the initiative, as most of the patents of the products produced through pipeline have expired. Meanwhile, other judicial actions are addressing the topic on a case by case basis. The Supreme Court's decision has extensive implications for access to medicines, since it sets a precedent for addressing old issues regarding the patenting in Brazil ¹⁰10. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2001.^{), (11}11. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2002.^{), (12}12. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2003.^{), (13}13. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2004.^{), (14}14. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2005.^{), (15}15. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2006.^{), (16}16. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2007.^{), (17}17. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2008.^{), (18}18. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2009.^{), (19}19. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2010.^{), (20}20. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2011.^{), (21}21. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2012..

International initiatives and local effects

Though the methods we have used in this study prioritized initiatives for overcoming patent barriers in Brazil, we also found international initiatives in the literature which deserve to be discussed in light of the price evolution.

Between 2006 and 2008, the Thai government issued compulsory licenses for seven medicines, including LPV/r ⁴²42. Mohara A, Yamabhai I, Chaisiri K, Tantivess S, Teerawattananon Y. Impact of the introduction of government use licenses on the drug expenditure on seven medicines in Thailand. Value Health 2012; 15 Suppl 1:S95-9.^{), (43}43. Limpananont J, Eksaengsri A, Kijtiwatchakul K, Metheny N. Acesso ao tratamento da Aids e proteção dos direitos de propriedade intelectual na Tailândia. In: Reis R, Terto Jr. V, Pimenta MC, organizadores. Direitos de propriedade intelectual e acesso aos antirretrovirais: resistência da sociedade civil no sul global. Rio de Janeiro: Associação Brasileira Interdisciplinar de Aids; 2011. p. 153-84.. In response to the Thai compulsory license, Abbott made changes to their price discrimination policy and to the offer of differentiated prices in middle-income countries. The reduction of LPV/r prices in 40 countries, including Brazil, shows the influence of the international context in other countries ²⁷27. Ford N, Wilson D, Chaves GC, Lotrowska M, Kijtiwatchakul K. Sustaining access to antiretroviral therapy in the less-developed world: lessons from Brazil and Thailand. AIDS 2007; 21 Suppl 4:S21-9.. As shown in Figure 1, from 2008 on, treatment costs for LPV/r was around US$ 1,000 per year, the value Abbott offered middle-income countries. In May 2007, Brazil issued a compulsory license for evafirenz. In the post-compulsory licenses context, LPV/r's price fell continuously.

The practice of differential prices (or tiered pricing) is the sale of essential medicines to low and middle-income countries at lower prices than in developed countries and has been proposed as an alternative to high prices of medicines. However, market segmentation according to consumers' alleged capacity to pay is also a profit maximization strategy and is not necessarily more effective than competition ⁴⁴44. Moon S, Jambert E, Childs M, von Schoen-Angerer T. A win-win solution? A critical analysis of tired pricing to improve access to medicines in developing countries. Global Health 2011; 7:39..

In special situations, especially when markets are small and uncertain, production capacity is limited or there are delays in overcoming barriers to competition, the practice of differential prices may contribute to increasing access, as in the case of drug-resistant tuberculosis. However, when markets are considerably large and several forms of production are available, price differentiation has a low performance when compared with competition in reducing sustainable prices - which has been shown for ARV, drug combinations for malaria, visceral leishmaniasis and vaccines against pneumococcus ⁴⁴44. Moon S, Jambert E, Childs M, von Schoen-Angerer T. A win-win solution? A critical analysis of tired pricing to improve access to medicines in developing countries. Global Health 2011; 7:39..

Other elements must be taken into account: price differentiation does not necessarily result in the lowest sustainable prices, nor does it ensure reductions over time; there are no clear international rules for establishing differential prices; and this practice gives little deciding power to governments, leaving this important issue in the hands of private companies ⁴⁴44. Moon S, Jambert E, Childs M, von Schoen-Angerer T. A win-win solution? A critical analysis of tired pricing to improve access to medicines in developing countries. Global Health 2011; 7:39..

Between 2009 and 2012, we can define a period with actions focused on pre- and post-grant oppositions. The use of Trips safeguard may be an important alternative in the change in the pattern of initiatives for challenge patent barriers, as generic versions available in the international market tend to decrease as a consequence of countries with production capacity are becoming Trips compliant.

In 2009, within the context of the Brazilian industry policy of incentivizing local production, there was one initiative by a national private company. In September, the pharmaceutical company Cristália presented a post-grant opposition in the Court regarding the LPV/r patent, granted in 1997 through the pipeline mechanism. With the same motivation as the ADIn, the allegation is that the patent was granted without an analysis of the patentability requirements and without an examination by Anvisa. In February 2012, the Federal Court of Rio de Janeiro ruled in favor of the post-grant opposition request, annulling LPV/r's original patent ¹⁰10. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2001.^{), (11}11. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2002.^{), (12}12. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2003.^{), (13}13. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2004.^{), (14}14. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2005.^{), (15}15. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2006.^{), (16}16. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2007.^{), (17}17. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2008.^{), (18}18. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2009.^{), (19}19. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2010.^{), (20}20. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2011.^{), (21}21. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2012.^{), (45}45. Tribunal Federal do Rio de Janeiro. Sentença - tipo "A". http://cdn.patentoppositions.org/uploads/court_case/user_uploaded_file/500eaae57718ea000200001d/17b9ecb0-b7c6-012f-0083-1231380e4d21.pdf (acessado em 10/Abr/2014).
http://cdn.patentoppositions.org/uploads... .

From 2009 on, the price of the international generic became comparable with the lowest price offered by Abbott to other countries. These prices dropped until 2012, reaching a value around US$ 400, probably close to production costs. A previous study showed the importance of raw materials cost in determining ARV prices; other factors, such as workforce, scale, transportation, among others, had a smaller impact. Since raw materials for certain second line medicines, such as LPV/r, are patented in many countries, this leads to an increase in the price of these ingredients and of an overall production costs ⁴⁶46. Pinheiro E, Vasan A, Kim JY, Lee E, Guimier JM, Perriens J. Examining the production costs of antirretroviral drugs. AIDS 2006; 20:1745-52..

In November 2011, groups defending public health in twelve countries launched a global campaign, challenging Abbott for the monopoly of the LPV/r fixed-dose combination. The "Global Kaletra Campaign" (Figure 2), as it was known, sought to give visibility to the globalization of problems that seemed to be local. The campaign aimed at stimulating competition with generic drugs in order to reduce price and to make new fixed-dose combinations possible through the presentation of patent oppositions (support to examinations) or requests for compulsory licensing ¹⁰10. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2001.^{), (11}11. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2002.^{), (12}12. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2003.^{), (13}13. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2004.^{), (14}14. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2005.^{), (15}15. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2006.^{), (16}16. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2007.^{), (17}17. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2008.^{), (18}18. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2009.^{), (19}19. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2010.^{), (20}20. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2011.^{), (21}21. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2012.^{), (47}47. Public Citizen. Public health groups launch global campaign against Abbott labs' monopoly on critical AIDS medicine. http://www.citizen.org/press-release (acessado em 10/Abr/2014).
http://www.citizen.org/press-release... .

Brazil participated in this campaign and one of its actions was the pre-grant opposition, preseented byby GTPI/Rebrip, against the patent application that covers the heat-stable dosage form, filed in 2004, by Abbott. This initiative sought to avoid the inappropriate extension of the monopoly. INPI granted a priority examination of this patent application in order to speed up the analysis. The patent application is still pending, but INPI's technical report states that the application does not meet patentability requirements, because it is obvious to someone with technical expertise in the subject ¹⁰10. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2001.^{), (11}11. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2002.^{), (12}12. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2003.^{), (13}13. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2004.^{), (14}14. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2005.^{), (15}15. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2006.^{), (16}16. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2007.^{), (17}17. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2008.^{), (18}18. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2009.^{), (19}19. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2010.^{), (20}20. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2011.^{), (21}21. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2012.^{), (48}48. Grupo de Trabalho sobre Propriedade Intelectual. Subsídio ao exame. http://cdn.patentoppositions.org/uploads/patent_opposition/user_uploaded_file/4fccce1504a7f927a6000008/43e1d4a0-9084-012f-9bf3-4040e16a13f4.pdf (acessado em 18/Abr/2014).
http://cdn.patentoppositions.org/uploads... .

Some medium term effects of the initiatives are: decisions due to judicial dispute and the Partnership for Productive Development (PDP) for the local production of LPV/r.

Within the current industrial policy, in 2012, a PDP was announced for the combination LPV/r, as shown in Figure 2. The proposal involves three public manufacturers (Farmanguinhos, Furp and Iquego) and one private manufacturer (Cristália) ¹⁰10. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2001.^{), (11}11. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2002.^{), (12}12. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2003.^{), (13}13. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2004.^{), (14}14. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2005.^{), (15}15. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2006.^{), (16}16. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2007.^{), (17}17. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2008.^{), (18}18. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2009.^{), (19}19. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2010.^{), (20}20. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2011.^{), (21}21. Médicines Sans Frontières. Accessing ARVs: untangling the web of price reductions for developing countries. Geneva: Médicines Sans Frontières; 2012.^{), (49}49. Ministério da Saúde. Parceria para o desenvolvimento produtivo - PDP. http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/581-sctie-raiz/deciis/l2-deciis/12090-parceria-para-o-desenvolvimento-produtivo-pdp (acessado em 10/Jun/2015).
http://portalsaude.saude.gov.br/index.ph... , without involving the patent holder as a responsible for the technology transfer. Among its goals, this policy seeks to reduce prices ⁵⁰50. Ministério da Saúde. Portaria MS/GM nº 2.531, de 12 de novembro de 2014. Redefine as diretrizes e os critérios para a definição da lista de produtos estratégicos para o Sistema Único de Saúde (SUS) e o estabelecimento das Parcerias para o Desenvolvimento Produtivo (PDP) e disciplina os respectivos processos de submissão, instrução, decisão, transferência e absorção de tecnologia, aquisição de produtos estratégicos para o SUS no âmbito das PDP e o respectivo monitoramento e avaliação. Diário Oficial da União 2014; 13 nov., but further studies are required to establish its benefits for this reduction.

It is interpreted that this approach, with the goal of establishing a local production, considered the possibilities established in the Brazilian legislation for experimental use and the Bolar exception, since these efforts are taking place during the patent term. National producer's bet to develop this medicine must have taken into account the fact that the last patent granted to LPV/r is about to expire - in 2017.

The period between 2009 and 2012, shown in Figure 1, shows that there was a 30% reduction in purchasing price in Brazil, without reaching the values of the two other curves, showing that price reduction possibly reached its limit.

Finally, analyzing the evolution of LPV/r's treatment costs in light of initiatives to challenge patent barriers enabled us to point out explanatory elements of the dynamics of the prices the Brazilian government obtained over time.

The variations between the different sources of data on treatment costs in Brazil and on international prices are limitations of this study. It is also not possible to guarantee the correlation of cause and effect between the initiatives and the prices, but we are able to suggest a relationship between these two variables.

Final considerations

Brazil is politically and legally committed to pharmaceutical services and treatment provision. However, the Trips Agreement represented a challenge to health policy makers, as the possibility of patenting pharmaceuticals made high prices for essential medicines possible.

The Trips Agreement establishes a minimum standard for the protection of intellectual property, and countries are free to establish their national standards and legislation, including the incorporation of safeguards for protecting public health. Though initiatives show that the safeguards established in Trips and incorporated into the LPI have not been used to their fullest potential, price reductions for medicines under monopolies also do not occur spontaneously and without direct or indirect efforts to put pressure on these monopolies.

Nationally, negotiating prices through threats of compulsory licensing was an important and widely used initiative. Different stakeholders also contested patent applications at different times. Though it was not this study's goal to compare the strategy which most contributed to price reductions, we suggest that a combination of strategies may establish a favorable environment for price reduction.

Internationally, identifying generic versions and mapping out initiatives for overcoming patent barriers in other countries may contribute to a price reduction environment, as evidenced by compulsory licensing in Thailand and changes to the company's price offer to other countries, including Brazil.

We were able to map out and characterize different stakeholders' actions and goals to challenge patent barriers, which include direct efforts to reduce price, a search for local production alternatives and greater visibility for the effects of patent protection on access.

More detailed studies are needed, with tools that are capable of overcoming this study's limitations and that may add other explanatory elements regarding price reductions of patented medicines in Brazil. However, we believe this study contributes to identifying some of these elements about the dynamics of medicines price.

Acknowledgements

We thank the graduate program in Public Health of the Sergio Arouca National School of Public Health, Oswaldo Cruz Foundation for the academic support at the early stages of the article's development during a writing workshop

References

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