The role of intellectual property in local production in developing countries: opportunities and challenges

Intellectual Property and Trade Financing Technology Transfer R&D, Innovation M onitoring and Reporting The role of intellectual property in local production in developing countries Opportunities and challenges Im proving Access

The role of intellectual property in local production in developing countries Opportunities and challenges WHO Library Cataloguing-in-Publication Data The role of intellectual property in local production in developing countries: opportunities and challenges. 1.Intellectual Property. 2.Technology Transfer. 3.Drugs, Essential. 4.Patents. 5.Developing Countries. I.World Health Organization ISBN 978 92 4 151030 1 (NLM classification: QV 704) © World Health Organization 2016 All rights reserved. Publications of the World Health Organization are available on the WHO website (http://www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: bookorders@who.int). Requests for permission to reproduce or translate WHO publications –whether for sale or for non- commercial distribution– should be addressed to WHO Press through the WHO website (http:// www.who.int/about/licensing/copyright_form/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Printed in Switzerland Editing and design by Inís Communication – http://www.iniscommunication.com Photo: Arne Hoel/World Bank Contents Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ii Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3 2. Designing a national system conducive to local pharmaceutical industry .5 2.1 Access to patent information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.2 Making policy choices to favour local production of pharmaceuticals in developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7 2.3 Patentability standards and opposition procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.4 Ensuring appropriate patent examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.5 Limiting divisional patent applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 2.6 Post-grant flexibilities: the example of compulsory licences . . . . . . . . . . . . . . . . . . . . . . 14 3. Enabling local production through agreements . . . . . . . . . . . . . . . . . . 16 4. Patent landscapes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.1 Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.2 Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 4.3 Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.4 Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.5 Further resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Annex 1 Atazanavir: analysis of patent landscape . . . . . . . . . . . . . . . . . . 25 Annex 2 Raltegravir: analysis of patent landscape . . . . . . . . . . . . . . . . . . 31 Annex 3 Imatinib: analysis of patent landscape . . . . . . . . . . . . . . . . . . . . 33 Annex 4 Sitagliptin: analysis of patent landscape . . . . . . . . . . . . . . . . . . . 35 Annex 5 Pegylated interferon alfa-2a: analysis of patent landscape . . . . . . 38 Annex 6 Gardasil human papillomavirus vaccine: analysis of patent landscape . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 ii Abbreviations AIDS acquired immunodeficiency syndrome ARIPO Africa Regional Intellectual Property Organisation HIV human immunodeficiency virus HPV human papillomavirus ICTSD International Centre for Trade and Sustainable Development I-MAK Initiative for Medicines, Access & Knowledge LDC least developed country OAPI Organisation Africaine de la Propriété Intellectuelle TRIPS Agreement Agreement on Trade-Related Aspects of Intellectual Property Rights UNCTAD United Nations Conference on Trade and Development UNDP United Nations Development Programme WHO World Health Organization WIPO World Intellectual Property Organization WTO World Trade Organization iii Acknowledgements We would like to express our sincere thanks to our colleagues from the United Nations Conference on Trade and Development (Christoph Spennemann), the World Intellectual Property Organization (Marco Aleman, Tomoko Miyamoto and Giulia Ragonesi) and the World Trade Organization (Roger Kampf), who reviewed different drafts of this paper and provided very valuable input. We also warmly thank the Initiative for Medicines, Access & Knowledge and Tahir Amin for developing the patent reports in the annexes, and F. Hoffmann-La Roche and Novartis, which kindly reviewed the patent data on pegylated interferon and imatinib, respectively, and filled in gaps in the data. At the World Health Organization, this work was led by Peter Beyer as part of the project “Improving access to medical products in developing countries through building capacity for local production and related technology transfer”, under the overall supervision and guidance of Zafar Mirza. Contributions were made by Moredreck Chibi, Sophia Georgeff, Ai Koba and Lena Schneider. The project is supported financially by the European Commission. iv Background This paper forms part of Phase 2 of a project undertaken by the World Health Organization and supported by the European Commission on improving access to medical products in developing countries through building capacity for local production and related technology transfer. Phase 1 of the project reviewed the main trends and barriers to local production of pharmaceuticals, vaccines and diagnostics. The evidence gathered in Phase 1 suggests that developing countries that have developed a viable and successful manufacturing industry adopted a long-term vision and followed it up with perseverance. It was identified that a mutually supportive, complementary and coherent combination of policies is required to ensure long-term sustainability. Alignment between medical regulation, industrial and investment policies, science, technology and innovation policies, intellectual property policies, health insurance policies, procurement policies and technology transfer policies appears to be particularly important (1). Phase 2 of the project seeks to continue to develop the policy framework identified in Phase 1 by conducting a deeper analysis of the areas identified in order to develop policy coherence. One of the policy areas where further analysis is required is the role played by intellectual property rights in local production and access to medical products in developing countries – in particular, how indirect government support can be provided by the development of policies to support incremental innovation and production and suitable intellectual property rights regimes. 1Executive summary Intellectual property plays an important role both for the researching pharmaceutical industry, which relies heavily on intellectual property to protect its products, and for generic companies, which produce copies of existing medicines once patent protection expires. Beyond patent protection, trademarks are another form of intellectual property rights used to identify and market pharmaceutical products. Trade secrets and protection of clinical test data are other important elements of this industry. Consequently, how a national intellectual property system is set up is important when considering options for local production of pharmaceuticals in developing countries. Using practical examples and patent landscapes, this report attempts to set out the various strategies and options available to facilitate local production. The report describes the options available to countries with a generic industry to design an intellectual property system that is favourable for local production and potentially for public health. The report highlights the importance of transparent and fair patent administration systems using the example of access to patent information. The report exemplifies how this can also support the use of certain pre-grant flexibilities to increase the space for local generic companies and facilitate local production. In this context, the questions of whether and how to examine patents are essential. Where countries decide to provide for substantive examination, they need to pay particular attention to what standards need to be followed to ensure implementation of pre-grant flexibilities in practice. Favourable interpretation of various provisions of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement) to support local industry is important: simply writing flexibilities into legislation will not achieve their intended impact without a good understanding by local producers of patent laws and patent systems. Competent intellectual property professionals and a transparent, fair and efficient court system also need to be in place to allow such policies to flourish. The existence of a patent does not mean local production is not possible. This report provides practical examples showing multiple ways that allowed for local production through cooperation and/or the use of TRIPS flexibilities. Collaboration by patent holders has increased over the past years. Licensing has become common in the area of HIV/AIDS, and we have also seen cooperation in the area of hepatitis C. In this context, implementing pre- and post-grant flexibilities and using them strengthens the negotiating position of local companies when they endeavour to enter into licensing and technology transfer deals. This report provides patent information on a number of medicines to show that it is a simplification to describe a medicine as “under patent”. Patents are granted for national or regional jurisdictions, and the complete landscape often reveals countries where patents have not been filed or granted and thus where local production could take place if the technical problems associated with the production of affordable good-quality medicines can be overcome. Local production depends on many conditions; the intellectual property environment is only one of these conditions and in itself will not be decisive. The mere absence of a patent in a country will not lead to local production of a medicine or ensure access to that medicine. The intellectual property system can, however, be used and designed to 2favour local pharmaceutical innovation and manufacturing. Local production does not necessarily lead to improved access and health outcomes, which require good-quality essential medicines to be produced and marketed at affordable prices. 31. Introduction A key feature for pharmaceutical production is intellectual property. This applies for both the researching pharmaceutical industry, which relies heavily on intellectual property protection to recoup its investment and defend its market position, and generic companies, which enter the market once patent protection expires or with the authorization of the patent holder. Beyond patent protection, trademarks are another form of intellectual property rights used to identify and market pharmaceutical products. Trade secrets and protection of clinical test data are other important elements of this industry. Consequently, the set-up of a national intellectual property system is important when considering options for local production of pharmaceuticals. The level of protection of intellectual property rights appropriate to meet the needs of the society and of the local pharmaceutical industry depends on the character of the local industry, its technological capacities and its business model. In developing the appropriate intellectual property rights regime to promote local pharmaceutical production, attention needs to be paid to the country’s level of economic and technological development and its industrial policy objectives. For example, local producers in developing countries may seek to file patents on incremental improvements of existing medicines or manufacturing processes, depending on their level of technological capability and commercial needs. The appropriate level of protection of intellectual property may differ between industry branches. For example, in the same country, the local generic pharmaceutical industry may be interested in a flexible patent system that allows for early entry of generic products, while the local textile industry may be interested in stronger design protection to prevent competing companies from copying its original designs. Therefore, consideration needs to be given to an environment that balances the long-term interests of society with the interests of (local) producers in different sectors for commercial needs. As such, there is no single approach to how a country’s national intellectual property rights laws should draw the line between exclusive rights on the one hand and the promotion of competition on the other hand. An analysis has to be carried out to assess what the appropriate policy should look like. Box 1 provides an overview of how local companies are concerned with intellectual property policies. Box 1 How are local generic companies in developing countries concerned with intellectual property? Local generic companies in developing countries: • need to know whether they infringe any patents when producing a specific medicine; • need to monitor the patent situation in potential countries of export; • may want to file patent oppositions against certain applications on products of interest; • may want to file patents on improvements of a medicine or production process in countries of interest; • usually file for a trademark to protect their company name and logo and their products to distinguish them from their competitors and earn a premium on branded generics; • may enter into licence agreements or transfer of technology arrangements with originator companies. 4Most countries do not start from scratch when developing their national intellectual property systems. The situation depends on which international World Intellectual Property Organization (WIPO) treaties the country adheres to, whether the country is a member of the World Trade Organization (WTO), and any obligations arising from other regional or bilateral agreements that include intellectual property protection. This study focuses on countries that are WTO members and that have a local generic industry with some capacity for innovation. The study highlights the features of the patent system relevant to pharmaceutical companies situated in developing countries and discusses how companies and governments of developing countries can use the system in an optimal manner to facilitate local production and improve access. The objective of this report is to: • provide guidance to policy-makers on designing an intellectual property system that is conducive for local production and public health; • show how and where local production can take place despite existing intellectual property regimes; • illustrate that even if a medicine is patented in certain countries and regions, the complete landscape of the patents could reveal that local production of the same medicine is possible in countries where the patents were not filed or granted. This report is part of a wider World Health Organization (WHO) and European Union project on local production, which covers the different aspects and challenges of local production and the conditions under which local production may increase access to essential medicines and thus benefit public health outcomes. Intellectual property considerations are only one aspect of this connection. Availability of a skilled workforce, technical knowledge, infrastructure and government incentives are dealt with in separate studies. Given the complexity of the current international standards for good manufacturing practices, the patented knowledge and consequently the knowledge disclosed in a patent are only a fraction of the technical understanding required to set up a production process for a given product. This is even truer for the increasing number of biological drugs. Thus, even in the absence of patent protection, a major challenge for generic companies remains to understand and absorb the patent information and apply it in such a way that it results in affordable good-quality medicines and enhancement of business – that is, where transfer of know-how and technology plays a decisive role, in particular for countries and companies that do not have generic industries that are as well developed as those in China and India. 52. Designing a national system conducive to local pharmaceutical industry For WTO members, except least developed countries (LDCs), the key consideration is how to implement the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS Agreement) when crafting national legislation. The TRIPS Agreement sets minimum standards for the protection of intellectual property, but countries retain considerable policy space that allows them to adapt intellectual property systems in general to their local needs. This policy space is often summarized as “TRIPS flexibilities” (2,3), but in reality it is beyond the well-known flexibilities and includes “exceptions” and interpretations of various TRIPS provisions to suit the national situations. Although the use of this policy space in crafting legislation can be used to facilitate local production of pharmaceuticals, it is not enough. To be of benefit in practice to the industry and the public, intellectual property administration infrastructure and procedures also need to be functional, coherent, transparent and fair. It is beyond the scope of this study to describe all the necessary features of a functioning intellectual property system. Instead, the study uses the example of patent information where the need for a functioning system is particularly striking. 2.1 Access to patent information The patent system requires the disclosure of inventions to the public and makes published patents and patent applications an important source of technical and legal information (2). The importance of easy access to reliable patent information is essential for a number of reasons. By having access to patent information, local producers can determine their business strategies; this could include determining whether relevant patents have been filed or granted that eventually could block them from manufacturing and coming to market with a generic version of a product, for input into research and development processes, and to identify potential needs for licensing from the patent holder. Access to patent information is critical to allow local producers or other parties to file pre- grant and post-grant oppositions, as shown in Box 2, or observations during the patent examination process where the patent law provides for such an option. During the examination process, patent applicants seek to overcome prior art, which is any evidence that the invention is already known by filing amendments to the scope of the claims in an application (4). Such amendments should be published electronically, to ensure that third parties when filing oppositions or observations address the claims as subsequently amended during examination. 6Box 2 New medicines to treat hepatitis C New treatments for hepatitis C exemplify the importance of access to reliable patent information within the context of access to medicines. Given the high prevalence of hepatitis C and the high cure rates associated with new treatments, an increasing number of countries are looking into procuring these treatments at affordable prices. For ministries of health and procurement agencies to be properly informed regarding from where they can legally procure these products, they need to know the patent status. Generic companies use this information to assess whether they can produce copies in countries where patents have not been filed or granted and to identify potential export markets. Generic companies and nongovernmental organizations may file patent oppositions if they consider that a patent application does not fulfil the necessary conditions, as for example in the case of sofosbuvir in India and at the European Patent Office. In October 2014 WHO published an analysis of the patent situation of seven new hepatitis treatments to aid achieving affordable access to medicines (5). Without the required patent information, health authorities cannot determine whether relevant patents have been filed in their country and whether it is necessary to seek the consent of the patent owner to manufacture or import a generic version of the product. For example, during the H5N1 crisis, some countries considered issuing compulsory licences, until the company that holds the market authorization for oseltamivir announced there were no patents that would prevent local production of generic versions in these countries (6). Finding and interpreting patent information is not an easy task, but there is an increasing number of sources for patent data that are more accessible for health practitioners, as shown in Box 3. Box 3 Accessing and finding patent information for medicines Sources for patent information on specific medicines • The Medicines Patent Pool database for antiretroviral medicines provides patent information for human immunodeficiency virus (HIV) medicines in low- and middle- income countries (7). • The UNITAID patent landscape reports provide patent information on specific medicines for HIV, acquired immunodeficiency syndrome (AIDS), hepatitis C, tuberculosis and malaria (8). • The “Orange Book” lists the patents of new medicines authorized by the Food and Drug Administration for the market in the United States of America (9). • The WHO hepatitis landscapes provide patent information for hepatitis treatments (5). • The WIPO patent landscape reports provide patent information for specific technologies (10). • The Initiative for Medicines, Access & Knowledge (I-MAK) patent landscape reports provide analysis and data on patents related to specific medicines (11). Manuals on retrieving patent information • The United Nations Development Programme (UNDP) explains how to search for patents in developing countries using publicly available sources (12). • WHO provides a starting point for health authorities, procurement bodies and others to identify whether patents relating to a pharmaceutical product exist in the country of interest (13). • General guidance on using patent information • WIPO provides a guide to searching for technology information using patent documents (14). 72.2 Making policy choices to favour local production of pharmaceuticals in developing countries Policy options available to WTO members within the TRIPS Agreement have the capacity to offer strategic opportunities. The policy options that help stimulate local pharmaceutical production have been well documented (2,15,16); less well documented are how these TRIPS flexibilities play out in practice and their opportunities and challenges. This section takes a closer look at the practical aspects of using the available flexibilities by providing examples from the patent landscapes discussed in Section 4 and the annexes and case studies of experiences of developing countries to date. Flexibilities available under the TRIPS Agreement can be separated into pre-grant and post- grant flexibilities. Pre-grant flexibilities apply before the grant of a patent and thus normally concern the granting process. They can contribute to preventing the issuing of patents for products or variations of products that do not merit a patent for lack of innovative or novel content. Post-grant flexibilities include the exception of post-grant oppositions or revocation mechanisms, and different exceptions for acts that would otherwise amount to infringement of patent rights. Both pre-grant and post-grant flexibilities allow policy- makers to shape intellectual property systems to suit their respective needs. Pre-grant flexibilities include (2): • to further define on a national level the patentability criteria and what is constituted as patentable subject matter; • exclusions from patentability; • observation or pre-grant opposition mechanisms that permit any third party to file evidence as to why a pending patent application does not meet patentability or patentable subject matter criteria; • a well-designed disclosure requirement that can support access to relevant knowledge, for example by requiring the patent applicant to disclose the best method in line with Article 29 of the TRIPS Agreement. Post-grant flexibilities include (2): • post-grant opposition, revocation or invalidation mechanisms that permit third parties to challenge a patent after its grant; • the ability of researchers and pharmaceutical companies to carry out experimentation on patented substances without the patentee’s authorization and risk of infringement; • the regulatory review exception (also known as the Bolar exception), which allows local producers to use the patented substance and, for example, to produce a first batch of a patented medicine in order to obtain marketing approval; • compulsory licences, including government use, whereby a government for the purpose of public interest can authorize itself or third parties to use the subject matter of a patent without the consent of the patentee; such licences can be issued for any grounds determined in national laws, including to rectify behaviour that impedes competition among market players (anticompetitive behaviour), to rectify abuse by the patentee 8of its exclusive rights, to address national emergencies and for noncommercial use for government needs;1 • the Paragraph 6 System under the Doha Declaration, which creates a framework for compulsory licences in order to enable manufacturing of medical products exclusively for export to countries with insufficient or no manufacturing capacities in the pharmaceutical sector; • the use of competition law in order to ensure that intellectual property rights holders do not abuse their rights, such as by not allowing reasonable access to a patented product or unreasonable pricing of a product; • allowing for parallel importation of products first marketed abroad on a regional or international level. In addition, the TRIPS Agreement lets members decide how to protect clinical trial data (also referred to as test data protection) against disclosure and unfair commercial use, which is important with respect to the approval of generic versions of originator products (2). It also provides for specific transition periods for LDCs that can delay the introduction of substantive provisions of the TRIPS Agreement, including the granting of pharmaceutical patents and the protection of clinical test data until 2021. The LDC group in 2015 also filed for the extension of the specific transition period for pharmaceutical patents (17). 2.3 Patentability standards and opposition procedures The refusal of a patent as a result of not meeting a country’s legal requirement of patentability can pave the way for local production. Strict patent standards alongside opposition procedures can therefore facilitate local production. An illustration of how pre- grant flexibilities can work in practice and pave the way for local production and access is presented in Box 4. Box 4 Case study: imatinib (India) In coming into full compliance with its TRIPS obligations, India installed a number of pre- grant flexibilities. Through using the full transitional period available under Article 65 of the TRIPS Agreement, India delayed the introduction of patent protection for pharmaceutical products until 2005. Consequently, the base patent covering imatinib as a chemical compound could not be filed in India before 1995. In countries that did not use the transitional period, such as Brazil, China and South Africa, the patent was granted (see Annex 3). During this transitional period, between 1995 and 2005 a number of local Indian manufacturers started manufacturing and selling generic versions of the drug at much lower prices. India in addition “grandfathered” those who had taken up production of medicines during this period, allowing them to continue to do so after 2005, even if patents were filed in the meantime through the so called “letterbox system” (Article 70.8 of the TRIPS Agreement). Later Novartis filed another patent on the beta-crystalline form of imatinib (imatinib mesylate; see Annex 3). This form related to the product produced by Novartis to treat chronic myeloid leukaemia and gastrointestinal stromal tumours. 1 Countries are free to determine the grounds for compulsory licences, which can, for example, include unaffordable prices or limited availability. 9The patent application for the beta-crystalline form of imatinib mesylate claimed to have improved bioavailability over the form described in the earlier patent for the base compound. Under India’s patent law, new forms of known substances would not be considered inventions unless they showed an enhancement of efficacy.2 Several generic companies and a non-profit-making organization filed pre-grant patent oppositions, making use of another pre-grant flexibility. The pre-grant opposition mechanism as set up in India allows any person to file an opposition before the grant of the application, thereby allowing noncommercial actors to also file oppositions. Moreover, it allows the opponents to respond throughout the proceedings to the patent applicant’s evidence and be heard in the matter. The key arguments raised in the oppositions were that the invention claimed for the beta- crystalline form of imatinib mesylate in the patent application was not novel and lacked an inventive step in light of the disclosures made in the earlier patent for the base compound imatinib. It was also argued that the beta-crystalline form did not meet the enhanced efficacy standards now required under Section 3d and therefore should not be considered an invention. After taking into consideration the oppositions, India’s patent office refused the patent application in 2006 on all grounds, including Section 3d. Novartis filed subsequent appeals, but in 2013 the Supreme Court of India upheld the decision to refuse the patent. This case study shows how using various pre-grant flexibilities can allow local production when secondary patents for incremental-type inventions would otherwise pose a barrier. Other examples demonstrating how enforcement of patent standards and non-patentability criteria alongside pre-grant patent opposition can remove potential patent barriers include decisions by the Indian Patent Controller relating to the HIV drugs nevirapine hemihydrate and tenofovir disoproxil fumarate. In both cases, the patents were rejected for lacking an inventive step and for not being patentable under Section 3d (18). India’s introduction of more stringent patentability standards and pre-grant oppositions has influenced other countries with local production capacity, such as Argentina (19), Brazil (20), the Philippines (21) and South Africa (22), to revise the patentability requirements with respect to pharmaceuticals. Alternative options or additional instruments can also be used. In Brazil3 and Egypt,4 for example, the ministries of health play an active role in the patent examination process for pharmaceutical patents, combining the expertise of patent and health experts to allow a more thorough examination of patent applications to determine whether they meet the requirements of novelty and inventive step. Moving towards stricter interpretation of patentability criteria to preserve space for further innovation is not a move unique to developing countries. Switzerland in 2007 revised its patent law and introduced stricter standards towards the patentability of genes. The 2 “The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant. Explanation—For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy” (Section 3(d)). 3 Brazilian Law No. 10 196 of 14 February 2001 determines that any patent application relating to pharmaceuticals needs consent by the Agência Nacional de Vigilância Sanitária. 4 Under Article 17 of Egyptian Law No. 82 of 2002 pertaining to the protection of intellectual property rights, the Egyptian Ministry of Health can oppose the publication and granting of patents with health implications. 10 revised law (Article 1b of the Swiss Federal Act on Patents for Inventions (Patents Act) of 25 June 1954) excludes from patentability naturally occurring gene sequences and partial sequences of a gene. Sequences derived from a naturally occurring sequence are patentable only if their function is specifically indicated. Australia in 2012 adopted the Intellectual Property Laws Amendment (Raising the Bar) Act 2012, which among other things raised the standards for patentability and disclosure. Introducing flexibilities does not necessarily have to happen through legislative changes. For patent examination, the way national guidelines for examination are drafted is key to ensuring thorough implementation of patentability criteria. An example of this approach is the adoption by Argentina in 2012 of guidelines that had the objective of limiting the proliferation of patent applications on marginal improvements or changes of existing pharmaceutical substances (19). ICTSD, WHO and UNCTAD published draft guidelines to contribute to the improvement of examination of pharmaceutical inventions, particularly in developing countries. Various other guidelines have been published that provide useful guidance to countries in this respect (see Box 5). Box 5 Patentability guidelines To support the examiners’ work and to ensure all patentability criteria are met, many patent authorities have established search and examination guidelines that describe in detail the application of patent law to particular circumstances. To aid this process, WIPO has published links to the guidelines produced by a range of patent offices (23) and has published Patent Cooperation Treatment international search and preliminary examination guidelines (24). ICTSD, WHO and UNCTAD have published draft guidelines for the examination of pharmaceutical patents (25). For local pharmaceutical producers, the way patents are examined and standards are applied for examination can make a difference. Stringent patentability standards for marginal changes of existing pharmaceutical products limit the granting of secondary patents.5 This can preserve space for local industry or – from a public health perspective – for importing generic versions. For example, for atazanavir, only the secondary patent for the formulation was applied for and granted in Egypt and Indonesia (see Annex 1); this secondary patent is a barrier for local producers in these countries unless they are able to work around the patent by developing an alternative salt form of the active ingredient for formulation purposes. Implementing a policy of more stringent patentability criteria can be a double-edged sword for developing countries: As the technological capability of local producers develops, they may also wish to seek patent protection on their own incremental inventions. Many of the secondary patents at the European Patent Office, for example on imatinib, are filed by 5 Secondary patents are follow-on patents filed after the main patent, which usually covers the key active ingredient or protein sequence. Secondary patents typically cover formulations, methods of administration and second or new uses of existing compounds. Industry refers to such patents as “incremental innovation” and they are part of lifecycle management strategies, allowing patients to switch from the existing version of a medicine to a slightly improved version. Public health advocates have coined the term “evergreening” for such practice, as some of these patents are aimed at delaying generic entry (26). 11 generic companies,6 showing that, where possible, they adopt similar patent strategies to originator companies and try to protect investment in any further improvements or changes. Typically, generic companies, when moving to invest in research and development, will start with incremental innovation, meaning improvements and further development of existing medicines. (For a more detailed discussion, see UNCTAD (15), pages 57–63.) If these are not patentable, then the incentive for investing in these improvements is lost to a certain extent. It is difficult to define the line between what is commonly called “evergreening” and deciding which incremental innovations or variations of an existing compound do or do not merit a patent. (For further details, see WTO, WIPO and WHO (2), pages 130–132.) When trying to make this distinction, it is important to recognize that from a public health perspective, improved efficacy of a medicine is not the only possible improvement. For example, creating a new version with considerably fewer side-effects, moving to a simpler form of dosing (such as from injection to oral) or producing a more heat-stable form that can be stored in a fridge rather than a freezer can make a huge difference to treatment, particularly in developing countries. Separating cases where such improvements are genuine innovations from those where no inventive step is involved needs careful assessment. The draft guidelines for the examination of pharmaceutical patents provide some useful guidance in this respect (25). 2.4 Ensuring appropriate patent examination Enforcing strict patentability standards requires a thorough patent examination that ensures patents are granted only in accordance with the standards required by a country’s law. This aspect of patent administration is important, because incorrectly granted patents can prevent legitimate local production from taking place, thereby unnecessarily impacting access to essential medicines. Ensuring a thorough examination is not straightforward. If countries want to use the policy space provided by the TRIPS Agreement and to ensure a strict examination, they have to develop certain examination capacities on their own. Currently, such expertise does not exist in many developing countries. In principle, every country could train its own examiners and implement its own examination practices to reflect national laws. This requires considerable investment in infrastructure and hiring and training of qualified technical examiners in the relevant fields of technology, who may not be available in every country or who may opt for better-paid jobs in the private sector. Where standards are comparable, it also leads to duplication of efforts, as examinations of the same patents are carried out again and again. These are the main reasons for the creation of regional patent organizations, such as the European Patent Office, the Eurasian Patent Organization, the African Regional Intellectual Property Organization (ARIPO) and the Organisation Africaine de la Propriété Intellectuelle (OAPI). One option for reducing the financial burden of examination of patents is to rely on or take into account search and examination reports of the patent offices of other developed or developing countries. This includes the preliminary examination reports prepared by national patent offices that are recognized as international search authorities under the WIPO Patent Cooperation Treaty. Adhering to standards of foreign patent offices, however, 6 Search results from esp@cenet for keyword “imatinib” in October 2013: Chinese applicants – 57; Indian applicants – 32; Novartis – 17. 12 bears the risk of importing their patent standards, which mirror their national patent legislation and consequently reflect their national policy. Relying on foreign examination thus means the importation of a certain standard that may not be adapted to local needs; in particular, it may reflect the interests and capacities of the researching pharmaceutical industry despite the importing country not having such an industry. If a country wants to implement the post-grant flexibilities linked to the patent granting process as described above, it has to develop examination procedures that reflect the peculiarities of the national law and implement the policy decisions, for example with respect to the patentability of first or second medical indications or excluded subject matter. This does not exclude taking into account foreign examination results or cooperating with other patent offices, but requires adaptation of the results to the local environment. Simply taking over patent standards bears risk for the local industry, as shown in Box 6. In this context, there may be options for more south–south cooperation between patent offices and their examiners that have similar approaches towards patentability of pharmaceutical products and processes. This could be particularly productive with developing countries that have invested more in their patent office infrastructure and have patent laws that have incorporated some of the flexibilities available in the TRIPS Agreement. Countries also need to engage more in the regional intellectual property organizations they are partner to, such as ARIPO and OAPI. Although members of, for example, the East African Community and the West Africa Health Organisation have adopted policies on TRIPS flexibilities, these have not been translated into amendments of the relevant regional agreements and practices and thus have only limited impact. Box 6 New trend of validation of European patents Following an agreement signed between the Moroccan Patent Office and the European Patent Office with effect from 1 March 2015, applicants that file patents at the European Patent Office have the possibility to validate European patent applications and patents in Morocco, where, after validation, they will confer essentially the same protection as patents granted by the European Patent Office for member states. The applicant requests the validation when filing a European or international patent application against payment of a validation fee (27). Although this is convenient for applicants, it means that in the future Morocco is likely to receive many more patent applications, including in the area of pharmaceuticals, consequently reducing the freedom to operate of local pharmaceutical manufacturers and the possibility of importing generic products. In October 2013 the State Agency on Intellectual Property of the Republic of Moldova and the European Patent Office signed a similar validation agreement, which, when finally approved, will allow European patent applications and patents to take legal effect in the Republic of Moldova without additional examination (28). 2.5 Limiting divisional patent applications When setting up patent administration systems and implementing rules, countries should seek to curb the use of divisional patents by patent applicants, as this can have a serious impact on local production of pharmaceuticals. 13 Under certain conditions, a filed patent application can be divided into different and independent applications. This can be important to enforce the principle of “unity of invention”, meaning that each patent application should claim only one invention or group of inventions that form a single general inventive concept. If the examiner considers an application to contain more than one invention or a group of inventions that do not form a single inventive concept, the examiner will require the applicant to split the parent application into one or more divisional applications (29).7 More problematic in practice are the numerous cases where the applicant on their own initiative files divisional applications when the parent application is facing refusal or has been opposed. This practice, in particular when divisional applications are divided again, can be used to delay the final decision on the merits in the hope that a different examiner will not raise an objection. By using divisional applications systematically, patent applications stay pending, despite the fact that the parent application may have been rejected. This creates uncertainty for potential competitors (30,31). This practice places an additional burden on patent offices and competing companies or third parties seeking to oppose or file observations because they have to use resources to keep monitoring the publication of patents to identify divisional patent applications and re-file their opposition or observations (29). India has attempted to combat this practice by including in its patent office examination guidelines that all divisional applications shall be examined referring back to the main application, meaning that the examiner, when examining a divisional application, must take into account the decision on the main patent (32). This practice ensures that parent applications that were refused during examination do not slip through the system as divisional applications. It also saves potential opponents from having to keep re-filing patent oppositions. Australia has restricted the practice of divisional applications through its Raising the Bar Act. Australia achieved this by limiting the timeframe available to make a divisional application, which ensures divisional applications cannot be filed late or converted in opposition proceedings. In addition, the commissioner must consent to withdrawal of an opposed application and can therefore refuse withdrawal of an opposed application where the applicant filed a divisional application claiming a substantially similar or the same invention. This limits the applicant’s ability to avoid a decision with respect to an invention claimed in one opposed application by withdrawing and pursuing a divisional application instead (33). The European Patent Office has introduced an additional fee as part of the filing fee for divisional applications. The filing of divisional applications in respect of earlier divisional applications (second-generation divisional applications) is subject to an additional fee. This fee is progressive and increases with each subsequent generation of divisional applications (34). 7 See Article 4G(1) of the Paris Convention, which allows the applicant to file divisional applications in cases where the examination reveals that an application contains more than one invention, and Article 4G(2), which allows the applicant, on their own initiative, to file a divisional application and recognizes the right of each contracting state to determine the conditions under which such division shall be authorized. 14 2.6 Post-grant flexibilities: the example of compulsory licences Compulsory licensing is a well-established feature of international, regional and national patent legislation (35,36,37). The Doha Declaration has restated the right of countries to use the TRIPS flexibilities, including compulsory licensing. This instrument is not limited to health emergencies or infectious diseases; unaffordable prices and unavailability of medicines are among the legitimate reasons for the use of compulsory licences. Thus, depending on the national legislation and on the situation within a country regarding access to and affordability of essential health products, a government may consider issuing a compulsory licence and allow the importation or local manufacturing of a medical product. Such licensing has to be in compliance with the requirements of the TRIPS Agreement and national legislation, which should include payment of a royalty (adequate remuneration, taking into account the economic value of the licence) to the patent owner and requires previous negotiations with the patent owner, unless it is for government use or for a health emergency.8 There are a number of examples for local production under compulsory licence (18), but two main challenges exist: Given the confrontational approach of production under a compulsory licence, a country needs to be able to set up good-quality production without any technical assistance from the patent holder. The patent discloses only the patented invention rather than the technical know-how needed to produce the medicine. Thus, if a country wishes to pursue this option, the ability of local manufacturers to overcome these technical barriers is required. The TRIPS Agreement requires that the products produced under a compulsory licence are “predominantly for the supply of the domestic market” (Article 31f). This limits the export of medical products produced under compulsory licences. Depending on the size of the domestic market, building up sustainable and competitive local production might be challenging. For these reasons, local production under compulsory licences is often not the most cost- effective solution (37,38). The threat of issuing a compulsory licence, however, can be an effective tool in negotiations with the patent holder and can lead to collaboration, as in the case described in Box 7. 8 When a non-voluntary patent licence is issued to remedy an anticompetitive practice, this may be taken into account when determining the amount of remuneration, which could be negligible depending on the circumstances (WTO TRIPS Agreement, Article 31(k)). 15 Box 7 Case study: collaboration on raltegravir in India The Indian generic company Cipla applied for a compulsory licence to manufacture the patented drug raltegravir on the basis that it was unaffordable for patients in need. India’s provision on compulsory licensing states specifically that there is ground for making an application for the grant of a compulsory licence on a granted patent where the patented invention is not available to the public at a reasonably affordable price (39). Subsequently, Merck and Cipla entered into a co-marketing agreement that allows Cipla to sell the Merck product in India under its own brand name at a lower price (40). Although this agreement did not lead to local production, it shows that using the threat of a compulsory licence can lead to cooperation. What might be in the interest of companies, however, does not necessarily improve access to medicines. In this case, the price at which Cipla will market raltegravir remains to be seen. In general, open competition leads to lower prices than co-marketing agreements with a limited number of companies. As the case studies in Boxes 4 and 7 show, the use of pre-grant and post-grant flexibilities can be used to create space to overcome patent barriers in order to help facilitate local production. Although many other factors play an important part, such as whether local producers have the required technical know-how to manufacture a particular product without the need for technology transfer, the availability of trained workforce, infrastructure, local market conditions and disease burden are important factors for local production; creating a national intellectual property system conducive to local production can be a contribution to fostering local production in the pharmaceutical area. 16 3. Enabling local production through agreements Although crafting legislation and ensuring a functioning intellectual property administration is in the competence of governments, the daily management of existing intellectual property is done by the intellectual property holders. The simple fact that there is a patent does not necessarily hinder local production; the decisive question is how the patent holder manages the patent. In cases where patents have been granted, various options are available that may allow local production to take place. These options include: • negotiation of an exclusive or nonexclusive voluntary licence agreement between the originator company and the local producer or government body; • non-assert declarations or non-assertion covenants and immunity from suit agreements where the patent holder will not assert their rights; • a joint-venture agreement between the patent holder and a local producer, which includes some form of technology transfer; • a joint venture with a third party that has technology that will allow the local producer to work around a patent and manufacture a competing product. Other relevant agreements that are regularly used to protect or share different forms of intellectual property include agreements for confidentiality, for the transfer of biological material, for development (in which the licensee is responsible for further development), for co-development (in which two parties collaborate on continued development) and for distribution of proprietary products (for example, see Box 7). It is beyond the scope of this study to describe the various options, challenges and opportunities linked with these agreements. Guidance on the different agreements and tips for the negotiations and model texts are available (41). The case studies in Boxes 8 and 9 illustrate how some of the above options can be used to manage patented inventions and some of the issues that can arise when managing intellectual property rights. Box 8 Case study: atazanavir (Brazil) In November 2011 Bristol-Myers Squibb and the Brazilian public laboratory Farmanguinhos entered into a licensing agreement to develop the ability to manufacture locally and sell the antiretroviral medicine atazanavir. As shown in Annex 1, the base compound patent covering atazanavir was granted in Brazil, as was a separate process patent. The patent application for the end formulation, the bisulfate salt, was refused, however. The terms of the agreement provided for technology transfer, including training. In exchange, the agreement requires the Brazilian Government to purchase the drug from Bristol-Myers Squibb until the end of the agreement. The agreement with Bristol-Myers Squibb has been criticized because: it prevents Farmanguinhos from manufacturing fixed-dose combinations of atazanavir with ritonavir, which is required as a booster to the former to enhance treatment compliance; it is restricted to Brazil only; Brazil will purchase the product from Bristol-Myers Squibb until the end of 2017, which is when the patent on the base compound expires anyway (42). 17 This case study illustrates the fine balance between seeking to develop local production capability and obtaining technology transfer, while trying to achieve affordable access to essential medicines. In 2013 Bristol-Myers Squibb also entered into a licence agreement with the Medicines Patent Pool that enables generic producers to apply for a sub-licence allowing Bristol-Myers Squibb to manufacture and market atazanavir in 110 countries and countries where the patent was not granted (43). There are numerous other examples of licensing agreements between originator companies and local producers, in particular in the area of HIV but more recently also in the area of hepatitis C (for example, see WHO (38)). As most of these agreements are not available publicly, it is difficult to judge the extent to which they contain transfer of technology or restrictions for the licensees. The agreements negotiated by the Medicines Patent Pool in the area of HIV are a notable exception and in general aim to achieve better health outcomes instead of focusing on the business considerations of the licensing partners. Licences negotiated via the Medicines Patent Pool “provide licensees with the highest level of flexibility and broadest geographic scope” (44). If not under the Medicines Patent Pool, negotiating agreements can be challenging for generic companies. Essentially, local producers and governments need to look at the options available and consider the best practices before signing such agreements (45). Although licensing terms offer some options, they are also designed to manage the competition and divide the market, which often draws the focus to business interests rather than public health needs. Box 9 The Medicines Patent Pool The Medicines Patent Pool was established in 2010 with the support of UNITAID to enhance access to affordable good-quality HIV medicines in developing countries through the voluntary licensing of patents on antiretroviral medicines. Since its establishment, the Medicines Patent Pool has negotiated licences on 12 antiretroviral medicines and has issued sub-licences to 10 generic manufacturers, including many of the leading suppliers of antiretroviral medicines in the developing world. The licences negotiated by the Medicines Patent Pool contain a number of public health-friendly provisions that contribute to opening up the market for patent antiretroviral medicines, promoting generic competition and enabling the development of formulations needed in developing countries, such as formulations for children. Medicines Patent Pool licences are issued on a nonexclusive basis to qualified manufacturers with the willingness and capacity to manufacture antiretroviral medicines in line with international quality requirements. Although most of the licences from the Medicines Patent Pool are available for sub-licensing to local manufacturers based anywhere in the world, some are limited to manufacturers based in certain countries, such as China and India. In some cases where patents have been granted, there are ways to achieve local production and more affordable access without having to enter into an agreement with the originator company or patent holder. The case study in Box 10 demonstrates a different way of managing intellectual property rights through working around a patent and obtaining technology transfer from a third party. 18 Box 10 Case study: pegylated interferon alfa-2a (Egypt) Pegylated interferon alfa-2a is used as a treatment for hepatitis C in combination with ribavirin. As pegylated interferon is a biological product (rather than a product made from small chemical molecules), there are no generic equivalents but only biosimilar versions. F. Hoffmann-La Roche, the originator of pegylated interferon alfa-2a, has applied for patents in several countries, including Egypt. F. Hoffmann-La Roche was granted a patent for its product in Egypt (see Annex 5). The patent covers a physiologically active pegylated interferon alfa conjugate in which the average molecular weight of the PEG units is between 26 000 and 66 000 daltons. In 2002–2003, when the product was first registered in Egypt, F. Hoffmann- La Roche charged 1400 Egyptian pounds (approximately US $ 200) per ampoule (46). In 2004 a local producer, Minapharm Pharmaceutical, registered its own version of pegylated interferon alfa-2a. The product is not biosimilar but uses a different molecular weight outside the claims of the granted patent and derived from Hansenula polymorpha (47,48). Minapharm Pharmaceutical’s development of a product that did not infringe the existing patent was helped by a joint venture project with a German scientific research office, which provided the required technology transfer of the H. polymorpha expression system (49). Minapharm Pharmaceutical introduced its product at 370 Egyptian pounds (approximately US $ 51) per ampoule. Following market introduction, F. Hoffmann-La Roche reduced the price of its product to 250 Egyptian pounds (approximately US  $  35) per ampoule after negotiations with the Egyptian Ministry of Health. To identify opportunities for local production of patented products, it can be worthwhile to study the patent policy of the pharmaceutical companies holding the relevant patents. Several major researching companies have committed to either not filing or not enforcing their patents in LDCs, with some companies also including low-income and lower- middle-income countries (see Table 1). Although it is important to note that LDCs have no obligation to grant patents under the TRIPS Agreement until 2021, these policies can still be useful for LDCs that do grant pharmaceutical patents, for example Ethiopia and the LDC members of OAPI. For example, Merck and Novartis commit to not filing or enforcing patents in countries classified as LDCs under the United Nations system; thus, even if a patent is granted in one of these countries, this should not constitute a barrier. F. Hoffmann-La Roche extents this policy beyond LDCs and includes all low-income countries under the World Bank system. Novartis recently expanded its policy: although it will file patents in LDCs, it commits not to enforce these patents and offers nonexclusive licences to qualified generic companies in and outside LDCs for the production and supply of any of their patented products exclusively to LDCs (50). Table 1 shows the different areas where companies have committed not to file or enforce patents based on the Access to Medicine Index 2014 (44). 19 Table 1 Patent filing and enforcement policies of major pharmaceutical companies No specific commitment Subset of products All patented products Subset of countries LDCs LDCs and a subset of LICs LDCs, LICs, some LMICs Astellas AbbVie Eisai AstraZeneca F. Hoffmann-La Roche Gilead Bristol-Myers Squibb Novo Nordisk Novartis Bayer Merck KGaA Pfizer Johnson & Johnson Merck Eli Lilly Takeda Sanofia LDC, least developed country; LIC, low-income country; LMIC, lower-middle-income country. a All countries low on the United Nations Development Programme Human Development Index. Despite the existence of granted patents, local producers may still be able to enter the field by using alternative technologies, by entering into joint ventures or licence agreements, or by other arrangements. A major advantage of such cooperation is that it is often linked with transfer of technology that is not necessarily disclosed in patent documents. Licence agreements will always be a compromise, for example when it comes to the question over which countries are included in the territory. 20 4. Patent landscapes The objective of the patent landscapes included in the annexes was to: • identify the most relevant patents with respect to the medicines; • identify the countries in which these patents have been filed and granted. There are often numerous patents relating to a single medicine. These patents cover different aspects and innovations around the same product. Not all patents are equally relevant, however, as many patents cover variations or production processes but do not prevent another company producing the medicine, for example by using a different process. The patent landscapes provide an analysis of the patent situation focusing on those patents most relevant to local producers. The landscapes do not constitute a freedom- to-operate analysis, and a full legal assessment of the patent situation in a given country is required to determine whether producing the respective medicine would constitute a patent infringement. The landscapes do, however, provide a first indication of whether the patent situation might allow for local production to take place in the countries included in this analysis. 4.1 Scope It is beyond the scope of this study to include patent information for all WHO Member States. A selection was made that includes developing countries from all WHO regions, with a focus on the African region in line with the focus of the overall project. The patent numbers provided enable readers to follow up the relevant patent applications in all other national and regional jurisdictions using publicly available databases such as Esp@cenet, WIPO Patentscope and national databases. The data can easily be used to assess the patent situation in countries not included in the annexes. The countries or regions of focus of the patent landscapes are Brazil, China, the European Patent Office, Egypt, Ethiopia, Ghana (ARIPO9), India, Indonesia, Jordan, Kenya (ARIPO), Morocco, Nigeria, South Africa, the United Republic of Tanzania (ARIPO), Uganda (ARIPO), the United States of America and patents filed via the regional systems provided by the European Patent Convention10 and OAPI.11 4.2 Products Following discussions with the advisory group of the overall project, it was decided to include products addressing both communicable and noncommunicable diseases. It was also decided not to limit the products to those already included in the WHO Model 9 ARIPO is the regional patent system covering Botswana, Gambia, Ghana, Kenya, Lesotho, Liberia, Malawi, Mozambique, Namibia, Rwanda, Sao Tome and Principe, Sierra Leone, Somalia, Sudan, Swaziland, Uganda, the United Republic of Tanzania, Zambia and Zimbabwe. 10 Countries covered by the European Patent Convention and the European Patent Office are Albania, Austria, Belgium, Bulgaria, Croatia, Cyprus, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Monaco, the Netherlands, Norway, Poland, Portugal, Romania, San Marino, Serbia, Slovenia, Sweden, Switzerland, Spain, The former Yugoslav Republic of Macedonia, Turkey and the United Kingdom of Great Britain and Northern Ireland. 11 Countries covered by OAPI are Benin, Burkina Faso, Cameroon, Central African Republic, Chad, Comoros, Congo, Côte d’Ivoire, Equatorial Guinea, Gabon, Guinea, Guinea-Bissau, Mali, Mauritania, Niger, Senegal and Togo. 21 List of Essential Medicines (51) but to include chemical medicines, biological products and vaccines. To identify the respective products not listed in the Model List of Essential Medicines, consultations were held with the relevant WHO departments. The inclusion of any of these products in this study does not imply they are endorsed or recommended by WHO in general or in preference to other products of a similar nature that are not mentioned. • Atazanavir is a protease inhibitor antiviral medicine indicated for treatment of HIV infection. It is included in the 19th edition of the WHO Model List of Essential Medicines. • The human papillomavirus (HPV) vaccine Gardasil is a quadrivalent recombinant vaccine for the prevention of cervical cancer and genital warts caused by HPV types 6, 11, 16 and 18. HPV vaccination is included in the WHO Model List of Essential Medicines based on WHO immunization policy recommendations. • Imatinib is an antineoplastic medicine for the treatment of some cancers and tumours. It is included in the WHO Model List of Essential Medicines to treat chronic myeloid leukaemia and gastrointestinal stromal tumours. • Pegylated interferon alfa-2a is an antiviral medicine indicated for treatment of chronic hepatitis C. It is included in the WHO Model List of Essential Medicines. • Raltegravir is an HIV integrase strand transfer inhibitor antiviral medicine indicated in combination with other antiretroviral agents for the treatment of HIV infection. It is not included in the WHO Model List of Essential Medicines. • Sitagliptin is an antidiabetic drug indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus. It is not included in the WHO Model List of Essential Medicines. 4.3 Methodology The patent landscapes and analysis were produced by I-MAK. The methodology used for the landscapes included identifying American patents via the United States Food and Drug Administration’s Orange Book and their related Patent Cooperation Treaty or European applications. Once the relevant American, Patent Cooperation Treaty and European patents were identified, the patent families for filings in other countries available from Esp@cenet, WIPO Patentscope and Thomson Innovation were checked. Additional sources used were the Medicines Patent Pool antiretroviral database, the WIPO patent landscape report on atazanavir (52) and an earlier study on patents for the HPV vaccine (53). The patent information provided in the landscapes reflects the patent status up to and including 12 June 2015. The draft patent landscapes were shared with the companies that hold the market authorizations for comments. F. Hoffmann-La Roche and Novartis shared relevant patent information and filled in the gaps in the landscapes on pegylated interferon and imatinib, respectively. 4.4 Limitations Every effort has been made to obtain comprehensive and accurate information, including on the legal status of the patents. In many countries, however, patent information is not readily available or is not updated on a regular basis. Thus, patent information in many 22 countries is difficult to retrieve, as reflected by the gaps in the annexes. N/A indicates that no information could be retrieved for the relevant patents; this can mean either that the information in the databases is not up to date or not complete, or that the patents were not filed in these jurisdictions. Certainty can be achieved only by checking the information with the local patent office The patent numbers provided in this report allow retrieval of information through national patent offices or national patent registries. A WIPO webpage provides links to all national online patent search tools to search national patent registries (54). The landscapes do not contain all patents related to the respective medical product. As this study endeavours to identify the most relevant patents, it does not include all patents and applications filed by the sponsor and other entities. More patent applications may have been published after the searches were conducted and thus may not be included in this study. This study is not a freedom-to-operate analysis. The information provides useful guidance but reflects the situation at a particular point in time. WHO does not accept any responsibility for the completeness of the data. Before taking any investment or other legally relevant decision, readers are advised to consult a local patent expert to provide a full assessment of the patent situation in a given country. 4.5 Further resources Box 3 contains links to further resources for accessing and finding patent information for medicines. Material on the relationship between public health and intellectual property can be found in the joint WTO, WIPO and WHO document (2). These publications and other relevant publications on issues related to public health and intellectual property can be found on the WHO website (55). 23 5. Conclusions Intellectual property plays an important role both for the researching pharmaceutical industry, which relies heavily on intellectual property to protect its products, and for generic companies, which produce copies of existing medicines once patent protection expires. Beyond patent protection, trademarks are another form of intellectual property rights used to identify and market pharmaceutical products. Trade secrets and protection of clinical test data are other important elements of this industry. Consequently, the set-up of a national intellectual property system is important when considering options for local production of pharmaceuticals in developing countries. Using practical examples and patent landscapes, this report attempts to set out the various strategies and options available to facilitate local production. The report describes the options available to countries with a generic industry to design an intellectual property system that is favourable for local production and potentially for public health. The report highlights the importance of transparent and fair patent administration systems using the example of access to patent information. The report exemplifies how this can also support the use of certain pre-grant flexibilities to increase the space for local generic companies and facilitate local production. In this context, the questions of whether and how to examine patents are essential. Where countries decide to provide for substantive examination, they need to pay particular attention to what standards need to be followed to ensure implementation of pre-grant flexibilities in practice. Favourable interpretation of various provisions of the TRIPS Agreement to support local industry is important: simply writing flexibilities into legislation will not achieve their intended impact without a good understanding by local producers of patent laws and patent systems. Competent intellectual property professionals and a transparent, fair and efficient court system also need to be in place to allow such policies to flourish. The existence of a patent does not mean local production is not possible. The decisive question is how the patent will be managed by the patent holder. This report has attempted to show this using some practical examples of multiple ways to cooperate and allow for local production to varying degrees. This depends a lot on the willingness of the patent holder, but collaboration has increased over the past years, sometimes blurring the line of distinction between originator and generic companies. Licensing has become common in the area of HIV/AIDS, and we have also seen cooperation in the area of hepatitis C. In this context, implementing pre- and post-grant flexibilities can strengthen the negotiating position of local companies when they endeavour to enter into licensing and technology transfer deals. This report provides patent information on a number of medicines to show that it is a simplification to describe a medicine as “under patent”. Patents are granted for national or regional jurisdictions, and the complete landscape often reveals countries where patents have not been filed or granted and thus where local production could take place if the technical problems associated with the production of affordable good-quality medicines can be overcome. Local production depends on many conditions; the intellectual property environment is only one of these conditions and in itself will not be decisive. The mere absence of a patent in a country will not lead to local production of a medicine or ensure access to that 24 medicine. The intellectual property system can, however, be used and designed to favour local pharmaceutical innovation and manufacturing. Local production can potentially lead to improved access and health outcomes when good-quality essential medicines are produced and marketed at affordable prices. 25 Annex 1 Atazanavir: analysis of patent landscape The patent search identified 12 patents that would be particularly relevant for a local producer to take into consideration. If granted, the various patents identified give a period of protection around atazanavir for up to 35 years from the date of the primary base compound patent (1996–2031) subject to the filing of additional patents covering further innovations around atazanavir. The key or main blocking patents that cover the current marketed product for atazanavir are patent number 1 (the primary patent), which covers the base compound or active ingredient, and patent number 2 (1 of 11 secondary patents), which covers the formulation. Subject to any patent term extensions, these patents are expected to expire around April 2017 and January 2018, respectively. In Brazil patent number 1 has been granted and thus in principle blocks local production until around April 2017, unless a licence or other agreement is entered into with the patent holder. As patent number 2 has been refused in Brazil, local producers could potentially manufacture atazanavir using the formulation identified in patent number 2, but only after patent number 1 has expired. Local producers would have to ensure they use a different process to that claimed in patent number 4, which is granted and is expected to expire around July 2021. Local producers would also have to monitor the status of patent numbers 3 and 7. Patent number 3, which is currently refused but under appeal, also covers a process and, if granted, is expected to expire in July 2021. Patent number 7 covering a process for the formulation is currently pending and would expire around May 2025 if granted. In China patent numbers 1–4 and 7 have been granted. Local producers would have to wait until at least around January 2018 until they could produce generic versions. If local producers are unable to work around the processes covered by patent numbers 3, 4 and 7, however, then they could be further delayed until around May 2025. Other patents for local producers to monitor are patent numbers 11 and 12, which cover different tablet formulations. In Egypt and Indonesia there is potentially only one patent, patent number 2, which expires in January 2018, that would be an obstacle to local producers. In India currently only patent numbers 3 and 4 for processes have been granted. Therefore, provided local producers can work around these process patents, they are free to produce the product. It must be observed, however, that despite the initial parent application having been refused, there are pending divisional applications for patent number 1. If granted, this patent would prevent local producers from making atazanavir without a licence or other agreement with the patent holder. Notably, there are pending applications for secondary patents, patent numbers 7–11, that could pose an issue if granted. In South Africa patent numbers 1,2 and 7 have been granted. Patents 1 and 2 block local production until they expire, while patent number 7 would have to be worked around. Notably, there appear to be no patents that would block production of atazanavir in Ethiopia, Ghana, Jordan, Morocco, Nigeria, OAPI countries, Uganda or the United Republic of Tanzania. 26 Bristol-Myers Squibb entered into a licence agreement with the Medicines Patent Pool in 2013. Under this agreement, generic producers can apply for sub-licences that allow then to produce and market generic atazanavir in 110 countries and in countries where the patents were not filed or granted. Further information, including the full licence agreement, is available on the Medicines. 27 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Pa te nt 5 Pa te nt 6 An tiv ira lly A ct iv e H et er oc yc lic Az ah ex an e D er iv at iv es (T his pa te nt co ve rs va rio us he te ro cy cli c a za he xa ne de riv at ive s th at ca n b e e m plo ye d a s r et ro vir al as pa rta te pr ot ea se s, inc lud ing th e b as e c om po un d a ta za na vir , th eir sa lts an d u se al on e o r in co m bin at ion w ith ot he r a nt ivi ra lly ac tiv e c om po un ds ) Bi su lfa te Sa lt of H IV Pr ot ea se In hi bi to r (T his pa te nt co ve rs th e cry sta llin e b isu lfa te of at az an av ir a nd it s ph ar m ac eu tic al do sa ge fo rm as us ed in th e m ar ke te d p ro du ct) A Pr oc es s f or th e Pr ep ar at io n of α ’ Ch lo ro ke to ne s (T his pa te nt co ve rs a p ro ce ss us efu l in th e s yn th es is of int er m ed iat es fo r at az an av ir) St er eo se le ct iv e Re du ct io n of Su bs tit ut ed Ox o- Bu ta ne s (T his pa te nt co ve rs a p ro ce ss us efu l in th e s yn th es is of int er m ed iat es fo r at az an av ir) Us e o f A ta za na vi r i n HI V Th er ap y (T his pa te nt co ve rs a m et ho d f or re du cin g e lev at ed pl as m a L DL an d/ or tr yg lyc er ide le ve ls in a H IV inf ec te d p at ien t u nd er go ing H IV pr ot ea se th er ap y w hic h c om pr ise s ad m ini ste rin g a n e ffe cti ve am ou nt of at az an av ir i n c om bin at ion w ith an H IV in hib iti ng am ou nt of at lea st on e H IV pr ot ea se in hib ito r) A M et ho d of Tr ea tin g HI V In fe ct io n in A ta za na vi rR es ist an t Pa tie nt s U sin g a C om bi na tio n of A ta za na vi r a nd A no th er Pr ot ea se In hi bi to r (Th is pa ten t c ov ers a m eth od of tre ati ng H IV, w he re th e H IV st rai n ha s b ec om e r es ist an t t o a ta za na vir , an d a ta za na vir is ad m ini ste red w ith at lea st on e o th er pr ot ea se in hib ito r) Ap pli ca nt /P at en t H old er No va rti s A G Br ist ol- M ye rs Sq uib b Co m pa ny Br ist ol- M ye rs Sq uib b Co m pa ny Br ist ol- M ye rs Sq uib b Co m pa ny Br ist ol- M ye rs Sq uib b C om pa ny Br ist ol- M ye rs Sq uib b C om pa ny In te rn at ion al Pa te nt Pu bli ca tio n No . o r U. S/ Eu ro pe an Pa te nt N o. W O 19 97 /4 00 29 W O 19 99 /3 64 04 W O 20 02 /0 14 25 6 W O 20 02 /1 45 28 W O 20 03 /0 20 20 6 W O 20 05 /0 58 24 8 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 14 Ap ril 20 17 20 Ja nu ar y 2 01 8 20 Ju ly 20 21 20 Ju ly 20 21 21 Au gu st 20 22 14 D ec em be r 2 02 4 PA TE NT ST AT US Br az il Gr an te d P at en t N o. PI 97 01 87 7 Ap p N o. PI 98 14 73 6 Re fu se d Ap p N o. PI 01 12 82 0 Re fu se d- un de r a pp ea l Gr an te d P at en t No . P I01 13 23 6 Ap p N o. PI 02 11 54 4 L ap se d No pa te nt Ch ina Gr an te d P at en t No . 1 08 25 08 Gr an te d P at en t No . 1 11 62 82 Gr an te d P at en t No . 1 26 47 92 Gr an te d P at en t No . 1 00 33 56 43 Gr an te d P at en t N o. 12 45 98 8 La ps ed du e t o n on -p ay m en t o f an nu al re ne wa l fe e No pa te nt Eg yp t No pa te nt Gr an te d P at en t No .23 93 6 No pa te nt No pa te nt NA No pa te nt Eu ro pe an Pa te nt O ffi ce (E P) Gr an te d P at en t N o. 09 00 21 0 Gr an te d P at en t No . 1 05 67 22 Gr an te d P at en t No . 1 30 95 35 Gr an te d P at en t No . 1 30 97 14 Gr an te d P at en t N o. 14 20 79 9 La ps ed du e t o n on -p ay m en t o f an nu al re ne wa l fe e Pu b N o. EP 16 96 91 8 W ith dr aw n Et hio pia No pa te nt No pa te nt No pa te nt No pa te nt N/ A No pa te nt Gh an a ( AR IP O) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt 28 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Pa te nt 5 Pa te nt 6 An tiv ira lly A ct iv e H et er oc yc lic Az ah ex an e D er iv at iv es (T his pa te nt co ve rs va rio us he te ro cy cli c a za he xa ne de riv at ive s th at ca n b e e m plo ye d a s r et ro vir al as pa rta te pr ot ea se s, inc lud ing th e b as e c om po un d a ta za na vir , th eir sa lts an d u se al on e o r in co m bin at ion w ith ot he r a nt ivi ra lly ac tiv e c om po un ds ) Bi su lfa te Sa lt of H IV Pr ot ea se In hi bi to r (T his pa te nt co ve rs th e cry sta llin e b isu lfa te of at az an av ir a nd it s ph ar m ac eu tic al do sa ge fo rm as us ed in th e m ar ke te d p ro du ct) A Pr oc es s f or th e Pr ep ar at io n of α ’ Ch lo ro ke to ne s (T his pa te nt co ve rs a p ro ce ss us efu l in th e s yn th es is of int er m ed iat es fo r at az an av ir) St er eo se le ct iv e Re du ct io n of Su bs tit ut ed Ox o- Bu ta ne s (T his pa te nt co ve rs a p ro ce ss us efu l in th e s yn th es is of int er m ed iat es fo r at az an av ir) Us e o f A ta za na vi r i n HI V Th er ap y (T his pa te nt co ve rs a m et ho d f or re du cin g e lev at ed pl as m a L DL an d/ or tr yg lyc er ide le ve ls in a H IV inf ec te d p at ien t u nd er go ing H IV pr ot ea se th er ap y w hic h c om pr ise s ad m ini ste rin g a n e ffe cti ve am ou nt of at az an av ir i n c om bin at ion w ith an H IV in hib iti ng am ou nt of at lea st on e H IV pr ot ea se in hib ito r) A M et ho d of Tr ea tin g HI V In fe ct io n in A ta za na vi rR es ist an t Pa tie nt s U sin g a C om bi na tio n of A ta za na vi r a nd A no th er Pr ot ea se In hi bi to r (Th is pa ten t c ov ers a m eth od of tre ati ng H IV, w he re th e H IV st rai n ha s b ec om e r es ist an t t o a ta za na vir , an d a ta za na vir is ad m ini ste red w ith at lea st on e o th er pr ot ea se in hib ito r) In dia Ap p N o. 80 5/ MA S/ 19 97 (P re -g ra nt op po sit ion – Ap pli ca tio n Ab an do ne d) Ap p N o. 31 0/ CH E/ 20 07 (D ivi sio na l-p en din g) Ap p N o. 32 34 /C HE /2 00 8 (D ivi sio na l-p en din g) Ap p N o. 32 35 /C HE /2 00 8 (D ivi sio na l-p en din g) Ap p N o. 64 25 / DE LN P/ 20 06 (P re -g ra nt op po sit ion – Re fu se d) Ap p N o. 29 33 / DE LN P/ 20 09 D ivi sio na l (P re -g ra nt op po sit ion – Ap pli ca tio n r efu se d) Gr an te d P at en t No . 2 10 49 6 Gr an te d P at en t No . 2 06 21 7 No pa te nt No pa te nt In do ne sia No pa te nt Gr an te d P at en t No . ID 00 09 86 0 No pa te nt No pa te nt N/ A No pa te nt Jo rd an No pa te nt No pa te nt No pa te nt No pa te nt N/ A No pa te nt Ke ny a ( AR IP O) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt M or oc co No pa te nt No pa te nt No pa te nt No pa te nt N/ A No pa te nt Ni ge ria No pa te nt No pa te nt No pa te nt No pa te nt N/ A No pa te nt OA PI No pa te nt No pa te nt No pa te nt No pa te nt N/ A No pa te nt So ut h A fri ca Gr an te d P at en t N o. 97 03 38 7 Gr an te d P at en t No . 9 90 05 6 No pa te nt No pa te nt Ap p N o. 20 04 01 41 2 La ps ed No pa te nt Ta nz an ia (A RI PO ) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt Ug an da (A RI PO ) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt US A Gr an te d P at en t N o. 58 49 91 1 Gr an te d P at en t N o. 61 10 94 6 Gr an te d P at en t N o. 63 00 51 9 Gr an te d P at en t N o. 61 66 00 4 Gr an te d P at en t No .60 87 38 3 Gr an te d P at en t No . 6 39 97 93 Gr an te d P at en t No . 7 08 39 73 Pe nd ing Pa te nt No .20 02 /0 04 21 24 Pu b N o. 20 03 /0 04 55 01 Ab an do ne d Pu b N o. 20 05 /0 14 85 23 Ab an do ne d 29 Pa te nt 7 Pa te nt 8 Pa te nt 9 Pa te nt 1 0 Pa te nt 1 1 Pa te nt 1 2 Pr oc es s f or p re pa rin g At az an av ir Bi su lfa te an d No ve l F or m (T his pa te nt co ve rs a p ro ce ss fo r pr ep ar ing at az an av ir b isu lfa te in th e f or m of Fo rm A cry sta ls) . Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a co m po sit ion co m pr isi ng at az an av ir b isu lfa te an d a p lur ali ty of gr an ule s to fo rm a co m pr es se d ta ble t) Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a c om pr es se d t ab let co m pr isi ng ra lte rg ra vir an d g ra nu les co nt ain ing at az an av ir s ulf at e an d a n i nt ra gr an ula r lub ric an t) Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a c om pr es se d t ab let co m pr isi ng ab ac av ir su lfa te an d g ra nu les co nt ain ing at az an av ir su lfa te an d a n int ra gr an ula r l ub ric an t) Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a c om pr es se d ta ble t c om pr isi ng rit on av ir a nd gr an ule s c on ta ini ng at az an av ir su lfa te an d a n i nt ra gr an ula r lub ric an t) At az an av ir Su lfa te Fo rm ul at io ns w ith Im pr ov ed p H Eff ec t (A co m pr es se d t ab let co m pr isi ng at az an av ir s ulf at e a nd an ac idi fyi ng ag en t) Ap pli ca nt /P at en t H old er Br ist ol- M ye rs Sq uib b C om pa ny Br ist ol- M ye rs Sq uib b Co m pa ny Br ist ol- M ye rs Sq uib b Co m pa ny Br ist ol- M ye rs Sq uib b Co m pa ny Br ist ol- M ye rs Sq uib b C om pa ny Br ist ol- M ye rs Sq uib b C om pa ny In te rn at ion al Pa te nt Pu bli ca tio n No . o r C or re sp on din g U .S/ Eu ro pe an Pa te nt N o. W O 20 05 /1 08 34 9 W O 20 09 /0 02 82 1 W O 20 09 /0 02 82 3 W O 20 09 /0 02 82 6 W O 20 09 /0 02 82 9 W O 20 11 /1 27 24 4 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 3 M ay 20 25 20 Ju ne 20 28 20 Ju ne 20 28 20 Ju ne 20 28 20 Ju ne 20 28 7 A pr il 2 03 1 PA TE NT ST AT US Br az il Ap p N o. PI 05 09 59 5 Pe nd ing No pa te nt No pa te nt No pa te nt No pa te nt N/ A ( Ap pli ca tio n m ay no t h av e y et en te re d n at ion al ph as e) Ch ina Gr an te d P at en t N o. 19 80 66 6 Gr an te d P at en t N o. 10 15 65 39 8 Pu b N o. 10 17 78 62 4 W ith dr aw n Pu b N o. 10 18 01 34 8 W ith dr aw n Pu b N o. 10 17 78 62 5 W ith dr aw n Pu b N o. 10 17 95 67 4 Pe nd ing Pu b N o. 10 29 17 69 5 Pe nd ing Eg yp t N/ A No pa te nt No pa te nt No pa te nt No pa te nt N/ A Eu ro pe an Pa te nt O ffi ce (E PO ) 17 55 59 6 P en din g 26 69 27 3 (D ivi sio na l o f 1 75 55 96 -P en din g) Gr an te d P at en t No . 2 17 02 92 Gr an te d P at en t No .21 78 51 1 Gr an te d P at en t No . 2 17 85 12 Gr an te d P at en t N o. 21 78 51 3 Pu b n o. 25 55 75 7 Et hio pia No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A Gh an a ( AR IP O) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A 30 Pa te nt 7 Pa te nt 8 Pa te nt 9 Pa te nt 1 0 Pa te nt 1 1 Pa te nt 1 2 Pr oc es s f or p re pa rin g At az an av ir Bi su lfa te an d No ve l F or m (T his pa te nt co ve rs a p ro ce ss fo r pr ep ar ing at az an av ir b isu lfa te in th e f or m of Fo rm A cry sta ls) . Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a co m po sit ion co m pr isi ng at az an av ir b isu lfa te an d a p lur ali ty of gr an ule s to fo rm a co m pr es se d ta ble t) Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a c om pr es se d t ab let co m pr isi ng ra lte rg ra vir an d g ra nu les co nt ain ing at az an av ir s ulf at e an d a n i nt ra gr an ula r lub ric an t) Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a c om pr es se d t ab let co m pr isi ng ab ac av ir su lfa te an d g ra nu les co nt ain ing at az an av ir su lfa te an d a n int ra gr an ula r l ub ric an t) Ta bl et ed Co m po sit io ns Co nt ai ni ng A ta za na vi r (T his pa te nt co ve rs a c om pr es se d ta ble t c om pr isi ng rit on av ir a nd gr an ule s c on ta ini ng at az an av ir su lfa te an d a n i nt ra gr an ula r lub ric an t) At az an av ir Su lfa te Fo rm ul at io ns w ith Im pr ov ed p H Eff ec t (A co m pr es se d t ab let co m pr isi ng at az an av ir s ulf at e a nd an ac idi fyi ng ag en t) In dia Ap p N o. 64 25 /D EL NP /2 00 6 ( Pr e- gr an t o pp os iti on – Re fu se d) Ap p N o. 29 33 /D EL NP /2 00 9 Di vis ion al (P re -g ra nt op po sit ion – Ap pli ca tio n r efu se d) Ap p N o. 83 28 / DE LN P/ 20 09 Pe nd ing Ap p N o. 85 24 / DE LN P/ 20 09 Pe nd ing Ap p N o. 83 30 / DE LN P/ 20 09 Pe nd ing Ap p N o. 83 32 /D EL NP /2 00 9 Pe nd ing Ap p N o. 90 97 /C HE NP /2 01 2 Pe nd ing In do ne sia No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A Jo rd an No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A Ke ny a ( AR IP O) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A M or oc co No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A Ni ge ria No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A OA PI No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A So ut h A fri ca Gr an te d P at en t N o. 20 06 09 08 4 No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt Ta nz an ia (A RI PO ) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A Ug an da (A RI PO ) No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt N/ A US A Gr an te d P at en t N o. 78 38 67 8 Gr an te d P at en t N o. 85 13 42 8 Gr an te d P at en t N o. 78 29 72 0 Pu b n o. 20 13 /0 26 66 48 Pe nd ing Pu b N o. 20 10 /1 78 33 9 Ab an do ne d Pu b N o. 20 10 /1 78 34 0 Ab an do ne d Pu b N o. 20 10 /1 83 71 6 Ab an do ne d Pu b N o. 20 13 /2 03 75 9 P en din g Pu b N o. 20 15 /0 80 39 9 P en din g * N /A – in fo rm at io n no t a va ila bl e * N o pa te nt – n o pa te nt fi le d 31 Annex 2 Raltegravir: analysis of patent landscape The patent search identified four key patents that would be particularly relevant for a local producer to take into consideration. The primary patent, patent number 1, covers the base compound and active ingredient. This patent is expected to expire around October 2022. The secondary patents, patent numbers 2–4, cover the salt form of raltegravir and various compositions for the marketed end-product. These patents are all expected to expire around December 2025. In Brazil patent numbers 1, 3 and 4 are still pending. In China all four key patents have been granted. As a result, unless such patents were to be invalidated or a licence agreement signed with the patent holder, local producers are blocked from coming to market until at least December 2025. In India patent number 1 has been granted and therefore blocks any generic production. The application for patent number 2 has been abandoned, and applications for patent numbers 3 and 4 are pending. Notably, patent number 4, covering the key formulation patent, has been opposed under India’s pre-grant opposition system. In Indonesia patent numbers 1 and 4 have been granted and would block local production. Information for patent numbers 2 and 3 was not available. Accordingly, local producers would have to conduct additional searches to establish whether these patents have been filed in Indonesia. In South Africa the primary patent, patent number 1, and patent numbers 3 and 4 have been granted and therefore block local production. In Egypt, Ethiopia, Ghana, Jordan, Kenya, Morocco, Nigeria, OAPI countries, Uganda and the United Republic of Tanzania, patent number 1 has not filed. In Egypt patent numbers 2–4 do not appear to have been filed and so there is potential for local production. For the other countries in this list, either the data were not available or only patent number 4 had not been applied for or granted (in Ghana, Kenya, Nigeria, OAPI countries, Uganda and the United Republic of Tanzania). Additional checks would be needed to assess any risks for these countries; this would not be necessary for countries classified as LDCs under the United Nations system (such as Ethiopia, Uganda and the United Republic of Tanzania), as Merck commits not to file or enforce patents in these countries. Patent number 4 has been granted in Morocco and so would likely block production there, even though the primary patent, patent number 1, has not been filed there. In 2015 Merck entered into a licence agreement with the Medicines Patent Pool signed for raltegravir for paediatric use that allows generic producers to apply for a sub-licence. Further information, including the full licence. 32 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 N- Su bs tit ut ed Hy dr ox yp yr im id in on eC ar bo xa m id e In hi bi to rs o f H IV In te gr as e (Th is pa ten t c ov ers N -S ub sti tu ted hy dr ox yp yri m idi no ne ca rb ox am ide s, inc lud ing th e b as e c om po un d r alt eg rav ir, th eir ph arm ac eu tic all y a cce pt ab le sa lts , s yn th es is an d us e a s i nh ibi to rs of th e H IV in teg ras e e nz ym e) Ph ar m ac eu tic al Co m po sit io n Co nt ai ni ng A n An ti- Nu cle at in g Ag en t (T his pa te nt co ve rs a p ha rm ac eu tic al co m po sit ion fo r o ra l a dm ini str at ion as a so lid do se co m pr isi ng an eff ec tiv e a m ou nt of a dr ug co m po un d i n t he fo rm of a sa lt, in clu din g t he po ta ssi um sa lt of ra lte gr av ir) Ph ar m ac eu tic al Fo rm ul at io n Co nt ai ni ng A Re le as e R at e C on tro lli ng Co m po sit io n (Th is p ate nt co ve rs a p ha rm ac eu tic al for m ula tio n for or al ad m ini str ati on as a so lid do se co m pr isi ng an eff ec tiv e a m ou nt of a ba se sa lt o f a co m po un d, inc lud ing th e p ot as siu m sa lt o f ra lte rg av ir, an d a rel ea se ra te co nt rol lin g c om po sit ion co m pr isi ng a so lub iliz ing ag en t a nd op tio na lly a wa ter so lub le fill er) Po ta ss iu m Sa lt of an H IV In te gr as e I nh ib ito r (T his pa te nt co ve rs po ta ssi um sa lts an d t he ir cry sta llin e f or m s o f a n H IV in te gr as e i nh ibi to r, inc lud ing ra lte gr av ir, an d p ha rm ac eu tic al co m po sit ion s) Ap pli ca nt /P at en t H old er Ist itu to D i R ec er ch e D i B iol og iaM ole co lar e P . An ge let ti SP A M er ck & Co . In c M er ck & Co . In c M er ck & Co . In c Ist itu to D i R ec er ch e D i B iol og iaM ole co lar e P . An ge let ti SP A *In te rn at ion al Pa te nt Pu bli ca tio n No .or U. S/ Eu ro pe an Pa te nt N o. W O 20 03 /0 35 07 7 W O 20 06 /0 60 68 1 W O 20 06 /0 60 71 1 W O 20 06 /0 60 71 2 W O 20 06 /0 60 73 0 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 21 O cto be r 2 02 2 2 D ec em be r 2 02 5 2 D ec em be r 2 02 5 2 D ec em be r 2 02 5 PA TE NT S TA TU S Br az il Ap p N o. PI 02 13 52 2 P en din g No pa te nt Ap p N o. PI 05 18 78 1 P en din g Ap p N o. PI 05 18 76 0 P en din g Ch ina Gr an te d P at en t N o. 17 00 91 8 Gr an te d P at en t N o. 10 10 68 53 3 Gr an te d P at en t N o. 10 10 68 55 0 Gr an te d P at en t N o. 10 10 68 79 3 Eg yp t No pa te nt No pa te nt No pa te nt Ap p N o. 20 07 53 4 Eu ro pe an Pa te nt O ffi ce (E PO ) Gr an te d P at en t N o. 14 41 73 5 Pu b N o. 18 19 32 3 P en din g Gr an te d P at en t N o. 19 04 06 7 Pu b N o. 25 86 44 4 Gr an te d P at en t N o. 18 19 70 0 Gr an te d P at en t N o. 18 19 68 3 Et hio pia No pa te nt N/ A N/ A N/ A Gh an a ( AR IP O) No pa te nt N/ A N/ A No pa te nt In dia Gr an te d P at en t N o. 21 24 00 Ap p N o. 40 29 /D EL NP /2 00 7 A ba nd on ed Ap p N o. 40 28 /D EL NP /2 00 7 P en din g Ap p N o. 41 87 /D EL NP /2 00 7 Pe nd ing  – Pr e g ra nt op po sit ion fil ed In do ne sia Gr an te d P at en t N o. 36 86 6 N/ A N/ A Gr an te d P at en t N o. 31 73 0 Jo rd an No pa te nt N/ A N/ A N/ A Ke ny a ( AR IP O) No pa te nt N/ A N/ A No pa te nt M or oc co No pa te nt N/ A N/ A Gr an te d P at en t N o. MA 29 12 0 Ni ge ria No pa te nt N/ A N/ A N/ A OA PI No pa te nt N/ A N/ A N/ A So ut h A fri ca Gr an te d P at en t N o. 20 04 02 79 6 No pa te nt Gr an te d P at en t N o. 20 07 03 86 6 Gr an te d P at en t N o. 20 07 04 13 0 Ta nz an ia (A RI PO ) No pa te nt N/ A N/ A No pa te nt Ug an da (A RI PO ) No pa te nt N/ A N/ A No pa te nt US A Gr an te d P at en t N o. 71 69 78 0 Gr an te d P at en t N o. 72 17 71 3 Gr an te d P at en t N o. 74 35 73 4 Gr an te d P at en t N o. 77 54 73 1 Gr an te d P at en t N o. 87 71 73 3 Gr an te d P at en t N o. 88 52 63 2 Gr an te d P at en t N o. 77 54 73 1 * N /A – in fo rm at io n no t a va ila bl e * N o pa te nt – n o pa te nt fi le 33 Annex 3 Imatinib: analysis of patent landscape12 The patent search identified three patents. Patent numbers 1 and 2 would be particularly relevant for a local producer to take into consideration. The primary patent, patent number 1, covers the base compound and active ingredient. This patent is expected to have expired around September 2014. Therefore, provided a country does not grant patent term extensions, patent number 1 should not be a hindrance to local producers. The key secondary patent, patent number 2, covers the crystalline form of imatinib and is used for formulating the marketed end-product (imatinib mesylate). This patent is expected to expire around July 2018. In Brazil patent number 1 has expired and is therefore no longer an obstacle to local producers. Notably, patent numbers 2 and 3 have been refused but are under appeal. Technically, local producers could commence production, but they would have to monitor the status of patent number 2 in particular to ensure it does not get granted. In China all three patents have been granted. Even though patent number 1 has expired, patent number 2 and possibly patent number 3 would block local producers. The situation is similar for Indonesia and South Africa. The situation may vary to a certain extent, depending on whether claims were amended. This will require a more detailed analysis of the granted patents. In Egypt none of the three patents identified appears to have been filed and so local production is potentially possible. In India patent number 1 was never filed, as India used the flexibility permitted under the TRIPS Agreement, namely the transitional period within which not to grant pharmaceutical product patents. Patent number 2 was refused and patent number 3 has not been filed. Accordingly, local production for imatinib is actually taking place in India as there are no patent barriers. No patents were filed in Egypt, Ethiopia, Ghana, Jordan, Kenya, Morocco, Nigeria, OAPI countries, Uganda or the United Republic of Tanzania. 12 Novartis kindly reviewed the patent data on imatinib and filled in gaps in the data. 34 Pa te nt 1 Pa te nt 2 Pa te nt 3 Fu rt he r P yr im id in e D er iv at iv es an d th ei r P re pa ra tio n (T his pa te nt fa m ily co ve rs a N -(fl ou ro alk ox yp he ny l)- 2- py rim idi ne am ine de riv at ive , in clu din g t he ba se co m po un d i m at ini b a nd a ph ar m ac eu tic all y a cce pt ab le sa lt, a m et ho d o f u se fo r t he ch em ot he ra py of tu m or s an d a pr oc es s f or pr ep ar ing th e c om po un ds ). Cr ys ta l M od ifi ca tio n of a N- Ph en yl -2 - Py rim id in ea m in e D er iv at iv e P ro ce ss es fo r i ts M an uf ac tu re an d its U se (T his pa te nt fa m ily co ve rs th e b et a c ry sta llin e f or m of th e m et ha ne su lfo nic ac id ad dit ion sa lt of im at ini b (im at ini bm es yla te ), its ph ar m ac eu tic al co m po sit ion , us e f or th e t re at m en t o f a tu m or di se as e a nd pr oc es s f or pr ep ar ing th e b et a c ry sta llin e f or m ). Tr ea tm en t o f G as tro in te st in al St ro m al Tu m or s (T his pa te nt fa m ily co ve rs th e u se of im at ini bm es yla te fo r tre at m en t o f g as tro int es tin al str om al tu m or s – G IST ) Ap pli ca nt /P at en t H old er Cib a- Ge igy A ssi gn ed to N ov ar tis AG No va rti s A G No va rti s A G, et al . *In te rn at ion al Pa te nt Pu bli ca tio n N o. or U. S/ Eu ro pe an Pa te nt N o. US 5, 52 1,1 84 / EP 0 56 4 4 09 W O1 99 9/ 03 85 4 W O2 00 2/ 34 72 7 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 25 M ar ch 20 13 16 Ju ly 20 18 26 O cto be r 2 02 1 PA TE NT ST AT US Br az il Gr an te d P at en t N o. PP 11 00 73 9 ( ex pir ed ) Ap p N o. PI 98 10 92 0 R efu se d – U nd er Ap pe al Ap p N o. PI 01 14 87 0 R efu se d – Un de r A pp ea l Ch ina Gr an te d P at en t N o. 10 43 53 1 ( ex pir ed ) Gr an te d P at en t N o. 11 34 43 0 Gr an te d P at en t N o. 12 76 75 4 Eg yp t No pa te nt No pa te nt No pa te nt Eu ro pe an Pa te nt O ffi ce (E PO ) Gr an te d P at en t N o. 05 64 40 9 ( ex pir ed – SP Cs ar e i n f or ce in so m e E U co un tri es ) Gr an te d P at en t N o. 09 98 47 3 Gr an te d P at en t N o. 13 32 13 7 Et hio pia No pa te nt No pa te nt No pa te nt Gh an a ( AR IP O) No pa te nt No pa te nt No pa te nt In dia No pa te nt Ap p N o. 16 02 /M AS /1 99 8 R efu se d f oll ow ing Pr e- Gr an t Op po sit ion s a nd Ap pe als up to th e S up re m e C ou rt No pa te nt In do ne sia Gr an te d P at en t N o. ID 00 05 12 7 ( ex pir ed ) Gr an te d P at en t N o. ID 00 28 43 2 Gr an te d P at en t N o. ID 00 19 53 1 Jo rd an No pa te nt No pa te nt No pa te nt Ke ny a ( AR IP O) No pa te nt No pa te nt No pa te nt M or oc co No pa te nt No pa te nt No pa te nt Ni ge ria No pa te nt No pa te nt No pa te nt OA PI No pa te nt No pa te nt No pa te nt So ut h A fri ca Gr an te d P at en t N o.9 30 23 97 (e xp ire d) Gr an te d P at en t N o. 98 06 36 2 Gr an te d P at en t N o. 20 03 02 15 5 Ta nz an ia (A RI PO ) No pa te nt No pa te nt No pa te nt Ug an da (A RI PO ) No pa te nt No pa te nt No pa te nt US A Gr an te d P at en t N o. 55 21 18 4 ( ex pir ed ) Gr an te d P at en t N o. 68 94 05 1 Gr an te d P at en t N o. 71 51 10 6 Gr an te d P at en t N o. RE 43 93 2 Gr an te d P at en t N o. 69 58 33 5 *N o pa te nt – n o pa te nt fi le d 35 Annex 4 Sitagliptin: analysis of patent landscape The patent search identified five key patents that would be particularly relevant for a local producer to take into consideration. The main patents that could affect local production are patent numbers 1 and 3. Patent number 1 covers the base compound/active ingredient and, if granted, is expected to expire around July 2022. Patent number 3 relates to the salt of the base compound and is the main patent covering the marketed formulation. This patent is expected to expire around June 2024 if granted. Patent number 3 could be problematic as it covers intermediate compounds and a process for making the active ingredient and would need to be worked around. Patent 4 covers a crystalline form and could be an issue, as sometimes base compound forms can seed into the crystalline/polymorphic form, given the polymorphic forms are inherent in the base. Patent number 5 is most likely a defensive secondary patent against alternative formulations that competitors may seek to adopt. In Brazil patent number 1 has been granted and would block local producers. Patent number 3 is still pending. In China patent numbers 1, 3 and 4 are granted. Therefore, local production is blocked until these patents expire, a licence of some form is entered into, or the patents are invalidated. In Egypt patent numbers 1 and 3 appear to have been filed, but their status is not available. Further checks would be needed to establish the current position of these applications. If granted, they would block any local production. In India a local producer has initially come to market, despite patent number 1 being granted. This was achieved partly by challenging the patent application for patent number 3 to remove that as a barrier, but the case is still pending before the courts, which have issued an interim injunction against further sales (56). In Indonesia applications were filed for patent numbers 1 and 3, but their status is not available. Further checks would be necessary to establish the status and determine whether these patents are an issue for local producers. In Jordan patent numbers 1 and 3 have been granted and so local producers would be prevented from production. In Morocco and South Africa patent number 1 has been granted and so local producers would be blocked from production. Patent number 2 has been granted in South Africa; the legal status for Morocco was not available and would need to be checked. Patent information for the other countries of interest was not available and so further checks would be necessary. This would not be necessary for countries classified as LDCs under the United Nations system (such as Ethiopia, Uganda and the United Republic of Tanzania) as Merck commits not to file and enforce patents in these countries. 36 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Pa te nt 5 Be ta -A m in o T et ra hy dr oi m id az o (1 , 2 -A ) Py ra zin es an d T et ra hy dr ot rio az ol o (4 , 3- A) P yr az in es as D ip ep tid yl P ep tid as e In hi bi to rs fo r t he Tr ea tm en t o r Pr ev en tio n of D ia be te s (T his pa te nt co ve rs be ta -a m ino te tra hy dr ot ria zo lo [4 ,3- a] py ra zin e co m po un ds , in clu din g s ita gli pt in, a ph ar m ac eu tic all y a cce pt ab le hy dr at e s alt th er eo f, p ha rm ac eu tic al co m po sit ion an d a m et ho d o f t re at m en t o f t yp e 2 di ab et es ). Pr oc es s a nd In te rm ed ia te s f or th e Pr ep ar at io n of B et a- Am in o Ac id Am id e D ip ep tid yl P ep tid as e – IV In hi bi to rs (T his pa te nt co ve rs an im pr ov ed pr oc es s f or th e p re pa ra tio n o f be ta -a m ino ac id am ide di pe pt idy l pe pt ida se – IV an d c er ta in us efu l int er m ed iat es co m po un ds . Ph os ph or ic Ac id Sa lt of a Di pe pt id yl Pe pt id as e- IV In hi bi to r (T his pa te nt co ve rs a m on ob as ic dih yd ro ge np ho sp ha te sa lt of sit ag lip tin an d c ry sta llin e h yd ra te s th er eo f, i n p ar tic ula r c ry sta llin e m on oh yd ra te , a pr oc es s f or pr ep ar ing th e s alt an d a m et ho d f or th e tre at m en t o f t yp e 2 di ab et es ). No ve l C ry st al lin e F or m s o f a Ph os ph or ic Ac id Sa lt of a Di pe pt id yl Pe pt id as e- IV In hi bi to r (T his pa te nt co ve rs cry sta llin e so lva te s a nd an hy dr at es of th e dih yd ro ge np ho sp ha te sa lt of sit ag lip tin , a ph ar m ac eu tic al co m po sit ion co m pr isi ng th e s am e a nd a m et ho d o f t re at ing ty pe 2 dia be te s). No ve l C ry st al lin e S al ts o f a Di pe pt id yl P ep tid as e I nh ib ito r (T his pa te nt co ve rs cry sta llin e hy dr oc hl or ic ac id, be nz en es ulf on ic ac id, p- to lue ne su lfo nic ac id, 10 -c am ph or su lfo nic ac id an d t ar tri c ac id sa lts of si ta gli pt in) . Ap pli ca nt /P at en t H old er M er ck & Co , In c M er ck & Co In c M er ck & Co In c M er ck & Co In c M er ck & Co In c In te rn at ion al Pa te nt Pu bli ca tio n No . o r U .S/ Eu ro pe an Pa te nt N o. W O2 00 3/ 00 44 98 W O2 00 4/ 08 76 50 W O2 00 5/ 00 31 35 W O2 00 5/ 02 09 20 W O2 00 5/ 07 25 30 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 5 J uly 20 22 23 M ar ch 20 24 18 Ju ne 20 24 27 Au gu st 20 24 12 Ja nu ar y 2 02 5 PA TE NT ST AT US Br az il Gr an te d P at en t N o. PI 02 10 86 6 PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Ap p N o. PI 04 11 72 6 P en din g No pa te nt No pa te nt Ch ina Gr an te d P at en t N o. 12 90 84 8 Pu b N o. 18 61 07 7 W ith dr aw n PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Gr an te d P at en t N o. 18 32 94 9 Gr an te d P at en t N o. 10 04 57 10 8 No pa te nt Eg yp t Ap p N o. 74 6/ 20 02 Le ga l s ta tu s n ot av ail ab le PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Ap p N o. PC T8 28 /2 00 5 Le ga l s ta tu s n ot av ail ab le N/ A N/ A Eu ro pe an Pa te nt O ffi ce (E PO ) Gr an te d P at en t N o. 14 12 35 7 Gr an te d P at en t N o. 16 25 84 7 Pu b N o. 22 26 32 4 P en din g PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Gr an te d P at en t N o. 16 54 26 3 Pu b N o. 16 62 87 6 W ith dr aw n Pu b N o. 17 08 57 1 W ith dr aw n Et hio pia N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A Gh an a ( AR IP O) N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A In dia Gr an te d P at en t N o. 20 98 16 PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Ap p N o. 59 48 /D EL NP /2 00 5 Ab an do ne d – Pr e- gr an t o pp os iti on fil ed Ap p N o. 11 30 /D EL NP /2 00 6 Ab an do ne d No pa te nt In do ne sia Ap p N o. W -0 20 04 02 62 6 Le ga l s ta tu s n ot av ail ab le PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Ap p N o. W -0 02 00 50 34 44 Le ga l s ta tu s n ot av ail ab le N/ A N/ A 37 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Pa te nt 5 Be ta -A m in o T et ra hy dr oi m id az o (1 , 2 -A ) Py ra zin es an d T et ra hy dr ot rio az ol o (4 , 3- A) P yr az in es as D ip ep tid yl P ep tid as e In hi bi to rs fo r t he Tr ea tm en t o r Pr ev en tio n of D ia be te s (T his pa te nt co ve rs be ta -a m ino te tra hy dr ot ria zo lo [4 ,3- a] py ra zin e co m po un ds , in clu din g s ita gli pt in, a ph ar m ac eu tic all y a cce pt ab le hy dr at e s alt th er eo f, p ha rm ac eu tic al co m po sit ion an d a m et ho d o f t re at m en t o f t yp e 2 di ab et es ). Pr oc es s a nd In te rm ed ia te s f or th e Pr ep ar at io n of B et a- Am in o Ac id Am id e D ip ep tid yl P ep tid as e – IV In hi bi to rs (T his pa te nt co ve rs an im pr ov ed pr oc es s f or th e p re pa ra tio n o f be ta -a m ino ac id am ide di pe pt idy l pe pt ida se – IV an d c er ta in us efu l int er m ed iat es co m po un ds . Ph os ph or ic Ac id Sa lt of a Di pe pt id yl Pe pt id as e- IV In hi bi to r (T his pa te nt co ve rs a m on ob as ic dih yd ro ge np ho sp ha te sa lt of sit ag lip tin an d c ry sta llin e h yd ra te s th er eo f, i n p ar tic ula r c ry sta llin e m on oh yd ra te , a pr oc es s f or pr ep ar ing th e s alt an d a m et ho d f or th e tre at m en t o f t yp e 2 di ab et es ). No ve l C ry st al lin e F or m s o f a Ph os ph or ic Ac id Sa lt of a Di pe pt id yl Pe pt id as e- IV In hi bi to r (T his pa te nt co ve rs cry sta llin e so lva te s a nd an hy dr at es of th e dih yd ro ge np ho sp ha te sa lt of sit ag lip tin , a ph ar m ac eu tic al co m po sit ion co m pr isi ng th e s am e a nd a m et ho d o f t re at ing ty pe 2 dia be te s). No ve l C ry st al lin e S al ts o f a Di pe pt id yl P ep tid as e I nh ib ito r (T his pa te nt co ve rs cry sta llin e hy dr oc hl or ic ac id, be nz en es ulf on ic ac id, p- to lue ne su lfo nic ac id, 10 -c am ph or su lfo nic ac id an d t ar tri c ac id sa lts of si ta gli pt in) . Jo rd an Gr an te d P at en t N o. 22 30 PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Gr an te d P at en t N o. 26 25 N/ A N/ A Ke ny a ( AR IP O) N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A M or oc co Gr an te d P at en t N o. 27 05 3 PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Ap p N o. PV 28 67 5 L eg al sta tu s n ot av ail ab le N/ A N/ A Ni ge ria N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A OA PI N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A So ut h A fri ca Gr an te d P at en t N o. 20 03 09 29 4 PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Gr an te d P at en t N o. 20 05 09 93 3 No pa te nt No pa te nt Ta nz an ia (A RI PO ) N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A Ug an da (A RI PO ) N/ A PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e N/ A N/ A N/ A US A Gr an te d P at en t N o. 66 99 87 1 Gr an te d P at en t N o. 71 25 87 3 Gr an te d P at en t N o. 81 68 63 7 Pu b N o. 20 06 27 06 79 Ab an do ne d Pu b N o. 20 13 21 76 95 Pe nd ing PC T a pp lic at ion do es no t a pp ea r t o ha ve en te re d n at ion al ph as e Gr an te d P at en t N o. 73 26 70 8 Pu b N o. 20 06 28 75 28 Ab an do ne d Pu b N o. 20 08 22 77 86 Ab an do ne d * N /A – in fo rm at io n no t a va ila bl e * N o pa te nt – N o pa te nt fi le d 38 Annex 5 Pegylated interferon alfa-2a: analysis of patent landscape13 The patent search identified seven key patents that local producers would need to take into consideration if they were intending to develop a biosimilar version of pegylated interferon alfa-2a. Patent numbers 4 and 5 are the most important patents to be avoided. These patents, if granted, are expected to expire around March 2016 and May 2017, respectively. In Brazil patent number 5 has been granted, and patent number 4 is pending. Therefore, local producers would be blocked from developing a biosimilar product, given that patent number 5 has been granted. Local producers could still develop an alternative product, however, provided they could stay outside the claims of patent number 5. Additionally, to avoid the risk of infringing patent number 4 should it be granted, local producers would have to develop a different formulation. In China patent numbers 4, 5 and 6 have been granted and would therefore block local producers from developing a biosimilar version. In India patent number 5 has been revoked following a post-grant opposition. Patent numbers 4 and 6 have been granted, however, and would have to be worked around, licensed or invalidated to produce a biosimilar version. In South Africa patent numbers 1–6 have been granted and therefore would be a block to any local producers considering manufacturing a biosimilar product. No patents were filed in Ghana, Kenya, OAPI countries, Uganda or the United Republic of Tanzania. F. Hoffmann-La Roche commits to not file or enforce patents in countries classified as LDCs under the United Nations system or low-income countries under the World Bank system; thus even if a patent is granted in one of those countries, this should not constitute a barrier. 13 F. Hoffmann-La Roche kindly reviewed the patent data on pegylated interferon and filled in gaps in the data. 39 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Im pr ov ed in te rfe ro n po ly m er co nj ug at es (T his pa te nt co ve rs a p ro ce ss fo r pr ep ar ing a lon g- ac tin g α -IF N co nt ain ing co m po sit ion , c om pr isi ng co nt ac tin g α- IFN w ith a su bs ta nt ial ly no n- an tig en ic po lym er in th e p re se nc e o f a su rfa cta nt un de r c on dit ion s w hic h a re su ffi cie nt to eff ec t c on jug at ion of th e p ro te in an d po lym er ). In te rfe ro n- po ly m er co nj ug at es an d pr oc es s f or pr ep ar in g th e s am e (T his pa te nt co ve rs a p ro ce ss fo r p re pa rin g IF- po lym er co nj ug at es by re ac tin g a n I FN w ith a bis -a cti va te d s ub sta nt ial ly no n- an tig en ic po lym er in a m ola r r at io of su bs ta nt ial ly no n- an tig en ic po lym er to IF N of fr om ab ou t 0 .12 5:1 to ab ou t 1:1 un de r c on dit ion s s uffi cie nt to eff ec t c ov ale nt co nj ug at ion of sa id IFN an d s aid po lym er an d f or m a r ea cti on m ixt ur e c on ta ini ng m on o- IFN po lym er co nj ug at es an d b is- IFN co nj ug at es ). Im pr ov ed in te rfe ro n po ly m er co nj ug at es (T his pa te nt co ve rs a p ha rm ac eu tic al co m po sit ion co m pr isi ng a m ixt ur e o f α- IFN po lym er co nj ug at e p os iti on al iso m er s, wh er ein on e o f t he sa id po sit ion al iso m er s c om pr ise s a n α -IF N co va len tly co nj ug at ed to a su bs ta nt ial ly no n- an tig en ic po lym er at a his tid ine re sid ue on sa id α- IFN ). In te rfe ro n So lu tio n (T his pa te nt co ve rs an aq ue ou s I FN so lut ion co nt ain ing an IF N- α, IFN -α -2 a o r PE G- IFN α2 A w ith a no n- ion ic de te rg en t, a b uff er fo r a dju sti ng pH 4. 4– 5.5 , b en zy l alc oh ol an d a n i so to niz ing ag en t). Ap pli ca nt /P at en t H old er En zo nI nc En zo nI nc En zo nI nc F. Ho ffm an -L a R oc he Lt d. *In te rn at ion al Pa te nt Pu bli ca tio n N o. or Eu ro pe an / U. S P at en t N o. W O1 99 5/ 13 09 0 W O1 99 7/ 18 83 2 W O1 99 9/ 32 13 9 EP 07 36 30 3 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 10 N ov em be r 2 01 4 31 O cto be r 2 01 6 16 D ec em be r 2 01 8 30 M ar ch 20 16 PA TE NT ST AT US Br az il No pa te nt No pa te nt No pa te nt Ap p N o. PI 96 01 27 6 P en din g Ch ina No pa te nt No pa te nt No pa te nt Gr an te d P at en t N o. 11 41 80 8 Eg yp t No pa te nt No pa te nt No pa te nt No t fi led Eu ro pe an Pa te nt O ffi ce (E PO ) Gr an te d P at en t N o. 07 30 47 0 Gr an te d P at en t N o. 08 62 45 5 Gr an te d P at en t N o. 10 39 92 2 Gr an te d P at en t N o. 07 36 30 3 Et hio pia No t fi led No t fi led No t fi led No t fi led Gh an a ( AR IP O) No t fi led No t fi led No t fi led No t fi led In dia No pa te nt No pa te nt No pa te nt Gr an te d P at en t N o.2 34 07 2 In do ne sia No t fi led No t fi led No t fi led No t fi led Jo rd an No t fi led No t fi led No t fi led No t fi led Ke ny a ( AR IP O) No t fi led No t fi led No t fi led No t fi led M or oc co No t fi led No t fi led No t fi led No t fi led Ni ge ria No t fi led No t fi led No t fi led No t fi led OA PI No t fi led No t fi led No t fi led No t fi led So ut h A fri ca Gr an te d P at en t N o. 98 11 59 0 Gr an te d P at en t N o. 96 09 55 7 Gr an te d P at en t N o. 98 11 59 0 Gr an te d P at en t N o. 96 02 55 3 Ta nz an ia (A RI PO ) No t fi led No t fi led No t fi led No t fi led Ug an da (A RI PO ) No t fi led No t fi led No t fi led No t fi led US A Gr an te d P at en t N o. 57 11 94 4 Gr an te d P at en t N o. 59 51 97 4 Gr an te d P at en t N o. 57 38 84 6 Gr an te d P at en t N o. 60 42 82 2 Gr an te d P at en t N o. 57 62 92 3 N /A – in fo rm at io n no t a va ila bl e 40 Annex 6 Gardasil human papillomavirus vaccine: analysis of patent landscape The patent search identified nine key patents that local producers would need to take into consideration if they were intending to developing a biosimilar version of the HPV vaccine. Given that patent numbers 1 and 2 should now have expired if they were granted in a country, the key patents for local producers to consider are patent numbers 6–9. If granted, patent numbers 6–8 would be expected to expire in 2024, and patent number 9 would expire in 2028. In Brazil patent numbers 6–8 are currently pending. In China these patents have been granted. In India patent numbers 6 and 8 have been granted and patent number 9 is pending. In South Africa patent numbers 6–8 have been granted. In Indonesia an application was filed for patent number 6, but further checks are required to determine the current status. Patent information for the other countries of interest for this study was not available. Merck commits to not file or enforce patents in countries classified as LDCs under the United Nations system; thus even if a patent is granted in one of these countries, this should not constitute a barrier. 41 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Pa te nt 5 Pa pi llo m a V iru s V ac cin e (T his pa te nt co ve rs a m et ho d f or pr od uc tio n o f p ap illo m a v iru s l ike pa rti cle s ( VL Ps ) i nc lud ing co ns tru cti ng on e o r m or e r ec om bin an t D NA m ole cu les w hic h e nc od e p ap illo m a vir us L1 pr ot ein or a co m bin at ion of pa pil lom a v iru s L 1 p ro te in an d pa pil lom a v iru s L 2 p ro te in) . Pr od uc tio n of H um an Pa pi llo m av iru s C ap sid P ro te in an d Vi ru s- Li ke P ar tic le s (T his pa te nt co ve rs a m et ho d o f ex pr es sin g t he ca ps id pr ot ein se qu en ce of pa pil lom av iru s i n a ce ll, co m pr isi ng tra ns fec tin g a ce ll w ith a re co m bin an t ex pr es sio n v ec to r c on ta ini ng a pa pil lom av iru s c ap sid pr ot ein co din g se qu en ce . T he H PV is se lec te d f ro m a gr ou p c on sis tin g o f H PV -6 , 1 1, 16 , 1 8, 33 , 3 5, 5 a nd 8) . DN A En co di ng H um an P ap ill om a Vi ru s T yp e 1 8 (T his pa te nt co ve rs an d i so lat ed an d pu rifi ed D NA m ole cu le, w hic h e nc od es HP V t yp e 1 8 o r a fu nc tio na l d er iva tiv e th er eo f). Or al Im m un iza tio n w ith Pa pi llo m av iru s- Li ke P ar tic le s (T his pa te nt co ve rs a m et ho d of va cc ina tin g a m am m al fo r pa pil lom av iru s c om pr isi ng ad m ini ste rin g p ap illo m av iru s V LP s or all y t o a m am m al in an am ou nt su ffi cie nt to in du ce an im m un e re sp on se to th e p ap illo m av iru s. T he HP V t yp es in clu de s H PV Ty pe s 1 6 a nd 11 ). Op tim ize d Ex pr es sio n of H PV 3 1 L1 in Ye as t (T his pa te nt co ve rs a h um an pa pil lom av iru s v ac cin e f or m ula tio n co m pr isi ng H PV VL Ps w hic h a re ab so rb ed on an al um ini um ad juv an t; a s alt ; a bu ffe r w hic h p ro vid es fo r a PH ra ng e o f t he va cc ine so lut ion of fr om ab ou t p H 6.0 to 6. 5 a nd a no n- ion ic su rfa cta nt ). Ap pli ca nt /P at en t H old er Th e U niv er sit y o f Q ue en sla nd an d C LS Lim ite d Un ive rsi ty of Ro ch es te r M er ck & Co In c Un ive rsi ty of Ro ch es te r M er ck & Co In c *In te rn at ion al Pa te nt Pu bli ca tio n N o. W O1 99 3/ 00 21 84 W O1 99 4/ 02 01 37 W O1 99 6/ 02 94 13 W O1 99 9/ 06 10 52 W O2 00 0/ 04 58 41 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 20 Ju ly 20 12 8 M ar ch 20 14 18 M ar ch 20 16 27 M ay 20 19 19 M ar ch 20 24 PA TE NT ST AT US Br az il Ap p N o. PI 11 00 18 3 R efu se d No pa te nt No pa te nt No pa te nt No pa te nt Ch ina No pa te nt No pa te nt Gr an te d P at en t N o. 11 00 87 6 No pa te nt No pa te nt Eg yp t No pa te nt No pa te nt No pa te nt No pa te nt No pa te nt Eu ro pe an Pa te nt O ffi ce (E PO ) Gr an te d P at en t N o. 05 95 93 5 Gr an te d P at en t N o. 16 18 88 8 Gr an te d P at en t N o. 06 88 22 7 Gr an te d P at en t N o. 08 17 85 1 Pu b N o. 10 79 85 8 W ith dr aw n Gr an te d P at en t N o. 11 50 71 2 Et hio pia N/ A N/ A N/ A N/ A N/ A Gh an a ( AR IP O) N/ A N/ A N/ A N/ A N/ A In dia No pa te nt No pa te nt No pa te nt No pa te nt In do ne sia N/ A N/ A N/ A N/ A N/ A Jo rd an N/ N/ A N/ A N/ A N/ A Ke ny a ( AR IP O) N/ A N/ A N/ A N/ A N/ A M or oc co N/ A N/ A N/ A N/ A N/ A Ni ge ria N/ A N/ A N/ A N/ A N/ A OA PI N/ A N/ A N/ A N/ A N/ A So ut h A fri ca No pa te nt No pa te nt Gr an te d P at en t N o. 96 02 24 5 No pa te nt No pa te nt 42 Pa te nt 1 Pa te nt 2 Pa te nt 3 Pa te nt 4 Pa te nt 5 Pa pi llo m a V iru s V ac cin e (T his pa te nt co ve rs a m et ho d f or pr od uc tio n o f p ap illo m a v iru s l ike pa rti cle s ( VL Ps ) i nc lud ing co ns tru cti ng on e o r m or e r ec om bin an t D NA m ole cu les w hic h e nc od e p ap illo m a vir us L1 pr ot ein or a co m bin at ion of pa pil lom a v iru s L 1 p ro te in an d pa pil lom a v iru s L 2 p ro te in) . Pr od uc tio n of H um an Pa pi llo m av iru s C ap sid P ro te in an d Vi ru s- Li ke P ar tic le s (T his pa te nt co ve rs a m et ho d o f ex pr es sin g t he ca ps id pr ot ein se qu en ce of pa pil lom av iru s i n a ce ll, co m pr isi ng tra ns fec tin g a ce ll w ith a re co m bin an t ex pr es sio n v ec to r c on ta ini ng a pa pil lom av iru s c ap sid pr ot ein co din g se qu en ce . T he H PV is se lec te d f ro m a gr ou p c on sis tin g o f H PV -6 , 1 1, 16 , 1 8, 33 , 3 5, 5 a nd 8) . DN A En co di ng H um an P ap ill om a Vi ru s T yp e 1 8 (T his pa te nt co ve rs an d i so lat ed an d pu rifi ed D NA m ole cu le, w hic h e nc od es HP V t yp e 1 8 o r a fu nc tio na l d er iva tiv e th er eo f). Or al Im m un iza tio n w ith Pa pi llo m av iru s- Li ke P ar tic le s (T his pa te nt co ve rs a m et ho d of va cc ina tin g a m am m al fo r pa pil lom av iru s c om pr isi ng ad m ini ste rin g p ap illo m av iru s V LP s or all y t o a m am m al in an am ou nt su ffi cie nt to in du ce an im m un e re sp on se to th e p ap illo m av iru s. T he HP V t yp es in clu de s H PV Ty pe s 1 6 a nd 11 ). Op tim ize d Ex pr es sio n of H PV 3 1 L1 in Ye as t (T his pa te nt co ve rs a h um an pa pil lom av iru s v ac cin e f or m ula tio n co m pr isi ng H PV VL Ps w hic h a re ab so rb ed on an al um ini um ad juv an t; a s alt ; a bu ffe r w hic h p ro vid es fo r a PH ra ng e o f t he va cc ine so lut ion of fr om ab ou t p H 6.0 to 6. 5 a nd a no n- ion ic su rfa cta nt ). Ta nz an ia (A RI PO ) N/ A N/ A N/ A N/ A N/ A Ug an da (A RI PO ) N/ A N/ A N/ A N/ A N/ A US A Gr an te d P at en t N o. 74 76 38 9 Gr an te d P at en t N o. 80 62 64 2 Gr an te d P at en t N o. 58 40 30 6 Gr an te d P at en t N o. 69 08 61 5 Gr an te d P at en t N o. 61 53 20 1 Gr an te d P at en t N o. 62 51 67 8 Pa te nt 6 Pa te nt 7 Pa te nt 8 Pa te nt 9 Op tim ize d Ex pr es sio n of H PV 3 1 L1 in Ye as t (T his pa te nt co ve rs a n uc lei c a cid m ole cu le co m pr isi ng a se qu en ce of nu cle ot ide s t ha t en co de s a n H PV 31 L1 pr ot ein an d a va cc ine co m pr isi ng VL Ps co m pr ise d o f r ec om bin an t L 1 pr ot ein + L2 pr ot ein s o f H PV 31 ). Op tim ize d Ex pr es sio n of H PV 4 5 L1 in Ye as t (T his pa te nt co ve rs a n uc lei c a cid m ole cu le co m pr isi ng a se qu en ce of nu cle ot ide s t ha t en co de s a n H PV 45 L1 pr ot ein an d a va cc ine co m pr isi ng VL Ps co m pr ise d o f r ec om bin an t L 1 pr ot ein + L2 pr ot ein s o f H PV 45 ). Op tim ize d Ex pr es sio n of H PV 5 8 L1 in Ye as t (T his pa te nt co ve rs a n uc lei c a cid m ole cu le co m pr isi ng a se qu en ce of nu cle ot ide s t ha t en co de s a n H PV 58 L1 pr ot ein ). Pa pi llo m av iru s V ac cin e C om po sit io ns (T his pa te nt co ve rs a p ha rm ac eu tic al co m po sit ion co m pr isi ng VL Ps of at le as t o ne H PV , a n a lum inu m ad juv an t, an IS CO M -ty pe ad juv an t a nd a ph ar m ac eu tic all y ac ce pt ab le ca rri er w he re in th e s aid VL Ps ar e c om pr ise d o f re co m bin an t L 1 p ro te in or re co m bin an t L 1 + L2 pr ot ein s of H PV an d w he re in th e s aid VL Ps ar e a bs or be d t o t he sa id alu m inu m ad juv an t). Ap pli ca nt /P at en t H old er M er ck & Co In c M er ck & Co In c M er ck & Co In c M er ck & Co In c *In te rn at ion al Pa te nt Pu bli ca tio n N o. W O2 00 4/ 08 48 31 W O2 00 5/ 03 25 86 W O2 00 5/ 04 73 15 W O2 00 8/ 11 21 25 Ex pe cte d E xp iry (i f g ra nt ed an d n ot su bje ct to pa te nt te rm ex te ns ion s) 19 M ar ch 20 24 24 Se pt em be r 2 02 4 10 N ov em be r 2 02 4 6 M ar ch 20 28 PA TE NT ST AT US Br az il Ap p N o. PI 04 08 63 9 P en din g Ap p N o. PI 04 08 63 9 P en din g Ap p N o. PI 04 16 39 3 P en din g No pa te nt Ch ina Gr an te d P at en t N o. 10 05 06 99 9 Gr an te d P at en t N o. 18 59 92 3 Gr an te d P at en t N o. 19 42 58 3 Pu b N o. 10 16 22 00 8 P en din g Eg yp t N/ A N/ A N/ A N/ A 43 Pa te nt 6 Pa te nt 7 Pa te nt 8 Pa te nt 9 Op tim ize d Ex pr es sio n of H PV 3 1 L1 in Ye as t (T his pa te nt co ve rs a n uc lei c a cid m ole cu le co m pr isi ng a se qu en ce of nu cle ot ide s t ha t en co de s a n H PV 31 L1 pr ot ein an d a va cc ine co m pr isi ng VL Ps co m pr ise d o f r ec om bin an t L 1 pr ot ein + L2 pr ot ein s o f H PV 31 ). Op tim ize d Ex pr es sio n of H PV 4 5 L1 in Ye as t (T his pa te nt co ve rs a n uc lei c a cid m ole cu le co m pr isi ng a se qu en ce of nu cle ot ide s t ha t en co de s a n H PV 45 L1 pr ot ein an d a va cc ine co m pr isi ng VL Ps co m pr ise d o f r ec om bin an t L 1 pr ot ein + L2 pr ot ein s o f H PV 45 ). Op tim ize d Ex pr es sio n of H PV 5 8 L1 in Ye as t (T his pa te nt co ve rs a n uc lei c a cid m ole cu le co m pr isi ng a se qu en ce of nu cle ot ide s t ha t en co de s a n H PV 58 L1 pr ot ein ). Pa pi llo m av iru s V ac cin e C om po sit io ns (T his pa te nt co ve rs a p ha rm ac eu tic al co m po sit ion co m pr isi ng VL Ps of at le as t o ne H PV , a n a lum inu m ad juv an t, an IS CO M -ty pe ad juv an t a nd a ph ar m ac eu tic all y ac ce pt ab le ca rri er w he re in th e s aid VL Ps ar e c om pr ise d o f re co m bin an t L 1 p ro te in or re co m bin an t L 1 + L2 pr ot ein s of H PV an d w he re in th e s aid VL Ps ar e a bs or be d t o t he sa id alu m inu m ad juv an t). Eu ro pe an Pa te nt O ffi ce (E PO ) Gr an te d P at en t N o. 16 08 76 7 Gr an te d P at en t N o. 16 73 10 6 Gr an te d P at en t N o. 16 87 32 9 Gr an te d P at en t N o. 21 29 39 4 Et hio pia N/ A N/ A N/ A N/ A Gh an a ( AR IP O) N/ A N/ A N/ A N/ A In dia Gr an te d P at en t N o. 23 79 41 No pa te nt Gr an te d P at en t N o. 29 30 /D EL NP /2 00 6 Ap p N o. 55 70 /D EL NP /2 00 9 P en din g In do ne sia Ap p N o. W O0 20 05 02 53 7 L eg al sta tu s n ot av ail ab le N/ A N/ A N/ A Jo rd an N/ A N/ A N/ A N/ A Ke ny a ( AR IP O) N/ A N/ A N/ A N/ A M or oc co N/ A N/ A N/ A N/ A Ni ge ria N/ A N/ A N/ A N/ A OA PI N/ A N/ A N/ A N/ A So ut h A fri ca Gr an te d P at en t N o. 20 05 07 17 8 Gr an te d P at en t N o. 20 06 01 96 1 Gr an te d P at en t N o. 20 06 03 10 6 No pa te nt Ta nz an ia (A RI PO ) N/ A N/ A N/ A N/ A Ug an da (A RI PO ) N/ A N/ A N/ A N/ A US A Gr an te d P at en t N o. 72 76 24 3 Gr an te d P at en t N o. 74 82 42 8 Gr an te d P at en t N o. 72 50 17 0 Gr an te d P at en t N o. 74 82 01 5 Gr an te d P at en t N o. 74 98 03 6 Gr an te d P at en t N o. 79 76 84 8 Gr an te d P at en t N o. 77 09 01 0 Pu b N o. 20 10 89 74 4 A ba nd on ed Pu b N o. 20 12 17 76 84 Ab an do ne d * N /A – in fo rm at io n no t a va ila bl e * N o pa te nt – n o pa te nt fi le d 44 References 1. Local production for access to medical products: developing a framework to improve public health. 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